News this Week

Science  30 Jun 2006:
Vol. 312, Issue 5782, pp. 1854
  1. CLIMATE CHANGE

    Yes, It's Been Getting Warmer in Here Since the CO2 Began to Rise

    1. Richard A. Kerr

    WASHINGTON, D.C.—The last decades of the 20th century were most likely warmer than any comparable period in the past 1000 years, a National Research Council (NRC) panel announced* at a press briefing here last week. The expert committee thus confirms the outlines of the near-iconic “hockey stick” temperature curve—a long cooling followed by a sharp warming during the past millennium—that had become a favorite target of greenhouse contrarians. But the committee also says the evidence in parts of the stick is fuzzier than the public and many scientists might have thought.

    Warped sticks.

    The latest millennial temperature records (produced since the “hockey stick” came out using proxies such as tree rings) may have more squiggles, but they support a recent sharp warming to record high temperatures.

    CREDITS (TOP TO BOTTOM): ADAPTED FROM NRC; ROYALTY-FREE/CORBIS

    The hockey stick arose from work published in 1998 and 1999 by statistical climatologist Michael Mann of Pennsylvania State University in State College and two colleagues. They compiled 12 Northern Hemisphere temperature records spanning the past millennium, using climate proxies such as the width of tree rings and the chemical composition of corals. The resulting temperature curve sloped gently downward for most of the millennium (the handle of the hockey stick), then rose sharply into the 20th century (the blade) until it topped the relative warmth of 800 to 1000 years ago. That turnaround suggested that humans played a hand in the recent warming.

    After the hockey stick appeared prominently in a 2001 international climate assessment, the critics rushed in. Skeptics said Mann and colleagues had erred badly in their statistical analysis, and some hinted at deliberate distortion.

    The NRC committee, chaired by meteorologist Gerald North of Texas A&M University in College Station, generally supported Mann's work. “We do roughly agree with the substance of their finding,” said North. Mann's group sometimes erred, the committee found. “Some of their choices could have been made better,” said statistician and committee member Peter Bloomfield of North Carolina State University, Raleigh, “but it was quite plausible at the time.” In any case, the missteps “didn't have a material effect on the final conclusion,” he said. And similar studies have followed from a half-dozen other groups, all giving the warm-cool-much warmer pattern.

    In addition, none of the three committee members at the press briefing—North, Bloomfield, and paleoclimatologist Kurt Cuffey of the University of California, Berkeley—had found any hint of scientific impropriety. “I certainly did not see anything inappropriate,” said North. “Maybe things could have been done better, but after all, it was the first analysis of its kind.”

    Although the committee generally supported the work Mann led, “there's a disagreement about how sure we are” about some of the study's conclusions, said North. The committee has “high confidence” that the late 20th century was the warmest period of the past 400 years—a time when high-precision proxy records are abundant. That's consistent with the idea that recent warming was in large part human-induced, Cuffey noted. But the committee has “less confidence” in Mann's conclusion that recent temperatures have set a record for the entire millennium. “The committee concluded that Mann and his colleagues underestimated the uncertainty” in the earlier part of the record, said Cuffey, for which records are of lower quality and fewer in number. “In fact, these uncertainties aren't fully quantified,” he said.

    When pressed, statistician Bloomfield characterized the committee's lesser confidence in the millennial result as “more at the level of 2:1 odds” that Earth is now warmer than it has been in at least 1000 years. The committee has “even less confidence” in Mann et al.'s 1999 conclusion that “the 1990s are likely the warmest decade, and 1998 the warmest year, in at least a millennium.” “That's plausible,” said Cuffey. “We don't know if it's true or not.” A year or a decade is just too short an interval for comparison to the older paleotemperature record, he said.

    Whether 2:1 odds for a millennial record are good or poor turns out to be in the eyes of the beholder. Long-standing critics saw the report confirming that the hockey stick had not stood up to scrutiny; defenders saw support for key findings. The committee, for its part, stressed that the hockey stick and other records resembling it are not the only evidence of human-induced warming, “and they are not the primary evidence.” Cuffey, for one, argued staunchly that the case for anthropogenic global warming is compelling, with or without the hockey stick.

  2. AVIAN INFLUENZA

    Journal Letter Spotlights China's Bird Flu Reporting

    1. Dennis Normile*
    1. With reporting by Gong Yidong and Jia Hepeng in Beijing.

    A bizarre episode surrounding the publication of a letter in this week's New England Journal of Medicine (NEJM) has again focused attention on China's willingness to share public health information.

    The letter details the case of a 24-year-old Chinese man who died in November 2003. SARS was initially suspected, the Chinese authors report, but tests for the SARS virus were negative. Subsequent tests on the patient's stored tissue samples turned up the H5N1 avian influenza virus, the letter states. The death occurred 3 months before China officially reported any H5N1 outbreaks in poultry and 2 years before it officially reported its first human case.

    The NEJM letter might not have made such a splash were it not for a last-minute attempt to retract it. On 21 June, the day before publication, NEJM received e-mails purportedly from corresponding author Wu-Chun Cao at the State Key Laboratory of Pathogens and Biosecurity in Beijing requesting that the article be withdrawn. Because the issue had already been printed, NEJM editors sent an e-mail to the journal's media subscribers and posted a note on its Web page advising that the letter had been retracted. Then on 23 June, NEJM sent out another announcement saying that Cao had contacted the journal by phone and fax and claimed that he had not sent the e-mails and had not requested that the report be withdrawn. “And so it stands as published in the issue of June 22,” reads the e-mail from Jeffrey Drazen, NEJM editor-in-chief. The episode prompted speculation about government censorship, but the interpretation remains murky. Science could not reach Cao or his co-authors for comment.

    Masato Tashiro, director of the World Health Organization (WHO) Collaborative Center for Influenza Surveillance and Research at Japan's National Institute of Infectious Diseases, says the initial suspicions about SARS described in the report are understandable. “Clinically, SARS looks just like avian influenza,” he says. Nor would it be surprising if cases of bird flu were missed among the thousands of patients presenting with flu symptoms and pneumonia in China each year, especially in the early days of the outbreak, he says.

    Flu experts have long suspected that H5N1 was circulating either undetected or unreported in southern China, probably since the first outbreak of the disease in Hong Kong in 1997. Among other evidence, two members of a Hong Kong family tested positive for H5N1 after a trip to the mainland's Fujian Province in February 2003, and bird flu is suspected in a third member of that family who died in Fujian.

    Roy Wadia, a spokesperson for WHO in Beijing, says the timing of events raises questions “about the information-sharing mechanism.” Cao's institute comes under the Academy of Military Medical Sciences, and his co-authors are affiliated with the Institute of Microbiology and Epidemiology, a People's Liberation Army hospital, and the Beijing Genomics Institute. Wadia believes that China's Ministry of Health was unaware of this case until news of the NEJM paper started circulating just before its publication. WHO has asked the ministry to investigate. “There is a public health significance [to the timely sharing of information] that can't be stressed too strongly,” says Wadia.

    A prominent Chinese military biologist who asked not to be identified says that Chinese civilian and military researchers often do not share key research results because of fears that findings will be poached. Although he has no direct knowledge of the NEJM letter, he speculates that “it is most likely that the H5N1 patient was hospitalized in a military hospital”; otherwise, the military-affiliated research group would never have acquired the tissue samples.

  3. AVIAN INFLUENZA

    Human Transmission But No Pandemic in Indonesia

    1. Dennis Normile
    Family tragedy.

    Surviving members of the extended Ginting family, which lost seven members to bird flu, gather to mourn.

    CREDIT: JEAN CHUNG/ONASIA

    Bird flu experts meeting in Jakarta last week concluded that a rare instance of human-to-human-to-human transmission had indeed occurred within a large family cluster in Indonesia. But they said there is no sign that the virus is becoming more dangerous and also discounted criticism of the government's handling of the cluster, which occurred in rural northern Sumatra in May.

    With 51 human cases and 39 deaths reported so far, Indonesia is the second-hardest hit country after Vietnam. Vietnam brought its bird flu outbreak under control last year, but the number of poultry outbreaks and human cases continues to rise in Indonesia. The Sumatra family cluster is the largest documented to date.

    Epidemiologic and genetic sequencing data suggest that a 10-year-old boy contracted the virus from his aunt and then passed it on to his father, concluded the experts, who were convened by the World Health Organization (WHO). (Six blood members of the family have died of H5N1 infection, and it is suspected in a seventh member who was buried before tissue samples were collected.)

    Although such localized “second generation” transmission has never been confirmed before, it is not unduly alarming, says Masato Tashiro, director of the WHO Collaborative Center for Influenza Surveillance and Research at Japan's National Institute of Infectious Diseases. The experts found evidence that the virus had mutated slightly as it circulated among family members, but the changes occurred in a genetic region that does not affect transmissibility, he says.

    Steven Bjorge, a WHO epidemiologist in Jakarta, defended the country's handling of the cluster, noting that health officials began investigating 2 days after family members appeared at a private clinic. He admits that the country faces an uphill battle in containing poultry outbreaks. Progress is being made tracking outbreaks in poultry with a pilot surveillance scheme that involves local officials and citizens, says Bjorge. But the country will need financial help if it is to extend such a program across Indonesia's 17,000 inhabited islands, which stretch over three time zones. Despite pledges made at an international donor meeting in Beijing in January, Indonesian officials said last week that not one cent had arrived in their country.

  4. WAR ZONE

    Targeted for Murder, Iraqi Scientists Named on a Hit List

    1. Richard Stone

    If you want to know how bad it is for scientists in Iraq these days, just ask Nazar Al-Anbaky. In the spring of 2005, a close friend, agronomist Awad Esa, director general of the Ministry of Agriculture's extension division, was gunned down by masked men as he was leaving work. Another colleague, Rafid Abdal Alkareem, head of the animal-welfare board, fled Iraq after surviving two assassination attempts. Faced with persistent threats, the ministry last fall dispersed most personnel around Baghdad. “I wasn't able to do my work. The danger was everywhere,” says Al-Anbaky, who was deputy chief of the ministry's plant protection research department. So in March, he too quit Iraq.

    For months, Iraqi academics have denounced what they view as an unspoken campaign to cripple the country's intellectual elite (Science, 30 September 2005, p. 2156). Now they face an overt new threat. An unidentified group is circulating a hit list of 461 Iraqi intellectuals. The existence of leaflets calling for the assassination of named individuals was reported by the newspaper Az-Zaman last month; Science has obtained a copy of the list, verified by several Iraqi scientists as authentic. Last week, rectors of six universities in Spain issued a statement warning of “a very grave outrage against the cultural and scientific development” of Iraq and urging authorities to investigate “the killing campaign.”

    For Iraq's beleaguered scientists, the hit list aggravates a desperate situation. Since the U.S.-led coalition invaded in April 2003, at least 188 Iraqi academics have been slain, according to a tally by the Spanish Campaign Against Occupation and for the Sovereignty of Iraq, based in Madrid. Over the past 3 years, the pace has increased (see graph). In that period, some 220 doctors have been killed and more than 1000 have left Iraq, the health ministry reported last February. Hundreds of scientists have fled the country. “This brain drain will adversely affect Iraq's development for years to come,” says Jafar Jafar, head of Iraq's nuclear program under Saddam Hussein. Jafar, general manager of Uruk Engineering Services in Dubai, says he has helped “many friends and acquaintances” find jobs elsewhere.

    Mounting toll.

    The murder rate of Iraqi academics has risen steadily since the April 2003 invasion.

