Abstract
This article encapsulates the career of Joshua Burn, whose work encouraged new lines of experimentation and paved the way for fundamental advances in our knowledge of the autonomic nervous system. His legacy also endures in his efforts as Department Chairman to oversee a very supportive environment which led to the development of many successful scientists. By producing a body of work that enabled the discipline of pharmacology to contribute in a major way to the advancement of clinical medicine, Joshua Burn stands out as a unique figure in the annals of true scientific pioneers.
Introduction
There were a number of outstanding scientists who were instrumental in developing our basis of knowledge in the biomedical sciences and ushering in the golden era of pharmacology during the first half of the 20th century. Joshua Harold Burn was a leading member of this group that included Sir Henry Dale, John Gaddum, William Paton, Edith Bulbring, and Marthe Vogt. Not only did Burn make valuable contributions to the emerging discipline of Pharmacology, he trained many researchers who became major contributors to the discipline. As a result, during the first half of the 20th century and beyond, pharmacology in the United Kingdom, Europe, and the United States had a very productive period in terms of developing new ideas, understanding pathophysiological mechanisms and discovering new and effective medications.
Background
In order to appreciate fully his achievements, some knowledge of the background of Joshua Burn (Figure 1) may aid in understanding why he became so instrumental in elevating the discipline of pharmacology. 1 As a student, Burn had varied interests that included politics, moral issues, religion, and literature, which taught him to form his own opinions and even defend them when evidence suggested otherwise.
Although he originally planned to study Chemistry, he decided to major in Physiology at Cambridge. Burn was introduced to Pharmacology when he briefly joined the famed Sir Henry Dale in 1914 at the Wellcome Research Laboratories. After a stint in the army during World War I and completion of his medical studies, Burn rejoined Dale in 1920 at the National Institute for Medical Research. Beginning in 1922, they authored papers on biological standards and in collaboration with Dale, Burn played a significant role in developing statistical methods for the bioassay of vitamins and hormones. 2 Burn was also fascinated by the methodology and recording systems that Dale utilized in analyzing various principles of ergot. So when Burn left Dale’s laboratory, he possessed a strong background in the principles of biological assay.
In 1926, Burn became Director of the Pharmacological Laboratories of The Pharmaceutical Society. He held this post for 12 years, during which time he was made Professor of Pharmacology at the University of London in 1933. While his publications reflected the effort he put forward into devising methods of standardization, he began directing his attention to physiological and pharmacological problems. After serving as Dean of the School of Pharmacy, Burn then moved to Oxford in 1937 where he occupied the Chair of Pharmacology until his retirement in 1959.
Joshua Harold Burn. Source: Taken from Vogt. M. Op. Cit. Ref. 1; p. 1).
Research
At Oxford, Burn went on a scientific journey that placed him in the ranks of true scientific pioneers. Research and its publication became his primary goal. His early tenure with Henry Dale established his penchant for ensuring that his experiments were well-designed and his papers clearly written with simple conclusions. These guidelines of quality were transmitted to his faculty. 3
A master experimenter, Burn employed a variety of preparations, including the canine spinal cord, the isolated rat diaphragm, the isolated rabbit atria, perfused superior cervical ganglion, and rabbit colon. Using these preparations, seminal work was carried out on the control of the autonomic nervous system and the release of norepinephrine from sympathetic nerves. Recognizing the need for active collaboration, his work with Edith Bulbring during the 1930s and throughout World War II on the sympathetic nervous system set the stage for her to become a leader in smooth muscle physiology/pharmacology. 4 The greater part of Bulbring’s investigations with Burn dealt with the effects of epinephrine and acetylcholine and their interactions. In 1941, Bulbring and Burn provided the first evidence of the release of acetylcholine from the central nervous system 5 and later demonstrated the formation of epinephrine from norepinephrine in the canine adrenal gland. 6
In collaboration with the future Nobel Laureate John Vane, Burn also showed that the negative inotropic action of acetylcholine was due to the efflux of potassium ions across the cell membrane to elicit repolarization. 7 Studies on ventricular fibrillation and ciliary movement, particularly involving acetylcholine, were also a focus of Burn’s attention. By recognizing a link between enzyme activity and pharmacological activity, Burn was also instrumental in developing the subject of biochemical pharmacology.
