Geoffrey Burnstock - An accidental pharmacologist.

Geoffrey Burnstock, the founder of the field of purinergic signaling research passed away in Melbourne, Australia on June 3rd, 2020, at the age of 91. With his death, the world of biomedical research lost one of its most passionate, creative and unconventional thought leaders. He was an inspiration to the many researchers he interacted with for more than 50 years and a frequent irritation to those in the administrative establishment. Geoff never considered himself a pharmacologist having being trained as a zoologist and becoming an autonomic neurophysiologist based on his evolving interests in systems and disease-related research. By the end of his life he had: published some 1550 papers; been cited more than 125,000 times; had an h-index of 156 and had supervised over 100 Ph.D. students. His indelible legacy, based on a holistic, data-based, multidisciplinary, unconventional "outside the box" approach to research was reflected in two of the seminal findings in late 20th century biomedical research: the purinergic neurotransmitter hypothesis and the concept of co-neurotransmission, both of which were initially received by his peers with considerable skepticism that at times verged on disdain. Nonetheless, while raising hackles and threatening the status quo, Geoff persevered and prevailed, becoming a mentor for several generations of biomedical researchers. In this review we provide a joint perspective on Geoff Burnstock's legacy in research.

One hundred years of Drosophila cancer research: no longer in solitude.

When Mary Stark first described the presence of tumours in the fruit fly Drosophila melanogaster in 1918, would she ever have imagined that flies would become an invaluable organism for modelling and understanding oncogenesis? And if so, would she have expected it to take 100 years for this model to be fully accredited? This Special Article summarises the efforts and achievements of Drosophilists to establish the fly as a valid model in cancer research through different scientific periods.

[Psychosomatic research in 2018: Lost illusions, renewed hopes]. / La recherche psychosomatique en 2018 : illusions perdues, espoirs renouvelés.

A critical analysis of the basic hypotheses of psychosomatic research and the sometimes hasty assertions drawn from the previous works makes it possible to better discern the data confirmed by the most recent works or the most rigorous meta-analyses and to highlight the emerging tracks. If the hypothesis of behavioral patterns specifically related to the risk of certain pathologies seems abandoned, the predictive value of depression in the cardiovascular field, more than in that of oncology, becomes clearer. Negative affect and impaired emotional awareness emerge as two complementary factors of somatic vulnerability. Several vulnerability factors seem all the more effective as they affect individuals of lower socio-economic status. Social exclusion feeling and its links with the inflammatory response appear to be a possible common denominator, both for depression and for many somatic conditions. A series of studies on the cerebral regulation of emotions and stress, as well as on bidirectional brain-bowel relations and on the mediating role of the gut microbiota, complements the available epidemiological data. The same is true for certain advances in behavioral neuro-economics, which inform the decision-making processes of patients facing preventive health choices. Lastly, it appears that a significant part of the excess mortality associated with the existence of severe mental disorders is not due to factors inherent to the patients themselves, but to disparities in the quality of the care provided to them.

[Claude Bernard and nicotinic receptors: from the neuromuscular junction to tobacco weaning]. / Claude Bernard et les récepteurs nicotiniques : de la jonction neuromusculaire au sevrage tabagique.

Claude Bernard (1813-1878) was fascinated by the pharmacological mechanisms of poisons. In particular, using a huge amount of ingenious and robust experiments, he demonstrated the peripheral toxic action of the natural compound curare. His work generated controversies in a period where scientific methodology and technical development followed the progression of concepts and ideas. From his intense debates with Albert Vulpian emerged the location of curare's toxicity at the neuromuscular junction. These two fascinating scientists could not imagine how important were these discoveries which allowed John Langley to propose the concept of receptor early in the 20th century. At the same time, the German immunologist Paul Ehrlich suggested that these receptors could be targeted by so-called "magic bullets", i.e., drugs that act on receptors, in order to treat patients. The molecular substrate of curare's activity was identified many years later as the nicotinic receptor of the motor end-plate. We now have curare molecules belonging to various chemical families that block receptors during anaesthesia. Suggamadex is the antidote for two of them, a drug that Claude Bernard perhaps dreamt of. We also have the recently marketed varenicline that acts as a partial agonist of nicotinic receptors in the central nervous system to treat patients from tobacco addiction. This rich story shows that biomedical research needs collaborations, imagination, perspicacity but also all results that it can have many years later, therefore challenging researchers about consequences of their discoveries.