    CREDIT: ADAPTED FROM PLIGHT OF IRAQI ACADEMICS, I. JALILI, MAY 2006

    The killers are largely unknown. Some murders are sectarian: Sunni militias targeting Shiite academics and vice versa. Overall, however, the assassinations “do not follow any religious or sectarian pattern,” says Ismail Jalili, an ophthalmic surgeon who presented an in-depth analysis at a conference in Madrid last April.

    In some cases, money is a motive. One recent victim was Ali Hassan Mahawish, dean of engineering at Al-Mustansiriya University in Baghdad, who told Science last September how several professors in his department had gone overseas on sabbatical, depleting the faculty. He was seized by gunmen in March. “The ransom was paid, but his family got a dead body,” says a colleague in Baghdad who asked to remain anonymous. The latest drama involves petroleum scientist Muthna Al-Badery, a top official in the Oil Ministry, who was kidnapped earlier this month. “Bargaining is still continuing for his life,” the Baghdad scientist says.

    The hit list includes scientists, university officials, engineers, doctors, and journalists in Baghdad and other cities. “The list is part of an organized, foreign-backed campaign to terrorize Iraqi brains,” an official with the Iraqi Writers Union told Az-Zaman. No one contacted by Science knows who issued the list. One prominent scientist with ties to Iraq's intelligence community says that Iraqi investigators are probing claims that Iranian intelligence agents are involved. The U.S. Embassy was not aware of the list, says spokesperson Dennis Culkin.

    One thing is certain: The campaign has cast a pall over Iraqi academia. Says one engineering professor who is sticking it out in Baghdad, “We carry our coffin every day we go to work.”

  5. ETHICS

    Blocking a Book, Dutch University Rekindles Furor Over Nobelist Debye

    1. Martin Enserink

    A controversy about the alleged Nazi sympathies of Dutch chemistry Nobel laureate Peter Debye has escalated. Utrecht University last week halted publication of a pro-Debye book by an employee and ordered staff not to discuss the issue with the press. The move follows a university decision last February to strip Debye's name from its institute for nanomaterials.

    A science historian, meanwhile, has spoken out in Debye's defense, as has another Dutch Nobel laureate, Martinus Veltman. Cornell University, where Debye was a professor from 1940 until his death in 1966, has concluded from its own 3-month investigation that there's no reason to distance itself from him, as has the American Chemical Society (ACS).

    The flap erupted after the publication of a harsh view of Debye—a physical chemist who led the Kaiser Wilhelm Institute for Physics in Berlin from 1935 to 1939—in Einstein in Nederland: Een intellectuele biografie by Berlin-based journalist and science historian Sybe Rispens. One chapter, excerpted in a weekly magazine, documented that Debye, as president of the German Physical Society (DPG), asked Jewish members to resign in a 1938 letter signed “Heil Hitler!” It also claimed that Debye stayed in touch with German authorities while at Cornell, even offering to return to Berlin in June 1941.

    Counter-counterattack.

    Utrecht University has halted the publication of a book that countered allegations about Peter Debye published in an earlier book (inset).

    CREDIT (LEFT): AP PHOTO

    In a brief statement issued on 16 February, Utrecht University's board said it would rename the Debye Institute, and Maastricht University said it would no longer award the Peter Debye Prize (Science, 3 March, p. 1239). Gijs van Ginkel, managing director of the “former Debye Institute,” as it now calls itself, responded by writing a book containing an analysis of historical documents, his view of the affair, and a sharp attack on Rispens.

    But the university has halted its publication. Van Ginkel referred questions to university spokesperson Ludo Koks, who denies that academic freedom is at stake; Koks says Van Ginkel had broken an agreement not to include personal comments in the publication. Koks confirms that institute staffers have been ordered not to talk to the press to “streamline communications.”

    Mark Walker, a historian at Union College in Schenectady, New York, who studies science and technology in the Nazi era, says that although Debye “didn't show civic courage, … all the evidence is that he was not a Nazi sympathizer.” For example, the DPG purged its Jewish members much later than most other scientific societies did, and without any enthusiasm whatsoever, he says. Signing official letters with “Heil Hitler!” was nothing unusual, even among those openly opposed to the regime. That Debye tried to keep communication channels to Germany open while at Cornell is also “absolutely reasonable,” Walker says, because his daughter still lived there.

    Walker recently gave a lecture about Debye at Cornell, where the affair “was something we just couldn't ignore,” says Héctor Abruña, chair of the Department of Chemistry and Chemical Biology. “Debye has had such a huge influence here.” In a 1000-word letter submitted for publication to Chemical and Engineering News, Abruña says a review shows that removing Debye's name from a professorship and a lecture series would be “unwarranted.” Banning books is “not what universities should be about,” Abruña adds.

    ACS sees “no compelling reason to do anything” about its Peter Debye Award in Physical Chemistry either, says Gordon McCarty, chair of ACS's Committee on Grants and Awards; DuPont, the awards sponsor, is “quite comfortable” with that stance, he adds.

    Rispens says he opposes silencing different views on Debye and would welcome a study that went beyond his own focus on Albert Einstein's circle. But the affair has cost Rispens the support of one enthusiastic fan: Veltman, who, in a foreword to Rispens's book, praised it as “a nugget of gold.” In a 5 May open letter to Debye Institute staff, Veltman says he took Rispens's assertions “at face value” at the time but now realizes “they should be assigned to the realm of fables.” The foreword will not appear in new editions or translations of the book, Veltman continued; the two universities “should admit their error, revoke their decision, and forget the matter,” he says.

  6. DIVERSITY

    Report Urges National Academies to Improve Status of Women

    1. Jeffrey Mervis

    Johanna (Anneke) Levelt Sengers stands at the top of her profession but confesses that “it can be a little lonely” as one of only two women in the 82-member engineering sciences section of the U.S. National Academy of Sciences (NAS). A scientist emeritus at the National Institute of Standards and Technology, she belongs to both NAS and its partner, the National Academy of Engineering, where she's one of seven women within the 173-member chemical engineering section. So in late 2004, when she was asked to co-chair an international panel on women in science with Manju Sharma of India, they decided to examine not just women's place in society but also their status within the 90 national academies that had requested the report.

    The report, posted last week by the InterAcademy Council (IAC) (http://www.interacademycouncil.net/), offers a refreshingly candid assessment of the problems facing women trying to enter and move up in the world of science and engineering. Although it strikes familiar chords about the need to remove barriers and increase opportunities for girls and women, it sings a new tune in commanding the national academies themselves to “first put their own houses in order.” In addition to choosing more women as members and leaders of their organizations, each national academy should form a standing committee on diversity to gather and discuss gender-related data, it says.

    “Wow. This is far more hard-hitting and to the point than I had expected,” says Donna Dean, president of the Association for Women in Science in Washington, D.C., and a former senior administrator at the National Institutes of Health, who is now at the Washington, D.C., science-lobbying firm of Lewis-Burke Associates. “It tells the various academies to stop pontificating about the right thing to do and start showing it in how they operate.”

    The report was funded in part by a $50,000 grant from L'Oreal. Since 1998, the France-based cosmetics company has honored outstanding women scientists around the world—including five of the eight women on the 10-person IAC panel. Jennifer Campbell, who heads the company's philanthropic efforts, says she would like to see across-the-board parity for women in science. But Levelt Sengers says she thinks that “a reasonable goal would be no major disparity between the percentage of Ph.D. degrees awarded to women in a particular field and the percentage elected in that field.” Most academies are a far cry from reaching even that level; the 2% figure for NAS women in chemical engineering, for example, pales beside the 14% of U.S. Ph.D.s awarded in the 1980s, much less the 22% awarded in the 1990s.

    Against the odds.

    Levelt Sengers helped write a report on women for an international council of national academies whose 15-member board (bottom) in January 2006) is all male.

    CREDITS (TOP TO BOTTOM): B. EYMANN, COURTESY OF THE FRENCH ACADEMY OF SCIENCES, Y. O'BANNON, COURTESY OF THE INTERACADEMY COUNCIL

    NAS President Ralph Cicerone says that there's “no magic bullet” for adding women to the academy's ranks but that NAS is trying to increase their chances of gaining the type of recognition—through service on academy panels, keynote speeches, and major scientific awards—that traditionally leads to NAS membership. NAS has no plans “to collapse its activities into one committee on gender issues,” he says, adding that the challenge calls for “a sustained effort … along the entire pipeline.”

    Levelt Sengers says that each academy must come up with individual remedies, which she hopes will be discussed during the council's next meeting in December in Cairo, Egypt. Dean suggests a radical approach to staffing the academies, many of which operate extensive networks of institutes and laboratories. “What about strategic buyouts to senior managers, like companies do?” she asks. “It wouldn't be easy or welcome. But business as usual just won't get you there.”

  7. PALEOCLIMATOLOGY

    Atlantic Mud Shows How Melting Ice Triggered an Ancient Chill

    1. Richard A. Kerr

    Eighty-two hundred years ago, a chill swept around the Northern Hemisphere, the last, feeble gasp of the mighty 100,000-year ice age that preceded it. Geologists looking for a cause had glimpsed evidence that a vast outpouring of glacial meltwater had gushed into the Atlantic Ocean less than a year after an ice dam busted. That meltwater outburst, seven times as voluminous as all five present-day Great Lakes, had come suspiciously close to the 8200-year, or “8K,” chill. But paleoceanographers couldn't answer the big question: How could it have affected deep-sea currents believed to play a pivotal role in controlling climate?

    Now, paleoceanographers report on page 1929 that they have found a single ocean sediment core that preserves the sought-for link. An ocean current, the so-called conveyor, carries climate-moderating heat into the far north, where it sinks to the bottom and heads south. The core recorded both a gush of freshwater far out into the North Atlantic and the nearly simultaneous slowing of that conveyor. “I'm a believer” in the meltwater-conveyor-climate link, says paleoceanographer Nicholas McCave of Cambridge University in the U.K., who is not an author of the paper.

    The core came from south of Iceland on the Gardar Drift, where muddy sediment collects 10 to 20 times faster than is usual in the deep sea. With more sediment per year to work with, paleoceanographers Christopher Ellison and Mark Chapman of the University of East Anglia and Ian Hall of Cardiff University, both in the U.K., could sample smaller bits of time and thus read a more detailed history. To gauge the changing temperature of surface waters, they measured the abundance of a cold-loving plankton species. They calculated the salinity of the seawater from the ratios of oxygen isotopes in the plankton's shells after adjusting for the effect of temperature. Finally, they inferred the speed of ancient currents from the varying size of silt particles in the mud. The more abundant the larger particles were, the faster the current was moving across the bottom.

    By reading the history of both surface and bottom waters in a single core, the U.K. researchers nailed down the order of events more than 8000 years ago. They found that the cold meltwater came in two pulses, the first about 8490 years ago, the second 200 years later. Late in the first freshening, the returning conveyor current sweeping southward along the Gardar Drift began to slow. Apparently, the fresher, more buoyant surface waters slowed the sinking of the conveyor's waters into the deep sea at the current's turnaround point. The second freshening repeated the pattern and further slowed the conveyor.

    The Gardar results are “a strong confirmation that this was a freshwater event,” says geochemist Wallace Broecker of Lamont-Doherty Earth Observatory in Palisades, New York. That's reassuring, Broecker says, because it helps clear up a vexing puzzle about an earlier, even more drastic cooling: the 11,000-year-old Younger Dryas cold spell, also supposedly due to a glacial outburst. Broecker and geologist colleagues reported recently that they couldn't find the route of the meltwater on land. That failure raised the troubling possibility that glacial meltwater had nothing to do with the Younger Dryas, the 8K event, or other abrupt coolings of the past 15,000 years. Now it looks as if theorists were on the right track after all.

