Medicine

5. Bush Stem-Cell Estimate Cut From 64 to Fewer Than 10 In August of last year, President George W. Bush announced that scientists who received public research money could use only the human embryonic stem-cell lines that already exist—a decision that dismayed many researchers. At the time, Bush's advisers estimated there were 64 such populations. This year researchers discovered the actual number is "certainly less than 10" and probably no more than six, says Doug Melton, a molecular biologist at Harvard University and one of the scientists the president consulted before his decision. Melton had argued for unlimited stem-cell generation and use. The limited number of permissible cell lines left, Melton says, cannot meet the medical needs of a population as genetically diverse as the human race. Furthermore, stem-cell lines from mice begin to lose their ability to produce many types of cells after as few as 20 generations, and researchers assume the same will prove true for stem cells from humans. The policy, Melton says, "is like setting out on a cross-country trip and someone saying, 'OK, here are six gallons of gas.' You know immediately you are not going to get to the end." In April an administrative ruling from the National Institutes of Health offered some relief. The NIH announced that it would not penalize those who are using private funds to study stem cells by denying them public funds for other kinds of research. Melton and other researchers have already begun generating new cell lines. He says the ruling will ease the problem but is far from a panacea, especially because the vast majority of research is funded by the federal government. In September the British Parliament funded an embryonic-stem-cell bank that may eventually store thousands of cell lines, which will help make Britain a leader in embryonic-stem-cell research. Meanwhile, some scientists in the United States are moving to Britain. — Rabiya S. Tuma 40. Finally, a Test for Alzheimer's The symptoms of Alzheimer's disease creep slowly into a patient's life, gradually erasing thoughts and memories. Definitive proof of the disease, however, has been elusive. Until last year, both patient and doctor could only guess at what was happening inside the brain because they had no way—short of an autopsy—to see the damage. In July William Klunk and Chet Mathis, researchers at the University of Pittsburgh, and their collaborators in Uppsala, Sweden, announced that they had developed a radioactive compound that, when injected into the veins of a patient, travels to the brain and sticks to plaques of beta-amyloid protein, the telltale evidence of Alzheimer's disease. The compound, tested so far in only nine patients and five controls, can be detected by positron emission tomography, an imaging system similar to a CT scan. If the brain contains no clumps of beta-amyloid protein, the tracer molecules flush out quickly, and the researchers know that the affliction is not Alzheimer's. This discovery is more than a clinical tool, says Klunk, because it may ultimately allow doctors not only to map the extent of the damage but also determine if treatments are working. "I sometimes think of the ability to see amyloid in the brain as seeing the enemy. If you can see the enemy, then you can tell if the shots being fired are hitting their target and having an effect." — Rabiya S. Tuma 46. It's Good To Be Around Sick Kids The number of chicken-pox cases in the United States has declined since a vaccine became available in 1995, and health officials are intent on eradicating the disease altogether. But in May doctors in England suggested that mass vaccination against chicken pox in children would bring on a more serious epidemic of shingles in adults. Both diseases are caused by the same virus, Varicella zoster. Adults get shingles when the chicken-pox virus they were exposed to as children breaks out of its dormant hiding place in the nervous system. The virus can reactivate because immunity to chicken pox fades with time. But Marc Brisson, an epidemiologist at the Public Health Laboratory Service in London, has found that exposure to children with the pox provides protection. "Exposure to chicken pox, and thus to the virus, reduces the risk of shingles by boosting specific immunity to the virus." In contrast, he found that adults who don't live with children—or who live with immunized children—are much more likely to have to face down shingles. Brisson estimates that wiping out chicken pox could result in 9 million more cases of shingles in the United States over the next 50 years. "The benefits of reducing chicken pox through widespread vaccination could be outweighed by the damage from the predicted increase in shingles," says Brisson, adding that shingles-related hospitalizations might increase. Meanwhile, immunologists are trying to develop other ways to boost adult immunity to shingles. — Jeffrey Winters 23. Dodging