2.Tissue Engineering Triumph: Lab-Grown Bladders
On April 15, the British medical journal The Lancet carried a landmark article showing that it is now possible to engineer a complex organ to replace one ravaged by disease. Anthony Atala, a surgeon and director of the Institute for Regenerative Medicine at Wake Forest University School of Medicine in Winston-Salem, North Carolina, reported that artificial bladders can be grown in the lab from a patient's own cells and successfully implanted. Over the past six years, seven children have received the organs, which are functioning well.
Atala's quest to build an artificial bladder began about 16 years ago when he was honing his skills as a pediatric surgeon at Harvard University. He became increasingly unsettled by a routine century-old procedure he was performing in young children: replacing damaged or diseased bladders with sections of the bowel or the stomach. Because the role of these tissues is to absorb chemicals (whereas the role of the bladder is to store and eliminate them), patients, especially young children, who underwent the procedure were often saddled with a suite of inescapable side effects. "When you replace bladder with intestine, you absorb chemicals you should get rid of, creating lots of problems," says Atala. Among them is a higher risk of cancer, stone formation within the walls of the transplanted tissue, and bone deformities due to calcium reabsorption by the tissue.
Atala wondered whether it would instead be possible to remove bladder cells from a patient and use them to grow a replacement organ, thus eliminating the risk of transplant rejection. "I had no idea how difficult it would be," says Atala. It took about a decade, but in 1999 he and his colleagues began implanting these engineered organs in spina bifida patients aged 4 to 19 who, in addition to spinal cord defects and nerve damage, had abnormal bladders.
For patient Kaitlyne McNamara of Middletown, Connecticut, who received her implant in 2001 at age 12, the timing could not have been more crucial, says her mother, Tracy McNamara. She had the "bladder capacity of a thimble," was wet all the time, and was forced to wear diapers. More critical was that her tiny, rigid bladder would spasm frequently, forcing urine back into her kidneys, where it triggered severe infections that were slowly destroying them. Her bladder condition disqualified her for a kidney transplant.
Six weeks prior to Kaitlyne's surgery, Atala and his team harvested a dime-size piece of tissue from her bladder, using this as the source of cells to create a new organ. A normal bladder has three layers: On the outside is muscle, in the middle is collagen, and the innermost layer consists of specialized urothelial cells that are impermeable to urine and protect the body from waste fluids. After a biopsy, Atala teased apart the three layers, cultivating the muscle and urothelial cells separately and discarding the collagen. Four weeks of cell division produced enough cells to build a new bladder. "The key to these technologies is, first and foremost, getting the cells to grow outside the body," says Atala. "Then you need to figure out how to attach them to a biodegradable scaffold."
Atala's method involved painting several coats of Kaitlyne's muscle cells on the outer surface of a bladder-shaped mold made of collagen. The inside of the scaffold was covered with her urothelial cells. The whole structure was then immersed in a nutrient bath and put in an incubator at 90 degrees Fahrenheit. Ten days later the bladder, looking like a shiny pink ball, was ready for implantation. Once in the body, if all went well, natural processes would take over and allow the tissue to mature. Five years after her implant, Kaitlyne lives without diapers, has normal bladder capacity, no longer suffers from kidney or urinary tract infections, and has a dramatically improved quality of life.
Critics caution that this is a small trial and that the implants need a longer follow-up. And technically, Atala has yet to create and implant an entire bladder; the ureters at the top and the sphincters at the base are still the originals. He is expanding clinical trials for the artificial bladder to include more populations who could benefit, such as bladder cancer patients. He is also working on engineering other body parts—the liver, nerves, heart valves, and pancreas. Next in line for clinical trials: blood vessels.
Bijal Trivedi
14. Fast-Food Fats Prove Health Hazard
The dangers of trans-fatty acids — a cornerstone of fast-food cooking — were confirmed in June, when a study at Wake Forest University in Winston-Salem, North Carolina, revealed that even small daily amounts of trans fats led to alarming patterns of weight gain, atherosclerosis, and insulin resistance in monkeys.
