NEWS

p5 Abstinence all p7 Vietnam’s winner: p10 Acid test: Many the way: New US Menno de Jong fights with painful cluster chief for local scientists’ headaches are self slams . rights. medicating with LSD.

Biomarkers trump behavior in mental illness diagnosis

Here’s how doctors decide which mental or illness can be drastically different, so pinning scientists are examining panels or ‘pathways’ neurological disorder their troubled patients down the diagnosis is crucial. of biomarkers. Even within the umbrella of a suffer from: they ask questions like, “Are you Scientists are increasingly turning to single disease as defined clinically, there may be hearing voices?” and “Do you feel like people are biomarkers—such as genes or proteins in tissues, several subtypes that could be distinguished at a out to get you?” blood and body fluids—to distinguish between molecular level. Not all that different from how they used to do symptomatically indistinct illnesses. For example, “It’s very unlikely that a it about 100 years ago. “This is the holy grail of research,” says Karoly schizophrenic from one end of the spectrum New techniques are set to radically change that Mirnics, associate professor of medical psychiatry to a schizophrenic on the other end of the approach—and perhaps define new categories at Vanderbilt University. Using techniques that spectrum will show the exact same biomarkers,” within each disease—relying more on changes have only become available in the past few years, says Mirnics. in physiology than in behavior. scientists are looking at the brain, serum and In a study published in August, Bahn’s group “Now we’re at the opposite end of the spinal fluid and asking which combinations of also found that treating schizophrenics who spectrum where we can take an unbiased look,” genes or proteins might be expressed differently had had only one psychotic episode—but not says Stephen Glatt, a psychiatric geneticist at the in these disorders. more than one—corrected abnormal patterns State University of New York in Syracuse. The field is still far from ready for the clinic, in the expression of some metabolites, including Delusions, hallucinations, disorganized but holds great promise: markers could allow glucose, lactate and acetate (PLoS Med. 3, thinking and other psychotic symptoms can for earlier treatment and a better prognosis, e327), underscoring the importance of early result from schizophrenia, Alzheimer disease, ultimately enabling scientists to intervene even intervention. bipolar disorder, manic depression or . before the full-blown disease strikes. Biomarkers are also revealing unexpected Even diabetes and syphilis can induce forms of In one study published in November, insights into the biology of diseases. For psychosis. researchers tested spinal fluid from patients at example, using gene chips, one team found The answers to doctors’ questions can help the first onset of schizophrenia. They found that some pathways involved in energy and whittle down the categories somewhat, but it’s higher levels of a small protein derived from the metabolism are affected in individuals with far from a perfect science. Less than a third of protein VGF, known to be important for energy schizophrenia—which is consistent with individuals with these disorders respond to metabolism, and lower levels of the protein Bahn’s finding (Proc. Natl. Acad. Sci. USA 102, medications, most likely because they are being transthyretin compared with healthy controls. 15533–15538; 2005). The role of metabolism, treated for the wrong one. The treatment for each Post-mortem tissues of schizophrenic brains says Glatt, lead researcher of that study, “could showed that same trend be something that we are not yet even thinking (PLoS Med. 3, e428). about.” Samples from individuals There are important caveats, however. with Alzheimer disease Genetics could account for 50% or fewer of and obsessive-compulsive schizophrenia cases, for instance. Shifts in the disorder did not show those expression of proteins that respond to external differences, but those from variables may be a more reliable predictor in individuals with depression those cases. did. Many of the techniques also lack the sensitivity “This is not really necessary to detect minute traces of molecules. surprising because people Scientists will also need to monitor individuals who have a family history over time, correcting for confounding factors of schizophrenia are also such as the effects of previous treatment, much, much more likely to nutrition and smoking as well as drug and grow up with depression alcohol abuse. or other forms of mental The most challenging aspect might yet turn illness,” says Sabine Bahn, out to be redefining a 100-year-old classification Brain teasers: Doctors director of the Cambridge system. “That will be a major upheaval,” Bahn struggle to distinguish Centre for Neuropsychiatric says. “There may be problems in implementing mental illnesses based Research. them because it would change our entire way of on symptoms alone. To drill down to trends thinking.” unique to a single disease, Amanda Leigh Haag, Denver

NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 3 NEWS

Alternative medicine loses its champion

Granting credibility to studies on alternative complementary and —, and medicine research enterprise that the like—is hard enough at the best of times. The is the model for the world,” he said US National Institutes of Health (NIH) is about in an emailed comment. to find out how much tougher it can get with the The center’s budget has grown from loss of Stephen Straus, who has for seven years $50 million in 1999 to nearly $123 million in overseen that research. 2006. Including projects with other institutes, Citing health reasons, Straus in November alternative medicine research in 2004 accounted announced his resignation as director of the for $305 million in NIH funds. NIH’s National Center for Complementary and Straus has also garnered plaudits as a bridge- Alternative Medicine. He is to take on a role as builder between alternative therapists and senior adviser to NIH director . mainstream biomedical scientists. The NIH has set up a committee to find a “There was great distrust in both communities replacement, but filling Straus’ shoes won’t be at the beginning of the adventure,” says easy. He achieved what few thought possible when General Hospital researcher Bruce he took the job in 1999: a modicum of respect Rosen, who has a grant to study the effects of for the center from scientists who normally have acupuncture on the brain using neuroimaging. Fringe loss: Stephen Straus (inset) has resigned as director of the US National Center for little patience for alternative remedies. “It’s clear [Straus] was really able to pull them Complementary and Alternative Medicine. Even Harold Varmus, who was the NIH together.” director in 1999, initially opposed the center’s Nonetheless, many scientists continue to view “misinformed.” He noted that nearly two-thirds creation. But when Congress ignored him and the center as conferring money and respectability of Americans report using alternative therapies. elevated the NIH’s Office of Alternative Medicine, on nostrums that deserve neither. In July Arthur “The public is using [these] without proof of created in 1992, from second-tier status to a Grollman, a clinical pharmacologist at the State efficacy or safety, which is the very reason that center with all the powers and prerogatives of University of New York at Stony Brook, and a [this] research is so important.” other NIH institutes, Varmus hired Straus, a colleague published a commentary chastising Grollman is unconvinced. The center virologist and immunologist, to lead the center. the center for funding proposals “of dubious spends millions of dollars on clinical trials of “Steve has a high degree of scientific acumen merit,” and calling for an Institute of Medicine questionable alternative remedies such as shark and he brought real science to the conduct of the committee to evaluate its charter and research cartilage, he says. “We do not believe this is center,” Varmus says. portfolio (Science 313, 301–304). justified when at the same time they are funding Straus doesn’t shy away from that Writing in the same issue of Science, Straus NIH grants at distressingly low levels.” characterization. “We and NIH built a shot back that many criticisms of his institute are Meredith Wadman, Washington DC

Europe’s sweeping chemical law puts medicines in peril The European Union is set to require extensive need to be registered within 18 months of the whether all the chemicals we use will still testing of nearly every chemical used in regulation's enactment. be on the market,” says Michael Laub, a manufacturing. The rules could bring many The reporting requirements and high communications officer at Denmark-based medicines on the market up for reapproval, but registration costs may force manufacturers to NovoNordisk. few companies are prepared to deal with the withdraw their chemicals from the market, says Though drugs exported to Europe fallout. Dirk Frenzel, a spokesman for the Germany- won't need to be registered, approximately Known as REACH—the framework for the based drugmaker Bayer. 80% of ingredients in US-made drugs are Registration, Evaluation and Authorization Pharmaceutical companies will then have imported—many from Europe. Drug makers of Chemicals—the rules require companies to to find new suppliers, or substitute chemicals in the US appear less prepared than their provide safety and handling information on for those taken off the market. Any new European counterparts. every chemical they make. That information is formulations will need to be resubmitted for “We haven't really thought about this,” not available for more than 90% of chemicals approval, which could take months. says Mark Grayson, a spokesman for the used. “There will be bumps,” says Guy Villax, chief Pharmaceutical Manufacturers of America, Although the regulations, which go into executive officer of Hovione, a Portugal-based the industry's trade organization. effect April 2007, have been eight years in the manufacturer of drug ingredients. Attempts by the US government and the making, “companies are only waking up about There are no estimates of the rules’ chemical industry to fight the rules have [the rules],” says Steffen Erler, a consultant for potential impact, but pharmaceutical giant slowed down the preparations even further, REACHReady, a UK-based industry group that AstraZeneca says at least two of its drugs may says Darryl Ditz, a senior policy advisor at the gives advice on meeting the requirements. need reapproval. Other companies say they're Center for International Environmental Law, The active ingredients in drugs are largely preparing for the rules, but decline to specify a Washington DC–based think tank. “The exempt from the rules, but other materials whether individual drugs could be threatened. government and US trade associations are used in drug manufacturing—such as solvents, “We're identifying all key raw materials and behind the curve.” reagents, cleaners and drug precursors—will contacting the suppliers. We need to find out Brandon Keim, New York

4 VOLUME 12 | NUMBER 1 | JANUARY 2006 NATURE MEDICINE NEWS

Abstinence activist to head US family planning

“Premarital sex is really modern germ secretary for the DHHS, declared in a written warfare,” read the PowerPoint slide presented at statement. “[He] has developed extensive first- a 2003 abstinence conference by Eric Keroack. hand knowledge of the needs of young pregnant Considering the source, this wasn’t surprising. women and teen parents and has almost 20 years’ Keroack, a Boston-area gynecologist and ardent experience in meeting those needs,” Agwunobi opponent, had long been making the said. rounds on the right-to-life circuit, where he The DHHS has refused to make Keroack promotes the theory—based partly on research available for interviews. “We usually let folks in prairie voles—that premarital sex depletes the get their feet on the ground and get settled in hormone oxytocin, impairing young people’s for a time in their position before putting them ability to form the social bonds needed for a before the media,” explained a spokesman. stable marriage. Never mind that Elias Zerhouni was quoted What is surprising is Keroack’s appointment in in the media on the explosive issue of stem November to become the Bush administration’s cells before he was sworn in as director of the top family-planning official. National Institutes of Health, which falls under As deputy assistant secretary of population DHHS purview. Or that Surgeon General affairs at the US Department of Health and nominee Richard Carmona discussed AIDS and Eric Keroack, the Human Services (DHHS), Keroack will oversee a terrorism publicly with the Senate committee new US family $283 million budget that funds the government’s poised to pass muster on his nomination. planning chief, only program dedicated to family planning. Keroack, 46, a Tufts Medical School graduate, advocates chastity. Called Title X, it has, since 1970, been providing was until recently medical director of A Woman’s

