B y now, I have lived in Northern California for more than half my life, but I remain a native New Yorker in temperament and humor. Born in 1955, 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 in the bottom flat 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 middle-class kid to experience transformative cultural 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. Junior high school – those amorphous two years (grades 7 and 8) between elementary and high school – coincided with social unrest and upheaval marked by, among other things, the civil rights movement, escalation of the war in Vietnam, and the slide of NYC toward fiscal insolvency. As such, I remember these years as mostly chaotic and subliminally stressful, when kids of my age worried about the possibility of older brothers being drafted and whisked from the streets of Brooklyn to the jungles of Southeast Asia. For those who had any sense of social awareness, it was a time to open one’s eyes and grow up quickly.
Perhaps sensing the precarious financial state of public schools, my father lobbied me to take the admissions test for one of NYC’s famous ‘magnet’ schools, which I didn’t mind doing since it meant a day off from school. Consequently, and unexpectedly, I was accepted to Stuyvesant High School, which attracted students interested in science and math. Thus, I spent my first year of high school commuting from Brighton Beach to the lower East Side of Manhattan, which on a good day involved a three-hour roundtrip experience navigating three rush hour-packed subway lines. Together with incessant testing and homework, this left no time for other important facets of teen life. Although holding my own academically, I was truly miserable and needed to make a change. So, with moral support from my older brother Martin, I reported to Stuyvesant on the first day of my sophomore year and went promptly to the principal’s office to de-enroll myself. My dad was, shall we say, unimpressed with my decision, but I never looked back or regretted this moment of self-determination.
I thus ended up at the local venue, Abraham Lincoln High School, from which my mother and other family members had graduated. While Lincoln may not have enjoyed the special academic status generally afforded Stuyvesant, it does boast an impressive list of alumni that includes notable writers (Arthur Miller, Joseph Heller, Mel Brooks), performers (Beverly Sills, Neil Diamond, Harvey Keitel, John Forsythe), and even distinguished scientists (after Arthur Kornberg, Paul Berg, and Jerome Karle, I am now Lincoln’s fourth Nobelist). In my own class, I graduated alongside Lee Mazilli, who went on to play and coach major league baseball with the NY Mets and Yankees. Signing my yearbook, he wrote, “Hope you see me in the bigs someday.” Touché Lee!
At Lincoln, I was thrilled to be on an early session that let out around noon, leaving ample time to socialize, play basketball, and explore all corners of NYC. Most of my friends were interested in literature, history, and politics and together we enjoyed the many cultural happenings in Manhattan that I never had time to experience when at Stuyvesant − exploring folk and jazz clubs in Greenwich Village, visiting the city’s grand libraries and museums, and seeing truly transformative performances on and off Broadway that opened my eyes to drama and the power of playwrights like Arthur Miller and Tennessee Williams. Group activities also included canvassing for George McGovern (whose unsuccessful bid for the US Presidency was aimed at unseating Richard Nixon and ending the disastrous war in Vietnam) and waiting on tables at local weddings or bar mitzvahs to earn a few dollars. In summertime, I scrounged around for any available jobs, such as packing and delivering merchandise or cleaning office buildings. These experiences gave me an appreciation for the many hard ways that people make a living, while also compelling me to seek a path that was self-motivating, self-directed, and fulfilling – and in which I did not have to punch a time clock!
One step in that direction was enrolling in a physics class taught by Herb Isaacson As a former minor league baseball player, Mr. Isaacson also coached the Lincoln team and was, as I recall, instrumental in getting Mazilli to the majors, adding to his aura as an exceptionally smart, suave and engaging teacher and mentor. He made physics approachable and fun (e.g., plotting the trajectory of a baseball) by challenging us with ideas, not facts, and insisting on participation by boys and girls, alike. Indeed, numerous alums credit Mr. Isaacson for making them seriously consider science as a career trajectory, and this was certainly true for me.
