Historic perspective

Historic Perspective M i l l a r d N. Croll

Recording the chronology of nuclear medicine instrumentation poses some difficult decisions as does the determination of the "father" of nuclear medicine?. Historians can agree on well-defined dates and events, but many of them are subjective and reside in the memories of those of us who were fortunate to experience the formative years of our field. We all search for the historical truth. The highlights of this story may begin with John Lawrence and phosphorus-32 therapy at Berkeley and continue with Enrico Fermi's sustained nuclear reaction, which lead to the Manhattan Project, then the Atomic Energy Commission, and finally, Sam Seidlin's treatment of thyroid metastases with iodine-131. The rectilinear scanner

came to us from Benedict Cassen and was followed by Hal O. Anger and his gamma scintillation camera, one of the most pivotal developments in the field. A plethora of cameras followed: Merrill Benders's digital autofluroscope, Dave Kuhl's efforts for tom9 imaging, and then on to single photon emission computed tomography. Finally, we come back to Hal O. Anger, who suggested and worked with the idea of a positron camera, with positron emission tomography becoming commercially available in 1985. Ours is a variegated history, and I hope that this account speaks the historical truth. Copyright 9 1994 by W.B. Saunders Company

in nuclear medicine I NSTRUMENTATION today represents a sophisticated blend of

fluorescent chemical. He realized that the light could only have come from some form of radiation from the Crookes tube, which was carefully covered with shields of black cardboard. These hitherto unrecognized rays emanating from the Crookes tube and penetrating the cardboard shield fell on the luminescent screen. Roentgen interposed his hand between the source of the rays and the luminescent cardboard and saw the bones of his living hand projected in silhouette. The great discovery had been made) Or was Georg Charles DeHevesy the true father of nuclear medicine, as proposed by the late William Myers, past historian of The Society of Nuclear Medicine:

electronics, computers, and mechanical devices. To chronicle the history of the development of these instruments is difficult. Ervin Kaplan , the former chief of the Nuclear Medicine Service at the Hines Veterans Administration Hospital, stated 15 years ago that The multi-disciplinary character of nuclear medicine presents the historian with a challenge of considerable proportion . . . . The generation of many controversies may be the means of clarifying our nearest approximation to historical truth. History is that interpretation of the past perceived by the observers or writers of history.1

As one peruses the volumes of historical data written about this relatively young discipline in medicine, Kaplan's statements ring true. Who is the father of nuclear medicine? What is the birth date of nuclear medicine, or when did it really start? C.L. Edwards believes that

Nuclear Medicine is endowed with an especially rich and variegated heritage, Paraphrasing Newton, 'we stand on the shoulders of giants'; and our activities stem from an integration of some of the insights of no less than three dozen Nobel Laureates and the sagacity of many other gifted scientists. Distinctly notable among our forebears was Georg Charles DeHevesy. 4

The birth date of nuclear medicine can probably be placed best somewhere between the discovery of artificial radioactivity in 1934 by F. Joliot and I. Curie and 1946, when reactor-produced radionuclides for medicine became available in abundance in the Oak Ridge National Laboratory. By 1940, a point midway between these landmarks, P-32 became the first radioisotope shown to concentrate in tumors. 2

The scintillation effects of ionizing radiation were known since the early part of the 20th century, and in the third decade John Lawrence at Berkeley used radiophosphorus, phosphorus32, for the treatment of leukemia. For the past five decades the progress of nuclear medicine

Or did nuclear medicine really start on November 8, 1895, when Professor Wilhelm Konrad Roentgen, working in the Institute of Physics in the University of Wurzberg in Bavaria, saw a faint, flickering, greenish illumination on a piece of cardboard that was painted with a

Historian, Society of Nuclear Medicine, formerly Professor and Chairman of the Department of Nuclear Medicine, Hahnemann University,Philadelphia, PA. Address reprint requests to Millard N. Croll, MD, 435 Hughes Rd, King of Prussia, PA 19406. Copyright 9 1994 by W.B. Saunders Company 0001-2998/94/2401-0001505.00/0

