By Wendy Elliman, Hadassah Magazine
December 2003 Vol. 85 No.4
Noam Turgeman's stomach problems began in high school. Doctors dismissed the boy's stomachaches and diarrhea as stress related. "Once your exams are over, you'll be fine!" they assured him. But Turgeman wasn't fine. "You're uptight about going into the army," they explained. "Don't worry. You'll be fine. Everyone is."
Four months after his Israel Defense Forces induction, Turgeman, then 19, was given a medical discharge. The stomachaches had become unbearable, an IDF physician had ordered a colonoscopy, and the test had incontrovertibly shown that the young man had Crohn's disease, a chronic inflammation of the intestines.
"By then, I was in really bad shape," Turgeman says. "In addition to the cramping and pain from my ulcerated intestines, I was suffering rectal bleeding and crippling fatigue. I was anemic, losing weight and had frequent fevers. The doctors gave me steroids and a bunch of other medications, most of which had awful side effects and did nothing to control the symptoms. Every few weeks I was back in the hospital."
During the next five years, Turgeman managed to complete college, but because of his illness he couldn't keep a job. "There wasn't a week I didn't call in sick at least once," he says. "What employer puts up with that?"
Close to desperation, Turgeman was among 10 people with resistant Crohn's disease who volunteered in the fall of 2002 for a 16-week medical trial at the Hadassah–Hebrew University Medical Center at Ein Karem. Today, over a year after completion of that trial, he is still symptom-free. "I sometimes forget I was ever ill," he says. "The treatment gave me back my life!"
"In nine of our ten study candidates, the results have been equally good," says Dr. Yaron Ilan, head of the Department of Medicine at Hadassah, and "father" of the new treatment. "They're enjoying their first complete remission in years, without any observable side effects. We don't know how long it will last, but these patients have been free of all medication for over a year."
The Hadassah team—Dr. Ilan (also head of the gastroenterology unit) with Drs. Eran Goldin, Eran Yisraeli, Oren Shibolet and Maya Margalit—presented their landmark study at the American Gastroenterological Association Conference in Orlando, Florida, in May 2003, and began their second-phase clinical trial at Hadassah shortly afterward.
"If the Phase 2 results are as good as expected, we'll move to a multicenter trial," says Dr. Ilan. "Mount Sinai Medical Center in New York wants to be involved; Dr. Burrill B. Crohn, in 1932 the first to describe the disease, was a physician there."
The treatment that has given Noam Turgeman back his life is not so much a new medication as a new approach to healing. "What we're doing is educating the defective immune system, teaching it not to attack the colon," says Dr. Ilan. "We hope this approach will ultimately heal not only inflammatory bowel disease but all illnesses resulting from malfunctioning immune systems."
The new approach actually has roots that go back over 2,000 years to a talmudic passage, bizarrely sanctioning consumption of a sick, unkosher animal. "A person bitten by a rabid dog is permitted to heal himself by eating the liver of that same mad dog," says Masekhet Yoma.
"Today, we call this ‘oral tolerance induction,'" explains Dr. Ilan. "We began not with the Talmud but with a question first asked scientifically about 100 years ago: ‘How can we eat chicken soup, hamburgers and other foreign proteins when the body's immune system is designed to protect us by ruthlessly hunting down the foreign proteins and eliminating them? Why doesn't the healthy immune system unleash itself on the food we eat?' We theorized there must be a special substance, an antigen, in our gut which prevents it from doing so."
Maybe, they thought, in inflammatory bowel diseases (Crohn's, ulcerative colitis), this all-important antigen is faulty or missing. Maybe the digestive system becomes inflamed because the immune system attacks the food passing through. And maybe, if the missing antigen is replaced, it will signal that food is not a life-threatening intruder—and thus end years of suffering for millions of people worldwide.
Five years ago, with funding from Enzo Biochem of New York, Dr. Ilan and his team made a preparation from colon-derived proteins from mice and rats. Fed to rodents with inflamed intestines, it blocked the autoimmune response that triggers inflammatory bowel disease.
"To our enormous excitement, the sick animals not only tolerated their food but also recovered from their disease," says Dr. Ilan. "Their symptoms—diarrhea, colon ulcers, swelling and adhesions in the intestines and peritoneum—diminished or completely disappeared. It was then we realized our findings were in line with the improbable rabbinic urging. The mad dog of the Talmud almost certainly produced antigens against rabies, and stored some of them in the liver. Eating them might combat the infection. So the talmudic theory of oral tolerance induction resembles what we found in Hadassah's labs—with the difference that today we have technology to isolate proteins and convert them into pills, rather than feed entrails to our patients."
This study, published in American Journal of Gastroenterology in April 1999, stirred interest worldwide. Patent in hand, the Hadassah team designed a clinical protocol.
"With Helsinki Committee and Israel Health Ministry permission, we recruited 10 subjects, Noam Turgeman among them," says Dr. Ilan. "We custom-designed their medication, isolating proteins from the mucosa of each patient's colon, and making the proteins into a drug taken orally, three times a week, for 16 weeks. With each patient receiving his own proteins, immune system suppression was needless and there were no side effects."
In this Phase 1 study, all 10 patients received a medication. Phase 2, however, is a double-blind, with half the 30 taking a placebo. Although neither patients nor researchers officially know who is taking what until the study ends, Nilla Hemed, R.N., has no doubts about who's getting the medication.
"The study subjects fill out weekly forms, which I compile, grading how they feel, how often they're in the bathroom, what they do there and the degree of stomach pain," she says. "Half the group feel terrible and are in the toilet 20 times a day. The others feel really good, have no pain and visit the bathroom at most four times a day."
Buoyed by their success so far in "educating" the defective immune system, Dr. Ilan and his team believe their discovery has far wider application.
"We're hopeful oral tolerance can be effective in other conditions complicated by the immune response," says Dr. Ilan. "The small bowel has a unique ability to medicate the immune system by exposing cells to specific proteins. We believe we can use this ability to educate cells that travel all over the body."
Educated cells could prevent graft- versus-host disease—the body's life-threatening rejection of grafts and organ transplants. Organ-transplant patients protect themselves against this immune system assault on foreign transplanted tissues by taking debilitating and costly immunosuppressive therapy for life.
Infectious diseases, too, may fall before the new technology. "The infectious agent triggers an immune response," explains Dr. Ilan. "But in some infections, this response wages war on healthy cells along with the sick ones, contributing to the disease process and causing more damage than the disease does. In hepatitis—especially its virulent B and C forms, for example—the immune system attacks the liver instead of the virus. If we can control the immune response to infection by inducing oral tolerance, we'll open the door to new ways of treating patients and ultimately managing the disease."
With Enzo Biochem, Hadassah has just finished a Phase 2 clinical trial in 50 hepatitis patients. They achieved a 40-percent response rate, which is higher than with interferon. (A protein that occurs naturally in the body, interferon is part of the immune response. First identified in 1957, a man-made copy of the substance is now used as therapy in cancers, hepatitis and other diseases.) There were no side effects, and they are now planning a Phase 3 study.
The team has also applied the oral tolerance induction technique to malignant liver tumors in animal models. "We're medicating the immune system via the small bowel to fight tumors, and the results so far have been very good," says Dr. Ilan.
If the promise held by Hadassah's revolutionary approach is borne out, it looks as though the stomach, increasingly discredited as the way to a man's heart, will instead become a major highway to health and healing.