My dear friend and mentor, Joseph R. Bertino, M.D., died Sunday, October 10, 2021 in New Brunswick, New Jersey, after an extended illness. He remained active in his laboratory until the last days of his struggle, as one would expect, knowing his passionate commitment to research. Joe was a unique man, one of the early physician-scientists comfortable in a basic laboratory, active in the clinic throughout his career, and “translational” in his work to better the treatment of cancer.

Joe's career and impact have been described in detail in a recent interview in The Cancer Letter and published online in the Cancer History Project: https://cancerhistoryproject.com/people/joseph-r-bertino-md-leukemia-and-lymphoma-pioneer/. He grew up in Port Chester, New York, one of three brothers, all of whom excelled in school and sports. Joe attended Cornell as a 6-foot 2-inch basketball player (a big guy in those days), found his love for science as an undergraduate, and attended medical school at SUNY Downstate. Following his medical residency, he discovered his true calling in the laboratory of Frank Huennikens, a brilliant biochemist who loved basketball and folic acid. Joe and Frank described the induction of dihydrofolate reductase (DHFR) by methotrexate in 1959. How that induction occurred was not clear, only later to be resolved when in 1977 Joe, on sabbatical from Yale, partnered with Robert Schimke, Rod Kellems, and Fred Alt in the discovery of gene amplification. This research represented a major breakthrough in understanding how tumors become resistant to tight-binding enzyme inhibitors such as methotrexate, 5-fluorouracil, and even the more contemporary molecularly targeted drugs. After these preclinical studies were published, my lab, in collaboration with John Minna, reported the first clinical case of gene amplification in a methotrexate-resistant small cell carcinoma.

In the first decades of cancer chemotherapy, methotrexate occupied center stage, as it was a critical component of combination regimens for childhood acute lymphoblastic leukemia and was curative for choriocarcinoma as a single agent. Joe's work pinpointed the target, DHFR, and the primary mechanism of resistance, gene amplification. In 1961, Joe was recruited to Yale by the fabled Arnold Welch, the chairman of pharmacology, who had assembled the finest team of researchers in the burgeoning field of cancer chemotherapy: Alan Sartorelli, Robert Handschumacher, William Prusoff, all of whom made significant contributions to chemotherapeutics. It was an environment unmatched in the few cancer centers then in existence. Joe rapidly ascended the Yale academic ranks and became the first director of the Yale Cancer Center.

Enter Bruce Chabner. In 1969, I was finishing my 2-year oncology fellowship, in lieu of Vietnam, at the National Cancer Institute, and had developed an abiding interest in biochemical pharmacology. My mentors, Vince DeVita and George Canellos, had taken me under their wing clinically, but I clearly needed more laboratory experience if I were to become a productive researcher. I had previously committed myself to a fellowship in hematology with Paul Marks at Columbia, but at the last minute changed my mind and chose to join the Bertino Laboratory in 1970 at Yale. Marks was none too pleased (who is this Bertino fellow?), although in 1986 he recruited Joe to Memorial to build translational research. They became close friends. Their intense tennis matches on top of a skyscraper raised the temperature in Manhattan.

Joseph Bertino, M.D.

The Bertino lab was a candy store for me. Under Joe's gentle, but watchful eye, I learned enzyme kinetics, protein purification, and data analysis. He tolerated my bumbling early attempts at purifying carboxypeptidase G, a Pseudomonas enzyme that cleaved folates and methotrexate. In one unfortunate weekend, my giant Sephadex column fell apart, flooding Joe's laboratory and the adjoining quarters of Paul Greengard, a future Nobel prize winner. Our work ultimately culminated in preparing enough enzyme to cause folate depletion in several leukemia patients in what was the first experimental use of an enzyme as a cancer therapeutic. While the enzyme failed as an oncolytic, it is now approved as glucarpidase for use in cleaving methotrexate in patients who experience renal toxicity and drug retention after receiving high-dose therapy. As a relatively naïve and altruistic pair of investigators, we did not patent the material. Henry Blair, our collaborator on the project, who prepared the raw material at the New England Enzyme Center at Tufts, eventually left academia for greener pastures, and became one of the founders of Genzyme.

Dr. Joe Bertino (left) in 1970 at Yale with Dr. Bruce Chabner, then his research fellow, and Joe's technician, Barbara Morrison.