Seminars in Nuclear Medicine, Vol XXIV, No 1 (January), 1994: pp 3-10

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has developed along parallel lines. Two elements are necessary in this field after the patient and the physician: radiopharmaceuticals and instrumentation. Based on the extensive research and development programs by the pharmaceutical manufacturers, one would have expected the growth in new radiopharmaceutical compounds for medical use to outdistance new developments in instrumentation. History has shown that this is not how it has occurred. Compared with the complex chemistry and research required to produce a new radiopharmaceutical for human use, the development of an instrument to simply detect, measure, and visualize the distribution of that radioactivity is considerably easier. However, due credit must be given to the instrument manufacturers, who have made every effort to stay several technical steps ahead of their colleagues in the radiopharmaceutical development field. This issue of Seminars m Nuclear Medicine is directed toward the current sophisticated instrumentation in our field. The sequence of events leading up to this current state-of-the-art instrumentation is an interesting story. THE FIRST STEP

The year was 1945, during World War II, and August 6th and 9th were infamous days with the first use of a U-235 bomb on Hiroshima and a PU-239 on Nagasaki. The events leading up to this singular event in our history began 3 years earlier. Enrico Fermi, one of the most famous Italian physicists, produced the first nuclear fission reaction. In January 1942, President Roosevelt approved the construction of an atomic bomb. In September the Manhattan Engineering District, more commonly known as the "Manhattan Project," was activated. From the period from September 1942 to January 1947, the Manhattan Project had complete control of secret nuclear science. In early 1943 the ground was broken, and in November of that year the Oak Ridge nuclear reactor went critical. In the interim the super secrecy surrounding the construction of the bomb resulted in many interesting anecdotes. One morning in 1944, a DC-3 and a C-47 airplane flew from Knoxville, TN, each with a package bound for Berkeley, CA. John Lawrence had been treating leukemia patients with radiophosphorus for

almost 7 years before this time. He had been making his 32p at the university until the Manhattan Project pre-empted their cyclotron to make the first plutonium. Thus, to keep the construction of the bomb secret, Lawrence was instructed to continue his 32p work with lots of publications and lectures. Radiophosphorous was supplied to him in lavish amounts, 1 Ci/mo, from the new reactor at Oak Ridge. The second "package" that left Knoxville at the time the 32p traveled westward was a child who had leukemia. Interestingly enough, the two packages arrived in Berkeley about the same time, and the child from Knoxville was treated 3,000 miles from home with 32p made in his own backyard.5 The events that occured after the atomic bomb are well documented in history. The first peace-time shipment of a radioisotope occurred 1 year later in August 1946; this was carbon-14, and it went to Martin Kamen, who had discovered carbon-14 6 years earlier on the Berkeley cyclotron. Kamen worked at the Barnard Free Skin and Cancer Hospital in St Louis, MO. The major player in the program, Paul Aebersold, made the best of the public relations value of the word cancer. T h e use of radionuclides for diagnosis and treatment in humans (aka nuclear medicine) was off and running! THE NEXT STEP

Political events followed rapidly. President Truman signed the Atomic Energy Act of 1946 to create the Atomic Energy Commission (AEC), which formally took over the Manhattan Project on January 1, 1947. Truman also signed an executive order creating a joint USJapanese Atomic Bomb Casualty Commission to study the medical effects of the bomb on the Japanese nation. The most significant event occurring at this time, however, and considered by historians as the most important medical paper published in nuclear medicine, was a report by Sam Seidlin, a New York internist from Montefiore Medical Center, who described in JAMA the complete disappearance of multiple functioning metastases in a patient who had had a malignant thyroid tumor removed a few years earlier. Seidlin had published this information almost 1 year earlier, but the paper was rejected by his colleagues as unrealis-

