Chelation-Therapy Heart Trial Draws Fire

IN FOCUS NEWS

stations across the Tibetan plateau and sur- rounding mountain ranges, at altitudes up to WHITE NOISE 6,000 metres, which will gather accurate snow The SPICE project aims to test the most advanced techniques for measuring snowfall at sites around the world. measurements across the region that could Sodankylä Caribou augment SPICE’s results. Voldai Creek Haukeliseter In the longer term, however, “there will Volga Bratt’s Lake Rikubetsu never be enough ground measurements Weissuhjoch Hala to cover an entire mountain”, says Michael CARE (Egbert) Gąsienicowa Boulder Lehning, a climate scientist at the Swiss Federal Joetsu Institute for Snow and Avalanche Research in Davos-Dorf, who is involved in the project. Results from SPICE will be used to calibrate airborne and satellite-based sensors, which use techniques such as microwave, radar and laser

SOURCE: CENTRE FOR ATMOSPHERIC RESEARCH EXPERIMENTS RESEARCH ATMOSPHERIC SOURCE: CENTRE FOR ranging to survey much larger areas. Mueller Hut “The idea is to push remote sensing to be Tapado Guthega accurate enough for use in mountains,” says Dam Lehning. “It’s still a long way off, but SPICE is a good starting point.” ■

ALTERNATIVE MEDICINE which can cost thousands of dollars per course. According to TACT, which the NCCAM co- funded along with the National Heart, Lung, and Blood Institute (NHLBI), the therapy Chelation-therapy shows signs of working. On 4 November at the annual meeting of the American Heart Asso- ciation in Los Angeles, California, trial lead- heart trial draws fire ers reported that 26% of patients who received infusions of disodium EDTA went on to suffer Critics not persuaded that metal-snaring treatment works. a heart attack, stroke or other heart problem, compared with 30% of patients on a placebo — BY EWEN CALLAWAY Administration has approved one salt, calcium a statistically significant difference. disodium EDTA, to treat lead poisoning. Many medical researchers were quick to ith millions of Americans regularly Proponents of chelation therapy for heart question the results. Perplexingly, the benefit using complementary medicines, disease initially speculated that EDTA could was observed only among participants with researchers usually applaud efforts also cleanse the blood of calcium ions, a com- diabetes, and 30% of participants dropped out Wto test and debunk folk treatments such as ponent of the atherosclerotic plaques that of the trial, undermining comparison between echinacea, a herbal supplement often deployed block blood vessels. But evidence against that the treatment and placebo. Critics also note against the common cold. But what if a trial hypothesis led them to suggest alternative that nearly two dozen trial co-investigators shows that an alternative therapy might work? mechanisms, for example that the molecule have been disciplined by state medical boards That is the case for a study funded by the captures other metals, preventing heart-dam- for infractions ranging from insurance fraud US National Center for Complementary aging inflammation. In spite of the uncertainty, to providing ineffective treatments. “They and Alternative Medicine (NCCAM), part the treatment is already big business: a 2007 US offer aromatherapy, crystal therapy and every of the National Institutes of Health (NIH) government survey estimated that, every year, imaginable wacky form of medicine. You can’t in Bethesda, Maryland. The trial hints that 110,000 Americans undergo chelation therapy, do high-quality research at sites like that,” says a fringe therapy intended to sop up metal Steven Nissen, a cardiologist at the Cleveland ions in the blood might reduce participants’ Clinic in Ohio. “We wasted $30 million and risk of heart attack. Critics are attacking 10 years on an unreliable study.” both the rigour of the study and the records He worries that the research will be used T. EVANS/SPL T. of some of its investigators, complicating the to support unapproved chelation therapies, NCCAM’s efforts to answer charges from some which have been linked to heart attacks and researchers that it funds quackery, and raising death. “Public harm is going to come out of questions about whether the centre’s US$128- this. People are going to get bilked out of a lot million annual budget is being spent wisely. of money. People are going to die.” The Trial to Assess Chelation Therapy Kimball Atwood, an anaesthesiologist at (TACT) was a 10-year, $31.6-million study Tufts University School of Medicine in Boston, involving 1,708 participants at 134 centres. It Massachusetts, and one of TACT’s most vocif- aimed to test whether weekly infusions of a salt erous critics, argues that the trial has been trou- of ethylenediaminetetraacetic acid (EDTA) can bled from the beginning. In a paper titled ‘Why lower the risk of repeat heart attacks. EDTA is the NIH Trial to Assess Chelation Therapy a chelating agent: the molecule is peppered (TACT) should be abandoned’ (K. C. Atwood with electron-rich nitrogen and oxygen atoms, The electron-rich oxygen (red) and nitrogen (dark et al. Medscape J. Med. 10, 115; 2008), he which can grab and hold onto positive metal blue) atoms in ethylenediaminetetraacetic acid claimed that trial proponents had mischarac- ions (see picture). The US Food and Drug can grab and hold onto positive metal ions (green). terized earlier studies of chelation therapy