Trans fats are the partially hydrogenated vegetable oils in the fryers at most fast-food chains; they are also used in many commercial cookies, pies, and crackers. These fats are commercially popular because they are shelf-stable and resistant to high heat. In recent years, though, they've become public health enemy number one, as evidence mounted that they contribute to heart disease, high cholesterol, and type 2 diabetes. In early 2006 new Food and Drug Administration rules went into effect requiring food labels to show trans fat content; in September the city of New York proposed severely limiting the use of trans fats in local restaurants.
Led by biochemist and pathologist Lawrence Rudel, the Wake Forest study set out to document the effects of a high trans-fat diet on atherosclerosis. But the results showed an impact far beyond hardened arteries. Two groups of male vervet monkeys were fed on different regimens for six years. Although the total calories and total dietary fat were the same for each group, the type of fat was not. One group received trans fats; the other received traditional monounsaturated fats. Over the six years, monkeys on the trans-fat diet added an average of 7.2 percent of their body mass, while the other group averaged just a 1.8 percent increase. Worse, the new weight from trans fats showed up mostly around the abdomen, a pattern strongly associated with cardiovascular disease in humans.
Ominously, the obesity-inducing monkey grub was not so different from a mainstream American diet. "The trans-fatty acids were roughly 8 percent of total energy," Rudel says. "That's high, but not outside the reported range for people who eat a lot of french fries and Krispy Kremes."
Commenting in the New England Journal of Medicine, Walter Willett, a nutritional epidemiologist at the Harvard School of Public Health, proclaimed that trans fats are probably a bigger public health problem than either food contamination or pesticides. Biochemists don't know exactly why they are so damaging, but the monkey study has one clear implication, Willett wrote: "Trans fats are clearly toxic to humans and have no place in human diets."
Kathleen McGowan
18.Drugs Aim to Silence Bad Genes
Less than a decade after a powerful gene-silencing method — RNA interference, or just RNAi — was discovered, the field's pioneers have not only won the 2006 Nobel Prize in Physiology or Medicine but have also helped launch an entirely new class of drugs into human clinical trials. Two of these drugs use RNAi to shut down genes involved in macular degeneration, the leading cause of blindness in the elderly, and a third disables a deadly pneumonia-causing virus. Other potential RNAi therapies target HIV, hepatitis B and C, high blood cholesterol, cancer, and even diseases like Huntington's.
Yet a mouse study reported in May by Mark Kay's lab at the Stanford University School of Medicine delivered some sobering news about RNAi. This form of gene silencing is triggered by a short piece of double-stranded RNA (the chemical cousin to DNA) that matches the gene. When given this signal, RNAi machinery already present in our cells takes over. So in an attempt to cure mice of hepatitis B, Kay's team flooded their livers with double-stranded RNA from a gene transfer vector. Within a few weeks, however, most of the mice died of liver failure. In expanded tests, 36 out of 49 different double-stranded RNAs caused liver injury, and 23 eventually killed the mice. It appears that the scientists' RNAs overloaded the natural RNAi machinery within the liver cells, preventing the cells' own double-stranded RNAs from doing their work of regulating certain genes.
All drugs can be toxic at sufficiently high doses, Kay emphasizes. The challenge with any new drug is to find a range of doses high enough to be effective, yet low enough to be safe. "Based on all the data we have," says Kay, "I'm still very optimistic that the therapeutic window is pretty big." One double-stranded RNA his lab tested was able to inactivate hepatitis B for more than a year without any apparent harm to the mice.
Kyla Dunn
19.World Trade Center Fallout Fails Health Test
Five years later, the health impact of the September 11 attacks is becoming more apparent. In September 2006 a report by the World Trade Center Worker and Volunteer Medical Screening Program, coordinated by the Mount Sinai School of Medicine in New York City, revealed widespread, persistent respiratory illness among rescue and recovery workers who were at the site on that fateful day.
The findings, published in the journal Environmental HealthPerspectives, found that of 9,442 workers screened — about one-fourth of the estimated total number of responders — 69 percent had new or worsening respiratory problems, including asthma, chronic sinusitis, wheezing, throat irritation, or the dry, hacking "World Trade Center cough."