HISTORIC PERSPECTIVE

tic! Within days of the release of this article, congressmen heard from their constituancies, and within hours the AEC commissioners learned that they now had two priorities: their previous one, to build bombs under strict secrecy wraps, and a new one, to provide radioisotopes to cure cancer with the greatest possible publicity. The physicists who worked with Dr Seidlin were Dr Rosalyn Yalow (later to win the Nobel prize) and her husband Aaron. Radioiodine had been in use before World War 11 and was provided by the Massachusetts Institute of Technology and by Berkeley. It was originally used to distinguish hypothyroidism from hyperthyroidism, and the thyroid uptake test that dominated nuclear medicine for a generation grew out of this as an obvious idea. The literature during the period from 1946 to 1951 was flooded with reports on the use of iodine-131 (131I) in thyroid disease. Seidlin's article on December 7, 1946, has again been proposed as the true beginning of nuclear medicine. INSTRUMENTATION

After the discovery of x-rays, particularly Marie and Pierre Curie's discovery of radium in 1898, the development of instruments that could detect ionizing radiation, and hopefully measure its quantity, reached high priority. X-rays were measured with varied devices such as the "cloud chamber" and the "radiometer." The first name that stands out in nuclear medicine instrumentation is Hans Wilhelm Geiger, a most innovative physicist. Geiger developed the first tube cathode with a central wired anode in 1908, and 5 years later he reported counting beta emissions in a charged tube. This was the first step to the development of the now famous Geiger-Meuller (G-M) tube. For the next 15 years the G-M tube was used in many configurations: end window, side window, shielded, and unshielded. In 1928 Geiger announced the beta avalanche G-M counter using the wall of his tube as a cathode. He then extended the G-M tube to alpha, beta, and proportional counting. Unfortunately, Wilhelm Mueller, Geiger's associate, immigrated to Australia, and his further activities are entirely lost to history.~ From 1926 to 1953 the developing young discipline of nuclear medicine was dominated

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by the use of radionuclides for therapeutic effect: primarily radioiodine for the thyroid and, as previously reported, the use of 32p for leukemia. Because each radioisotope was found to localize in a specific tissue, there was an uncontrollable urge to give large doses with the aim of providing localized therapeutic radiation. A rapid sequence of events leading to essentially a single diagnostic procedure changed the emphasis of nuclear medicine. Artificial isotopes were discovered in 1934, radioiodine was suggested in 1936 for the thyroid, the next year the first 32p treatment was administered, and in 1939 nuclear fission was discovered. The report in 1946 of radioiodine curing thyroid carcinoma metastases exploded the field of thyroid physiology and treatment. Unfortunately, the G-M tube had some severe limitations. Although it was the only external counting device available until 1949, the G-M tube was extremely insensitive to gamma rays. Even with extensive manipulation and shielding, the tubes responded to only 2% of the total gamma ray emission from a radioactive source. Attempts were made to collimate the Geiger tubes for the study of thyroid function and morphology with radioiodine. It was historically unfortunate that 1311was the first gammaemitting isotope to be used in the diagnosis of thyroid disease. The high energy precluded, for the most part, its use by the G-M detection system. As reported, the scintillation effects of ionizing radiation on certain crystals had been known since the early part of the century. Ernest Rutherford visually counted the individual scintillations produced in zinc sulfite crystals by alpha particles in his original studies of the nature of radioactivity. Heinz Kallmann in Germany in 19486 reported that photomultiplier tubes could detect the individual scintillations and amplify them so that they could be counted and used. This breakthrough led directly to one of the next major steps in the evolution of nuclear medicine. THE CASSEN ERA

Although the early experience of nuclear medicine with 131Iwas devoted to its therapeutic use, considerable effort was expended to detect the localization of the radionuclide in the organ both as total accumulation and on a regional

