NEWS

p1336 Blood simple: p1339 Blue-chip p1340 Conflict-of- Dwindling reserves biochemist: Patrick interest conundrum: appear set to create a Brown sees the world How much money hemo-global crisis. through rose-colored does it take to skew a glasses. researcher’s bias?

New NIH project could be road to ruin for basic research

The ambitious US National Institutes of Health The plan comes at a time of transition for the map on the table when he appeared before a (NIH) Roadmap for Medical Research arrived in NIH. After five years of funding increases— joint Senate/House committee two days after October to glowing press reports and enthusi- doubling the agency’s budget to $27 billion— announcing the program. Rather than focus on astic endorsements from top scientists. But scientists are bracing for a return to the lean the initiative, the lawmakers questioned some researchers are worried that the plan will years. An Institute of Medicine report on the Zerhouni about budget accountability, the give the NIH director authority to set a top- future of the NIH, released this summer, called ethics of research into human sexuality and down agenda at the expense of bench scientists. for many of the initiatives in Zerhouni’s plan, stem cells, and NIH personnel issues. The plan is designed to transform NIH including more authority for the director (Nat. If the roadmap is to succeed, it will have to research, says director Elias Zerhouni. Med. 9, 1098; 2003). But it also warned that survive the politics of the NIH, an organization Developed during Zerhouni’s 17-month tenure, major organizational changes—such as com- seen by many as “a collection of fiefdoms” pan- the program will create a $2.1 billion fund to bining institutes—might promote efficiency dering to special interests, and controlled by an pay for a long list of interdisciplinary projects over good science. academic elite, says Liu in Singapore.“My con- focusing on clinical research, structural biology Some of the push for combining institutes cern is whether the special interests will derail and informatics (Nature 425, 438; 2003). comes from Congress, which has its own this unique effort.” “The historic frustration that people have agenda for the NIH. Zerhouni put his road Tinker Ready, Boston had is that the NIH is not responding fast enough to emerging areas or new trends in sci- ence,” Zerhouni said. “This is designed to do Taiwanese scientists find genetic link to SARS that.” The plan drew praise from groups such as A genetic variant in the immune system might the American Association of Medical Colleges, render some groups of people more susceptible and from noted scientists such as Harold to severe acute respiratory syndrome (SARS) Varmus, Zerhouni’s predecessor at the NIH. infection, Taiwanese researchers report. The road map is long overdue, says Edison Marie Lin, a hematologist at the Mackay Liu, a researcher who led the US National Memorial Hospital in Taipei, says subtypes of Cancer Institute’s Division of Clinical Sciences human leukocyte antigen (HLA) class I are asso- from 1996 to 2001. ciated with severe SARS infection “It breaks from the disease- or systems-ori- Lin and her team compared blood samples ented approach...and concentrates on the entire from 65 suspected SARS patients (including 37 Richard Chung/Reuters research machinery,” says Liu, who now heads probable cases) with samples from 101 high- Waiting to exhale: People in South China and the Genome Institute of Singapore, that coun- risk, uninfected health-care workers. The Taiwan may be genetically susceptible to SARS. try’s flagship program in genetic research. “I researchers used 190 healthy, unrelated think [the road map] is visionary.” Taiwanese individuals as controls. The results explain why south China was the Disease-oriented research is one of the NIH’s People with the HLA-B*4601 allele are most epicenter of the SARS epidemic, the researchers strengths, says Murray Goldstein, who served as likely to fall victim to SARS, the researchers suggest. The finding tallies with the scenario in director of the National Institute of reported (BMC Med. Genet. 4; 2003). Of the 37 Taiwan: no probable SARS cases were reported Neurological Disorders and Stroke from 1982 probable cases,15 had HLA-B*4601,and 5 severe among indigenous people. It might also explain to 1993. But Goldstein, now director of the cases had a significantly higher frequency of the why the disease left Caucasian people largely United Cerebral Palsy Research and allele when compared with controls. The HLA unaffected—except in Toronto, which has a Educational Foundation in Washington, D.C., system is often used to search for the origins of high Asian population. says he is worried about who will lose out at the infectious diseases and autoimmune disorders. Lin suggests screening health-care workers NIH with a shift in funds and authority. Each The HLA-B*4601 allele is found in about for HLA-B*4601 to prevent the spread of SARS. institute is expected to contribute a percentage 10% of the Taiwanese population and among But other scientists are cautious about extrapo- of its budget to fund the plan. other southern Asians, including people from lating results from a small study. “The investigator-initiated research project China’s southern coast, Hong Kong, Singapore “It’s too [early] to talk about mass screening has been and continues to be the strength of and part of Vietnam—areas hit hard by SARS. now,”says Yuh-Shan Jou, a researcher in Taiwan’s American biomedical science,” says Goldstein. But it is seldom seen in the indigenous people of National Health Research Institutes.“The lack of “Will this be cut back to provide the resources Taiwan—about 1.5% of the total Taiwanese data from other areas hit by SARS makes Lin’s needed to accomplish these broader cross-cut- population—in Caucasians or in people of scientific evidence comparatively weak.” ting objectives?” African origin. Yu-Tzu Chiu, Taipei

NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1335 NEWS

Fear flows as efforts to ease blood shortage continue in vein

Emerging infections such as West Nile virus, Creating substitutes for blood is challenging mad cow disease and foot-and-mouth disease because of the multitasking nature of the vis- are shrinking the global blood supply, which cous life force: blood carries oxygen, nutrients was already threatened by the AIDS epidemic. and waste products, and helps repair injuries. The dwindling reserves, say experts, could spell Most substitutes are derived from oxygen-car- doom for hospitals worldwide. rying perfluorocarbons or natural hemoglobin. US blood banks have enough blood to meet But Fluosol, the only blood substitute ever demands for roughly two or three days. But a approved by the US Food and Drug five-to-seven day margin is optimal, says Roger Administration (FDA), was taken off the mar- Dodd, president of the American Association of ket because patients given Fluosol breathed Blood Banks. Worldwide, the picture is equally pure oxygen—which can be toxic. grim: there are about 75 million blood collec- Hemoglobin-based substitutes stem from tions every year, but the majority of the world’s outdated human blood, cow blood or recombi- population has access to only 40% of the avail- nant hemoglobin produced by bacterial cells. able blood. The reserves are also falling because Recently, the common marine worm was sug- of a shifting demographic, adds Dodd. “People gested as another promising alternative. But seem less and less inclined to give blood,” he hemoglobin-based substitutes also carry the says. risk of toxic side effects, such as inflammation For years, scientists have been trying to create Blood lines: Screening for infectious agents is and oxygen stress. viable blood substitutes, but that goal has been bleeding reserves dry, experts warn Some researchers are trying to grow blood elusive. Two US products are now close to vessels in a test tube. A Harvard University reaching the clinic: Hemopure, made by regardless of blood type, says Biopure research team also recently reported that Cambridge-based Biopure, and PolyHeme, spokesman Douglas Sayles. Hemopure also has adding uridine diphosphate-galactose to blood developed by Northfield Laboratories of a three-year shelf life—much longer than the platelet cells increases their shelf life from 5 days Illinois. Neither can replace blood entirely— 42-day life span of red blood cells. to 12 (Science 301, 1531–1534; 2003) most substitutes focus primarily on transport- Once inside a patient however, Hemopure The real test for any substitute, says Tom ing oxygen—but will at least serve as a “bridge” lasts only for 12–24 hours, whereas transfused Moore, chief executive officer of Biopure, is get- in emergency situations, their makers say. red blood cells can live for up to 50 days. ting FDA approval. “It is a challenge to run a Hemopure, made from purified bovine Scientists remain skeptical about blood substi- clinical trial against a natural product,” Moore blood, is farthest along in the regulatory tutes for that reason, calling them a short-term says. “Blood has never really been character- process. Already approved in South Africa, it solution useful only for specific indications ized, so the standards we are putting ourselves delivers oxygen three times more efficiently such as military operations and heavy trauma against are murky.” than red blood cells and can be administered episodes, where physicians need blood quickly. Paroma Basu, New York