    Next, researchers need to figure out why the far smaller meltwater release of the Younger Dryas triggered a cooling so much greater than the 8K's. “The 8K was the biggest flood,” says glaciologist Richard Alley of Pennsylvania State University in State College, “but it's the one that didn't stick,” climatically speaking. Had the climate system by then developed some protective property that warded off the abrupt chill? If so, will the present climate be able to do the same as the greenhouse sends more freshwater—rain and Greenland meltwater—into the North Atlantic?

    In sync.

    When North Atlantic surface waters freshened (top), bottom currents slowed.

    CREDIT: ADAPTED FROM ELLSION ET AL., SCIENCE
  8. ANIMAL BEHAVIOR

    Signs of Empathy Seen in Mice

    1. Greg Miller

    Empathy is one of the nobler human attributes, which may explain why we're often reluctant to ascribe it to other animals. A debate has simmered for years about whether chimps display empathy, for example. Now on page 1967, scientists argue that even lowly mice have a rudimentary form of it.

    The research team, led by Jeffrey Mogil at McGill University in Montreal, Canada, reports that mice become more sensitive to pain when they see a familiar mouse in pain. That probably doesn't qualify as empathy as the word is understood in everyday conversation, says ethologist Frans de Waal of Emory University in Atlanta, Georgia. Still, de Waal and others say it does suggest that mice have some ability to sense what their fellow rodents are experiencing. “They're in tune with each other,” de Waal says.

    Commiserating mice.

    Observing a cagemate can influence pain sensitivity in mice.

    CREDIT: MONA LISA CHANDA

    In one experiment, Mogil and colleagues injected mice in the belly with a weak acetic acid solution. Solitary mice react to the injection with a stereotyped writhing behavior, stretching repeatedly and extending their back legs. Mice spent more time writhing when the researchers placed them in a Plexiglas cylinder with a cagemate—a mouse they'd lived with for at least a week—given the same injection at the same time. When the researchers paired mice who'd never met, however, no significant increase in writhing occurred.

    The researchers also injected cagemates with formalin in one paw, causing them to lick the presumably painful area. In some cases, both mice received the same concentration of formalin, either a low dose or a high dose. Not surprisingly, pairs of mice given the high dose spent more time licking their paws than did pairs given the low dose. But when a mouse given the low dose was paired with a cagemate given the high dose, it licked more, on average, than if it had been paired with another low-dose mouse. More importantly, the high-dose mouse licked less, on average, than did a high-dose mouse paired with a cagemate that also got a high dose. Observation, it seems, can reduce pain behavior as well as enhance it, Mogil says.

    Finally, the team repeated the acetic acid experiment and incorporated a different gauge of pain sensitivity, measuring the time it took for a mouse to withdraw its paw from a hot spot on the floor of the test cylinder. When observing a cagemate writhing from an acetic acid injection, mice withdraw their feet from the heat more quickly—even if they'd received no injection themselves. That's the most important experiment, Mogil says, because it indicates that the mice aren't simply imitating what they see the other mouse doing. “It suggests the pain system is being sensitized in a general manner” by seeing a cagemate in pain.

    Is that empathy? It depends on whom you ask, says Tania Singer, a cognitive neuroscientist at the University of Zurich in Switzerland who has studied pain and empathy in people (Science, 20 February 2004, p. 1121). “Philosophers would argue you can only have empathy if you have consciousness,” she explains. “Psychologists would want to see evidence of altruistic behavior and altruistic motivation.” Mice probably don't meet those criteria, she says.

    And not everyone agrees that Mogil's experiments actually address the issue of empathy in the first place. Writhing and paw licking are reflexive behaviors mediated by the spinal cord, notes Charles Vierck, a neurobiologist at the University of Florida, Gainesville. “So what we have here is modulation of a reflex response during observation … of the reflex responses of other animals.” And that, says Vierck, is nothing new.

    Still, Singer and others, including Mogil, interpret the findings as evidence that mice have “emotional contagion,” a primitive kind of empathy. “Emotional contagion means one baby starts crying and all the babies start crying,” explains Peggy Mason, a neurobiologist at the University of Chicago who studies pain. Unlike higher forms of empathy, it doesn't require understanding what others are experiencing. “The second baby doesn't have to realize that the first baby is upset because it has a dirty diaper,” notes Mason.

    Many researchers see emotional contagion as a steppingstone toward the more sophisticated kind of empathy that evolved in humans. “To imagine that empathy just started de novo in primates seems biologically implausible,” says Mason.

  9. CHEMISTRY

    Sugary Recipe Boosts Grow-Your-Own Plastics

    1. Robert F. Service

    Motorists aren't alone in feeling the pain of rising oil prices. Some commodity chemicals, such as the polypropylene that's found in everything from textiles to dashboards, have tripled in price in the past few years. That surge has spurred new interest in the once-sleepy field of converting crops and other renewable feedstocks into commodity chemicals. Chemical companies have made progress in recent years. But up to now, it has been difficult and costly to make the kinds of compounds that serve as starting materials for most oil-derived chemicals. Now, work by researchers in the United States may give plant-derived chemicals a new push.

    On page 1933, University of Wisconsin, Madison, chemical engineer James Dumesic and colleagues report a new process for turning fructose, the sugar in fruit, into a compound called 5-hydroxymethylfurfural (HMF), which can replace key petroleum-derived chemical building blocks. Unlike previous schemes for turning sugar into HMF, the new process is efficient, easy, and potentially low cost. “It looks real good to me,” says Thomas Zawodzinski, a chemical engineer at Case Western Reserve University in Cleveland, Ohio. “This is the direction things need to go in.”

    Sweet prospects.

    Sugars from fruits and grains could replace petroleum as the basis for commodity chemicals such as plastics, if a new process pans out.

    ILLUSTRATION: TERRY E. SMITH

    Because of its current high cost, HMF isn't produced commercially in large volumes. But it is easily converted into other compounds, such as one abbreviated FDCA that can serve as the starting material for commodity chemicals such as polyesters. On paper, converting fructose, a small, ring-shaped sugar, to HMF is simple. It requires stripping off what amounts to three water molecules. Researchers have developed numerous acid-based catalysts that do that quickly. Once formed, however, HMF readily reacts with fructose, other intermediate reactants in the mix, and even itself to form a chemical zoo of unwanted byproducts, which sharply limits the amount of HMF that's recovered at the end. In hopes of solving that problem, researchers have tried adding an organic solvent that sits atop the water like oil in salad dressing. HMF's affinity for the solvent spirits it out of the aqueous phase, during which the unwanted side reactions take place. Unfortunately, separating HMF from the solvents proved difficult. Researchers had to boil away the solvents at very high temperatures.

    To improve the process, Dumesic and his students Yuriy Román-Leshkov and Juben Chheda had to solve these and other problems simultaneously. They did so by adding a series of different compounds both during the aqueous phase, in which catalysts convert fructose into HMF, and to the solvent. In the aqueous phase, the additives—abbreviated DMSO and PVP—suppressed side reactions, thereby encouraging HMF production. Unfortunately, they also increased HMF's solubility in water, making it harder for the solvent, known as MIBK, to remove HMF from the aqueous phase before it could react further. The Wisconsin team overcame that obstacle by spiking the MIBK with a dash of a compound called 2-butanol, which increased HMF's affinity for the solvent. Finally, because MIBK has a low boiling point, the Wisconsin team could easily evaporate it along with the 2-butanol, recover the HMF, and return the solvents to the reactor.

    The changes doubled the percentage of fructose that gets converted into HMF, to 85%. With that boost and related improvements, “now you can make some pretty compelling arguments” for producing HMF commercially, says Todd Werpy, an expert on producing bio-derived chemicals at Pacific Northwest National Laboratory in Richland, Washington. Producing commodity chemicals from renewable feedstocks “is really in its infancy,” Werpy says. But with top research groups now training their sights on the problem, he adds, “renewables could make a major contribution to the chemical needs in the United States.”

  10. MOUSE GENETICS

    A Mouse for Every Gene

    1. David Grimm

    A global initiative to knock out every mouse gene struggles to get its act together

    Buyer beware.

    Deactivating the same gene in Black 6 (left) and 129 mice may yield widely different phenotypes.

    CREDIT: ED MATHIS/BMC, HEALTH SCIENCES CENTRE, WINNIPEG

    In Adriano Aguzzi's experience, getting hold of a new mouse strain can be nothing but trouble. A neuropathologist at the University Hospital of Zurich in Switzerland, he is one of thousands of researchers who study mutant mice for clues to what particular genes do. “Once I requested a mouse, and the guy wanted everyone from himself to his grandmother to be a co-author on everything we published with that mouse,” says Aguzzi. “It was like scientific prostitution.” Another time, he says, a researcher promised him a mouse but took more than a year to deliver: “[The investigator] should have just said his cat ate it; it would have saved us a lot of trouble.”

    Most mouse researchers can tell similar horror stories. But help is on the way. Several large-scale projects plan to disable every gene in the mouse genome and make the resulting mice readily available to the research public. In January, Europe and Canada embarked on ambitious efforts that together will produce more than 30,000 knockouts. And this summer, the U.S. National Institutes of Health (NIH) will announce the Knockout Mouse Project (KOMP), which will add another 10,000 to the list. China, too, is gearing up to make 100,000 mutants, with the goal of making 20,000 lines of mice, each with a different gene knocked out. (see sidebar, p. 1864). All told, these efforts will cost almost $100 million. Although separate entities, “the plan is to have every center work together, much like [what] was done with the Human Genome Project,” says Allan Bradley, director of the Wellcome Trust Sanger Institute in Cambridge, U.K., which is part of the European effort.

    Indeed, overall, the knockout effort is arguably the largest international biological research endeavor since the Human Genome Project. And it is the next major step in figuring out what makes us tick. The human and mouse genome projects each identified some 25,000 genes, most quite similar between the two species. But researchers have no idea what more than half of these genes do. Because the mouse is so amenable to genetic manipulation, and so well studied, mass-produced mutant mice offer a window into these unknown genes. “The Human Genome Project wasn't done just to get the sequence,” says Christopher Austin, director of the NIH Chemical Genomics Center and KOMP's founding father. “It was a prerequisite for figuring out what our genes do.”

    Holy Grail?

    Marina Picciotto would love to find a mouse that caves to peer pressure, but chances are it's hidden away or hasn't been made yet.

    CREDIT: TERRY DAGRADI/MED MEDIA GROUP, YALE SCHOOL OF MEDICINE

    How the individual mass-knockout projects will work together is still being ironed out. Each project is embarking on a different—and not necessarily compatible—approach to making its mutant mice, and the logistics of keeping track of all the mutants made are daunting. In addition, each effort will need to work out an efficient way to catalog and distribute the mice it creates. They will also have to deal with intellectual-property claims when one of the new mutants turns out to be a previously patented mouse strain. “The mouse project could open up huge areas of science, just like the Human Genome Project did,” says Marina Picciotto, a molecular neurobiologist at Yale University, “but there are likely to be hiccups along the way.”

    Although Picciotto and most of her colleagues are optimistic about mass-produced knockouts, some wonder whether the efforts are the best use of public resources. Knocking out genes is really just the beginning. Those tens of thousands of mutant mice won't do many researchers much good until the behavior, morphology, and physiology of these knockouts have been described. Characterizing each mouse will not be easy. “You can knock out every gene, but if you don't have assays to evaluate them, it's hard to figure out what the gene is doing,” says Marnie Halpern, a zebrafish geneticist at the Carnegie Institution of Washington in Baltimore, Maryland.

