Celebrating eighty years of radionuclide therapy and the work of Saul Hertz

March 2021 will mark the eightieth anniversary of targeted radionuclide therapy, recognizing the first use of radioactive iodine to treat thyroid disease by Dr. Saul Hertz on March 31, 1941. The breakthrough of Dr. Hertz and collaborator physicist Arthur Roberts was made possible by rapid developments in the fields of physics and medicine in the early twentieth century. Although diseases of the thyroid gland had been described for centuries, the role of iodine in thyroid physiology had been elucidated only in the prior few decades. After the discovery of radioactivity by Henri Becquerel in 1897, rapid advancements in the field, including artificial production of radioactive isotopes, were made in the subsequent decades. Finally, the diagnostic and therapeutic use of radioactive iodine was based on the tracer principal that was developed by George de Hevesy. In the context of these advancements, Hertz was able to conceive the potential of using of radioactive iodine to treat thyroid diseases. Working with Dr. Roberts, he obtained the experimental data and implemented it in the clinical setting. Radioiodine therapy continues to be a mainstay of therapy for hyperthyroidism and thyroid cancer. However, Hertz struggled to gain recognition for his accomplishments and to continue his work and, with his early death in 1950, his contributions have often been overlooked until recently. The work of Hertz and others provided a foundation for the introduction of other radionuclide therapies and for the development of the concept of theranostics.

made possible by rapid developments in the fields of physics and medicine in the early twentieth century. Although diseases of the thyroid gland had been described for centuries, the role of iodine in thyroid physiology had been elucidated only in the prior few decades. After the discovery of radioactivity by Henri Becquerel in 1897, rapid advancements in the field, including artificial production of radioactive isotopes, were made in the subsequent decades.
Finally, the diagnostic and therapeutic use of radioactive iodine was based on the tracer principal that was developed by George de Hevesy. In the context of these advancements, Hertz was able to conceive the potential of using of radioactive iodine to treat thyroid diseases. Working with Dr. Roberts, he obtained the experimental data and implemented it in the clinical setting. Radioiodine therapy continues to be a mainstay of therapy for hyperthyroidism and thy- Only five years earlier, on November 12, 1936 Leading up to Dr. Hertz's question, four discoveries and advancements first needed to occur: the understanding of the role of iodine in thyroid function, the discovery of radioactivity, the development of the tracer principle, and the artificial production of radioactive elements. 1

| IODINE AND TH E THYROID
The condition known as "goiter", that is, pathological enlargement of the thyroid gland, was recognized in many parts of the ancient world including China, India, and the Mediterranean. The Romans attributed the high incidence of goiter in people living in the Alps to the drinking of water from mountain streams. The Renaissance physician, philosopher, and alchemist Paracelsus and others also recognized an increased prevalence of congenital goiter and mental retardation in the mountainous regions of Europe, 2 but treatment of goiter was limited and typically not successful. However, some early experiences suggested that treatment with sea water, sponge, or seaweed (all now known to be iodine-rich) might have some beneficial effect. 3,4 In the 18 th and 19 th centuries, several physicians, including Robert Graves, published reports describing what is now called Graves' Disease, with an association of goiter, exophthalmos, and cardiac palpitations. 5 In 1811, Bernard Courtois isolated iodine from the ashes of seaweed. 6 Soon after, Gay-Lussac confirmed that iodine was a new element, and derived the name from the Greek ioeides, thyroid contained "thyroiodine", a proteinaceous substance containing 10-15% iodine, and that the administration of thyroiodine could reverse myxedema (severe hypothyroidism). 3,4 Around the same time, Adolf Oswald was able to isolate thyroglobulin. In 1919, Edward Kendall at the Mayo Clinic isolated crystalline thyroxine. 8 During this time Charles Mayo, who introduced the term "hyperthyroidism", worked to develop improved surgical management of thyroid diseases. For patients with hyperthyroidism, this included preoperative medical management of Graves' disease with administration of large doses of non-radioactive iodine under the supervision of Henry Plummer. 9 Thus, by 1920, the association between iodine and the thyroid was clearly established, and the use of non-radioactive iodine to treat thyroid diseases was becoming more widespread.

