Joshua Sanes, PhD, is the Jeff C. Tarr Professor of Molecular and Cellular Biology at Harvard University. Last month he completed a sixteen-year term as the Paul J. Finnegan Family Director of the Center for Brain Science (CBS) and a six-year term as co-director of the Harvard Brain Science Initiative (HBI). He has been with both CBS and HBI since their founding in 2004 and 2014, respectively.
Sanes is a world leader in cellular and molecular neuroscience who has won many accolades, primarily for his discoveries about synapse development. His research endeavors have over the years spanned work on the neuromuscular junction, cell lineage, retina, the classification of neuronal cell types, innovations in transgenic methods (e.g., Brainbow), single cell analysis, and most recently evolutionary issues as his lab compares cell types in a variety of mammals (mice, monkeys, and humans) with those in birds and fish.
Sanes did his undergraduate work at Yale University, majoring in Biochemistry and Psychology. He received his PhD in Neurobiology from Harvard and completed postdoctoral work at UCSF. His mentors have included Paul Greengard, John Hildebrand, and Zach Hall. Before he came to Harvard, Sanes was a faculty member at Washington University School of Medicine for over two decades. In addition to his academic work, Sanes serves as an advisor for the biotechnology company Biogen.
We will be celebrating Sanes’s service to the Harvard science community with a Zoom party on August 26th. In advance of that, we asked him to share a little of his career story:
Tell us about your childhood. How did you become interested in science?
All four of my grandparents were immigrants from Eastern Europe. In various circuitous ways, they all ended up in Buffalo, where my parents grew up and met. They were just parents by the time I knew them, but they had a more interesting younger life. My dad was in the army, in World War II, then moved to New York. My mom moved to California for an adventure – starting out in college, but then facing financial challenges and deciding to try something else, she become a pilot in the civil air patrol.
Once my parents moved back to Buffalo, my dad went into business with his father, who sold auto parts. My dad had not gone to college but was very intellectual. So I grew up in a book-laden house. He was friends with all sorts of academicians, but more in the humanities. I’d say I was probably best in English back at that point. But then I got interested in psychology. Abnormal psychology, psychopathology.
What did you do with that interest in psychology? Is that what led you to the lab?
There was a super wonderful guy who lived in my Buffalo suburb named Robert Guthrie. He was in the Josh Lederberg group of early bacterial geneticists. In the ’50s he had a son with severe mental retardation and he completely reoriented his research and invented the PKU test. He then spent years going around and trying to get state health departments to adopt it, successfully eventually. In addition, he really thought it was very important to get young people involved in science. So I ended up getting a job in his lab that was quite transformative. It was the kind of research where you could be really useful even as a high school kid, growing bacteria and picking colonies. I just loved doing that – and even helped find a mutant that was used in a test for another PKU-like disease, called MSUD (it’s called JP3 for Josh and Paula). You know, I never liked lab courses. I actually like getting results and so this was a great experience of getting results that were actually useful.
Then I went to college. I was going to be a biochemistry major for a while—until I ran into physics and math. I just didn’t want to do that at the time. I ended up becoming a psychology major, which was super interesting. Yet I still liked “hard” science. So I ended up applying for this program that let you spend your whole senior year doing a thesis. I found two mentors, one was a psychologist and one was a biochemist. The idea was to do a combined thesis that would reveal the biochemical defects in schizophrenia. Obviously this didn’t work, but I ended up very enjoyably doing the two parts separately. The psychology part was great. I got to go down to Bellevue Hospital in New York. They didn’t have HIPAA in those days, so you could just take some kid like me and set him free in the records room, trying to think about diagnostic categories. The biochemist was Paul Greengard, who became a lifelong mentor – and of course eventually a Nobel laureate. He was a super important person in my life, all the way until he died last year. Just a loving, wonderful yet intensely competitive person. I learned so much from him.
It sounds like your high school experience in Guthrie’s lab was pivotal. How did you get into that lab?
This is one of the ways in which Guthrie was wonderful. He had gotten some very early NSF grant to host high school students and had hired a high school biology teacher to kind of run the program. That teacher was tasked with finding people in his classes to recruit, so he found me. (By the way, I should say, this high school teacher was such a nice man. I was just learning to drive and he let me drive his car, a stick shift, when we went to the lab after school. I was an awful driver. Can’t believe how many gears I went through.)
And then you got to work in Nobel laureate Paul Greengard’s lab.
