NEWS

p359 Shot down: p362 A rare breed: p363 Fighting fat: Vaccines for cervical Neuroscientist Pasko The obesity epidemic cancer are impractical, Rakic embraces the is spawning some experts say. best of science and art. unusual solutions.

Bitter criticism sours new diabetes research plan

On the face of it, the Juvenile Diabetes Research diabetes. The regeneration program, which repre- by the JDRF, says he would not have signed up Foundation’s (JDRF) new research program sents five percent of the charity’s annual research for such controlled oversight. “It’s an interesting to fight juvenile diabetes seems like a good budget, is at least $10 million for two years, experiment,” Keating says. “But it’s very difficult thing. The fast-track, milestone-driven program during which 16 investigators in five countries to coerce academics to do this—it’s like herding pledges an innovative route to drug candidates will collaborate closely, sharing data in monthly cats, really.” for juvenile, or type 1, diabetes. But several conference calls and quarterly progress reports. Beta cells destroyed by autoimmunity in researchers have opted out of the program, Insel says donors like having that type 1 diabetes have been shown to sharply criticizing the model as inappropriate accountability written into the program. But he regenerate in animal models and possibly for academic research. says some high-profile scientists opted out of the even in humans (J. Clin. Invest. 115, 5–12; The JDRF on 2 March launched the first program because they could not commit to the 2005). These advances—and the popularity phase of its program on beta cell regeneration, a heavy time requirements, or were uncomfortable of regenerative medicine—have generated a process that would replace the insulin-producing with the near real-time sharing of data. flurry of money and interest. pancreatic beta cells destroyed in type 1 diabetes. Because most researchers in the community Preliminary results are promising and a The team includes several beta cell experts and receive funding from the JDRF, they asked not couple of drug candidates are already in non-diabetes regeneration experts. to be quoted. But off the record, many said that trials. But how regeneration in humans But many big names in beta cell biology— the program’s level of oversight is unacceptable, occurs, and under what conditions, is still including a few who, at a spring 2004 workshop, and may be restrictive to the nonlinear manner up for heated debate. helped the JDRF set the research agenda—are of scientific discovery. Too much emphasis is being placed on notably missing. Some of those researchers say Mark Keating, a cardiac regeneration expert mouse models that have significant biological regeneration is just the latest in a long line of at Children’s Hospital Boston who is not funded differences with humans, says Peter Butler, who research trends—including gene therapy, islet works on human beta cells at the University transplants and embryonic stem cells—that the of California in Los Angeles. “There have been JDRF has embraced to satisfy its donors. But the hundreds of papers on curing diabetes in mice charity is not sustaining support to any one area and none in humans,” Butler says. long enough for real progress, they say. Butler questions whether the JDRF’s program Richard Insel, JDRF’s executive vice can compete in drug discovery against pharma- president for research, says there is a natural ceutical companies with far greater resources. overlap between work in transplants, embryonic A two-year timeframe might also be rushing

stem cells and regeneration. “It is incumbent Diabetes the science in a very early field, adds Massimo upon us to promote all of the different areas,” he Trucco, director of the Diabetes Institute at says, adding that the regeneration program does Children’s Hospital of Pittsburgh. “There’s an not detract from other projects. Butler et al., old Italian saying, ‘fast and well, they don’t go The JDRF is a big player in diabetes research, Beta blockers: Some experts say beta cell together,’” Trucco says. funding nearly 40% of all studies on type 1 regeneration in humans is poorly understood. Kendall Powell, Denver Therapies come closer with ‘cleaner’ stem cell lines Scientists have for the first time created a line use. In January, scientists announced that at extracted stem cells from a human embryo of human stem cells without using animal least one of the Bush-approved stem cell lines and grew them on a specially created sterile cells, a potential source of contaminants. The was contaminated with an animal sugar protein matrix. The cells maintained their breakthrough raises hopes that researchers (Nat. Med. 11, 228–232; 2005). ability to grow into different types of tissues, can grow cells that are safe for human therapy. Researchers had previously developed even after six months in the undifferentiated Most available stem cell lines, including ways to grow embryonic stem cells without state. That report was published online in those approved for US federal funding, using animal cells (Nat. Methods 2, 185–191; The Lancet. were either generated or grown on animal 2005), but had yet to create a new cell line Emily Singer, Boston feeder cells, a nourishing scaffold often used without the feeder cells. Robert Lanza and to support the cells. Scientists have been colleagues at Advanced Cell Technology For more news and analysis go to concerned that these animal products could in Worcester, Massachusetts, announced pass viruses or other contaminants to the in March that they have derived a new cell www.nature.com/news human cells, making them unfit for clinical line free of any animal cells or serum. They

