Judy Lieberman: Stay curious and excited about science

I grew up in a first-generation Jewish family that emphasized education and encouraged my curiosity. I was a math prodigy—when I was 6 or so, I was rediscovering theorems about numbers; when I was about 11, I built a rudimentary computer; and I taught myself calculus when I was 12. Marie Curie was my hero. I also read voraciously and saw movies about scientists that influenced me a lot (Microbe Hunters by Paul DeKruif, about scientists who discovered the infectious agents that cause globally important infectious diseases; Marie Curie’s biography by her daughter Eve; a 1936 movie about Louis Pasteur starring Paul Muni). My uncle Sam Granick was a biochemist at Rockefeller who worked out heme and chlorophyll biosynthesis, and I often visited his lab; he gave me experiments to do at home with Euglena (that got contaminated), and I used to have lunch with him in the Rockefeller dining room and visit him at Cold Spring Harbor Laboratory (CSHL) where he spent summers, where I saw an early electron microscope and heard about the new molecular biology and central dogma (I remember a ditty from a CSHL postdoc show to the tune of “Mares eat oats”: “DNA makes RNA and RNA makes protein—a virus could do it too, couldn’t you?”)

I loved nature and explored the seashore on summer vacations, spent a lot of time at the Museum of Natural History fixated on the dioramas and at the planetarium, and read everything I could find about plants and birds. When I was a child, the Russians sent up the Sputnik satellite, and there was a push for science education for kids in the US because of fears that the US was not competitive in science. As a result, many science programs for children were set up, and I was lucky to participate in them when I was in high school—an all-day Saturday science program at Columbia, a sciences and arts camp in the summer, and a National Science Foundation summer program in modern physics at Cornell. In these programs, I learned symbolic logic, human physiology, and about relativity and elementary particles. They crystallized my interest in becoming a scientist. My first love was biology (I had an amazing biology teacher in high school), but the Columbia program biology courses I took focused on taxonomy instead of more exciting recent discoveries (i.e., about DNA), and I became bored with biology and switched my interest to physics. Partly, I wanted to show that girls could do physics!

My career path was circuitous. I majored in physics in college and got my PhD in theoretical physics at an exciting time that saw the unification of the theory about the forces between elementary particles. My thesis was about the Higgs boson, which at the time was just a mathematical construct, not an actual particle. I then moved to the famous Institute for Advanced Study at Princeton (where Einstein had been) as a visiting member and worked on unified field theories and attempted to develop a theory to unify quantum field theory with general relativity—a difficult problem that remains unsolved 50 years later. When I was at the Institute, there were very few women in physics. I was incredibly shy (and the guys were even shyer), and I began to feel isolated staring at a blank piece of paper in my office by myself most of the day and dissatisfied with my work (I had the unrealistic goal of becoming a physicist like Newton or Einstein).

I was 30 years old and decided that I wanted to give up research and do something less abstract and more gratifying and socially useful that helped people—so I applied to medical school with the idea of becoming a physician. Although I had decided never to do research again, I enrolled in the innovative joint Harvard–MIT interdisciplinary medical school program, whose goal was to teach a scientific version of medicine to train physician scientists. When I finished medical school, I did a residency in internal medicine and hematology–oncology and practiced hematology part-time in a tertiary care hospital for a decade after that.

As part of my heme-onc training, I had to do 2 years of research. Because research in the hospitals was not as cutting edge, I did my postdoc at MIT with the immunologist Herman Eisen, who discovered that antibodies continue to mature to develop higher affinity over time. At the time, MIT was at the forefront of molecular biology research and the Eisen and Tonogawa labs had just cloned T cell receptor genes. It was an exciting time. Cellular immunology was just taking off. Our lab was studying cytotoxic lymphocytes and discovered granzymes, responsible for killing target cells. My project was to try to figure out why there were two types of T cell receptors and the function of γδ T cells.

The first AIDS cases occurred when I was an intern in medicine—it was a horrifying and deadly illness for which there was no treatment. Many young doctors in my cohort wanted to do something about AIDS. I knew that you could cure leukemias and lymphomas in mice caused by retroviruses (that are related to the AIDS lentivirus which had just been discovered) by adoptively transferring viral-specific cytotoxic T cells. This led me back to research—I decided that I wanted to test this strategy as immunotherapy for AIDS.

When I was finishing my postdoc, I was offered a faculty job (80% research and 20% clinical work, which was a standard arrangement at that time) in heme-onc at the hospital I trained in (New England Medical Center). I set two goals for my research—to figure out the molecular basis of how cytotoxic T cells kill their targets, and to develop adoptive immunotherapy with patient-derived antigen-specific cytotoxic T cells for AIDS. My lab mapped the T cell epitopes recognized by HIV-infected patients and used individual patient antigens to expand billions of HIV-specific T cells. I designed small pilot clinical trials to adoptively transfer these T cells to AIDS patients and with National Institutes of Health support got an IND (investigational new drug application) from the Food and Drug Administration, grew these patient-customized T cells in my lab, verified that they were safe, and did the trials. Although one of my patients with late-stage AIDS responded and the treatment cured his opportunistic infection, the therapy did not appear to help most patients. In seeking to understand why, I discovered CD8 T cell exhaustion in humans (simultaneous with Rafi Ahmed’s work in chronic lymphocytic choriomeningitis virus infection in mice)—I found that most of the CD8 T cells in HIV-infected chronic patients were impaired in their activation, could no longer kill, and lost expression of the cytolytic effector proteins, perforin and granzymes.