European researchers up in arms over new clinical trials edict

European researchers are appealing to their mia, industry, charities and government bodies. research will come to a standstill and global col- national governments to reject a sweeping new The model closely resembles one currently used laboration will cease.” directive on clinical trials. The edict, which by the pharmaceutical industry and makes Under the directive, nationwide trials will be must first be incorporated into the law of each researchers responsible for sponsorship, manu- subject to review by a single ethical committee. European Union (EU) country, is expected to facturing authorization and good manufactur- But assessing the suitability of staff and loca- take effect on 1 May 2004. ing practices (GMP), as well as a huge amount tions at distant sites is virtually impossible and is The directive is intended to standardize and of paperwork on trial authorization and regis- likely to be delegated to the host institutions, simplify the rules governing clinical trials. But tration, data verification and pharmacovigi- notes Simon Thomas, a clinical researcher at the researchers fear that layers of bureaucracy will lance. University of Newcastle upon Tyne. As a result, only add to the regulatory hurdles and cost of Unlike the drug industry, academic centers Thomas says, “independent review of locality clinical trials, without improving patient rarely have the expertise required to build and issues for multicenter studies will be lost.” safety or trial quality (Nat. Med. 7, 1264; 2001). run GMP-compliant facilities, and some Another issue is cost. According to a study by “There is a real risk that European public observers already foresee competition with Cancer Research UK, increased bureaucracy health policy makers and national authorities industry for suitable staff. Critics of the direc- from the legislation will double the paperwork may marginalize key areas of biomedical and tive argue that it was primarily designed with and quadruple the cost of publicly funded clin- health research by developing [these] policies,” industry in mind, and that the reality of aca- ical trials.As a result, warns Peter Selby, director says Françoise Meunier, director general of the demic trials was ignored. of the organization’s clinical center at St. James Brussels-based European Organization for “The EU rules must move into line with real- University in Leeds, there will be fewer trials Research and Treatment of Cancer. ity and feasibility,” says Jaap Verweij, a available to patients, and important clinical The measure proposes one model for all clin- researcher at the Erasmus Medical Center in questions will remain unanswered. ical trials, including those sponsored by acade- Rotterdam. “[Otherwise], academic clinical Xavier Bosch, Barcelona

1336 VOLUME 9 | NUMBER 11 | NOVEMBER 2003 NATURE MEDICINE NEWS

Scientists closing in on true identity of the ‘great imitator’

Imagine a disease with no cure, no known Because they produce autoantibodies, B cells cause and an elusive diagnosis. Dubbed the have an essential role in lupus pathogenesis. ‘great imitator’ because it mimics so many Rituxan, an antibody to CD20, can block pro- other diseases, systemic lupus erythematosus duction of B cells in patients with non- (SLE) has remained an enigma—until now. Hodgkin lymphoma. Researchers hope that by With new genetic technologies and the com- interrupting autoantibody production by the B plete sequence of the human genome, scientists lymphocyte, Rituxan might be an effective are poised to take a quantum leap in unraveling therapy for lupus as well. its mysteries. Lupus is more common in women of SLE is an autoimmune disease where the Hispanic, Asian and Native American descent. body attacks its own cells and tissues, causing Children and adolescents represent 15% of SLE Courtesy: Edward Zabawski inflammation in various parts of the body, Skin deep: The characteristic butterfly rash in patients. As more afflicted children survive into including the skin, kidneys, heart and nervous lupus can be indicative of a severe disease affect- adulthood, atherosclerotic cardiovascular dis- system. It affects 1.4 million people in the US ing internal organs. ease has emerged as a major concern. alone. In its worst form, lupus can be fatal: 15% Laura Schanberg, associate professor at Duke of patients die from kidney disease, cardiovas- in lupus patients. A phase 1 clinical trial spon- University Medical Center, is planning to test cular disease or infections. sored by the US National Institutes of Health is whether the statin Lipitor can reduce choles- The discovery of potential biomarkers will investigating the safety and effects of the mono- terol levels in children with lupus. “This