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David Julius Probes the Molecular Mechanics of Pain

For nearly 30 years, the UC San Francisco researcher has delved into unexplored corners of the nervous system.

Jan 1, 2018
Anna Azvolinsky

David Julius
 Professor and Chair, Department of Physiology, University of California, San Francisco,
 School of Medicine 2010 Shaw Prize in Life Sciences and Medicine 2013 Paul Janssen Prize for Biomedical Research 2017 Canada Gairdner International Award 
SUSAN MERRILL, UCSF
David Julius entered the biochemistry graduate program at the University of California, Berkeley, in 1977. “It was all one foot in front of the other. I wasn’t trying to figure out what I would be doing in 10 years,” says the University of California, San Francisco (UCSF) professor of physiology. “When I arrived, I thought, ‘Classes are pretty much over. This is like a real job, and I can just go in the lab and do my thing.’”

Julius joined the UC Berkeley lab of Jeremy Thorner, who was studying hormonal signaling and trying to understand how budding yeast cells switch mating type. Randy Schekman, a Berkeley researcher who worked on protein secretion and vesicular transport, served as Julius’s coadvisor. “What was great about Jeremy and Randy was that they were both trained as biochemists and then had decided to take advantage of the yeast genetic system to understand the biochemistry of cellular signaling.”

Haploid yeast cells can be either “type a” or “type α,” and mate with cells of the opposite type. Julius worked on the synthesis of alpha factor, one of two mating hormones produced and secreted by yeast. His graduate studies produced three Cell papers. The first, published in 1983, reported that a class of enzymes, the dipeptidyl aminopeptidases, is necessary to cleave a longer precursor of alpha factor into the final 13-amino-acid peptide. To identify the specific dipeptidyl aminopeptidase and elucidate its role, Julius took advantage of yeast mutants, including one called ste13 (for sterile 13), which cannot produce normal alpha factor. It was the first time anyone had characterized the biochemical functioning of one of the yeast sterile mutants.

No one in my family had gone to a private college, so I assumed I would go to SUNY Stony Brook.

In another of the Cell papers, Julius and his coauthors reported the discovery of a pro-protein convertase called KEX2 that cleaves polypeptide precursors between certain pairs of basic amino acids, resulting in an active hormone. Again, Julius worked with yeast strains that had mutations, this time in the gene kex2, using a bevy of peptide substrates to assay for dibasic residue cleavage. “I was able to get linear activity using this assay in wild-type yeast and didn’t see any activity in my mutants,” Julius says. “I thought that was super exciting, so I dove right in, working like a maniac for three months.”

While the findings Julius generated as a PhD student aided science’s understanding of yeast mating type systems, more broadly they shed light on how peptide hormones, such as insulin and endorphins, are synthesized. “Peptide hormones are generally made from large precursors, and one [major goal] was to identify the enzymes that cleave between basic residues, such as an arginine and lysine,” he says—as KEX2 does.

“I remember Randy had been on sabbatical when I was doing the work,” Julius says. “When he came back he said to Jeremy, ‘When did he get all of this done?’” The research set the stage for subsequent identification by others of mammalian pro-hormone convertases, something Julius didn’t expect to accomplish as a grad student.

As a postdoc and in his own lab at UCSF, Julius went on to study the biochemical and neurological processes of the mammalian nervous system. Here, Julius talks about his choice to attend his neighborhood New York City high school over a prestigious, selective one; why he was drawn to studying sensory systems; and how science has always fostered an international community.

Julius Jumps

Back to the neighborhood. “Brighton Beach was a good place to grow up,” says Julius of the Coney Island neighborhood where he spent his boyhood. “It was New York City, so we had access to everything, but also felt out of the city because there was plenty of green.” As a teenager, Julius decided to try testing into the STEM-focused Stuyvesant High School and was accepted. But it was a long haul from Brighton Beach. The commute “was a grind, but what was even worse was the constant testing. I noticed that many of the kids were burning out before college. I remember going in my first day of sophomore year and just looking around and deciding, ‘I can’t do this anymore.’” So Julius—much to his father’s disappointment—switched to Brighton Beach’s Abraham Lincoln High School, which boasts notable alumni such as Arthur Miller (one of Julius’s favorite writers), Neil Diamond, and Nobel laureates Paul Berg and Arthur Kornberg. “The move was transformative for me. I met interesting people, and we got out of school early, so would take the train into the city and actually enjoyed museums, shows, and music.”

