SCIENCE & MEDICINE Secretin and Autism: A Clue But Not a Cure by Clarence E. Schutt, Ph.D. he world of autism has been shaken by NBC’s broadcast connections could not be found. on Dateline of a film segment documenting the effect of Tsecretin on restoring speech and sociability to autistic chil- The answer was provided nearly one hundred years ago by dren. At first blush, it seems unlikely that an intestinal hormone Bayless and Starling, who discovered that it is not nerve signals, regulating bicarbonate levels in the stomach in response to a but rather a novel substance that stimulates secretion from the good meal might influence the language centers of the brain so cells forming the intestinal mucosa. They called this substance profoundly. However, recent discoveries in neurobiology sug- “secretin.” They suggested that there could be many such cir- gest several ways of thinking about the secretin-autism connec- culating substances, or molecules, and they named them “hor- tion that could lead to the breakthroughs we dream about. mones” based on the Greek verb meaning “to excite”. As a parent with more than a decade of experience in consider- A simple analogy might help. If the body is regarded as a commu- ing a steady stream of claims of successful treatments, and as a nity of mutual service providers—the heart and muscles are the pri- scientist who believes that autism is a neurobiological disorder, I mary engines of movement, the stomach breaks down foods for have learned to temper my hopes about specific treatments by distribution, the liver detoxifies, and so on—then the need for a sys- seeing if I could construct plausible neurobiological mechanisms tem of messages conveyed by the blood becomes clear. The hor- for the alleged successes of these treatments. At first, the mones are like “letters” borne by the blood “postal system” to the secretin story seemed overinflated because secretin is not found receptor “mailboxes” on the surfaces of cell “factories”. in the brain. All that secretin does, according to most medical texts, is regulate the amount of bicarbonate in the stomach if the While a telephone system—and, now, electronic mail—provides acid levels get too high—a built-in Alka-Selzer dispenser! for instant delivery of information, much like the nervous system of the body, a postal system But, the more I studied, and Peptides, Polypeptides, Neuropeptides, provides reliable “hard copy” learned from my Princeton of essential, secure, and specif- colleagues who work in the Proteins and Hormones ic orders. Speed of delivery fields of molecular biology, may not be as important as peptide: When researchers use the term “peptide” they are referring to a neurobiology, and very short string of amino acids—-a string far too short to be a protein. fidelity as the message passes immunology, the clearer it These very short strings are called peptides because whenever two amino through numerous check- became that the research acids combine they expel a molecule of water and form a bond called a points along the way. Studies community has entered an “peptide bond.” on complex systems have entirely new phase in con- polypeptide: The term “polypeptide” simply refers to more than two amino shown that when a few of sidering the “brain-gut” acids linked together. these orders are lost, or mail- molecular communication boxes cannot be found, a sys- links, of which the secretin neuropeptide: a peptide or polypeptide found in the brain. tem can spin out of control in family of hormones forms protein: a protein is, essentially, a polypeptide that is long enough to form unexpected ways. an important part. a 3- dimensional structure. Secretin is a polypeptide with 27 amino acids that coils up into a helix, thus becoming a (very small) protein. The Today, we know of hundreds I believe that the family of researcher who developed purification schemes for secretin and of hormones and their secretin receptors holds sequenced its amino acids, Victor Mutt of the Karolinska Institute in “receptors,” including nerve Stockholm, called secretin a “mini-protein.” (Ironically, Mutt died a few promise for developing weeks before the DATELINE broadcast.) Glucagon, another member of growth factors, which stimu- treatments for autism. But the secretin family, is also a small protein with a helical structure, and is late growth of nerve cells; because it is not normally sometimes called a “minimal protein.” The key to the polypeptide/protein interleukins, which stimulate found in the brain, more distinction is this: once a polypeptide is long enough to develop a 3-dimen- immune cell proliferation; and than likely secretin itself is sional structure it is called a protein. insulin, whose secretion from not going to turn out to be hormone: The word “hormone” is simply a term for a chemical signal in the the pancreas is controlled by the answer. Secretin is a body. Some hormones are proteins (secretin