Beyond the Book of Life

If the amount of clinical testing seems surprising, it's probably because the medical part of the epigenetics story is unfolding in reverse: doctors had the drugs long before they had a theory suggesting how to use them properly. Indeed, several of the drugs now being tested against cancer have been around for decades, but in the past were used in the wrong way for the wrong reason. Azacitidine, for example, was first discovered in Czechoslovakia in the 1960s as a traditional chemotherapy drug, and doctors used it to kill cancer cells the old-fashioned way: giving as much as patients could tolerate. Jones, a South African by birth who now heads the Norris Comprehensive Cancer Center at USC, discovered in the 1980s that the drug had another mode of action: it could turn genes back on by stripping away the "duct tape" of DNA methylation that muffled genes. This suggested a different kind of attack on cancer—not by killing cancer cells outright, but by reversing the epigenetic changes that make a cell cancerous in the first place.

In the 1980s, as a young oncology fellow at Mount Sinai School of Medicine in New York, Lewis Silverman proposed testing azacitidine as an epigenetic drug—that is, at lower doses than is typical for traditional chemotherapy, where it still might be effective reversing silenced genes. Silverman has since shown that low doses of the drug reduce the symptoms of a type of leukemia and allows patients to live longer. The Food and Drug Administration approved azacitidine in May 2004; the drug is now marketed as Vidaza.

A different class of epigenetic drug has emerged from work at Harvard, Columbia and Memorial Sloan-Kettering Cancer Center in New York. In addition to the silencing effect of methylation, genes can be turned on and off by enzymes that tighten or loosen the packaging of DNA. Paul Marks and Ronald Breslow at Columbia created a small molecule, called vorinostat, that blocks the action of the enzymes that tamper with DNA's packaging, thus turning inactivated genes back on. That drug was approved by the FDA in 2006 for a rare form of lymphoma and is now being tested against a number of other cancers; Merck markets the drug as Zolinza. Part of the current clinical excitement is that there are already hints that combinations of these and second-generation drugs may be more effective at reversing the epigenetic changes in cancer cells.

Researchers remain guarded in their optimism. Issa concedes that the first-generation epigenetic drugs have not included a home run like Gleevec, the molecular treatment for chronic myeloid leukemia that produces dramatic and lasting remissions. And it is not unusual for deleterious side effects to become more apparent as drugs are used more widely—a particular concern in the case of drugs that have the potential to modify gene expression broadly in normal cells. But people who have witnessed the explosion of promising results in the past year have difficulty suppressing their excitement. "The promise is staggering," says Allis.

The stakes in epigenetics go well beyond clinical therapies, however. There have been hints from laboratory experiments and epidemiological studies that epigenetic changes in one generation—caused, for example, by smoking or diet—can be passed on to children and even grandchildren. Reik, who is also associate director of the Babraham Institute in Cambridge, is investigating how the overlay of epigenetic changes is erased from DNA when mice make their germ cells—how all the epigenetic changes, like some microscopic version of duct tape, get stripped off the DNA that goes into the sperm in males and eggs in females. "People are now beginning to realize that there are probably things that don't get wiped out or erased in the germ cells," he says, "so these are so-called epimutations that can be passed on from parents to children and to grandchildren—not genetic changes passed on, like Mendel, but an epimutation.

"We don't know how common this might be," Reik adds, choosing his words carefully, "but it's potentially quite revolutionary. It's not only challenging Mendel, but potentially challenging even Darwin. We are very careful when we talk about these things."

© 2009