By David Julius Few Blocks Away, in the Same Pre-War for More Than Half My Life, but I Remain a Apartment Where My Father Grew Up

Home , David Julius, Jerome Karle, Kavli Prize, Randy Schekman

By now, I have lived in Northern California by David Julius few blocks away, in the same pre-war for more than half my life, but I remain a apartment where my father grew up. native New Yorker in temperament and Quarters were close, but largely convivial, humor. I grew up in a seaside Brooklyn making for a small, close-knit and loving neighborhood – immortalized by Neil family unit in which modest resources Simon’s play ‘Brighton Beach Memoirs’ were devoted to providing opportunities – that’s been a landing pad for Eastern and experiences for us kids. My brothers European immigrants like my and cousins have pursued careers in grandparents, who fled Czarist Russia and research, education, engineering and law. antisemitism in pursuit of a better life. They are fantastic people who, like our Consequently, my parents are first- parents, are warm, generous and socially generation Americans. They grew up in minded. this NYC enclave, attended public schools, and earned first-class higher educations Brighton Beach was dense and somewhat at tuition-free Brooklyn College, gritty, but not a bad place to grow up, with exemplifying what some of us still cherish easy access to the beach and just a as the American credo of open borders subway ride from the metropolis of and opportunity for all. Manhattan. And in the days before ‘dynamic pricing,’ museums, concerts and My father, an electrical engineer, designed Broadway shows were generally and maintained emergency power affordable, enabling even a middleclass systems for the telephone company. My kid to experience transformative culture mother was an educator and teacher in moments. At the same time, there was the NYC elementary school system. plenty of opportunity for pickup games of Together with my two brothers, Martin basketball or summer frolicking at the and Arthur, we lived on the bottom level beach alongside a million or more New of a rather small ‘semi-attached’ house in Yorkers who would flock to Brighton or Brighton Beach, with the top floor nearby Coney Island to catch a breeze on occupied by my maternal grandmother, a hot and muggy summer day. aunt, uncle, and two cousins, Hope and Rachel. My paternal grandparents lived a With brother and mom in Brooklyn family had attended a private college, but I was Ned Seeman, at the time a decided to give it a try and was shocked postdoctoral fellow in Alex’s lab, who went when a letter of acceptance showed up in on to become an originator of the mailbox. MIT wasn’t exactly the nanobiology and a Kavli Laureate in freewheeling college scene that some of Nanoscience. I was even able to publish a my friends were enjoying elsewhere, but it modest paper from my efforts in the lab, was an unusual place that I learned to providing some evidence that I could be appreciate for its quirkiness and intensity. productive in this line of work. For me, the magic path was UROP – the Undergraduate Research Opportunity Another great outcome of working in Program – that helped students find Alex’s lab was meeting Simon and Laura laboratories in which they could gain Litvak, Chilean nucleic acid biochemists hands-on research experience. In my who were on sabbatical from the sophomore year, I worked with Janis University of Bordeaux, France. I somehow Fraser, a graduate student in Joel convinced the Litvaks to let me work in Huberman’s lab who was determining how their lab during the summer between Okazaki fragments are incorporated into junior and senior years, which turned out replicating DNA. When Janis stopped to be one of the most formative and doing bench work to write her thesis, I memorable times in my life. Aside from then moved down the hall to work with purifying a couple of enzymes (tRNA As a child in Brooklyn

Like my parents, we all attended public schools. I was pretty much a reluctant student who often turned in my assignments late (or not at all) and generally tried to stay below the teacher’s radar. At some point, around 5th grade, I decided that it was time to put in a little more effort and be less afraid of failure, and then things got easier and more inspiring academically. I attended Abraham Lincoln High School which has a storied past with an impressive list of alumnae ranging from notable writers (Arthur Miller, Joseph Heller, Mel Brooks) and performers (Beverly Sills, Neil Diamond, Harvey Keitel, John Forsythe) to scientists (Arthur Kornberg, Paul Berg, Jerome Karle). In my day, the student body was perhaps not as distinguished, but I met some smart and fun friends with MIT graduation whom I explored the theaters and Greenwich Village clubs of NYC, which is her husband, Tom, in Alex Rich’s lab, nucleotidyl transferase from wheat germ what I remember most about this where I spent the next two years using and yeast), I thoroughly enjoyed Bordeaux formative time in my life. Academically modified transfer RNAs to study the and its environs, learned something about speaking, I was exceedingly fortunate to kinetics and specificity of aminoacylation red wine, and came to appreciate the fact enroll in a physics class taught by Mr. and how this might influence the fidelity of that scientists are privileged to be part of Herb Isaacson, a minor league baseball ribosomal protein synthesis. Working in a vibrant international community. Simon player turned educator. Mr. Isaacson was Alex’s lab was a great experience and a and Laura were amazing mentors and we a fireball who challenged us with ideas, sanctuary from classes and problem sets. have remained in touch ever since. not facts, and expected enthusiastic And I came to realize that designing, participation in return. He made physics executing and interpreting experiments Having decided on a career in biomedical fun (and even relevant to baseball) and I satisfied my intellectual curiosity while also research, I applied to several graduate credit him for making me wonder whether providing an outlet to do something programs but