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The Discovery of the Second Brain
THOSE OF US WHO deal in science, even the most enlightened of us, have a strong and objectionable tendency to hubris. Hubris for scientists comes from an inadequate knowledge and appreciation of the past. Discoveries are thus made and claimed that are really rediscoveries—not new advances at all, but history lessons.
Neurogastroenterology: A Rediscovery Brings Hope for the Future
Not long ago, the New York Times ran an article about the second brain in its science section. David Wingate, a gastroenterologist with an academic practice in London, was cited as a source for a comment that identified me as the father of the new field of neurogastroenterology. I admit to being the father only of three children. Clearly, David did not insult me by attributing to me the fatherhood of a field. In fact, I would love to be able to just send him a note saying something nice, like “David, you’ve noticed.” Unfortunately for my ego, however, I know better.
I have made discoveries in my scientific career, but the basic principles on which my work is based are about to celebrate their one hundredth anniversary. That bit of information is very good for putting down my own particular brand of hubris. I am not really disappointed, because I have to concede priority to people who came before me. Rediscovery is every bit as good as discovery, if what is rediscovered is important and was forgotten. It is better still when the rediscovered information has the capacity to improve the lives of those around us.
Neurogastroenterology began when the first investigators determined that there really is a second brain in the bowel. The seminal discovery that established its existence was the demonstration that the gut contains nerve cells that can “go it alone”; that is, they can operate the organ without instructions from the brain or spinal cord. Those of us who qualify as neurogastroenterological fathers in David Wingate’s estimation are really children. None of us discovered the existence of the second brain. That discovery had passed, however, like the Roman Empire, into oblivion. What I have done, with a great deal of help from colleagues around the world, is to find it again and return it to scientific consciousness. To me, that accomplishment, which will soon provide relief to millions of people suffering from the misbehavior of an ill-tempered bowel, is sufficient. Dayenu.
Ecclesiastes Was Right: There Really Is Nothing New Under the Sun
Neurogastroenterology really started with Bayliss and Starling, two investigators whose work in nineteenth-century England established them as immortals in the Pantheon of Physiology. I love to envision what life must have been like in the laboratories of England at the turn of the century. It was a time when notorious fogs descended on London and mixed with the smoke of thousands of coal stoves to clog lungs and blot out the view. This was the time of Jack the Ripper, David Copperfield, and Ebenezer Scrooge. I had experienced an update of an English laboratory in 1965–1966, when I was a postdoctoral fellow at Oxford. One needs to read Dickens to appreciate the conditions under which English scientists work.
Winters in England are not usually very cold. Certainly, New York is colder than Oxford or London. The trouble with England is that there is very little difference in most of the country between the indoor and the outdoor temperatures. I worked at my laboratory bench with my scarf on, and I wore gloves with the fingertips cut off so that I could feel what I touched. The benches tended to be high, and we sat on backless wooden stools. Since these laboratories were the result of half a century of progress, the working conditions faced by Bayliss and Starling must have been almost penal. Whatever their laboratories were like, the accomplishments of Bayliss and Starling were quite startling. In fact, until Margaret Thatcher became prime minister and suffocated British science, the physiological laboratories of England were a match for those of any other nation.
The Law of the Intestine
Bayliss and Starling worked with dogs. They isolated a loop of intestine in anesthetized animals and studied the effects of stimulating the bowel from within its internal cavity, thereby mimicking the effects that normal intestinal contents might exert on the wall of the gut. In their critical experiments, Bayliss and Starling increased the pressure within the loop of bowel. The gut responded with a stereotyped behavior that, in its reproducibility, caught their attention. Whenever its internal pressure was raised sufficiently, the bowel would exhibit muscular movements that had the effect of propelling the contents of the intestine in a startlingly one-way direction. The propulsive movements consisted of a coordinated descending wave of oral contraction and anal relaxation that forced the intestinal contents relentlessly and inevitably in an anal direction.
Bayliss and Starling called this response of the gut to increased internal pressure “the law of the intestine.” Bayliss and Starling were very much into “laws.” Their physiological legacy includes a “law of the heart” and a “law of the circulation” as well as the “law of the intestine.” They probably used the word “law,” which now seems quaint, to imply that they had discovered an everlasting principle that governs the behavior of a biological system. Perhaps it was the contemporaneous notoriety of the case of Jarndyce versus Jarndyce in Dickens’s great book Bleak House that focused their terminology in such a legal direction. In any case, the “law of the intestine,” despite its catchiness as a phrase, failed to persist. Not that Bayliss and Starling were wrong. In fact, their work has stood up well over time and is easily reproduced. The “law of the intestine” that Bayliss and Starling formulated still describes the behavior of the bowel, but the name of the activity has changed. The “law of the intestine” is now known as the peristaltic reflex, a much more prosaic term but one that is more descriptive of what the gut is actually doing, and certainly less evocative of an unknown higher power. After all, if there are laws, surely there must also be law enforcement, which as a scientific concept leaves something to be desired.