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basis. A remark often made, and attributed to Hippocrates in speaking to a medical student, stated that "you really ought to look at a patient before making a diagnosis." Benedict Cassen, PhD, an honored and revered pioneer in the field of nuclear medicine, worked in the Laboratory of Nuclear Medicine and Radiation Biology in the Department of Biophysics and Nuclear Medicine at the University of California at Los Angeles (UCLA). Recognizing the severe limitations of the G-M tube, understanding the scintillation effects of ionizing radiation, and encouraged by the progress made with photomultiplier tubes, Cassen explored the possibility of making a sensitive directional gamma-ray detector. He used the high-absorption efficiency of calcium tungstate, and the first results of this arrangement were excellent. In 1950 Cassen collaborated with the Radioisotope Service at the Los Angeles Veterans Administration Hospital, and a cooperative program was set up by Dr Herbert Allen, Jr, then chief of the service. 7 At the same time Bill Maclntyre at Western Reserve showed that a large increase in sensitivity could be obtained with the use of an anthracene crystal. 8 The group had to convince the infamous but beloved Dr Edith Quimby, a member of the AEC's Human Usage Committee, that thyroid uptake could be measured with an administered dose of less than 40 IxCi of 1311! An initial application of the directional gamma-ray detector with increased sensitivity was an attempt to visualize the morphology of the thyroid gland. This was done by tedious, manual, point-by-Point counting over the thyroid gland using a grid with 400 counting positions. The tediousness of this procedure immediately pointed the way for automation, and the first scintillation scanner was built at UCLA in 1950 and described by Cassen and Curtis. 9 It is believed that the first thyroid scintillation scans ever obtained on human patients were performed by this instrument. The scans were recorded by a stationary relay printer, which marked a sheet of paper that moved with the detector and was mechanically coupled directly to it. 10At about the same time, automation and recording of the distribution of radioiodine in the thyroid was approached on the East Coast by a radiological physicist, Theodore Sopp and this author. Working at Hahnemann University,

MILLARD N. CROLL

we constructed a similar device with a scintillation detector that would move over the thyroid, and the recording mechanism was a solenoidactuated metal point that made dots on paper. After the development of the scanner at UCLA, Larry Curtis and Clifton Reed, who had been employed at the UCLA Atomic Energy Project, left to start the RC Scientific Instrument Company (Los Angeles, CA) to make and sell scintillation instruments, including scanners. Reed originated the term scintiscanner, and this became a generic label. During this time hermetically sealed thallium-activated sodium iodide crystals were made commercially by Harshaw Chemical Company (Solon, OH). The availability in 1951 of large sodium iodine crystals and end window multiplier tubes led to a further development of major proportion. Bob Newell and the group at The Medical Division of the Oak Ridge Institute for Nuclear Studies promoted the focused multichannel collimator. 11 During the next few years there was a great flurry of activity to explore the possibility of using radioisotope scanning for clinical problems other than thyroid disease. A significant improvement in the data from the scanners came about with the introduction by P.R. Bell of a medical spectrometer, affectionately known as the "Oak Ridge spectrometer." At about this time the results in early liver scanning were marginal, and efforts were made to improve the recording techniques. This included background cut-off and contrast enhancement procedures. It promoted the development of a photographic recording system (photoscanner) developed by David Kuhl and the group at the University of Pennsylvania. 12With this development the scanner took a second leap in a flurry of activity, and organs throughout the body were considered for scanning. Photoscanning appealed to radiologists, because the scans were printed On standard size x-ray film. By examining these on the familiar x-ray viewing box, they appeared to convey more information than the "dot" scan printed on paper. In 1956 Bender, working at Buffalo, used this photoscanning system with ~31I-labeled serum albumin as a tracer to obtain the first photoscans of brain tumors. Cassen's invention of the rectilinear scanner, with its progressive sophistication, represented a significant advance in diagnostic nuclear medicine. What history now regards as

HISTORIC PERSPECTIVE

the most significant advance in the entire field is the next step. HAL O. ANGER AND HIS SCINTILLATION CAMERA

