Stuart Lipton: UFOs and flying tigers.

www.thelancet.com/neurology Published online March 26, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00011-3 1 Stuart Lipton was up in the middle of the night fielding emails when he saw his first UFO. No ordinary flying saucer, this UFO was staring up from the text of the review article he was struggling to finalise. The sticking point was to come up with finding a catchy way to explain the unique mechanism of action of an Alzheimer’s disease drug called memantine, which he had characterised, developed, and patented in the late 1980s and early 1990s. The drug works by modulating NMDA receptor-operated ion channels through a unique profile of low-affinity, uncompetitive inhibition with a relatively fast off-rate, which doesn’t exactly slip off the tongue. “I needed to come up with something people will remember”, he recalls, so he took the Uncompetitive, the Fast, and the Off-rate, and he called memantine a UFO drug. “Even big pharma calls them UFO drugs now”, he laughs, and they’re likely to become part of the wider neurological lexicon over the coming years, as Lipton’s group at the Sanford-Burnham Medical Research Institute and University of California San Diego, La Jolla, CA, USA, pursue a series of successors to memantine. Memantine was subsequently approved for the treatment of moderate-to-severe Alzheimer’s disease by the US Food and Drug Administration in 2004, with Lipton intimately involved in every part of the discovery process, through to some of the clinical trials. According to Pierluigi Nicotera, scientific director for the German Center for Neurodegenerative Diseases, Bonn, Germany, Lipton is one of the “world’s leading scientists in research on brain diseases, because he has been able to bridge fundamental research with translation, both in the case of memantine and, together with Jonathan Stamler [Case Western Reserve University, OH, USA], with the discovery of the biochemical reaction called S-nitrosylation”. S-nitrosylation is a post-transcriptional modification analogous to phosphorylation, Lipton explains, “but we’re about 50 years behind phosphorylation in studying it”. As it turns out, S-nitrosylation is “possibly the most ubiquitous post-translational modification there is”, he says, and further study of several S-nitrosylated protein targets is already yielding useful clinical insights. In most of the world, characterising a class of Alzheimer’s disease drug and a ubiquitous biological process is pretty much guaranteed to ensure you’re a hot ticket on the conference circuit, but in South China the crowd go particularly wild for Lipton. His father, who like Lipton trained as a physician-scientist, served as the flight surgeon for the famed Chennault’s Flying Tigers, an American air squadron based in and around Burma that helped fend off Japanese attacks in southern China. “When I’m announced at seminars in southern China as the son of this flight surgeon, who was known as Dr Ling Ting Put, probably a transliteration and rearrangement of the name Lipton in Mandarin, people get up and cheer”, says Lipton. “As I’ve gotten older it’s meant more and more to me, what those guys went through to preserve life and liberty for the future generation, and I was greatly influenced by my father”. Wanting to follow in his father’s illustrious footsteps, Lipton enrolled in a 6-year PhD programme at Cornell University, NY, USA, paid for by the New York-based Ford Foundation. He later attended the University of Pennsylvania, PA, USA, and Harvard University, MA, USA, to obtain his MD and PhD degrees, respectively. “One of the great things about that programme at Cornell, apart from the fact it was paid for, was that you had a lot of really close associations with professors there. We were in special classes of just five or six people, and that really ignited my sense of what science was about”, he recalls. His training also brought him into contact with several scientists who would go on to have a big influence on him. “One was Howard Rasmussen at the University of Pennsylvania, and another was John Dowling at Harvard, who I ended up doing my PhD thesis research with”, Lipton explains. John always played to people’s strengths, and I really learned how to run a lab based on that experience”. After completing his neurological clinical training at Harvard with Norman Geschwind, “another huge influence and just a wonderful guy”, Lipton moved on to a postdoctoral fellowship, also at Harvard, in the laboratory of Torsten Wiesel, winner of the Nobel Prize in 1981 for his work on neuronal processing in the visual cortex. “That was probably one of the most important things that happened to me; it was then that I really learnt to do careful, deepthinking science, and Torsten was just a fantastic mentor. And, I just happened to be in his lab when he won the Nobel, which was a very cool experience”, says Lipton. He was tempted to California in early 2000 by the opportunity to found the Center for Neuroscience, Aging, and Stem Cell Research at the Sanford-Burnham Institute, which has developed to have over 300 staff. When we spoke, Lipton was just about to embark on a whistlestop tour of Europe, with talks in Paris and Nice, France, and then on to Barcelona, Spain, for The Lancet Neurology Autoimmune Disorders Conference. And, if you’re lucky enough to see him speak, make sure you find out where he’s planning on dining afterwards because, under the recommendation of his attorney-turned-gourmet-chef wife, it’s guaranteed to be a good night.