Burn had a penchant for controversy and could be described as a visionary in terms of formulating theories that were far ahead of the time. While most research scientists are very cautious in their speculations because of the stigma associated with being wrong, Joshua Burn was unique in the sense that although employing analytic rigor, he was not deterred by criticism. He felt strongly that even if his conclusions, based upon documented evidence, were proven wrong, the hypothesis would still eventually lead to the development of new concepts. While a less zealous advocate of a theory might engender doubts, Burn’s exuberance inspired confidence in his theories.
One can document numerous instances in the history of great discoveries when progress was impeded by the inability of even eminent scientists to extend their work and/or draw conclusions that would only become apparent years later. Henry Dale, for example, failed to champion the theory of neurotransmission proposed by Thomas Elliott in the early 1900s because Dale noted that the administration of epinephrine did not faithfully reproduce all of the effects of sympathetic nerve stimulation. 8 Another example involves Alexander Fleming, who accidentally discovered a mold on a Petri dish which contained a substance he called penicillin. Fleming’s findings were published in a single descriptive article in a low-profile journal; moreover he never conducted an animal experiment to examine the possibility that penicillin could serve as a curative agent for systemic infections, as did Chain and Florey several years later. These two examples represent counterpoints to the manner in which Burn conducted his experiments. In essence, Burn was not afraid to be wrong if he thought that science would progress from the conclusions that he derived from his experiments.
Administration
Burn’s legacy also endures in the form of colleagues that he mentored and influenced. His department at Oxford gained a superb reputation as a center for biomedical research and teaching. No other Department of Pharmacology in the United Kingdom could compare with that of Oxford under Joshua Burn’s leadership for the training of future pharmacologists and advancing pharmacology globally. The Department of Pharmacology at Oxford became renowned throughout the world and was a coveted destination for pharmacologists. In particular, he put forth prodigious efforts to mentor his colleagues in their research, many of whom became distinguished members of the international research community. 9
In addition to Edith Bulbring and John Vane, Herman Blaschko was a biochemical pharmacologist of great distinction who pioneered the work that led to the elucidation of the biosynthesis, storage, and inactivation of catecholamines. 10 Another faculty member, Vaughan Williams, developed a widely used scheme for classifying anti-arrhythmic agents targeting irregular heart beats. 11 Mention should also be made of H.W. Ling who moved to Oxford with Burn and was a valued member of his research team. Ling also helped to design the Pharmacology course for medical students together with Edith Bulbring.
Long before it was fashionable, Burn campaigned against smoking and even scolded colleagues for smoking in the laboratory. In addition to his open door policy, there was the communal lunch in the library, which was an occasion for the younger members of the department to become acquainted with the senior members, as well as eminent visitors.
Another facet of his quest for excellence involved the Department’s regular custom for any presenter at a scientific meeting to give his/her communication to the members of the Department beforehand. If the initial talk proved unclear, the presenter, whether a graduate student or senior member of the Department, would be asked to give more than one rehearsal. It was Burn’s opinion that the significance of an oral communication would be judged in part by the clarity of its presentation. 12
Scientific Legacy
Cocaine paradox
The legacy of Joshua Burn may be highlighted in the form of two major areas of research. In 1930, Burn began a study of the effects of tyramine on the sympathetic nervous system after Sir Henry Dale identified the sympathomimetic amine as one of the active substances in a watery extract of ergot. Burn’s work was based upon the original observation made by Tainter and Chang in 1927 that cocaine blocked the pressor effect of tyramine but enhanced the action of epinephrine. 13 Burn and Tainter addressed the problem of the cocaine-paradox by showing that following tyramine-induced depletion of intraneuronal stores of epinephrine (now known to be norepinephrine), the pressor effect could be restored if epinephrine was added to the circulation. 14 This study provided the first key step in the elucidation of catecholamine metabolism. Twenty-five years later, Burn found that tyramine was devoid of pressor activity in an animal treated with reserpine and that the pressor effect was restored by the infusion of norepinephrine, and he presciently proposed the concept of uptake of norepinephrine into sympathetic nerve endings. 15
Unfortunately, direct evidence supporting the concept of norepinephrine uptake was not forthcoming until Julius Axelrod gained access to a small supply of radioactive norepinephrine and demonstrated the active uptake of norepinephrine into sympathetic nerves. For this work, Axelrod was awarded the Nobel Prize in 1970. However, some 30 years earlier, Burn had laid the foundation for the concept of catecholamine uptake using more limited techniques available at the time.