NATURE MEDICINE VOLUME 11 | NUMBER 4 | APRIL 2005 357 NEWS

Money, manpower missing from Europe’s new agency

The long-awaited European Centre for Disease vast array of voluntary cooperation programs. Prevention and Control (ECDC) will in May The European Influenza Surveillance Scheme, open its doors in Stockholm. But some experts for instance, tries to harmonize work at 31 say the center may not be up to its task of laboratories in 23 countries and the European preparing Europe for major outbreaks. Network for Diagnostics of Imported Viral Led by former Hungarian state secretary Diseases (ENIVD), active during the SARS Zsuzsanna Jakab, the new center’s staff and outbreak, connects 36 labs in 24 countries. budget are too small to make a real difference, But many of the networks operate on a shoe- some experts note, while its focus on known string budget and brave monstrous amounts of diseases won’t help combat new illnesses. Without Courtesy: European Commission paperwork to get partial, short-term funding, says Full speed ahead: Director Zsuzsanna Jakab says its own labs, the ECDC could also have trouble the center will hire 16 high-profile researchers. Matthias Niedrig, a virologist at the Robert Koch- establishing the authority it needs, they say. Institut in Berlin. The ENIVD, which Niedrig coor- Creation of a European counterpart to the Jakab, currently the center’s only employee, dinates, ran out of cash last summer, and a new US Centers for Disease Control and Prevention says she hopes to alleviate some of the grant from the commission has yet to materialize. (CDC) gained momentum after the outbreak skepticism by quickly filling all 16 highest-paid In a poignant example of European bureaucracy, of severe acute respiratory syndrome (SARS), jobs this year with “high-grade researchers he recalls how the commission reminded him that during which Europe was notably absent. known and respected throughout Europe.” To work on the SARS coronavirus—a newly imported “Information coming through [European lure them, she says she is open to the idea of virus—was not in the network’s contract. Union] channels often trailed that of the World having them retain some part-time research. Debates about the center are likely to reappear Health Organization by days, if not a week,” says The ECDC’s task is complicated by the frac- when it faces evaluation in 2007. Sprenger says it Dutch virologist Albert Osterhaus. tured nature of European disease control. The 25 could be vitally important for the ECDC to get The ECDC’s primary task is to “enhance EU member states treasure their own institutes more control over the funding of communicable synergy” between national institutes, says Marc and policies on issues ranging from antibiotic use disease networks it is now asked only to coordi- Sprenger, who chairs the ECDC’s management to child vaccination. Current treaties don’t allow nate. “Politicians might even conclude the ECDC board and leads the Dutch National Institute for the European Commission to prescribe much does need its own labs,” Sprenger says. “But then Public Health and the Environment (RIVM). public health regulation. Instead the commis- we’ll really need a lot more money.” The center’s initial focus, Sprenger says, will sion’s directorate of Public Health helps fund a Peter Vermij, Amsterdam be to bundle surveillance data on diseases such as HIV/AIDS, tuberculosis and influenza from national centers, and present them to policy Politics roils US infectious disease center makers. A second priority will be to provide Just as a new European agency steps into and transparent communication from CDC independent scientific advice to Europe’s govern- the battle against infectious diseases, its … seemed constrained by unknown external ments, such as during surprise outbreaks. much larger US counterpart is responding influences,” the committee said. But to speak with authority, the center will to charges that it prioritizes politics over CDC spokesman Tom Skinner says any need high-profile scientists, says virologist John science. Staff at the US Centers for Disease suggestion that the CDC was “constrained Oxford of Barts and The London Hospital. And Control and Prevention (CDC) are also or muzzled” in its ability to communicate is to attract top-notch scientists, “you need a lab, reportedly chafing under a reorganization “totally unfounded and totally untrue.” you need research projects,” none of which initiated by the Bush administration. The report was released at the same time ECDC will have, Oxford notes. A report released in early March on the as a Washington Post news report detailing Relying on networks won’t be enough, he adds. US smallpox vaccination program took aim internal dissent at the CDC, including “The WHO already has people on telephones. at the apparent influence of the White House concern about the agency’s ‘Future’s We need G-men ready to hop on a plane within on CDC policies (http://www.nap.edu/ Initiative.’ The reorganization is designed 24 hours, not just swing e-mails at each other,” books/0309095921/html/). A National to improve the CDC’s ability to respond to Oxford says. “If there is a problem in Timbuktu, Academy of Sciences committee reported public health concerns such as bioterrorism, within 18 hours it will be in Brussels too.” that political constraints, presumably from the aging population, obesity and emerging But the G-men will have to wait. the “top levels of the executive branch,” infectious diseases, and involves a major “The [ECDC’s] budget is quite modest indeed, contributed to poor coordination and low administrative reshuffling. whether we like it or not,” says Sprenger. The acceptance of the program. Discontent among CDC staff has become center is expected to have an annual budget of “We feel that the CDC is too important intertwined with the perception of political €29 million (about $38 million) and a staff of and historically has been too well respected interference, says Georges Benjamin, 70 by 2007, compared with the CDC’s $8 billion to risk its credibility in this way,” says Brian executive director of the American Public and 8,500 employees. Strom, committee chair and professor of epi- Health Association. “It is important that Sprenger says the center needs epidemiologists, demiology at the University of Pennsylvania. political leadership understand how imp- not big buildings and labs. But during a surprise The report concluded that the healthcare ortant it is for science-based organizations to outbreak, says Marion Koopmans, chief virolo- community and the public never bought be free of political influence,” he says. “Even gist at the RIVM, “the ECDC will need strong into the vaccination program because the the perception of political interference can connections with people in top laboratories, not government’s rationale for the vaccinations be devastating to good science.” just epidemiologists gathering data.” was not fully explained. “The typically open Tinker Ready, Boston

