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Reflections |
1 From the Department of Radiology, Michigan State University, 160 Radiology Bldg, East Lansing, MI 48824. Received August 31, 1999; revision requested October 6; revision received October 26; accepted October 28. Address reprint requests to the author (e-mail: Jim.Potchen@radiology.msu.edu).
Abstract
In the early years of nuclear medicine, physicians explored applied nuclear physics, and physicists pursued uncharted areas in medicine. Reflections from Jim Adelstein, MD, PhD, John McAfee, MD, Henry Wagner, MD, Fred Bonte, MD, Dave Kuhl, MD, and Alex Gottschalk, MD, add to the appreciation of the diversity in those early years. These reflections may serve many purposes. For some, they may provoke nostalgia for the better life gone by. For others, reflections may create an awareness of the people and the process of what it took to be where we are today. For still others, this may provide some impetus to better understand the origins of modern imaging technologies and their diffusion. Which techniques in use today will be in use 30 years from now? Why will some survive and others go by the wayside? From research into the process of technology transfer and diffusion, can we learn to put our efforts today where they will have the greatest benefits to human beings some 30 years from now? How can we maximize the present value of our efforts to improve diagnostic imaging? Reflections from the past may help.
Index terms: Radiology and radiologists, history • Radionuclide imaging • Radionuclides • Reflections
In the early years, nuclear medicine was composed of a small community of intensely interested individuals. An appreciation of these individuals and their reflections is relevant to our visions of the future. The early pioneers had to travel outside the boundaries of their traditional disciplines. Physicians explored applied nuclear physics, and physicists pursued uncharted areas in medicine. This cross-fertilization between diverse disciplines accounts for the rich heritage that has evolved from those early years.
The views and aspirations of these involved individuals heavily influenced nuclear medicine and its subsequent developments. In the preparation of this reflection, I have sought the advice of some of these pioneers and have asked them to discuss how the field of nuclear medicine has changed from the early years into the late 1990s. Jim Adelstein, MD, PhD, John McAfee, MD, Henry Wagner, MD, Fred Bonte, MD, Dave Kuhl, MD, and Alexander Gottschalk, MD, have written personal reflections of "then and now." These individuals, along with George Taplin, MD, Ed Coleman, MD, Barry Siegel, MD, Leonard Holman, MD, Phil Alderson, MD, Michel Ter-Pogossian, PhD, Mike Phelps, PhD, Jim Quinn, MD, Doug Maynard, MD, Tom Budinger, MD, PhD, and Leon Partain, MD, PhD, represent some of the people I knew in those early years. These individuals worked closely together to produce much of what we see as nuclear medicine today.
This is not meant to be an inclusive survey of all of the scholars who have contributed to the development of the field; rather, it represents highly personal reflections by some of the individuals who have made important contributions. Thus, I will discuss the reflections as viewed from the perspective of individuals from Harvard University, Johns Hopkins Medical Institutions, the University of Michigan, Washington University, the University of Chicago, and Southwestern University Medical School. As it is impossible to completely cover the political and scientific development of the discipline, my emphasis will be placed on my early clinical experiences and the people I have known from that time.
My experiences in nuclear medicine began at Harvard and Washington University. Jim Adelstein, in reflecting on the Boston history of nuclear medicine, reports that in the 1920s,
Hermann Blumgart and Soma Weiss use 214Bi (Radium-C) in the first clinical use of radionuclides to measure the velocity of blood flow across the lungs in heart failure, thyrotoxicosis, etc. In a landmark paper, Blumgart and Yens [1] elaborate the Tracer Principle for physiologic studies. [They concluded that the] (substance should not be toxic, not previously present in the body, not disturb the phenomenon under investigation, readily detectable in small amounts and desirable that it leave the body promptly) [Adelstein SJ, written communication, June 1999].
In the 1930s, Robley Evans was the first, to our knowledge, to demonstrate
the utility of radio-iodine in the study of thyroid physiology with Hertz and Roberts using 128I produced from a neutron source. Subsequently Evans and John Irvine produce 130I on the MIT [Massachusetts Institute of Technology] cyclotron (built for medical radionuclide production), which is used by Hertz to treat thyrotoxicosis in 29 patients [Adelstein SJ, written communication, June 1999].
