Obituary A tribute to Rosalyn S. Yalow

On May 30, 2011, after a decade and for her was spotty. It was two years before Novices teach one another a half of physical and cognitive decline, she joined the Veterans Administration The two novices taught one another how to Rosalyn S. Yalow died, just before her Hospital (“Bronx VA”) as a consultant and do research (1–3). Soon, they were publish- ninetieth birthday. Two days later on five years until she was hired as a full-time ing in first-line journals. When their ele- a green hillside in New Jersey, a short physicist (1, 2). gant studies of radioactively labeled albu- drive from the Bronx, a dozen intimates Through talent, hard work, and good min were upstaged by Ken Sterling’s prior gathered to bid farewell. After a round of luck, in 1950 Ros became the fledgling publication, they turned to , one of informal testimonials and traditional rec- head of the nascent radioisotope unit the few other pure proteins available. In the itations, we took turns gently shoveling at the Bronx VA. Novel applications of fateful experiment, the actual result was earth to cover the pine box that protected radioisotopes to medicine were burgeon- the opposite of the expected result. Radio- her remains. The rhythm of the shovels, ing. She developed a solid program of actively labeled insulin disappeared from the camaraderie of the mourners, and the service, teaching, and research but recog- the circulation of the diabetic patients at a glow of the sun brought forth kaleido- nized that to reach its full potential the slower rate than in normal subjects — due scopic flashbacks — Stockholm, Atlantic unit needed a physician. After the rejec- to heretofore unsuspected anti-insulin City, and the Bronx. tion of many candidates, Bernard Straus, antibodies in the blood of patients who Rosalyn Yalow lived nearly all of her life the highly regarded chief of the medical had received insulin therapy (4). Use of in the Bronx, where she was born, educat- service, introduced Ros to the smartest the term “antibody” in that 1956 paper led ed and worked, raised her family and met MD he had ever trained. After an hour, to its initial rejection by the JCI. (That JCI Solomon Berson, her scientific partner for Ros was certain that Sol Berson was the rejection is probably more famous than the many years (1). Yalow and Berson were born smartest MD she had ever met (1). rejection by Nature of the 1937 Krebs paper in , children and grandchildren of immigrants from Europe (1–3). For both families finances were constrained due to shortage of capital, anti-Semitic impedi- ments to employment, and the Great Depression. Both Berson and Yalow were educated in public schools. Berson graduated from the legendary , then all-male and tuition-free. After graduation, it took him three years (earning a master’s degree and working as an assistant in the Anatomy Department) before he broke through the extreme barriers then in place for Jewish applicants to medi- cal school. Berson bragged about his hun- dred or more medical school rejections. A classmate of Berson at New York University School of Medicine recalled that on Day One it was obvious to all that Berson would be the leading student in their class. Yalow was a top student at Hunter Col- lege, the tuition-free, all-female counter- part of City College, where she majored in physics. Despite a brilliant record, she failed to gain admission to any gradu- ate programs in physics, specifically and openly because she was female and Jewish. Finally, as a favor to one of her Hunter Col- lege professors, the University of Illinois accepted her into their PhD program in nuclear physics with the condition that they bear no responsibility for placing her in a job after graduation. Indeed, despite a Figure 1 brilliant school record and the World War Rosalyn S. Yalow accepting the Nobel Prize in Physiology or Medicine presented by King Carl II shortage of civilian males, employment XVI Gustaf of Sweden on December 10, 1977. Photo courtesy of Ben Yalow.