With the firm establishment of the scintillation scanner, all efforts were then directed toward improving imaging capability for the nuclear medicine physician. After Cassen's first description of the rectilinear scanner, Hal O. Anger, a physicist working in the Donner Laboratory at the University of California Berkeley and impressed by Cassen's discovery, set about to develop an improved instrument. His first gamma-ray imaging instrument was a wholebody scanner, which employed 10 scintillation counters, called the Mark I Whole Body Scanner. A variation of this scanner was built commercially by Picker (Northford, CT) as the Dynapix. However, Anger was convinced that the best approach for an imaging device was to develop a stationary detector instrument. He felt more confident in depending on electronics for data collection than mechanical transport of a detector. Anger described his version of the camera in 1957.13 This first camera had only a 4-inch diameter, 0.25-inch thick, sodium iodide crystal. He used a single pin-hole collimator and successfully imaged human thyroid glands. Because sodium iodide crystals larger than 4 inches were not available at that time, it was 4 years before a commercial version of the Anger camera was produced. In 1962 Nuclear Chicago Company (Chicago, IL) installed the first commercially built Anger scintillation camera, known as the Pho-Gamma. Historians agree that no single discovery or invention has been so pivotal in the emergence of nuclear medicine as a major discipline than Anger's development of the scintillation camera. Perhaps the best measure of Anger's contribution to clinical medicine is the following report. By the 1970s the scintillation camera was in use worldwide; multiple camera manufacturers had sold more than 5,000 units. The Anger camera had become the primary instrument for nuclear medicine imaging. FURTHER DEVELOPMENTS

After the introduction and commercial availability of the Anger single-crystal scintillation camera in 1962, additional cameras using differ-

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ent modes of operation began to appear. One of the problems presented by the Anger type of camera, with its thin crystal detector, was that it worked quite well with low-energy radionuclides such as technetium-99m, but higher energy photons simply went through the crystal without interacting. To address this problem, in 1962 Merrill Bender and Monte Blau at Roswell Park in Buffalo introduced a camera with a new concept; a matrix of 293 sodium iodide crystals 1 cm square and approximately 5 inches in depth. This matrix was connected to a series of photomultiplier tubes in an X-Y axis so that positioning could be obtained. The camera was named the Autofluoroscope and was shown to efficiently use higher energy radionuclides. Two years later in 1964, the Baird Atomic Company (Bedford, MA) made the units commercially available as the Digital Autofluoroscope. A number of specialized cameras made their appearance: a camera using x-ray image amplifi' cation produced by Michael Ter-Pogossian and a kinetic brain study camera by William Gross. Additionally, work continued on axial emission tomography by Dave Kuhl and the production of gold collimators by Craig Harris and P.R. Bell, and in 1965 Hal O. Anger presided at the first Gamma Scintillation Camera Symposium. Powell Richards at Brookhaven devised a 1,045hole low-energy collimator, and in 1968 Paul Hoffer produced a device for thyroid fluorescence scanning. By 1969 Polaroid (Cambridge, MA) film dominated the camera systems, and for those without a rapid film changer, tile technique of "fast pulling" of Polaroid film became an art to learn. THE TOMOGRAPHIC SCENE

During the 1970s refinement and sophistication of the available cameras continued. Robert L. Hayes developed an IliA-inch diameter crystal camera in 1971, and Dave Kuhl was showing transverse section scans on his emissions scanner. It was just about this time that George Hounsfield introduced the computerized axial tomographic (CAT) scanner for radiology, and EMI (London, England) installed a CAT scanner in Massachusetts General Hospital (MGH). In the middle of the decade Henry Wagner converted the VanDyke instrument into what he termed "the nuclear stethoscope." Single crystals were enlarging, and reports compared

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MILLARD N. CROLL

Fig 1. The first 32-detector, cross-sectional positron unit developed at Brookhaven National Laboratory by Jim Robertson in 1960 and called the "hair dryer that finds tumors.'"

the results between 15-inch and 10-inch camera screens in 20 patients. Near the end of the decade, Gordon Brownell scanned u c on the positron camera at MGH, and Michael TerPogossian made his fourth positron emission instrument. But I am getting ahead of the story, because the main event in 1979 was the appearance of the single photon emission computed tomographic (SPECT) camera by Jaszcar. However, it was 5 years later before SPECT units became commercially available. The early work with the available SPECT cameras showed 3-dimensional reconstructions on the scans. As SPECT cameras populated established departments of nuclear medicine alongside the stationary large-field-of-view cameras, it was found that they were delivering such high-quality im-

ages that they were frequently used only for static imaging, and their rotational function was underutilized. THE FINAL (?) DEVELOPMENT

