Excerpted from: Fahey JW, and TA Shapiro (2019) In Memoriam: Inimitable Paul Talalay (1923 - 2019). Trends in Pharmacological Sciences 40(6): 358-361. https://doi.org/10.1016/j.tips.2019.04.011.
Pharmacology lost a pioneer and champion with the passing of Paul Talalay. A brilliant scientist and inspiring mentor, he had been the John Jacob Abel Distinguished Service Professor of Pharmacology and Molecular Sciences at Johns Hopkins Medical School. He died at age 95, after a full life, on 10 March 2019.
Paul Talalay was a founder and international leader in the pharmacology of chemoprotection, the science of modulating the body's defense system against oxidative, inflammatory, radiation or xenobiotic assault. His contributions; however, included much more than this. He initiated the field of steroid-metabolizing enzymes, described a quantitative method for assessing drug interactions, and was a highly successful program builder and educator.
As recounted in a poignant and gracefully written autobiography [1], Paul and his family came to the United States in 1940, after making serial moves across Europe to escape the Nazis. His education included undergraduate studies in biophysics at MIT, medical school at the University of Chicago and Yale, and surgical training at the Massachusetts General Hospital. After thirteen years on faculty at the University of Chicago he came to Johns Hopkins to direct for eleven years the Department of Pharmacology and Experimental Therapeutics. He remained at Hopkins, the John Jacob Abel Distinguished Service Professor, for the rest of his life. Over his long career Paul enjoyed many fruitful, sometimes decades-long collaborations; appreciatively described in his Reflections [1].
An enduring fascination with enzymes
Paul Talalay's research interest in enzymes began in earnest when he was a medical student working in Charles Huggins's laboratories at the University of Chicago. Huggins and colleagues had shown that patients with metastatic prostate cancer could be improved dramatically by steroid hormone therapy, landmark studies recognized by the 1966 Nobel prize in Physiology or Medicine.
Investigations into metabolism of the steroid A ring, and the desire to devise novel antitumor agents, led to studies of substrate analogs to inhibit methionine adenosyltransferase. An unexpected byproduct of his experiments in steroid metabolism which included multiple inhibitors applied simultaneously, was the rational and simple 'Chou-Talalay equation' for diagnosing drug interactions as additive, synergistic or antagonistic. Described in some of the most highly cited publications in the scientific literature, this method has become a standard tool in molecular, animal and clinical pharmacology [2].
An unexpected pivot to chemoprotection
Despite the risk, which he clearly recognized [1], Paul seized the serendipitous opportunity to transition his focus from steroid enzymes to enzyme induction for cell protection. He recognized early that a wide variety of chemical agents, including dietary phytochemicals, induce a cytoprotective response in mammalian cells. Reflecting his training as a physician, he also realized that upregulating a cytoprotective response could impact not just the risk of cancer but also the risk of other chronic diseases. His subsequent research spanned the full range of pharmacology, from structure-activity of novel phytochemical (and synthetic) inducers [3], to large interventional field trials [4]. His work was supported by longstanding NIH grants, and by the philanthropic generosity of Lewis B. and Dorothy Cullman. The latter funding afforded flexibility to shift quickly in response to new discoveries, and to explore high risk ideas.
To delve into the science of cytoprotection, Paul first focused on the induction of Phase 2 drug-metabolizing enzymes (e.g., the glutathione S-transferases) and the protection this afforded against carcinogens. Typically, he started by inventing a simple and robust in vitro bioassay, for quinone reductase as a sensitive reporter for enzyme induction [5]. Over thirty years later this foundational assay continues to contribute to significant research worldwide. It underpinned the landmark discovery of sulforaphane, one of the most potent naturally occurring Phase 2 enzyme inducers, in broccoli [6,7]. This finding captured popular imagination, leading to his identification as the 'Broc Doc', a nickname he both relished and regretted. Collaborative studies then identified cysteine-rich Keap1 as the intracellular sensor that triggers migration of Nrf2 into the nucleus, where it binds to the Antioxidant Response Element and induces synthesis of cytoprotective proteins [8]. Translational studies documented the efficacy of broccoli sprout extracts in animals, and evaluated their safety, metabolism and pharmacokinetics in humans.
To demonstrate efficacy in humans, Paul turned to indications with timelines shorter than that for carcinogenesis. One fascinating and important mechanism-driven inquiry showed that social and behavioral symptoms of autism can be reduced by regular ingestion of a broccoli sprout extract [9], a remarkable finding for an intractable condition, since corroborated by others. Studies in China have shown that administration of broccoli sprout extract improves biomarkers for both liver cancer and air pollution injury [4]. Numerous Phase 2 placebo-controlled trials of broccoli and sulforaphane efficacy in humans, undertaken in the final years of Paul's life and still ongoing, have brought his work squarely into the clinical setting, a fitting capstone to his exceptional career.