I still work on studying killer lymphocytes—for example, my lab recently discovered that the most evolutionarily conserved and ubiquitous natural killer (NK) reactivating receptor NKp46 recognizes ER stress and externalization of the ER-resident protein calreticulin; killer cells induce programmed cell death in bacteria and parasites; and a novel mechanism of immune protection against intracellular pathogens by decidual NK cells in pregnancy.

However, my lab’s focus is now on innate immunity. In 2016, my lab (with Hao Wu, at the same time as Feng Shao’s lab) identified the mechanism of membrane damage in inflammatory cell death (pyroptosis)—pore formation by gasdermin D, which is activated in myeloid cells and mucosal epithelia by inflammasomes that sense pathogens and sterile danger signals. We initiated this project when my postdoc Xing Liu put the N-terminal fragment of cleaved gasdermin into a Basic Local Alignment Search Tool (BLAST) search that suggested that it might form a pore that loosely resembles perforin pores. Pyroptosis is undoubtedly the most inflammatory process in our body. We extended this work to help solve the structure of gasdermin pores and identified by a high throughput screen a potent gasdermin D/pyroptosis inhibitor that protects mice from sepsis. My lab also showed that another gasdermin (gasdermin E, or GSDME), which is activated by caspase-3, is a potent tumor suppressor. GSDME is not expressed in most cancers and is epigenetically suppressed by DNA promoter hypermethylation. Expression of GSDME in tumor cells induces immunogenic cell death and ignites a potent immune response in which exhausted Tumor infiltrating lymphocytes become potent antitumor killers. We also showed that although killer cells have always been thought to induce noninflammatory cell death, killer cell granzyme B causes inflammatory cell death in GSDME⁺ target cells because granzyme B directly cleaves and activates GSDME. Our other work on pyroptosis showed that gasdermins destroy mitochondrial membranes, which is critical for executing pyroptosis. Our recent work identified important roles for pyroptosis in killer cell antitumor immunity, SARS-CoV-2, Yersinia, group A streptococcal infection, and neurodegeneration. We are now studying how pyroptosis is regulated, the involvement of organelles and cellular biochemical pathways in pyroptosis, and identifying the diseases in which pyroptosis plays a key role. We have found ways to suppress or activate pyroptosis to inhibit or enhance inflammation.

I am very excited about studying the role of innate immunity in antitumor immunity and ways to enhance it to broaden the range of tumors that can be treated by cancer immunotherapy that might synergize with or go beyond checkpoint inhibition. We just published the first genome-wide study of tumor immunoediting in a breast cancer genetically engineered mouse model and found that suppression of multiple innate immune pathways dominates tumor immunoediting and that derepressing the genes that are epigenetically suppressed during immunoediting induces immunogenic cell death of the tumor, stimulates innate immunity, and restores immune control. There are hints that tumors that have defects in DNA repair that lead to chromosomal instability are inflamed and responsive to checkpoint inhibition. We would like to see if we can make immunologically cold tumors more inflamed and immunogenic.

My advice is to stay curious and excited about science, especially about what’s happening outside your field. You never know where your next good idea will come from. It’s also important to not work all the time and not be disheartened or anxious. Ideas come to you most when you are relaxed and not consciously thinking about your work. A lot of experiments don’t work, and it is easy to get discouraged. The best advice is to keep faith in yourself when things don’t work or your work is rejected, pick yourself up, and keep at it. If you have been given a lab, the people who chose you and invested in you are confident that you have what it takes to succeed. Look at paper and grant reviews carefully, because most of the criticisms are not out to get you but are well-intentioned. There’s a good chance that either you didn’t explain yourself clearly or additional work will improve your manuscript or proposal. And make friends with your peers and find good mentors—being part of a community with shared interests and finding collaborators and people to talk to about science will make your work more fun and productive.

Yes! When I started my career, it was incredibly difficult for women, the women who succeeded had to be both incredibly capable and determined. There was little support for women and combining science with motherhood was almost impossible. For example, there was no daycare at Harvard Medical School or any of the Harvard hospitals. When I had a baby during my medical training, I wasn’t given a day off, wasn’t permitted to take a leave, and had to use my vacation time to have my baby. Conditions have certainly improved. It is now a lot easier for women to get academic jobs. However, there is still a lot of unconscious bias—I feel that, despite my track record, I still have to do more to prove my credibility and make a case for my work in my papers and grants. The other issue is that the top awards and honors are still more difficult for women to get despite the extensive efforts to improve diversity because women are underrepresented in the honorific posts and in the nominating and award committees. But this is clearly changing—there are now “old girls’ networks” that seek to support young women scientists, not just “old boys’ networks.”

Yes, I had a lot of support throughout my career from older (male!) scientists, who were open-minded and recognized my potential. These included Sidney Coleman, Bram Pais, and Steve Adler in physics; Irving London and Herman Eisen at MIT; Shelly Woolf and Bob Schwartz at New England Medical Center; and Fred Rosen and Fred Alt at Harvard.

My inspiration comes from the experimental data my lab obtains, “ah ha” moments when I have a new idea, and a strong desire to better understand basic immunology and molecular biology and develop and test new therapeutics in proof-of-principle mouse experiments that can lead to better treatment to help sick patients.

I have a house on an island in Cape Cod Bay and like to go for walks on the beach and kayak. I also like to spend time with my extended family that includes five grandchildren. I am a serious amateur painter (mostly landscape oil painting). The sensuousness of the paints and conveying how I feel about what I am painting counterbalances my rationalistic work in science. Lately, I have been too busy to do much painting—but I hope to say “no” to more research-unrelated work, do a better job of combatting workaholism, and set aside more time for painting.