Celiac Disease and the Unforeseen Path to Discovery

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By Ellen Barlow

Mass General Hospital’s Alessio Fasano, MD, has transformed conventional thinking about autoimmune diseases.

Alessio Fasano, MD, is everywhere these days. The renowned head of the MGH Center for Celiac Research and Treatment has been in the news clarifying misconceptions about the gluten-free diet, at seminars demonstrating with finesse how to cook a gluten-free Italian meal, and flying around the world to present his latest research findings about celiac disease.

But most days are filled with seeing the patients who inspire him and tending to the daily details of critical research projects, knowing that even he may be surprised by where they lead. “Discovery often takes an unforeseeable path,” says Dr. Fasano, who is also chief of MassGeneral Hospital for Children’s division of pediatric gastroenterology and nutrition.

Dr. Fasano’s research has transformed conventional thinking about the causes of autoimmune diseases, which arise when the immune system mistakenly attacks the body’s own tissues. They are becoming alarmingly more common, and represent the third most common category of illness in the United States, after cancer and heart disease.

Celiac disease, one of the most common autoimmune disorders, is triggered by the gluten protein found in wheat, rye and barley. It affects approximately 1 in 133 people. People with celiac disease must eliminate gluten from their diet. Otherwise, their immune system can attack the lining of the small intestine. Untreated, celiac disease can trigger an array of other medical problems, some life-threatening.

Dr. Fasano’s serendipitous journey of medical discovery began with a failed attempt to develop a cholera vaccine while he was working at the Center for Vaccine Development at the University of Maryland School of Medicine. The cholera vaccine seemed promising in animal trials but, in humans, it triggered the diarrhea it was meant to prevent.

Determined to find out why, he tenaciously followed the clues. In 2000, several years after joining the University of Maryland faculty, he made a crucial discovery.

A Major Breakthrough

Conventional thinking held that the intestines weren’t supposed to leak. But Dr. Fasano  discovered a protein called zonulin that triggered the walls of the gut to open and allow in molecules from the environment. He and his team subsequently found that this “intestinal  permeability” was also how gluten entered the body to activate the chain of events leading to celiac disease.
In the years since, the scientific community has embraced the concept of gut permeability. It has been implicated in other autoimmune diseases, including multiple sclerosis, inflammatory bowel disease and diabetes. “It has gone viral,” Dr. Fasano says with the mischievous smile of someone who has patiently spent years explaining his discovery.

“If we’re able to stop the autoimmune process,” Dr. Fasano says, allowing himself to dream, “an entire world of possibilities opens for treating autoimmune diseases for which there are currently no solutions.”

The possibility that disease processes can be stopped by blocking overzealous zonulin action is tantalizing. Larazotide acetate­, an anti-zonulin drug created by his team, is now being developed and tested by Alba Therapeutics. It has progressed successfully through the early stages of clinical trials for celiac disease and will soon be undergoing advanced clinical trials. It could eventually prove useful for other diseases as well. Other researchers have found zonulin involved in diseases of the nervous system and cancers.

Listening to His Patients

“Dr. Fasano is a beloved figure in the celiac community because of his warmth, passion and drive to find a cure,” says Marilyn Geller, CEO of the Celiac Disease Foundation, on whose medical advisory board he serves. “People get a true sense that he cares about them.”

When Dr. Fasano moved to the United States 20 years ago, few people, including physicians, had heard of gluten or thought celiac disease was a problem outside Europe. This seemed odd to him so he convinced the Red Cross to sell him unusable blood samples to test for celiac. In 2003, he published his results, which showed that celiac disease is much more common than previously thought in the United States. Awareness makes earlier diagnoses much more likely now.

Another revelation arose from listening to patients who complained of celiac symptoms, but tested negative for the disease. He investigated and demonstrated the existence of a related disorder, now called non-celiac gluten sensitivity or gluten sensitivity. Symptoms may be similar—especially abdominal pain, chronic fatigue, headaches, diarrhea or constipation—but gluten sensitivity does not result in damage to the intestines or possibly lead to lymphoma, as can happen with celiac disease.

The Gluten-Free Diet

Currently the only way to treat celiac disease and gluten sensitivity is to avoid eating anything with even trace amounts of gluten. That’s hard. Gluten is in bread, pasta and baked goods. Often used in processed foods as an additive or preservative, it may lurk in salad dressing, soups and even candy.

Dr. Fasano suspects a fair number of the 100 million Americans currently consuming gluten-free products may in fact have gluten sensitivity or undiagnosed celiac disease. He strongly urges people who suspect they have a problem to be tested for celiac disease and other conditions that cause similar symptoms before going on the gluten-free diet, however.

“This is not the South Beach diet,” he says. “Treat this diet with respect as a medical treatment. For people with celiac disease, the gluten-free diet is like insulin for diabetics.”

The best way to stay healthy while eating gluten-free, Dr. Fasano believes, is to eat a variety of meats, seafood, fruits and vegetables that naturally don’t contain gluten. There are many commercially available gluten-free foods, but these products can be higher in fat and calories.

When he talks to patient groups about the gluten-free diet, he likes to demonstrate how easy it is to prepare healthy gluten-free meals liked the ones his mother cooked for him growing up. Like his mother—who still lives in Salerno on the southwest coast of Italy—he is a fantastic cook. In his book, Gluten Freedom, he includes adaptations of favorite recipes he learned from his mother.

“I can put together a great, healthy meal from scratch in a half hour,” Dr. Fasano says. In fact, he does just that at the end of long day, after he’s gone for a run or played tennis if there’s time.

There’s not much time in his day for hobbies, he admits. He owns a vintage Maserati car and a Harley Davidson motorcycle, both known for speed. But it is their beauty and engineering that he adores. It is similar to the awe he feels for the exquisite machinery of the human body.

More Clues to Find

Whether it’s his patients, Harvard Medical School students or doctoral candidates working in his lab, Dr. Fasano relishes teaching and mentoring others. At 58, he knows he’ll one day pass his quest for better therapies on to others, but for the foreseeable future, there is much more that he wants to do.

Dr. Fasano wants to know:  Among people with a genetic predisposition for celiac disease, some develop the condition at age 2, others at age 72 and some never at all. What accounts for the difference and can we prevent the switch from happening?

He has commenced an ambitious long-term study, called CDGEMM, following infants from birth who are at risk for celiac disease. Preliminary research indicates that there are metabolic changes in the patterns of bacteria in the intestines, months before someone develops celiac disease.

Identifying these changes could present an opportunity to prevent the autoimmune disorder. As he has many other times in his career, Dr. Fasano is setting off to prove it. “To be able to intervene and re-establish the balance would be the Holy Grail,” he says.