The Legacy of My Mentors
As told by David Julius
By now, I have lived in Northern California for more than half my life, but I remain a native New Yorker in temperament and humor. I grew up in a seaside Brooklyn neighborhood – immortalized by Neil Simon’s play ‘Brighton Beach Memoirs’ – that’s been a landing pad for Eastern European immigrants like my grandparents, who fled Czarist Russia and antisemitism in pursuit of a better life.
Consequently, my parents are first generation Americans. They grew up in this NYC enclave, attended public schools, and earned first-class higher educations at tuition-free Brooklyn College, exemplifying what some of us still cherish as the American credo of open borders and opportunity for all.
My father, an electrical engineer, designed and maintained emergency power systems for the telephone company. My mother was an educator and teacher in the NYC elementary school system. Together with my two brothers, Martin and Arthur, we lived on the bottom level of a rather small ‘semi-attached’ house in Brighton Beach, with the top floor occupied by my maternal grandmother, aunt, uncle, and two cousins, Hope and Rachel. My paternal grandparents lived a few blocks away, in the same pre-war apartment where my father grew up. Quarters were close, but largely convivial, making for a small, close-knit and loving family unit in which modest resources were devoted to providing opportunities and experiences for us kids. My brothers and cousins have pursued careers in research, education, engineering and law. They are fantastic people who, like our parents, are warm, generous and socially minded.
Brighton Beach was dense and somewhat gritty, but not a bad place to grow up, with easy access to the beach and just a subway ride from the metropolis of Manhattan. And in the days before ‘dynamic pricing,’ museums, concerts and Broadway shows were generally affordable, enabling even a middleclass kid to experience transformative culture moments. At the same time, there was plenty of opportunity for pickup games of basketball or summer frolicking at the beach alongside a million or more New Yorkers who would flock to Brighton or nearby Coney Island to catch a breeze on a hot and muggy summer day.
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 whom I explored the theaters and Greenwich Village clubs of NYC, which is what I remember most about this formative time in my life.
"I met some smart and fun friends with whom I explored the theaters and Greenwich Village clubs of NYC, which is what I remember most about this formative time in my life."
Academically speaking, I was exceedingly fortunate to enroll in a physics class taught by Mr. Herb Isaacson, a minor league baseball player turned educator. Mr. Isaacson was a fireball who challenged us with ideas, not facts, and expected enthusiastic participation in return. He made physics fun (and even relevant to baseball) and I credit him for making me wonder whether science could be a career trajectory.
"A classmate suggested that I apply to MIT, which I had never heard of."
Like my older brother, Martin, I expected to enroll in a NY State college, but a classmate suggested that I apply to MIT, which I had never heard of. No one in my family had attended a private college, but I decided to give it a try and was shocked when a letter of acceptance showed up in the mailbox. MIT wasn’t exactly the freewheeling college scene that some of my friends were enjoying elsewhere, but it was an unusual place that I learned to appreciate for its quirkiness and intensity. For me, the magic path was UROP – the Undergraduate Research Opportunity Program – that helped students find laboratories in which they could gain hands-on research experience. In my sophomore year, I worked with Janis Fraser, a graduate student in Joel Huberman’s lab who was determining how Okazaki fragments are incorporated into replicating DNA. When Janis stopped doing bench work to write her thesis, I then moved down the hall to work with her husband, Tom, in Alex Rich’s lab, where I spent the next two years using modified transfer RNAs to study the kinetics and specificity of aminoacylation and how this might influence the fidelity of ribosomal protein synthesis.
Working in Alex’s lab was a great experience and a sanctuary from classes and problem sets. And I came to realize that designing, executing and interpreting experiments satisfied my intellectual curiosity while also providing an outlet to do something creative at the bench – much like a hobby. I also sensed that science attracted an interesting and eclectic group of people who accepted the uncertainty of discovery for a somewhat more independent and self-determined lifestyle. A case in point was Ned Seeman, at the time a postdoctoral fellow in Alex’s lab, who went on to become an originator of nanobiology and a Kavli Laureate in Nanoscience. I was even able to publish a modest paper from my efforts in the lab, providing some evidence that I could be productive in this line of work. Another great outcome of working in Alex’s lab was meeting Simon and Laura Litvak, Chilean nucleic acid biochemists who were on sabbatical from the University of Bordeaux, France. I somehow convinced the Litvaks to let me work in their lab during the summer between junior and senior years, which turned out to be one of the most formative and memorable times in my life.