Bayliss and Starling correctly associated the coordinated nature of the “law of the intestine” with nerves. A surprising finding, however, was made when they cut all of the nerves entering or leaving the loops of dog bowel that exhibited the “law of the intestine.” They knew that if they were to cut all the nerves to limbs or other organs, reflexes would be lost. Reflex behavior anywhere but the gut always involves the participation of the brain or spinal cord. Other organs do not make decisions for themselves; instead they inevitably follow the instructions they receive from the central nervous system. Cutting the nerves that connect these organs to the brain or spinal cord deprives them of their directions and the organs become paralyzed, like an airline ticket agent whose computer has crashed.
Bayliss and Starling reasoned that severing all of the nerves entering or leaving a loop of bowel would cut all nerve-mediated communication between the gut and the central nervous system. When they did this, however, the “law of the intestine” still prevailed. Increases in internal pressure continued to be followed by the same descending wave of oral contraction and anal relaxation that they saw before the nerves were cut. Since a reflex behavior could thus be elicited in segments of bowel after all input from the brain or spinal cord had been eliminated, Bayliss and Starling attributed the “law of the intestine” to what they called the “local nervous mechanism” of the gut. In other words, if outside nerves are not required, then inside nerves must be the ones that do the job.
There Is a Nervous System Inside
The conclusion that intrinsic nerves are responsible for the “law of the intestine” was a reasonable one for Bayliss and Starling to reach because they were aware, even before they began their studies, that a complicated nervous system is embedded in the wall of the bowel. The existence of the enteric nervous system had been discovered in Germany while the Civil War was raging in America. Working with a primitive optical microscope, a German scientist by the name of Auerbach had found that the bowel contains a complex network, or plexus, of nerve cells and fibers. This plexus, wedged between the two layers of muscle that encircle the gut, is still called Auerbach’s plexus, as if he owned it. Since some scientists hate to include a person’s name in the nomenclature of body parts, Auerbach’s plexus is also known as the myenteric (my = muscle; enteric = gut) plexus.
After Auerbach’s discovery, another smaller plexus was found in a layer of the bowel called the submucosa. The submucosa gets its name from its location, which is just beneath the lining of the gut’s internal cavity, where the business of digestion takes place. The inner lining is called the mucosa; therefore, the layer under the mucosa, logically enough, is the submucosa. The submucosa is a region of dense connective tissue that is so tough and resistant to stretch that it enables gut, to literally be used to make surgical sutures and strings for tennis rackets. The second network of intestinal nerve cells is called Meissner’s plexus, by those who like to award structures to their discoverers, and the submucosal plexus by others who hate people’s names in the nomenclature. Since Bayliss and Starling knew that the gut contains a large nervous system, they felt free to postulate that this system, the “local nervous mechanism” of the bowel, could provide the gut with the means to manifest reflex activity, even in the absence of external nervous input.
It Works All by Itself
Eighteen years after Bayliss and Starling first published their observations, Ulrich Trendelenburg, on the German side of the trenches that divided Europe from the Swiss border to the English Channel, mounted an isolated loop of guinea pig’s intestine on a hollow J-shaped tube. This experiment, published in 1917, turned out to be a critical one. Trendelenburg suspended the bowel, on its tubular support, in a test tube containing a warm nutritive solution, which he supplied with oxygen. The bowel survived well in this artificial environment. The apparatus, within which living organs survive for several hours, is called an organ bath.
When Trendelenburg blew through the J-shaped tube into the bowel, the gut blew back. This experiment sounds terribly simple, and it is. The consequences of the phenomenon Trendelenburg observed and recognized, however, are profound. In order to blow back, the segment of guinea pig intestine isolated in an organ bath had to display the same reflex behavior that Bayliss and Starling had observed many years previously in an intact dog. To do this, the segment of gut needed to be able to detect the increase in pressure that blowing into the tube had caused to occur within its internal cavity. Then, to blow back, the isolated bowel had to respond with a coordinated descending wave of oral contraction and anal relaxation, mimicking Bayliss and Starling’s “law of the intestine.” In Trendelenburg’s laboratory, moreover, this behavior did not occur in an intact animal. The brain, spinal cord, and sensory ganglia had all been discarded with the rest of the guinea pig. There was nothing in the organ bath but gut.
The modern term “peristaltic reflex” was introduced by Trendelenburg to describe the pressure-induced propulsive activity of the gut. This caused the equivalent phrase, “the law of the intestine,” to fade from use. The observation that the peristaltic reflex could be elicited in a segment of gut isolated in an organ bath confirmed that Bayliss and Starling had been correct in attributing the pressure-induced descending wave of oral contraction and anal relaxation to the “local nervous mechanism” of the bowel. For the reflex to take place in a system that contains no other organ but the intestine, all of the necessary elements have to be intrinsic components of the wall of the gut. That they all should be there is striking, because a similar neural apparatus does not exist in any other organ. Cut the connections between the bladder, the heart, or the skeletal muscles and the central nervous system, and all reflex activity ceases. Trendelenburg’s simple experiment, therefore, was nothing short of revolutionary. Trendelenburg had demonstrated that the intrinsic nervous system of the gut actually has properties that are like those of the brain and its subservient appendage, the spinal cord. To a neurobiologist, this is like saying that the bowel is close to God.
