The Year in Science: Medicine

The human gut's vulnerable to HIV, race-based drugs approved, fetal skin grafts mend burns, and more.

Sunday, January 08, 2006

A Little Klotho In Your Cereal Couldn't Hurt

Mice with a defect in the gene that produces a protein called Klotho are born normal but start to age quickly, developing skin and muscle atrophy, osteoporosis, arteriosclerosis, and pulmonary emphysema—all symptoms of aging in humans. In September a team of researchers reported that extra Klotho produces the opposite effect, lengthening mouse life span by up to 30 percent.

Researchers developed a transgenic line of mice that overexpress the gene for Klotho and then observed that they lived longer than their wild cousins. Little is known about the exact molecular mechanisms by which Klotho suppresses aging. Although caloric restriction also can lengthen life, the researchers found that their transgenic mice ate no more or less than ordinary mice.

The overproduction of Klotho had few side effects on the mice. Although too much of it does cause problems with blood sugar levels, it was not enough to lead to diabetes. The protein also had some effect on reproduction. The transgenic mice gave birth to fewer offspring than their normal relatives, which fits well with the evolutionary theory that there is a trade-off between longer life span and fertility.

The next step, says Makoto Kuro-o, an assistant professor of pathology at the University of Texas Southwestern Medical Center, is to study Klotho in humans. "We want to know whether blood Klotho levels are associated with any common age-related diseases like arteriosclerosis, osteoporosis, or cancer," he said. —Nicholas Bakalar

FDA Approves First Race-Based Drug

The Food and Drug Administration's formal approval in June of BiDil, a medicine designed to treat heart failure in blacks, ignited a furious debate over the role of race in medicine. The Association of Black Cardiologists, a paid sponsor of the clinical trial, cheered the FDA's action. But the idea that a drug can be race based was roundly criticized by prominent medical researchers who argued that race is a crude and invalid scientific concept.

BiDil is derived from two generic compounds: hydralazine, an antihypertension drug, and isosorbide dinitrate, a blood vessel relaxant. The combination therapy was rejected by the FDA in 1997 because trials showed inconclusive benefits for patients overall. But Jay Cohn, the University of Minnesota cardiologist who developed the drug, had observed that BiDil appeared to be more effective for black patients. So he designed a study of 1,050 self-identified black patients and found in 2004 that the medication decreased their death rates by 43 percent. Cohn and his colleagues were taken aback by the negative reaction among sociologists, geneticists, and ethicists when the drug was approved. "We thought they'd realize we've found an effective drug for treating an underserved group with a high mortality rate from heart disease," Cohn says.  "We thought that would overwhelm the racial concerns."

Critics contend that approving a drug for use only by blacks could be interpreted as validating a genetic basis to race that does not exist. In recent years, researchers have identified subtle genetic differences between populations—such as Europeans, Africans, and Native Americans—but these differences aren't as clearly defined as  "black" and "white." Even so, scientists hope to use these variations to understand why drugs have different effects in different people. It may be genetics. It may be environment (diet, exposure to pollutants) or sociological factors (access to good health care). Most likely it's a combination of all three. But one thing is clear: Race is defined by society, not by science.

Ironically, Cohn agrees. "I don't propose that I can genetically identify who's black and who's white," he says. "These patients simply checked a box; they designated themselves as black." —Rebecca Skloot

Flap Erupts Over Fat

In April the Centers for Disease Control and Prevention dropped a bombshell by declaring that people who are slightly overweight are less at risk of dying at a given age than people of normal weight. The report even suggested that being too thin could boost the risk of untimely death. Before the media could trumpet the prospect of guilt-free pounds for long, several experts, most notably a group from the Harvard School of Public Health, declared the report flawed and said they feared it would set back the fight against obesity, one of the nation's gravest health problems.

The controversy erupted when Centers for Disease Control scientists published research in The Journal of the American Medical Association based on numbers collected by the agency's National Center for Health Statistics. The figures included the number of dead and their body mass index, which is a combined measure of height and weight. The calculated number of obesity-related deaths—112,000—contradicted a CDC report last year that placed the number of obesity-related deaths at around 365,000.