Aside from purifying a couple of enzymes (tRNA nucleotidyl transferase from wheat germ and yeast), I thoroughly enjoyed Bordeaux and its environs, learned something about red wine, and came to appreciate the fact that scientists are privileged to be part of a vibrant international community. Simon and Laura were amazing mentors and we have remained in touch ever since.
"I thoroughly enjoyed Bordeaux and its environs, learned something about red wine, and came to appreciate the fact that scientists are privileged to be part of a vibrant international community."
Having decided on a career in biomedical research, I applied to several graduate programs but received mostly rejections. However, sometime late in the academic year I got a telegram informing me that I’d been accepted to the Biochemistry Graduate Program at Berkeley, initiating my long-term association with an amazing public institution, the University of David Julius in the laboratory at UC Berkeley California. Owing to some unforeseen events and good luck, I came to carry out my graduate studies under the joint mentorship of two young dynamos, Jeremy Thorner and Randy Schekman, who were exploiting Saccharomyces yeast to study pheromone signaling and protein secretion, respectively. I worked on a project at the interface of their two labs that involved understanding how a peptide mating pheromone called alpha factor is synthesized and secreted by these cells. Like many mammalian peptide hormones, alpha-factor is proteolytically cleaved from a larger polyprotein precursor and thus stood as an excellent model system for identifying enzymes and secretory pathways involved in their biosynthesis. Together with Buff Blair and Tony Brake, we succeeded in this endeavor, with the most exciting discovery emerging in the last few months of my graduate studies when I identified the KEX2 pro-protein convertase as the defining member of a family of furin/ subtilisin-like proteases that cleave polypeptide precursors at paired basic amino acids to liberate bioactive hormones, activate viral surface glycoproteins, etc. Such enzymes had been sought for decades, but it was the combined power of yeast genetics and biochemistry that finally brought one to light.
Clarity and confidence
When I was in Alex Rich’s lab, Ned Seeman told me that graduate training was a process of gradual maturation leading to a moment of crystallization in which you would suddenly realize that you had reached a state of intellectual clarity and confidence. I think there is some truth to this, which I experienced in my last year or so at the University of California, Berkeley and have witnessed with many of my own students. But this is really a product of daily cumulative influences from all of one’s lab mates, collaborators and mentors – and in this regard, I was incredibly fortunate to have come under the tutelage of Jeremy and Randy. They were (and still are) passionate, intense and rigorous in their approach to science, and attracted likeminded students and fellows to their labs.
At the same time, they gave us latitude to be creative and make our own mistakes. Both were approachable and have a cutting sense of humor, which helped foster a more informal ‘West Coast’ atmosphere in the lab that appealed to me and likely influenced my decision to eventually settle in the Bay Area.
After an exhilarating and very productive era at Berkeley, it was time to move on. Yeast was such a powerful system with a bright and broad future, but I decided to use my time as a postdoctoral fellow to explore new and different territory. Two streams of thought converged: my focus on pheromone processing made me wonder about the molecular and physiological actions of hormones and neurotransmitters in the brain; and perhaps influenced by Bay Area history, I became fascinated by the pharmacology of hallucinogens, opiates, and other natural products that societies have used over millennia to alter consciousness and sensory experience. I began reading books and articles from cultural figures and writers like Timothy Leary and Tom Wolfe but was mostly influenced by papers from scientists - notably Sol Snyder and George Aghajanian - who had used LSD and related ergots to probe serotonergic and other endogenous neurotransmitter systems. Their studies suggested that monoamines like serotonin and dopamine each interact with pharmacologically distinct sites in the brain, but there was no understanding of how such receptor subtype diversity might be manifest at a molecular level. This seemed like a fantastic problem to explore, with great relevance to neuropsychiatric disease.
