Graduation Ceremonies 2017 Academic Oration 30 November 2017 “Wanderings in the Gardens of the Mind” Professor Neville Vassallo M.D.,M.Phil.,Ph.D. It is a great honour for me to address you, this evening, on the occasion of your long-awaited gradu- ation as medical doctors and, for the Ph.D. graduates, as biomedical scientists. As you are surely aware, today is an important watershed moment in your lives - one you will cherish forever and re- call with fondness and, why not, pride. I know, the road to here hasn’t been easy. It was replete with numerous hurdles you had to over- come, dangerous pitfalls, unexpected detours, and at times journeying alone (in the form of sleep- less nights poring over your books). I know, because I was one of your lecturers. I know, because I passed through the same winding road myself, albeit an odd two decades ago. Nonetheless, you persevered. You are here. And this is perhaps one important life-lesson that reading for an M.D., or a Ph.D, degree teaches you: never give up your goals. As the father of modern neurobiology, Santiago Ramon y Cajal (whom I’m sure you’ll remember from your neuroscience lectures) once said: “All great work is the fruit of perseverance.” I recall my own goals, as a fresh medical doctor barely 23 years of age. And I have to admit, they weren’t mainstream. Although interested in patient care, I was also interested in research and dis- covery. In addition, the gruelling schedule of my St. Luke’s Hospital internship further dampened my enthusiasm for pursuing a career exclusively in clinical medicine or surgery. Thus, shortly after the two-year internship at St. Luke’s Hospital, I found myself in a molecular biology laboratory - quietly observing Saccharomyces cerevisiae cells grow. Or was I? Was I merely observing and meticulously recording the growth of my cells? Or was I doing something more profound, more stimulating? In- deed, perhaps for the first time in my life, I was actually testing my own scientific hypothesis: will an oxidant insult to my yeast cells stimulate the 3-phosphoglycerate kinase (PGK) gene? More general- ly, could I establish a link between oxidative stress and glycolysis in cellular physiology? Could this be a driver for the so-called ‘Warburg Effect’, first reported by Otto Warburg in 1925, which describes the phenomenon whereby most cancer cells rewire their metabolism to derive their energy from glycolysis? My mind was teaming with ideas. I was driven by an intense excitement and intellectual curiosity. In truth, tending to, and especially healing, sick people does give a wondrous sense of per- sonal satisfaction - something you will experience time and time again in your profession as medics, and which will keep motivating you to get back to your work. But now I was seriously considering a career that brings together medicine and basic science. I was “hooked on discovery”, as Peter Doherty (1996 Nobel laureate in Physiology or Medicine) aptly wrote in his entertaining book The Beginner’s Guide to Winning the Nobel Prize. Indeed, there are countless examples of M.D.s who have actually been awarded the Nobel Prize, the world’s most prestigious award for achievement in Physiology or Medicine - not surprisingly per- haps, because medical degrees do provide an excellent grounding in all fields related to human biol- ogy and disease, from molecular biology and genetics, to physiology, pathology, microbiology, pharmacology and so many others. To mention a few examples of these celebrated physician- scientists: Thomas Südhof in 2013 for discoveries related to synaptic vesicle release, Ralph Steinman in 2011 for discovery of the dendritic cell, which plays a key role in activating our immune systems against bacteria and viruses; Luc Montagnier in 2008 for the discovery of human immunodeficiency virus; Barry Marshall in 2005 for the discovery of the bacterium Helicobacter pylori and its role in peptic ulcer disease; Eric Kandel in 2000 who first uncovered the mechanisms of short-term and long-term memory by studying a marine snail; and Stanley Prusiner in 1997 for identifying the agent (which he called a “prion”) responsible for ravaging the brains of humans with Creutzfeldt-Jakob dis- ease (CJD) and which discovery is now helping unravel the mechanisms of other neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease. In his book, Madness and Memory: the discovery of prions - a new biological principle of disease, Prusiner recounts how during his medical school years he had become “bedazzled by the science bug” and was “astonished that people actual- ly got paid to solve puzzles every day - what a fantastic way to make a living!” During his neurology residency at the University of California, San Francisco, he encountered a female patient with CJD, and was struck by how rapidly her neurological status declined every day, so