358 VOLUME 11 | NUMBER 4 | APRIL 2005 NATURE MEDICINE NEWS

Tysabri withdrawal calls entire class into question

The future of a promising treatment for multiple The US Food and Drug Administration (FDA) The FDA in November 2004 granted Tysabri sclerosis (MS) is in question after two patients has halted a phase 2 trial of a GlaxoSmithKline fast-track approval, after initial phase 3 results takinag the drug were diagnosed with a rare drug that targets the same protein, alpha-4 showed the drug reduces the frequency of MS neurological disorder. integrin, as Tysabri. Australian biotech Antisense attacks by as much as 66%. Scientists are scrambling to determine the Therapeutics stopped phase 2 trials in March Tysabri was expected to be a major exact relationship between the drug, Tysabri, for a similar MS drug, which the company had blockbuster for its manufacturer Biogen Idec, and progressive multifocal leukoencephalopathy also planned to develop as an asthma treatment. with predicted sales of $3 billion annually. (PML). If the drug is deemed to pose a significant Switzerland-based Roche also has a similar But the company suspended sales of Tysabri risk, it could be a serious setback for the entire compound in early clinical trials, but declined in February, after learning of the two PML class of drugs, which work by blocking passage to comment on its plans for the trial. cases, one of which was fatal. The company of immune cells into the brain. Steinman has warned for more than a decade also halted trials of the drug for rheumatoid “Other cell-migration inhibitors in that such drugs might carry nasty side effects. arthritis and Crohn disease. development will have to be carefully tested,” In 1992, he was one of the first to develop this There has never previously been a says Howard Weiner, director of the Partners MS new approach—to block the homing molecules documented case of PML in MS patients, Center at Brigham and Women’s Hospital. that allow immune cells to access the brain. But even though these patients have been treated Several companies are developing drugs he says he soon realized that targeting these with many types of immunosuppressants. that use the same rationale to treat Crohn molecules also blocks immune cells from entering Both patients diagnosed with PML had disease, rheumatoid arthritis and asthma. infected tissue outside the brain, leaving patients taken Tysabri with Avonex, another MS But according to Lawrence Steinman, an MS susceptible to infections. This might have led to drug, for two years in clinical trials. Biogen specialist at Stanford University, all of these the cases of PML, a disorder most often seen in is testing all patients who took Tysabri for drugs are likely to carry a similar risk for people with compromised immune systems, signs of PML. infections. such as those with AIDS, Steinman says. Emily Singer, Boston Experts inject reality into cervical cancer prevention schemes

Two rival vaccines to prevent cervical cancer and have shown efficacy of are being launched with great fanfare as a more than 90% in phase 1 long-awaited solution to a pressing public and 2 trials. health problem. But distributing and But key scientific administering the vaccines in developing questions such as the countries, which bear much of the global duration and correlates of burden of the infection, is likely to be costly protection, the effect of the and complicated, scientists warn. menstrual cycle and the Because the vaccine must be given to girls need for a booster vaccine before they are sexually active, convincing remain answered, cautions parents to vaccinate prepubescent girls against John Schiller, a researcher a sexually transmitted infection will be fraught at the US National Cancer with cultural issues, experts say. Institute.

Cervical cancer is the second biggest cause The vaccines are also AFP Photo/Jorge Uzon of female cancer mortality worldwide, with expensive to make and Culture shot: Parents in developing countries might be reluctant 288,000 deaths annually. About 510,000 difficult to distribute, to vaccinate their young daughters against cervical cancer. cases are reported each year, 80% of them in Schiller says. Administering developing countries. India alone has one- three injections, Another significant problem will be getting third of the global burden. maintaining clean, sterilized needles and consent to vaccinate girls. For example, Drug giants GlaxoSmithKline and Merck creating a cold chain for transport to rural convincing parents in India—where sex have both developed vaccines that target areas in resource-poor countries are all likely education is taboo in most parts—to inject the human papilloma virus (HPV), which to pose significant hurdles, Schiller notes. their daughters against a sexually transmitted is linked to three-quarters of the infections. Developing countries may have to wait infection will be impossible, says Bhudev Both vaccines are in large phase 3 trials and are for a second-generation vaccine that is Das, director of the Institute of Cytology and expected to reach the market in two years. cheaper and easier to administer, protects Preventive Oncology in Delhi. The vaccines carry the L1 capsid protein against more HPV types and that better Although a vaccine may be the most and need to be given in three doses to generate suits their needs. But “such a vaccine promising approach to prevent new infections, high levels of neutralizing antibodies. The is not really on the horizon now,” says in many developing countries, experts say, GlaxoSmithKline vaccine is designed against Schiller. Alternately, they could make their screening with cheap tests—including visual the two most infectious HPV strains, HPV 16 own cheaper vaccine—which could be inspection—continues to be the best hope for and 18, and the Merck vaccine against four difficult with existing patent rights on the prevention and treatment. strains—HPV 16, 18, 6 and 11. Both are safe technology. T V Padma, New Delhi

NATURE MEDICINE VOLUME 11 | NUMBER 4 | APRIL 2005 359 NEWS

Cancer vaccine field gets shot of optimism from positive results

An experimental cancer vaccine has for the first produce a robust immune response. time been shown to significantly extend the The Provenge trial has raised several ques- lives of men with prostate cancer, Seattle-based tions of its own: 34% of men given Provenge, Dendreon announced in February. The vaccine, compared with 11% on placebo, were alive Provenge, is based on dendritic cells, which help three years on, and lived 4.5 months on average the immune system recognize tumors. longer. But paradoxically, the vaccine does not “If these results are true, this represents the delay ‘time to progression,’ a measure of effi- first proof of principle of a dendritic [cell] cacy used in most cancer trials to denote the vaccine altering the natural history of a solid time before a tumor begins growing again, and tumor,” says Philip Kantoff, chief of solid tumor Dendreon’s primary endpoint in this trial. oncology at the Dana-Farber Cancer Institute in “Because of this, we were all somewhat