Back in NYC
Around this time (1983), a paper from Richard Scheller, Eric Kandel and Richard Axel caught my eye in which they cloned cDNAs encoding precursors for peptide hormones controlling egg laying and related behaviors in Aplysia sea snails. This was relevant to my thesis project, but more importantly enticed me to enter the new frontier of molecular neurobiology. I applied to Richard for a postdoctoral position (not realizing that he was already quite well known for developing methods for gene transfer into animal cells), expressing my interest in cloning a serotonin receptor gene. Richard agreed that this was a worthwhile goal and I returned to NYC in the winter of 1984 to begin my fellowship with him at Columbia University.
Richard is a person of intense curiosity and intellect who encouraged his fellows to pursue challenging projects and establish their own scientific persona. Consequently, and especially in the preolfaction days of the lab, many of us forged our own trajectories along diverse areas, but often with an immediate goal of cloning genes that define a key cell type or physiological process.
Having come to the lab with no experience in neurobiology, vertebrate physiology, or mammalian molecular genetics, I had a lot to learn and spent several years spinning my wheels. But I also had the benefit of advice from great Axel lab friends (Greg Lemke, Moses Chao and Dan Littman) and local collaborators (Amy MacDermott and the late Tom Jessell) and after many false starts, I finally achieved my goal by cloning a serotonin receptor (the 5-HT1c/2c subtype) from a rat brain using a function based screening strategy. Altogether, my postdoctoral stint lasted six years with a burst of productivity in the last two. Those middle years, fraught with competition, tested my endurance and confidence, but Richard supported me throughout and never (at least to my knowledge) lost faith – something that I have always appreciated and bear in mind when encouraging my own trainees to undertake exciting but risky projects.
I also learned from Richard how important (and intellectually rejuvenating) it is to have fellows develop an independent scientific trajectory that they can then take with them. Indeed, no one has a more impressive list of protégés than Richard, which is a part of his legacy that many of us strive to emulate.
Back in the Bay Area again
Having at long last accomplished my goal, I accepted a faculty position at University of California, San Francisco and moved back to the Bay Area in late 1989 to start my own group. UCSF seemed like a good choice because, in addition to having a stellar reputation in familiar areas (molecular genetics and biochemistry), it was also home to a first-class neuroscience community, which I knew would be essential for my future growth and development. Indeed, the challenge now was to begin thinking more like a physiologist, which can be a tough transition for someone trained as a reductionist biochemist. While intending to spend my time immersed in the vast biology of serotonergic systems, I realized that the world of G protein-coupled receptors was getting immensely crowded and I therefore pivoted to ion channels, transitioning with cloning of 5HT3R (the one ionotropic serotonin receptor subtype), followed by nucleotide-gated (P2X2) channels.
One important outcome of this work was to bring our attention to primary afferent sensory neurons, where these channels are highly expressed. I became intrigued by the idea of studying somatosensation, which was arguably less well understood at a molecular level compared to other sensory systems - and possibly more mechanistically complex in having to detect both chemical and physical stimuli. Moreover, the goal of linking molecular events to behavior seemed more attainable with sensory systems, with the added benefit of possibly finding new inroads to diagnose and treat an unmet clinical problem, chronic pain. Another major selling point was the possibility of exploiting natural product pharmacology to gain a toehold in this area, bringing me back to what had enticed me into neuroscience in the first place. Jancsó and his team in Hungary had famously shown that capsaicin, the pungent principle in chili peppers, was an excitatory agent for a subset of somatosensory neurons, making capsaicin sensitivity a defining functional hallmark of nociceptors. Thus, identifying a mythical capsaicin receptor became something of a Holy Grail in the pain field, but also a frustratingly elusive goal.