is the soon allow doctors to predict the severity of the clonal antibody MRA, which blocks the action first ever drug intervention trial in pediatric disease, says Timothy W. Behrens, professor of of interleukin-6, thought to lead to organ dam- SLE,” says Schanberg. The researchers have rheumatology and autoimmune diseases at the age in SLE patients. started enrolling patients into the trial at a few University of Minnesota. “We are very close to The US National Institute of Allergy and sites, with the rest of the sites expected to start the identification of several of the genes that Infectious Diseases is conducting a phase 1 enrolling later this year. increase a person’s chances for developing study that explores the possibility of B-cell Amy K. Erickson, Washington,D.C. lupus,” Behrens says. Behrens and others pre- depletion as a potential treatment for lupus. sented their research at a meeting in September in Washington, D.C. Using gene expression microarrays, Behrens and his colleagues have identified a ‘signature’ Japanese scientists plan MMR alternative of genes activated by interferon in patients with The Japanese government has approved a five- HIV antigens in varicella. lupus. Although the precise biochemistry is year grant, with ¥56 million slated for the first Another advantage of varicella is that unknown, evidence suggests that the disease is year, to create a single recombinant vaccine for compared with other vaccines, such as somehow activating the interferon pathway, four common childhood diseases. Researchers measles, its side effects are relatively mild. says Behrens. The researchers analyzed thou- at Osaka University and Toyama Medical and “The varicella backbone is very safe,”says sands of genes in the peripheral blood cells of Pharmaceutical University plan to insert Anne Gershon, director of the pediatric 48 lupus patients and 42 healthy controls. genes encoding the antigens for measles, infectious disease division at Columbia Nearly 80% of the SLE patients have higher mumps and rubella into the varicella University. But Gershon cautions that the expression of 14 genes, referred to collectively (chickenpox) virus. There are currently no safety and efficacy testing process could take a as the interferon gene expression signature, the recombinant vaccines against multiple long time—the researchers aim to have a researchers found (Proc. Natl. Acad. Sci. USA diseases licensed for human use. vaccine ready for clinical trials within five 100, 2610–2615; 2003). The signature seems to Improving vaccine coverage, particularly years. Gershon also notes that current be a marker for patients with the more severe for measles, is a priority for Japanese health vaccines are safe and effective. type of lupus, which can involve the brain, kid- officials, says Keiko Taya, chief of the Yamanishi says Japan’s problem may not be neys and blood cells, Behrens says. immunization program at Japan’s Infectious related to the effectiveness of the vaccines, but “We believe that there is potential for the Disease Surveillance Center. The government to the time it takes to receive them. Japanese development of new diagnostic tests based on is currently assessing its vaccine policies— children now receive four separate the signature,” says Behrens. Many patients statistics indicate that measles coverage in vaccinations for measles, mumps, rubella and now go up to four years before a definite diag- 2001 was only 50% for one-year-olds, and that varicella, a process prone to delays. Japan nosis is made. “In the near future,” Behrens adult cases are on the rise. discontinued use of the MMR vaccine in 1993 adds, “these types of data—the genes a person According to project leader Koichi over concerns that the Urabe mumps strain carries and the pattern of gene expression in Yamanishi, the researchers decided to use used in Japanese MMR vaccines was associated their blood cells—will be used by doctors to varicella as the vector because it has a with adverse side effects such as meningitis.A individualize therapy in a way that has never relatively large amount of dispensable DNA, new MMR vaccine isn’t likely to be available been possible.” which makes it a good candidate for accepting for several more years.“If [a child] catches even The results have also spurred interest in initi- foreign genes. The team—which includes a common cold during [that] year, the next ating clinical trials with drugs that block the Michiaki Takahashi, who developed the Oka injection gets delayed,”says Yamanishi.“One interferon pathway. Several trials are under way varicella vaccine now used worldwide—has injection could be much more convenient.” to explore manipulation of chemical pathways already successfully expressed hepatitis B and I-han Chou, Tokyo

NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1337 NEWS IN BRIEF

Microsoft cofounder funds NIH funds biodefense labs WHO adopts bold plan mouse brain atlas project Amid public concerns over safety, federal for AIDS drug distribution Microsoft cofounder Paul Allen in September health authorities in September announced donated $100 million to launch a nonprofit that they have selected Boston University and Calling the failure to distribute drugs to AIDS- research institute that will try to craft a genetic the University of Texas Medical Branch at ravaged countries a “global health emergency,” atlas of the mammalian brain. By studying the Galveston to each house a top-security level 4 the World Health Organization (WHO) in human-like genome of the common mouse, biodefense research facility. The US National September announced its plans to provide anti- scientists at the Seattle-based Allen Institute for Institute of Allergy and Infectious Diseases retroviral drugs to 3 million patients by 2005. Brain Science plan to uncover each of the will award $120 million to each university to Worldwide, nearly 6 million HIV-positive indi- roughly 20,000 genes that build and drive the construct a National Biocontainment viduals—the majority of them in sub-Saharan human brain. Laboratory, where scientists will develop Africa—require AIDS drugs to survive, but The new institute’s first endeavor—the Allen vaccines and treatments against deadly only about 300,000 receive them. Brain Atlas project—is the creation of a three- pathogens such as Ebola and bubonic plague. The WHO’s director-general Jong-Wook Lee dimensional gene expression map that will The institute also plans to grant awards of says the agency will implement emergency outline the function of every gene in the brain. up to $21 million for the creation of nine new response mechanisms similar to those it used The map will include anatomical resolution on Regional Biocontainment Laboratories to during the outbreak of severe acute respiratory the level of ‘nuclei’, or groups of specialized provide support to the national laboratories syndrome and during health emergencies in nerve cells. Using high-power computing tech- (Nat. Med. 9, 805; 2003). Much of the war-torn countries. The organization plans to nology, institute researchers plan to analyze research at the new facilities will originate dispatch emergency response teams to make about 10,000 genes a year—a pace that far from the eight recently announced Regional regional assessments on how best to improve exceeds other ongoing ‘brain map’ projects. Centers of Excellence for Biodefense and access to AIDS drugs. It will also establish an The US National Institute of Mental Health’s Emerging Infectious Diseases (Nature 425, AIDS Drugs and Diagnostics Facility to help Brain Molecular Anatomy Project, for 110; 2003). The new consortia will each countries purchase drugs more efficiently. instance, probes only 600–800 genes each year. receive $50 million over five years to advance Among other highlights of the new initiative The institute’s researchers—whose numbers bioweapons research. is a plan to publish simplified treatment guide- could eventually reach 100—plan to complete The two national laboratories are lines and create tools to effectively monitor all the map in three to five years. The achievement scheduled to begin operations by 2008. They antiretroviral programs. The WHO will unveil a could spawn treatments for neurologic dis- will bring to five the number of level 4 global AIDS action plan on 1 December, World eases and shed light on how genes underlie research centers in the country. Citizen AIDS Day. behavior and other traits such as language, groups are denouncing the decision to build The agency plans to increase its AIDS pack- memory and emotion. The scientists plan to the laboratories near densely populated age from $50 million to $150 million a year to publish their results in a free online database, neighborhoods: community advocates plan support the new initiative, and will solicit addi- and hope to release their first round of data in to sue Boston University over safety and tional funding from governments worldwide. early 2004. PB environmental concerns. PB PB Nobel Prizes bestowed for MRI, membrane channels The truth about rats and dogs For their pioneering work on magnetic After Cc the cat and Idaho Gem the mule, scientists resonance imaging, two scientists have won in September presented 10-month-old Ralph, the the 2003 Nobel Prize for medicine. Research world’s first cloned rat. With a small scientific trick, in the 1970s by American Paul Lauterbur of researchers at France’s Institut National de la the University of Illinois at Urbana- Recherche Agronomique and the biotechnology Champaign and Briton Sir Peter Mansfield company GenOway created duplicates of the popular of the University of Nottingham led to the laboratory animal. widely used diagnostic technique that Genetically altered rat clones will help research on Science produces three-dimensional images of diseases such as diabetes and cancer. But scientists internal organs. have struggled to clone rats because their eggs begin Image © The Nobel Prize for chemistry went to US to multiply immediately after their extraction from the animal. The French team bypassed the scientists Peter Agre of Johns Hopkins problem by exposing the eggs to an inhibitor protein that blocks their activation. Three live University and Roderick MacKinnon of The pups—and one that died after birth—emerged from 129 cloned embryos that the researchers Rockefeller University. Agre was honored for injected into two females. The clones have since been mated to produce two more rats. his work on water channels and McKinnon, News of the cloned rats followed another advance in genetics—the first draft of the canine whom Nature Medicine in 2001 pegged as genetic sequence. Using Shadow, a family poodle, as their specimen, researchers at The odds-on favorite to win the prize (Nat. Med. Institute for Genomic Research and the Center for Advancement of Genomics announced 7, 648; 2001), won for his work on ion that dogs carry roughly 2.4 billion DNA base pairs (Science 301, 1898–1903; 2003). Dogs are channels. PB good models for medical research because they share about 360 of the same genetic disorders as humans. The US National Institutes of Health is expected to finish a more complete canine sequence in 2004. PB News briefs written by Paroma Basu