counseling, contraceptives, abortion referrals Concern, a network of six pregnancy counseling News/KRT Mercury Jose Louie/San Eugene and screening services—from Pap smears to centers in eastern Massachusetts. The centers HIV tests—to poor women. It serves about 5 oppose contraception and advise abstinence His appointment has outraged reproductive million women each year. until marriage. They do provide ultrasound rights groups. “Dr. Keroack is a highly qualified and well- scanning, which Keroack has used to dissuade “This country needs someone in charge of respected physician,” John Agwunobi, assistant pregnant women from having . the nation’s family planning programs who is an advocate for family planning,” says Elizabeth Toledo, vice president of communications for Australia embraces cloning research the Planned Parenthood Federation of America, which runs 860 health centers nationwide. “Dr. Australian scientists will be able to apply for system where party-line voting is the norm. Keroack’s appointment threatens the health a license to undertake therapeutic cloning Studies will be administered by the of the nation’s poorest women and we think it research from mid-2007. National Health and Medical Research should be withdrawn immediately.” On 6 December, Australia’s House of Council, the main source of funding for After the elections in November, when Representatives voted 82 to 62 in favor medical research in Australia. Licensing Democrats took control of the Congress, “We of a bill legalizing the creation of human guidelines and procedures are expected to would have hoped that the Bush administration’s embryos by somatic cell nuclear transfer and be finalized by July 2007, when at least five practice of choosing ideology over competence the harvesting of embryonic stem cells for research institutions are expected to submit would have been over,” adds Sean Tipton, research purposes. applications. a spokesman for the American Society for The new law is a welcome move for The law allows for the creation of human Reproductive Medicine, which represents 8,500 Australian scientists, some of whom were embryos other than by fertilization of a medical professionals. rumored to be looking offshore for more human egg by a human sperm, stipulating These groups and 24 others signed a 20 supportive government regulations. In their that these embryos must not be implanted November letter to DHHS Secretary Michael campaign for the reforms, scientists avoided into a woman and must be destroyed after Leavitt, demanding Keroack’s ouster. the term ‘therapeutic cloning’ to prevent any 14 days. The normally staid American College of confusion with reproductive cloning. A previous version also allowed for the Obstetricians and Gynecologists also weighed “We used the term ‘somatic cell nuclear creation of chimeras—created by inserting in with its own letter, saying, “We urge this transfer’ so that we could then describe human DNA into enucleated animal individual to advocate a wide range of family specifically what the technique was,” says eggs—but a Senate amendment outlawed planning policies.” Stephen Livesey, chief executive officer of the such research. Predictably, Keroack’s appointment has Australian Stem Cell Centre. “I found that if The bill mandates licenses for therapeutic pleased the constituency at which it was aimed. you started off with ‘therapeutic cloning’, you cloning, with a penalty of imprisonment “We think he’s a good choice,” says Wendy couldn’t get to the explanation.” for up to ten years for creating an embryo Wright, president of Concerned Women for The bill passed the Senate in November without a license and up to five years for America, an activist group whose mission is “to by the finest margin—34 to 32. working with such an embryo without a protect and promote Biblical values among all Parliamentarians in both chambers were license. citizens.” allowed a conscience vote, a rare freedom in a Simon Grose, Canberra Meredith Wadman, Washington DC

NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 5 NEWS

Practical malaria tests promise results in remote regions

You’re in a small village in Mali. You have a fever, Health Organization. headaches and nausea, classic signs of malaria. Rapid tests—usually dipsticks The most sensible thing would be for a that work like pregnancy tests— technician at a clinic to prick your finger and detect proteins that are produced examine the blood under a microscope. More by malaria parasites. The tests are likely, they’ll simply assume you have malaria simple and effective, and about 40 and hand you the medicines. million of them were made in 2006. Most healthcare workers in remote African But their quality is inconsistent, communities are ill-equipped, lacking the and manufacturing flaws, such training or tools necessary to make sophisticated as differences in the quantity of diagnoses. But indiscriminately treating all reagents and components, affect infections with malaria drugs is a sure way to their sensitivity (Nat. Rev. Microbiol. exacerbate resistance to valuable drugs. 4, 682–695; 2006). Images Lauro/Getty Di Marco Confronted with this problem, scientists are The most accurate blood test scrambling to develop diagnostic tools that detects the parasite’s nucleic acids. But the need to decide how best to use the tests there. are practical and easy to use in even the most technique is expensive and samples have to be The saliva- and urine-based test, which must resource-poor settings. sent to trained technicians in far-off labs. also be sent to labs, may prove more effective for In November, Johns Hopkins University FIND’s new test, called loop-mediated research. In many countries where needles are scientists reported the first successful screening isothermal amplification, or LAMP, is an taboo and AIDS is rampant, it can be difficult to technique based on DNA from saliva or urine inexpensive DNA test that any health worker convince healthy people to undergo a blood test. samples, rather than from blood. Researchers with a heating source and basic lab skills and A less invasive technique would allow researchers from the Geneva-based Foundation for materials could use. The test will be ready for to collect samples, for instance to track emerging Innovative New Diagnostics (FIND) have also manufacturing in mid-2008, says Mark Perkins, drug resistance in a community. devised a DNA-based test that, unlike other chief scientific officer of FIND. The test needs to be validated, however. molecular tests, does not have to be sent away But highly sensitive assays such as LAMP Malaria parasites aren’t normally found in to a lab. can also detect parasites in people who are urine or saliva, so the researchers don’t know “Bedside tests that can detect DNA and are just carriers of the parasite and do not require why they found the traces of parasite DNA in quite cheap are the potential future,” says David treatment. In endemic regions there may be those samples. Bell, a malaria diagnostics expert at the World many of these individuals, and scientists will Emily Waltz, New York

