The Race to Explore the Pathway to Cough: Who Won the Silver Medal?

JOHN WIDDICOMBE

Department of Human Physiology and Aerospace Medicine, GKT School of Biomedical Sciences, London, United Kingdom

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The paper I have selected to discuss is "Receptors in the trachea and bronchi of the cat" (Widdicombe JG, J Physiol Lond, 1954;123:71-104). It is the middle of three consecutive papers. On rereading them after many years, I find them like what they are, the basis of a D. Phil. thesis; they are stodgy, somewhat long-winded (60 journal pages in all), and with signs of overconfidence and lack of discrimination. I, like the papers, may still have these characteristics.

I have chosen the paper for two reasons: first, I think it is important and had an influence on future research, as I shall explain later; and second, it taught me that I could do independent research and, more importantly, greatly enjoy it. It confirmed and established my future career.

The paper analyses in detail, by single fiber recording from the vagus nerve, the afferent pathways from the trachea and bronchi for coughs, deep breaths, and other reflexes, and shows that the same pathways cause changes in bronchomotor tone. It was a forerunner of fifty years of research in many laboratories on the sensory mechanisms from the airways relevant to respiratory diseases such as asthma.

I have always been interested in why research students choose their subjects; although they may be lead to their field of study by personal enthusiasm, the choice of detailed topic is usually, as in my case, due to a combination of chance and an inspiring mentor. As a science student at Oxford I always loved physiology and wanted a career in basic medical research. I was advised first to take medical degrees, and I have never regretted doing so, for two reasons: a medical degree led me to applied and clinical physiology; and my "internship" was in the department of Ronald Christie at St. Bartholomew's Hospital, London. He had a fine team of young doctors working on respiratory medicine, and they led me to the subject of my future studies, applied respiratory physiology. Christie was a chronic cigarette smoker although, like Bill Clinton, he claimed never to inhale. I said to him once "With respect, professor, you do cough occasionally so the smoke must be getting into your lungs". He replied "You may be right, but then nobody knows anything about cough". I didn't know so at the time, but this comment influenced my choice of research topic; there was an important gap to be filled.

I returned to Oxford in 1950 to do research with Geoffrey Dawes, Director of the Nuffield Institute for Medical Research. He was an inspiring and enthusiastic supervisor. Then as now one had to have a licence to do animal research, but in those days the process took four weeks, whereas nowadays it takes over eight months. To fill the gap he advised me to learn German, of which I knew a little ("It is still the language of science"not true, even in 1950), and to study the innervation of the esophagus (then as now "the most neglected tube in the body"). This was before the days of the internet, and for four weeks I browsed along the dusty bookshelves in library basements. I found little in German on the esophagus, but I translated the great German classics by Breuer and Hering, von Bezold and Hirt, and Kratschmer on respiratory reflexes; none described a cough reflex from the lower airways. I also found and translated a little-known paper by Keller and Loeser (Z Biol, 1926;89:373-395). They were one of the first to record afferent activity in the vagus nerves. They used a primitive oscillograph with only multifiber records; their illustrations look like blurred seismographs of a Richter Scale 1 earthquake. But they did report rapidly adapting receptor (RAR) discharges from the trachea, which they speculated, with supporting evidence, came from "cough receptors." So we did know something about the afferent pathway for cough!

I moved forward to the great classic papers by Adrian and by Knowlton and Larrabee, with beautiful single fiber analysis of vagal discharges from the lungs. Adrian (J Physiol Lond, 1933; 79:332-358) studied mainly slowly adapting receptors (SARs), but also reported "some nerve endings of the more rapidly adapting type," responding to deflation. He nowhere discussed their reflex action and nowhere mentioned cough (although the Keller and Loeser paper is in his reference list). Knowlton and Larrabee (Amer J Physiol, 1946;147:100-114) did a brilliant single-fiber analysis of SARs and RARs and argued convincingly that the latter caused deep breaths or sighs (subsequently confirmed to be true for those RARs deep in the lungs). Keller and Loeser is not in their reference list; their paper contains only one reference to cough, almost as a footnote, to suggest that RARs "can cause the deep inspiration of cough."

