Jonathan R. Keller, Ph.D.
The scientific career of Jonathan R. Keller, Ph.D., has been marked by serendipity. From his earliest days as an external graduate student at George Washington University, Keller was involved in research at the NCI campus in Frederick, a location at which he would remain for more than four decades. As a graduate student in the lab of James Ihle, head of the Immunobiology of Viral Carcinogenesis Section, he had access to cutting-edge equipment in nearby labs. This allowed Keller to purify and characterize IL-3, a cytokine that helps stem cells differentiate into the wide array of immune cells deployed in the body.
Since the establishment of his lab in 1995, Keller has focused on defining the cellular and molecular regulation of hematopoiesis, the process by which blood cells are generated. This has included identifying and defining the function of transcription factors, epigenetic regulators and the target genes and pathways they regulate in these processes and their role in leukemia. In recent years, he has investigated the role of inhibitor of DNA binding proteins (ID) in hematopoietic development and discovered that ID1 drives stem cells to proliferate and differentiate to exhaustion during chronic stress, including cancer. He is concluding his career with an exploration of a small molecule inhibitor of ID1 that may be able to delay the onset of leukemia in a mouse model – and potentially the onset in humans.
Q: Tell me about your career journey. What has been the most surprising thing about it?
I’m kind of an unusual scientist in the sense that I've pretty much been at the same place my whole career.
When I joined James’ lab as a graduate student, he was using a mouse model and the Moloney virus to show that the immune system, specifically T cells and the factors they produced, were required for the progression and development of leukemia. At the time, many laboratories were purifying and characterizing novel cytokines produced by T cells. We were using standard column chromatography techniques to purify a novel growth factor from T cells that regulated the earliest stages of T cell development using an arduous assay to measure its biological activity.
Our lab was next door to Steve Orozlan’s laboratory, and they were using high-performance liquid chromatography to purify retroviral proteins: nobody had really used it for cytokines, and we thought, “Hey, let's give it a shot.” I gave it a go, which turned out to be the final step in the purification of IL-3 and its amino acid sequence identified.
We were also fortunate to have access to the new fluorescent activated cell sorters (FACS) to purify primitive hematopoietic stem cells, which allowed us to evaluate the activity of our purified T cell factor on the growth of isolated stem cells. To our surprise, we observed the growth of neutrophils, macrophages, red blood cells, megakaryocytes and mast cells! This factor was actually promoting proliferation of the most primitive cell we knew of at the time, the stem cell.
James called it interleukin-3 because it was produced by T cells, which is a hallmark of an interleukin. So, we purified the interleukin, and that launched my career into experimental hematology, which is what I did for the next 30 years.
Q: What scientific achievements are you most proud of – what sets them apart from other work in the field?
We’ve recently been looking at the molecular mechanisms that regulate stem cell development. In 2018, we discovered a novel function for a family of genes that regulate stem cells, and one member of the family, ID1, was induced during times of stress. We found that if you ablate or remove ID1 in vivo, you prevent exhaustion of stem cells during chronic stress and aging. This finding has the therapeutic potential to protect stem cells from exhaustion during bone marrow transplantation, chemotherapy, or other chronic inflammatory environments, including cancer.
Following that, we employed a mouse model of leukemia that lacks the expression of TET2, an epigenetic regulator that's commonly mutated in human beings as we age. We found that reducing the levels of ID1 in these mice slows the expansion of cells that give rise to leukemia and delays the onset of the disease.
My former laboratory members are continuing their research and currently collaborating with the Center for Advanced Preclinical Research (CAPR) in the NCI to determine if a small molecule inhibitor of ID1 can delay the onset of leukemia in this mouse model.
Q: What do you see as some of the most exciting frontiers in cancer research?
To exploit induced pluripotential stem cells (iPSCs), the mother of all stem cells, which can be derived from any individual for cell therapy and regenerative medicine. Scientists can potentially derive any organ or tissue from iPSCs if they know how to direct its differentiation. Many labs are now focused on developing protocols to generate cardiac, neural, skin, breast, prostate, hematopoietic and many other tissues in vitro. These cells are being used for drug discovery and studying cancer.
I also think AI will help us develop treatments for the early pre-leukemic stages of leukemia, other cancers and diseases as we amass and assimilate the information from large datasets.
Q: How did the intramural environment of CCR and NIH help your research, and what advice do you have for those starting their career here?
The CCR and NIH has allowed me to pursue my passion. And, I'm grateful for the opportunity to mentor young scientists and students.
I have one guiding principle from a quote from the microbiologist Louis Pasteur, “chance favors the prepared mind.” You prepare your mind by reading, listening, observing and learning, which opens you to see and understand the chance discovery, whatever the result.
Q: What are you looking forward to most in your retirement?
I’m kind of a person that stays in the moment. I don't look too much ahead, and I don't look too much behind — I try to enjoy right where I am.
My goal is to continue my journey to learn from everyone and everything that's around me.
Dr. Jonathan R. Keller retired from the Frederick National Laboratory, where he worked in support of CCR and NCI, on January 31, 2024.