New possibilities for relief from digestive diseases

As a researcher in neurogastroenterology for 40 years, professor Khalil Bitar has spent his professional life studying the causes of perplexing and what frequently become embarrassing problems for humans—issues such as constipation, diarrhea and colon disease.

"Problems of the GI tract do not get as much light shined on them. But it's a serious problem,'' Bitar says. "If your colon is not working, you're constipated. One bowel movement a month? That's not a life.''

Bitar's years studying the complexities of smooth muscle and nerves from the GI tract, combined with the emergence of regenerative medicine, are bringing to the forefront new possibilities for relief. This summer, Bitar moved his research lab to Wake Forest Baptist Medical Center's Institute for Regenerative Medicine.

Besides collaborating with experts there, Bitar is working in partnership with Wake Forest Baptist physicians who specialize in neuromuscular or paralytic disorders of the stomach, small intestine and colon.

Bitar hopes that his work—his team has developed the first functional, laboratory built anal sphincter—will lead to treatment options for patients with severe forms of nausea and vomiting or constipation.

As Bitar's team honed its work in recent years, Dr. Kenneth Koch, chief of the section on gastroenterology at Wake Forest Baptist, was paying close attention. What he saw was a unique opportunity to combine Bitar's research with a clinical specialty area in need of new solutions.

Because Koch's patients face some of the most difficult motility disorders, as much as anyone he understood the significance of the work being done by Bitar and his team at the University of Michigan.

"Not only are neuromuscular disorders of the gastrointestinal tract frequently under-recognized by doctors or sometimes attributed to psychological problems, but even when diagnosed, there are few drugs available to treat such disorders, Koch says.

As for the existing surgical solutions, some of the problems can require the implantation of a stomach pacemaker or insertion of tubes into the stomach or small intestine. Other patients face removal of the entire colon, which requires the use, post-surgery, of a device such as a colostomy bag or cap, which can be difficult to cope with.

It was natural for Koch to suggest that Bitar join WFIRM, founded in 2004 under the leadership of Dr. Anthony Atala.

WFIRM has gained an international reputation in the field of regenerative medicine; its scientists were the first to implant an engineered organ, a bladder, into a human being in 1999. Other landmark research includes looking for ways to create cells in the laboratory for therapy, engineer solid organs experimentally, such as the liver and kidney, and applying regenerative medicine technologies to battlefield injuries.

After discussions with Atala and a visit that included a lecture at Wake Forest, Bitar decided to move his team to Winston-Salem.

"WFIRM is built to foster this kind of research,'' Bitar says. "And I was sold on the idea. I was convinced that this is a better place to be able to move this project faster into the clinical field.''

Larger implications

The adult patients seen by Koch and pediatric patients treated by Dr. John Fortunato at Wake Forest Baptist's Brenner Children's Hospital, often are diagnosed with paralysis of the muscles of the stomach (a condition called gastroparesis), which causes nausea and vomiting.

These and other patients also may have bloating and abdominal pain because of pseudo-obstruction (paralysis of the stomach, small bowel and colon). Some patients have abdominal pain and distention as a result of colonic inertia (paralysis of the colon) which causes severe constipation. Others have fecal incontinence, which is loss of regular control of the bowels because of paralysis of the anal sphincters.

The bioengineered anal sphincter Bitar's regenerative team created in mice is now close to being tested in large animals, the last step required by the U.S. Food and Drug Administration before human testing. If successful, the sphincters could resolve problems of fecal incontinence suffered by millions of patients.

Many people, mostly women, have "leakage," or fecal incontinence, and the bioengineered sphincter could cure that psychologically and socially devastating problem. Fecal incontinence is most often a result of anal sphincter damage during vaginal delivery of babies.

Bitar notes that problems with fecal incontinence may happen when doctors perform an episiotomy to help with delivery of the baby. During this procedure the sphincter may be injured and disrupted. When a sphincter is damaged, it's like an old rubber band with a small section stretched out and cut, he says. The damaged rubber band doesn't provide the same kind of closure force to stop the leakage.

Unless the tear is noticed and repaired at the time of delivery, the damage to the sphincter will at some later point in time result in incontinence, Bitar says.

"Even if they fix it three months later there is a possibility it's not going to regain its function,'' he says.

Bitar's work has implications beyond the sphincter.

As part of its research with the smooth muscles of the GI system, the team is creating tissue with its own nerves and muscles, unique to the GI system and built from the harvested cells of the subject. Bitar believes it may be possible to replace damaged GI organs or replace the paralyzed areas with bioengineered neuromuscular patches made from the person's own cells, rather than have entire organs removed because of an isolated problem.

"We would like to build pieces of intestine for replacement to help those patients instead of having to go for total removal of the colon. Maybe we can see if helping that paralyzed portion of the colon can regain some neuromuscular function.''

Bitar's work also holds out hope in helping children who are born with a paralyzed colon because of missing nerve and muscle elements or who are born with anal malformations. In both of those afflictions, current surgical procedures do not guarantee an acceptable solution.

Koch and Fortunato say they can envision regenerative medicine providing a better form of relief for some of their patients.

"Regenerative medicine approaches will lead the way to new treatments where portions of the weakened stomach muscle will be restored with bioengineered muscle and nerve, stomach function will be improved, and nausea and vomiting will be improved,'' Koch says.

Teaming up

The interaction of researchers with clinicians is a key piece to the success of regenerative medicine, says Rosemarie Hunziker, program director for the Division of Discovery Science and Technology with the National Institute of Biomedical Imaging and Bioengineering.

"It's absolutely essential,'' Hunziker says. "Researchers look at the underlying mechanics, but clinicians look at things from the practical point of view. Even though they have a very similar understanding of the problem, only the clinician … is going to implement the solution. So solutions have to be designed that they're practical enough to be utilized.''

WFIRM's director, Atala, agrees.

"As both a clinician and a researcher, I personally know that clinical work can inspire research,'' he says. "The clinicians who work with our institute make a wide range of contributions, from helping to identify medical problems that may be solvable with regenerative medicine therapies to co-leading projects to sharing their clinical expertise as we strategize about possible solutions and helping us evaluate new therapies.''

Another advantage of teaming clinicians with researchers in regenerative medicine is that one field builds off of another.

Bitar says he believes the work he is doing with sphincters can benefit researchers studying urinary incontinence.

"It's the same kind of muscle … there's a very great potential for helping people with urinary incontinence.''

The collaborative factor is evident already.

Since he started at Wake Forest Baptist in June, Bitar, whose WFIRM office is in the Piedmont Triad Research Park in downtown Winston-Salem, meets regularly with Koch and Fortunato, who are based on the medical center's main campus.

Bitar on occasion makes patient rounds with the doctors, putting a human face to some of the issues he's hopeful of having new solutions for within a few years.

"They're mothers, they're wives, having to suffer,'' he says. "I listened and saw them after surgery. It's essential for patients to know that in the future there might be a solution—and for us to know the human dimension of the problem.''