Companies balk at California’s patent rules for stem cell research California is set to adopt rules that will are expected to follow later in 2007. president of the California Healthcare guarantee public return on its state-funded Nonprofits and commercial ventures will Institute, which represents more than stem cell research, requiring grantees to share both be required to notify the California 250 biomedical companies and research patented materials, send a portion of revenues Institute for Regenerative Medicine, institutions. to the state and guarantee cheap treatments to established by the state to oversee grants, Mary Maxon, deputy vice chair of the Californians. when their state-funded research results in California Institute for Regenerative But the rules, which could set the tone for a publication or patent and to freely share Medicine, says companies shouldn’t worry other state-funded science programs, are research materials—cell lines, compounds or and that specific access proposals will be too restrictive and might put off companies, DNA sequence information—they develop. judged on an individual basis. “You sign a industry representatives warn. The state will also receive a share of the contract saying you'll provide these things, The regulations are more stringent than revenues from licensing agreements and sales but we won't tell you how to do it. We don't the federal Bayh-Dole Act, which doesn't of therapies developed. want you to go out of business,” she says. mandate revenue sharing or treatment access. Although the biomedical industry has Reynolds says the industry is also worried “The stem cell program in California questioned whether some of the material- about the precedent California could set. launched two experiments. The obvious one sharing policies are feasible, it has reserved Nine other states fund or plan to fund stem is the research being done, and the other is its harshest criticisms for rules on discounted cell research, and their intellectual property an enormous policy experiment,” says Jesse pricing and broad access. approaches vary vastly. Connecticut, for Reynolds, project director on biotechnology Under the proposed rules, companies example, receives royalties on commercial accountability at the Oakland-based must make treatments developed using state- developments but other terms are negotiable. nonprofit Center for Genetics and Society. funded research accessible to Californians Illinois’s plan resembles California's but the The state is finalizing patent rules for who don't have health insurance and at a specifics have not yet been determined. nonprofit grantees and the companies that discount through the state’s healthcare plans. “If California's policy works,” Reynolds work with them, and will begin enforcing Companies may decide not to license says, “then when other policies are revisited, it them once the first grants are awarded in patents if they have to provide deep discounts could set a precedent.” February 2007. Requirements for companies on their products, says David Gollaher, Brandon Keim, New York