Alzheimer's With Clever Genetics The woman was only 30, but she had already foreseen her own terrible fate: Her oldest sister slipped into dementia at 38, her brother started growing forgetful in his mid-thirties, and her father, plagued by memory lapses, died at 42. A flawed gene runs in her family that causes a very rare and devastating early form of Alzheimer's disease, and a test had shown that she carried it too. Although she was still unaffected, her turn was coming. Wishing nonetheless to have a healthy child of her own, she sought out Yury Verlinsky, director of the Reproductive Genetics Institute in Chicago. The geneticist used a delicate technique called preimplantation genetic diagnosis to peek into the woman's eggs and, after analyzing their DNA, select those free of the Alzheimer's mutation. The gene variant creates an abnormal protein that forms clumps in the brain, eventually causing disease. During maturation, her eggs all started out with four copies of the gene: two normal and two flawed. Each egg randomly discarded all but one of the copies by pushing the extras out in two blobs, called polar bodies. By extracting and testing the polar bodies, Verlinsky and his colleagues could see which genes had been thrown out, deduce what was left in the egg, and pick out the healthy candidates. After fertilizing those eggs with her partner's sperm, doctors transferred four healthy embryos into the woman's uterus. In February Verlinsky announced that she had delivered a baby girl who will escape the family curse. The case has become controversial. Doctors and ethicists wonder if it's acceptable to use this technique to screen out any disorder that threatens future health. Obstetrician-gynecologist Marian Damewood, director of women and children's services at York Hospital in York, Pennsylvania, doesn't think so. "Then we'd be getting very close to designing a human being who's going to have no flaws and live forever. That would be disturbing." She wonders if a future society of mostly disease-free people would discriminate against the few who are sick or disabled. Some critics fear a day when designer genetics allows parents to custom order kids with the looks of a Cameron Diaz or the virtuosity of a Yo-Yo Ma. But James Grifo, a reproductive endocrinologist at New York University, says that all we've been able to do so far is tinker. "There is no way I could select for hair color, eye color, genes for intelligence," Grifo says. "We don't know how to do it. Can we, in the future? Maybe. I doubt it." — Ingfei Chen 31. Frozen Hope For a young woman with ovarian cancer, the options can be grim. Surgery or radiation may save her life but leave her infertile. Therefore, doctors hope they will someday be able to remove and preserve the ovaries of women undergoing cancer treatment so they can implant them once the disease has been cured. That dream moved closer to reality last January when Roger Gosden, a reproductive biologist at Eastern Virginia Medical School in Norfolk, announced that his team had transplanted into seven rats ovaries and fallopian tubes that had been frozen and stored in liquid nitrogen. Scientists have been preserving sperm and embryos for more than a decade, but freezing more complicated tissues has proved problematic. Ice crystals that form during cooling and rewarming can break, puncturing cells and bursting blood vessels. But ovaries have a simpler circulatory structure than most organs, enabling them to better withstand freezing. They are also better able to repair ice-related damage because the organs are very plastic and rich in polypeptides that make blood vessels grow. Of the seven rats that received the frozen ovaries, one that had been paired with a male became pregnant within 10 weeks. — Jeffrey Winters 24. Courts Deny Drug Tests For Children It seems like a reasonable demand: Before doctors can prescribe adult drugs for kids, pharmaceutical companies should have to test those drugs to see if they're safe and effective for children. So in 1998, the Federal Drug Administration declared that they should do just that. But drug companies balked, and last March the administration of President George W. Bush sought to abandon this so-called pediatric rule. Then Sam Kazman, general counsel at the Competitive Enterprise Institute, filed suit to throw the rule out. Rather than imagine children who might be harmed, Kazman sees children who would benefit from medications they can't get now. "Families who are told that there's nothing the doctors can do won't know that the FDA is withholding potentially lifesaving treatments," Kazman says. However, Richard Gorman, chairman of the American Academy of Pediatrics' committee on drugs, says, "Children deserve the same protection taken for granted by adults." Every time a doctor prescribes an adult-tested medication for a child, Gorman says, it is an unregulated experiment. He cites the case of chloramphenicol, a powerful