    Hiding out

    As a group, the knockout projects are trying to create something akin to the international superstore IKEA, where, in a single trip, customers can buy a houseful of easy-to-assemble furniture at reasonable prices. In this case, however, researchers wouldn't even have to make a trip to the store. Ideally, they would simply go to a central database and click their own computer mouse to order the knockout mouse of their choice. Within weeks, frozen embryos would arrive at their door. Like IKEA, some assembly would be required: turning those frozen embryos into live mice. But that requirement is minimal compared to the tens of thousands of dollars and a year or more of work involved in creating an average knockout mouse.

    Such a resource would be a far cry from today's mouse trade, which is more like buying furniture from neighbors. Selection is limited, quality varies, and some items just aren't for sale. Part of the problem, says Francis Collins, director of NIH's National Human Genome Research Institute in Bethesda, Maryland, is that until recently, researchers often didn't know what the lab down the street—let alone one in another country—was doing. Investigators aren't required to place their mice in public repositories, and some never write up knockouts they don't find useful.

    To remedy this situation, NIH went on a mouse hunt. It started its inquiry at the Jackson Laboratory (JAX) in Bar Harbor, Maine. JAX stores more than 800 varieties of mutants and maintains a database of every published mouse knockout. Then NIH went door-to-door, publishing a request asking investigators go to a JAX Web site and list any knockouts they had created and were willing to share with the research public.

    The findings were dispiriting. All told, the mouse community had knocked out about 11,000 genes, but many labs were repeating work done elsewhere. More than 700 knockouts had been created three times or more; in one case, a single mouse had been duplicated 11 times. And of the 4000 unique knockouts that have been published, more than 3000 are not in public repositories, meaning most are either unknown or unavailable to the wider community. “It's embarrassing,” says Collins. “A graduate student shouldn't spend a year making a knockout that's already been made. It's not a good use of resources.”

    Yale's Picciotto is a case in point. As a researcher who studies the genetics of addiction, she would love to find a mouse that caves to peer pressure. So far, she's managed to make a few handy knockouts. Some shun nicotine; others dig opiates. One even seems to be operating on a natural antidepressant. But for a complete picture of the mouse social psyche, Picciotto needs an animal that wants drugs just because his companions have them.

    Setting out to make her dream mouse is not really an option, however, because she has no clue what gene might influence peer-pressure sensitivity. Picciotto might be able to find the mouse in the community after an exhaustive search, but, if it exists, there's a good chance it's tucked away in a cage in a lab somewhere or frozen down as a clump of embryonic stem cells in a biotech company. Either way, it's as good as gone.

    Even if Picciotto finds what she is looking for, that's hardly the end of the story. “I'm sorry to say that there are a few labs out there [that] won't share their mice even if they've published them in a journal [such as Science or Nature] that requires them to do so,” says M. Celeste Simon, a developmental and cancer biologist at the University of Pennsylvania Cancer Center in Philadelphia. And as Aguzzi knows all too well, reticent mouse-makers can effectively quash efforts to use their mice by stalling delivery or making outrageous demands about co-authorship.

    Different strokes.

    There's more than one way to knock out a mouse, but each has its pros and cons.

    ILLUSTRATION: K. SUTLIFF/SCIENCE

    Assuming the source of the mouse is cooperative, “transferring mice is an extremely difficult and time-consuming process,” says Simon. Some of Simon's Penn colleagues lost 2 years of work when mice they ordered from a government facility turned out to be infected with an extremely contagious virus that can alter phenotypes. “It strikes fear into one's heart,” she says. “Two years is a lifetime in the world of science.” Other investigators complain about the cost and hassles of shipping or draconian material transfer agreements.

    Over the past 6 years, several efforts have popped up to help address some of these problems. The International Gene Trap Consortium, for example, runs a database that enables researchers to track down about 20% of the existing unique mouse knockouts. And repositories themselves—most of which are publicly funded and store anywhere from 500 to 4000 mice—are beginning to work together under the Federation of International Mouse Resources to help make sure researchers around the world can get any mouse in any repository.

    The big push

    Realizing that these were just baby steps, mouse researchers from several countries decided in 2003 to take a giant leap. At a meeting at the Cold Spring Harbor Laboratory in New York, they called for a comprehensive international mouse knockout program. Besides shooting for an IKEA-like superstore, the participants agreed that it would be most economical to avoid trafficking in live mice and instead decided to maintain the knockouts as embryonic stem (ES) cells: clumps of tissue that can be frozen down and later grown up into full-fledged mice. Researchers could request ES cells or be provided with easier-to-use frozen embryos or sperm. They also proposed to use NIH's National Center for Biotechnology Information as their clearinghouse. Its Web site would act as a sort of Google to scan mouse repositories for the desired knockout. “The ultimate goal is to have one-stop shopping [for these mice],” says KOMP Program Director Colin Fletcher.

    Two years after the meeting, Wolfgang Wurst, director of the Institute of Developmental Genetics at the German National Research Center for Environment and Health (GSF), and his colleagues set up the European Conditional Mouse Mutagenesis Program (EUCOMM). To get the program rolling, the European Union has promised $16.3 million over the next 3 years. The bulk of the EUCOMM effort is divided between two institutes: GSF and the Sanger Institute. GSF will use “gene trapping” (see diagram) technology to randomly knock out 12,000 genes in ES cells. The Sanger Institute and GSF will use “gene targeting” technology to disable 8000 preselected genes (see diagram, above right).

    “It's an ambitious program,” says Bradley, who is leading the Sanger effort, “but we're fairly confident we can meet our goals.” So far, GSF has produced about 3700 unique knockouts, which researchers can order for $631 apiece. Bradley expects Sanger's lines to start becoming available by late 2007.

    At the same time EUCOMM was getting started, Canada came out with the North American Conditional Mouse Mutagenesis Project (NorCOMM). Over the next 5 years, Genome Canada will spend $8 million for knockout work primarily at the University of Toronto and the University of Manitoba. The project has produced 3000 gene-trapped knockouts and hopes to make 9000 more over the next 18 months.

    NIH's upcoming knockout effort is similar in scope and direction. KOMP expects to spend $50 million at up to four soon-to-be-named centers to build a library of 10,000 knockouts (see sidebar, p. 1863). Like EUCOMM, KOMP will likely use a combination of gene trapping and gene targeting to produce its knockouts. Targeting allows researchers to make precise mutations in their gene of choice, says Fletcher, and targeting will be easier to coordinate among KOMP centers and with the international partners because each group will know exactly what gene it's going after.

    But there are important differences between KOMP and the other programs. EUCOMM and NorCOMM are making so-called conditional knockouts, in which the genes that are swapped into the genome have a self-destruct sequence. The new gene encodes information that tells it at which point in development or in which tissue to disappear. The strategy is especially important for determining the function of essential genes, which, if shut off too early, can kill a mouse while it's still an embryo, short-circuiting studies of the gene's effects.

    Gone, but not completely.

    Without the Dicer gene, a mouse embryo (inset, left) is small compared to a normal embryo (inset, right) and dies within a week. But when the gene is programmed to turn off just in skin cells, this conditional knockout mouse is born, but has very little hair (above).

    CREDITS: T. ANDL AND S. E. MILLAR/UNIV. OF PENNSYLVANIA, E. P. MURCHISON AND G. J. HANNON, COLD SPRING HARBOR LABORATORY; (INSET) EMILY BERNSTEIN ET AL., NATURE GENETICS 35, 215–217 (2003)

    When KOMP knocks out a gene, however, it's dead from day one. More embryos may die than with conditional knockout technology, but these “frank null” knockouts are still very informative, says Fletcher. They tell researchers whether a gene is necessary for development.

    Also, of all the mouse efforts, only KOMP will focus on “repatriation.” Thanks to NIH's detective work, the agency has compiled a list of the “lost” mice in the community. Recently, in a sort of mouse version of American Idol, NIH posted a request asking researchers to vote for the top 20 mice on this list that they'd like to see in a public repository. “That helped us prioritize 500 to 600 mice to repatriate,” says Fletcher.

    Part of the KOMP effort will involve contacting the owners of these mice and asking them to put their animals in a globally accessible repository. NIH kicked off this program earlier this month, with $800,000 split between the University of California, Davis, and the University of Missouri, Columbia, to acquire 300 of these lines. KOMP leaders hope the repatriation effort will conserve resources by obviating the need to make these lines again.

    Trouble ahead?

    But before a global knockout mouse emporium opens it doors, the international effort must overcome a number of hurdles. Topping the list is figuring out how to avoid the knockout duplication already seen in the mouse community. That's going to be a challenge, especially once each effort is cranking out hundreds of knockouts a month, often in random genes. EUCOMM's Wurst admits it will be “hard to coordinate” his gene-trapping program with NorCOMM's, because neither can predict which genes it's going to knock out. And the American and European groups have yet to factor in the knockouts coming in from China.

    Even if redundancy can be addressed, it will still be caveat emptor for researchers who need to compare mice made by different projects. KOMP plans to use a strain of mouse called Black 6, whereas EUCOMM and NorCOMM are making their mutants in strain 129. That could cause studies of behavioral genes, for example, to yield skewed results. “Some 129 strains are really stupid, while Black 6 has a reputation for being smarter,” says Yale's Picciotto. “You can't compare the two.”

    Another unresolved issue is what to do about knockouts that are knockoffs of an already-patented mutant. Several biopharmaceutical companies, including Deltagen in San Carlos, California, make their money selling big-ticket knockout mice. Deltagen, which last year earned $6.7 million from its catalog of 900 knockouts, is seeking “broad patents” on the majority of its lines, says CEO Robert Driscoll. Driscoll would not comment on what steps, if any, the company would take if KOMP or another effort remade one of its patented mice.

    On the academic side, some researchers question the way the global endeavor is taking shape. “I'm not totally convinced [this effort] is going about things the right way,” says University Hospital of Zurich's Aguzzi. He worries that the variety of strains and technologies being used will lead to glitches in these high-throughput enterprises. The global effort is “layers of magnitude more complicated than the Human Genome Project,” he warns.

    Aguzzi also emphasizes the need to take one step at a time. He argues that plenty of knockouts have been made with specific biological questions in mind and that these questions should be answered first. “Putting so much effort into creating a bunch of lines that people may not be able to ask the right questions with may not be the best use of resources,” he says.

    Each effort will try to address this concern by growing a subset of its frozen lines into live mice and then characterizing them. This information will then be uploaded into the central database, so researchers such as Picciotto might find their dream mouse. But a massive phenotyping effort is still years away—the next big step after this big step.

    Despite these caveats, the global project should have a dramatic impact on both basic and biomedical research, says Picciotto. “Ordering a mouse is never going to be as easy as ordering an antibody,” she says. But as the global project matures and begins to characterize the knockout lines in its libraries, even researchers in small labs and those who are not mouse geneticists will be able to delve into the world of the knockout mouse. “Before, scientists were limited by their experience and their resources,” she says. “Now they'll only be limited by their imagination.”

  11. MOUSE GENETICS

    NIH Knocks Out Key Mouse House

    1. David Grimm

    When the Texas Institute for Genomic Medicine (TIGM) applied to be part of a new $50 million U.S. National Institutes of Health (NIH) program to knock out as many mouse genes as possible, it seemed to be a shoo-in. Thanks to a partnership with Lexicon Genetics in The Woodlands, Texas, TIGM already has in its freezers knockouts for nearly a third of all mouse genes—twice what global knockout projects have achieved so far (see main text). “Taking us on would have made it easy for [NIH] to fulfill its mission,” says TIGM President Richard Finnell.