Julius also recalls an agent of scientific inspiration from his high school days—his physics teacher, Herb Isaacson. “He made me think that science might be something I wanted to do. I wrote about him for an autobiography tied to an award I received. Afterwards, I received letters from others who attended Lincoln and had similar fantastic experiences with this one teacher who encouraged them to go into medicine or science.”

Fitting in. “No one in my family had gone to a private college, so I assumed I would go to SUNY [State University of New York] Stony Brook,” says Julius. But on a whim, he applied to MIT, was accepted, and started as an undergrad there in 1973. “It was disorienting at first. There were a of lot smart people, which was intimidating.” But Julius says that as he settled into the university, he realized that he wasn’t too different from other students. “I remember a chemistry class where I couldn’t understand one of the professors and started to panic because I saw lots of people just sitting in the lecture reading the newspaper. I thought, ‘Wow, I guess they know all of this stuff.’ So I asked one of them, and he said, ‘Nah, I can’t understand a thing, so I gave up 20 minutes ago.’ I realized that everyone was in the same boat except for the few geniuses among us, and I began to relax more.” Julius decided to focus on biology, enrolling in MIT’s Undergraduate Research Opportunities Program. “This was the late ’70s, and not many colleges had opportunities for undergraduate students to engage in research. At MIT, through this program, they even placed people over the summer at companies. So MIT undergrads, instead of just saying, ‘One day I will be an engineer or a scientist,’ actually started living that life right away.”

Escape from class. In 1974, Julius began research in Joel Huberman’s DNA replication lab with then–grad student Janis Fraser. Fraser asked him to help with a pulse-chase experiment—radiolabeling DNA and putting it through a sucrose gradient and then chasing it to see when the Okazaki fragments from replication got incorporated into the longer, newly replicated DNA strand. “I set up a device to hold the pipette really still so that I could gently layer the sample on top of the gradient and spin it.” The result was beautiful, according to Julius, and got him excited about hands-on lab work. “I thought, ‘Wow, I can figure out how to do this.’”

While he was making strides in the lab, Julius admits that classes were not his forte. “Laboratory research is what got me through college. I liked that combination of hands-on experiments and abstract problem solving to figure out what your data mean.” In his junior year, he switched to Alexander Rich’s biophysics lab, where he became interested in the mechanics of protein synthesis and worked with Fraser’s husband Tom, a chemical biologist who synthesized transfer RNA (tRNA) analogs. Using the analogs, Julius and Tom Fraser worked on understanding the specificity of protein-synthesis enzymes for particular tRNAs and amino acids.

Julius Journeys

Head trip. One night, after Julius had left Boston for the Bay Area, he was lying on a bench outside the lab at Berkeley at 11 o’clock, waiting for his yeast cultures to grow, when he was approached by “two typical Berkeley denizens” who claimed that a scientist had made and sold them LSD a few years back. That these guys were still recalling an LSD experience they had years ago got Julius thinking about what actually happens when the brain is exposed to hallucinogenic drugs. “So I started reading about this topic, and that sparked the beginning of my interest in understanding how chemicals and natural products interact with the nervous system.”

In 1984, Julius joined Richard Axel’s lab at Columbia University as a postdoc to attempt to clone a serotonin receptor. “This was believed to be the target for many hallucinogens,” Julius says. “No one had yet identified genes for receptors in the brain. I was in Richard’s lab for four years before there was any glimmer that something was going to work.” But gene expression technology caught up, and in 1988, Julius used a functional Xenopus oocyte screen to clone the serotonin 1c (5-HT1c) receptor from rat brain tissue.