and all of its relatives are pro- the hormone glucagon. The clue, not a cure. teins). Other hormones are not proteins or peptides at all, but instead are occurrence of many diseases, based on carbon rings. The steroid hormones, for example, such as corti- sol, are not proteins. Whenever you see the term “hormone” think “signal.” such as diabetes and How Hormones Work In other words the term “hormone” indicates a function rather than a par- Addison’s disease, can be In the last century, physiolo- ticular structure or chemical content. traced to deficiencies in these gists believed that signalling molecular signalling systems. between organs occurred solely by conduction of electrical signals Once the deficiency is identified, even though the range of symp- along nerves, by analogy to the brain-muscle connection. The toms can be quite broad (as in autism), specific interventions, brain controls our muscles by means of meter-long neurons (or such as insulin injections for the treatment of diabetes, or new “nerve cells”) that shoot down the spinal column and make con- drugs, can be developed. tact with muscle fiber, telling it when to contract and when to relax. How an Intestinal Hormone Might Affect the Brain But with organs like the pancreas, there were no nerve cells How could an intestinal hormone produce the improvement in linking the pancreas to any other organ of the body. An out- brain function we saw in the videotape of Parker Beck? standing riddle for these early pioneers was to explain how the pancreas could be stimulated to secrete bicarbonate and diges- One answer may lie in the complexity of the secretin family of tive enzymes into the upper intestines when the expected nerve (continued on page 22~Secretin~) NAARRATIVE, Number 4, Winter 1998 • Newsletter of the National Alliance for Autism Research • 1-888-777-NAAR 21 (continued from page 21 ~Secretin~) SCIENCE & MEDICINE hormones. Although secretin was the first hormone to be dis- Such a secretin “cross-talk” effect could have produced the covered, it is no longer viewed as just a simple signal to the startling improvements in Parker Beck because certain members pancreas to release bicarbonate and water. Indeed, there of the secretin family are extremely important to brain function. remains a great deal yet to be discovered. Receptors for PACAP, another secretin cousin, are found on the surfaces of neurons in the hippocampus, the dentate gyrus and We know that secretin is a small protein having 27 amino acids other areas of the brain’s primary learning circuit. VIP-contain- along its backbone (see figure). Although this was known ear- ing cells (“astrocytes”) also appear in large numbers throughout lier from classical biochemical work, modern genetic analysis the cerebral cortex, where their presumed role is to regulate ener- has shown that secretin is the defining member of a family of gy levels in memory- forming neurons. The secretin-family hor- hormones having similar, but not identical, ordered sequences mones are so powerful that pharmaceutical companies are vig- of amino acids along their backbones. orously pursuing the possibility of treating ALS and stroke by administering secretin relatives intravenously to rescue “sick The backbone sequences of these three hormones (secretin, VIP, cells” in the brain. glucagon) are so similar that it is likely that their three-dimensional structures are alike. The dif- It may seem surprising that ferences in structure (protru- The Secretin Family the brief “pulses” of secretin sions, cavities, and charged infused into Parker Beck’s patches on the molecular sur- bloodstream activated long- face) will tell us what deter- lasting effects; however, mines how these hormones many hormones work via an are able to recognize and bind “autocrine effect” whereby different receptors. These they cause their target cells to genomic analyses often toss produce even more copies of up extraordinary surprises, themselves. It is possible that such as the fact that the major the infused secretin, by bind- peptide constituent of gila ing to the receptors for other monster venom is a member members of the family, of the secretin family! caused those cells to produce more of whichever “secretin Secretin receptors are pro- cousin” actually produced the teins embedded in the mem- therapeutic effect. branes of target cells. On the outside of the cell, por- We can only speculate about tions of the receptor form a The amino acid sequences for five members of the secretin family of hor- how secretin, once it began to pocket uniquely shaped to mones are shown at the top of the figure. VIP: vasoactive intestinal pep- bind with secretin-family recognize secretin. On the tide; PACAP: pituitary adenylate cyclase-activating peptide; PHM: peptide receptors in the brain, may histidine methionine. Secretin is a peptide hormone having 27 amino acid inside, the secretin receptor residues (top row).