Dr. John Graham Nicholls, FRS
John Graham Nicholls, a key figure in the development of modern neuroscience, died at his home in Trieste, Italy, on July 13, 2023. He was 93. Dr. Nicholls trained with leading neuroscientists in England and the U.S. in the 1950s and 1960s when the application of cellular electrophysiology, chemistry and electron microscopy was giving birth to the modern era. He became a leader himself through his career-long research aimed at identifying mechanisms of fundamental nerve and glial cell functions. His influence was greatly augmented by his authorship with Stephen W. Kuffler of the first widely used textbook on modern neuroscience. His lectures on the field’s basic principles to students, professionals and general audiences were admired for their insights, usefulness, and captivating artistry. He pioneered in organizing short courses that spread progress in neuroscience research to scientifically underfunded countries. Nicholls was recognized in 1988 by election as a Fellow of the Royal Society (FRS) of the UK.
Nicholls’ interest in the nervous system ranged from molecules to consciousness, but his own research primarily focused on a cell by cell understanding of how the nervous system wires itself together, how it can rewire after injury to restore function, and how, given the cells’ plastic properties, networks of nerve cells (neurons) produce such essential functions as reflexive movement and breathing (respiration). For these studies, Nicholls developed novel tissue preparations—from, for example, leeches, opossums, and fetal rodents—that he realized would be experimentally favorable for answering fundamental questions about the brain. Moreover, he taught countless others how to use such preparations.
His scientific discoveries, lectures and writing in themselves propelled him to prominence as a world-class scientist, and his ability to do neuroscience research and teach throughout the world made him peerless. His interest in neuroscience on an international level might have been related to his remarkable ear for languages. He was heard to converse with natives in at least 9 different languages, exchanging words in Swedish on the elevator in Basel, where he taught in German as well as English, lecturing in Spanish in Mexico and Peru, and chatting in Italian, French, Russian, and Swiss German. Nicholls’ international reach was less surprising considering that he was in turn on faculties at major universities and institutes in the UK (University College London and Oxford), USA (Yale, Harvard, and Stanford), Switzerland (Biozentrum, University of Basel), and Italy (Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste), where he did his pioneering research and taught neuroscience. In addition, short courses he led on nearly every continent resulted in his forming strong friendships with teams of nationally diverse scientists. Originally a citizen of the UK, he gained both US and Swiss citizenship.
Nicholls earned his Ph.D. under Sir Bernard Katz at University College London in 1955. He used quantitative electrophysiology to show that muscle cells deprived of synaptic input increased their excitability and their sensitivity to the neurotransmitter acetylcholine. His study of muscle fibers and of sensory-motor reflexes then continued at University College London and Oxford, where he held the position of Demonstrator. This was followed by postdoctoral training with Stephen Kuffler at Harvard Medical School. Building on Kuffler's work with David Potter, Nicholls and Kuffler characterized the physiological relationship between neurons and the glial cells that ensheath them, both in vertebrates and medicinal leeches, which have large glial cells that function like those in vertebrates. This led to a wealth of discoveries in Nicholls’ own lab using the medicinal leech, where he and his students found sensory and motor neurons in its segmental brains, or ganglia, and were the first to show, in any system, that severed axons could regenerate synaptic connections precisely, at the level of single, identified neurons. They also showed how branched axons act as switches and regulate signaling in the nervous system. And they devised means for selectively deleting single neurons with all their branches from living animals, which proved to be key to understanding neuronal function and plasticity in the fashion of transgenic animals before knockouts existed, yet with more specificity than conditional knockouts. This work, begun on the faculties of Yale and Harvard in 1965 and 1968, respectively, continued for 10 years at Stanford beginning in 1973.