antibiotic marketed in the 1960s as a cure for meningitis in newborns. Although the drug had been approved for adults after rigorous testing, it had not been tested on children, so there was no way to know that the livers of newborns couldn't metabolize it. Clinical testing on children would have picked up the problem, Gorman says; instead, many children died, and it took five years to discover the patterns of deaths. In October a federal judge struck down the FDA's pediatric rule, saying the agency overstepped its authority. The American Academy of Pediatrics will seek legislation to get children equal protection with adults in the development, testing, and marketing of new drugs. — Jeffrey Winters 21. Overcoming Bush's Stem-Cell Manifesto For stem-cell researchers, this has been a year of struggling to find politically acceptable cells—or substitutes for those that aren't. Tensions have escalated since August 2001, when President George W. Bush limited publicly funded research on embryonic stem cells to already existing lines. In September California's Democratic governor, Gray Davis, crystallized the politics by signing the first state legislation permitting research on the embryonic cells, the master cells that can morph into any tissue in the body. Scientists hope that one day they can use the cells to cure diseases such as Alzheimer's, Parkinson's, and diabetes. The law signed by Davis was immediately assailed by antiabortion and religious groups, most of which maintain that stem-cell research is repugnant because human embryos must be created to supply the cells, then destroyed to harvest them. They argue that scientists should concentrate on adult stem cells, which can be pulled from a patient's own body. The big question is whether adult stem cells can fill the shoes of their embryonic counterparts. "I am a big fan of adult cells," says Ronald McKay, a biologist at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. McKay announced that he had mitigated the symptoms of Parkinson's in rats by using mouse embryonic stem cells that he had turned into dopamine-producing brain cells. "But the question is, really, what do they do? The Parkinson's patient doesn't need something that is roughly or approximately the right kind of cell. They need exactly the right kind of cell, which is what we are reporting with embryonic stem cells. If we could say that for adult stem cells, I'd be happy." Before September, researchers had pinned their hopes on adult hematopoietic stem cells—blood-producing stem cells. Previous work suggested they were as malleable as embryonic stem cells and so could be reprogrammed to make any kind of tissue. To find out if this was true, workers in stem-cell biologist Irving Weissman's lab at Stanford University Medical School took one blood stem cell from an adult mouse and tagged it with a marker that glowed green under fluorescent light. Then they injected the cell into a mouse whose bone marrow had been destroyed by radiation. In a matter of weeks, the single stem cell repopulated the mouse's blood and immune system but did not create other types of cells. Only eight glowing green cells appeared elsewhere in the body—one in the brain and seven in the liver—out of 15 million examined. The results make it clear, says stem-cell biologist Amy Wagers, who headed the study, that these hematopoietic stem cells can do a lot for blood diseases but not for diseases affecting other kinds of cells. If blood stem cells aren't the next big thing, another cell, discovered by researchers at the University of Minnesota's Stem Cell Institute in Minneapolis, might be. Institute director Catherine Verfaille and her team pulled multipotent adult progenitor cells, referred to as MAPCs (and pronounced map-seas), from the bone marrow of mice and rats. The cells were meticulously cultured in the lab and then injected into four-day-old mouse blastocysts. In June the team announced that the cells had given rise to almost every type of tissue—neurons, blood, liver, muscle, and more (researchers have not yet spotted sperm or egg tissue but hope to find them). A good omen: These stem cells didn't create the tumors that transplanted embryonic stem cells often trigger. MAPCs, says Wagers, "have terrific promise," but other researchers caution that the Minnesota team isn't exactly sure how they arise. "Do those cells actually exist in the body, or are they created from the culture conditions?" wonders molecular biologist Stuart Orkin of the Dana-Farber Cancer Institute at Harvard. "One has to worry if cells tweaked like that in culture are normal and whether something might happen way down the line. Are they really safe?" The lead author of the Minnesota study, Yuehua Jiang, counters that the same reservations apply to embryonic stem cells: "Are they cultured naturally?" Verfaille and Jiang are trying out MAPCs on animals with Parkinson's and liver disease. Jiang estimates that human