Fifteen years ago, any knowledge of the Cells of Cajal was buried deep in the basement of scientific discovery. It took more than a century for an extraordinary set of circumstances to bring, what is now one of the hottest areas in digestive tract research, to light. Here's how it happened.

The History

In 1893, Spanish physician and neuropathologist Santiago Ramon y Cajal, was the first to describe cells that are located between the nerve endings and smooth muscle cells in the gastrointestinal tract. Their location prompted him to call them "interstitial." They are now known as the Interstitial Cells of Cajal (ICC). Dr. Cajal is best known for proving that neurons, or nerve cells, are the basic unit of the central nervous system. He published, but did not pursue his ICC discovery -- he was absorbed in other research that later earned him the Nobel Prize .

"Not much else happened for a hundred years," recounts Mayo gastroenterologist and investigator Gianrico Farrugia, M.D. "It's odd how science is filtered and transferred. We could not have gotten to where the story is now heading had it not been for Cajal, a few coincidences, and Joe Szurszewski's discovery some years ago that electrical activity in smooth muscle of gut is not regular."

1969 Mayo Discovery in Gut Motor Patterns

Not many people would understand the license plate MMEC 69 that Mayo physiologist, Joseph Szurszewski, Ph.D., sports on his car. Clearly, he is proud of his discovery of the migrating myoelectrical complex (MMEC). Dr. Szurszewski recorded this interdigestive complex in the intestines of fasting dogs (Am J Physiol. 1969 Dec; 217(6):1757-1763). The discovery was a critical turning point in understanding the motor patterns of the GI tract. Almost a decade later, his findings were confirmed in humans by another group and the MMEC has been found in other mammals as well as in rodents and birds.

Listening to Dr. Szurszewski talk about gut motility is like listening to Mark Twain describe the Mississippi:

"Now I don't know when you had breakfast, but if you had it when I did around six o' clock, there would be a migrating motor complex, a band of strong contractions, somewhere in your GI tract now. You have a tube about 30 feet long. The complex starts in the stomach and majestically moves to the large intestine. That may take 90 minutes. When it reaches the large intestine, another complex begins in the stomach, as long as you are fasting. And it takes 90 minutes for it to travel the length of the small intestine, pushing ahead of it everything that's in the intestine. If you don't eat, still another one begins. But as soon as you do, it stops it cold wherever it happens to be. What's remarkable is whenever digestion from that meal is complete and the non-absorbable material needs to move on, another interdigestive complex begins, usually where the last one ended, and moves on. It's a remarkable pattern. It's been found in every animal species where we've looked for examples."

Serendipity

In the early 1990s, Kenton Sanders, Ph.D., a former postdoctoral fellow in Dr. Szurszewski's lab who now chairs the Department of Physiology & Cell Biology at the University of Nevada, Reno, was zipping across Japan at 160 mph on the Shinkansen High Speed Bullet Train, proofreading a translated manuscript for a group of Japanese hematologists. Although outside his field, he had agreed to the task -- a happy coincidence that led to the discovery of a new potential target for GI studies.

The hematologists had discovered that the protein they were studying in mice is also expressed in the wall of the intestine, specifically in the Interstitial Cells of Cajal. The mice had disturbances in gastrointestinal motility but the hematologists didn't make much of these disturbances because that was not the focus of their work. In looking at the images and reading about the changes in motility, Dr. Sanders hypothesized that the ICC failed to develop in animals that lacked the protein and that the change in motility was due to the absence of ICC.

"That was the turning point of what became a deluge of excellent scientific work, both basic and clinical, to discover the role of these cells," explains Dr. Szurszewski. "The Japanese hematologists were interested because of a cell receptor, called TK receptor. It turns out that the ICC are also dependent on TK receptor...so Kent Sanders ran with it, and others ran with it...and today it's probably one of the hottest research areas in the GI tract."

The Discovery of ICC as a Pacemaker of Motility

This research found that there were several specialized types of ICC, each playing a different role in relation to the smooth muscle of the gut. One type of ICC generates a pacemaker signal. Dr Farrugia's group found that calcium levels inside the ICC rise and fall several times a minute and that these calcium changes results in an oscillation in the membrane potential of smooth muscle cells.

"It moves up and down in a frequency," says Dr. Farrugia. "This is important because the muscle contracts at the positive part of the wave. The frequency of the wave therefore determines how often the gut contracts and the height how strongly it contracts."

Dr. Farrugia's group applied these observations to one of the most common GI ailments: constipation. Importantly, Simon Gibbons, Ph.D., in Dr Farrugia's laboratory found that where ICC had been depleted through excessive apoptosis (cell death), there was more constipation. They published these findings (Gastroenterology 118(1):14-21, 2000 and Gut 2002 Oct; 51(4):496-501) with National Institutes of Health funding, began exploring the mechanism by which the cells die.

"There are substances that cells require to stay alive, called trophic factors," explains Dr. Farrugia. "And it turns out that several trophic factors that are secreted from surrounding cells determine if the ICC live or die."

Dr. Farrugia's lab is now working with industry to determine targets that can be used to either decrease the apoptotic factors or increase the factors that keep ICC alive. The goal is a drug aimed at this target; a drug to combat constipation.

The research team has also furthered the understanding of the role that ICC play in other diseases, including diabetes. Complications of diabetes include a failure of the gut to work properly. The research team has been strengthened by the recruitment of ICC specialist, Tamas Ordog, M.D., and has now begun experiments to attempt to reverse the damage diabetes causes to ICC.

Drs. Farrugia and Szurszewski have also identified key molecules that underlie the specialized functions of ICC. One of these turns out to be carbon monoxide. Remarkably, ICC generate and release small amounts of the gas. Carbon monoxide acts as a signaling molecule to gut smooth muscle cells, controlling their excitability.

Says Dr. Farrugia, "It's been fascinating because we found a new function for a gas thought to be just a toxic gas to be avoided at all costs. Carbon monoxide is generated by ICC in a tightly regulated fashion, allowing the excitability of smooth muscle to be set to just the right level, then the muscle responds accordingly."

Multidisciplinary Collaboration

Mayo Clinic surgeon, Michael Sarr, M.D., is an important member of the research team. Dr. Sarr not only runs his own research program and participates in the development of experiments for the team but also isolates key tissue samples that allow experimental tests to be done in a timely fashion. The three researchers work together, consulting or serving as co-investigators on each others' grants.

"What we find in our experiments changes the way we treat patients," says Dr. Sarr. "We have something to offer the gastroenterologists because we see things in the OR that internists don't. And we're smart enough to ask them for help when we don't understand something. By collaborating in this multidisciplinary way at Mayo, everyone benefits. Besides, it's fun, a lot of fun."

Dr. Szurszewski concurs.

"We constantly benefit from the cooperation and confidence of our surgical colleagues," he says. "They know we are available to work with a biopsy any hour of the day or night. And that whatever we discover, we will get back to them for the benefit of their patients. At scientific meetings, we always try to relate our work to examples of human biology."

Dr. Farrugia and his colleagues are also pursuing a genetic link to constipation. Studies conducted with Mayo's cardiovascular investigators and with his gastroenterology colleagues has shown that people with an abnormality in a sodium channel not only have cardiovascular problems but also gut problems. Ongoing studies may uncover genetic links between gut problems and heart disease. But that's another story...Meantime, with scientists having discovered ICC in the urogenital tract, the pancreas, and possibly, the arteries, getting to the bottom of ICC function takes Cajal's discovery into its second century.

Note: see http://www.nature.com/nrc/journal/v5/n11/fig_tab/nrc1741_F6.html for Cajal's original drawings and slides of ICCs.