Book Reviews |
The soups and the sparks
These two books describe, in very different styles, the key individuals and scientific discoveries that were involved in one of the great debates of neuroscience—how they interacted with each other, and the trajectory of their science. The debate under discussion is that of how nerve cells communicate, identified as a fundamental scientific problem by the end of the 19th century. In 1877, DuBois Reymond wrote, considering how nerves cause muscle contraction, ‘Of known natural processes that might pass on excitation, only two are, in my opinion, worth talking about—either there exists at the boundary of the contractile substance a stimulatory secretion ... or the phenomenon is electrical in nature’. Early in the 20th century, two key advances were made: nerve action potentials were first recorded by the use of the string galvanometer; and the ability of chemicals to mimic the functions of autonomic nerves was discovered. Thus, the stage was set for the great debate, in essence a contest between the physiologists and the pharmacologists—or as Valenstein calls it, The War of the Soups and the Sparks. The outcome, as we all know, was that, although electrical transmission does occur in some situations, chemical transmission is far and away the most important mechanism by which neurons communicate with each other, and with the effector cells that they control. The dominance of this ‘Big Idea’ is reflected in the fact that, for the past 60 years or more, a major focus of neuroscientific endeavour has been on understanding these signalling chemicals, their sites of release and the stimuli that cause them to be released, their receptors and the signal transduction mechanisms through which they influence the cells on which they act.These two books describe, in their very different ways, how the idea of chemical transmission emerged, against the background of prevailing scientific knowledge, and political upheavals in Europe, over the 30-year period starting soon after the turn of the 20th century culminating in the award of the Nobel prize jointly to Loewi and Dale in 1936. Though aspects of the story have been told before, these two books provide a satisfyingly complete coverage, and both are well researched and a pleasure to read.
The major part of Donnerer and Lembeck's book consists of an annotated anthology of writings by and about three of the main characters in the story, Otto Loewi (1873–1961), Henry Dale (1875–1968), and Wilhelm Feldberg (1900–1993), all of them interesting characters in their own right quite apart from the discoveries that they made. Otto Loewi spent about 30 years of his long career as Professor of Pharmacology at the University of Graz, in Austria—Donnerer's and Lembeck's scientific home—and he occupies centre stage in their book. We have Loewi on Loewi (a long and revealing autobiographical sketch) and also Dale on Loewi (an appreciation of his work written as a Royal Society obituary), as well as personal memoir by Brücke, a friend and colleague of Loewi in Graz. Dale's life is described in an obituary by Feldberg and an article by Koelle written to commemorate the 50th anniversary of the Nobel Prize. Feldberg provides his own entertaining eye-witness account of the discovery that acetylcholine is the transmitter at the neuromuscular junction, a discovery in which he, with Dale and G. L. Brown, played a key role.
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111.50. ISBN: 3-8055-8004-5
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The structure of Donnerer and Lembeck's book inevitably makes for a somewhat disjointed read because it is largely a compilation, but the personalities and scientific styles of the three scientists come over very well. Loewi and Feldberg were both Jewish, and their personal and scientific lives were flung into disarray by the rise of Nazism in the 1930s. Loewi, by the time he was forced to leave Austria in 1938 at the age of 64, had completed his best work and had already won the Nobel Prize. Stripped of all his possessions (including his Nobel Prize money, which had to be left in a Nazi bank account), he arrived in England with the help of his old friend and fellow Nobel-laureate Henry Dale. Soon afterwards he moved to New York University, where he remained, a kindly, entertaining and inspiring mentor to many young scientists, for the rest of his life.