For the final chapter of this history of the development of nuclear medicine imaging instrumentation, we come back to Hal O. Anger. After developing his gamma-ray camera in 1957, Anger made a parallel development using a conventional scintillation camera detector on one side of the patient and a single-crystal, position-sensitive detector on the opposite side of the patient to develop what was reported as the first positron coincidence camera. ~4 This device provided better resolution and sensitivity for the difficult-to-image positron emitters. One

HISTORIC PERSPECTIVE

can only imagine the extensive research and development over the past 36 years that brought this technique to its present level of sophistication. A singular example will suffice. As radioisotopes became available after World War II, it was noted that a few isotopes decayed by the emission of positrons, which combined with electrons to produce two 510-keV gamma rays going in opposite directions. The potential use of these isotopes for medical applications was examined by Brownell et al at MGH, among others. In 1960 Jim Robertson and his group at Brookhaven National Laboratory were interested in designing a positron scanning instrument at Brookhaven. He and William Higinbotham, the head of the Brookhaven Instrumentation Division, visited Brownell and returned to Brook-

Fig 2. The revised configuration of the original multidetector positron unit, which increased the spatial resolution.

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haven to build the first arrangement of the camera, which employed 32 sodium iodide detectors (Fig 1). Although this arrangement was relatively efficient, it provided very poor spatial resolution. The next year, Seymour Rankowitz and Marty Rosenblum from Brookhaven revisited MGH, and on their return they rearranged the 32 detectors in a circle to provide information on the distribution of the positron emitters in one plane of the subject (Fig 2). Several variations of this configuration were developed over the following years, and in 1966, Lucas Yamamoto of the Montreal Neurological Institute came to Brookhaven and proposed the use of the circular detector array to study cerebral blood circulation (J.S. Robertson, personal communication, May 16, 1991).

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In June 1978, the first International Symposium on Positron Emission Tomography was held in Montreal, Canada. In his initial address, Yamamoto stated: Positron tomography, since it is almost cyclotron dependent, will necessarily be limited to a relatively small

number of medical centers in the first instance. But the history of radionuclide scanning and of computed tomography indicates that wider acceptance of this promising clinical tool is an eventuality.

Clearly, this was a prophetic statement and only one of many to come in the ensuing years.

REFERENCES 1. Kaplan E: A letter from the guest editor. Semin Nucl Med 3:148, 1979 2. Edwards CL: Tumor-localizing radionuclides in retrospect and prospect. Semin Nucl Med 3:186-189, 1979 3. Brucer M: A Chronology of Nuclear Medicine. St Louis, Mo, Heritage, 1990, p 51 4. Myers WG: Georg Charles DeHevesey: The father of nuclear medicine. J Nucl Med 20:590-594, 1979 5. Brucer M: A Chronology of Nuclear Medicine. St Louis, Mo. Heritage, 1990, p 263 6. Blahd WH: History of external counting procedures. Semin Nucl Med 9:159-163, 1979 7. Cassen B, Curtis L, Reed C: A sensitive directional gamma-ray detector. U.C.L.A Report 49, 1949; and Nucleonics 6:78, 1950 8. Maclntyre WJ: A scintillation counter for measure-

ment of 1-131 uptake in the thyroid gland. Proc Soc Exp Biol Med 75:561, 1950 9. Cassen B, Curtis L: The in vivo delineation of thyroid glands with an automatically scanning recorder. UCLA Rep 130, 1951 10. Cassen B, Curtis L, Reed C, Libby R: Instrumentation for 1-131 use in medical studies. Nucleonics 9:46, 1951 11. Newell R, Saunders W, Miller E: Multiehannel collimators for gamma scanning with scintillation counters. Nucleonics 10:36, 1952 12. Kuhl DE, Chamberlain RH, Hale J, et al: A highcontrast photographic recorder for scintillation counter scanning. Radiology 66:730, 1956 13. Anger HO: A new instrument for mapping gammaray emitters. Biol Med Q Rep U Cal Res Lab-3653:38, 1957 14. Anger HO: Scintillation and positron cameras. U Cal Res Lab 9640, 1959