Boston, who was not involved with the study. Systems Initiative Courtesy: David Hunt & U Wash-Cell pleasantly surprised that Provenge showed a Cancer vaccines vary widely: they may Rays of hope: Scientists have shown that dendritic survival benefit,” says E. Roy Berger, director of employ whole proteins, tumor antigens, den- cell vaccines can help cancer patients live longer. the Prostate Cancer Consultation and Treatment dritic cells, killed tumor cells or tumor lysates. Service in East Setauket, New York. The goal of the vaccines is to prime the patient’s dardized vaccine production methods, says Nina The vaccine only benefited a subgroup of immune system to recognize and destroy the Bhardwaj, director of the tumor vaccine program men at earlier stages of the disease in a previ- tumor without harming normal cells. at New York University School of Medicine. ous shorter trial, but even men with aggressive Provenge carries the patients’ own dendritic There are also questions about which cells and disease lived longer in this trial. One reason for cells engineered to express a protein found on antigens to use in vaccines and the mode and fre- that discrepancy may be that immunotherapy about 95% of prostate cancer cells. It is one quency with which they should be administered. does not work as quickly as chemotherapy, which of more than 15 vaccines in trials for a range For example, mature dendritic cell vaccines seem has a direct, cytotoxic effect, says Berger. “Cancer of cancers, including lymphoma, melanoma, to produce the best immune response when vaccines prime the immune system to attack breast, lung and colorectal cancers, but the first to given either subcutaneously or intradermally, but cancer, a slower, more indirect process,” he says. increase lifespan in advanced cancer patients. not intravenously (Blood 10, 2235–2246; 2004). This may mean that survival, and not time to For years cancer vaccines have been dogged Researchers are also trying to determine whether progression, is a better measure of efficacy for by questions and controversy (Nat. Med. 10, 3; vaccines will be need to be designed for specific cancer vaccines, Berger suggests. 2004). One ongoing concern is a lack of stan- cancers, or whether a universal vaccine could Vicki Brower, New York Aggressive HIV strain sets off dubious public health measure The media frenzy that erupted over the would entail the creation of a new rule, which resistance is not useful. The tests can help announcement in February of a highly is under discussion, says Frieden. Officials decide treatment regimens, but they are virulent and multidrug-resistant HIV strain are also discussing how best to tackle the expensive, time consuming and do not always has triggered a somewhat thorny debate on the technical details of reporting drug resistance. detect resistance in HIV patients who have future of HIV surveillance and prevention. The recently erected citywide Commission on lived with the virus a long time. “Until we have Scientists and activists criticized the HIV/AIDS is also expected to release a report sufficient data to suggest that the prevalence New York City Department of Health and outlining strategies on HIV/AIDS prevention, [of drug-resistant strains] is five percent or Mental Hygiene for prematurely inflating treatment and control in a few months. higher in a population, it is a guess on the part the significance of a single case of HIV. The New York may become the first US state of clinicians as to the utility of the test,” says department is once again inviting controversy to require AIDS drug resistance data. The Tracy Sides, an HIV epidemiologist at the by promoting a public health measure that Minnesota Department of Health also in Minnesota Department of Health. some experts say is ineffective. February e-mailed 300 infectious disease With fewer federal dollars supporting In a departure from current practice, city specialists asking them to consider resistance AIDS work, the best use of the resources is to health commissioner Thomas Frieden is testing in newly diagnosed patients, but the boost existing HIV prevention infrastructure urging doctors and laboratories to provide request is by no means a mandate. Across the rather than require resistance tests that may data on multidrug resistance in newly US, the so-called ‘AIDS superbug’ propelled not be entirely effective, says Julie Davids, diagnosed HIV patients. Officials are also public health officials to check locally for executive director of the Community HIV/ debating whether to enforce a rule requiring evidence of similar strains, and to reissue AIDS Mobilization Project, a New York– labs to provide that information. The data public health messages about HIV. But the US based advocacy organization. “Clinicians, would help “to both guide treatment and help Centers for Disease Control and Prevention epidemiologists, researchers and activists us monitor the AIDS epidemic,” Frieden says. has no plans to implement federal public should together discuss what measures are Under New York state law, all laboratories health measures until more information most cost effective,” she says. must inform the city and state health emerges about the lone New York case, says Scientists in January detected the potent new departments of new HIV infections, AIDS Karlie Stanton, a spokeswoman for the HIV strain that progressed to full-blown AIDS diagnoses, viral load results and T-cell counts. agency’s HIV prevention office. within four months. HIV infections normally Requiring reports of multidrug resistance Some experts say although drug-resistant take about ten years to turn into AIDS. would not need changes in legislation but HIV strains may be on the rise, testing for Paroma Basu, Madison

360 VOLUME 11 | NUMBER 4 | APRIL 2005 NATURE MEDICINE NEWS IN BRIEF

UN panel passes Obesity researcher Skepticism greets FDA’s anti-cloning resolution admits to faking data drug safety schemes