The descriptions of Loewi, his background, family, mentors and career, give us some fascinating insights. He, came from a comfortable middle-class Jewish German home, and was as a young man much more interested in literature, music and the arts than in science. Family pressure made him study medicine, and in 1891 he was fortunate to enter the University of Strassburg, a major research centre which had attracted many of the leading scientists of the day. However, he found the medical course mostly boring, commenting wryly ‘Right there and then, I found that a great scientist is not inevitably a good teacher’, and often played hooky by attending lectures in philosophy or going to the opera. He scraped through his exams, and finally became inspired by the teaching of the Professor of Medicine, Bernhard Naunyn, which was a far cry from the dry factual recitations of his former teachers. Surprisingly, given his passion for the arts, it was the science and not the art of medicine that captivated him, and he soon decided on a career as a scientist rather than a clinician. In Strassburg, he met Oswald Schmiedeberg, one of the founding fathers of European pharmacology, whose laboratory was a magnet for scientists from all over the world, many of whom became Loewi's lifelong friends. Thus he gained for the first time a taste for experimental science, and in his mid-20s moved to Marburg, where he began a research career that lasted for more than 50 years. An inquisitive and outgoing personality, Loewi made a number of scientific visits to England in 1903 and 1904, including a period with Bayliss and Starling at University College London, where the concept of hormones was evolving on the basis of their recent discovery of secretin. He also spent time in Cambridge, where Langley and Gaskell were engaged in analysing the structure and function of the autonomic nervous system, and where he met Dale—his near-contemporary—for the first time. He also met T. R. Elliott, the first to suggest a role for adrenaline as a sympathetic transmitter. This suggestion, in 1904, attracted no support whatever for, since the discovery of the electrical events accompanying nerve transmission at the end of the 19th century, it was thought obvious that the same mechanism would account for transmission of nerve impulses to effector organs. Loewi had studied in detail the effects of stimulating the vago-sympathetic nerve trunk, and of various chemical agents, on the beating of isolated frog hearts, and was struck by the fact that either could, under different conditions, cause stimulation or inhibition of the heartbeat. So in 1903, he speculated on the possibility that nerve stimulation might work by releasing chemical agents, but it was not until 1920 that there came to him, out of the blue, a way to test the idea. His famous experiment was simplicity itself:
set-up a frog heart at the end of cannula,
allow a small volume of saline in the ventricular cavity to be removed,
apply this to another frog heart by the same route,
stimulate the nerve to heart number one to inhibit the beat,
remove the fluid and apply it to heart number two.
Sure enough, in Loewi's hands, heart number two was inhibited when the fluid was applied to it. It sounds very simple, but in fact the result was far from repeatable—many others tried it and failed—and the interpretation was by no means unambiguous. How, for example, did one know that the released chemical came from the nerves rather than the heart muscle?
Though Loewi's classical experiment was far from conclusive, it effectively started the ball rolling, and led him to piece together, in a succession of short pharmacological studies, a thoroughly convincing case for the inhibitory transmitter, ‘Vagusstoff’ being acetylcholine, which Dale had earlier identified as a highly potent synthetic compound with parasympathomimetic properties.
It is illuminating to read how these scientists persevered despite the political tribulations of the times. In 1938, 2 years after receiving the Nobel prize, Loewi and his two young sons were summarily arrested when the Nazis took over Austria. By his own account, when Loewi was arrested, his main concern was that he would be killed before his latest experiments could be published, and he persuaded his guard to give him a paper and pencil, so that he could write up the work for the guard to mail to ‘Die Naturwissenchaften’. It is revealing of his character, that Loewi seems to have been oblivious to the Nazi threat, even though the exodus of scientists had already been going on for some years. Immersed in the world of arts and sciences, he seems to have had no time for politics.
Wilhelm Feldberg's background and personality were similar in many ways to Loewi's. He came from a wealthy Berlin family, and studied medicine at Heidelberg and Berlin, qualifying in 1925. Like Loewi, he preferred experimental science to clinical medicine, and took up a research position in Berlin with Professor E. Schilf, to work on aspects of autonomic physiology. He spent some time in Cambridge with J. N. Langley, and also met Henry Dale, who invited him to work for a while in his laboratory in London before returning to Berlin. Like Loewi, Feldberg was surprisingly dismissive of the Nazi threat, which he thought would come to nothing, but in the middle of an experiment in April 1933 he was summoned to the director's office and told that, being Jewish, he must leave that day. His immediate concern was whether he had time to finish his experiment. Even if this was a piece of autobiographical bravado, it reveals a startlingly focussed mind. How could he, one wonders, think first about finishing an experiment when his life and circumstances, not to mention those of his wife and family, were so savagely disrupted? His political naivety seems similar to Loewi's, though Feldberg was in his early 30s, and much more vulnerable than the already-famous Loewi.