1338 VOLUME 9 | NUMBER 11 | NOVEMBER 2003 NATURE MEDICINE PROFILE Patrick Brown

Even when the chips are stacked against him, microarray pioneer inspired his students and colleagues when their own faith was in short Patrick Brown remains an incurable optimist. After defeating supply. dogma in biochemistry and genetics, Brown is taking on the world “When you are in the middle stages of the project and things are not of publishing—and he still hasn’t run out of breath. going well, and you go to see Pat Brown—when you come out the door, things are rosy again,”says Joe DeRisi, a former graduate student, now a researcher at the University of California in San Francisco. In the spring of 1995, Stanford University researcher Daniel Herschlag Faced with an obstacle, Brown does not hesitate to venture outside the introduced his friend and colleague Patrick Brown to the joys of running. life sciences to surmount it. Building the first microarray required engi- The two researchers began jogging regularly on the Stanford campus. neering expertise, for instance. Brown enlisted the help of Dari Shalon, “Almost as soon as [Brown] started, he said, ‘I want to run a then a graduate student in mechanical engineering at Stanford. marathon’,” recalls Herschlag. Just four months later, on the cold and In the mid-1990s, Brown stumbled across a different kind of problem. damp day of the Sacramento Marathon, Brown woke up with the flu and He found that analyzing microarray data from thousands of genes a temperature of 102 F, and missed his bus to the starting line. involved long, tedious sessions with cumbersome PDF files and massive Undaunted, he began running directly from his hotel and finished the tomes in libraries. He came to the conclusion that to mine the literature race near the head of the pack in just under 3.5 hours. systematically, published results would need to be easily accessible to any- That same indomitable spirit has allowed Brown to go the distance as a one.“Suddenly, the problem for research was this kind of political, social scientist, Herschlag says. Brown is perhaps best known for his work on problem,” Brown says. “But as far as I’m concerned it’s fundamental to microarrays and HIV integration, but his eclectic interests run the gamut [science].” from basic science to translational medicine. With a network of some of the best scientists in the world—his website lists 36 collaborations—he has examined the genetic signature of cancer and other diseases, used microarrays to analyze chromosome breakage and gene copy number, “It bothers me that a and delved into RNA dynamics. good paper winds up in “Pat tends to create an atmosphere where people feel empowered to go out and do things and explore—that leads to a lot of new discoveries,” a journal that doesn’t says Herschlag.“His intellectual force and personality really make people deserve it ... I would die gravitate towards him.” before I publish a paper In academic circles, Brown is famous for his unconventional approach to science, his tendency to talk in superlatives, and his unbending opin- in Science.” ions. In person, he can be surprisingly shy and unassuming—until he begins talking about one of his pet projects. “One of the things I like about Pat is that he has a great combination of imagination and enthusiasm on one hand, and very hard-core, solid Along with such scientific heavyweights as Harold Varmus (Nat. Med. 7, principles on the other,”says Richard Tsien,Brown’s collaborator and col- 10; 2001) and Michael Eisen, Brown helped found—and spends a signifi- league at Stanford. “There is an almost messianic zeal about the way he cant amount of time promoting—the business model of the Public does things.” Library of Science (Nat. Med. 9, 154–155; 2003), which published its first Throughout his career, Brown has taken stances that challenge the pre- open-access journal in October. He now refuses to publish in journals that vailing ways of thinking. While still in graduate school, he found that the don’t fit his criteria for open access.“It bothers me that a good paper winds enzyme topoisomerase II slices DNA before passing a double helix up in a journal that doesn’t deserve it,”he says. Although his first microar- through the break. Initially met with skepticism, the finding has since ray paper appeared in Science, “I would die before I publish a paper in earned a solid place in textbooks. Science,” he now says. “He’s very iconoclastic—he’s always been that way,” says Nick Brown also expects his collaborators, students and postdoctoral fel- Cozzarelli, his graduate advisor. “And a surprising number of times, his lows to publish in a select few journals. He says he “bends over back- ideas have turned out to be correct.” wards” to promote his students’ careers in other ways, but his zeal has Perhaps the most telling illustration of Brown’s unerring instinct is his made for some tense situations (Nature 425, 334; 2003). work on microarrays. In 1992, he submitted a grant proposal to the US Brown can afford to turn his nose up at publications such as Science, National Institutes of Health (NIH) that included a piece on microarrays. Nature and Cell because he has already established a reputation as a solid “I had the whole thing laid out,” Brown recalls. “I was just so sure [they researcher, notes Larry Steinman, Brown’s colleague and collaborator at would fund it].”Much to his chagrin, the NIH specifically nixed the part Stanford. But young researchers need to publish in high-profile publica- about microarrays. It wasn’t until he took out that part that the agency tions to launch their careers, Steinman says. “When it comes down to agreed to fund his proposal. thinking of what [Brown] wants or what they want, [his students] might Brown’s vision has been more than validated since then. His 1995 first have to think of themselves.” paper on the technology has been cited more than 1,700 times. He says These days, Brown is training for his eighth marathon. He is a familiar the episode taught him a valuable lesson: “If people tell you [a project] is figure on the Stanford campus, jogging with his three children or his dog. a waste of time, it’s going to be good.” “He finds a way to enjoy almost any situation,” says Herschlag. Despite what anyone else may think, Brown says, his unshakeable faith “Nothing will slow him down.” is the key to his success. His oft-repeated phrase—“Blast ahead!”—has Charlotte Schubert, San Francisco, and Apoorva Mandavilli, New York

NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1339 NEWS FEATURE

Between 1994 and 1999, the number of new university-linked start-up companies The color of money rose from 241 to 344 per year, and income from licensing agreements jumped from As the line between academia and industry blurs, conflict-of- $360 million to $862 million, according to the Association of University Technology interest issues have gone from black and white to all the shades in Managers. With this trend came tales of between. Tinker Ready scans the spectrum for clarity. industry sponsors limiting access to data or trying to prevent the publication of negative findings. Meanwhile, the institutions were grappling with conflicts of their own. The Harvard University hematologist Thomas Deadly dispute Bayh-Dole Act of 1980 gave universities the Stossel has discovered a coveted method for The debate over how to best handle conflicts right to commercialize publicly funded freezing platelets that could revolutionize of interest has been simmering for more than research. Because the universities control the transfusion therapy. Stossel is seeking an a decade. But it was the 1999 death of teenager patents and take a share of licensing fees, they industry partner and stands to earn a fortune if Jesse Gelsinger that moved the discussion began encouraging researchers to patent the technique works. But here’s the rub: if he from conference halls to newspaper head- their work. In 2001, universities began 494 succeeds, Harvard’s rules on conflict of interest lines. Gelsinger died during a clinical trial for new companies and collected more than $1.2 will bar him from future research. an experimental form of gene therapy at the billion in licensing fees. “I would love to be involved in the study University of Pennsylvania. The study’s prin- The Washington meeting was “an eye- design [of the trial],”says Stossel.“[But] I can’t, cipal investigator was a founder of the com- opening experience,” recalls Edward Miller, according to the rules—you either take the pany that held the rights to treatments dean of the School of Medicine at Johns academic credit or you take the money.” emerging from the research. The US Food Hopkins University. “There was no unifor- Harvard’s rationale for the ban is simple, and Drug Administration (FDA) later found mity of opinion,” Miller says. “Some institu- and one many ethicists have repeatedly voiced: several violations of the study protocol. tions had no disclosure. Some institutions like when researchers stand to gain from the suc- Overnight, the focus shifted from research Hopkins had full disclosure, [and] there were cess of a trial, it can affect their objectivity and integrity to patient protection. differences about what had to be disclosed.” pose a potential risk to enrolled patients. “The In November 2000, representatives from Three years later, little has changed. appearance of a conflict itself breaks down the some of the top academic medical centers— Although one stated goal of the meeting was trust between the public and the scientific including the University of Pennsylvania, the to develop a uniform policy, attendees could community,” says Sheldon Krimsky, a Tufts University of California at San Francisco and not agree on the details. The group instead University professor who recently published the University of Washington—met quietly in deferred to the American Association of the book Science in the Private Interest. a Washington, D.C. hotel. Joseph Martin, dean Medical Colleges, which last year released Beginning next year, at least one professional of Harvard Medical School, had convened the general guidelines allowing each school to society—the 20,000-member American group for a private discussion about how to tailor its own approach. Johns Hopkins Society of Clinical Oncology—will no longer best handle the ethical issues emerging with researchers who have a ‘significant financial accept research papers or abstracts on clinical the rise of industry-sponsored research and interest’ in a company—more than $25,000 trial results if the author has a financial interest academic entrepreneurship. per year in income or publicly traded stock— in the findings. Even the Pope has weighed in, declaring that “overriding financial interests prompt decisions and products which are con- trary to truly human values.” All this attention on industry-academia rela- tionships, Stossel says, is leading to “an orgy of disclosure.” In reality, however, Harvard is one of only a few institutions that have rules barring researchers from benefiting from trials. Many institutions and journals now ask scientists to disclose financial interests, but don’t ban them. Some have set arbitrary ceilings on how much researchers can benefit from a product before they are required to disclose it. Even Harvard is considering revising its strict rules to allow more scibiogenscib interaction between scientists and industry. iogen “[Universities] form committees, establish rules or have someone be the dean of some- thing,” says Eric Campbell, who has been studying the issue for Harvard’s Institute for Health Policy. “What we don’t know is, what

