During the past fifty years I have seen many advances in our understanding of how the brain works. None of these advances, however, has had a more revolutionary impact on our ideas about the brain than the discovery that nerves secrete chemical neurotransmitters when communicating with other nerves and the muscles they innervate. Yet few people, including most neuroscientists, know much about how neurotransmitters were discovered, the fierce and lengthy dispute about their very existence, or the scientists involved and the social and political events that affected their lives and work.
I first became interested in how neurotransmitters were discovered when I was writing the book Blaming the Brain. After I became aware that all the early drugs used to treat mental illness had been discovered accidentally, it occurred to me that such discoveries could not have happened any other way.1 So little was known about brain chemistry in the 1950s that it would not have been possible to predict the physiological or psychological effects of any of these drugs. Moreover, because neurotransmitters were not thought to exist in the brain, for a number of years it was not even possible to offer a reasonable explanation of what the drugs might be doing there even after their effects were discovered.
When I finished Blaming the Brain, I started to look into the history of the discovery of neurotransmitters, to satisfy my own curiosity. I was soon captivated by what I found to be a fascinating story. When I talked to my friends about what I was uncovering, it became clear that very few knew much, if anything, about this history. Here was a little-known and fascinating account of an important subject. I decided to make this history the focus of my next book.
Initially I concentrated on learning how the evidence for neurotransmitters had been acquired. As I learned more about the scientists involved, however, I felt that it was essential to include in my book something about their lives, how their scientific interests developed, and the different ways they responded to evidence suggesting that chemical substances were involved in transmission of the neural impulse. I have therefore included considerable information about the lives of many of the scientists and more extensive biographical details about Henry Hallett Dale, Otto Loewi, and Walter Bradford Cannon, the three most central to this history. The first two shared the Nobel Prize for the discovery of neurotransmitters, and Walter Cannon might have shared the prize with them had he not been persuaded to adopt and defend a controversial theory.
Political events greatly affected the lives and work of a number of the scientists important to this history. During World War I, many changed the direction of their research in order to contribute to the war effort. For some, the disruption was much greater during the period leading up to World War II. Otto Loewi, for example, already a Nobel laureate, was arrested by Nazi storm troopers and thrown in jail. Many German scientists were dismissed from their positions because of the Nazi “racial” policies, and the more fortunate were able, often with the help of colleagues and money from the Rockefeller Foundation, to join laboratories abroad. There an impressive number made major contributions to science, some of which are relevant to this history. I have included several accounts of these events because the historical context is necessary for understanding what transpired.
An important part of this history involves the episode called the “War of the Soups and the Sparks,” a dispute over whether nerve impulses are transmitted chemically or electrically. The dispute was mainly between pharmacologists, who had uncovered the first evidence of chemical transmission, and neurophysiologists, experts on the nervous system, who dismissed these new findings and remained committed to electrical explanations of neural transmission. Although initially there were good scientific reasons to question the possibility of chemical transmission, the controversy was sustained and fueled by the competing interests of the two disciplines.
There is always the question of where to begin the history of any topic. It seemed to me that the logical place to begin this story is the period around 1900. It was then that, after several decades of controversy, the “neuron doctrine” was finally accepted. This doctrine asserted that the nervous system is comprised of nerve cells separated from each other. Although the instruments that eventually made it possible to see the gap between nerve cells would not be available for another fifty years, there were good arguments, although these were disputed, that at least a functional gap existed between the terminals of neurons. This controversy, and how it set the stage for investigating whether the gap was bridged electrically or chemically, is the subject of the first chapter.
Also important in setting the stage for the eventual discovery of neurotransmitters were early investigations of the effects that different drugs have on visceral organs. Many new drugs had become available during the second half of the nineteenth century, and the effects of these drugs were commonly tested on visceral organs such as the heart, lungs, blood vessels, intestines, and glands, as well as on skeletal muscles. These studies provided the basis for the observation that some drugs produced the same effects on these organs as did stimulating the nerves that innervate them. Chapter 2 describes how we learned about the so-called autonomic nerves, which innervate visceral organs, and how this research paved the way for early speculation that a chemical process might somehow be involved in transmission of a nerve impulse.
Chapter 3 describes how some gifted British scientists came to speculate that a chemical process was involved in neurotransmission. Their speculations arose mainly from the observation that adrenaline seemed capable of mimicking the effects of sympathetic nerve innervation at all sites. Although this line of research came tantalizingly close to proving the existence of chemical neurotransmitters, it was virtually ignored, for reasons that will be explored in that chapter.
The early speculation that neural transmission could involve a chemical process was ignored for about fifteen years. During that period, however, Henry Dale began to investigate the properties of a number of drugs that evoked or blocked visceral responses, and in the process he accumulated much of the basic information that was essential for eventually proving that autonomic nerves secrete chemical neurotransmitters. Chapter 4 describes Dale’s life, education, research style, and personality, as well as the circumstances that led him into this particular line of research.
