Genetic haul lifts hopes on Crohn's

Researchers find 32 links to disease

If finding disease-related genes is like fishing, then scientists have recently shifted from rods and reels to big nets, and they have just announced their biggest haul ever.

Researchers have pinpointed 32 genes linked to Crohn's disease, a dire gastrointestinal disorder that affects a half-million Americans, they said in the journal Nature Genetics last week.

That is the biggest reported catch for any disease, and the number may well rise to 100 genes or more, said Mark Daly of Massachusetts General Hospital and the Broad Institute in Cambridge, the study's senior author.

Crohn's disease is fast becoming a model of success in human genome research, scientists say, but not only for its numbers. Among the newly discovered genes, some are pointing the way to previously unsuspected biological villains that may help cause the disorder, and may prove vulnerable to attack by drugs.

Until now, public attention has largely focused on how the massive effort to discover genes will help individuals determine their risk of certain diseases.

But genome researchers say that it is more important by far to use the genes to ferret out what goes wrong in disease, and ultimately use that knowledge to design treatments - as they are beginning to do with diabetes and macular degeneration.

"I would say Crohn's disease has proved the paradigm," said Dr. Francis S. Collins, outgoing director of the National Human Genome Research Institute. "Namely, that by studying the genetic factors involved in a complicated disease, you can shine bright light on its causes that you never could have achieved any other way."

Crohn's patients suffer from chronic inflammation of the digestive tract, and while symptoms can vary greatly, they include abdominal pain, diarrhea, bleeding, and fever. More than two-thirds of patients need surgery at some point. To treat the disease, doctors mainly use drugs that ease inflammation or suppress the immune system, and the symptoms sometimes abate on their own, but there is no known cure.

Doctors long knew that Crohn's disease and other gastrointestinal problems tend to run in families, but had no way of knowing which genes were involved. And they knew patients' immune systems seemed to be overreacting, but it was not clear how.

Their best early clue came from mice with Crohn's-like defects: When the animals were raised in sterile conditions, they developed no symptoms. But when exposed to normal bacteria, the intestinal inflammation would begin.

In 2001, the same year that scientists completed a first-draft sequence of the full human genome, the first gene variant linked to Crohn's disease was identified. Tools for sequencing the genome -the full complement of genes - advanced rapidly, and by last year, 11 Crohn's genes had turned up.

Finding the genes is no simple task. The new Nature Genetics findings involved sifting through 635,000 bits of DNA on each of the genomes of more than 8,000 people, searching for places of variation between Crohn's patients and healthy control groups.

But the gene-fishing is only the beginning. Take, for example, the gene with the clunky name of "autophagy 16-Like 1," now confirmed as a risk factor for Crohn's.

The gene is known to be involved in a process called autophagy (pronounced aw-TAW-fa-jee) that has broad functions in the innate immune system - the body's first line of defense against infections - such as helping a cell chew up and spit out bacteria.

When researchers blocked the gene's action in normal human cells, they found the cells could no longer use autophagy to surround intestinal germs and target them for destruction, said Dr. Ramnik Xavier of Massachusetts General Hospital, who led that work.

Such findings are pushing a radical shift in the theory of how Crohn's develops, Xavier and others say. It appears that at least in some patients, the innate immune system is involved in Crohn's.

The genome research has helped produce a "fundamentally new concept" of Crohn's, said Dr. R. Balfour Sartor, chief medical adviser of the Crohn's and Colitis Foundation of America.

The idea, he said, is that in Crohn's disease, cells in the intestine have trouble using the weapons of the innate immune system - such as autophagy - to get rid of bacteria, so the immune system's second line of defense, big-gun T-cells, get called in, causing inflammation.

"As the T-cells are shooting at the bacteria, the body is the innocent bystander," Sartor said.

Along with their impact on research, the genome findings raise the prospect of finding new drugs for Crohn's - some of them possibly already available for other diseases.

One gene that the Crohn's genome studies have caught, IL23R, is known to be involved in the immune response and to make a protein that sits on the surface of white blood cells, meaning easy access for drugs to "fix" it.

In genomics parlance, it is a "druggable target," and researchers say efforts to develop an IL23R drug are well underway.

"This, of course, is the dream we all harbored for doing this work," Collins said. "That we would bump into some low-hanging fruit for therapeutics that wouldn't take another 12 or 15 years" to develop.

The autophagy findings are also prompting efforts to find drugs that will correct that process. There are compounds known to affect autophagy, Daly said, and researchers might need a year or two of experiments in test tubes and mice before they could begin human clinical trials.

There is one thing the genome findings decidedly do not do, researchers say.

The newfound genes cannot be used to screen people for Crohn's disease because they do not definitively determine who will get the disease; they merely increase the risk. The great majority of people who carry the risky genes do not develop Crohn's. And there is no known way of preventing it.

The abundant gene harvest represents important progress but also daunting complexity, said Dr. John Rioux of the University of Montreal and the Broad, who was involved in the Nature Genetics study.

"If it had been only a half-dozen genes that led to Crohn's disease, you could imagine splitting up the work - 'six genes, let's beat them to death in a very traditional way,' " he said. But "in a year or two, it's likely to be 100 or so."

Fortunately, the genes tend to cluster in a handful of key processes, such as autophagy or the T-cell response, which makes the numbers seem more tractable, and also raises the prospect that Crohn's patients could be divided into subtypes, each with its own optimal treatment.

But many of the genes have no known function, and it is critical to develop ways to determine quickly what they do, Rioux said.

For all the challenges ahead, the genomic work is changing the long-term outlook that Dr. Richard Grand, director of the Center for Inflammatory Bowel Disease Treatment and Research at Children's Hospital Boston, gives his patients.

"It's fair to say that the gene variants associated with Crohn's disease are an enormous breakthrough," and they offer the best "reasonable hope" in decades that the disease may be prevented or cured, he said.

When he speaks with patients these days, Grand said, "I tell them this is a time of breakthroughs."

Carey Goldberg can be reached at goldberg@globe.com.