clinical trials could begin within a decade: "At first, the cells could be used to treat diseases with single missing or malfunctioning cell types, like hemophilia, diabetes, Parkinson's disease, and muscular dystrophy. Later, they could be used to repair damaged or diseased body parts." — Kathy A. Svitil 18. Mainstream Painkillers Stop Broken Bones From Healing Last may, patrick o'connor, assistant professor of orthopedics at the New Jersey Medical School in Newark, reported that some popular pain relievers slow or stop broken bones from healing. O'Connor had been following a hunch that grew out of his study of fibrodysplasia ossificans progressiva, in which bone growth goes into overdrive, leading to deadly complications and early death. "Abnormal bone growth seemed to be triggered by an initial inflammation," he says. If inflammation stimulated bone growth, he wondered, might normal healing be deterred by anti-inflammatory painkillers, such as Vioxx and Celebrex, that work by inhibiting COX-2 enzymes? O'Connor and colleagues tested the drugs on rats with broken legs. Two months postfracture, untreated rats had healed normally, but those taking COX-2 inhibitors hadn't healed at all. Rats given indomethacin, a related drug, experienced a 25 to 50 percent delay in healing. O'Connor's colleagues immediately switched patients to other painkillers. Following up with "human studies won't be easy," O'Connor says, because of ethical considerations. Who would want to be in the group that gets the drugs? — Jeffrey Winters 59. Warning: In Vitro Fertilization May Be Riskier Than You Thought This has become the way 30,000 babies are born in the United States each year: Sperm and eggs are introduced to each other at the lab bench, selected embryos are inserted into a woman's uterus, and finally, nature takes over. The technology is impressive, but last March two controversial studies questioned whether it produces healthy infants. Epidemiologist Jennifer Kurinczuk of the University of Leicester in England and colleagues at the University of Western Australia and the Western Australia Department of Health surveyed birth defects in 1,138 infants conceived by in vitro fertilization or through intracytoplasmic sperm injection, in which sperm is injected directly into the egg. About 9 percent of these test-tube babies had significant congenital defects—twice the number seen in a comparison group of 4,000 babies conceived traditionally. The defects ranged from life-threatening heart abnormalities to hand deformities. A second study, led by Laura Schieve, an epidemiologist at the U.S. Centers for Disease Control and Prevention, examined birth records of 42,463 babies conceived through in vitro fertilization or related procedures. Single full-term babies were found to be 2.6 times as likely to have low birth weights as babies conceived in traditional ways. Low-birth-weight babies are more vulnerable to respiratory disorders and death or to developmental difficulties later in life. Researchers suspect the health risks could arise from the treatments themselves, perhaps from drugs used to trigger ovulation or from changes that occur as a result of freezing and thawing embryos. But the culprit may also be the underlying problem that caused the infertility. "These results are something [infertile couples] need to weigh in the balance, alongside all the other risks," says Kurinczuk. — Ingfei Chen 93. Folic Acid Aids Sperm Count Infertile men may be able to increase their sperm count just by adding a little extra folic acid and zinc to their diet. The two ingredients are essential for making DNA, and pregnant women have long taken folic acid to prevent birth defects. Researchers put 103 low-count males on regimens of either zinc sulfate or folic acid, a combination of both, or a placebo for 26 weeks. Those who received both nutrients increased the number of swimmers in their semen from an average 7.5 million per milliliter to 12 million. That may be a far cry from the teeming 20 million to 150 million per milliliter produced by healthy, fertile men, but it could make a difference. "I would recommend consuming folate-rich foods such as green leafy vegetables, grains, and fruits, and zinc-rich products such as oysters and meat," says Régine Steegers-Theunissen, associate professor of epidemiology and obstetrics at the University Medical Center in Nijmegen in the Netherlands. "However, a low-dose supplement including folic acid and zinc could be recommended as well." — Michael Abrams 11. The End of the Estrogen Myth Millions of older women ping-ponged between shock, confusion, alarm, and anger in July when researchers dropped a bombshell: Hormone replacement therapy (HRT), long touted as a panacea that would slow aging, does more harm than good. Until then, an estimated 14 million postmenopausal American women were taking some form of estrogen, a widespread practice since the 1960s. Experts supported its use to ease