    Out cold.

    Lexicon is making thousands of mouse knockouts in embryonic stem cells. These frozen lines will become part of the TIGM resource.

    CREDIT: LEXICON GENETICS INCORPORATED

    Instead, he says, NIH has rejected his institute's application, potentially forcing NIH's Knockout Mouse Project (KOMP) to start from scratch and positioning TIGM as a possible competitor. NIH won't comment on the move until it announces the winners of the competition later this summer, but some in the mouse community feel that Lexicon's reputation for tough intellectual property (IP) restrictions may have hurt TIGM's chances. Finnell insists, however, that TIGM will place no IP restrictions on its knockouts.

    Founded as a nonprofit organization last summer with a $50 million award from the Texas Enterprise Fund—a $295 million pot set up by the state to create jobs—TIGM's mission is essentially identical to that of the global knockout effort: Establish a massive mouse-mutant resource in embryonic stem cells and distribute these lines to academic scientists at cost. But while the global program's players are just beginning to churn out knockouts, TIGM, which is based in Houston and College Station, has lept ahead.

    It has used $30 million of its $50 million to purchase Lexicon's growing library of knockouts in the coveted Black 6 strain of mice; starting this month, researchers can order any of 7500 unique knockouts—representing about a third of the mouse genome—and they'll have access to knockouts covering more than two-thirds of the genome by late 2007, says Finnell.

    Becoming part of KOMP would not only have helped NIH achieve its goals more quickly and cheaply, says Finnell, but it would have also made TIGM's mouse lines more economical for researchers. Without NIH support, TIGM will still be supplying knockouts years before KOMP, says Finnell, although researchers may have to pay more for them. (Pricing details are still being worked out.)

    Lexicon CEO Arthur Sands is confounded by NIH's decision. “It just doesn't make sense,” he says. “[Our] resource is already on the ground.” Neither Sands nor Finnell would speculate on why NIH decided not to collaborate with the institute. And outside scientists were hesitant to speak on the record. But some researchers Science spoke to said IP restrictions Lexicon has imposed in the past—such as requiring labs and universities to sign away certain rights related to discoveries made using its mice—have been problematic. Under the TIGM deal, however, those restrictions are lifted, says Finnell, “so that wouldn't have been an issue.”

    Others say NIH is interested in more cutting-edge science than Lexicon is using to make its lines. Ideally, for example, KOMP centers will use gene-specific targeting technology in addition to random gene-trapping technology. According to Finnell, Lexicon's library is being made almost exclusively by means of gene trapping (see figures), although he says that—with NIH funding—TIGM would have tried to complete the remaining third of the resource using gene targeting.

    Despite the NIH setback, TIGM is planning to make its mark in the mouse world. “It will cost more now, but we're going to get these lines out to researchers,” says Finnell. “When people think about knockout mice, they'll think about TIGM.”

  12. MOUSE GENETICS

    China Takes Aim at Comprehensive Mouse Knockout Program

    1. Dennis Normile

    SHANGHAI—Geneticist Xiaohui Wu looks through a window into a clean room on the campus of Fudan University here and proudly points to a growing collection of mutant mice. To a visitor, the 4000 cages and 20,000 mice representing 400 mutant strains look pretty impressive. To Wu, the scale of the operation is a frustrating limitation.

    “We plan to mutate 70% of the mouse genome over the next 5 years,” he says. Yet, their current facilities are filled to capacity. A new building will provide space for 10,000 more cages. But Wu needs 50,000 more, enough for about 100,000 mutant mice. Those cages, he says, require a lot more space and “a lot of money.”

    Throughout the world, researchers are setting up programs to shut down the mouse genome gene by gene to learn what each gene does (see main text). The Fudan University mouse facility—a joint effort with Yale University—is shooting to be a key player and hopes to team up with the U.S. National Institutes of Health (NIH) Knockout Mouse Project.

    The driving force behind the tentatively named Mammalian Functional Genome Project is Tian Xu, a geneticist at Yale University School of Medicine who is also an adjunct professor at Fudan. The Fudan-Yale group, along with colleagues at the University of Colorado, Boulder, and Duke University in Durham, North Carolina, has come up with an efficient way to knock out mouse genes. They use a transposon, a short segment of DNA that invades genomes, sometimes inserting itself into a gene and deactivating it.

    Developmental biologists have used transposons to disable genes in plants, worms, and fruit flies for years, but they had not found one that worked well in mammals. After 8 years of searching, Xu and his colleagues found “piggyBac,” which was first identified in the cabbage looper moth by molecular virologist Malcolm Fraser of the University of Notre Dame in Indiana. “We don't know why it works,” says Xu. But it does. The group reported its finding in the 12 August 2005 issue of Cell.

    Loyal alum.

    Yale's Tian Xu and his alma mater are making mutant mice.

    CREDIT: PHOTO COURTESY OF TIAN XU

    The technique is similar to gene trapping in that it randomly disables genes. But using a transposon avoids the laborious manipulation of embryonic stem cells required by other knockout techniques. The researchers made a line of mice that carry both the transposon and DNA that causes the transposon to move. When they mate these mice with wildtype mice, the transposon hops to a new place, preferably to a gene. “All you need to do is just breed mice, and each has different genes mutated,” Xu says. This approach can hit genes other knockout approaches tend to miss, he adds.

    In the pink.

    UV light reveals which mice (hot pink) carry a transposon with a fluorescing protein gene.

    CREDIT: SHENG DING ET AL., CELL 122, 473–483 (AUGUST 12, 2005), COPYRIGHT © 2005 ELSEVIER INC.

    Also, the Fudan-Yale group has put the gene for red fluorescent protein into the transposon. Mice that wind up with the transposon in their genomes are pink under ultraviolet light. “You just look at it, and you can tell” if the genome is carrying the transposon, Xu says.

    The Fudan-Yale team opted to set up its large-scale mouse facility in China to save money. Xu estimates that this project could cost one-fifth to one-fourth what it would cost in the United States. But it is still not cheap, and international researchers are impressed by the $12.5 million already pledged from national and local government funding agencies. “I think it's great that [the Chinese] are doing this,” says Phil Soriano, a developmental biologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. Wolfgang Wurst, director of the Institute of Developmental Genetics at the National Research Center for Environment and Health in Munich, Germany, thinks the project is a welcome indication of China's increasingly international orientation. “It is a sign that they are serious research partners,” he says.

    To leverage support from China itself, Xu and Wu are asking for $30 million from NIH to start mass-producing, preserving, and distributing mutant mice. For the cost of shipping and handling, researchers will receive frozen embryos or sperm, with no intellectual-property-rights restrictions attached. Also, the NIH money would go a long way toward producing the 100,000 strains of transposon-modified mice. Wu and Xu need that number of strains to be sure they have 20,000 genes covered, because the transposon also lands on noncoding regions. If they don't get NIH funding, they may have to recoup some costs by charging fees or placing restrictions on mutant mice, Wu says.

    At this point, the other programs are simply making knockout strains, But here, researchers are busy screening the more than 400 mutant mice they have generated over the past year, looking for phenotypes from neurophysiological, immunological, and disease angles, among others. That information will go up on the Web prior to publication, making it easier for potential users to see which mouse will best suit their needs, the duo point out. Four hundred mutants is about the limit until the team's new facility comes on line. After that, the view through these new clean-room windows will get even more interesting.

  13. HUMAN BEHAVIOR AND EVOLUTION SOCIETY MEETING

    Long-Ago Peoples May Have Been Long in the Tooth

    1. Constance Holden

    PHILADELPHIA, PENNSYLVANIA—Life may have been nasty and brutish for our prehistoric forebears, but it wasn't necessarily short. Contrary to the notion that it was rare for someone to reach the age of 40 in prehistoric societies, studies of modern hunter-gatherer groups suggest that a substantial proportion of our ancestors survived into their 70s, says an anthropologist who has been studying indigenous people in Bolivia.

    Age old pattern.

    A Tsimane senior citizen in Bolivia.

    CREDIT: PHOTO COURTESY OF MICHAEL GURVEN

    Speaking last week at the meeting of the Human Behavior and Evolution Society in Philadelphia, Pennsylvania, Michael Gurven of the University of California, Santa Barbara, reported on mortality data collected from 10 modern-day groups of hunter-gatherers and forager-horticulturists, including the Tsimane Indians in north-central Bolivia, which he and Hillard Kaplan of the University of New Mexico have studied since 2001.

    Gurven's analysis revealed that 40% to 50% of the members of these groups never make it to age 15. But their prospects brighten after that, he says: A 15-year-old has a 40% chance of reaching 65, and by the time they reach 70, the mortality rate is no higher than for a U.S. resident. Evolutionary psychologist Daniel J. Kruger of the University of Michigan, Ann Arbor, says the new work “challenges current thought on … the shape of the hominid survival curve.” Gurven and other scientists estimate ages and mortality of contemporary indigenous groups through a variety of convergent techniques, including interviews, old missionary records, historical events, and photographs. In contrast, reconstructions of prehistoric populations rely primarily on skeletal data.

    “Some reconstructions of prehistoric populations tend to show life expectancies of 15 to 25 years,” Gurven says, “with relatively low infant and child mortality but extremely high adult mortality.” Not only is Gurven's work at odds with that scenario, but he says that “adult life expectancy is remarkably similar across these groups.”

    The research points to an existence structured around longevity. “Adult-level production is controlled by skills and knowledge rather than physical restraints,” says Gurven. Although the men in these groups reach the height of their physical powers in their 20s, it is not until their 40s that they reach the peak of hunting prowess, he notes. Rice production by males peaks in their 50s, as they turn from hunting to less rigorous agricultural pursuits. And there is a pattern of resource flow from old to young that continues into the 70s.

    Kruger says the research indicates that “once individuals pass the concentrated risk in infancy and early childhood, they are more likely to survive into the older age range (65–75) than previously thought.” University of Michigan, Ann Arbor, anthropologist Rachel Caspari, who studies ancient populations, says that it's not possible to know whether prehistoric people were living as long as modern hunter-gatherers without “high-resolution” ways of determining ages of death from fossils. However, she says Gurven's results make sense and that her research supports the notion of a “modern human demographic pattern” that probably has pertained for the past 30,000 years.

    Gurven reported that the leading causes of death among those middle-aged and older appear to be from infections and violence. But these indigenous groups share some of the same scourges of aging that affect modern societies. By the age of 65, he says, “almost all have significant pain” from orthopedic problems, especially back pain.

  14. HUMAN BEHAVIOR AND EVOLUTION SOCIETY MEETING

    An Evolutionary Squeeze on Brain Size

    1. Constance Holden

    PHILADELPHIA, PENNSYLVANIA—Despite the huge individual differences in mental abilities, the size of the human brain varies remarkably little from person to person. In fact, brain volume is evolutionarily more stable than that of any other bodily organ, researchers reported last week. They speculate that our brain, after increasing dramatically in size in early human evolution, ran up against the skull-size limitations imposed by the female birth canal.

    Evolutionary psychologists Geoffrey Miller of the University of New Mexico, Albuquerque, and Lars Penke of Humboldt University in Berlin calculated for the human brain a measure called “coefficient of additive genetic variance,” or CVA. A formula involving the size range of a physical feature and its heritability, CVA reflects “evolvability”: that is, the extent to which the relevant genes are susceptible to change through mutation and natural selection.

    The heritability of brain is remarkably high—about 0.9, studies have shown. That makes brain size even more genetically influenced than height, according to Miller. Despite the brain's complexity, he says, “at the genetic level, [brain size] seems as if it's a really simple trait like fruit fly bristle number, … astonishingly ironclad against any environmental perturbation.”