During the 1940s, as radionuclides became
available in quantity from the AEC [Atomic Energy Commission], Francis Moore used a number of radionuclides to study the metabolic response to surgery. Gray and Sterling [2] learn to label erythrocytes with 51Cr to study red cell mass and survival, and Selverstone and Solomon [3] use 32P to probe for brain tumors. The 1950s saw Brownell and Sweet [4] [at Massachusetts General Hospital] image brain tumors with the positron emitter 74As [Adelstein SJ, written communication, June 1999].
My own involvement in nuclear medicine began in the early 1960s. To quote Jim Adelstein,
desperate to meet Donald Matson's [a successor of Harvey Cushing as the Chief of Neurosurgery] request for a brain scan, radiology resident James Potchen discovers a rectilinear scanner in a protein chemistry lab at the Children's Hospital (mistakenly purchased to scan radioactive chromatograms), wheels it across Shattuck Street to the PBBH [Peter Bent Brigham Hospital] where he produces the first radionuclide image in the Longwood area [Adelstein SJ, written communication, June 1999] [Fig 1].
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Figure 1a. An example of the images from an early 203Hg brain scanning procedure of the type performed at the Peter Bent Brigham Hospital on Dr Donald Matson's patient with glioblastoma multiforme. Increased radioactivity indicates the tumor. Focused collimation provides selective signal detection from the hemisphere closest to the detector. (a) Left-sided view. (b) Frontal view. (c) Right-sided view.
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Figure 1b. An example of the images from an early 203Hg brain scanning procedure of the type performed at the Peter Bent Brigham Hospital on Dr Donald Matson's patient with glioblastoma multiforme. Increased radioactivity indicates the tumor. Focused collimation provides selective signal detection from the hemisphere closest to the detector. (a) Left-sided view. (b) Frontal view. (c) Right-sided view.
View larger version (134K):
[in this window]
[in a new window]
[Download PPT slide]
Figure 1c. An example of the images from an early 203Hg brain scanning procedure of the type performed at the Peter Bent Brigham Hospital on Dr Donald Matson's patient with glioblastoma multiforme. Increased radioactivity indicates the tumor. Focused collimation provides selective signal detection from the hemisphere closest to the detector. (a) Left-sided view. (b) Frontal view. (c) Right-sided view.
That first image was produced at night, somewhat surreptitiously, because all clinical radioisotopes at "the Brigham" were in the domain of the departments of surgery, endocrinology, or hematology. Radiology did not have permission from the "clinical chiefs" to be using isotopes on patients. Don Matson gave us permission to try the first scanning procedure on his patient, who had been scheduled for surgery without an image of the lesion. This case broke the permission barriers, and subsequently, most patients scheduled for brain tumor excision had a preoperative "radioisotope brain scan." Initially, we used mercury 203 (5) but, because of its high energy and radiation dose, switched to 197Hg. It was some years before technetium 99m and the gamma camera became available (6). As late as 1968, Dr Adelstein and I participated in a public debate held at Washington University on the question of "Can a gamma camera ever obtain sufficient resolution to compete with the rectilinear scanner?" History has amply answered that question.
Adelstein reflects on these early years,
Harvard debates whether "Nuclear Medicine" is a medical specialty and, since radionuclides are used for clinical research in several departments (Medicine, Surgery, Pediatrics, Radiology), where it belongs. Potchen is given responsibility for radionuclide imaging at PBBH [Peter Bent Brigham Hospital] and promptly leaves for St Louis [to set up nuclear medicine at the Mallinckrodt Institute at Washington University under Juan Taveras]. Herbert Abrams then settles the debate by creating a division of nuclear medicine within the Harvard Department of Radiology.
Tracer kinetics and compartmental analysis are central to nuclear medical thinking in studies of the kidney, lung and the thyroid. With time, image analysis takes center stage. With the advent of PET, the importance of quantitative study has been reinstated [Adelstein SJ, written communication, June 1999].
When I left, Jim Adelstein became chief of Nuclear Medicine at the Brigham. When Jim was called to serve in the dean's office at Harvard, Len Holman, who had trained with me at Washington University, was appointed chief of Nuclear Medicine in the Department of Radiology. In that role, Len developed single photon emission computed tomography (SPECT) for both brain and cardiac applications. Holman is to be given much of the credit for bringing cardiac nuclear medicine to the clinical forefront (7). Perhaps his greatest contribution was the cultivation of research and research careers as essential to the long-term viability of radiology. The early years of nuclear medicine were conducive to the development of careers in medical research. As an example, Tom Budinger, currently a professor at the Donner Laboratory of the University of California, Berkeley, gives us credit for introducing him to a career in nuclear medicine when he was a medicine intern at the Peter Bent Brigham Hospital.