Convinced his discoveries could help people at risk of cancer and other conditions, mindful of the largely unregulated health food market, and fueled in part by tremendous public interest in cancer prevention by broccoli and sulforaphane, Paul realized the need for a company to make high-quality sulforaphane-rich broccoli sprouts available [10,11]. He co-founded Brassica Protection Products 'to develop chemoprotective foods and extracts', which now provides a market source for broccoli products and well-characterized material for lab and clinical trials. Talalay himself never profited from this company.
Lasting impact
Paul Talalay's legacy comprises not just his impactful discoveries. The pharmacology department at Hopkins, illustrious in its early years, had declined by the time he arrived as Director in 1963. With a keen eye for talent he hired a series of splendid young faculty who entirely revitalized the department – Snyder, Coffey, Cuatrecasas – all of whom themselves became distinguished. With great foresight he purchased the first mass spectrometer in any medical school. He was a quiet but effective champion for women: nominating Gertrude Elion for the Nobel Prize, appointing Catherine Fenselau to the Hopkins faculty (the second woman to become full professor in the basic sciences after Florence Sabin in 1917), and from the start enrolling a high proportion of women in training programs.
Paul was mindful of history, indeed wrote histories of pharmacology and clinical pharmacology at Hopkins, but his eye was firmly on the future. He relished nothing more than meeting with and advising young colleagues, hearing their latest discoveries, celebrating their accomplishments. Students of his own trainees were greeted as his 'intellectual grandchildren'. He founded the MD/PhD Medical Scientist Training Program at Hopkins. With classic Talalay charm and resourcefulness, in 1978 he established a Young Investigators' Day celebration, at which outstanding trainees receive prizes from endowments he gathered from grateful families of former trainees. Fittingly, the event now includes a Talalay prize.
Paul was known for his brilliance, humor and judgment, which combined to make him a peerless confidant and advisor to international committees, deans, department chairs, faculty, trainees, and housekeeping staff alike. His prodigious memory and quick wit were legendary; his kindness was instinctive, unobtrusive and effective. After the 2011 tsunami he sent money and lab supplies to a colleague in Japan, declaring that if red tape got in the way he would deliver this personally (and there is no doubt he would have). His beloved family includes Pamela, his wife of 66 years, a Cambridge-trained PhD and scientific editor supreme, and their four children, Antony, Susan, Rachel and Sarah, all respected professionals in their own rights.
Science and scientists have been impacted by the elegance and rigor of Paul Talalay's work; by his optimism, warmth and uncanny wisdom; and by his visionary leadership. He has left all of us a wonderful and lasting legacy.
For an additional, excellent biography of Paul Talalay by friend and scientific writer Teresa Johnson, see: https://tljcommunications.files.wordpress.com/2022/02/paul-talalay-the-catalyst.pdf.
1. Talalay, P. (2005) A fascination with enzymes: The journey not the arrival matters. J. Biol. Chem. 280, 28829-28847
2. Chou, T. C. and Talalay, P. (1984) Quantitative analysis of dose-effect relationships: The combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regul. 122, 27-55
3. Fahey, J. W. et al. (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56, 5-51
4. Kensler, T. W. et al. (2012) Modulation of the metabolism of airborne pollutants by glucoraphanin-rich and sulforaphane-rich broccoli sprout beverages in Qidong, China. Carcinogenesis 33, 101-107
5. Prochaska, H. J. et al. (1992) Rapid detection of inducers of enzymes that protect against carcinogens. Proc. Natl. Acad. Sci. USA 89, 2394-2398
6. Zhang, Y. et al. (1992) A major inducer of anti-carcinogenic protective enzymes from broccoli: Isolation and elucidation of structure. Proc. Natl. Acad. Sci. USA 89, 2399-2403
7. Fahey, J. W. et al. (1997) Broccoli sprouts: An exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc. Natl. Acad. Sci. USA 94, 10367-10372
8. Dinkova-Kostova, A. T. et al. (2002) Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of Phase 2 enzymes that protect against carcinogens and oxidants. Proc. Natl. Acad. Sci. USA 99, 11908-11913
9. Singh, K. et al. (2014) Sulforaphane treatment of autism spectrum disorder (ASD). Proc. Natl. Acad. Sci. USA 111, 15550-15555
10. Talalay, P. (1999) The war against cancer: New hope. Proc. Amer. Philosophical Soc. 143, 52-72
11. Fahey, J. W. et al. (2012) Notes from the field: "Green" chemoprevention as frugal medicine. Cancer Prev. Res. 5, 179-188