    Miller notes that he and Penke were surprised at the relatively low CVA for the human brain, because they assumed it had been subject to intense selection. CVAs are likely to be higher for traits that are fitness-related and therefore good candidates for natural selection. But the brain's CVA of 7.8, low for a volumetric trait, means there is limited potential “evolvability.” Other features with substantial heritability, such as breasts and kneecaps, have much higher CVAs, said Miller.

    Certainly, there has been selection for brain volume in the past, said Miller: As hominids became more intelligent, their brain size tripled over a 2-million-year period to about 1400 cubic centimeters, compared with 370 for chimps. But its growth plateaued about 200,000 years ago, Miller speculates, when it “reached the physical constraint of pelvic size.” As a result, he says, brain size “is not a good index of IQ in recent evolution.” Adds Penke: “Virtually all theories of brain and intelligence evolution propose a recent history of directional [i.e., ‘more is better'] selection for both.” But “recent directional selection” on intelligence must have worked on brain features other than absolute size.

    That notion is corroborated by brain-imaging studies, says Richard Haier of the University of California, Irvine. Although the correlation between brain size and IQ is only a modest 0.4, he says, the latest imaging studies show much higher correlations of IQ with a “small number of discrete areas” of gray matter.

  15. CELL BIOLOGY

    Podosomes and Invadopodia Help Mobile Cells Step Lively

    1. Jean Marx

    These feetlike structures aid the necessary migrations of immune and other cells, but also the deadly wanderings of cancer cells

    Anyone who has taken an introductory biology class is familiar with the migratory prowess of the simple amoeba. But many of our own cells could give amoebae a run for their money. Immune cells have to sprint to infection sites to ward off invading pathogens. And cells that help maintain the skeleton nimbly patrol bones. On the minus side, however, cancer cells can travel throughout the body and seed new tumors.

    Recently, a couple of hitherto-obscure cellular structures, known as podosomes and invadopodia, have come under increasing scrutiny as possible contributors to such perambulations. These microscopic assemblies, which are possibly related, both form on the bottom surface of the leading edge of migrating cells—a location consistent with the idea that they help cells move. The composition of each reinforces that suspicion: Both contain proteins, such as actin, that have previously been linked to cell motility (Science, 10 October 2003, p. 214), as well as enzymes that can break down the proteins of the extracellular matrix (ECM).

    Establishing the roles of podosomes and invadopodia hasn't been easy, however, because they have so far been studied in cells maintained on artificial surfaces rather than in live animals. “As far as I know, no one has seen these structures in vivo,” notes Gareth Jones of King's College London.

    Still, recent research suggests that these cellular features are crucial for understanding and perhaps treating a variety of diseases as diverse as cancer and osteoporosis. Indeed, scientists have already implicated malfunctioning podosomes as a cause of a rare hereditary disease that impairs the immune system. Research on podosomes and invadopodia “is heating up because they've really become physiologically important for things such as metastasis,” says cell biologist John Condeelis of Albert Einstein College of Medicine in New York City.

    Feet for cells

    Podosomes first appeared on cell biologists' radar screens in the mid-1980s. Pier Carlo Marchisio, currently at San Raffaele Scientific Institute in Milan, Italy, and his colleagues discovered the structures on a variety of migratory cells, including immune cells called macrophages and osteoclasts, which help maintain bone by dissolving away areas that need repair. In all cases, the structures appeared where the cells made contact with a surface. This suggested that they might be involved in cell adhesion, and thus in cell motility, because cells have to stick to the surface over which they are migrating in order to move. Because the structures appeared to act like cellular feet, the Marchisio team coined the name podosomes for them.

    Invadopodia came along just a few years later, identified in 1989 by Wen-Tien Chen, now at Stony Brook University in New York. He found that cells transformed by Rous sarcoma virus (RSV) form protrusions at their leading edge when moving on a surface containing ECM proteins such as fibronectin. More intriguing, Chen noticed that holes appeared in the protein substrate at the precise spots where the protrusions were located—an indication that they carry proteases that digest the ECM. “Invadopodia are more than just feet,” Chen says. “They have a functional effect.” The ability to digest ECM proteins would be very useful to migrating cells, including cancer cells that need to burrow through blood vessel walls in order to spread to distant sites.

    Marchisio and his colleagues found similar structures in cells transformed by RSV but considered them to be podosomes. Both researchers now say that they think they were looking at the same thing, yet the precise relationship between podosomes and invadopodia remains a burning issue in the field. Most researchers today define podosomes as more dynamic than invadopodia and smaller—1 to 2 micrometers in diameter compared to 8 to 10 micrometers. But both structures have a core of actin filaments and contain other proteins that regulate actin polymerization. Some researchers, including Roberto Buccione of the Consorzio Mario Negri Sud in Chieti, Italy, and Mark McNiven of the Mayo Clinic in Rochester, Minnesota, have suggested that podosomes form first and then mature into invadopodia, but the jury is still out on this idea.

    The buzz about WASp

    Research on podosomes took off in the late 1990s when they were linked to the then-newly-discovered mutant gene that causes Wiskott-Aldrich syndrome (WAS). Because the gene is on the X chromosome, the disease afflicts mainly boys, causing them to be severely immunodeficient. Without a bone marrow transplant, the children usually die before age 20 of infections or of immune-cell cancers to which they are also prone.

    Early analysis of WASp, the protein product of the gene that was found to be mutated in the immune syndrome, suggested that it helps control actin function. Then in the late 1990s, Stefan Linder of Ludwig Maximilians University in Munich, Germany, and his colleagues detected WASp in the actin core of macrophage podosomes. Linder's group and another team led by Jones and Adrian Thrasher of University College London also found evidence that podosome formation requires WASp. “Normal macrophages and dendritic cells have these structures, but cells from boys with Wiskott-Aldrich had none at all. That was a bit of a shock,” Jones recalls.

    Going mobile.

    In a moving macrophage (bottom), podosomes (stained red for actin and green for vinculin) congregate on the cell's leading edge while they ring the bottom of a quiescent macrophage (top, stained red for actin).

    CREDITS (TOP TO BOTTOM): IMAGE MADE BY BARBARA SCHROEDER AND STEFAN LINDER; R. BUCCIONE ET AL., NATURE REVIEWS/MOLECULAR CELL BIOLOGY 5, 647 (2004), IMAGE BY S. LINDER

    The London team found that the patients' macrophages had also lost the ability to respond to chemokines and cytokines, the chemical signals that normally activate immune cells and attract them to infection sites—a possible explanation for the impaired immunity of WAS patients. Both podosome formation and the ability to migrate in response to chemical signals were restored by putting the normal WAS gene into patient macrophages. “This was the first link [of WASp] to something physiological,” Linder says.

    Further evidence for a physiological link came from a study that Jones, Thrasher, and their colleagues described in Blood in February of last year. Dendritic cells serve as sentinels throughout the body, detecting foreign invaders and initiating immune responses to them. The London team found that the dendritic cells of mice in which the WAS gene had been deactivated could not migrate to their normal locations in the lymph nodes, presumably because they can't form podosomes.

    Cancer connection

    The ability to form podosomes and respond to chemokines could have a dark side: Cancer cells may exploit those same skills to spread. In recent work, Condeelis and his colleagues have been teasing out the changes in gene expression that characterize metastatic cancer cells. Having previously shown that the metastatic potential of cancer cells correlates with the cells' ability to migrate toward epidermal growth factor (EGF), the researchers inserted tiny needles containing EGF into mammary tumors in rodents and then analyzed the gene expression patterns of the cells that moved into the needles. These cells had increased expression of numerous genes that promote motility and podosome/invadopodia formation, including WASp. Activation of the genes “determines the willingness and ability [of cancer cells] to move to a portal to escape the tumor,” Condeelis says.

    Other work by the Albert Einstein team indicates that macrophages and their podosomes are partners in the crime of metastasis. The researchers find that as mammary cancer cells migrate into the blood vessels, they move along with the immune cells. The two cell types pair up because each produces a growth factor that attracts the other: Macrophages associated with the blood vessels attract metastatic cancer cells by secreting EGF, and the cancer cells emit a protein called CSF-1 that attracts more macrophages and stimulates further EGF secretion by the immune cells.

    The CSF-1 made by cancer cells also induces in macrophages the expression of WASp and other genes involved in podosome formation; similarly, macrophage-made EGF fosters invadopodia formation by the cancer cells. Macrophages could further help tumor cells penetrate the blood vessel wall; recent work by the Condeelis team has shown that the immune cells' podosomes, like invadopodia, carry enzymes that can digest the ECM. Chen suggests that inhibiting such enzymes, particularly one called seprase that his team has found in the invadopodia of melanoma cells, may thwart metastasis.

    In the 1 May issue of Cancer Research, Chen's group reports that seprase and a similar enzyme, DPP4, are also located in a complex on invadopodialike structures in endothelial cells. Because tumor growth depends on the creation of new blood vessels by migrating endothelial cells, that finding hints at yet another anticancer strategy: Chen's team blocked endothelial cell migration in lab dishes with monoclonal antibodies targeting the seprase-DPP4 complex.

    Boning up on podosomes

    The osteoclasts of bone are also migratory cells that may depend on podosomes for their mobility—and perhaps for much more. The cells seek out those areas of bone that need repair. Once there, an osteoclast settles down and forms a structure called a sealing ring, a tight connection between cell and bone. This protects adjacent bone from the osteoclasts. “For an osteoclast to be functional, it needs to isolate its target from the rest of bone; it secretes lots of concentrated acid,” says Olivier Destaing of Yale University School of Medicine.

    Podosomes appear to be involved in sealing-ring formation. Pierre Jurdic of the École Normale Supérieure de Lyon in France and his colleagues, including Destaing, found that as osteoclasts develop, they first produce individual podosomes that arrange themselves in small rings. These rings then expand to the periphery of the cell, where they form a stable podosome belt. The early view was that the podosome belts might coalesce to form sealing rings, which are thicker, but efforts to detect that transition had produced contradictory results, with some suggesting that the two structures are independent of each other.

    Jurdic, Destaing, and their colleagues have found, however, that sealing belts only form when osteoclasts are in contact with apatite, the mineral that forms the solid framework of bone. Apatite somehow activates both the Rho and Src kinase enzymes, both of which are needed for sealing-ring formation. The researchers also found that inhibiting Rho induces the transition of sealing rings into podosome belts.

    Bone repair.

    In an osteoclast, podosomes (stained red for paxillin and green for actin) form a belt on the cell periphery. The podosome belt may form the sealing ring that attaches an osteoclast (inset) to a bone mineral site that needs repair.

    CREDITS: CHEN LUXENBURG, LIA ADDADI, AND BENJAMIN GEIGER/THE WEIZMANN INSTITUTE OF SCIENCE; (INSET) DAFNA JUSTUS, BENJAMIN GEIGER AND LIA ADDADI/THE WEIZMANN INSTITUTE OF SCIENCE

    Further support for the idea that the structures are related comes from Benjamin Geiger's group at the Weizmann Institute of Science in Rehovot, Israel. His team found rearrangements in podosome proteins—in particular, a marked increase in their levels—at locations where sealing-zone structures appeared to be forming from podosome rings. This would be consistent with the notion that sealing rings are thicker versions of podosome belts. If so, drugs that inhibit podosome function in osteoclasts could form the basis of a new osteoporosis therapy; the disorder typically results when the bone-dissolving activities of osteoclasts outpace the bone-forming capacities of their partners, the osteoblasts.