The Journal of Clinical Investigation http://www.jci.org Volume 121 Number 8 August 2011 2949 obituary describing the citric acid cycle.) Yalow and By early 1963, our fledgling immuno­ tions with other proteins, and (c) swift, Berson then studied anti-insulin antibod- assay gave a burst of new findings about convenient approaches to separating free ies in great detail, leading them to create as an acute metabolic from protein-bound labeled hormones. the radioimmunoassay only ten years after hormone (8). Although Yalow and Berson Also, as Pastan and I embarked on our they first teamed up (5, 6). were essential full partners in our devel- earliest receptor studies, we incorporated Late in the afternoon of May 2, 1960, as opment of the growth hormone work, insights we had gained from Berson’s part of the plenary session of the 52nd annu- they shunted the credit and the speak- acerbic critique of Stadie’s pre-modern al meeting of the American Society for Clini- ing invitations to Glick and me. Simul- studies (14). cal Investigation, the most prestigious venue taneously, the four of us began work on for new biomedical science, Ros strode to the ACTH immunoassay (9), while “the Berson’s death and aftermath the podium, introduced by Society president bosses” were also debuting the parathy- In April 1972, suddenly and unexpect- Robert Berliner. Over the next ten minutes, roid hormone radioimmunoassay with edly, Sol Berson died of a massive heart with a dozen 5-inch by 5-inch glass slides the NIH’s Gerald Aurbach and John Potts, attack while attending a FASEB meeting hand fed into a carbon arc light projector, who had just purified the human hor- in Atlantic City, just a few days before his she showed the 4,000 academic researchers mone. Selna Kaplan and Mel Grumbach, 54th birthday (1–3). Grief was everywhere crowded into the musty auditorium of the under the tutelage of the two masters, — for the Berson family, for the Yalow old Steel Pier in Atlantic City how she and were introducing their immunoassay of family, and for Berson’s many colleagues her research partner, Berson, had managed human placental lactogen. Immunoassays and admirers. Soon, we realized that a to measure the amount of insulin in a frac- were pouring forth throughout the field. collateral loss might be the endocrine tion of a milliliter of whole plasma from 100 Glick moved to Brooklyn, where he pio- community’s Nobel expectations for Ber- patients undergoing glucose tolerance tests. neered the immunoassay of oxytocin. son and Yalow. The physiological insights were novel and Berson helped me find an excellent spot Yalow was grief stricken at the loss of her enlightening, but the cognoscenti among at the NIH in Bethesda, where I worked research partner and possibly of her Nobel the audience immediately recognized that on immunoassays for vasopressin and the dreams (1). Good fortune placed Eugene they were witnessing a major revolution pituitary gonadotrophins. Straus, son of Bernard Straus, in Yalow’s in all of endocrinology. For the first time The radioimmunoassay for insulin lab as a fellow. In addition to providing since the work of early pioneers of endocri- led to assays of countless proteins and vital psychological support, he energized nology such as Claude Bernard and Oskar peptides, as well as a very broad range the lab’s research (1). Over the next several Minkowski, the amount of a hormone in of other biological molecules, e.g. drugs, years (1973–1977), the pair produced a blood could be measured — with precision steroids, cyclic AMP, and viruses. All substantial corpus of new studies of hor- and specificity. could be measured with high sensitivity mones from the gastrointestinal tract and The 19-page article in the JCI of July 1960 and specificity, even in complex biologi- the brain (1). This remarkable burst of new with all of the details of the assay remains cal fluids (10). Typically each new assay work won over any doubters — it was then one of the journal’s most highly cited papers added novel biological insights and novel widely recognized that Yalow herself was a (6, 7). Besides being a blueprint for those tools for the management of human dis- fully worthy laureate. who wished to measure insulin, it rapidly eases. Among individual assays, the larg- My most vivid image is Ros Yalow (Fig- became the indispensable guide to pioneers est effect on human welfare was likely ure 1), clad in a brilliant blue evening who, along with Yalow and Berson, adapted derived from the method’s extension to dress, stepping forward to accept her the method to all other peptide hormones viruses, specifically hepatitis B (11) and Nobel Prize from Sweden’s King Carl and extensions beyond endocrinology. HIV. In addition to their essential role in XVI Gustaf (1, 2). That evening in the diagnosis, the tests prevented life-threat- Grand Hall of the Swedish Academy, rep- Explosion of assays ening transfusion-borne infections. No resenting all of the Nobel laureates, Ros In 1961, fourteen months after the first listeners in May 1960 or readers in July responded eloquently to the traditional public presentation of radioimmunoassay, of that year, even those with a hypertro- challenge to the awardees from the uni- Seymour (Shimon) Glick and I arrived phied prophetic sense, could have imag- versity students of Sweden (2). A couple to start postdoctoral fellowships at the ined the extent of this revolution, not of days earlier in her Nobel Lecture at Bronx VA with Yalow and Berson. By only in endocrinology but also in all of the Karolinska Institute, she recounted then Roger Unger in Dallas had reported biology and medicine. the scientific work that led to this spe- an immunoassay for glucagon. Sheldon From 1963 to 1973, my most impor- cial moment, including the vital role Rothenberg, working in the Yalow-Berson tant new work at the NIH was introduc- played by her scientific partner, the late lab, extended the method by using intrin- ing, with Ira Pastan and colleagues, the Solomon Berson (1–3). Once again she sic factor to measure vitamin B12. Based on concept and methods for studying cell showed a slide that included the famous the synergy of his partnership with Yalow, surface receptors: first ACTH, followed 1956 letter from JCI’s editor-in-chief Stan Berson enthusiastically encouraged Glick by insulin and then growth hormone (12, Bradley rejecting Yalow and Berson’s ear- and me to work together to develop an 13). Crucial to this work was the deep liest paper on antibodies to insulin (4, immunoassay for growth hormone. Our sophisticated knowledge I brought with 7). At each event I was there applauding two mentors were there in the lab working me from the Bronx of (a) the intricacies along with her family (husband Aaron all the time — at the bench doing experi- of labeling peptides with radioactivity and children Ben and Elanna) and col- ments, writing speeches and papers, review- at high specific activity, (b) quantitative leagues Eugene Straus, Roger Unger, ing our data, and teaching us (1–3). methods for measuring hormone interac- Harold Rifkin, and Susan Roth (1).