Smoke and dust clouds from Ground Zero carried thousands of tons of caustic dust, as corrosive as drain cleaner, laced with powdered building materials like glass, gypsum, and asbestos. Chlorine from paper and plastics combined with organic materials, creating poisonous metal-rich gases and ultrafine particles. One analysis likened the air to samples from the eruption of Mount St. Helens. "Due to the horrific and unprecedented nature of the exposures at Ground Zero and the Staten Island landfill, we can only begin to guess at what the future holds for these responders," Robin Herbert, codirector of the screening program, told Congress during testimony after the report's release.
The report affirmed what whistle-blowers have alleged all along: that the burning pile of debris at the World Trade Center site was extremely hazardous. During the weeks directly after the attacks, the Environmental Protection Agency insisted that the air was safe to breathe — a reassurance repeated by officials, including New York City mayor Rudolph Giuliani. (EPA officials now say that their statements at the time referred to the air in lower Manhattan overall.)
"This is bittersweet vindication," says attorney Joel Kupferman of the New York Environmental Law and Justice Project, who is representing affected residents, workers, and students in the World Trade Center area. The Mount Sinai team plans to release other studies regarding physical and psychological problems among the workers.
Kathleen McGowan
23.Mouse Breast Grown in Lab
In January an international team proved that to make a breast, all you need is a single cell — in lab mice, at least. After isolating a mammary stem cell from mouse breast tissue, molecular biologist Jane Visvader and oncologist Geoffrey Lindeman of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, managed to grow a functional breast, complete with milk-producing glands and ducts.
The discovery of this stem cell could explain why some breast cancers recur despite aggressive chemotherapy. Chemotherapy drugs tend to target rapidly dividing cells, because fast replication is a hallmark of cancer cells. But stem cells are slower paced, which means that mutant versions — which might give rise to a variety of tumor-causing cells — could survive the treatment. Those malignant cells might then reseed the breast with cancer.
Visvader and Lindeman are looking for breast stem cells in normal and cancerous human tissues. The researchers are also hunting for marker proteins that could distinguish normal stem cells from cancerous ones, making it possible to target the abnormal ones with therapeutic drugs. In theory, healthy stem cells could also be incited to regrow breast tissue after cancer surgery, offering an alternative to reconstructive surgery. The catch is that the hormones needed for breast development could also promote cancer growth.
Kathy A. Svitil
24.Bird Flu Risk Explained
In the first two months of 2006, the spread of avian flu strain H5N1 in Africa and Europe fanned fears that it might also spread among humans. Yet despite killing more than half the humans it infected, H5N1 has been implicated in little more than 150 deaths since 2004. This year virologists began to decode why H5N1 can be so lethal and yet difficult to spread.
In March University of Wisconsin virologist Yoshihiro Kawaoka looked for H5N1 receptors in the human respiratory tract and found them only deep within the lungs, on the tiny air sacs through which oxygen passes into blood. That deep location would make it difficult for an infected person to spread the avian flu virus through coughing or sneezing.
When it does infect, though, H5N1 is a killer. A reconstruction of the 1918 flu, which killed more than 20 million people, may explain why. When University of Washington School of Medicine virologists John Kash and Michael Katze infected mice with a reconstructed 1918 virus, the animals produced high levels of cytokines, chemical messengers that trigger a powerful immune response. In a separate study, Menno de Jong of the Oxford University Clinical Research Unit in Ho Chi Minh City, Vietnam, found higher levels of cytokines in tissues from H5N1 victims than in those with ordinary seasonal flu.
The implication is that avian flu, like the 1918 flu virus, may trigger an unusually intense, potentially lethal inflammatory response. Such a reaction is likely to be stronger in young, healthy adults, Kash notes, which could help explain why H5N1, like the 1918 flu, is just as adept at killing young adults as it is the elderly and very young.
Jocelyn Selim
25.First Face Transplant
On November 27, 2005, a team of French surgeons led by Jean-Michel Dubernard of the Édouard Herriot Hospital in Lyon successfully performed the world's first partial face transplant. The patient was Isabelle Dinoire, a 38-year-old Frenchwoman who had been so severely disfigured when her dog scratched and chewed off her face six months earlier that normal surgical repair was impossible. The procedure, which involved attaching the nose, chin, cheeks, and lips of a 46-year-old brain-dead woman, set off a firestorm of criticism that lingered even after the French surgeons declared in July 2006, in the medical journal The Lancet, that the graft was "successful with respect to appearance, sensitivity, and acceptance by the patient."