In the years between 1965 and 1971, the group in training at Washington University included Len Holman, Barry Siegel, Ron Evens, Mike Phelps, Mike Welch, Ed Coleman, Phil Alderson, Mike Ter-Pogossian, and myself. All of these individuals have gone on to develop substantial careers contributing to nuclear medicine. Mike Phelps, who subsequently invented positron emission tomographic (PET) scanning, began his career as a graduate student and postdoctoral student in organic chemistry with us at Washington University. Early in his career, he demonstrated a remarkable technical facility and a capacity for hard work. He is currently the Norton Simon Professor and chair of the Department of Molecular and Medical Pharmacology at the University of California, Los Angeles (UCLA). He and others are to be credited for clearly demonstrating the utility of PET scanning in cancer diagnosis and molecular imaging (8,9). In our formative years, we had a critical mass of people working as a team with a common agenda. We were able to share knowledge and ideas and to grow together.
John McAfee and Henry Wagner initiated the development of nuclear medicine at Johns Hopkins. This has been the major center for the growth and development of the discipline and its clinical applications (10–12) (Figs 2, 3).
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[today, the] field is vastly different. For one thing, the number of personnel in the old days was much smaller. Every one of us knew all the others on a first-name basis. There was so much to do in research—new, exciting knowledge was generated almost daily. Today, progress in the development of new "radiopharmaceuticals" seems much slower. As we all know, the instrumentation is now totally different for radionuclide imaging and is vastly superior. On the other hand, in those old days, the number of radionuclides that you could explore for imaging was much greater, and the national laboratories were able to supply free radionuclides on a trial basis. Today, of course, the number of radionuclides available for experiments and especially for clinical use is very limited, and experimental trials in humans is [sic] tightly regulated. I am still not convinced that the early unregulated years inflicted any harm to patients.
The only real problem in the "pioneer days" were pyrogen reactions from contaminated disposable syringes! In the memorable era working with Henry Wagner, Dick Reba and others, after a few preliminary animal experiments, we would try one or more new radionuclides and their tracer compounds in one or a few patients, and found out quickly which ones were going to work in humans. Such an approach would be unthinkable today, and would require many years to reach the same conclusions. Somewhere, an error was made in neglecting the concept that radiopharmaceutical agents are radiotracers devoid of any pharmacological effects and treating them as radioactive DRUGS subject to regulations similar to those of stable drugs used therapeutically.
An interesting problem encountered in the "early years" was the difficulty in obtaining research funding. Thanks to the diligence of many scientists in the different disciplines of nuclear medicine, this funding has increased tremendously. At one time, Wagner, Reba and I had an NIH [National Institutes of Health] grant rejected because the reviewers believed that no radioactive agent could ever successfully image the kidneys because the extra-renal background activity would be too high. Moreover, such an agent was not needed because of the superior spatial resolution of intravenous pyelography. However, we promptly sent them the first successful renal images, and they approved the grant [11].
Mannie Subramanian and I had a similar experience in proposing a Tc-99m bone agent to the NIH [13]. The rejection report stated that everyone knows that this radionuclide does not localize in the bone. However, we obtained a little funding from the American Cancer Society. After several dog experiments, we imaged a patient with prostatic bone metastases with Tc-99m polyphosphate and Fed Ex-ed the slides to one of the Society of Nuclear Medicine meetings in time for Mannie Subramanian's presentation. Such quick progress would take much longer today. We did eventually get NIH funding for skeletal imaging.
Ages ago, the late Giovanni Di Chiro [14] at the NIH established the value of F-18 FDG [2-(fluorine-18)fluoro-2-deoxy-D-glucose] in differentiating malignant brain tumors from benign lesions by positron emission tomography. Many years elapsed before several investigators tried it in other malignancies, resulting in another great successful clinical application. After decades of commendable research projects in PET imaging without important undesirable effects, we are now battling FDA [Food and Drug Administration] lengthy guidelines for clinical FDG PET. Nuclear medicine has become the most over-regulated field in medicine. It is ironic that the burden of regulation in radiological disciplines is inversely related to the radiation doses involved—minimal restrictions in radiation oncology, intermediate for diagnostic radiography and CT [computed tomography] and maximal for radionuclide imaging. Nonetheless, the current scientists in nuclear medicine seem steadfast in their optimism for more progress in the future [McAfee JG, written communication, May 1999].