At Stanford, he and his group also developed methods to study synapse formation between specific cells growing in tissue culture medium in a dish. They recreated axon growth and synapse formation in vitro, where they could distinguish separate events and create unusual cell combinations. In this way, they identified key molecules and cellular events underlying the growth and specificity of synaptic connections. Throughout this time and after moving to Basel in 1983 and then to Trieste in 1998, Nicholls trained many students and postdocs who went on to establish their own illustrious academic careers, and he attracted leading scientists who spent sabbatical periods with him.
Before moving back to Europe, Nicholls took a sabbatical year studying sensory-motor integration driving respiration in cats with Prof. Tom Sears at the Institute of Neurology, Queen Square, London. Thus, in Basel he was able to launch a new program using newborn opossums that combined his interest in mammalian respiration and development with work on regeneration, which occurs in newborn opossums, but not adults. For this he was joined by a new team of graduate students, post-docs, visiting scientists, technical assistants and Biozentrum staff. Others continued to work with him on cellular and molecular determinants of regeneration in leeches. Together, they were an unusually productive group. The opossum team identified molecular controls on neurotransmitter receptor expression, found the precise time during development that axon growth in the CNS became non-permissive, identified molecules whose expression changed at that time, and located sources of respiratory rhythms arising in the developing hindbrain. The leech team used monoclonal antibodies and other tools to discover extracellular matrix molecules that controlled axon growth, charted the sequence in development of gap junctional synapses from rectifying to non-rectifying, showed that microglial cells laid down laminin to promote axon regeneration in vivo and in vitro, and identified ionic channels in those microglia. More recent experiments, done in part at the Woods Hole Marine Biological Laboratory with Larry Cohen and Jaime Eugenin, used optical recording and fluorescent probes to monitor respiratory networks containing scores of active neurons in the fetal mouse hindbrain.
Like his mentors Katz and Kuffler, who did not take credit by putting their names on papers from their labs when they had not contributed hands-on to the experiments, Nicholls typically did not co-author papers of students in his own lab even though he guided and helped with their experiments and paper writing. Thus, many of his eminent students were sole authors, and he had far fewer publications than the number of papers to which he contributed substantially.
Also like his mentors, Nicholls loved working long hours dissecting tissue preparations and doing experiments, usually with a colleague with whom he could chat. Advances in electrophysiology often rely on custom made equipment constructed and maintained by clever staff, and the staff are often the unsung heroes of neuroscience, but both Kuffler and Nicholls made sure their staff got credit and that their importance to the experiments was appreciated. For decades Bob Bosler was Kuffler's assistant and good friend, and Bosler for the rest of his life remained Nicholls' friend, too, traveling together to teach in remote parts of the globe. Nicholls was sure to recognize his technical staff, typically interacted with them on a first name basis, took an interest in their lives, and included them in activities outside the lab, as he did for example by paying for their travel from Basel to Miami for his 65th birthday celebration.
Nicholls was a consummate teacher, throughout his career conveying the wonder of the nervous system and the thrill of discovery in colorful writing, lively lectures, discussions, and hands-on laboratory courses. His lectures were legendary for their clarity. Prior to giving a lecture Nicholls was often seen walking on campus rehearsing its various segments with a stopwatch, making certain he had them perfectly tuned and segued, and he would end precisely on time. He was once asked why he went to such trouble. He replied, “Your students are your clients. You must never let them down.”
His book From Neuron to Brain (Sinauer), written in its first few editions with Stephen Kuffler and then with other colleagues through a 5th edition, was translated into many languages and reached a worldwide audience. He gave intensive (2-3 weeks long) courses, initially during summers in the United States at Cold Spring Harbor Laboratory and the Woods Hole Marine Biological Laboratory, then at academic institutions throughout the world, many under the auspices of the International Brain Research Organization. Leading by example, he headed teams of neuroscientists to give scores of interactive lecture courses and hands-on laboratory courses throughout the Americas, Africa, Asia, Oceania, Europe, and the Middle East. His warm sense of humor, informality, and concern for others drew younger scientists to him, and added to the many close friendships he maintained going back to school days. By watching his students doing experiments, listening to them give talks on their work and interacting with them in discussions, he and others in his teaching teams were able to write informed letters on behalf of the students that helped them to find training positions abroad, advance their careers, and develop neuroscience in their home countries. Into his last year he continued to tutor students at SISSA in giving 10-minute talks, similar to those presented at international meetings.
