The US National Institutes of Health (NIH) handed out the first payments in a multi-million-dollar project to explore epigenomics last month. But some researchers are voicing concerns about the scientific and economic justification for this latest 'big biology' venture.

Epigenetics, described as "inheritance, but not as we know it"1, is now a blisteringly hot field. It is concerned with changes in gene expression that are typically inherited, but not caused by changes in gene sequence. In theory, epigenetic studies can help explain how the millions of cells in the human body can carry identical DNA but form completely different cell types, and perhaps why certain cells are susceptible to disease.

It’s not that epigenetics is totally useless. I just don’t see why it’s worth 190 million dollars. Kevin Struhl , Harvard Medical School

The NIH's epigenomics initiative is a plan for such studies on a grand scale including, for example, surveys in different human cell types of all the chemical tags, or epigenetic marks, that might control genes. The agency has now announced the recipients of the first US$18 million of funding. The project will eventually command$190 million over five years as part of the agency's 'Roadmap' programme.

The announcement has amplified rumbling criticism of the initiative. Eight prominent scientists in the field laid out their concerns in a letter2 published in Science on 3 October. Molecular biologist Hiten Madhani, the letter's lead signatory, has also set up an online petition to encourage others to register their opposition. "I hope the next NIH director just eliminates the programme lock, stock and barrel," says Madhani, who works at the University of California, San Francisco.

"We think it's a humongous waste of money for a lot of reasons," says Kevin Struhl of Harvard Medical School in Boston, Massachusetts, who is one of the letter's signatories.

Gene switches

Chromosomal DNA is a prime target of epigenetic studies. Credit: K. EWARD/BIOGRAFX/SPL

As the emphasis in biology is switching away from genetic sequence and towards the mechanisms by which gene activity is controlled, epigenetics is becoming increasingly popular. Many studies in the field focus on chemical alterations that can switch genes on and off, including modifications to the histone proteins with which DNA is packaged into chromatin.

As part of the NIH initiative, various groups will produce 'reference' epigenomes — maps in which the genetic sequence is overlaid with chemical tags in stem cells, embryonic cell lineages and other cell types. The project will also fund efforts to find new gene-regulating marks, as well as technologies that can identify these marks in individual cells, and projects to find links between such marks and disease.

But Madhani and others say that focusing on these types of modifications — which are found all over the genome — overlooks key processes, such as the work of transcription factors and other DNA-binding proteins, that determine where these marks go. A perfect illustration of how transcription factors trump epigenetic marks, they say, is recent work by researchers in Japan showing that just four proteins can reprogram an adult cell and transform it into an embryonic-like state3. The problem, says Struhl, is that "transcription is passé and epigenetics is cool. It's not that epigenetics is totally useless. I just don't see why it's worth \$190 million."

Some researchers in the field roll their eyes at these criticisms and say that this group and others have harped on for too long about the neglect of transcription factors. At meetings, "there is always a shouting match across the floor", says Peter Fraser, head of the chromatin laboratory at the Babraham Institute in Cambridge, UK. "It's going to be a combination of things that explain gene expression. Trying to integrate this stuff is what's important. When funding is tight," he says, "people squeal."

Alan Krensky, director of the NIH's Office of Portfolio Analysis and Strategic Initiatives, who is one of those leading the epigenomics initiative, says that the scientific community was consulted extensively over the programme and that a key aspect will be to integrate the information into ongoing research on transcription factors and other control mechanisms covered by different NIH grants. "This is not either/or by any means," he says. "Everything they're in favour of is part of the big picture."

The debate has implications beyond the United States — other countries are already running epigenomic projects. Earlier this year some researchers, led by Peter Jones of the USC/Norris Comprehensive Cancer Center in Los Angeles, California, called for the research community to coordinate an international human epigenome project4 — something Madhani calls "an ill-conceived, wasteful boondoggle".

Some of these issues might be thrashed out in December at a small meeting on epigenetic mechanisms to be held at Cold Spring Harbor Laboratory's Banbury Center in New York. But the discussion is likely to be heated. Mark Ptashne of the Memorial Sloane-Kettering Cancer Center in New York, warns: "My topic at Banbury is: can anyone stand up and defend an epigenome project?"