A theme throughout these books is the role of colleagues, collaborator and friends, in not only supporting science, but at times offering sanctuary for families as well as work, in perilous war-torn Europe. Henry Dale came to Feldberg's rescue, and found an appointment for him at the National Institute for Medical Research in London, of which Dale was director. It was here that Feldberg and Dale, with G. L. Brown, showed conclusively that acetylcholine was the transmitter, not only at parasympathetic nerve endings, but also at autonomic ganglia and the skeletal neuromuscular junction. Feldberg was a brilliant experimenter, and rekindled Dale's enthusiasm for experimentation, which had become overshadowed by the increasing demands put on him to give scientific advice to the government, and to use his excellent managerial and administrative skills in running the institute. Feldberg brought with him expertise in using the leech muscle preparation to assay acetylcholine, a temperamental but highly sensitive assay that played a vital role in demonstrating acetylcholine release under physiological conditions. Feldberg also introduced the use of eserine (an anticholinesterase), without which the released transmitter was hydrolysed so fast that it could not be detected. G. L. Brown, the third member of the team, was an electrophysiologist. In the mid-1930s, pharmacologists, who favoured chemical transmission, and electrophysiologists, who favoured electrical transmission, rarely worked together. Instead, each side worked with its own techniques to gather evidence in favour of its position, and paid scant attention to what the other side was doing. Feldberg and Brown were able to bridge this technological divide, which brought the idea of chemical transmission firmly into the physiological mainstream. Sparring between the opposing factions continued nevertheless, with a number of very distinguished electrophysiologists sticking firmly to their views, most notably John Eccles, arguing that both excitation and inhibition could be transmitted electrically by ‘eddy currents’ given the right anatomical relationship between the cells. Eccles himself, using the newly invented intracellular microelectrode recording technique in 1951, disproved this view, and his famous conversion effectively brought the argument to an end. Some eminent figures, such as David Nachmansohn, took the chemical theory even further and argued that axonal transmission, as well as synaptic transmission, was mediated by acetylcholine released as a wave down the length of the axon. After some heated skirmishes, the invention of the voltage clamp technique resolved the matter unequivocally in favour of electrical propagation of the axonal impulse. This ‘Soups and Sparks’ dispute, which had gone on for more than 70 years since Du Bois Reymond's original statement of the issue, is certainly a classic, on a par maybe with the Cajal/Golgi dispute over the neuron theory.
Valenstein, a neurophysiologist, gives a wide-ranging and very readable account of this whole epic story. While Donnerer & Lembeck deal exclusively with the European contributions to the chemical transmission story, Valenstein balances this with an excellent account of the work of the American scientist, Walter B. Cannon. (1871–1945). Cannon was toying with the idea that sympathetic nerves might function by releasing a chemical mediator even before Loewi published his famous experiment on the frog heart, and went on to establish the role of the adrenal glands in controlling physiological reactions, and their relationship with the sympathetic nervous system. Cannon's exceptional talents had shone out in his earliest days as a medical student at Harvard, and when he became a junior faculty member his reputation grew as a highly successful teacher and researcher, and friend to many. A truly remarkable man, Cannon also found time to involve himself actively in the local politics and educational projects in the Cambridge area, and in later life he had a major influence as an adviser to the US Government on medical and scientific matters, as well as throwing himself into international political issues. Cannon's early work concerned the control of the digestive tract, and he noted that any kind of stress reduced intestinal motility in experimental animals. This response was abolished by removal of the adrenal glands, and Cannon showed that adrenaline, which had earlier been purified from adrenal glands and synthesized, had a similar effect to that of stress. Further experiments showed that the adrenal glands did indeed release adrenaline into the bloodstream under conditions of stress, or if the splanchnic nerve supplying the gland was stimulated electrically, which convincingly proved adrenaline to be an important hormone involved in ‘fight-or-flight’ reactions (Cannon's phrase). Recognition of the transmitter role of