6 VOLUME 12 | NUMBER 1 | JANUARY 2006 NATURE MEDICINE PROFILE Menno de Jong

He is so soft-spoken you may have to strain to catch his words, calls for all researchers to receive credit for their contributions—something but on the topic of recognition for scientists in resource-poor de Jong is thrilled about. regions, Menno de Jong is ready for a fistfight. “This whole initiative should be more than another old boys’ club of scientists who have more access,” he says. Without the help of local scientists, he adds, an outbreak might not be recognized until it is out of control. The first victim was an eight-year-old girl whose pet duck had died. On that front, de Jong found great support from Peiris, one of the 72 It was December 2003 in Vietnam and the fear of a bird flu pandemic researchers who signed the initiative. “It’s in everyone’s interest if these front was looming. lines are strengthened,” Peiris says. The Vietnamese government flailed initially, uncertain of the extent of On the ground in Vietnam, de Jong is doing his part to build defenses. the outbreak or how to combat it. Over the next few years, the country He’s training local scientists to take over the lab in the next two would see 93 of the more than 250 cases of the disease worldwide. years and helping to build laboratory capacity in 11 hospitals in Indonesia, But Vietnam has had one advantage that has helped it avert disaster: Thailand and Vietnam through the Southeast Asian Clinical Menno de Jong, a virologist who had joined the Hospital for Tropical Research Network. Diseases in Ho Chi Minh City just three months before the young girl Bringing together scientists from these countries is no easy task—but de was brought in. Jong is up to it, says Jeremy Farrar, de Jong’s superior at the hospital. “Not Faced with the crisis, de Jong’s reaction was “to stand firmly with both many have that extra personality on top of being a great clinical scientist,” feet on the ground and make decisions,” as he puts it. Although he had says Farrar. “It’s a colorful, warm relationship that Menno has within the never worked on bird flu before, he knew how to set up a state-of-the-art unit and with other units.” virology lab while scrambling to diagnose the disease. It was in the early 1990s, when de Jong visited his girlfriend Constance “There were some sleepless nights and everybody in the lab was working Schultsz—now his wife—who was working at the International Center for crazy hours,” de Jong recalls. “The whole world was watching.” Diarrheal Disease Research in Bangladesh, that he decided to work in the Using samples from the first victim as a positive control, the team region. “This was a great research clinic with local presence, but doing really, developed sensitive diagnostics. They also polished their protocols and, really good research,” de Jong recalls. Both were “so amazed” by the model with future analysis in mind, took twice the number of samples needed that they agreed to finish their degrees and work in a similar place. for diagnosis. Those samples provided some of the first answers to why “We didn’t want to go to a country like Cambodia or Vietnam as junior the virus is so deadly, how to detect it and how the disease might spread doctors, sort of adventurers,” says de Jong. “We came to Vietnam when we in humans. could add something.” In collaboration with Hong Kong’s Malik Peiris, de Jong and his Even as a graduate student at the University of Amsterdam studying team reported that the H5N1 bird flu strain prefers to grow in the lower HIV, de Jong was collaborative, seeking experts in other disciplines, such respiratory tract and kills much the same way the Spanish flu pandemic as mathematical modeling, to improve the team’s approach. of 1918 did—high levels of the virus trigger an intense immune response, “He very much broadened the scope of what we were doing,” says which can lead to lung failure (Nat. Med. 12, 1203–1207; 2006). Joep Lange, director of the National AIDS Therapy Evaluation Centre in “[de Jong] has really made some of the most valuable contributions to Amsterdam and de Jong’s advisor. the understanding of the disease in people,” says Fred Hayden of the World In those days, de Jong was so focused on his research that daily chores Health Organization’s Global Influenza Program. “He’s a very rigorous such as cleaning his desk often fell to the wayside. “He would have these thinker, creative in his approaches, and a real problem solver.” fungal cultures coming out of his cups going down the leg of the table, and In person, de Jong is quiet and unassuming, but quick to smile. At a bird it wouldn’t bother him in the least,” Lange says. flu meeting in October at the New York Academy of Sciences, he spoke so It didn’t bother de Jong’s many admirers either. “He had a whole gallery softly, even with a microphone, that audience members leaned forward in of female suitors in those days,” Lange recalls. “But he chose Constance.” unison to better hear him. The family plans to stay in Vietnam for another three years, until That image is hard to reconcile with the feistiness that surfaces when the oldest of their three children turns 12. In the meantime, the he speaks about recognition for local scientists’ contributions to bird flu urgency over bird flu has diminished somewhat, allowing de research. It’s the only issue, he says, that might cause him to “get into a Jong to shift his focus to other research. He’s building a database fistfight.” of the viruses circulating in the region and studying encephalitis, Over the past two years, the World Health Organization has come under acute respiratory illness and fire for allowing only scientists affiliated with the organization to access bird emerging infections. “Local scientists should flu data. At the same time, some scientists have criticized governments and But he continues to keep become more equal teams for keeping their data private, in part to ensure that local researchers an eye on bird flu. receive credit for their work. Whether H5N1 disappears partners in science.” “If you really want to open it up and get governments and local scientists or becomes a pandemic, to make their sequences and viruses available,” says de Jong, “you should de Jong says he hopes the scientific community has make sure that those local scientists become more equal partners in the learned from the situation. “To have capacity in a science.” country, even simply to diagnose disease by more In the end, the scientific community decided in August to set up the modern methods,” he says, “that’s the only guarantee Global Initiative on Sharing Avian Influenza Data to rapidly release genetic that you’ll early on recognize a new SARS or a new sequences of emerging strains and allow researchers to collaboratively pandemic threat.” analyze and publish findings (Nature 442, 981; 2006). The initiative also Alisa Opar, New York

NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 7 NEWS IN BRIEF

16 Nov 17 Nov 19 Nov Standard oral polio , which The FDA lifts a 14-year ban on silicone Two research teams independently contain three strains of the poliovirus, breast implants (Nat. Med. 9, 251), but identify stem cells that proliferate are less effective than single-strain requires manufacturers to conduct long- indefinitely and fuel metastasis vaccines for the Indian provinces of term health studies and to tell recipients in colon tumors, suggesting a Uttar Pradesh and Bihar, where polio that they will probably need additional target for future therapies (Nature skyrocketed in 2006, UK researchers surgery to remove or replace the doi:10.1038/nature05384; Nature report (Science 314, 1150–1153). devices. doi:10.1038/nature05372).

30 Nov 29 Nov 29 Nov The William J. Clinton More than a third of nearly 600 Institutional Review Strains of influenza that circulated Foundation negotiates Board members have commercial ties to drug in the early- to mid-20th century are with four companies to companies, and some members, violating federal law, preserved in thawing Siberian lakes provide low-cost drugs voted on studies despite having conflicts of interest, and could cause new epidemics when to more than 100,000 according to a survey. A second study of 253 individuals picked up by migratory birds, scientists HIV-positive children in with cancer suggested that more than 90% ignore the warn (J. Virol. 24, 12229–12235). the developing world. researchers’ financial conflicts, believing that the system would take care of them (N. Engl. J. Med. 355, 2321– 2329, N. Engl. J. Med. 355, 2330–2337).