For us, the Eureka moment came when Michael Caterina joined my group and successfully spearheaded our efforts to identify the capsaicin receptor (now called TRPV1) using an elegant expression cloning strategy. Together with Makoto Tominaga and others, he then showed that TRPV1 is a heat-activated ion channel, providing a cogent molecular explanation for a widely appreciated psychophysical experience – the ‘hotness’ of chili peppers. Taking this approach to its logical ‘flip side’, David McKemy and Werner Neuhausser used menthol to identify a related ion channel (TRPM8) as a cold receptor. These studies revealed a molecular logic of thermosensation while more generally illustrating how somatosensory neurons can detect noxious chemical or physical stimuli. Subsequent discoveries by us and many groups have further highlighted roles for TRP channels (and neurons that express them) in acute and chronic pain and itch, reflecting the ability of these beautifully complex polymodal signal integrators to regulate excitability of the nociceptor in the face of injury or other physiological perturbations. Exploiting these channels to develop non-opioid analgesics remains an important translational goal that has not yet come to fruition, but about which I remain optimistic.
"It’s still hard to believe that I’ve been at UCSF for 30 years!"
A lot has happened since I started my own lab, but it’s still hard to believe that I’ve been at UCSF for 30 years! No institution is perfect, but I’ve stayed at this one because it is home to so many energetic and creative colleagues who have expanded my scientific horizons, and with whom I have developed wonderful, longlasting friendships and collaborations. Chief among these is Allan Basbaum, who has inspired me and our trainees to connect molecular and biophysical findings to pain behaviors and chronic pain syndromes, giving our work greater intellectual depth, impact and translational relevance. Roger Nicoll, my immediate neighbor and legendary neurophysiologist, has been a mentor and role model for me and my trainees - always challenging us to put our hypotheses to the test with the cleanest, most rigorous experiments. Allan, Roger and I also share a similar brand of humor, which is a mainstay of our interactions.
And then there is Yifan Cheng, with whom we have experienced another Eureka moment by leveraging recent advances in electron cryo-microscopy (cryo-EM) to visualize our favorite TRP channels in atomic detail. Seeing is, indeed, believing and the thrill of capturing these channels in various conformational states and in complex with drugs and toxins has been breathtaking. This work began as a synergistic collaboration between two fellows, Erhu Cao and Maofu Liao, and flourished from there over the past seven years to include other channels and trainees. Being part of the cryo-EM ‘resolution revolution’ has been a thrill as we have watched its impact go far beyond sensory neuroscience. Importantly, our timely contributions to this area were made possible by transformative innovations from the Cheng and Agard labs here at UCSF, once again validating this institution as a special place to do science.
The other great collaboration in my life has been with my wife, Holly Ingraham, also a scientist and professor at UCSF. Holly is well known for her molecular and biochemical studies of neuroendocrine physiology and development, and any appreciation that I may have for integrative physiology comes from watching her intuitive and creative approach to science. Aside from that, she is a talented, generous and loving partner who makes the world a better place for me, our families, friends and colleagues. Together, we have raised a boy, Philip, whose interest cleave more to the arts than science, but I think he is actually the most creative spirit in our household. And both Holly and Philip tolerate my attempt to play trumpet music, which also speaks to their gracious flexibility.
The Julius lab
My other family, of course, is the community of superbly talented students and fellows who have honored me by choosing to spend part of their career in the Julius lab doing exceptional and impactful science. My group has never been large (usually around eight members at any given time), but an intense, yet collegial and collaborative atmosphere has created synergy that works to the benefit of all. I am proud to say that many Julius lab alums now head their own successful research groups and are leaders in their fields, thus carrying on the legacy of my own mentors.
In closing, I would like to thank the Neuroscience Kavli Prize Committee for choosing somatosensation and pain as a topic worthy of recognition. Chronic pain remains a largely unmet medical need (as highlighted in this country by the opioid epidemic) and it is only through basic, curiosity-driven research that we will find new mechanism-based solutions to this pressing problem. I’ve written this autobiography from my home, where we have been ‘socially isolating’ in the initial phase of the coronavirus pandemic. We live in a paradoxical time when increased access to information is accompanied by a strain of anti-intellectualism and a distrust of those with knowledge and expertise. But it is only through fact-based thinking and decision making that we will navigate through the current situation and other challenges that come our way. The Kavli Prizes hopefully inspire and remind us about the importance that intellectual pursuit, discovery and basic scientific research play in the vibrancy, health and general well-being of our world.