Assaying the unknown (Rosalyn Yalow)

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Rosalyn Yalow: Assaying the unknown This pioneering woman physicist received a Nobel Prize for her work in the development of the radioimmunoassay.

One of the most important American research scientists of the 20th century was also one of the most unlikely. Rosalyn Sussman Yalow grew up at a time when women were assumed to be less intellectually qualified than men and were given little access to scientific training. Yet with talent and good fortune, Yalow eventually earned a Ph.D. in physics, and in 1977 was awarded the Nobel Prize in Physiology or Medicine for the development of the radioimmunoassay (RIA), a method of quantifying minute amounts of biological substances in the body using radioactive-labeled material.

Yalow’s achievements are not only essential to the story of modern medical research, they also help provide a broader understanding of the role of women in American science.

Born in 1921 in the Bronx, New York, Sussman discovered in elementary school that she was extraordinarily talented in mathematics. An influential high school teacher stoked her interest in chemistry, but when she matriculated at Hunter College, she was drawn to physics. Influential in her intellectual development were Eve Curie’s biography of her mother, Nobel laureate Marie Curie, and a college colloquium given

by Enrico Fermi on nuclear fission. Although Sussman was enthusiastic about a career in physics, she realized that it was unlikely that good graduate schools would admit (and offer financial support to) a woman interested in science, much less a Jewish woman. Immediately after graduation, she was forced to take work as a secretary to a Columbia University biochemist, but when an unexpected assistantship offer came from the University of Illinois in 1941, she jumped at the chance to pursue her dream.

Sussman was the first woman at the university’s College of Engineering since 1917, and her opportunity came in part because the United States was mobilizing for war.

As men were drafted into the military, many universities began accepting women into graduate programs rather than close the schools. No matter why she was admitted to Illinois, her academic performance once she was there was outstanding. Upon graduation in 1945 with a Ph.D. in nuclear physics, Rosalyn Yalow (she had married a fellow student, Aaron Yalow, in 1941) accepted a position as an engineer at the

Federal Telecommunications Laboratory, and then in 1946 a full-time teaching position at her alma mater, Hunter College.

During her graduate training in Illinois under the renowned nuclear physicist Maurice Goldhaber, Yalow became proficient in the construction and use of apparatus for the measurement of radioactive substances, a skill that would prove critical in her later research. In 1947, while still on the faculty at Hunter, Yalow became a consultant in nuclear physics at the Veterans Administration (VA) Hospital in the Bronx, where the staff was conducting research on medical applications of radioactive materials. The VA decided to establish Radioisotope Services in several of its hospitals nationwide.

Yalow helped develop the service at the Bronx VA and started research projects with Bernard Roswit, chief of radiotherapy services.

In 1950, Yalow left Hunter and accepted a full-time position with the VA. Soon after, she was introduced to Solomon Berson, a talented resident who joined the radioisotope unit and within four years became its chief. Yalow and Berson began a research partnership that was to last 22 years, until Berson’s untimely death in 1972.

Their joint investigations began with an attempt to use radioisotopes to obtain more accurate estimates of blood volume, but their first major contribution was a study of how the thyroid gland and kidneys remove iodine from the blood. They developed a method of discerning the quantity of blood cleared of iodine by the thyroid gland per unit of time. Using radioisotopes, Yalow and Berson could readily ascertain clearance rates in a 35-min sitting, providing a quick determination of thyroid activity.

Expanding these measuring techniques to the study of globins and other serum proteins, Yalow and Berson were determined to apply their methods to one of the most important classes of small peptides: hormones. According to Yalow, they chose insulin as a subject of research because it was the hormone most readily available in a purified form and was easier to work with in the laboratory than other hormones. But Yalow had a familial reason to be interested in insulin, as her husband, Aaron, was diabetic. Among the endocrine gland disorders, diabetes affects the greatest number of people, making insulin uniquely important. Without insulin and its ability to lower blood sugar, death is inevitable.