Yes, I’m just so lucky. I was an undergraduate in his lab during the first of five years in which he really upended neuroscience. He pretty much discovered protein phosphorylation in the nervous system. Huge stuff. How cyclic AMP works, how cyclic GMP works, how they mediate, as we say now, metabotropic responses: adrenergic receptors, muscarinic receptors. Essentially people had worked out this system in terms of glycolysis and received a Nobel prize for it, but he was the first person to say, “Well, maybe this isn’t just about metabolism, maybe it also plays important roles in the nervous system.” Then he moved on from there.
In grad school, I started out with a collaborative project that would make use of what I loved about working with Greengard, but situated in Ed Kravitz’s lab at Harvard. Basically, at that point, cyclic nucleotides were totally new and the idea was to see if electrical stimulation could affect nucleotide levels or whether putting on membrane soluble cyclic AMP derivatives could affect physiological properties. That didn’t work out so I moved to John Hildebrand’s lab and turned into a developmental neurobiologist with a molecular bent.
So you went from an initial interest in psychopathology to a deeply biochemical exploration of the developing nervous system. How did that happen?
I got into neuroscience because I was interested in mental illness. But it soon became clear that research on the biological basis of mental illness at that point was an utter crock. There was just no way to do good work. There’d be a report saying that people with schizophrenia had high levels of ascorbic acid in their serum, then the next year somebody would come out and say, well that’s because they took the blood sample at the same time every day and that was right after those individuals got their orange juice, but right before the control group got their orange juice.
It’s just that there were no methods. There weren’t 2D gels, there wasn’t molecular biology, there weren’t monoclonal antibodies, there weren’t cDNAs, there weren’t transcriptomes or genomes. And you couldn’t deal with membrane proteins. When my first grad school project bombed out, I ended up drifting more towards development and if I look back, I could say that it’s because it was increasingly apparent that psychiatric diseases are probably neurodevelopmental disorders—thought I’m sure I didn’t think about it clearly at the time. But pretty early on, I wanted to work on synapses and synapse formation and synapse specificity. By then it was pretty clear that synapses somehow were involved in the pathology of mental illnesses.
Throughout my career, I would say what I’ve ended up trying to find fairly simple systems to look at problems that you would like to look at in the cerebral cortex, but you can’t because it’s a jungle. From looking at the neuromuscular junction to study synapse formation, to using the retina to study synapse specificity.
What are the best and worst parts of your job?
I still love what I’m doing. When people ask, I’d say, there are certainly people who want to die in the lab—they want to work to the very last day, there’s nothing else they want to do. Whereas I’d say I’ve always felt that it’s just better than anything else I could ever think of at any given moment in time. I went and worked in Congress for a year right after my PhD, because it seemed like a fun break and a chance to try out something else. It was fascinating, but not nearly as much fun as science, so I was happy to come back to a postdoc. I don’t think there’s been a day in my life when I didn’t want to go to work.
What else do I really like? I like writing. It’s kind of painful, but I like it. I would say I have especially liked sitting at my desk with students and postdocs, going over experiments, talking about ideas, filling out yellow pads. Many ex-students now want to throw up when they see a yellow pad. But those things are all good and fun. I like them.
What don’t I like? There isn’t a lot. I guess there’s a certain amount of bureaucracy that I find irritating.
What do you do for fun outside of science?
Unlike a lot of people, who have these incredibly full lives, I don’t have that much else in my life other than my family and work. I have two kids, who are now adults and I spend a lot of time with them. And I’ve been together with my wife for 45 years. I don’t collect stamps or coins or guns. I don’t do carpentry and my musical talents are minimal. I do love reading. I read a lot of novels. Also, I love traveling, both for vacation and for science. I’ve taken several sabbaticals that are just so wonderful, and I’ve really loved. They’re kind of based in science, but they’ve also shown me a different part of the world. I lived in Paris for a year, and for semesters in the South of France, Cambridge (UK), Pasadena and Manhattan. All peak experiences!
Wow, that sounds nice! So for the novels you mentioned — what kind do you like?
Mostly 20th century novels, usually American or British. I’ll read anything by Michael Chabon, Jonathan Coe, Margot Livesey, or Ann Patchett, for example. And now that Zoom life renders me brain dead by 6 and I don’t work in the evening the way I used to, I sometimes just watch TV. One show I recommend is Little America. It’s a network show about the immigrant experience. Half hour long interesting, upbeat tales. Fun to watch.
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To learn more about Sanes’s career story, check out this 2005 PNAS biography by Tinsley Davis: https://www.pnas.org/content/102/1/5
To get some of Sanes’s tips on how to tell a good story in a scientific paper, check out this 2019 eLife perspectives piece: https://elifesciences.org/articles/50527