The United Nations (UN) on 8 March A well-known obesity researcher has A US Food and Drug Administration (FDA) approved a resolution calling for member admitted to one of the largest cases of advisory panel voted in late February to allow nations to ban all forms of human cloning. scientific fraud in the last 20 years. In restricted use of the painkillers Vioxx, Celebrex But some countries, including Britain, South a plea agreement announced in March, and Bextra. The drugs should carry stiff Korea and the Netherlands, said they would Eric Poehlman, who held posts at the warnings, and prescriptions should be limited to continue to support research on therapeutic University of Vermont and the Université those with low risk of cardiovascular disease or cloning because it could ultimately provide de Montréal, agreed to plead guilty to those with gastrointestinal problems, the panel treatments for currently incurable diseases. making false claims in a 1999 grant said. The European Medicines Agency and The resolution, which is not legally binding, application to the US National Institutes Britain’s Committee on Safety of Medicines have calls on member states “to prohibit all forms of of Health, which brought Poehlman issued similar warnings on Cox-2 inhibitors. human cloning in as much as they are incom- $542,000 in research funds. According to The FDA plans to establish an independent patible with human dignity and the protection the Maryland-based Office of Research review board to monitor drug safety. But critics of human life.” The UN last year abandoned Integrity, Poehlman submitted 17 other say the move does not go far enough, and say attempts to draft a legally binding ban. grants with falsified data. all drug safety operations should be indepen- The US and Costa Rica called the decision, Poehlman will be banned for life from dent from the FDA. Senator Charles Grassley which comes after four years of discord and seeking federal funding as part of his is also preparing legislation to establish an delay, an ethical victory. But scientific agen- plea bargain. The scientist could face up independent drug safety office with the power to cies such as the UK Royal Society and the to five years in prison for the fraud, order pharmaceutical companies to add warning European Society for Human Reproduction though lawyers involved in the case say labels to dangerous medicines. & Embryology condemned the resolution, he is likely to see little or no jail time. Drug maker Merck pulled Vioxx from the saying it does not distinguish between repro- He resigned from the the Université de market in September 2004 after studies showed ductive cloning, which many groups have Montréal in January. it increases the risk of heart disease. Public health already banned, and therapeutic cloning. The University of Vermont investigated experts have criticized the FDA’s handling of the scientist between 2000 and 2002, after drug safety issues throughout the Vioxx debacle. Congo battles outbreak one of his research assistants reported The most recent criticism focuses on the panel suspicious data analysis in a long-term members’ ties to the painkillers’ manufacturers. of pneumonic plague study of aging. The study was published The Center for Science in the Public Interest, in the Annals of Internal Medicine in 1995, an advocacy group, said that 10 of the 32 advi- Emergency aid workers are trying to then retracted in 2003 as a result of the sors who supported use of the painkillers had contain an outbreak of the plague in the investigation. Poehlman is to ask journals consulted for the drugs’ manufacturers. Without Democratic Republic of Congo. As of to correct or retract ten other papers as those votes, Bextra and Vioxx might not have 15 March, 130 suspected cases, including part of his plea agreement. The fraudulent been allowed to remain on the market. But the 57 deaths, had been reported. research exaggerated the impact of aging FDA says these industry ties did not represent a The outbreak began in late December at and menopause on women’s health. significant conflict of interest in this case. a recently reopened diamond mine in the Bas-Uele district in the northern part of the Harvard faces Summers of discontent country. The World Health Organization Harvard University faculty in March gave its president was notified in February and dispatched a Lawrence Summers a vote of no confidence, an team of public health experts to the area. unprecedented event in the famed university’s history. The experts have set up two isolation Summers sparked a nationwide firestorm in January centers to contain and treat suspected cases when he suggested that intrinsic differences between men and are conducting intensive surveillance and women are responsible for the scarcity of women in activities to trace those who may have been science. His remarks fueled an already brewing resentment in contact with infected people. over his aggressive leadership style (Nature 433, 190– Almost all confirmed cases are of 192; 2005). After a series of contentious faculty meetings, Photographer Showcase pneumonic plague, an infection that the Faculty of Arts and Sciences voted 218 to 185 to pass the lack-of-confidence motion. can be controlled with antibiotics but None of Harvard’s other schools have announced plans for a similar motion. can also be deadly if left untreated. The The vote carries no binding consequences, so Summers’ immediate future is unclear. The pneumonic form of plague is the most university’s governing board—the only group with the power to fire the president—issued a virulent and least common variant and can statement of support for Summers after the vote. be transmitted between people. Two cases Although some faculty members are calling for his resignation, Summers has given no were of the septicemic form of plague, indication he will resign. Others say that the pervasive lack of confidence will cripple his but no cases of bubonic plague have yet ability to lead. Several professors questioned his ability to raise funds to support a massive been reported. campus expansion project that Summers has spearheaded during his presidency. The former US treasurer became president of Harvard in 2001. Summers’ other goals as president include investing more heavily in science and revamping undergraduate education. News briefs written by Emily Singer