received mostly rejections. science could be a career trajectory. creative at the bench – much like a hobby. However, sometime late in the academic I also sensed that science attracted an year I got a telegram informing me that I’d Like my older brother, Martin, I expected interesting and eclectic group of people been accepted to the Biochemistry to enroll in a NY State college, but a who accepted the uncertainty of discovery Graduate Program at Berkeley, initiating classmate suggested that I apply to MIT, for a somewhat more independent and my long-term association with an amazing which I had never heard of. No one in my self-determined lifestyle. A case in point public institution, the University of students. But this is really a product of more importantly enticed me to enter the daily cumulative influences from all of new frontier of molecular neurobiology. I one’s lab mates, collaborators and applied to Richard for a postdoctoral mentors – and in this regard, I was position (not realizing that he was already incredibly fortunate to have come under quite well known for developing methods the tutelage of Jeremy and Randy. They for gene transfer into animal cells), were (and still are) passionate, intense expressing my interest in cloning a and rigorous in their approach to science, serotonin receptor gene. Richard agreed and attracted likeminded students and that this was a worthwhile goal and I fellows to their labs. At the same time, returned to NYC in the winter of 1984 to they gave us latitude to be creative and begin my fellowship with him at Columbia make our own mistakes. Both were University. Richard is a person of intense approachable and have a cutting sense of curiosity and intellect who encouraged his humor, which helped foster a more fellows to pursue challenging projects and David Julius in the laboratory at UC Berkeley informal ‘West Coast’ atmosphere in the establish their own scientific persona. lab that appealed to me and likely Consequently, and especially in the pre- California. Owing to some unforeseen influenced my decision to eventually settle olfaction days of the lab, many of us events and good luck, I came to carry out in the Bay Area. forged our own trajectories along diverse my graduate studies under the joint areas, but often with an immediate goal of mentorship of two young dynamos, After an exhilarating and very productive cloning genes that define a key cell type or Jeremy Thorner and Randy Schekman, era at Berkeley, it was time to move on. physiological process. Having come to the who were exploiting Saccharomyces yeast Yeast was such a powerful system with a lab with no experience in neurobiology, to study pheromone signaling and protein bright and broad future, but I decided to vertebrate physiology, or mammalian secretion, respectively. I worked on a use my time as a postdoctoral fellow to molecular genetics, I had a lot to learn and project at the interface of their two labs explore new and different territory. Two spent several years spinning my wheels. that involved understanding how a streams of thought converged: my focus But I also had the benefit of advice from peptide mating pheromone called alpha- on pheromone processing made me great Axel lab friends (Greg Lemke, Moses factor is synthesized and secreted by wonder about the molecular and Chao and Dan Littman) and local these cells. Like many mammalian peptide physiological actions of hormones and collaborators (Amy MacDermott and the hormones, alpha-factor is proteolytically neurotransmitters in the brain; and late Tom Jessell) and after many false cleaved from a larger polyprotein perhaps influenced by Bay Area history, I starts, I finally achieved my goal by cloning precursor and thus stood as an excellent became fascinated by the pharmacology a serotonin receptor (the 5-HT1c/2c model system for identifying enzymes and of hallucinogens, opiates, and other subtype) from a rat brain using a function- secretory pathways involved in their natural products that societies have used based screening strategy. Altogether, my biosynthesis. Together with Buff Blair and over millennia to alter consciousness and postdoctoral stint lasted six years with a Tony Brake, we succeeded in this sensory experience. I began reading burst of productivity in the last two. Those endeavor, with the most exciting discovery books and articles from cultural figures middle years, fraught with competition, emerging in the last few months of my and writers like Timothy Leary and Tom tested my endurance and confidence, but graduate studies when I identified the Wolfe but was mostly influenced by Richard supported me throughout and KEX2 pro-protein convertase as the papers from scientists - notably Sol never (at least to my knowledge) lost faith defining member of a family of furin/ Snyder and George Aghajanian - who had – something that I have always subtilisin-like proteases that cleave used LSD and related ergots to probe appreciated and bear in mind when polypeptide precursors at paired basic serotonergic and other endogenous encouraging my own trainees to amino acids to liberate bioactive neurotransmitter systems. Their studies undertake exciting but risky projects. I also hormones, activate viral surface suggested that monoamines like learned from Richard how important (and glycoproteins, etc. Such enzymes had serotonin and dopamine each interact intellectually rejuvenating) it is to have been sought for decades, but it was the with pharmacologically distinct sites in the fellows develop an independent scientific combined power of yeast genetics and brain, but there was no understanding of trajectory that they can then take with biochemistry that finally brought one to how such receptor subtype diversity might them. Indeed, no one has a more light. be manifest at a molecular level. This impressive list of protégés than Richard, seemed like a fantastic problem to which is a part of his legacy that many of When I was in Alex Rich’s lab, Ned Seeman explore, with great relevance to us strive to emulate. told me that graduate training was a neuropsychiatric disease. process of gradual