    Many questions about podosomes and invadopodia remain to be answered. In particular, researchers are searching for markers that would let them observe the structures in living tissue—and perhaps put to rest the nagging doubts about the relevance of lab-dish studies. That would certainly give them a step up on understanding these cellular feet that are now attracting so much interest.

  16. WATER QUALITY

    High Court Asks Army Corps to Measure Value of Wetlands

    1. Erik Stokstad

    A divided Supreme Court wants the government to adopt rules on which wetlands deserve federal protection, but scientists say they all matter

    Which wetlands are important enough to protect? That's the question the U.S. Supreme Court put to the U.S. Army Corps of Engineers last week when it ruled on two Michigan cases involving wetlands that property owners wanted to develop. The answer, which will require the corps to define more precisely its jurisdiction under the Clean Water Act, will have ramifications for wetlands across the country.

    The 1972 act requires landowners to get a permit for certain actions that might harm wetlands. The corps has claimed an expansive reach that covers any wetland from which water eventually drains into larger lakes and rivers. But on 19 June, in Rapanos v. United States, the Supreme Court told the corps that's not good enough. For wetlands that aren't next to a navigable river, the key opinion said, the corps should draw up criteria to determine whether they provide significant enough benefits for clean water downstream to be regulated. “It is a critically important decision for our nation's waters,” says ecologist Judy Meyer of the University of Georgia, Athens.

    The diversity of wetlands makes that task a tough challenge. Meyer and other scientists fear that more-complicated regulations could translate into less wetlands protection, as developers could lobby for some kinds of wetlands to be left out of the rule. In the meantime, lawyers are likely to have a field day as the corps struggles to interpret the Supreme Court's decision on a case-by-case basis.

    The lead plaintiff in the Michigan cases, developer John Rapanos of Midland, argued that the corps had no jurisdiction because the wetlands on the contested property were 32 kilometers from navigable waters and connected to them by a mere ditch. Four justices rejected the corps' argument that it can regulate wetlands adjacent to any tributary of navigable water, with Justice Antonin Scalia writing that the corps could only regulate wetlands with a continuous surface connection to “relatively permanent bodies of water.” Four other justices took the opposite view, arguing that the corps' existing jurisdiction is reasonable.

    That tie set the stage for Justice Anthony Kennedy's decisive vote. He agreed with Scalia that the two cases should go back to the lower courts for further consideration, but he said the corps should have jurisdiction over any wetlands that provide a significant benefit to the “chemical, physical, and biological integrity” of downstream waters. Those whose contributions are “speculative or insubstantial,” he wrote, should be outside the corps' purview.

    The corps has aimed for rules that are relatively simple and easy to interpret. To decide whether a particular locale falls under its jurisdiction, for example, it has relied upon aerial photographs or topographic maps showing how surface water moves from that wetland to navigable waters. Likewise, the new rule will need to be “easily understandable for the corps analysts and the permittees,” says Richard Ambrose, a wetland ecologist at the University of California, Los Angeles. “If you make it too complicated, it will be paralyzing.”

    But wetlands—and their functions—resist easy categorization. Their impact on water quality varies by location and other factors; wetlands near an agricultural field, for example, will likely process more nitrate and retain more sediment than wetlands near a pristine forest. And relatively undisturbed wetlands are likely to increase biological diversity in downstream waters, a factor the Clean Water Act is meant to protect. Water levels and flows also vary enormously, ranging from drenched cypress swamps to ephemeral vernal pools. Wetlands in the arid west pose a particular conundrum: When water flows only irregularly, what metrics should be used?

    Scientists say rough indicators exist to determine whether a wetland is having a positive impact on water quality. Joy Zedler of the University of Wisconsin, Madison, suggests looking at water birds and other aquatic wildlife, the potential to trap sediment and reduce floods, and other factors that can be readily seen or inferred. But those indicators don't answer what Justice Kennedy most wants to know: Which wetlands have enough of an impact on the integrity of waters to qualify for protection? “It is difficult to draw a bright line that works in the practical world of regulation,” says wetlands scientist Barbara Bedford of Cornell University.

    Even tiny wetlands, like those in headwaters and along small streams, can have a large cumulat ive impact, studies have shown. A weak current is better than larger streams at trapping silt that would otherwise degrade habitat for salmon and other fish. A slow flow also means that microbes have more time to convert excess fertilizer and prevent downstream algal blooms. In an experimental study published last September in the Journal of Environmental Quality, Stefanie Whitmire and Stephen Hamilton of Michigan State University, Hickory Corners, showed that small wetlands in southwestern Michigan were responsible for half of the nitrate removal in the watershed. These benefits diminish when the wetlands are degraded, scientists say.

    No limits.

    Scientists say a new rule should cover even small wetlands, like this Michigan fen, that excel at cleansing water.

    CREDIT: STEPHEN HAMILTON

    The corps says it's reviewing the decision and declined further comment. Observers expect the agency to start work right away on interim guidance, although it could take a year or longer to issue a final rule. Until a rule is in place, the courts will proceed case by case. And so will the corps, which each year reviews about 85,000 requests for permits.

    Reed Hopper of the Pacific Legal Foundation, which represented Rapanos, has already claimed victory. “The court rejected the idea that there are no limits on the federal government's regulatory authority under the Clean Water Act,” he said in a statement. “It is not the role of the federal government to micromanage every pond, puddle, and ditch in our country.” But environmentalists say that a seat-of-the-pants approach offers great potential for mischief. “It's an invitation to development interests to contest the corps' authority over wetlands,” says Jason Rylander of Defenders of Wildlife in Washington, D.C.

  17. The Baby Deficit

    1. Michael Balter

    As fertility rates decline across the developed world, governments are offering big incentives for childbearing. Experts don't expect them to have much effect

    Doing her part.

    Minister for Families Ursula von der Leyen (with her children) oversees Germany's effort to increase fertility rates.

    CREDIT: JOCHEN LUEBKE/AFP/GETTY

    Last month, from the podium of the Kremlin's grandiose Marble Hall, Russian President Vladimir Putin expounded on subjects vital to his nation's future—economic growth, technological modernization, and world trade—then he turned to the “most important” matter. “What I want to talk about,” Putin said in his annual speech before the Federal Assembly, “is love, women, children. I want to talk about the family, about the most acute problem facing our country today—the demographic problem.” Reminding the deputies that Russia's 143-million-strong population was declining by almost 700,000 people each year, Putin proposed a fistful of incentives to boost the country's flagging birthrate. They include raising the childcare benefit of 700 rubles ($26) per month to 1500 rubles for a first child and 3000 rubles for a second child, and paying 18 months of maternity leave equal to at least 40% of a mother's previous wages.

    Putin is not the only politician talking about babies these days. Earlier this year, Poland's Parliament approved a one-time payment of 1000 zlotys ($328) for each child born, and this month, German Chancellor Angela Merkel proposed a 1-year paid leave for women who have children. When Australia introduced its own generous “baby bonus” in 2004, the country's treasurer Peter Costello exhorted parents to have “one for Mum, one for Dad, and one for the country.” On 1 July, Australia's bonus will jump from $2250 to $3002 per child (in U.S. dollars) and will reach $3762 by 2008. Meanwhile, pro-family inducements have been in place for many years in France, Sweden, and other European countries.

    Political leaders and economists see plenty of justification for spending all this money. In the European Union (E.U.), for example, low birthrates have already begun to shrink the population, and demographers project that the E.U. will lose between 24 million and 40 million people during each coming decade unless fertility is markedly raised (Science, 28 March 2003, p. 1991). Population losses could bring a raft of negative economic consequences in the industrialized world, as well as greater stresses on social security and health care systems as the proportion of older citizens increases. “The changes projected for the United States are not as dramatic as those projected for other areas—particularly Europe and Japan—but they nonetheless present substantial challenges,” then-Federal Reserve Board chair Alan Greenspan told a 2004 symposium on population aging in Jackson Hole, Wyoming.

    Although these trends are most pronounced in the developed world, fertility declines are now also being detected even in less affluent areas of Latin America and Asia. Roughly half of the world's nations, with more than 40% of the human population, now have birthrates below replacement levels, and fertility rates are falling steadily in most developing countries as well. To be sure, demographers predict that the world's population will continue to increase for decades to come, rising from its current 6.5 billion to somewhere between 8 billion and 11 billion by 2050 (see sidebar, p. 1896). But nearly all of this increase will be in developing countries.

    Population researchers nevertheless are currently engaged in a lively debate over just what, if anything, developed countries can do to increase family size. Some believe very low fertility rates are here to stay. “The popularity of baby-bonus schemes among governments is difficult to understand,” says Anne Gauthier, a sociologist at the University of Calgary in Canada. “While the additional financial support is bound to be welcomed by parents, the overall effect on fertility is likely to be small.”

    Others argue that even modest boosts in the birthrate can make a difference. “We can only expect relatively small effects of policy on fertility, but relatively small effects are important when fertility is low,” says demographer Peter McDonald of the Australian National University (ANU) in Canberra, whose advocacy of pro-family policies helped bring about Australia's baby bonus. Yet both sides agree that falling fertility rates might be irreversible once they drop below a certain level—what some demographers have begun to call the “low-fertility trap.”

    The demographic transition

    Predicting population trends is a tricky business, fraught with assumptions about what humans are likely to do in the future. Most demographers rely on a complex parameter called the total fertility rate (TFR). For any particular country and year, the TFR is a hypothetical measure of the average number of children that nation's women would bear during their lifetimes if, at each stage of their lives, they behaved exactly like women in each age group did during that year. By comparing TFRs from one year to another, demographers can track fertility trends. Leaving aside the effects of immigration and emigration, if a population is to remain the same size, both parents must replace themselves. For industrialized countries, demographers define a replacement-level TFR as 2.1—slightly more than a flat rate, to account for the small fraction of children who die before reaching reproductive age.

    Proud papa.

    Australian Treasurer Peter Costello fathered a baby-bonus scheme.

    CREDIT: DAVID CAIRD/THE SUN HERALD

    Yet nearly all of the world's industrialized nations have TFRs well below this magic number. Russia's current TFR is only 1.28 (which ties it with Italy and Spain), Poland's is 1.25, Germany's is 1.39, and Australia's is 1.76, which helps explain the alarm expressed by political leaders in those countries. Even the E.U. nations with the highest birthrates, France and Ireland, are falling short of replacement, with TFRs of 1.84 and 1.86, respectively. Nor is the baby shortage restricted to Europe: South Korea's TFR is 1.27 and Japan's is 1.25. Only the United States, exceptional in the developed world, hits the replacement mark, with a TFR of 2.09.

    Today's low TFRs are an unexpected consequence of a so-called demographic transition to lower fertility rates that began in Europe in about 1800 and is still taking place in much of the world. As advances in health and hygiene increased the likelihood of a child surviving to reproduce, both death and birthrates started to fall, especially in industrialized countries. Although TFRs remain high in some of the world's poorest countries—Niger has the highest TFR, 7.46—the demographic transition is either under way or completed in most nations. The process has taken place even in relatively poor countries such as Mexico, where TFR dropped from 6.5 to 2.5 between 1975 and 2005, and the Philippines, which saw a decline from 6.0 to 3.2 during the same period. However, demographers had assumed that the decline would stop when replacement-level TFRs were reached. “During the early 1970s, everyone talked about the magic floor of replacement,” says David Reher, a population historian at the Complutense University of Madrid, Spain. “Nobody thought it would go below 2.1.”