NATURE MEDICINE VOLUME 11 | NUMBER 4 | APRIL 2005 361 PROFILE Pasko Rakic

Pasko Rakic might be best known in the popular press for arguing that the adult cerebral cortex can grow new neurons. Rakic says he finds that the cortex cannot generate new neurons. But his peers say that aspect of his reputation unfortunate. “This was a response to one paper Rakic combines a scientist’s intellect with an artist’s grace. several years ago,” he says. The idea of adult cortical neurogenesis has obvious appeal, and remains a focus of intense research in several labs. Manipulating that process, if it exists, Pasko Rakic is walking briskly across the Yale University campus in could treat a wide range of neurodegenerative diseases. But Rakic remains Connecticut on an unseasonably mild afternoon in early March. He unconvinced that primates can generate new cortical neurons. Even if they is explaining how the university’s original layout mimics Oxford and could, he argues, the surrounding neurons would have to form thousands Cambridge, but what he really wants to show is a more recent addition of new connections for the new cells to have any clinical benefit. to the grounds. Thinking about clinical applications is second nature to Rakic. Born in Entering the Beinecke Rare Book and Manuscript Library, a Yugoslavia, he studied medicine at the University of Belgrade, then embarked modern cube built in the early 1960s, Rakic has an animated, almost on a career as a neurosurgeon. He says surgeons usually repeat the same childlike, glee as he describes how the architect brilliantly combined classical procedures during their careers, and he wanted more variety. But his training materials with modern techniques. Instead of windows, the innovative stayed with him. “One of the things I take away from my period of time with structure uses reinforced concrete to support ultra-thin panels of marble, [Rakic] was his desire to always challenge me to think about what we were allowing an amber glow of sunlight to penetrate while protecting the books doing ... and how that might relate to disorders,” says Levitt. “He’s had that from ultraviolet rays. Rakic explains this sophisticated design, enthralled [slant] for a long time, but it was not in vogue back in the ‘70s or ‘80s.” with the interplay of science and art, then turns to the stacks of beautiful Rakic’s research career began in 1962, with a fellowship at Harvard rare books in the inner part of the building. “Both [science and art] want to University. At the time, developmental neuroscience was largely descriptive; find some meaning or order in the larger picture of chaos,” he says. scientists knew where the neurons were at various points in development, Rakic, who chairs the neurobiology department at Yale, balances these but not how they got there. Soon after entering the field, Rakic conceived elements in his own work, often illustrating papers and presentations a breathtaking strategy to change that. with original pen-and-ink drawings he creates in a small studio adjacent to his office. Some of these pictures, which show how neurons migrate into position in the developing brain, have become standard textbook “Both [science and illustrations. Produced with classical techniques, the black-and-white art] want to find some figures have a timeless quality, like a microscopist’s drawings from a previous century. meaning or order Other researchers see a similar timelessness in Rakic’s science. “I in the larger picture consider Pasko to be one of the most brilliant neuroscientists not just of this generation but in the history of neuroscience,” says Susan Hockfield of chaos.” (Nat. Med.11, 110; 2005), former provost of Yale and now president of the Massachusetts Institute of Technology. “What he’s contributed to neuroscience is really on the order of Cajal or Golgi.” The experiment required a special grant, nearly 200 rhesus monkeys But Rakic himself is almost self-deprecating when discussing his and so much radioactive thymidine that manufacturers had to retool their accomplishments. After mentioning that a particular paper of his was entire production system to provide it. Describing this historic work, Rakic widely cited, he quickly apologizes for sounding boastful, saying he is only walks to the hallway outside his office, which is lined on both sides with tall trying to put the result in context. Though he does not shy away from metal cabinets. Opening one at random, he reveals that it is packed from scientific debates and competition, colleagues say Rakic’s generosity is his top to bottom, two layers deep, with boxes of histological slides. On each most notable trait. “He is a delightful collaborator,” says Richard Flavell, slide is a slice from the brain of a fetal monkey. Rakic injected each monkey chair of immunobiology at Yale, who has collaborated with Rakic on several with radioactive thymidine at a particular time after conception. Because papers. With Rakic, “egos do not get involved at all,” Flavell says. only replicating cells took up the radioactive label, he could trace the lin- The only challenge in collaborating with Rakic seems to be his eages of the brain cells that arose at different times during development. perfectionism. “The first paper I did with him, we had 26 drafts. He is Though he was primarily interested in the visual system, Rakic realized compulsive about communication,” says Pat Levitt, a former postdoctoral that nobody would repeat such a costly and complex experiment. For the fellow in Rakic’s lab who now directs the John F. Kennedy Center at benefit of future studies, he and his technician sliced the entire brain of Vanderbilt University in Tennessee. each monkey into 7,000 sections. Rakic often collaborated with his wife, Patricia Goldman-Rakic, Combining this tour de force with innovative experiments in mice, Rakic considered by many to be one of the most successful female scientists in worked out the fundamental processes of mammalian neural development. the world, until her tragic death in 2003. Rakic was attending a meeting in Among other things, he discovered and named the subventricular zone and Japan when his wife was struck by a car while crossing a New Haven street. demonstrated that neurons of the cerebral cortex originate there and then He rushed home to find her in a coma, from which she never awoke. migrate to their final positions, rather than being generated in the cortex. “He and Pat together were an extraordinary team. They both had To date, the monkey slides have yielded more than two dozen papers, and enormously productive labs and ... a single-minded pursuit of their Rakic continues to collaborate with neuroscientists who want to study the research programs,” says Hockfield. collection. Because he used a radiolabel that decays slowly, the slides should Though much of Rakic’s work is so fundamental that it is now taken for be useful for years—much like a well-preserved archive of rare books. granted, he is best known in the popular press for his skepticism of the idea Alan Dove, New Haven