| X -RAYS AND RADIOACTIVITY
In November 1895, while performing a series of experiments with cathode-ray tubes, Wilhelm Röntgen discovered a previously undescribed radiation that he called "x-rays." His findings were published by the end of that year and, within 6 months, x-rays were being used for diagnostic medical imaging. For his discovery, Röntgen was awarded the first Nobel Prize in Physics in 1901. A few months after Röntgen's discovery, Henri Becquerel, who had been studying possible photoluminescence of uranium salts sought to determine if x-rays were being emitted from the uranium salts. He demonstrated that similar rays were being emitted from the uranium, even without prior excitation by sunlight, and, thus, represented an inherent property of the material. Marie Curie, a graduate student at the time, coined the term "radioactivity" to describe this phenomenon.
Over the next several years, Marie Curie and her husband, Pierre Curie, were able to isolate and identify two additional and previously unknown radioactive elements, radium and polonium. For their work in discovering radioactivity and discovering these radioactive elements, Becquerel and the Curies were awarded the Nobel Prize in Physics in 1903. In 1911, Marie Curie also was awarded the Nobel Prize in Chemistry, making her the only person to ever receive the Nobel Prize in the fields of both physics and chemistry. The potential therapeutic action of radioactivity was appreciated very early on, and, in 1909, Marie Curie and the University of Paris established the Radium Institute, later renamed the Curie Institute, to investigate the biological and medical effects of radioactivity. 10,11 Although it was now clear that there existed radioactive elements such as radium and polonium, it was later shown that there were radioactive isotopes of some elements that also had nonradioactive isotopes. For example, Georg de Hevesy demonstrated in 1913 that a radioactive species resulting from the radioactive decay of radium and referred to as "radium-D" was actually a radioisotope of lead, 210 Pb.
However, the question remained as to whether these radioisotopes behaved in a biologically identical manner to the nonradioactive isotopes of the same element. In 1923, George de Hevesy reported that, in plants, the absorption and translocation of radioactive lead was similar to that of non-radioactive lead and demonstrated the potential of radioactive indicators to study living organisms. 12 In 1943, Dr. de Hevesy would be awarded the Nobel Prize in Physiology and Medicine for what is now referred to as the "tracer principle," i.e. a small amount of a radioactive indicator can be used to characterize the physiological behavior of its non-radioactive congener. The tracer principle is the foundation of diagnostic and therapeutic nuclear medicine, as well as other approaches to molecular imaging.

| THE LUNCHEON AND THE QUESTION
This brings us to the Harvard Medical School faculty luncheon on November 12, 1936. At this point, the importance of iodine to thyroid function is known and iodine is being used routinely to treat thyroid diseases. Radioactivity has been discovered and had been the subject of intense research for nearly forty years, and the tracer principle was utilized as a tool to study biologic processes. In the two years prior to this luncheon, radioactive isotopes of many elements had been produced artificially. Dr. Hertz's boss Dr. Means had investigated the treatment of toxic goiter with externally applied xrays. So Dr. Hertz was primed to ask his question, "Could iodine be made radioactive artificially?". Dr. Means noted in a later application to The Markle Foundation, "...it at once occurred to Hertz that we might make use of them (radioactive iodine isotopes) to solve a problem we were already working on." 16 In subsequent correspondence ( Fig. 1)

between Compton and Hertz, Compton informed
Hertz that a radioactive isotope of iodine (now known to be 128 I, Table 1) was available, and Hertz clearly stated his hypothesis that radioactive iodine might be used to treat thyroid diseases. Dr. Hertz's response to Compton's letter indicating that radioactive iodine may provide "a useful method of therapy in cases of overactivity of the thyroid gland." developed by Enrico Fermi. 17,18 Utilizing the resulting small amounts of 128 I, in vivo experiments in rabbits confirmed that radioactive iodine was concentrated in the thyroid gland (Fig. 2). 19 Even at this early stage, Hertz postulated that radioactive iodine might also be used to treat thyroid cancer.

| PRELIMINARY E XPERIMENTS
Although small quantities of 128 I (25-min half-life) were satisfactory for studies of iodine biodistribution, Hertz and Roberts realized that larger quantities of longer-lived iodine radioisotopes would be necessary for the therapeutic use of radioactive iodine. 130 I and 131 I were the most appropriate candidates (Table 1) T A B L E 1 Isotopes of iodine, including stable 127 I which occurs naturally with 100% abundance, and longer lived radioactive isotopes.

Isotope
Half    25 Unfortunately, he had little time to advance his studies of radionuclide therapy (using radioactive iodine and radioactive phosphorus) and radiation detection before his sudden death because of a heart attack at age 45 in 1950.

| LEGACY OF SAUL HERTZ
In the 80 years since Dr. Hertz treated Elizabeth D, an untold number of patients around the world have been treated with radioiodine for both benign and malignant thyroid disease. Although our understanding of radiobiology and dosimetry has advanced, patients continue to be treated in much the same way as Dr. Hertz treated his patients. During subsequent decades, radionuclide therapy was introduced for other diseases, but these other therapies never achieved the success or acceptance that radioiodine had for treatment of thyroid diseases.
In the past decade, the use of targeted radionuclide therapy has expanded dramatically with the promise of being a mainstay for the treatment of neuroendocrine tumors, and prostate cancer. In recent years, the term theranostics, a portmanteau of therapeutics and diagnostics, has been used to describe the use of similar (and usually radioactive) drugs to both image and treat disease. As the promise of theranostics develops, it is important to remember Saul Hertz and to have the courage to ask the right question, to understand the import of the moment, and to not let an opportunity to develop a breakthrough therapy pass by. For these reasons, we continue to honor and celebrate the pioneering, visionary work of Dr. Saul Hertz.