Critics say the newer estimate is more reasonable than the older, higher number, but they question the study's methodology. For instance, not excluding those who might be thin because of a chronic illness may have artificially inflated the number of deaths in the underweight group. Katherine Flegal, the study's lead author, says recalculating the numbers that way does not make a significant difference.

The public dispute over the studies prompted CDC director Julie Gerberding to address the matter at a press conference in June. "It is not OK to be overweight," she said. "I'm very sorry for the confusion."

Flegal insists that the results reflect population trends in deaths and are in line with previous studies. Moreover, because the researchers only considered deaths, the study did not address the impact of extra pounds on overall health. Experts agree that obesity increases the risk of diabetes, heart disease, and some cancers.

"There's nothing about our findings that changes the public-health message," says Flegal. "Everybody should eat right, get some exercise, and not smoke."  —Apoorva Mandavilli

Fetal Skin Grafts Mend Burns And Eliminate Need for Surgery

A team at University Hospital in Lausanne, Switzerland, reported in September that they had perfected a technique of growing skin from fetal tissues and attaching it to burned areas without having to resort to surgery. Standard burn treatment involves slicing skin from one part of the body and then sewing it to the burned area.

Using a 3¼-inch-square piece of skin from an aborted 14-week-old fetus, researchers nurtured skin cells on a collagen matrix, creating sheets about the size of a 3-by-5-inch index card. They believe a single donation of fetal skin could produce millions of patches, called constructs.

In a painless procedure, the physicians placed the patches over badly burned skin on eight children and covered them with petroleum jelly–coated gauze. The burns ranged in size from about 2 square inches on an infant's hand to a wound that covered more than 82 square inches on an 8-year-old's back and buttocks. Every three to four days they changed the bandages and added more skin sheets as needed. After two weeks, on average, the wounds had healed.

None of the eight children in the study required skin grafts, and the constructs healed normally with no stitching, gluing, or stapling. Because the skin sheets molded easily to small areas, children with burned hands, fingers, and feet regained total mobility. One youngster with dark skin recovered her normal skin pigmentation.

The donor fetus was male, so the researchers checked one of the female burn patients after six months. No male Y chromosomes were apparent in her skin cells. The researchers speculate that fetal cells secrete growth factors that nourish existing skin.

The technique may have applications other than burns. Biologist Lee Ann Laurent-Applegate says, "We have also worked on large physical wounds in some children as well as chronic wounds, primarily venous ulcers in adults, with equally encouraging results."  —Nicholas Bakalar

Nasal Spray Halts Alzheimer's in Mice

A drug combination that stirs up an immune response in the brain might provide a treatment to halt the devastating course of Alzheimer's. Researchers believe the disease progresses because of sticky clumps of beta-amyloid proteins that form and build up between neurons, eventually killing them. In July a team of neurologists at Brigham and Women's Hospital in Boston reported that a nasal spray containing the drugs cleared more than 80 percent of the toxic clumps in mice.

Howard Weiner, Danny Frenkel, and their colleagues built on the results of a failed 2003 Alzheimer's vaccine trial. That vaccine, which included bits of beta-amyloid to arouse immune-system T cells, cleared the clumps, but it also provoked dangerous brain inflammation in several patients. So Weiner's group decided to try a completely different approach. Instead of stirring up powerful T cells through an injected amyloid vaccine, they used a nasal spray containing two drugs that provoke a less robust but more manageable immune response.

One drug, Protolin, contains bacterial components that rev up immune-system cells in the brain, called microglia, to chew through the beta-amyloid. The other, Copaxone, a drug approved for multiple sclerosis, damps down an immune response. Combining the two medications in a nasal spray seemed the simplest delivery system. Because the two drugs have long been used safely, says Weiner, "I think the potential is very great, and we are planning clinical trials in 2006."

A full-force immune-system attack still has the potential to cause swelling, cautions Cynthia Lemere, a researcher who worked on the first vaccine and who has previously collaborated with Weiner's group. "I think a lot of people have reservations about stimulating a huge immune response in the brain." Nonetheless, she says, "Alzheimer's is such a horrible disease that people will do anything."  —Jessa Forte Netting

Drug-Resistant Bacterium Strikes Soldiers Fighting in Iraq

An unusually drug-resistant bacterial infection among  soldiers who served in the Middle East first showed up in 2003 when a handful of cases were identified in military hospitals. By October 2005, more than 300 cases had been reported, sending military physicians scrambling. The bacterium, Acinetobacter baumannii, is similar to a strain that was a common source of infection among U.S. soldiers in the Vietnam War. But this variant of the bacterium has evolved so much resistance to antibiotics that to combat it doctors must rely on drugs that haven't been widely used in decades.