Like my older brother, Martin, I expected to enroll in a NY State college, but a classmate suggested that I apply to M.I.T., of which I had never heard. Indeed, no one in my family had attended a private college, but I decided to give it a try and was rather surprised when a letter of acceptance showed up in the mailbox. Tuition, even in those days, was a stretch for my parents, but in their usual fashion of devoting hard-earned resources to the kids, they encouraged me to enroll with the proviso that I might have to switch to a state college if things got dicey financially. But I led a rather frugal lifestyle and did my part by finding summer employment, and so things somehow worked out.
M.I.T. wasn’t exactly the freewheeling college scene that some of my friends were enjoying elsewhere, but it was an unusual place that I came to appreciate for its quirkiness and intensity. Academically, I was drawn to biology and chemistry because I initially thought about a career in medicine. However, I soon realized that I had no real desire to be a clinician and was instead captivated by biochemistry and the elegance of bacterial genetics. I was especially inspired by the work of Monod, Jacob and Lwoff, the legendary French microbiologists who shared a Nobel Prize in 1965 for elucidating mechanisms of gene regulation. While I did not appreciate all the nuances of their work, I was generally amazed at how these scientists could abstract models of complex molecular pathways from seemingly simple and elegant experiments. I was also fascinated by the ingenious ways in which they leveraged chemistry together with genetics to solve puzzles and construct and test these models. Indeed, one of my best classroom experiences at M.I.T. was sitting in on a graduate-level course in molecular genetics taught by Ethan Signer, who had studied at the Pasteur Institute with these legendary scientists and was able to bring their work and these exciting times to life.
But didactic classes and problem sets were not my forté, and 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, she suggested that I 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. Indeed, Alex’s lab was a rather messy and freewheeling place inhabited by some very entertaining and colorful personalities, forever dispelling any misconceptions I might have had about laboratories being pristine ivory towers for dispassionate research. But underneath this chaos was an energetic and interactive vibe focused on serious science. And to my everlasting benefit, Tom let me know that he expected as much of me, even though I was just a pipsqueak undergraduate intern. I worked hard, enjoyed thinking about and planning experiments, and even published a modest paper from my efforts, providing evidence that I could be inspired and 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. In those days, the Litvak lab was situated in the Biochemistry Department on the Talence campus, just across the corridor from the Enology Department, where bottles from the great châteaux of Bordeaux, Saint-Émillion and the Medoc could be found in the hallway awaiting analysis. Of course, there were often a few sips left over for sampling during department pastry and coffee breaks in the late afternoon. And so aside from purifying a couple of enzymes (tRNA nucleotidyl transferases from wheat germ and yeast), I thoroughly enjoyed Bordeaux and its environs, learned something about red wine and French culture, and came to appreciate the fact that scientists are exceedingly privileged to be part of a vibrant international community. Simon and Laura were amazing mentors and we have remained in touch ever since.
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 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, yeast alpha-factor is proteolytically cleaved from a larger polyprotein precursor and thus stood as an excellent model system for identifying enzymes and secretory mechanisms involved in their biosynthesis. Together with Lindley (Buff) Blair and Tony Brake (two postdoctoral fellows in the Thorner lab), 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. In mammals, these enzymes cleave polypeptide precursors at paired basic amino acids to liberate bioactive hormones, activate viral surface glycoproteins (including the spike protein of SARS-CoV-2), etc. Such enzymes had been sought for decades, but it was the combined power of genetics and biochemistry that finally brought one to light.
When I was in Alex Rich’s lab, Ned Seeman (a senior fellow who later became a pioneer of DNA nanotechnology) 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 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 multifaceted 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.
Around this time (1983), a paper from Eric Kandel and Richard Axel’s labs caught my eye in which they described genes 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 pre-olfaction 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 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, which is an aspect of Richard’s career and legacy that many of us strive to emulate.