The cholinergic link
Strong testimony for the prestige that Burn possessed as an experimentalist involved the concept of a putative cholinergic link in noradrenergic neurotransmission. The Burn–Rand Hypothesis was published first in Nature in 1959 and indexed in the third edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 16 Not satisfied with the newly developed concept of one nerve ending—one neurotransmitter, Burn formulated a theory which rested on the assumption that acetylcholine possessed a nicotinic action on a site peripheral to sympathetic ganglia. 17 After depletion of norepinephrine stores, sympathetic nerves would behave as though they were cholinergic (muscarinic) in nature. However, later work based upon results obtained using blocking agents such as hemicholinium and botulinum toxin indicated that a cholinergic link was not involved in the release of norepinephrine from postganglionic nerve endings. 18
Although ultimately proven to be incorrect, this hypothesis led to questioning the one nerve-one transmitter concept. In light of present day knowledge, the findings of Burn and Rand would be interpreted in terms of the inhibition of norepinephrine transmission by acetylcholine acting on presynaptic muscarinic receptors. Thus, the conclusions of Burn and Rand spawned subsequent studies which led to concepts of multiple transmitter release from nerve endings, co-transmission and/or feedback modulation of transmission, all of which were described a number of years later. Relevant to this issue, Ullrich Trendelenburg in a tribute to Joshua Burn noted that “… in pharmacology it is often less important whether certain hypotheses or theories are right or wrong, provided they are fruitful in stimulating research.” 19 There is little doubt that the lines of work that were spawned by Burn’s experiments had significant implications for enhancing fundamental knowledge of the autonomic nervous system.
Epilogue
Joshua Burn was not wedded to antiquated concepts or dominated by unimaginative thinking. Harboring strong convictions, he was always steadfast in his conclusions. While a more diffident advocate of a new concept might retreat from a negative reception, Burn’s tenacity only inspired confidence. The fact that Burn was not reluctant to admit his failures was another refreshing aspect of his persona. He unabashedly confronted his skeptics by emphasizing the value in challenging assumptions which were accepted without question.
Burn disseminated his views on diverse subjects, moral as well as scientific. In addition to publishing a large number of research papers, Burn was a gifted writer of books and frequent articles for the practicing physician or the layman. He authored eleven books on such subjects as blood pressure and asthma. His last book was published in 1964 entitled Our Most Interesting Diseases.
Burn earned the acclaim of his colleagues by being elected a Fellow of the Royal Society in 1942 and in 1979 was the first recipient of the British Pharmacological Society’s Wellcome Gold Medal. He was also awarded an honorary doctorate from Yale and the University of Mainz and was an honorary member of the German Pharmacological Society. He also served as Editor of the British Journal of Pharmacology. 20
Joshua Burn was a memorable figure in the parade of scientific luminaries who were responsible for developing the discipline of Pharmacology during the 20th century. In the broad scheme, he was unique among his fellow scientists for promoting new ideas. In addition to his major contributions, his willingness to delve into unchartered territory helped to orchestrate new knowledge in the field of autonomic pharmacology and enabled the discipline of pharmacology to contribute extensively to major advances in clinical medicine.
Footnotes
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Dr Harriot Kezia Hunt. Nineteenth-century physician and woman's rights advocate (ISBN 9781625343765; Amherst and Boston: University of Massachusetts Press, 2018) by Myra C Glenn is a carefully contextualised account of a remarkable Bostonian (b.1805-d.1875) and her times. In her medical practice, pursued from 1835, she titled herself physician, although she had no formal medical school training, and was much beloved by her female patients, whose "heart histories'' prompted a wider involvement in advocating for women's rights including enfranchisement (she was eloquent about her experience of taxation without representation), health reform, and education, including medical education. The author has afforded us many insights into antebellum American society in general as well as contemporary female medical practice. One understands why Hunt ordered her patients medical records to be destroyed at her death but this may still be regretted, what additional insights they may have bequeathed.