World War I interrupted any further progress on the question of possible chemical transmission. From 1914 to 1918 Dale, like most British scientists, was heavily committed to war-related research. It was not until 1921, then, that new interest was suddenly aroused about the possibility of the existence of neurotransmitters, or neurohumoral secretions, as they were called at the time. At that time Otto Loewi reported that he had obtained evidence that the nerves controlling heart rate secrete neurohumoral substances; his data were derived from a simple experiment that had occurred to him in a dream. Chapter 5 describes Loewi’s background, his close friendship with Dale, and the experiences that may have inspired his dream. Also described in chapter 5 is the fierce opposition to Loewi’s conclusion and the way he responded to the challenge.
Dale, who was preoccupied with other interests and administrative responsibilities after the end of World War I, remained on the sidelines during much of the controversy over Loewi’s work. Dale was persuaded, however, by Loewi’s evidence that neurohumoral transmissions regulate heart rate, and he began to investigate whether other parts of the nervous system might also utilize neurohumoral secretions. With the help of some brilliant young collaborators and a technique brought to his laboratory by Wilhelm Feldberg, one of the many scientists forced to flee Nazi Germany, Dale was able to prove that virtually all peripheral nerves secrete chemical neurotransmitters. This part of the story, which led to Loewi and Dale sharing the Nobel Prize, is told in chapter 6.
Paralleling the work of Loewi and Dale in Europe was that of Walter Cannon, who inadvertently stumbled on other evidence that the sympathetic nervous system secretes adrenaline. Unfortunately, Cannon was persuaded to adopt a theory about these neurosecretions that became controversial and eventually was proven wrong. Although Cannon was nominated for the Nobel Prize a number of times, this controversial theory may have been responsible for his not being selected to share the prize with Loewi and Dale. Cannon was unquestionably the most eminent physiologist in the United States. He was a remarkably interesting man, not only because of the broad theoretical concepts he introduced but also because of his willingness to become actively involved in social and political issues. Chapter 7 describes Cannon’ s life and work.
Opposition to the notion of chemical transmission seems to have intensified after the awarding of the Nobel Prize. Opponents might have been willing to concede that neurohumoral secretions were adequate for innervating visceral organs, but they argued that this process would be much too slow to produce the swift responses manifested by skeletal muscles. Moreover, there were not many people willing to entertain even the possibility that nerves in the brain communicate by secreting neurotransmitters.
The dispute was exacerbated by the fact that the techniques of the pharmacologists and the neurophysiologists differed so greatly that the evidence each side generated tended to be ignored by the other. Beyond that, the dispute about chemical transmission seems to have been partly fueled by the resentment of some neurophysiologists at the intrusion of pharmacologists into a field where they were the experts. This “War of the Soups and the Sparks” is described in chapter 8.
When their Nobel Prize was awarded in 1936, Otto Loewi and Henry Dale were over sixty, as was Walter Cannon. Their most productive research years were behind all of them, but they remained active in supporting the research of others and the causes they believed in. A description of the final years of these three remarkable, but very different, scientists is presented in chapter 9.
Even after resistance to the theory of chemical transmission in the peripheral nervous system had significantly diminished, opposition to the notion of chemical transmission in the central nervous system, especially in the brain, continued. It was much more difficult to obtain evidence of neurohumoral secretions in the brain, as the neurons there are much more tightly packed, making their connections much harder to study. Moreover, there were no clear responses evoked by neurons in the brain that were comparable to those of visceral organs responding to signals from nerves in the autonomic nervous system. Convincing evidence of chemical transmission in the brain had to wait for the development of a number of anatomical, chemical, and physiological techniques and instruments that cumulatively made it possible to gradually acquire compelling evidence that neurotransmitters were secreted by brain neurons. Over time, attitudes evolved from a general skepticism about there being any neurotransmitters in the brain to the view, widely held today, that there may be as many as one hundred different chemicals that act as neurotransmitters in the nervous system. These later developments form the subject of chapter 10.
A few comments about the value of history in general, and this historical account in particular, are presented in a brief epilogue.
N O T E S
1. The initial psychotropic drugs discovered in the 1950s include chlorpromazine, the first antipsychotic drug, which was marketed in the United States as Thorazine; iproniazid, the first antidepressant, marketed as Marsilid; and the first anti-anxiety drugs: meprobamate, marketed as Miltown and Equanil, chlordiazepoxide, marketed as Librium, and diazepam, marketed as Valium. How these were accidentally discovered is described in chap. 2 of E. S. Valenstein, Blaming the Brain: The Truth About Drugs and Mental Health (New York: Free Press, 1998).