As noted above, and like many cloning projects of the time, the goal of identifying a serotonin receptor gene was both elusive and competitive. Our main challenger was a very formidable group at the California Institute of Technology led by the neurophysiologist, Henry Lester, and the legendary molecular biologist, Norman Davidson. Richard and Norman were old friends and thus when we ultimately succeeded, we sent the Caltech group a preprint of our manuscript describing the cloning of the 5HT1c serotonin receptor subtype. Henry and Norman responded by sending us a couple of bottles of champagne accompanied by a card reading,
“To David Julius and Richard Axel – Here’s an expression of warm congratulations from your friendly competitors. We’re delighted with your success. Let’s hope for lots of interesting further results from both labs.”
I have saved this note through the years as a memento of these times, and more importantly as an exemplar of what science and scientists can be at their best.
Having at long last accomplished my goal in the Axel lab, it was again time to move on. I accepted a faculty position at UCSF, returning to the Bay Area in late 1989. Mike Bishop and Harold Varmus had just become UCSF’s first Nobelists and the Loma Prieta earthquake had just shaken the city up and so there was both joyful and nervous energy in the air. UCSF seemed like a good choice for me 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.
To my great fortune, the transition to faculty independence was made smoother and more tolerable when Tony Brake, my friend and collaborator from graduate days in Berkeley, joined the lab. Following his postdoctoral stint in the Thorner lab, Tony started a yeast genetics and protein expression group at Chiron Corp., one of the first local biotechnology ventures. When I moved back to the Bay Area, Tony took what was supposed to be a brief sabbatical leave from Chiron to work in my lab; he never went back and worked with me for almost 10 years before retiring from science. During this time, Tony shared his deep knowledge of biochemistry and molecular genetics with our group and many others at UCSF, and his generous and gracious demeanor helped to ground a fledging new lab in its formative years.
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 the 5HT3 receptor (the one ionotropic serotonin receptor subtype), followed by nucleotide-gated (P2X2) channels – projects in which Tony played a key part through his own efforts at the bench or by providing advice and inspiration to others. 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. Like other groups fascinated by this problem, we tested any relevant and newly cloned channel, such as 5HT3 and P2X receptors, for sensitivity to capsaicin. But this low throughput candidate receptor approach never panned out, necessitating an unbiased, function-based screening strategy.
For us, the Eureka moment came when Michael Caterina joined my group and spearheaded our efforts to identify the capsaicin receptor (now called TRPV1) using an elegant expression cloning scheme. 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.
A lot has happened since I started my own lab, but it’s still hard to believe that I’ve been at UCSF for over 30years! 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, long-lasting friendships and collaborations. Chief among these is Allan Basbaum, with whom we have worked to connect molecular and biophysical findings to pain behaviors, giving our studies greater intellectual depth, impact, and translational relevance. Roger Nicoll, legendary neurophysiologist and lab neighbor, 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. Robert Edwards, another neighbor and neurologist and synaptic physiologist, has been a friend and colleague throughout my time at UCSF and a partner for daily banter of crazy ideas, strategies, and frustrations. Allan, Roger, Robert, 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 few 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 ion channels and 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 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 patience and flexibility (and perhaps their discovery of noise-cancelling headphones).
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, creative, and impactful science. My group has never been large (usually around 8 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.
The other shout-out goes to public support of science. Indeed, the National Institutes of Health has been the great engine driving biomedical research and training here in the US. In addition to funding projects with direct clinical relevance, the NIH had the foresight to support basic curiosity-driven research such as ours, which so often lays the groundwork for important advances in modern medicine. Maintaining this balanced portfolio is the secret sauce for continued success and vigor of biomedical research here in the US and elsewhere, and for our trainees and collaborators who hail from around the globe.
In closing, I would like to thank the Nobel Assembly for selecting 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 support of both applied and basic, curiosity-driven research that we will find new mechanism-based solutions to this pressing problem. While Nobel Prizes are awarded to specific individuals, their power is in inspiring the world to value and trust fact-based thinking and other intellectual and creative pursuits that make life better, richer, and fairer for all.