362 VOLUME 11 | NUMBER 4 | APRIL 2005 NATURE MEDICINE NEWS FEATURE One step at a time The big question remains: will people Turning the tide on the obesity epidemic is going to require a take advantage of the changes? A few myriad lifestyle changes—and a few communities are rising to the preliminary studies say yes—at least for some part of the population. The National Institute challenge. Kendall Powell cruises the neighborhood. of Environmental Health Sciences in North Carolina plans to evaluate 25 communities like Stapleton during the next five years to On a sunny Thursday morning in February, the Schmid and his colleagues have found that see how residents’ physical fitness compares Stapleton community ten miles east of down- people who live in suburbs are more likely to to those in 10 control communities. The town Denver is bustling. Moms push strollers be obese than their urban and walking counter- prospective study will help establish whether to jungle gyms in large playgrounds. A family parts. For every additional hour spent driving, a there are causal connections between of three is walking off a big breakfast. A retiree person’s likelihood of becoming obese increases environment, transportation and health, says enjoys mountain views from a bench and about six percent3, they found. Their work is part of lead investigator Allen Dearry. 15 dogs and owners romp in the dog park. a growing realization that the environment can The scene might seem unexceptional, hold back even the most determined dieter. Pounding the pavement but compared to the average suburb where In December 2004, the US government Stapleton, built on the remnants of Denver’s people drive even to the corner store, Stapleton’s raised the recommended daily fruit and old airport, was designed to recreate the best of residents do an inordinate amount of strolling or vegetable servings from five to nine and the city living—inviting sidewalks, neighborhood biking. These residents might also be the lucky time spent on moderate activity from 30 storefronts and economic diversity—with few to escape the insidious obesity epidemic. minutes to 60–90 minutes per day—high some of the safety, quiet and convenience of Many factors have been linked to the standards for even the fittest among us. But traditional suburbs. obesity epidemic worldwide—genetics, stress after 20 years of telling patients to eat healthier The typical American suburb, which hormones, the easy availability of cheap, and be more active, experts note that individual evolved during the ‘car is king’ mentality of processed foods, even fewer hours of sleep1 approaches rarely work in the long term. To the 1960s, built wide streets, cul-de-sacs and (see Food fights and sleepless nights). In the US, combat the obesity epidemic, they say, problems garage-in-front housing designs at the expense obesity prevalence increased by about 35% must be addressed at the community level. of parks and walking paths. from 1994 to 20002. But one factor has crept so “We are getting nowhere by yelling louder Stapleton, in contrast, is four square miles gradually into people’s lifestyle that, until recently, and moving guidelines up,” says James Hill, of high-density mixed-income housing, obesity researchers paid it little notice. director of the Center for Human Nutrition at schools, mini-parks, ‘main-street’ shops and “The way we became a car-dependent the University of Colorado. a town green, all connected by sidewalks society had some implications. We engineered But how can we design activity back into and greenways. The goal was for the activity out of our lives,” says Tom Schmid, a peoples’ lives? Researchers spanning the neighborhood paths to lead to real behavioral scientist in the Division of Nutrition public health, city planning and transportation destinations such as the playground, school or and Physical Activity at the US Centers for Disease sectors are coming up with solutions that seem grocery store, says Tom Gleason, spokesman Control and Prevention (CDC) in Atlanta. The deceptively simple: better bike paths and pedestrian for Forest City, Stapleton’s developers. conveniences of modern, affluent living—drive- -friendly policies to compete with driving, new Destinations are crucial for most people through windows, suburban sprawl, computer communities designed around active living and to become pedestrians. “We are busy people, workstations—have drastically reduced physical worksite changes to encourage employees to get we are not going to walk just for the sake of activity in daily routines, Schmid says. up from their desks more often. walking,” says Lawrence Frank, an expert at the University of British Columbia. The idea works for Stapleton resident Heidi Crum who frequently walks or bikes with her children to the pool, the farmer’s market or to the ice cream parlor in the summer. But Colorado’s Rocky Mountains attract people with active lifestyles. What about more couch-bound people? Frank points to two possibilities: funding pedestrian improvements and rezoning to have shops closer to where people live and work.

Fighting inertia The Sprint Corporation headquarters in Overland Park, Kansas, was built to encourage more physical activity at work. In 1999, the company worked with architects to Courtesy: Forest City Stapleton, Inc. Friendly neighborhood: The Stapleton community near Denver, Colorado, offers all the benefits of design a campus to encourage better employee city living—including sidewalks, parks and outdoor markets—that foster fitness. interactions and improve wellness. The