Clinicians and researchers have raised ethical questions about the transplant, as well as concerns about whether Dinoire was stable enough to give informed consent for the procedure—which dips into uncharted issues involving the relationship between the face and personal identity—and for the regimen of immunosuppressive drugs she must now take for the rest of her life. However, regenerative medicine expert Patrick Warnke of the University of Kiel in Germany (who was not part of the transplant team) points out that "there was no quality of life for the patient without major parts of her face. After the procedure she seemed to feel much better. She was involved in the decision about the means of her reconstruction, according to my information. If she can compete with the restraints of lifelong immunosuppression, then we must respect this somehow."
Kathy A. Svitil
28.New HIV Drugs
Medical researchers launched a new assault on AIDS in 2006, announcing that three new categories of anti-HIV drugs are in the pipeline. Whereas most previous HIV drugs block enzymes the virus uses to copy itself, the new ones take aim at different stages in the virus's life cycle (the virus is colored green in the micrograph below). Drugs known as entry inhibitors (Pfizer's maraviroc and Schering-Plough's vicriviroc) stop the virus from entering healthy cells by binding to receptors on the cells' surfaces. Integrase inhibitors (Merck's MK-0518 and Gilead Sciences' GS 9137) prevent viral DNA from incorporating itself into the human cell's chromosomes. Finally, maturation inhibitors (Panacos Pharmaceuticals' bevirimat) prevent one of HIV's key structural proteins from forming. All could reach the market by 2009. "Every time we can find a new mechanism to inhibit the virus, it gives us a big advantage," says Bruce Walker, director of the Partners AIDS Research Center at Massachusetts General Hospital and a professor at Harvard Medical School. "Considering that 20 years ago we had nothing, it's an amazing accomplishment."
Susan Karlin
31.British Clinical Drug Trial Goes Spectacularly Awry
In March the British clinical trials company Parexel gave an experimental drug called TGN1412 to eight patients. TGN1412, a monoclonal antibody developed by TeGenero of Germany, was intended to treat leukemia and autoimmune diseases like arthritis. Instead, six of the test subjects wound up with massive organ failure; the only two unaffected were those who received a placebo.
Tests in mice and nonhuman primates had shown TGN1412 to be safe, but when it was injected into humans — in a dose less than 1/500 of what was given to monkeys — it caused a massive release of infection-fighting T cells that overstimulated the patients' immune systems, resulting in multiple organ failure. The discrepancy in effect may result from a subtle difference between animal and human immune systems, says immunologist James Riley of the University of Pennsylvania. In mice, TGN1412 primarily triggered regulatory T cells, which block the action of other T cells (and thereby reduce autoimmune reactions, wherein immune cells turn on the body's own cells). In humans, however, the drug seemed to activate regular T cells, sparking the immune-system meltdown. Riley believes that the design of this particular trial was inadequate. "Clinical trial designs that test such novel and potentially dangerous biologic therapies should only treat one patient at a time, followed by a reasonable period of time so that adverse events can be monitored," he says.
Regulatory agencies in Europe and the United States are reviewing how to use this new information to improve safety in future drug trials. The British equivalent of the F.D.A. investigated but found "no critical or major deficiencies" in the manufacture and handling of TGN1412, or in the testing and handling of the subjects. The agency did, however, find that the company had inadequate procedures for dealing with emergencies. TeGenero filed for bankruptcy in July. Meanwhile, the six subjects continue to suffer from severely damaged immune systems, and they are likely to be more vulnerable to disease for the rest of their lives.
Nicholas Bakalar
44.Stem Cells Reverse Parkinson's in Rats
Injecting neurons derived from human embryonic stem cells into rats suffering from Parkinson's-like symptoms allowed the animals to regain movement, according to a study led by neurologist Steven Goldman of the University of Rochester Medical Center. The downside is that the transplanted cells also fostered the growth of benign brain tumors.