My 15 months with Joe at Yale formed the basis for a life-long friendship. We connected on science as our first priority, but as a second objective, created our own baseball team on which my wife, Davi-Ellen, played first base, despite the protests of the team from Obstetrics and Gynecology, who wanted to disallow women. The cagey Sartorelli organized a softball team of all-stars who beat us with a bases-loaded seventh inning homer. Later Joe and I became partners in a golf team that actually won trophies at the annual Beinecke tournament at the incredible Yale golf course. The big man had a soft touch with the chipper and putter. Without a doubt, the comradery and intellectual stimulation at Yale convinced me that an academic career in cancer research was what I wanted. I left for NCI in 1971, ever grateful for Joe's mentorship and friendship.

While in Joe's lab, I had occasion to meet Joe's lovely wife Mary Patricia, a nurse and mother of four children, and have remained friends with his daughter Amy, a Ph.D. scientist at Mass General Cancer Center, and am following the career of her son, a budding collegiate pitcher, Max Gieg, at Boston College. Joe's son Fred, a quarterback at Boston University, has had a formidable career in advertising in Boston. A second son, Tom, has a passion for rebuilding antique automobiles, and a third son, Paul, has had a career in cinematography in Los Angeles. There are ten grandchildren. Pat preceded Joe in passing in 2011.

Joe's storied 25-year career at Yale, then 16 years at Memorial Sloan Kettering, and finally, for the past 2 decades, at the Medical College of New Jersey (Rutgers), never missed a beat. He was the lead prophet of the antifolate group that met yearly at AACR and in the summer at Gordon conferences, a group that included David Goldman, Frank Sirotnak, and other notables. Joe gets credit for his early trials of high dose methotrexate with leucovorin rescue in head and neck cancer and lymphomas, but beyond his own clinical studies, he inspired many others to explore novel therapies. Among his trainees, Bill Hait achieved the most profound influence through his leadership of drug discovery and development at Johnson & Johnson, and Bill remained a devoted friend and confidant. Ed Chu, now the Director of the Cancer Center at Einstein, was the son of cancer researchers at Yale and Brown, and a long-time friend and mentee of Joe. Joe's colleague at Memorial, Vicky Richon, a brilliant biochemist and pharmacologist, left the Marks/Bertino fold at Memorial to become a leader in biotechnology at Merck, Epizyme, and Ribon. These are just a few of the many people and careers he guided, and all remained devoted to him as a friend.

Thoughtful Joe at a Society for Translational Oncology symposium, 2019.

And then, there are his many faculty colleagues from the Yale and elsewhere, among whom perhaps the closest were biochemists Frank and Gladys Maley from the New York Department of Health and Kathy Scotto at Rutgers. Frank shared Joe's passion for golf and horse racing at Saratoga, and recalls parring the 18th hole at the Old Course in St. Andrews, Scotland, a feat which pleased Joe very much. Joe owned several racehorses. On occasion, Frank traveled to Saratoga, NY with Joe to the racetrack to see Joe's ponies run, place a few bets, and admired Joe's ability to pick the winners. Frank later discovered that Joe's strategy was to bet on every horse, hoping the longshot would win. Joe also taught me to recoup my losses in blackjack by doubling my bet after losing. It never failed.

Joe was elected President of both ASCO and AACR and was chosen to be the first editor of the Journal of Clinical Oncology, the official publication of the American Society of Clinical Oncology. As further evidence of his stature in the field, he received the Bob Pinedo Cancer Care Prize of the Society for Translational Oncology in 2006 and the Lifetime Achievement Award of the American Association for Cancer Research in 2018, recognizing his extraordinary impact on the field.

The joy of academic careers derives from discovery and from relationships with colleagues. Joe Bertino had it all, a brilliant mind, a nurturing presence, humility, and a zest for enduring relationships. We were so lucky to fall within his sphere, and have tried to emulate him, a most difficult task.

(A): Amy Bertino, Joe, Tito Fojo, and Bruce Chabner. (B): Joe, Pat, and Bob Pinedo celebrating Bruce's 70th birthday. (C): Paddy Johnston and Joe. (D): The first publication describing enzymatic folate depletion by the Bertino Laboratory. (E): Joe and daughter Amy, a cancer researcher, in Boston, 2017. (F): Joe and Amy in Beijing 1997. (G): Oliver Sartor and Joe. (H): The two golfers take a break from the Great Wall Open in China, sitting in front of a Gongshi (供石), also known as a scholar's rock that is traditionally appreciated by Chinese scholars and placed in traditional Chinese gardens, 1997.