Like Staphylococcus, another common pathogen, A. baumannii poses the biggest threat to hospitalized patients whose immune systems are already weakened by injury or illness. The bacterium can live on the skin and survive for weeks on dry surfaces, so it infiltrates and lingers in hospitals, poised to colonize new patients. A ward of soldiers wounded by land mines, mortar fire, or bombs may be especially vulnerable to infection.

"Once it has established itself, it is difficult to eliminate," says Colonel Bruno Petrucelli, one of the U.S. Army's senior epidemiologists.

At least five patients have died because symptoms of their illness were aggravated by the infection, despite their receiving intravenous antibiotic treatment.
"What makes this special is that we can run out of drugs that we can count on," says Petrucelli. "There's always that fear that we're running out of options, that this organism is going to grow and there is nothing that's going to knock it down."  —Susan Kruglinski

HIV Attacks the Gut First

For more than a decade, scientists have tracked the insidious progression of HIV by measuring the amount of virus in a patient's blood. Over a period of years, the replication of the virus gradually and steadily destroys the immune system's defenses—or so it was thought.

In April two studies of simian immunodeficiency virus, a kin of HIV that infects monkeys, reported that the virus swiftly infects and decimates key immune cells in the gut within days, not years, of infection. "This basically changes our whole view of the pathogenesis of HIV infection," says Daniel Douek, chief of the Human Immunology Section at the National Institutes of Health's Vaccine Research Center.

Virologists have long known that HIV infects and kills CD4+ T cells, which mediate the body's immune response to viruses. What has emerged over the past few years is that the virus thrives not only in the blood and the lymph system but also in mucosal tissues, which are rich in immune cells. The mucosae line parts of the body, such as the mouth, nose, and rectum, that are exposed to the environment. The gut, the largest of the mucosal tissues, harbors most of the body's CD4+ T cells.

"What we now know is that within the first few weeks of infection, probably two to three weeks, the majority of those cells are depleted by HIV infection," says Douek. During that early stage of infection, about half the T cells in the gut can be wiped out in just four days.

The findings have profound implications for the control of HIV infection. They not only underscore the importance of starting antiretroviral therapy very early in the infection but also highlight the need for a vaccine that can protect mucosal surfaces. —Apoorva Mandavilli

Vaccine Protects Against Cervical Cancer

Each year cervical cancer kills about 250,000 women around the world, most of them in developing regions without basic health care. Since the 1980s, when scientists discovered that human papillomavirus plays a role in nearly all cases of cervical cancer, researchers have worked to create a vaccine. This year they succeeded. In October Merck completed a study showing that its vaccine, Gardasil, was 100 percent effective in protecting a group of more than 5,000 women.

Of the 30 strains of papillomavirus that can be sexually transmitted, about half can provoke the cellular changes that lead to cancer. Gardasil protects against two strains responsible for 70 percent of all cervical cancer cases and another two that cause noncancerous genital warts. The vaccine includes one key viral protein—not enough of the virus to cause infection but enough for the body to react and create immunity. GlaxoSmithKline has developed a similar vaccine that protects against the two cancer-provoking strains.

If the vaccines get approval from the FDA, the next formidable obstacle will be getting them to those who need them most. The vaccine will not protect the 75 percent of sexually active adults who are already infected with the virus. The biggest pool of those who can be helped are young boys and girls. But some researchers worry that religious and conservative groups will speak out against vaccinating children because they fear it might condone sexual activity.

Laura Koutsky, an epidemiologist at the University of Washington who led the studies on Gardasil, says that the abstinence-only message doesn't protect children who ignore it. And even if a child abstains from early sexual activity, she is still unprotected, Koutsky says: "Your child may abstain until marriage, but her partner might not. You don't know what that partner will bring to the marriage."