Henry Wagner entered the field of nuclear medicine in 1958, 5 years after the founding of the Society of Nuclear Medicine. He was president of the society in 1971, the year when the American Board of Nuclear Medicine was founded. Merrill Bender, as previous president of the society, had set the direction for the formation of the Board and for the establishment of a recognized specialty. Wagner reflects that he faced a
hostile environment waiting to attack the concept of a new specialty. These early days manifest rampant territoriality in the struggle to gain control of radioactive materials in medicine. Recognition of nuclear medicine as a medical specialty played a major role in getting us to where we are today. Among the threats in the past was HCFA's [Health Care Financing Administration's] failed attempt to fold nuclear med into the ACR/RVS [American College of Radiology/relative value scale]. It is not correct to imply that pioneers of nuclear medicine, such as Merrill Bender [5,15, 16], a person unknown to most young persons in nuclear medicine today, were only concerned with the science and not the practice of nuclear medicine.
Nevertheless, although a defensive posture was needed during much of the past, today it is time for "outreach" to be the keynote of our specialty. Nothing illustrates this better than the history of the development of nuclear cardiology, a great force for good in medicine in general, and nuclear medicine in particular. In no field of medicine are the principles of nuclear medicine better accepted than in cardiology. This should be the example for future directions that will let nuclear medicine become all that it was expected to be at the time of its founding after World War II.
Integration is the key to the future. For example, integration with radiology is no longer a negative factor in the growth and development of nuclear medicine, but because of the recognition of the value of PET, radiology and other medical specialties are increasing their interest in the field. Many years ago I said that the worse thing that could happen to nuclear medicine would be if cardiologists were not interested in it. Radiology is becoming more like nuclear medicine, as radiologists become more involved with patients and are not just "image interpreters" [Wagner H, written communication, May 1999].
In 1946, the Atomic Energy Commission was charged to develop peaceful uses of atomic energy. National laboratories were developed to explore the potential of nuclear sciences. Many of the early pioneers got their start through the Atomic Energy Commission. Fred Bonte, the former dean of Southwestern Medical School, is credited with developing blood pool scanning (17) (Figs 4, 5) and inventing infarct avid imaging (18). He reports,
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in 1948 I left the Army Air Corps to become a Fellow in the new Atomic Energy Commission Laboratory at Western Reserve, in Cleveland, where I learned to use radionuclides as tracers. In the years that have followed, the radioactive tracer method, devised by de Hevesy and his colleagues, has assumed a dominant role in medical research. As an example, almost 90% of the funded grant projects here at The University of Texas Southwestern Medical Center at Dallas use this vital modality to study the life processes in health and disease. The development of the radioactive tracer method is truly one of the great achievements of this century [Bonte FJ, written communication, May 1999].
Dave Kuhl, initially at the University of Pennsylvania, then UCLA, and now chief of Nuclear Medicine at the University of Michigan, has had an illustrious career. At Pennsylvania, he developed photoscanning (19), which replaced the dot printer we were all using before Kuhl's contribution. He then developed three-dimensional imaging, from which evolved SPECT, CT, and PET scanning (20). He succeeded George Taplin at UCLA and while there worked with Mike Phelps in developing PET scanning (21). The Nuclear Medicine Department at the University of Michigan, under the direction of Bill Beierwaltes, was one of the first departments to reach early distinction as a separate specialty. Beierwaltes trained many leaders in the field, including Jim Thrall, who is the current chief of Radiology at the Massachusetts General Hospital. Beierwaltes also wrote the textbook many of us used in the early days. This early compilation of what was known in textbooks went a long way to provoking cohesion and defining the field. Two other early nuclear medicine textbooks deserve special note. Henry Wagner and Bill Blahd independently edited comprehensive books on nuclear medicine that many of us used as the core textbooks in teaching the first nuclear medicine fellows.
