March/April 2006

Epigenetics

Alexander Olek has developed tests to detect cancer early by measuring its subtle DNA changes.

By Peter Fairley

This article is the third in a series of 10 stories we're running over two weeks, covering today's most significant (and just plain cool) emerging technologies. It's part of our annual "10 Emerging Technologies" report, which appears in the March/April print issue of Technology Review.

Sequencing the human genome was far from the last step in explaining human genetics. Researchers still need to figure out which of the 20,000-plus human genes are active in any one cell at a given moment. Chemical modifications can interfere with the machinery of protein manufacture, shutting genes down directly or making chromosomes hard to unwind. Such chemical interactions constitute a second order of genetics known as epigenetics.

In the last five years, researchers have developed the first practical tools for identifying epigenetic interactions, and German biochemist Alexander Olek is one of the trailblazers. In 1998, Olek founded Berlin-based Epigenomics to create a rapid and sensitive test for gene methylation, a common DNA modification linked to cancer. The company's forthcoming tests will determine not only whether a patient has a certain cancer but also, in some cases, the severity of the cancer and the likelihood that it will respond to a particular treatment. "Alex has opened up a whole new way of doing diagnostics," says Stephan Beck, a researcher at the Wellcome Trust Sanger Institute in Cambridge, England, and an epigenetics pioneer.

Methylation adds four atoms to cytosine, one of the four DNA "letters," or nucleotides. The body naturally uses methylation to turn genes on and off: the additional atoms block the proteins that transcribe genes. But when something goes awry, methylation can unleash a tumor by silencing a gene that normally keeps cell growth in check. Removing a gene's natural methylation can also render a cell cancerous by activating a gene that is typically "off" in a particular tissue.

The problem is that methylated genes are hard to recognize in their native state. But Olek says Epigenomics has developed a method to detect as little as three picograms of methylated DNA; it will spot as few as three cancer cells in a tissue sample.

To create a practical diagnostic test for a given cancer, Epigenomics compares several thousand genes from cancerous and healthy cells, identifying changes in the methylation of one or more genes that correlate with the disease. Ultimately, the test examines the methylation states of only the relevant genes. The researchers go even further through a sort of epigenetic archeology: by examining the DNA in tissues from past clinical trials, they can identify the epigenetic signals in the patients who responded best or worst to a given treatment.

Philip Avner, an epigenetics pioneer at the Pasteur Institute in Paris, says that Epigenomics' test is a powerful tool for accurately diagnosing and understanding cancers at their earliest stages. "If we can't prevent cancer, at least we can treat it better," says Avner.