works best?” Susan Wolsborn

1340 VOLUME 9 | NUMBER 11 | NOVEMBER 2003 NATURE MEDICINE NEWS FEATURE cannot conduct related research on human 33% of academic investigators have personal subjects without special permission from the financial ties with industry sponsors (JAMA of academic institute’s Committee on Conflict of Interest. 289, 454–465; 2003). investigators have The University of Pennsylvania had two More recently, journals in the Nature personal financial thresholds for clinical researchers—$10,000 Publishing Group (of which Nature ties with industry for equity interest, salary or royalties, and Medicine is one) came under fire for their sponsors. $25,000 beyond the cost of clinical trials for policies when Nature Neuroscience ran a studies conducted as part of an FDA New review on depression therapies. The review, of articles in major Drug Application. But earlier this year, the written by Charles B. Nemeroff, chair of the medical journals are latter threshold was lowered to $10,000. psychology department at Atlanta’s Emory written by lead University of California researchers must School of Medicine, included positive com- authors with relevant comply with state law, which requires disclo- ments about a lithium patch. Nemeroff financial interests. sure of income of $500 or more, and invest- holds the patent on the patch, a fact that ments of $2,000 or more. Some individual remained unmentioned because the journal California schools have campus-specific poli- did not require disclosures for review arti- of faculty on cies. For example, the University of cles. They do now. institutional review California in San Francisco bars faculty from “We take these concerns seriously and we boards overseeing receiving any compensation from a clinical are now extending our existing policy to clinical trial safety trial sponsor while the trial is ongoing. include review articles,” reads an editorial in serve as industry Because no two situations are alike, the the October issue of Nature Neuroscience. consultants. policies need to be flexible, says Stanford That policy was in the works before the University bioethicist Mildred Cho. Of 89 Nemeroff story hit the New York Times and of research centers institutions from 1998 to 2000, Cho found will apply to all of the Nature Publishing require disclosures that half required disclosure for all faculty Group’s journals, says Charles Jennings, from all faculty, members, whereas the other half required executive editor of the research journals. 45% only from lead them only from principal investigators. Only Ultimately, however, the journals have lim- investigators. 19% of institutions set limits on faculty ited power to apply sanctions to authors who financial interests. are not forthcoming about their conflicts, of institutions set But the varying policies have led to much says Jennings. “Our role is to ensure that limits on faculty confusion, Cho says. Fewer than half of the authors make a statement on the record,” he financial interests. scientists interviewed by Cho could accu- says. “It is then for the scientific community rately describe the conflict of interest policies to decide how to deal with false statements.” at their own institutions. “There are so many Last year, a group of 32 researchers and Source: JAMA 289, 454-465; 2003 variables, it would be impossible to write a academics—led by the consumer group policy that could account for all of their per- Center for Science in the Public Interest— to sign off on them. The “recommendations mutations,”says Cho.“Having said that, there asked both Nature and Science to strengthen present an impediment to research innova- could be more clarity.” and better enforce their disclosure policies. In tion,” she noted in the report. A newer set of general, journals could do a better job of voluntary guidelines is in the works at the Writing a wrong reminding authors of what constitutes a con- Department of Health and Human Services Like academic research centers, scientific flict of interest, says Donald Kennedy, editor (Nat. Med. 9, 630; 2003), but opinion is also journals are also struggling to adopt the right of Science,adding that his journal is planning divided on them. policies on disclosure, but most still depend to be more diligent about getting disclosure Back at Harvard, there is a chance Stossel on their researchers to be forthcoming. In for opinion pieces. might find a solution to his dilemma. Four 2001, the International Committee of “A surprising number of authors, once these years ago, there were rumors that a commit- Medical Journal Editors beefed up their issues are raised, will say,‘Oh yeah, I was a con- tee had recommended Harvard relax its guidelines, calling on members to make sure sultant to that drug company but it didn’t seem rules. Then, Jesse Gelsinger died, and Martin, authors disclose industry sponsorship and to me like it was a conflict. I didn’t feel con- the dean, announced there would be no retain full access to their trial data. However, a flicted’,”Kennedy says.“We’ve got to emphasize change. But Harvard is taking another look at recent Duke University study (N. Engl. J.Med. to them that perception is important.” its rules, and an announcement is expected 347, 1335–1341; 2002) found that few univer- before the end of the year. Early indications sities ensure these conditions—in particular, Too much of a bad thing suggest that the restrictions will remain full access to data—are met before researchers Not everyone in the medical research com- intact for clinical research, but may be launch industry-sponsored studies. munity believes that the emerging system for amended for basic research. Until last year, The New England Journal of monitoring and managing conflicts of inter- That’s good news for Stossel. If the current Medicine tried to bar researchers from pen- est is inadequate. Not surprisingly, some want focus on disclosure continues,“we’re going to ning editorials or review articles if they had a less regulation, and complain that the array of become a police state,” Stossel says. “There’s financial interest in the topic. But the journal policies is an overreaction to isolated cases. nothing wrong with disclosure, but I’m a bit changed that policy after editors were unable Susan Hellmann, medical director for the bemused by the tortuousness of it.” to find enough researchers without industry biotech giant Genentech, sat on the commit- ties to do the job. A review of MEDLINE cita- tee that debated the American Association of Tinker Ready writes for Nature Medicine tions from 1980 to 2002 found that about Medical Colleges’ new guidelines, but refused from Boston.

NATURE MEDICINE VOLUME 9 | NUMBER 11 | NOVEMBER 2003 1341