Arthur B. Pardee (1921-2019).

On 24 February, Arthur Beck Pardee died at the age of 97. Pardee pioneered the study of cellular regulation in the 1950s and sought thereafter to elucidate the molecular basis of regulatory mechanisms. Several of his breakthrough studies have become textbook examples. Throughout his long life, he remained close to laboratory research, enjoyed discussing research results and ideas with students and colleagues, and encouraged young people in their career pursuits. Born in Chicago, Illinois, on 13 July 1921, Pardee received his undergraduate degree in chemistry from the University of California, Berkeley, in 1942. After conducting 2 years of wartime research, he joined chemist Linus Pauling at the California Institute of Technology in Pasadena, where he earned his Ph.D. in 1947. Pardee conducted postdoctoral work on intermediary metabolism in mammalian cells with biochemist Van Rensselaer Potter II at the McArdle Laboratory for Cancer Research, University of Wisconsin. He then took a faculty position in 1949 in the Biochemistry Department and Virus Laboratory at his Berkeley alma mater, where he began his studies of cellular regulation. In 1961, he moved to Princeton University to chair a new Biochemical Sciences Department until 1975, when he became a professor at Harvard Medical School. He remained a Professor Emeritus of Biological Chemistry and Molecular Pharmacology and a researcher at the Dana-Farber Cancer Institute until his death. Pardee knew how to identify important questions. He and his student Richard Yates discovered a feedback regulatory loop in the Escherichia coli pyrimidine nucleotide biosynthetic pathway in 1954. In whole cells, a pyrimidine nucleotide end product, cytidine triphosphate (CTP), inhibited the enzyme aspartate transcarbamoylase (ATCase). When nucleic acid synthesis removed the inhibitory pyrimidine end product, the pathway produced more ATCase—a simple and effective control process. Soon the pathways for other nucleotides and amino acids of E. coli were found to have similar feedback loops, and later the same processes were found in eukaryotic life forms as well. Pardee and Yates were the first to reconstitute feedback inhibition in the test tube. One of us (J.G.) joined the Pardee lab in 1959 to look for special properties of the ATCase protein that might underlie its newly recognized regulatory functions. Because inhibitors and substrates differed so much stereochemically, Pardee proposed that they have separate binding sites that interact somehow to effect inhibition. Evidence showed that his instinct was correct. The most striking result was desensitization. ATCase could be dissociated into catalytic and regulatory subunits, of which the catalytic subunit alone showed full activity, no inhibition by CTP, and no sigmoidal saturation curves for substrates and inhibitors. All regulatory properties were lost; they were restored when the subunits reassociated. Other regulatory proteins were found to share these behaviors. By 1964, ATCase was perhaps the best analyzed of the metabolic regulatory enzymes, and the information about it contributed substantially to the development of the allostery concept and model by Monod, Wyman, and Changeux in 1965. ![Figure][1] PHOTO: DANA-FARBER CANCER INSTITUTE Pardee pursued allosteric enzyme regulation with intensity while also exploring the relationship between gene expression and protein synthesis. In 1952, he began to study enzyme activities in phage-infected E. coli , and in 1954, he published experiments with E. coli mutants in which he suggested presciently that “the continuous formation of RNA is essential for protein formation.” In 1957, he went on sabbatical to the Pasteur Institute, where he, Monod, and molecular biologist Francois Jacob established the first evidence for a repressor gene product from one gene controlling the expression of another gene in findings that were dubbed “the PaJaMo experiment.” Upon returning to Berkeley, Pardee and his student Monica Riley extended this experiment by using P32 decay to break the gene and show that continued synthesis of its product was required for enzyme production to be sustained. This finding and the Paris experiments conducted by Pardee were only one short step from the formal discovery of messenger RNA in 1961. Pardee later turned to eukaryotic cells and cancer. In 1974, he recognized a “restriction point” interval in which mammalian cells would arrest or not depending on factors present in the culture medium. He showed that restriction point requirements are relaxed in cancer cells, likely contributing to their greater proliferative capacity. His insight about the restriction point later became part of the breakthrough concept of checkpoints in cell cycle progression. Art was not a man who added flourish. A reserved, formal, private person not interested in projecting a grand persona, he wore a jacket and tie to lab every day. He was also a supportive mentor, not just in words but in action. He directed members of his lab, including J.G., to work on nonoverlapping research projects, urged us to get good results and write papers, and allowed us to take our projects with us when we left. As his record of accomplishments vividly reveals, Art was confident in his experimental ingenuity, but he never bragged. In conversations in his later years, when T.P. knew him best, he would offer light criticism such as, “I have been reading some papers and things just aren't adding up,” but he would never say, “I have a better idea.” His understated tone led many to view him as shy. Although he preferred to stay out of the limelight, he thought it important to support the national scientific enterprise, and for that reason he took his turn as president (1980) and treasurer (1964 to 1970) of the American Society of Biological Chemists and president of the American Association for Cancer Research (1985). Art traveled widely, read history, had a sophisticated appreciation of music, and curated a fine collection of anthropological specimens, but he would have wanted these interests to be mentioned only as secondary to his highest passion—science. Over many decades, Art inspired us with his happy union of longevity, intellect, and enduring interests. True to form, at his 97th birthday party, he handed T.P., with a smile, a copy of the proofs of his latest manuscript. [1]: pending:yes