30 Nov 30 Nov 1 Dec HIV-positive individuals who cycle on and Fearing a brain drain and hoping to spur HIV-positive individuals off antiretroviral drugs are nearly three economic growth, the European Commission will be allowed to enter times more likely to die than patients on proposes to spend €54 billion over the next the US for up to 60 continuous therapy, and nearly twice as likely seven years on science—a yearly jump of days, officials announce, to develop heart, kidney and lung diseases, a about 40%—but biomedical research overturning a ban in study of more than 5,000 individuals in 33 will continue to be funded at place since 1987. countries concludes (N. Engl. J. Med. 355, roughly the current rate of 2283–2296). €1 billion per year.

8 Dec 8 Dec 8 Dec NIH researcher Trey Sunderland Malaria and HIV Ebola may have killed more than 5,000 great pleads guilty to accepting exacerbate each other by apes in the northwest Congo and without approval $285,000 weakening individuals’ of the disease between from Pfizer in exchange for defenses, fueling the spread apes might have his expertise and the institute’s of the diseases through helped spread the tissue samples, concluding the sub-Saharan Africa, US disease, scientists first financial conflict–related scientists report (Science say (Science 5805, prosecution of an NIH scientist 5805, 1603–1606). 1564). since 1991.

8 Dec 9 Dec 11 Dec 12 Dec Members of an FDA advisory Using a printer filled with adult The FDA proposes to Male circumcision halves panel are split on the risks stem cells instead of ink, muscle make drugs still in phase 1 the chance of HIV infection, posed by drug-coated stents, and bone cells can be ‘printed’ testing available to seriously trials in Kenya and but recommend that the agency on a gel scaffold, a technique ill people with no other Uganda suggest, warn users that the devices are that could someday produce treatment options. confirming only safe for limited use in joints or organs, researchers previous studies. relatively healthy people. report at the American Society for Cell Biology’s annual meeting.

8 VOLUME 11 | NUMBER 8 | AUGUST 2005 NATURE MEDICINE NEWS IN BRIEF

21 Nov 22 Nov 22 Nov Global HIV infection rates remain stable The US Environmental Protection Agency Heart muscles and blood vessels are not at nearly 40 million but are rising rapidly announces that products containing derived from many different progenitor in Eastern Europe and Central Asia, says a silver nanoparticles—used in such items cells, as is currently thought, but from UNAIDS/World Health Organization report. as air fresheners and shoe liners to kill a single type of stem cell, Harvard China saw a 30% rise in new cases for 2006 bacteria—must be proven to pose no University researchers report (Cell through October compared with all of 2005. human or environmental health risks. 10.1016/j.cell.2006.10.029).

27 Nov 23 Nov 23 Nov US President Bush signs Representatives from 56 Islamic At least 12% of human genes have the Animal Enterprise nations agree to establish the Islamic duplicate or deleted DNA sequences Terrorism Act, expanding Ethical Network on Science and that vary from person to person, government powers to Technology, a group of scientists suggesting that the emphasis wiretap and prosecute and scholars that would assess the of medical research on single- animal rights activists who ethics of new technologies. nucleotide polymorphisms is inadequate, threaten researchers. researchers say (Nature 444, 444–454).

2 Dec 3 Dec 4 Dec 4 Dec Pfizer abandons torcetrapib, Reversing its previous position that The World Health Organization Scientists launch the expected to be the first of HIV-positive people should treat launches the Malaria Malaria Atlas Project, many drugs that raise good themselves by eating garlic and Technology Roadmap, meant to which uses data from (HDL) cholesterol, after beetroot, South Africa’s government develop and test vaccines against surveys, censuses and learning that 82 people died promises to halve infection rates within Plasmodium falciparum, satellites to show while receiving the drug five years by training medical workers the deadliest of the four where treatments compared with 51 deaths and improving drug distribution. parasites that cause and interventions in the control group of a malaria. are needed (PLoS clinical trial. Med. 3, e473).

7 Dec 6 Dec 6 Dec 5 Dec DNA sequencing of HIV Cell phone use doesn’t University of biolo- The US Senate votes to establish subtypes suggests that increase cancer risks, gist R. Michael Roberts says a the Biomedical Advanced Libyan children were infected Danish scientists report, postdoctoral student digitally Research and Development with the virus before the six based on the cancer altered images in a February Authority, which would foreign medical workers accused rates of 420,000 cell paper to suggest that not all coordinate the development of of infecting them arrived in phone users (J. Natl. cells in an early-stage embryo vaccines and treatments against the country, scientists report Cancer Inst. 23, are identical (Science 311, potential bioterrorism agents. (Nature doi:10.1038/444836a, 1707–1713). 992–996). Nature 444, 658–659).

13 Dec 14 Dec 15 Dec 18 Dec An FDA advisory panel Breast cancer diagnoses The FDA approves the A Libyan court sentences to death six recommends that antidepressant fell by seven percent in painkiller Celebrex foreign medical workers accused of labels should warn against 2003, perhaps due to the (celecoxib) for treating infecting children with HIV. The verdict, suicide risk for all those under drop in previous years of severely arthritic children, reached without admitting evidence 25, not just children and women taking hormone but mandates further showing that the infections predated adolescents, based on a review replacements, US researchers research on the drug’s long- the workers’ arrival, will be reviewed of trial data from nearly announce at the San term safety. by Libya’s Supreme Court and Judicial 100,000 individuals. Antonio Breast Cancer Board (Nature doi:10.1038/news061218- Symposium. 3, Nature 444, 658-659).

NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 9 NEWS FEATURE Cluster busters

Ignored by mainstream medicine people who suffer bizarrely painful headaches are helping to test hallucinogenic drugs as a cure. Arran Frood talks to these citizen scientists.

It began the same way, every day at 3 p.m. First young children, had never even considered if untreated or if the medication fails. came the dull ache, then a sharp pain behind the taking mind-expanding drugs. But after trying The intense pain derives from stimulation right eye followed by debilitating agony. The only a veritable medicine chest of legal remedies, none of the trigeminal nerve, which is responsible difference was how long it would last—anywhere of which are designed to treat cluster headaches for sensation in the face. But the problem is not from 45 minutes to three hours on a bad day. and none of which worked, May was desperate local to the nerve, eye or face—it lies within the “It’s a hundred times worse than the worst pain for relief. brain. you’ve ever felt, but pulsating and persistent, like Like May, many individuals who suffer from Brain-imaging studies indicate the someone is trying to pull your eye out,” says Peter cluster headaches have found that the illegal hypothalamus as the area of pathogenesis, unlike May, who has suffered from cluster headaches drugs are their only choice. Neglected by the migraines where the brain stem is activated. Still, since 1999. scientific community and forced underground most prescribed medicines are those given for The headaches are so horrible that each year by the law, they have turned to the Internet to migraines, antidepressants or calcium channel people who endure them take their own lives, secretly find, research, promote and even sell the blockers designed to reduce blood pressure. earning the condition the gruesome moniker of treatments that work. There are no drugs specifically for cluster ‘suicide headaches’. In a classic example of ‘citizen science’, they headaches. “Really, you wouldn’t wish it on your worst have even roped in scientists to validate what Some migraine drugs such as sumatriptan enemy,” May says. “Once I was looking at a their experiences have shown and plan clinical (Imigran, Imitrex) are effective when inhaled pneumatic drill… wondering if drilling into trials and other research to take the treatments or injected, but May began to notice a worrying my head would relieve the pain. That’s when I forward. “I don’t believe that even any of the big increase in the frequency of his daily attacks after realized that things weren’t right and I had to get pharma companies would have got any further taking sumatriptan. it sorted somehow.” in the same period of time,” says May. The best abortive treatment isn’t even a drug. On the Internet, where many like May Inhaling pure oxygen works for about 80% of had begun to congregate, news had gained Periodic pain cluster headache sufferers, although the attack momentum that hallucinogenic drugs such as Often misdiagnosed as migraines, cluster must be caught within five minutes. Access to the LSD and psilocybin, the active ingredient in headaches were noted as early as 1745 by Gerhard bulky cylinder also isn’t always possible. ‘magic’ mushrooms, could provide sweet relief van Swieten, personal physician to the Austrian Frustrated with the poor functionality of from the headaches. Empress Maria Theresa. The doctor observed existing equipment, lifelong chronic sufferer Ben May, a respectable middle-aged man with that a healthy, robust man of middle age suffered Khan invented the ‘Clustermasx’ which, Khan from a “troublesome pain which came on every says, uses less oxygen, is more effective and can day at the same hour at the same spot above the abort an attack in five minutes. One reviewer of orbit of the left eye.” The man, the doctor said, his method raved that “a layer of pain is shaved “felt as if his eye was slowly forced out of its orbit off with every inhalation.”

Gary Carlson Gary with so much pain that he nearly went mad.” About one in five sufferers is resistant to all More than 250 years on, doctors know little approved treatments, including oxygen. May, more about the condition, if they have heard of who had transitioned to chronic attacks in it at all. 2002, feared he’d soon be one of them. Then he Cluster headaches are a type of neurovascular stumbled on to a flurry of excited activity on the headache affecting about 1 in every 1,000 people. popular website www.clusterheadaches.com. Their hallmark is the curious periodicity of attacks, which occur at the same time each day Magic mushrooms and in the same spot, usually in otherwise healthy Typical posts on the website raved about middle-aged men. Only one in five sufferers is a mushrooms of the genus Psilocybe, which have woman. been used for centuries by traditional healers and The episodic forms of the headache, which shamans to commune with the spirit world. account for about 90% of the cases, are nothing Wary of experimenting with illegal drugs, May short of bizarre: one month of headaches in the researched them for six months before yielding in spring and one in the fall is typical. This semi- late 2002. The results were everything he’d hoped annual regularity based around the equinoxes for. “It worked immediately. I had ten pain-free defies explanation, but at least provides some days and I thought, ‘I’m cured’,” he says. The intense pain of cluster respite from the pain. Through trial and error, May discovered that a headaches derives from the The remaining 10% of sufferers live with the small dose—too small to cause hallucinations— trigeminal nerve. chronic form and are subjected to up to eight of the dried mushrooms taken every one or two attacks a day, each of which can last three hours months was enough to keep his daily attacks