Sugar industry sponsorship of germ-free rodent studies linking sucrose to hyperlipidemia and cancer: An historical analysis of internal documents.

In 1965, the Sugar Research Foundation (SRF) secretly funded a review in the New England Journal of Medicine that discounted evidence linking sucrose consumption to blood lipid levels and hence coronary heart disease (CHD). SRF subsequently funded animal research to evaluate sucrose's CHD risks. The objective of this study was to examine the planning, funding, and internal evaluation of an SRF-funded research project titled "Project 259: Dietary Carbohydrate and Blood Lipids in Germ-Free Rats," led by Dr. W.F.R. Pover at the University of Birmingham, Birmingham, United Kingdom, between 1967 and 1971. A narrative case study method was used to assess SRF Project 259 from 1967 to 1971 based on sugar industry internal documents. Project 259 found a statistically significant decrease in serum triglycerides in germ-free rats fed a high sugar diet compared to conventional rats fed a basic PRM diet (a pelleted diet containing cereal meals, soybean meals, whitefish meal, and dried yeast, fortified with a balanced vitamin supplement and trace element mixture). The results suggested to SRF that gut microbiota have a causal role in carbohydrate-induced hypertriglyceridemia. A study comparing conventional rats fed a high-sugar diet to those fed a high-starch diet suggested that sucrose consumption might be associated with elevated levels of beta-glucuronidase, an enzyme previously associated with bladder cancer in humans. SRF terminated Project 259 without publishing the results. The sugar industry did not disclose evidence of harm from animal studies that would have (1) strengthened the case that the CHD risk of sucrose is greater than starch and (2) caused sucrose to be scrutinized as a potential carcinogen. The influence of the gut microbiota in the differential effects of sucrose and starch on blood lipids, as well as the influence of carbohydrate quality on beta-glucuronidase and cancer activity, deserve further scrutiny.

Procaine and Local Anesthetic Toxicity: A Collaboration Between the Clinical and Basic Sciences.

In 1924, the Therapeutic Research Committee of the American Medical Association appointed a special committee to investigate deaths following the administration of local anesthetics. The Committee for the Study of Toxic Effects of Local Anesthetics found procaine, although a safer clinical alternative to cocaine, was capable of causing death when large doses were injected into tissues and advised that it should be used with caution. This article describes a collaboration beginning in 1928 between Dr John Lundy of the Mayo Clinic and Dr Robert Isenberger of the University of Kansas, which arose from a controversy surrounding systemic adverse reactions to procaine. Isenberger then traveled to the Mayo Clinic to conduct research on various procaine local and spinal anesthesia doses and sodium amytal's protective effect against procaine-induced toxicity. Lundy and Isenberger's work would add to the ongoing discovery of systemic reactions to local anesthetics.

William Burroughs: Sailor of the Soul.

In 1953, William Seward Burroughs made several important and largely unrecognized discoveries relating to the composition and clinical pharmacological effects of the hallucinogenic plant potion known as yagé or ayahuasca. Illustrations of Burroughs' voucher sample of Psychotria viridis and his letter to the father of modern ethnobotany, Richard Evans Schultes, are published here for the very first time.

Artemisinin and Chinese Medicine as Tu Science.

The story of discovery of artemisinin highlights the diversity of scientific values across time and space. Resituating artemisinin research within a broader temporal framework allows us to understand how Chinese drugs like qinghao came to articulate a space for scientific experimentation and innovation through its embodiment of alternating clusters of meanings associated with tu and yang within scientific discourse. Tu science, which was associated with terms like native, Chinese, local, rustic, mass, and crude, articulated a radical vision of science in the service of socialist revolutionary ideals. Yang science, which signified foreign, Western, elite, and professional, tended to bear the hallmarks of professionalism, transnational networks in education and training, and an emphasis on basic or foundational research. With respect to medical research, the case of artemisinin highlights how the constitution of socialist science as an interplay of tu and yang engendered different scientific values and parameters for scientific endeavor. Modern medical research in Maoist China could harness the productive energies of mass participation to technical expertise in its investigations of Chinese drugs, and under the banner of tu science, it became possible and scientifically legitimate to research Chinese drugs in ways that had previously provoked resistance and controversy.