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End of an era Acknowledgments in the circulation of insulin treated subjects. J Clin We relatives, friends, former students, and The author is indebted to Alessandra L. Invest. 1956;35(2):170–190. 5. Berson SA, and Yalow RS. Quantitative aspects of colleagues will carry with us our personal Szulc for excellent editorial assistance; the reaction between insulin and insulin binding collections of images of this most remark- to Mitchell T. Rabkin, Seymour M. antibody: relation to problem of insulin resistance. able individual. Yalow’s own words (2), Glick, Ann Danoff, Goran K. Hansson, J Clin Invest. 1959;38:1996–2016. 6. Yalow RS, Berson SA. Immunoassay of endog- addressed to the university students of and Seymour Reichlin for review of the enous plasma insulin in man. J Clin Invest. 1960; Sweden, will continue to inspire us: manuscript and many helpful sugges- 39:1157–1175. tions; and to Ben Yalow for the photo- 7. Kahn CR, Roth J. Berson, Yalow, and the JCI: It is all too easy to be pessimis- graph published here. the agony and the ecstasy. J Clin Invest. 2004; 114(8):1051–1054. tic if we consider our multiple 8. Glick SM, Roth J, Yalow RS, Berson SA. The regu- problems: the possible deple- Jesse Roth lation of growth hormone secretion. Recent Prog tion of resources . . . hostilities Feinstein Institute for Medical Research, Horm Res. 1965;21:241–283. between nations . . . unemploy- North Shore–Long Island Jewish Health 9. Yalow RS, Glick SM, Roth J, Berson SA. Radioimmunoassay of human plasma ACTH. J Clin ment and vast inequalities among System, Manhasset, New York, USA; Albert Endocrinol Metab. 1964;24:1219–1225. different races and different Einstein College of Medicine, Yeshiva 10. Yalow RS. Radioimmunoassay: a probe for the fine lands. Even as we envision and University, New York, New York, USA. structure of biologic systems (Nobel Lecture, 8 Decem- solve scientific problems . . . we E-mail: [email protected]. ber 1977). Science. 1978;200(4347):1236–1245. 11. Walsh JH, Yalow RS, and Berson SA. Radio­ appear ill-equipped to provide immunoassay of Australia antigen. Vox Sang. 1970; solutions for the social ills that 1. Straus E. Rosalyn Yalow, Nobel Laureate: Her Life and 19(3):217–224. beset us. We bequeath to you, the Work in Medicine; A Biographical Memoir. New York, 12. Roth J. Peptide hormone binding to receptors: New York, USA: Plenum Trade; 1998. next generation, our knowledge a review of direct studies in vitro. Metabolism. 2. The Nobel Prize in Physiology or Medicine 1977. 1973;22(8):1059–1073. but also our problems . . . let us Nobelprize.org. http://nobelprize.org/nobel_prizes/ 13. Roth J, Taylor SI. Information transfer cell regula- join hands, hearts and minds medicine/laureates/1977/. Accessed June 22, 2011. tion and disease mechanism: insights from stud- to work together for their solu- 3. Roth J. Solomon A. Berson. . 1973; ies of cell surface receptors. Harvey Lect. 1982; 22(1):66–68. tion so that your world will be 77:81–127. 4. Berson SA, Yalow RS, Bauman A, Rothschild MA, 14. Newerly K, Berson SA. Lack of specificity of insu- better than ours and the world Newerly K. Insulin-I131 metabolism in human sub- lin-I131 binding by isolated rat diaphragm. Proc Soc of your children even better. jects: demonstration of insulin binding globulin Exp Biol. 1957;94(4):751–755.

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