Hot, hot, hot. Julius joined the faculty of UCSF in 1989 and continued his study of neurotransmitter receptors. In 1990, his team cloned another member of the serotonin receptor family, the 5-HT3 receptor, and they published their findings in 1991. Julius and his collaborators also developed their own knockout mouse models to study the functions of these and other receptors. Because many of these receptors were expressed in somatosensory neurons, Julius became interested in understanding mechanisms underlying somatosensation and pain. “A big question in the somatosensory field was: Can one find functional markers for somatosensory neurons that are involved in pain sensation? And the Holy Grail in this area was the mythical capsaicin receptor,” says Julius. Capsaicin is the chemical that gives chili peppers their kick. “The somatosensory system was less well understood compared to other sensory systems, and there were comparatively fewer biochemical or genetic leads to go after.” Julius chose a pharmacological approach, which also satisfied his proclivity for natural products.

While the project initially seemed like a blind alley, Julius’s postdoc Michael Caterina cloned the receptor in 1997. Called vanilloid receptor type 1, it was among the first identified pain-specific ion channels, but it also demonstrated an unexpected functionality. “We started throwing nonchemical stimuli at the receptor and found, to our surprise, that heat could activate the channel,” opening the way to understanding the molecular biology of somatosensation.'

I realized that sensory systems are beautiful things to work on because it is basically how we view the world. The colors we can see and the things we can smell are just a product of the molecular detectors that we have.
 

Sticking to pain. That surprising discovery got Julius interested in thermosensation. In 2007, his lab used the menthol molecule, which is perceived as a cool sensation, to identify the TRP (transient receptor potential) melastatin 8 (TRPM8) ion channel, activated by menthol but also by cold temperatures. Along the way, Julius’s lab searched for toxins from spiders and snakes that activate various receptors on pain-sensing neurons, and that have become valuable tools for studying these receptors and the pathways they activate (see "Mining Spider Toxins for Analgesic Clues"). “There are lots of toxins we know now from plants and animals that zero in on TRP channels to generate pain,” says Julius.

More recently, Julius’s lab has completed the atomic structure of the TRPV1 ion channel as well as of the TRPA1 ion channel, which is activated by wasabi as well as other forms of horseradish, mustard, and other pungent phytochemicals. “It’s been thrilling to obtain the three-dimensional atomic structures of TRP channels,” says Julius. “These have stood as among the last mountains to climb because there was no structural information about these channels. For many TRP channels, we still don’t understand what activates them, so spices have given us a big pharmacological advantage for mechanistic and structural studies of TRPV1 and other receptors.”

Julius Jams

NYC childhood. Julius credits a childhood spent marinating in the cultural milieu of 1960s and early 1970s New York City with his lifelong love of film, art, and music. “I loved being in New York in high school, getting to see shows on Broadway or at Lincoln Center for $5. I remember seeing Death of a Salesman with Lee J. Cobb, and A Streetcar Named Desire with James Farentino. My brothers and I would go down to the Village and sneak into music shows and just take in the scene. That was fantastic.”

Tuning his senses. Julius found that tackling his preferred neuroscience topic of sensory biology has been psychologically satisfying. “I realized that sensory systems are beautiful things to work on because it is basically how we view the world. The colors we can see and the things we can smell are just a product of the molecular detectors that we have. Every animal sees and perceives the world in a different way based on its biophysical detectors. The systems are nice because you can really understand mechanisms of signal detection and how circuitry begets specificity.”

Open horizons. Julius doesn’t shy away from sharing his scientific opinions, or his political ones. “I gave a talk at a neuroscience meeting at the time of the result of the [2016] presidential election and was compelled to say that the rise of nationalism in politics is so antithetical to the life of a scientist. We as scientists live in this fantastic international community, and we have to protect that. We have scientists come to the U.S. to train, and we go to other places to train and be hosted. This is the lifeblood of scientists, and we need to resist closed-border policies.” 

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