Beyond the Book of Life

The interest in epigenetics has assumed critical mass in the past 10 years for several reasons. The Human Genome Project, often touted as "biology's moonshot," provided the basic text of life, in the form of the complete human sequence of DNA, but scientists have had a hard time linking specific genetic causes to many common illnesses. The role of "misspelled" DNA (in the form of both classic mutations and genetic variation, first teased out in the 19th century by the monk Gregor Mendel) has turned out to explain, in the words of a recent New England Journal of Medicinecommentator, "only a small fraction of disease." "We were all raised on the Watson and Crick concept of DNA-driven inheritance," Allis says. "It turns out that epigenetics may be even more responsible for gene expression and disease than DNA alone, especially in more advanced multicellular organisms." In the 1990s, meanwhile, scientists like Allis reported basic but breathtaking discoveries that showed how several groups of enzymes, common to every cell, could create epimutations without ever changing the DNA script.

Basic research has shown that enzymes can tamper with genetic information in at least two distinct ways. In some cases, the on-off switch of a gene can be smothered when an enzyme attaches chemicals to the DNA; known as DNA methy-lation, this process essentially silences a gene that should be on. In other cases, a separate class of enzyme improperly disrupts the normal cellular packaging of DNA. Typically, the gossamer thread of DNA is wound around a spool of protein called histone; when this second class of enzymes strips away part of the packaging, the DNA becomes so tightly wound up that it can't loosen up enough to be read by the cell. In effect, the slip jacket for specific genes is so tight that it's impossible to crack open the spine and get a glimpse of the genetic text. Conversely, sometimes genes that should remain permanently interred in a tomb of histone suddenly come back to life, like some cellular version of Night of the Living Dead.

In the past five years, the evidence has become "absolutely rock solid" to cancer researchers that epigenetic changes play a fundamental role in cancer, according to Robert A. Weinberg, an elder statesman of cancer biology at the Whitehead Institute in Cambridge, Mass. DNA methylation, he adds, "may ultimately be far more important than gene mutation in shutting down tumor suppressor genes," one of the cell's main mechanisms to short-circuit an incipient cancer.

Each epigenetic change seems to leave a chemical flag, or "mark," on the DNA, and hence researchers are intensely cataloging these marks into "epigenomes" as a possible clue to diagnosis, prognosis and perhaps even prevention of disease. Unlike genetic markers, which reveal small "typographic" variations in the spelling of genes, epigenetic markers indicate places where entire genes have been silenced or activated. Paula Vertino of the Emory University School of Medicine, for example, has identified patches of DNA that seem especially prone to be inappropriately silenced or activated in breast and lung cancer; researchers at Johns Hopkins have used epigenetic markers in brain-cancer cells to predict which patients are likelier to benefit from chemotherapy. Recent laboratory findings suggest that deciphering the layers of genetic control modifying DNA has implications not just for cancer, but also for chronic diseases associated with aging, like heart disease and diabetes; for mental disorders like autism and depression; for stem-cell biology; and even for our notions of what constitutes an inherited disease. Everything is up for grabs.

"There's only one genome," says Wolf Reik, professor of epigenetics at the University of Cambridge in England, "but hundreds of epigenomes." And unlike string theory in physics, for example, epigenetics is neither an exotic intellectual idea nor a theory awaiting verificationby future data. The biology is real, and the practical effects have already reached the bedside.

In the 1990s, Stephen Baylin of Johns Hopkins University led the effort showing that epigenetic changes in DNA were associated with cancer; in fact, disruptions in tumor suppressor genes, which normally protect cells against cancer, are more often due to epigenetic silencing than outright mutation. In May, Baylin and Peter Jones of the University of Southern California received a three-year, $9.1 million grant to launch accelerated testing of epigenetic therapy in patients with lung, colon and breast cancer, with interim results promised within a year. The Hopkins group has presented preliminary results at recent meetings showing that a combination of two epigenetic drugs produced several responses (including one complete remission) in patients with advanced lung cancer. "The trials are still ongoing, and we don't know what percentage of patients will respond, if it will be 10 or 20 percent," says Baylin. "But we have had very robust responses, of both primary tumors and metastases, in non-small-cell lung cancer." "That's just extraordinary," says Foti of AACR, noting the poor prognosis for patients with these advanced cancers.