the hot flashes and mood swings of menopause, keep bones strong, possibly prevent dementia—and reduce the risk of heart attack by as much as half. Then on July 9, the National Institutes of Health abruptly shut down a clinical trial of HRT because of safety concerns. In the first rigorous test of the treatment's cardiovascular benefits in healthy women, 16,608 volunteers had been randomly assigned to take Prempro, a mix of estrogen and progestin, or a placebo pill every day. Five years of therapy helped prevent hip fractures and colorectal cancer. However, HRT also led to eight more breast cancer cases, eight more strokes, and 18 more episodes of hazardous blood clots for every 10,000 women using Prempro each year. The big shocker: The drug boosted the odds of cardiac damage by 29 percent, causing seven additional heart attacks per 10,000 participants annually. The extra hazards outweighed the payoffs. Investigators advised women to stop using Prempro to avoid heart disease and consider other steps to ward off osteoporosis. "It's kind of an earthshaking and astounding event," says Deborah Grady, director of the Mt. Zion Women's Health Clinical Research Center at the University of California at San Francisco. Still, she argues, the scientific process didn't break down. What happened was that doctors leaped in and started prescribing HRT before a carefully designed, randomized clinical test like the 10-year NIH study could be carried out. Why? A compelling heap of observational and lab data had supported the hormones' rejuvenating powers. Also, Grady says, there was aggressive marketing by drug firms and a pervasive "magical thinking" that estrogen must be good for women. Meanwhile, many doctors continue to prescribe estrogens, apparently convinced that other forms will help their patients' hearts. The evidence favoring that view? According to Grady: "Slim to none." — Ingfei Chen 76. Autism Rates Soar When pediatric epidemiologist Robert Byrd of the University of California at Davis heard three years ago that the state's Department of Developmental Services had reported a near tripling of autism cases between 1987 and 1998, he decided to investigate. Was the rate increasing because the childhood disorder was being better diagnosed? He studied a sample of 684 California children who had been diagnosed with either profound autism or mental retardation. About half were born in the mid-1980s and the other half in the mid-1990s. Byrd found no significant changes over time in the criteria used to diagnose autism. He also excluded several other possible explanations for the rise in cases and reported his data to the state legislature in October. An increase in autism awareness could be prompting more parents to seek help for their children, but Byrd suspects that environmental factors are at work. "There are thousands of chemicals in the environment we've never had to be around," he says. "I think we certainly need to address that." Meanwhile, an updated report this year from the California Department of Developmental Services now shows a sixfold increase in children diagnosed with autism between 1987 and 2002. — Josie Glausiusz 22. Alzheimer's Clue Seen Like strings of yarn, strings of amino acids (which form proteins) can fold into many shapes. Specific shapes can determine the protein's task in a cell. They can also bend into abnormal shapes, called misfolds. For example, clumps of proteins called amyloid fibrils are thought to be the cause of Alzheimer's disease as well as several other devastating illnesses. Treatment ideas for Alzheimer's have thus focused on preventing the misfolds. But researchers in Italy and the United Kingdom reported in April that many different types of normal proteins—with no known link to diseases—can also fold into shapes indistinguishable from the dreaded amyloid fibrils. "These findings suggest that the ability of proteins to aggregate into amyloid fibrils can be considered a more general property of proteins than previously believed," says Massimo Stefani, a protein chemist at the University of Florence in Italy who co-led the project. He and his colleagues also reported that the improperly folded proteins found in the brains of Alzheimer's patients aren't what cause cells to die. Instead, they think the mortal blow occurs earlier, at a stage just before the strand misfolds into a fibril. This revelation has huge implications because any potential treatment to halt cell death from misfolded proteins will succeed only if it prevents this early misstep. All these findings, however, are based on forced conditions in laboratory work. Other researchers caution that it is not yet known whether misfolding occurs under normal conditions in healthy cells. — Rabiya S. Tuma

Medicine

Discover the latest about embryonic stem-cell research, its limited cell lines, and the impacts on future treatments for diseases.

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