    CREDIT: SOURCE: U.N. POPULATION PROSPECTS

    Yet by 1975, several European countries, as well as the United States and Canada, had already dipped below this floor. (Although the United States has now come back up to replacement level, Canada's TFR has continued to plummet and now stands at 1.61.) This trend, which many demographers and economists call the “second demographic transition,” has its roots in the social changes that swept much of the Western world during the 1960s and 1970s. As women entered the labor force in increasing numbers and obtained easier access to effective contraception and as conflicts between work and childbearing intensified, parents began to delay the timing of their first child, which inevitably led to a reduction in the total number of offspring. These shifts were accompanied by a constellation of new attitudes toward family, career, and personal autonomy that are not easily quantified, researchers say. “Human reproductive behavior is profoundly social,” says Jennifer Johnson-Hanks, a demographer and anthropologist at the University of California, Berkeley. “It is structured by social categories, value systems, and power relations.” John Bongaarts, a demographer at the Population Council in New York City, adds that personal choice has come to play a much bigger role in reproductive decisions. In earlier days, Bongaarts says, “people tended to do what society expected of them. Over time, individual agency has become more important.”

    Social factors also explain the United States's anomalously high fertility rate, population experts say. Although relatively higher birthrates among some ethnic groups and more recently arrived immigrants, including Hispanics, explain part of the difference, the TFR for non-Hispanic whites is still about 1.85, equivalent to the highest rates seen in Europe. “There are several factors that make the TFR in the U.S. higher than in many European countries,” Bongaarts says, including a higher rate of unwanted pregnancies due to restrictions on birth-control information, a lower unemployment rate, and a greater tendency for women to have children earlier in life than in Europe. Gauthier adds that a stronger emphasis on religion and “traditional values” in the United States also tends to favor larger families.

    Aged and dependent

    The key reason that economists and other experts are worried about low fertility rates is that they accelerate an overall “aging” of a population, in which the proportion of elderly adults relative to the active labor force increases. The consequences of an increase in this so-called dependency ratio are hard to predict, says demographer James Trussell of Princeton University. “The economic burden of the elderly will depend on their health, on employment opportunities, and on the social institutions that support their care,” Trussell says. “But it is clear that it will be a challenge.” One way that many developed countries meet the challenge now is through immigration, which tends to increase the number of younger workers. Yet few demographers see immigration as the answer.

    “As a short-term solution, it is necessary, and it is happening,” says Reher. “But there are very serious doubts about whether it is a long-term solution. Migrant fertility starts higher than that of the native population but very quickly descends towards local fertility levels.” Trussell agrees: “To have an appreciable effect on the aging of a population, you would need massive immigration, which is not politically acceptable in either Europe or the U.S.”

    That leaves raising birthrates as the only solution, assuming that a solution to low fertility rates is possible—and desired. Some demographers take heart in an apparent gap between how many children parents would ideally like to have if they felt they could manage it and how many they actually do have. In this gap, some see wiggle room for fertility-enhancing policies. Thus, public-opinion surveys carried out by the E.U. as part of its Eurobarometer program have suggested that this gap amounts to an average of about 0.5 children per woman. Indeed, baby bonuses and other pro-family measures are in part designed to make it easier financially for families to fulfill this ideal. But Gauthier questions whether the gap is actually that large. In a study in press at the journal Population Research and Policy Review, she concludes that the “window of opportunity” for family policies might actually be as little as 0.1 to 0.2 children per woman.

    Gauthier and other researchers agree nevertheless that pro-family policies have had some positive effect on fertility rates in countries such as France, whose TFR of 1.84 is the second highest in the E.U. after Ireland. “There are no fewer than 38 measures in favor of families with children,” says demographer Laurent Toulemon of the National Institute of Demographic Studies in Paris. For example, mothers receive 16 weeks of maternity leave at more than 80% of their normal pay, which is extended to 26 weeks beginning with a third child. Parents also receive numerous direct allowances to help provide for young children, and the number of publicly funded nursery schools has expanded in recent years to the extent that nearly every child is guaranteed a place. In fact, there are so many pro-family policies, says Toulemon, “that it is almost impossible to evaluate the impact of each one” on fertility.

    Allons les enfants!

    France guarantees nursery school spots to nearly all children.

    CREDIT: CHARLES JEAN MARC/CORBIS SYGMA

    Despite these generous allotments, however, France's relatively high fertility rate in European terms is still below replacement. The same is true of Sweden, where government officials credit bountiful policies designed to make life easier for working parents with recent gains in TFR from about 1.6 to 1.8. Yet Gigi Santow, formerly of Stockholm University and now an independent demographer in Sydney, Australia, says that this fertility jump was not due to baby bonuses or other direct attempts to create a baby boom. “Swedish fertility rates may well have responded to the government's integrated web of cradle-to-grave social policies,” Santow says. She adds that fertility plummeted during the economic recession that hit Sweden during the 1990s, despite the policies then in place.

    Proving that financial incentives can actually raise fertility rates is very difficult—and demographers do not always agree. “We cannot carry out an experiment,” says Gauthier. “We can only look historically at what has happened and rely on cross-national differences in policies.” Earlier this month, for example, Australia's news media were abuzz with reports of the latest birth figures from the Australian Bureau of Statistics, showing that 261,404 babies were born in 2005, 2.4% more than the previous year and the highest number since 1992. Treasurer Costello was quick to credit the baby bonus: The daily newspaper The Australian quoted Costello as “delighted that at least some families have been taking up the challenge.”

    ANU's McDonald says that although it is too early to carry out “rigorous research” on the reasons for the increase, most of the additional births are to women in the middle to late part of their childbearing years. This suggests that the message may have been heard: “If you want to have children, it is risky to delay too long,” McDonald says. And although McDonald concedes that “most of the 261,000 women who gave birth in 2005 would have had the baby without” the baby bonus, the extra money “can make a difference” to middle income families who make “close calculations” about the impact of parenting. McDonald estimates that Australia's TFR for 2005, when published in November, should rise from about 1.76 to 1.82.

    But Robert Birrell, director of the Center for Population and Urban Research at Monash University in Clayton, Australia, says that a number of other factors may have weighed much more heavily, especially “the impact of the current economic boom in Australia, which has seen an increase in the rate of employment for men and particularly women in recent years.” Santow agrees: “I would not leap immediately to the conclusion that Peter Costello should be given the credit.”

    Low-fertility spiral

    The uncertain response to incentives suggests to some demographers that governments need to do even more to make child rearing attractive. “Many things that we've tried aren't big enough,” says Bongaarts. “To move behavior, you need real incentives; you need thousands of dollars. … You have to pull all the levers you have, and maybe you will get halfway there.” But pulling those levers might end up being too costly, Trussell says. “Policies that would work would be so expensive that they will never be implemented.”

    And some researchers have begun to think that it might actually be too late to reverse the trend in countries with the lowest fertility levels. At several recent population meetings, for example, McDonald has warned that once a nation's TFR falls below 1.5, a downward demographic spiral sets in that makes it much more difficult to recover. “This is the safety zone,” McDonald says. “Countries should try hard to avoid falling below it.”

    A team led by Wolfgang Lutz, a demographer at the International Institute for Applied Systems Analysis (IIASA) in Laxenburg, Austria, has taken McDonald's observation further and argued that countries with a TFR of 1.5 or lower may have crossed into permanent negative population growth. Lutz calls this hypothesis, which he presented most recently at this spring's annual meeting of the Population Association of America in Los Angeles, California, the “low-fertility trap.” Lutz and other colleagues at IIASA and the Vienna Institute of Demography argue that the new social norms created by low fertility rates create a self-reinforcing negative feedback loop. It is locked in place by a reduction in ideal family size, aging of the population, and other effects on the labor market that make having fewer and fewer children inevitable. As evidence, Lutz and his colleagues cite data from the Eurobarometer survey showing that in Germany and Austria—nations with TFRs of 1.39 and 1.36, respectively—young adults now consider their ideal family sizes to be as low as 1.7 children on average.

    “Germany is the extreme example of this phenomenon, with around 30% of young people not intending to have children,” says McDonald. On the other hand, McDonald does not agree that there is no turning back for countries whose TFRs fall this low: “This does make Germany a tougher nut to crack, but I would never declare the game as over.”

    SOURCE: OECD

    Yet Reher sees little reason for optimism. “When fertility is drastically below replacement, it doesn't go up, no matter how many policies and how much money is thrown at it,” he says. “We are in the midst of a cascading fertility decline. Even a TFR of 1.7 is not safe; it is a disaster if you look a couple of generations down the line.”

    Indeed, Reher, at the July 2005 annual meeting of the International Union for the Scientific Study of Population in Tours, France, presented a paper suggesting an even more dismal picture. Reher argued that low fertility rates were now entrenched in the social structure of developed countries and a growing number of developing countries as well. Although the momentum of past high fertility rates would continue to fuel an increase in the entire world's population for some decades to come, this would eventually stop. Rather, Reher maintained, much of the world is now on the cusp of a prolonged period of population decline. The resulting population aging would lead to labor shortages even in developing countries. The result could be an economic disaster, Reher warned. “Urban areas in regions like Europe could well be filled with empty buildings and crumbling infrastructures as population and tax revenues decline,” he prognosticated, adding that “it is not difficult to imagine enclaves of rich, fiercely guarded pockets of well-being surrounded by large areas which look more like what we might see in some science-fiction movies.”

    Most population researchers agree that there is plenty to worry about in current worldwide demographic trends. Yet few are ready to accept the direst parts of Reher's doomsday scenario—at least not yet. “I wouldn't be surprised” if population shrinkage “happens in a lot of places in the world,” says Gauthier, although she adds that “it is much harder to believe in Africa,” where the population is expected to at least double by 2050. And Santow comments that although Reher's predictions “may well be sensible,” she sees “nothing terrifying about a drop in the size of Europe's population. Any decline will take time, and economies will adjust. Governments should not expend energy to maintain the status quo. Governments should plan for the future, not try to reintroduce the past.”

  18. The Bomb That Wasn't

    1. Michael Balter

    When Stanford University entomologist Paul Ehrlich published The Population Bomb in 1968, the world's human population was about 3.5 billion. Today, it is approximately 6.5 billion. Yet the worst of Ehrlich's widely publicized predictions, including the starvation of hundreds of millions of people in mass famines, have not come true. Still, the world's population is expected to continue to grow until at least 2050, according to estimates by the United Nations Population Division (esa.un.org/unpp). Just how much it will increase depends on future fertility, which is very difficult to predict. U.N. population experts have examined three hypothetical fertility trends, which they term medium, low, and high. Under the medium scenario, population would reach 9.1 billion by 2050, but the low and high scenarios project as few as 7.6 billion people and as many as 10.6 billion.

    Nearly all of this growth will be in developing countries, with major contributions from nations such as India, Pakistan, Nigeria, Bangladesh, and China. (Even the United States, with its relatively youthful population, will add significant numbers.) Fueled by very high fertility rates, between now and 2050, population is expected to at least triple in some nations, such as Afghanistan, Burundi, Chad, Democratic Republic of Congo, Mali, and Uganda—despite high HIV infection rates in many African countries. Yet over the long term, fertility is expected to drop dramatically in even the poorest countries, from an average of five children per woman now to about 2.6 in 2050; and under the U.N.'s medium scenario, average worldwide fertility will decline to 2.05 by 2050, and to just over 1.5 in the low scenario, well below the replacement level.

    “Virtually all countries are headed towards replacement-level fertility or below,” says Ronald Lee, a demographer at the University of California, Berkeley. “But there may be pauses and reversals along the way, sometimes lasting decades.” If so, the population bomb may ultimately fizzle out—that is, assuming an already stressed planet can survive the onslaught of 9 billion human beings.

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