Goldman's work builds on previous studies that explored the developmental cues involved in directing an embryonic stem cell to become a functioning neuron. He improved the technique by culturing the stem cells with astrocytes, cells that guide the maturing neurons, that he had taken from the dopamine-producing region of the rat brain. Up to 80 percent of the stem cells cultivated this way then began functioning like dopamine-producing neurons, Goldman reported in November in the journal Nature Medicine. When injected into rats with an artificially induced form of Parkinson's, the cells worked, as demonstrated by the animals' renewed ability to move.
The benign tumors — masses of dividing cells — that formed around each injection site may have been caused by immature precursor cells, neural cells that did not transform into neurons but that retained the ability to divide. Selecting for injection only the neural cells that are destined to become neurons will be the key to success, Goldman says.
Kathleen McGowan
49.
Power of Hallucinogenic Mushrooms Revealed
Call it a 'shroom with a view: Researchers at Johns Hopkins University found that people who took psilocybin, the active ingredient in hallucinogenic mushrooms, ranked the experience as one of the most meaningful experiences in their life. This is the first detailed examination of the psychological impact of psilocybin since the late 1960s, when hallucinogens came under regulatory scrutiny.
Roland Griffiths and his colleagues worked with 36 subjects who had never taken hallucinogens before, but all reported at least intermittent participation in religious or spiritual activities such as church services, prayer, or meditation. In two or three eight-hour sessions, with two months in between each session, the volunteers were given either psilocybin or Ritalin. Seven hours later, and again months afterward, they completed questionnaires about their experience. More than 60 percent of the subjects who received psilocybin had what they described as a "complete mystical experience." Only 11 percent of the placebo group did. Two months later, 71 percent recalled it as one of the five most spiritually significant events in their lives.
Griffiths and a growing number of researchers believe that psilocybin may yield further benefits for the treatment of depression and anxiety. At the same time, he strongly advises against recreational use of the drug. "The risks are substantial," he says. Taking 'shrooms "can precipitate an enduring psychological illness such as schizophrenia. It can lead to panic, fear, paranoia, and, as a consequence, dangerous behaviors."
Stephen Ornes
53.Low-Fat Diet A Bust?
The largest-ever experimental study examining whether a low-fat diet can prevent cancer and heart disease brought discouraging results. After following 48,835 postmenopausal women for eight years, scientists concluded that cutting fat from the diet doesn't significantly reduce the incidence of breast or colorectal cancer, heart disease, or stroke. Results of the $415 million trial, part of the National Institutes of Health's Women's Health Initiative, were reported in three papers in the Journal of the American Medical Association.
Revised ideas about the role of fat in disease could help explain the murky data, notes Michael Thun, who heads epidemiological research for the American Cancer Society. For example, women in the study cut their total fat intake rather than specifically targeting saturated fats and trans fats, which are now known to contribute to heart disease risk. Cancer researchers are also starting to focus more on risks from obesity. "The evidence base has become very strong that it's being fat rather than eating fat that's associated with risk," Thun says.
He and others plan to follow the women for an additional five years for more information. Meanwhile, the best advice from experts is to eat less saturated and trans fats and more fruits and vegetables.
Apoorva Mandavilli
98.Fat Vaccine Works in Rats
In August, immunologist Kim Janda of the Scripps Research Institute grabbed headlines with reports of a vaccine against obesity. The vaccine triggers an immune response that targets ghrelin, a hormone naturally made in the gut and transported to the brain; ghrelin spikes with hunger and is thought to stimulate the storage of body fat.
In the study, rats that received the vaccine ate the same amount of food as the control group, but they gained less weight and had 20 percent less body fat. "I expected them to eat less, but it appears that what we saw was a result of metabolism," Janda says. "Losing weight, losing fat — can't ask for anything more than that!"
Now the reality check: The researchers followed the rats for only one week after the animals received their last booster shots. Long-term results could be very different. Michael Schwartz, professor of medicine at the University of Washington at Seattle, warns that the weight loss could prompt the body to compensate by making more of other weight-related hormones. Meanwhile, neuroscientist William Colmers of the University of Alberta worries about the wisdom of vaccinating the body against one of its own molecules. "It's an intriguing idea, but it worries me considerably," he says. "I sure as hell wouldn't take it, no matter how fat I was."
Apoorva Mandavilli