NATURE MEDICINE VOLUME 11 | NUMBER 4 | APRIL 2005 363 NEWS FEATURE campus has a parking lot that is a five-minute walk away from buildings, elevators that are Food fights and sleepless nights deliberately slower than taking the stairs, a Limiting food intake is still the most direct way to curb obesity—and several programs have walking trail and sports fields. begun following this simple maxim. Early this year, Kraft Foods and PepsiCo said they would Sprint does not track employee health limit marketing of soft drinks, cookies and other junk foods to children younger than 12. because of privacy reasons, but spokeswoman Several other manufacturers also plan to label products to help consumers identify lower-fat Jennifer Bosshardt says people take advantage and lower-calorie choices. of the walking path, have dropped pounds by “We need to teach kids about the relationships between energy, food and physical activity working out with colleagues and even hold just like we teach them about money,” says James Hill, director of the Center for Human walking meetings. Nutrition at the University of Colorado. His program, America on the Move, suggests 100 Skeptics might say that for most people, the ways to cut 100 calories per day, such as substituting chips and salsa with raw veggies, car culture is far too ingrained to make a dif- opting for thin-crust pizza or splitting a restaurant meal with a friend. ference. A report released in February4 suggests Another prescription for staying slim might be as simple as adding an extra 20 minutes of otherwise. In one of the first studies to objectively sleep per night, according to a study released in January2. By monitoring the total sleep of measure the relationship between neighborhood 1,001 patients, the researchers observed that patients with a normal body mass index sleep walkability and a person’s physical activity, Frank 16 minutes longer on average than those classified as overweight or obese. Although a causal and his colleagues measured the activity levels relationship between sleep loss and obesity has yet to be established, there is a clear trend of 357 people in the greater Atlanta region using that Americans now sleep less and weigh more than they used to. accelerometers worn on the participant’s hip, Combining these strategies—walking more, eating healthier, getting enough sleep—may which measure the vertical movement associated benefit more than the body. A study released in January7 found that older beagles that exer- with walking. They also calculated a neighbor- cise regularly and eat a diet rich in antioxidants are better at performing mental tasks.—KP hood’s walkability from housing density, street connectivity and land-use mix in a 1-km area surrounding a subject’s home. Hill says telling people to make big changes Minnesota, compared total activity from ten People in the most walkable regions are 2.5 is not sustainable. Instead, he starts people on lean subjects and ten mildly obese subjects for times more likely to get 30 minutes or more programs such as America on the Move that ten-day periods6. The lean subjects spent two of moderate activity per day than those living begin with small, daily goals like walking an extra hours on average more each day doing non- in the least walkable regions, the researchers 2,000 steps (about a mile) or cutting 100 calories purposeful activity—fidgeting, pacing, going found. But only 37.5% of all people in the highly (about one soda). Once people reach 2,000 steps, to the water cooler—than the more sedentary, walkable neighborhoods reached the 30 they are encouraged to add 2,000 more. obese volunteers. That extra activity amounted minutes or more mark. “It’s not a prescription for Setting realistic goals is key, adds Bess to 350 additional calories burned each day, or everyone,” says Frank. “But there’s no question Marcus, professor of psychiatry at Brown roughly 30 pounds over the course of a year. that how we design our communities matters.” Medical School in Providence, Rhode Island. This means that small, sustained activi- “The number-one barrier to exercise is lack of ties of daily life can shift energy balance, says Small steps time or perceived lack of time,” she says. Dearry. “Maybe one of the best approaches to Those who study exercise motivation say changes Luckily, she notes, the notion that we need help people stay lean would be to encourage to the so-called built environment fit nicely with hours of vigorous, spandex-clad exercise at the activity and discourage sitting,” he says. the types of activities adopted by successful exer- gym to lose weight is falling by the wayside. Hill describes his successful registry ‘los- cisers. The US National Weight Control Registry Walking can be done all at once or incorpo- ers’ as people who have learned to “swim tracks people who have lost 30 pounds or more rated into everyday activity with the same upstream in their obesogenic environment.” and have kept it off for at least one year. Hill, results, she says. And exercise doesn’t have to He suggests that changes to communities or who co-directs the registry, says the overwhelm- be boring: moderate activity could be dancing worksites that lower the barriers to physical ing majority keep weight off by getting plenty of or shooting hoops with the kids. activity might increase the numbers of people daily physical activity, and not by dieting. But can simply taking the stairs more often who can succeed. or parking farther away really Encouraging people to drive less is the first stop the waistband from expand- step toward getting the daily activity our bod- ing? An analysis of studies from ies are designed to handle, Hill says. And while 1970–2003 on physical activ- you’re at it, you might reduce air pollution and ity interventions confirms that meet your neighbors, too. Go on, take a hike. simple environmental changes, Kendall Powell is a freelance writer such as easier access to stairs, can based in Denver. promote increased activity5. Hill’s 2,000 extra steps would keep off 1. Vorona, R.D. et al. Arch. Intern. Med. 165, 25–30 the one or two pounds per year (2005). 2. Hill, J.O. et al. Science. 299, 853–855 (2003). an average American gains; sim- 3. Frank, L.D. et al. Am. J. Prev. Med. 27, 87–96 ply monitoring steps with a pedo- (2004). 4. Frank, L.D. et al. Am. J. Prev. Med. 28, 117–124 meter could stop weight gain in (2005). 1 90% of the population, he says . 5. Matson-Koffman, D.M. et al. Am. J. Health Promot. In one of the most controlled 19, 167–193 (2005). Fringe benefits: The campus of the Sprint Corporation 6. Levine, J.A. et al. Science. 307, 584–586 (2005). studies of its kind, researchers 7. Milgram, N.w. et al. Neurobiol. Aging. 26, 77–90 headquarters in Kansas is built to encourage employees to walk. at the Mayo Clinic in Rochester, (2005).

364 VOLUME 11 | NUMBER 4 | APRIL 2005 NATURE MEDICINE