On February 24, 2019, the biomedical research community lost Dr. Arthur B. Pardee, whose numerous and diverse contributions to molecular and cancer biology will never be forgotten. In a field where most of us would be thrilled to make one major contribution, Art Pardee's legacy is vast, having shaped disparate areas of research including enzymology, DNA repair, gene regulation, cell-cycle control, and novel technologies that ushered in the era of global gene expression profiling. His seminal findings thus contribute to numerous aspects of biology as we understand them today. He was also a pioneer in the discipline we now call translational research and his many contributions, which applied basic research discoveries in the laboratory to preclinical studies, have helped move several treatment strategies more seamlessly to the clinic. But Art's legacy is not only defined by his many important discoveries. He trained hundreds of students and postdoctoral fellows who became successful scientists in their own right, and who could not have succeeded without the generous support, incredible mentorship, and kindness of Art Pardee.
Art began his scientific career at the University of California (UC) at Berkeley, where he received a Bachelor of Science degree in 1942. He then did graduate work at the California Institute of Technology where he studied the biochemistry of antibodies under the tutelage of Linus Pauling, one of the few people to receive two Nobel Prizes. Art greatly admired Pauling, who he considered among the best chemists of all time. After obtaining his PhD in 1947, Art did a two-year Merck-funded postdoctoral fellowship in the lab of Van Potter at the University of Wisconsin, where he studied tumor cell metabolism and cancer progression, an interest fueled by the death of his mother from cancer and one that ignited his later career.
Art's first faculty position at UC Berkeley in 1949 was marked by several key discoveries. He discovered ribonucleoprotein particles in bacteria (later named ribosomes) as well as photosynthetic particles (later named chromatophores). Together with Richard Yates, he made major contributions to our understanding of enzyme regulation. In two seminal papers published back to back in the Journal of Biochemistry in 1956, Pardee and Yates demonstrated the existence of a control mechanism in the pyrimidine pathway, in which the end product of the pathway inhibited the initial enzymatic reaction. This was the first description of the now well-known phenomenon of feedback inhibition, and it formed the groundwork for another major discovery by Pardee and John Gerhardt, who together demonstrated that enzymes could be inhibited through allosteric mechanisms.
In 1959, Art spent a sabbatical year at the Pasteur Institute in Paris, working in the laboratories of François Jacob and Jacques Monod on genetic regulation of enzyme expression. There, he collaborated on the famous PaJaMo experiment (Pardee, Jacob, Monod). The three investigators used the lac operon in E. coli to demonstrate how gene expression can be controlled by repression—the first step in our current understanding of gene regulation in prokaryotes and eukaryotes, leading to the identification of mRNA in 1960. These and subsequent studies led to a 1965 Nobel Prize in Physiology or Medicine for Jacob and Monod (along with André Lwoff), and a 3M Award from the Federation of American Societies for Experimental Biology in 1980 to Art Pardee.
Art next moved to Princeton University to become the first chair of the newly formed Biochemical Sciences Department. True to form, Art was not content to work in one field, and began to study sulfate-binding proteins as well as cell-cycle regulation. He often stated that it may have been a mistake not to stick to one field and become the world's expert, but he always felt compelled to address “big” questions, regardless of whether they took him in new directions. He thrived on such challenges. Art's movement between fields was to the great advantage of the scientific community, as he continued to make influential discoveries in every area he pursued.
While at Princeton, Art hypothesized the existence of a point in the G1 phase of the cell cycle, during which, cells would commit to completing DNA replication, even in the absence of growth factors. He experimentally demonstrated the existence of such a point, which he called the restriction point (R-point), at times referred to as the Pardee-point. This work, published in 1974 in The Proceedings of the National Academy of Sciences, was followed by several elegant studies from his laboratory demonstrating the existence of a labile protein that controlled the R-point. He went on to hypothesize and then show that the R-point is dysregulated in cancer cells, and that this fact could be exploited to selectively kill them. These studies formed the basis of our understanding of cell-cycle control today and are the foundation of modern anti-cancer therapies that exploit critical differences between normal and cancer cells.
In 1975, Art moved to Harvard Medical School as Professor of Biological Chemistry and Molecular Pharmacology, and became Chief of the Division of Cell Growth and Regulation at the Dana Farber Cancer Institute. He continued his work on cell-cycle control, with a focus on identifying unique vulnerabilities in cell cycle pathways in cancer cells. Art's idea that alteration of the R-point could lead to loss of G1 to S regulation in cancer cells, which could be exploited to selectively kill them, was quite revolutionary at that time, as it was before oncogenes, cyclins, CDKs, or signal transduction pathways were discovered. The discovery of the G1-phase cyclins by Art and others led to the molecular identity of the R-protein, and to the findings that inappropriate activation of cyclins leads to inactivation of the Rb pathway, causing unabated and deregulated cell-cycle progression in cancer cells. These seminal basic science discoveries were instrumental in the identification of the class of CDK4/6 inhibitors that have been recently FDA approved for the treatment of advanced estrogen receptor–positive breast cancer, which has doubled the progression-free survival of these patients. Art also sought to identify novel proteins that were differentially regulated throughout the cell cycle, but was frustrated by the limitations of available techniques. Together with his postdoctoral fellow Peng Liang, Art developed differential display, a novel method to examine global gene expression. This PCR-based strategy identified all differentially expressed mRNAs between cell populations and, importantly, allowed recovery of those mRNAs such that they could be cloned as cDNAs and identified by sequencing. The method was published in Science in 1992 and to date has been cited over 4500 times. Art was at the forefront of biomedical science, developing this technique before the ‘omics revolution began.
Art's many accomplishments led to his election to the National Academy of Sciences, the American Academy of Arts and Sciences, the Institute of Medicine, and the American Philosophical Society. He served as President of the American Society of Biochemistry and Molecular Biology (1980), as well as the American Association for Cancer Research (1985). He received numerous awards during his scientific career, including the Paul Lewis Award (1960), the Federation of European Biochemical Societies Krebs Medal (1973), the Rosenstiel Medal (1975), the Federation of American Societies for Experimental Biology 3M Award (1980), the Boehringer Mannheim Award (1998), and the Distinguished Alumni Award from the California Institute of Technology (1999).
But one cannot remember Art without remembering his human side. With all his accomplishments, Art remained humble, kind, extremely generous with his time, and a champion of his students and fellows and of their ability to do innovative and creative science. Those late-night cell-cycle time courses were eased by a key to his office for access to his recliner chair and a pair of airplane eye masks. Frustrations over inconsistencies in experiments were met with pep talks and encouragement (and then perhaps a follow-up tennis match, which Art could still win well into his 70s!). Every idea was entertained and discussed, and these rich discussions continued throughout Art's life. Further, each student and fellow had the freedom to pursue their interests, taking the projects they developed with them as they started independent faculty positions and even at times taking grants that Art relinquished to them. In an environment that can be very competitive, Art never worried about competition, nor felt that he or his laboratory should not openly share their discoveries. Perhaps this was because his ideas were so often ahead of his time. Whatever the reason, he created a fabulous environment in which to train, where everyone worked together and where the goal was to have fun discovering new biology. This rich and supportive scientific environment enabled many of the numerous postdoctoral fellows that left his lab for faculty positions to thrive. His trainees are now scattered throughout the world. As his trainees, we pass forward several of his many life lessons that include (i) a little kindness goes a long way, (ii) don't be afraid to think outside of the box, and (iii) let the data lead the way. The scientific community owes much to Art's legacy and his trainees continue to treasure his mentorship; he was a true giant in all ways and will be sorely missed.
- ©2019 American Association for Cancer Research.
Volume 79, Issue 9
