Allan and Jocelyn Weissman with grandchildren Ethan (left) and Liam (right). Photo taken by Weissman’s daughter, Shira Tyndall.
For Allan M. Weissman, M.D., cellular membranes and their receptors were a pathway from medicine to a career in scientific research. A physician by training, Weissman has spent the last three decades exploring how the ubiquitin-proteasome system, a process that determines the function, trafficking and degradation of proteins, relates to physiology and disease, while also establishing proof-of-principle for new therapeutic modalities for cancer.
As a postdoctoral fellow at the National Institute of Child Health and Human Development (NICHD), Weissman cloned and characterized the zeta subunit of the T-cell receptor, which he continued to explore in his lab at the NCI starting in 1989. Following a chance discovery in 1992 that zeta ubiquitination was integral to T-cell activation, Weissman refocused on the ubiquitin-proteasome system. This led to his lab’s discovery in 1999 of RING finger proteins as the largest family of ubiquitin ligases or E3s, which are responsible for targeting specific proteins for ubiquitination. RING finger proteins play critical roles in modulating protein levels and their functions, and include many proteins implicated in either promoting or suppressing cancer, such as BRCA1.
Weissman and colleagues went on to establish that RING E3s and other components of the ubiquitin-proteasome system could be targeted by small molecules in cancer cells, develop a new paradigm for the structural basis of RING E3 function and demonstrate novel roles for ubiquitination at mitochondria and in infectious diseases. He also provided new insights into the ubiquitin-proteasome system in cancer and metastasis, including demonstrating that a specific RING E3 facilitates metastasis in sarcoma. More recently, Weissman and colleagues demonstrated that the same E3 predicts poor outcomes in breast cancer, specifically in African-American women. In addition to his science, Dr. Weissman served as a CCR Laboratory Chief from 2001 until 2022.
In the Q&A that follows, Weissman reflected on his career journey, the future of the field and his retirement plans.
Tell me about your career journey. What has been the most surprising thing about it for you?
I was interested in science early on; my dad was a pharmacist, as was his father. My father also taught chemistry and biology and had been a medic in the Army. I went to college at Stony Brook on Long Island in the mid-1970s, where I met my wife, Jocelyn, and became interested in chemistry and biochemistry. At this time, the use of recombinant DNA was taking off, so, in addition to working in a biochemistry lab, I had the opportunity to take a graduate course in bacterial transcriptional regulation, where the foundational work of recombinant DNA was being done. I also took a course on cellular membrane biology, which was probably most important in shaping my future interests.
I then attended medical school at Albert Einstein College of Medicine in New York. There, I was fortunate to be mentored by Ora Rosen, who did groundbreaking early research on insulin signaling. Ora suggested I spend some time at NIH. I came to Bethesda in 1980 as a medical student for a clinical rotation in endocrinology, and was exposed to a group of exceptional physician-scientists who challenged me; I came away enamored with NIH.
I graduated from Einstein in 1981 and did my internal medical residency at Barnes Hospital at Washington University in St. Louis, and then came back to NIH for my research training, where I trained in the laboratory of Richard Klausner in NICHD.
I was with Rick for five years in what was an amazing scientific environment filled with extraordinarily talented young scientists. During my fellowship, we cloned the zeta subunit of the T-cell receptor, which eventually became the basis for CAR T-cell technology. I was then recruited to the NCI as an independent investigator in 1989, and I’ve been here ever since.
One important lesson I’ve learned over the years is that unexpected and seemingly small things can turn out to be the most important. My lab was studying zeta and T cell activation and we were running two-dimensional gels looking at tyrosine phosphorylation of zeta, which has a characteristic pattern. On some gels, we saw ladders of small spots appearing above both the phosphorylated and non-phosphorylated protein when T cell receptors were activated. At first, we didn't know what to make of these, but then we realized that this could be the ubiquitination of zeta. At the time only a handful of cellular ubiquitination substrates had been identified, and its overall significance was not appreciated — so this was a big deal. Following those spots on gels changed the direction of my career from studying the T-cell receptor to ubiquitination and regulated protein degradation.
This led to our discovery that proteins containing RING fingers work with ubiquitin-conjugating enzymes to stimulate ubiquitination, that is, RING finger proteins are ubiquitin ligases or E3s. This was probably the single most important discovery that my lab made and helped lead to the explosive growth of the ubiquitin field that has followed. The finding that RINGs are E3s also served as a basis for much of our subsequent research.
What do you see as some of the most exciting frontiers in cancer research, both in your field and broadly?
The post-genomic era that we're in, with the ability to rapidly look at genetic changes, and to carry out gene sequencing and measure gene expression, certainly lends itself to personalized medicine, and there’s an appropriate focus on this. However, our interest is predominantly in proteins, and what we know from our work, and that of others, is that changes in protein levels aren’t necessarily reflected in gene expression. With all the new tools we have, it now becomes critically important to systemically analyze protein expression and function in cells, and assess how these are altered in different diseases.
How did the intramural environment of CCR in NIH help your research?
NIH is a wonderfully nurturing place that is unique in that it allows you to follow your nose and change the direction of your research. When we discovered that the T-cell receptor was ubiquitinated, it wasn’t clear how important it was going to be, but we were supported to pursue this work. I think that's really just an incredible selling point for CCR, and I would emphasize that for anyone starting their career.
What are you looking forward to the most in your retirement?
My wife and I will retire at the same time from CCR, and we look forward to spending more time together. We’re also eager to have more time to spend with our two young grandchildren, and I have a bunch of interests that I haven't had time to pursue and travel to new destinations is high on our agenda.
I'm closing my lab, but I don't think of myself as really retiring. I'll be an NIH Scientist Emeritus affiliated with the Women’s Malignancies Branch and will lend my expertise to CCR research and help train younger scientists, as well as writing and reviewing. I won't be doing this full-time anymore but, as a scientist, I can’t just turn it off.
Dr. Allan Weissman retired from CCR on December 30, 2023.