Ira Pastan, M.D.
After more than 66 years at the NIH, Ira Pastan, M.D., a pioneering endocrinologist, receptor biologist and immunologist who mentored several generations of scientists, has announced his retirement from the NCI.
Pastan has had a decorated career. He is a member of the National Academy of Sciences, the American Academy of Arts and Sciences and the Institute of Medicine of the National Academies, and a Fellow of the American Association for the Advancement of Science, the American Association for Cancer Research (AACR), and the American Academy of Microbiology. He received the Van Meter Prize in 1971, the G. Burroughs Mider Lectureship at NIH in 1973, the International Feltrinelli Prize for Medicine in 2009, the Nathan Davis Award of the American Medical Association for Government Service in 2010, the AACR Team Science Award in 2014, the Hubert Humphrey Award from the Department of Health and Human Services in 2019, and a Paul A. Volcker Career Achievement Medal in 2020. Additionally, his many mentees included future Nobel laureates Harold E. Varmus, M.D., and Robert J. Lefkowitz, M.D.
Pastan was drawn to science from a young age. He attended the Boston Public Latin School, followed by Tufts College, from which he graduated in 1953 with a bachelor’s degree in biology. He also married Linda Pastan, who would have a lauded career in poetry, the same day as his graduation. Pastan then attended Tufts Medical School, where he got his first research experience investigating iodide transporters in bovine thyroids and murine small intestines under Edwin “Ted” B. Astwood, graduating in 1957. He then began a residency at the Yale School of Medicine, where he delved further into endocrinology, investigating patients who were being treated for hyperthyroidism. In 1959, Pastan joined the NIH as part of the Public Health Service.
Through these early decades, and those to follow, Pastan would thread his research interests between endocrinology, receptor biology and the then-nascent field of molecular biology.
“He had this uncanny sense of what was going to be significant and impactful in the future,” said Glenn Merlino, Ph.D., a cancer biologist and NIH Scientist Emeritus who trained under Pastan as a postdoctoral fellow beginning in 1980. “And, so, time and time again, he would pivot into a new field. He started with cyclic AMP, and then he made big strides in multiple drug resistance. He decided to begin a study of transcription when I was there, and also began working on receptor tyrosine kinase oncogenes, which I was part of and loved, and ultimately into drug development for hairy-cell leukemia.”
At the NIH, Pastan was assigned to the Clinical Endocrinology Branch of the National Institute of Arthritis and Metabolic Diseases, now the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). Here, he began investigating the role of thyroid stimulating hormone in glucose metabolism with James B. Field, M.D., and also pursued applied biochemistry in the laboratory of Earl Stadtman, Ph.D. With his own lab at the Clinical Endocrinology Branch in 1963, Pastan continued studying how thyroid stimulating hormone controlled thyroid function. He began exploring how hormones interacted with receptors on cell surfaces with Jesse Roth, M.D., in 1965 — along with then-postdoctoral fellows Varmus and Lefkowitz — and investigating gene regulation in E. coli with Robert Perlman, M.D., Ph.D. Aided by the discovery of cyclic AMP and its role in mediating the effects of epinephrine on oxygen metabolism in the liver, Pastan and Perlman found that cyclic AMP is a crucial regulator of gene activity in E. coli, publishing their results in 1970. That same year, Pastan founded the Laboratory of Molecular Biology at the NCI alongside geneticist Max E. Gottesman, M.D., Ph.D.
Varmus, who went on to serve as Director of NIH (1993 to 1999) and NCI (2010 to 2015), attributes the drive of his early research career as a clinical associate at the NIH to Pastan’s remarkable skills as a mentor. “Ira encourages experimental risk-taking, pushed his colleagues into the limelight, inspired us to read and think, and generally provided the kind of environment in which research seemed like the best possible thing to do,” Varmus says.
With the Laboratory of Molecular Biology up and running, Pastan and Gottesman began recruiting a core group of postdoctoral fellows with expertise in biochemistry or genetics — these skillsets are now recognized as fundamental components of molecular biology. Throughout the decade, Pastan, Gottesman and their postdocs explored how cyclic AMP worked using recombinant DNA in bacteria. During this time, Pastan and his lab also began to work with Mark C. Willingham, M.D., studying how hormones and peptides bound to cell surfaces, behaved on cell surfaces, entered cells and which pathways they used. They developed a technique, video intensification microscopy, to look at the hormones and proteins moving in vesicles within cells, and named the system the receptosome, though it would ultimately be called the endosome.
In the late 1970s, Pastan began focusing on mammalian cells, specifically the Epidermal Growth Factor receptor (EGF-R), a transmembrane protein that interacts with the EGF signaling protein. Pastan’s lab found that the EGF-R oncogene is amplified and over-expressed in many human cancers, and made significant strides on the cloning and sequencing of the EGF receptor after Merlino joined his lab in 1980.
“Ira had made major discoveries in at least half a dozen fields by the time I was deciding on an advisor. I knew that he was willing to change and think about new things and go in different directions, which is why I ultimately picked him,” Merlino said. “He had drive and a real passion for the science and helping people. I was drawn to his leadership style as well — he has a quiet but very firm manner. He was directly responsible for training me not only in my research, but also how to be a leader and mentor for others — and then really changing my career trajectory by allowing me to lead a program focused on transgenic mouse models, which I was extremely interested in.”
Pastan’s lab continued to explore EGF-R through the decade, finding, in a collaboration with Douglas R. Lowy, M.D., that over-expression of EGF-R in the presence of EGF can transform normal cells into cancer cells. These studies provided essential evidence that antibodies able to inactivate the EGF receptor could be useful in treating many cancers.
Pastan then pivoted once again, focusing on the bacterial toxin pseudomonas toxin A and the methods it uses to enter cells. This led to a method of targeting cancer cells with recombinant immunotoxins, one that Pastan would pursue all the way through the drug development process in the coming decades. Pastan’s work came to fruition in 2018, when the FDA approved the groundbreaking drug moxetumomab pasudotox (Lumoxiti), as a treatment for hairy-cell leukemia.
Pastan also crucially collaborated with Michael M. Gottesman, M.D., on the biochemical basis of multi-drug resistance in cancer therapy. This involved the isolation of the first human multi-drug resistance gene, MDR1, and the demonstration that MDR1 encodes a multi-drug transporter that is highly expressed in many human cancers. Now, his team hopes to use the drug for treating pancreatic cancer and solid tumors.
A generous scientific citizen, Pastan served on numerous editorial and scientific advisory boards, and trained generations of scientists over the years. “One of the major indicators of the influence that somebody has in science is if you look at the number of people that they produced and what they’re doing in the field,” said Merlino. “If you look at the number of people that have come out of his lab and where they are now, it is incredible. There are Nobel Prize recipients, many people who became chairs of departments or in charge of an industry or are in leadership roles,” Merlino said.
In a 2008 interview with Jason Gart, a senior historian at History Associates Incorporated at the time, Gart posed the question: “If you have one lesson learned over your career that you would want to pass on to a future scientist or researcher operating ten or twenty years in the future, what would that be?”
Pastan responds, “I would say do something that you like doing and enjoy doing every single day, because that is the most important thing. If you like doing science, do science. But you really have to like doing experiments and like being in the lab and like being around scientists. It has to really occupy a lot of your thoughts to do it. Find something that you really like doing, and hopefully you can make a living at it, too.”
Dr. Ira Pastan retired from CCR on March 31, 2025.