After four weeks my licence arrived. Unlike today's multi-page requirements it was wonderfully liberal and consisted of only one sentence. I was permitted "to study the physiological systems of the body"; there were ethical limitations concerning the use of anaesthetics, and I mustn't use "horses, asses, or mules," presumably because they were loved by English gentry and Members of Parliament (then much the same?). But within reason I was licensed to do what I wanted. I went back to Geoffrey Dawes and said, in effect: "I have done my best with German. Germans are not interested in the esophagus, and neither am I. The innervation of the trachea and bronchi is as neglected and far more interesting. Cough is the commonest and least studied sign of airways' diseases (Christie). May I study its afferent pathway?" He agreed, and it was the start of three years' research.

But not full-time. Geoffrey was a wonderful pioneer in the study of fetal and neonatal respiration and circulation, and I was dragged willingly into his team as a kind of glorified technician. It was a superb education in research: major large and small animal surgery and instrumentation; assessment of apparatus and calibrations ("Never trust a manufacturer's claims"); building one's own apparatus (using lathes and milling machines) and electronic units (at the oral examination for my D. Phil. I was asked "Did you build your own amplifiers?" I proudly replied "Yes"); glass-blowing; photography; even typing. Geoffrey taught that language should be a sharp and precise tool of the scientist. (In the first draft of my chosen paper I included the phrase "One type of atypical response . . ."; this earned a marginal exclamation mark.)

But there was a growing problem. Geoffrey Dawes involved me so much in his team research that there was not enough time for work for my thesis. Only when lambs were not available and when he went to meetings (often) or on holiday (seldom) could I do my own thing. Then in early 1953 fate, in the form of the Government, struck. I received a letter saying that in eight weeks I had to report for two years' military service. A medical student during the war, as I had been, was exempt from immediate conscription on the grounds that he would be of greater value to his country when medically qualified. Although the war had been over for eight years, official talons kept their grip. I was sharing a house at the time with John Vane, future Nobel Laureate, who was not conscripted; he was younger and had no medical degree. I had eight weeks to finish my research, do the typing and photography myself, and bind and submit the thesis. I just made it, but many loose ends remained untied.

Why is the research important? It came at the beginning of, and I believe influenced, a half century of work on the role of vagal afferent nerves in respiratory physiology and in pathological conditions such as asthma. My thesis listed 57 referencesall I could find, and many not very relevant. In reviewing much the same area in 1986, John and Hazel Coleridge (San Francisco) listed 258 references; I am sure today the number could easily be quadrupled. Pioneering research, starting in the early 1950s by Autar Paintal (Delhi) and greatly extended by the Coleridges, established the role and importance of lung and airway C-fiber receptors in vagal reflexes; but it was only in the 1980s that C-fiber receptors were shown to play a part in cough, and the nature of that part is still vigorously debated today. More recently, the role of RARs and C-fiber receptors in hyperreactivity, neurogenic inflammation, and airway pathology in conditions such as asthma has been much studied. Also, importantly, Kappagoda and Bonham (Davis) and Undem and Canning (Johns Hopkins) and their colleagues have been studying interactions between afferent pathways at the peripheral, ganglionic, and central nervous levels. These studies of neuronal plasticity could have profound implications for mechanisms in chronic lung and airway disease. Of course I claim no credit for these wonderful studies and many others, but my 1954 paper may have pointed towards some of them.

The paper also has a personal importance. In the 1960s and 1970s I established my own laboratories, first in Oxford and then at St. George's Hospital Medical School, London. I was joined by a superb group of research students, assistants and visitors from, in particular, the USA, Poland, and Czechoslovakia. We began to tie up the loose ends of the research left behind in 1953. This was the most productive and happy period of my career, and for me the 1954 paper was like an acorn that grew into a tree.

Thinking back on the paper, I believe that research is always a race against, inter alia, time, statistics, career changes, and personal limitations. It is essential to enjoy it and that, for me but perhaps not for others, demands team collaboration. Publishing one's first paper gives a great sense of achievement a seed has been sown; this feeling is even stronger in future years when the tree bears fruit.

However, in the 1950s, unlike today, research was seldom a competitive race. Had it been so one might have said that, on the racetrack to explore the pathway to cough, Keller and Loeser limped first past the finishing post; they easily outstripped me, who finished second in fine form and ahead of the rest of the field. Some very distinguished runners never left their starting blocks. Do I deserve a silver medal?

	Footnotes

Correspondence and requests for reprints should be addressed to John Widdicombe, Department of Human Physiology and Aerospace Medicine, GKT School of Biomedical Sciences, Shepherds's House, Guy's Campus, London Bridge, London SE1 9RT, UK.