that in a number of weeks she ended up unable to sit up, feed herself, or speak. Prusiner was perplexed by the fact that although he had learnt in medical school that the aetiology was supposedly an unknown “slow vi- rus”, she exhibited no signs of an infectious disease. “I was baffled”, he writes, “my curiosity thor- oughly aroused…I could not let it go.” So this CJD patient effectively launched four decades of scien- tific research which led to the discovery of prions - infectious proteins that replicate and cause dis- ease but surprisingly contain no genetic material. Prusiner enthuses: “The privilege of spending time discovering something that no one else had ever known before became an insatiable thirst.” Moreo- ver, Prusiner’s story nicely illustrates how physician-scientists are professionals who combine the clinical skills and knowledge of a medical doctor with a scientist’s inclination to pursue the study of disease through hypothesis-driven research. Science is about discovery and excitement. My own (admittedly less illustrious than Prusiner’s) re- search, which, starting from my Ph.D., was in fact very much inspired by Prusiner and his discovery of prions and led me to specialise in the field of molecular neurodegeneration, has given me great personal satisfaction over the years. I vividly recall those ‘eureka moments’ when, for instance, I first hit upon a physiological role for activation of the phosphoinositide-3-kinase (PI3K) survival pathway in neurons by the cellular prion protein - and the wonderful excitement I felt at the end of yet an- other long day of experiments, one cold, wintry evening in Munich, when I initially confirmed my hypothesis to be true. Which brings to mind another of my favourite quotes by Cajal: “Nothing for the scientific scholar is comparable to the things that he has discovered.” How true! These unique moments, give you the inner strength and stamina to persevere when the going, as is often the case, gets tougher. “Research is not just going from mountain top to mountain top, you also have to work in the valleys and that takes time and freedom” (Aaron Klug, 1982 Nobel laureate in Chemistry). Eve- ry researcher can recount countless stories when for instance experiments didn’t work as expected, or when repeated but with inexplicably different results, when weeks of gruelling experiments went down the proverbial drain because of a buffer contamination. In brief, many moments of frustration. But I have learnt an important lesson: that these frustrations and setbacks are actually necessary, part-and-parcel of a tortuous path which starts from what I referred to earlier as ‘a hypothesis’ but which can be better defined as ‘an imaginative preconception’. “Hypotheses appear in the mind along unchartered by-ways of thought; they are imaginative and inspirational in character; they are indeed adventures of the mind” (Peter Medawar, 1960 Nobel laureate in Physiology or Medicine). But perhaps the most prosaic description of the travails of research, and their usefulness, was given by Cajal in his enlightening and insightful book, Advice for a Young Investigator (this is a book that would surely stimulate the tastebuds of any scientist, or physician-scientist, among you; I myself still find in it an inexhaustible wealth of ideas about how science should be done): “The first glaring er- rors, as well as the wrong turns ventured on by the imagination, are necessary because in the end they lead us down the correct path. They are part of the final success, just as the initial formless sketches of the artist are part of the finished portrait.” A ‘black box’ warning: day-to-day scientific life can certainly be exciting and fulfilling. However, only a few scientists become very wealthy. If there are those amongst you who look to science (or medi- cine, for that matter) as a way of acquiring gold instead of the personal satisfaction associated with the very act of discovery (or of helping the sick in the case of medicine), they have probably chosen the wrong path. For a scientist, intellectual beauty is sufficient unto itself. In this oration, therefore, I am seeking to captivate your young, vigorous minds with a career that combines scientific passion and the beauty of the generative act in science, with thorough clinical knowledge and contact with patients. Physician-scientists have an ideal vantage point to facilitate the bedside to bench to bedside cycle that moves both medicine and science forward. Opportunities for the next generation of physician-scientists abound, as medicine and science come together to necessitate interdisciplinary approaches to solving disease. To mention just one example from my own field, many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are being increas- ingly studied using the tools of structural biology and knowledge of protein folding.