maturation leading to a Having at long last accomplished my goal, moment of crystallization in which you Around this time (1983), a paper from I accepted a faculty position at University would suddenly realize that you had Richard Scheller, Eric Kandel and Richard of California, San Francisco and moved reached a state of intellectual clarity and Axel caught my eye in which they cloned back to the Bay Area in late 1989 to start confidence. I think there is some truth to cDNAs encoding precursors for peptide my own group. UCSF seemed like a good this, which I experienced in my last year or hormones controlling egg laying and choice because, in addition to having a so at the University of California, Berkeley related behaviors in Aplysia sea snails. stellar reputation in familiar areas and have witnessed with many of my own This was relevant to my thesis project, but (molecular genetics and biochemistry), it was also home to a first-class David McKemy and Werner Neuhausser trainees. Being part of the cryo-EM neuroscience community, which I knew used menthol to identify a related ion ‘resolution revolution’ has been a thrill as would be essential for my future growth channel (TRPM8) as a cold receptor. These we have watched its impact go far beyond and development. Indeed, the challenge studies revealed a molecular logic of sensory neuroscience. Importantly, our now was to begin thinking more like a thermosensation while more generally timely contributions to this area were physiologist, which can be a tough illustrating how somatosensory neurons made possible by transformative transition for someone trained as a can detect noxious chemical or physical reductionist biochemist. While intending stimuli. Subsequent discoveries by us and to spend my time immersed in the vast many groups have further highlighted biology of serotonergic systems, I realized roles for TRP channels (and neurons that that the world of G protein-coupled express them) in acute and chronic pain receptors was getting immensely crowded and itch, reflecting the ability of these and I therefore pivoted to ion channels, beautifully complex polymodal signal transitioning with cloning of 5HT3R (the integrators to regulate excitability of the one ionotropic serotonin receptor nociceptor in the face of injury or other subtype), followed by nucleotide-gated physiological perturbations. Exploiting (P2X2) channels. these channels to develop non-opioid analgesics remains an important One important outcome of this work was translational goal that has not yet come to Me and my parents to bring our attention to primary afferent fruition, but about which I remain sensory neurons, where these channels optimistic. are highly expressed. I became intrigued by the idea of studying somatosensation, A lot has happened since I started my own which was arguably less well understood lab, but it’s still hard to believe that I’ve at a molecular level compared to other been at UCSF for 30 years! No institution sensory systems - and possibly more is perfect, but I’ve stayed at this one mechanistically complex in having to because it is home to so many energetic detect both chemical and physical stimuli. and creative colleagues who have Moreover, the goal of linking molecular expanded my scientific horizons, and with events to behavior seemed more whom I have developed wonderful, long- attainable with sensory systems, with the lasting friendships and collaborations. added benefit of possibly finding new Chief among these is Allan Basbaum, who inroads to diagnose and treat an unmet has inspired me and our trainees to clinical problem, chronic pain. Another connect molecular and biophysical major selling point was the possibility of findings to pain behaviors and chronic Hiking with family in Thailand exploiting natural product pharmacology pain syndromes, giving our work greater to gain a toehold in this area, bringing me intellectual depth, impact and translational back to what had enticed me into relevance. Roger Nicoll, my immediate neuroscience in the first place. Jancsó and neighbor and legendary his team in Hungary had famously shown neurophysiologist, has been a mentor and that capsaicin, the pungent principle in role model for me and my trainees - chili peppers, was an excitatory agent for a always challenging us to put our subset of somatosensory neurons, making hypotheses to the test with the cleanest, capsaicin sensitivity a defining functional most rigorous experiments. Allan, Roger hallmark of nociceptors. Thus, identifying and I also share a similar brand of humor, a mythical capsaicin receptor became which is a mainstay of our interactions. something of a Holy Grail in the pain field, but also a frustratingly elusive goal. And then there is Yifan Cheng, with whom we have experienced another Eureka For us, the Eureka moment came when moment by leveraging recent advances in Michael Caterina joined my group and electron cryo-microscopy (cryo-EM) to successfully spearheaded our efforts to visualize our favorite TRP channels in identify the capsaicin receptor (now called atomic detail. Seeing is, indeed, believing Hiking with Holly in Patagonia TRPV1) using an elegant expression and the thrill of capturing these channels cloning strategy. Together with Makoto in various conformational states and in innovations from the Cheng and Agard Tominaga and others, he then showed complex with drugs and toxins has been labs here at UCSF, once again validating that TRPV1 is a heat-activated ion channel, breathtaking. This work began as a this institution as a special place to do providing a cogent molecular explanation synergistic collaboration between two science. for a widely appreciated psychophysical fellows, Erhu Cao and Maofu Liao, and experience – the ‘hotness’ of chili peppers. flourished from there over the past seven The other great collaboration in my life Taking this approach to its logical ‘flip side’, years to include other channels and has been with my wife, Holly Ingraham, The Norwegian Academy of Science and Letters Drammensveien 78, 0271 Oslo, Norway

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