Health & Medicine

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

Read Discover's interview with Craig Mello, whose discovery of RNAi with Andrew Fire won the 2006 Nobel Prize in Physiology or Medicine.

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 Health Perspectives, 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

Tracking the 9/11debris: a new simulation helps pinpoint whose health is at risk.

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

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

The science of avian flu: answers to frequestly asked questions.

The finances of avian flu: a theoretical physicist uses dollars to track bird flu.