Soon after Nicholls had returned to Harvard in 1968, he attended a meeting in San Diego with his Harvard colleague Torsten Wiesel, who suggested they return home via Mexico City. From that visit Nicholls developed a passionate interest in Latin America and pre-Columbian culture. He found a way to make almost annual detours to Latin America if lectureships, courses, and collaborations did not bring him there directly. Pre-Columbian poetry graced the holiday cards he sent, and he was always keen to explore a newly discovered pyramid in Central America.
Born in London and educated in British boarding schools, Nicholls was the only child of parents to whom he remained devoted throughout their lives. His initial choice of medicine and award of the British equivalent of an MD was doubtless influenced by his father Nick’s medical practice in London. His mother, Lotte, served as an impresario in helping to develop the careers of a host of now legendary musicians, including Heinrich Szeryng and Raphael Kubelik; she fostered a remarkably refined ear and critical thinking in her son. As a youth, he corresponded with Sibelius, and throughout his life his heroes included pianists Vladimir Horowitz, Arthur Rubinstein, and Daniil Trifonov. A proud moment was sharing the stage with Rubinstein at Stanford’s “Majesty of Man” Symposium in 1975. Nicholls’ knowledge of and passion for classical music was so deep that when he heard it, even recorded, it drew his undivided attention. His 65th birthday was celebrated at a gathering of hundreds of his friends from around the world who commissioned his former student Elaine Bearer, a physician-scientist and professor of music, to compose the “Nicholls Trio'' as a “musical biography.” A recording of its premier at the birthday celebration in Miami remains widely available; it was featured on National Public Radio and it was performed again following his Forbes lecture at the Marine Biological Laboratory. After its premier, friends commissioned the cellist and violinist to record it again, but without the piano, so that John could play the piano part himself.
Nicholls was a quick and voracious reader with eclectic tastes that went well beyond science. He remembered nuances and details of everything he read, and he often formed strong opinions, including about works of fiction, engaging in lively but friendly discussions with others who knew the works well. A disagreement over Flaubert's attitude toward the characters in Madame Bovary springs to mind. Always reading for relaxation, he devoured everything written by Eric Ambler, Elmore Leonard, Carl Hiaasen, Laurence Sterne, and many others. After learning of his son Stephen's interest in the Victorian novelist Anthony Trollope, John read everything Trollope wrote. He was an early convert to electronic readers, but for books he particularly enjoyed, he gave hard copies to friends. Keeping the interests of the friends in mind, these ranged from biographies (Faraday, Stalin, Thomas Platter) to books on Japanese battleships and the origin of the universe, in addition to diverse novels, plays, and poetry. He remained an engaged reader until becoming blind with macular degeneration in his 90s, when his beloved Bettina read to him.
To Nicholls’ many friends, it was his remarkable combination of keen insights, wit and puckishness, loyalty, empathy, and affection that helped make him so endearing. With his broad background in the arts and other intellectual pursuits, his passion for excellence, his talents as a neurobiology experimentalist and inspiring lecturer/teacher, and his exceedingly generous nature, it is not surprising that he leaves an indelible imprint on his profession.
Nicholls was devoted to his sons, Stephen and Julian (with his former wife Marie Louise Nicholls née Wood), Julian’s wife Julie, his grandsons, Sam and Jack, and his longtime partner, Bettina von Hacke. Each brought him much joy and occupied special niches in his heart. Bettina’s whimsical sketches and caricatures grace and enliven his recent and humorous book of recollections entitled Pioneers of Neurobiology, published by Sinauer/Oxford, which conveys his playfulness, warmth, and brilliance.