Yalow and Berson began their insulin research by attaching radioactive iodine to molecules of insulin derived from beef and injecting tiny amounts of the radioactive hormone into normal subjects and diabetics. They wanted to learn what happened to insulin once it entered the bloodstream in Type II diabetics as opposed to normal subjects. Trace amounts of the labeled insulin were injected into volunteers, and frequent blood samples were taken over the course of several hours to determine how fast the insulin was metabolized and disappeared from the bloodstream. Yalow and Berson discovered that globulins bound radioactive insulin in the blood of insulin-

treated diabetics. They concluded that treatment with insulin injections immunized patients so that they developed insulin-binding antibodies, which kept the insulin molecules in the bloodstream.

This was the first real proof that so small a protein could stimulate an immunologic response. The scientific establishment was reluctant to accept such a finding, and the two researchers had difficulty publishing their paper. The results were eventually published in 1959, and when their observations were confirmed by others, the significance of the discovery was clear. Not only had they proven that the human immune system could recognize and respond to smaller molecules than previously thought possible, but they had done so using a breakthrough technology.

Yalow and Berson called their method radioimmunoassay—the first technique to use radioisotopic techniques for the study of the primary reaction of antigen with antibody. Yalow and Berson had provided a means to observe the previously invisible world of antigen–antibody reactions that take place in solution. Before their ideas and methods, scientists were restricted in the analysis of reactions between antigens and antibodies to those that produced visible precipitation or other evidence, such as the clumping of red blood cells. The development of RIA stimulated a revolution in theoretical immunology and, in point of fact, all biology.

The RIA diagnostic process was, and continues to be, used by researchers in myriad ways. Investigators use it to screen blood for hepatitis virus in blood banks, determine effective dosage levels of drugs and antibiotics, detect foreign substances in the blood, treat dwarfed children with growth hormones, and test and correct hormone levels in infertile couples. RIA is remarkably sensitive. It measures incredibly low concentrations of many substances. Adaptations of the RIA principle are also possible. Nonradioactive labels, such as linked enzymes and fluorescent markers, can be used in place of radioisotopes. Because of its almost limitless applicability, the RIA concept has spawned innumerable innovations in basic research and practical applications.

The commercial possibilities for RIA were enormous, but while Yalow and Berson recognized this, they refused to patent the method. Instead, they made every effort to get RIA into common use, putting its value to humanity ahead of their own financial interests. Yalow asserted, “We never thought of patenting RIA. . . . patents are about keeping things away from people for the purpose of making money. We wanted others to be able to use RIA.” The seemingly inextricable connection between money and medicine was never a primary concern to Yalow. Indeed, Yalow and Berson performed all their work without ever receiving a research grant! This stands in sharp contrast to much contemporary medical research, which is corporate-sponsored and profit-oriented in the quest for intellectual property.

In 1968, Rosalyn Yalow became acting chief of the Radioisotope Service at the Bronx VA, when Berson left to become chair of the department of medicine at the Mount Sinai School of Medicine in New York. She assumed leadership of the RIA reference laboratory in 1969 and was the head of the nuclear medicine service from 1970 to 1980. Berson died of a heart attack in 1972, and although Yalow was grief-stricken, she continued to work; her laboratory published 60 articles between 1972 and 1976.

She was elected to the National Academy of Sciences in 1975, and in the next year became the first woman to be awarded the Albert Lasker Prize for Basic Medical Research. Although extremely prestigious in its own right, the Lasker Prize is generally considered a precursor to the Nobel Prize in Physiology or Medicine. And true to form, in 1977 Yalow received the Nobel for her work on RIA. Her only regret was that Berson was not alive to share it with her.

Yalow retired from the VA hospital in 1991. Her achievements in medical research are impressive by themselves, yet considering the barriers to women in science, her success is particularly inspiring. Only the second woman to receive a Nobel Prize in Physiology or Medicine, Rosalyn Yalow overcame institutional prejudice and demonstrated that women’s accomplishments are limited not by any innate deficiencies, but only by the social and cultural restrictions imposed on them.