Besides, in rare cases the virus can be spread by any sexual contact, even touching, so abstaining from intercourse does not always prevent transmission. "Using the same flawed logic, we should eliminate Pap smears because they're looking for the same sexually transmitted disease this vaccine prevents," Koutsky says. She is confident that parents' concerns will outweigh philosophical issues. "You know, I just hope most people would rather give a vaccine like this than watch their daughters struggle with abnormal Pap smears and cervical cancer."—Rebecca Skloot

FDA: Over The Counter Warning

For decades, the Food and Drug Administration endorsed over-the-counter painkillers as largely safe and effective. But in April the agency warned that the medicines might carry a risk of heart attack, stroke, and gastrointestinal problems—and requested that manufacturers' packaging provide information on the product's risk. 

The debate over painkiller safety began in the late 1990s when competition for the arthritis market erupted between Merck's Vioxx and Pfizer's Celebrex. The new drugs, which target the COX-2 enzyme, were seen as better than traditional painkillers like aspirin because they don't have gastrointestinal side effects. But as early as 1997, researchers began warning that the drugs increase the risk of heart attack.

On September 30, 2004, Merck withdrew Vioxx after trial results unquestionably showed that the drug increased the risk of heart attack and stroke. The FDA began scrutinizing all nonsteroidal anti-inflammatory drugs, a group that includes COX-2 inhibitors and over-the-counter painkillers.

On April 7 reports of adverse skin reactions and heart problems prompted the FDA to ask Pfizer to withdraw Bextra, another COX-2 inhibitor, and to include a warning about the health risks for Celebrex. It also asked for a similar label for over-the-counter ibuprofen drugs, such as Motrin and Advil, and for naproxen (Aleve) and ketoprofen (Orudis, Actron).

Eric Topol, chairman of cardiovascular medicine at the Cleveland Clinic, says labeling all painkillers is "absurd." Although he had questioned Vioxx's safety, Topol contends that the more generic warning is an overreaction. Traditional anti-inflammatories such as ibuprofen and naproxen have been widely used for more than a decade, Topol says. "If there were any significant risks—life-threatening risks—with these drugs, we would know about it by now."

Garret FitzGerald, director of the Institute for Translational Medicine and Therapeutics at the University of Pennsylvania, adds that the FDA's European counterpart has said there is not enough information to change how the public uses the over-the-counter drugs.

Meanwhile, Merck is facing more than 7,000 lawsuits from Vioxx users and their families. At the end of the first lawsuit, a Texas jury in August awarded $253.4 million in damages to the family of 59-year-old Robert Ernst, who died in 2001 after taking Vioxx for eight months. In the second Vioxx-related suit, Merck won against 60-year-old Frederick Humeston, who suffered a heart attack after taking Vioxx for knee pain for two months. The jury found that Merck had not been misleading or fraudulent in selling Vioxx.

If the FDA and Merck had both acknowledged the problems when they first appeared, says Topol, Vioxx might still be on the market and prescribed only for people who respond well to it and who understand the risks. The result of the Vioxx scare, he says, is that people are left with a lot of uncertainty. "Who do they believe?" he asks. "Not the companies, not the FDA. It didn't need to be like this."  —Apoorva Mandavilli

Gene Therapists Break Through Blood Barrier

Scientists have now crossed the biggest barrier to the delivery of therapeutic genes: the blood vessels. In a series of studies this year, molecular geneticists at the University of Pittsburgh School of Medicine used a harmless virus to ferry new genes through the bloodstream, across blood vessel walls, and into almost every muscle cell in the bodies of hamsters bred to have human genetic diseases. "We've never seen such a dramatic therapeutic effect," says Xiao Xiao, head of the research team.

This is the first time anyone has been able to deliver genes efficiently through blood-vessel walls without the aid of wall-weakening drugs or vessel-distending pressure. Xiao's team first used AAV8, a strain of adeno-associated virus, to carry a gene for a marker, green fluorescent protein, into an unprecedented number of muscle cells. Then they showed they could deliver genes to repair deteriorated muscles and reverse congestive heart failure.

The technique holds the greatest potential for treating diseases like muscular dystrophy, in which billions of far-flung cells need new DNA. As for worries about harmful effects, researchers say AAV8 isn't likely to disrupt healthy genes, a side effect that stalled a promising gene-therapy trial for an immune-deficiency disorder in 2002. Xiao is optimistic about the clinical applications but cautions, "Hamster to a human—that's a long way to go!"  —Jessica Ruvinsky

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