adrenaline (or something very like it) came from experiments showing that it was released by sympathetic nerve stimulation in adrenalectomized animals. The amounts were small, the experiments were difficult, and the result was disputed, but eventually proved correct. Cannon called the substance ‘sympathin’ since he was not sure that it was actually adrenaline, and he thought it most likely came from the tissues innervated by sympathetic nerves, rather than from the nerves themselves. He took another wrong turning in concluding, on the basis of pharmacological experiments with ergot compounds (which we now know to block certain types of adrenoceptors) that there were two distinct sympathins, E (excitatory) and I (inhibitory). This had the effect of muddying the waters considerably, and initiating much unilluminating controversy, until the work of von Euler in 1946, who showed that noradrenaline, rather than adrenaline, was the main sympathetic neurotransmitter, and that of Ahlquist (1949) whose demonstration of the existence of two distinct adrenoceptor subtypes removed the need to invoke two distinct sympathins. These advances sadly came after Cannon's death in 1945. Had it not been for the ‘sympathin wars’ Cannon would surely have shared the 1936 Nobel prize for his studies on adrenaline secretion. Valenstein's book describes these discoveries and disputes in fascinating detail, against the background of Cannon's high profile involvement in public affairs.
Of course, after reading these two books, one cannot help comparing the four principal characters. All came from comfortable middle-class backgrounds. There was no medical or scientific tradition in their families; nevertheless all began by studying medicine, but never engaged in clinical practice. Loewi, Dale and Cannon all did important work in many different physiological, biochemical and pharmacological fields. Feldberg was much more focussed on neurochemical transmission, and unlike the others remained active as an experimenter well into his 80s. Dale and Cannon both became important public figures, taking on many social and public duties alongside their scientific work. Loewi and Feldberg remained scientists first and foremost. They loved laboratory work, and helping junior scientists to make a success of their experiments, but neither engaged in the social and political issues of the day, as did Cannon and Dale. Some have suggested that Loewi and Feldberg reacted to Nazi persecution in the only way they could, by turning their back on politics and getting on with their experiments.
Loewi, though he worked successfully on many problems, can claim only one major discovery, and it was clearly an inspired leap of imagination, rather than incontrovertible evidence that led him to it. The evidence caught up by degrees, and proved him right. Would he have minded if the evidence had proved him wrong? Who knows? But he certainly would not have been so famous. Dale was no speculator, insisting on basing his ideas on solid experimental ground. Of the four scientists, Dale's work has arguably provided the least shakeable and most extensive foundations for our current ideas, though Cannon's, much more speculative, comes close, and both have major discoveries to their names, in addition to their contributions to the Soup and Sparks debate. The sympathin muddle, which may have cost Cannon his share in the Nobel Prize, stemmed from his readiness to speculate one step too far. Feldberg was also meticulous in drawing conclusions from carefully planned experiments, and continued for many years to make significant discoveries in neuropharmacology, though none that matched the beautiful work on cholinergic transmission.
The accounts in these two books complement each other neatly, with Donnerer and Lembeck using a lot of contemporary source material to illustrate their theme while Valenstein uses his own considerable literary skills to tell the tale. Both books supplement the historical tale of the discovery of neurotransmitters with a short chapter on brain transmitters (Valenstein), or a series of chapters on the discovery of a range of different neurotransmitters and their pharmacology (Donnerer and Lembeck). Useful, certainly, if you want to know who discovered what, and when, but lacking the punch of the main story. Oddly, neither book has more than a passing mention of amino acid transmitters, despite their overriding importance in the brain.
Now that the dust has settled on the Soups and Sparks controversy, we can see that both sides were right: cells communicate both electrically and chemically, and we know a lot about the mediators, receptors and ion channels that make this possible. At the time, as these books remind us, the pursuit of chemical transmitters was exciting and passionate.
London
E-mail: humphrey.rang{at}btopenworld.com
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