by suggesting that their results were BIOTECHNOLOGY equivocal and necessitated a larger follow- up. Atwood says that the earlier studies in fact found that the treatment was ineffective at preventing heart attacks. Pig geneticists go In 2008, TACT was suspended after regu- lators learned that subjects were not being given calcium disodium EDTA, as implied on informed-consent forms — instead, they the whole hog were being infused with the slightly differ- ent salt disodium EDTA, for which the FDA had revoked approval. The trial resumed Genome will benefit farmers and medical researchers. after consent forms were reworded to include warnings, such as “death is a rare BY ALISON ABBOTT complication of EDTA infusions”. Josephine Briggs, director of the NCCAM, . J. Tabasco is something of a porcine declined to comment on TACT until the goddess at the University of Illinois, results are published in a journal. The prin- Urbana-Champaign, where her ruddy, cipal investigator, cardiologist Gervasio Ttaxidermied head looks down from the office Lamas of Mount Sinai Medical Center in wall of geneticist Lawrence Schook. Now she Miami Beach, Florida, says that the study’s has been immortalized in this week’s Nature1 — findings were a surprise and deserve follow- not by name, but by the letters of her DNA. ing up. He adds that the trial consent forms Scientists are salivating. For the past couple were approved by the NIH and multiple of decades they have been slowly teasing infor- institutional review boards. Gary Gibbons, mation from the pig genome, applying it to director of the NHLBI, says that his institute breed healthier and meatier pigs, and to try to stands by the study’s methodology. create more faithful models of human disease. But critics charge that TACT is simply This week’s draft sequence of T. J.’s genome (see the latest example of dubious research page 393), with its detailed annotation — a ‘ref- T. J. Tabasco, into unproven therapies supported by the erence genome’ — will speed progress on both star of the show. NCCAM. Some argue that even high- fronts, and perhaps even allow pigs to be engi- quality studies would have little value, neered to provide organs for transplant into symptoms resembling those in humans. because negative results are unlikely to human patients. “Agriculture in particular will Geneticist and veterinarian Eckhard Wolf at sway ardent practitioners. “Show me one benefit fast,” says Alan Archibald of the Roslin the Ludwig-Maximilian University in Munich, alternative medication or procedure that Institute in Edinburgh, UK, one of the paper’s Germany, has exploited the similarity between was studied, found to not work, and was lead authors. “The pig industry has an excel- the human and pig gastrointestinal system abandoned by practitioners. I’m not aware lent track record for rapid adoption of new and metabolism — like us, pigs will eat almost of any,” says Steven Novella, a neurologist technologies and knowledge.” anything and then suffer for it — to develop at Yale University in New Haven, Con- T. J., a domestic Duroc pig (Sus scrofa domes- models of diabetes. One pig model carries a necticut. Briggs, who previously led the ticus), was born in Illinois in 2001. The next mutant transgene that limits the effectiveness NIH’s kidney-disease research, points out year, Schook and his colleagues generated a of incretin, a hormone required for normal that echinacea sales fell after an NCCAM- fibroblast cell line from a small piece of skin insulin secretion3. Mice with the transgene funded study showed it was ineffective from her ear and commissioned clones to be developed unexpectedly severe diabetes, but against colds (R. B. Turner et al. N. Engl. J. created from it, so that they could work on ani- the pigs have a more subtle pre-diabetic con- Med. 353, 341–348; 2005). With the centre’s mals all with the same genome. One set of clones dition that better models the human disease. research showing that Americans spend was created at the National Swine Resource “This shows the importance of using an animal about $34 billion on alternative medicine and Research Center (NSRRC) in Columbia, with a relevant physiology,” says Wolf. each year, “we think it’s really important to Missouri, along with genetically engineered pigs Pig models are now being developed for other bring some science into this”, she says. with genes added or deleted to mimic human common conditions, including Alzheimer’s Briggs adds that the NCCAM’s critics diseases.“Making such pigs has got increasingly disease, cancer and muscular dystrophy. This often misrepresent the centre’s research, easier as knowledge of the genome increases,” work will be enriched by the discovery, reported focusing on studies of herbal supplements says physiologist Randall Prather, a co-director in the genome paper, of 112 gene variants that such as lavender oil but ignoring multi of the NSRRC, which is funded by the National might be involved in human diseases. Knowl- million-dollar grants for more-mainstream Institutes of Health (NIH). edge of the genome is also allowing scientists science. Among the largest studies funded The NIH launched the NSRRC in 2003 to to try to engineer pigs that could be the source by the centre this year are a computational encourage research in pig disease models. Pigs of organs, including heart and liver, for human analysis of the human microbiome and an are more expensive to keep than rodents, and patients. Pig organs are roughly the right size, effort to use brain imaging to understand they reproduce more slowly. But the similarities and researchers hope to create transgenic pigs and treat chronic back pain. between pig and human anatomy and physiol- carrying genes that deceive the immune system Novella and other NCCAM critics ogy can trump the drawbacks. For example, of recipients into not rejecting the transplants. do praise Briggs for bringing increased their eyes are a similar size, with photorecep- Back on the farm, early knowledge about accountability to the centre, and for boost- tors similarly distributed in the retina. So the the pig genome led to the discovery in 1991 of ing the rigour of the research it funds. But pig became the first model for retinitis pig- a gene involved in porcine stress syndrome, in “even if you did pristine research under the mentosa, a cause of blindness. And four years which the stress of overheating, being moved or NCCAM”, says Novella, “it’s what you’re ago, researchers created a pig model of cystic even having sex causes the animals to die sud- studying that is the problem”. ■ fibrosis2 that, unlike mouse models, developed denly4. It then became possible to test for the