10 VOLUME 12 | NUMBER 1 | JANUARY 2006 NATURE MEDICINE NEWS FEATURE

with rare disorders can band A controversial procedure called deep-brain together to become a more cohesive stimulation, used to treat Parkinson disease, force to advocate for themselves,” is another option. In that technique, doctors says Halpern, who knows of two implant electrodes in the hypothalamus to people at his institution who have stimulate an area associated with the attacks. The committed suicide because of cluster exact mechanism of action is unknown and may headaches. “I feel like we have a moral be complex, but the high-frequency stimulation obligation to pursue this because may inhibit or modulate the nerve cells that treatment-resistant people are killing initiate the pain. themselves,” he says. Massimo Leone of Milan-based Istituto Nazionale Neurologico Carlo Besta and his Citizen science team have treated 19 chronic, treatment-resistant Halpern and his colleague Andrew patients. “About 70% show a very good clinical Sewell began collecting the medical response and are mainly pain free,” says Leone, records of those who were using adding that some individuals seem to respond hallucinogens to relieve cluster better to conventional medicines after the headaches, and set up interviews procedure. and online surveys for a retrospective Unfortunately, some individuals appear analysis. to become tolerant to the treatment. The Their results show that psilocybin technique is not without risk, either. Of six cases is better at aborting acute attacks at a different institution, one individual died of than either oxygen or sumatriptan, a brain hemorrhage after the operation. “At this and LSD and psilocybin are both stage the surgery is the last resort,” says Leone. better at triggering and extending In another technique, doctors implant remission than are standard drugs electrodes under the scalp to stimulate the Psychedelic cure: Many with cluster headaches have (Neurology 66, 1920–1922; 2006). occipital nerve, which runs from deep inside the turned to LSD and magic mushrooms. The researchers are planning clinical brain to the spine, to override the pain. “Occipital trials using LSD and psilocybin. nerve stimulation is going to open up a whole at bay. If a headache did force its way through, The hallucinogens may be effective new chapter in treating medically intractable small doses of mushroom tucked under the because they are similar in structure to the headache,” says Peter Goadsby, an expert in tongue could sometimes abort an attack in just neurotransmitter serotonin and each affects a cluster headaches at the Institute of Neurology, 15 minutes. different suite of serotonin receptors in the brain. University College London. As the clusterheads collated their experiences, LSD and psilocybin, for example, both bind to His results, due to be published in The Lancet, chronic sufferer Bob Wold set up a new site, the same receptors as sumatriptan, but also bind suggest that the technique does not work for www.clusterbusters.com, specifically to spread to serotonin receptors that may be involved in everyone but the benefits accrue over time. the message about the psychedelic drugs. “The the circadian response to light, which suggests an Goadsby says a controlled study of first order of business is to let people know this effect on the biological clock to break the cluster hallucinogens is needed, as are follow-ups of life-changing treatment is out there,” says Wold. cycle. people already using them. “Only with that data “The second is to do what needs to be done to Although these drugs can be dangerous, could you make a sensible comparison between get clinical trials underway.” there are models in place for their distribution. intervention methods,” he says. Anecdotal evidence is all very well, but only a For instance, the infamous drug thalidomide In the meantime, the clusterheads are few were brave enough to try the hallucinogens. is prescribed for treatment-resistant stomach continuing with their attempts at citizen science. Most others were sceptical, or scared of breaking ulcers and for leprosy, but its makers have May and others began using seeds that contain the law. patented a system to ensure it never reaches a lysergic acid amide, a less potent precursor to One group, the evocatively named OUCH, for pregnant woman. Xyrem, a drug prescribed LSD, when the UK banned the sale of magic Organisation for the Understanding of Cluster for narcolepsy, contains as its active ingredient mushrooms in 2005. The seeds seem to work too, Headaches, banned discussion of the alternative gamma-hydroxybutyrate or GHB, a date-rape but data on correct dosage are sparse, so users treatments from their message boards. The drug that appeared in the 1990s. are saving batches of seeds from different plant highly charged arguments quickly devolved A national registry to monitor the drugs’ use species for a rigorous chemical analysis. into personal attacks, eventually forcing the and distribution could minimize the risk of May says despite the legal risks his self- resignations of many of the group’s members. misuse, Halpern says. “If we can do that for GHB medication poses, it is less scary than brain It was clear that the community needed real and thalidomide, then I believe we can for LSD surgery, and he is determined to get the treatment scientists to give their results some credibility. and psilocybin.” validated by scientists. He also has more reason Most scientists they approached baulked at the than some others to find a treatment that tricky legal situation. Then they found John Last resort works—he is worried because the headaches are Halpern, assistant professor of psychiatry at Choosing a treatment can often come down thought to have a genetic component. Harvard Medical School, who had experienced to the best of the worst. Psychosis aside, LSD is “My biggest fear is that I might pass on the the bureaucratic quagmire of trying to work with known to affect the expression of at least seven condition to my children,” he says. “There’s hallucinogenic drugs. genes. And almost nothing is known about no way you could give them the alternative “It’s unbelievable that they came to me. It the long-term effects in humans of ingesting treatment.” shows the power of the Internet that people psilocybin, especially in small doses. Arran Frood is Nature’s web editor.

NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 11