Dave Kuhl was recently recognized by the Radiological Society of North America as a pioneer in the field of nuclear medicine for his "monumental contributions to both radiology and nuclear medicine [that] began while he was in medical school and continue today" (22, p 10). Dr Kuhl reports,
my research grant experience began as a first year radiology resident in 1958. I asked the physicist Dr John Hale for $5 to purchase Ping-Pong balls, which could serve as tumor models for phantom experiments of emission tomography. He balked and said I should ask the radiologist Dr Antolin Raventos for $20. Raventos balked and said I should apply to the school's American Cancer Society [ACS] Institutional Grant for "seed" money, but I should ask for $200. I applied for $2,000 and got it. The ACS committee chair, Dr. David Goddard, said such an award assumed I would seek external funding and he gave me an NIH RO1 grant application form. I completed this form, asking for $15,000 annually for three years. When told that Vice President Isadore Ravdin should sign the front sheet for the University, I naively cornered him in the dressing room of his operating suite, had him sign it, and mailed the forms directly to NIH, completely bypassing the proper University channels. The application was funded. The University grants personnel were appalled to have no record of the submission. Finally, the University accepted the award, but only after I promised never to bypass them again, and also to leave Dr. Ravdin alone. This NIH grant funded my early work with emission tomography. Its direct descendants have been funded continuously since then, a period of over 40 years. (I did buy the Ping-Pong balls. I still have some of them.)
In the months that followed, I worked out the scan strategies for transverse and longitudinal emission tomography, and drew up a scanner design (Mark II) which the shop director, Roy Edwards, felt confident he could build. The most important mode, cross-sectional or transverse section imaging required completely new backprojection apparatus which we finally got to work correctly on 21 August 1959, when Roy and I worked through the night to perform successfully the world's first transverse section emission tomography. The machine shop's Bridgeport Milling Machine served as our "scanner" and a radioactive plastic bottle in a water bath was our "patient."
Over the next 15 years, in the basement of Radiology, in the Hospital of the University of Pennsylvania, we invented a series of computerized emission tomographs and procedures that introduced cross-sectional reconstruction tomography to medicine and were the true forerunners of present day SPECT, PET and CT. I am fortunate to have been a part of this [Kuhl DE, written communication, June 1999].
George Taplin was a pulmonologist who in 1948 moved from Rochester University to Los Angeles with Stafford Warren when Warren became the first dean at the new UCLA School of Medicine. Taplin had been studying inhaled penicillin aerosols, as penicillin became available after the war. Warren had been studying radiation effects for the Atomic Energy Commission. Together, they were interested in inhaled radioactive materials, initially to study radiation effects and then as a diagnostic tool. Ben Cassen (23), an engineer who worked with Taplin and Bill Blahd, invented the first rectilinear scanner that could be used to map the anatomic location of a radionuclide in humans. Thus, the UCLA group had the first access to a usable nuclear medicine imaging device. They were instrumental in the early development of thyroid scanning, liver scanning, kidney scanning, and brain scanning. Taplin was responsible for perfusion lung scanning (Figs 6, 7).
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The use of perfusion lung scanning spread with remarkable speed. It answered an important clinical need for the early diagnosis of pulmonary embolism. To our knowledge, data from the first series of patients were published by Jim Quinn (who trained Doug Maynard at Bowman Gray) when Quinn moved to Northwestern. Wagner published the findings from his series shortly thereafter. Phil Alderson had taken his residency and fellowship with Jim Potchen at Washington University. It was there that Alderson began developing ventilation-scanning techniques. He refined these in a junior faculty position under Henry Wagner at Johns Hopkins. From there, Alderson was appointed to lead nuclear medicine at Columbia, where he is now the chair of the Radiology Department.
Alexander Gottschalk is primarily known today for the many years he spent refining our knowledge of the patterns of perfusion lung scans in patients with pulmonary embolic disease. Gottschalk was a research associate working with Hal Anger at the Donner Laboratory at the University of California, Berkeley, from 1962 to 1964. Anger had just developed a stationary imaging system, the Anger camera. Gottschalk reflects, "the first Anger Camera brain pictures Hal and I made were made pre-Technetium by Ga-68 using Hal's camera in positron mode" (Gottschalk AL, written communication, August 1999). This was important when deciding to build the first positron camera that led to PET scanning. Paul Harper at the University of Chicago took a lead from Powell "Jim" Richards at Brookhaven National Laboratory and developed 99mTc for clinical use. The characteristics of this radionuclide (140 keV) were ideally suited to the thinner crystal used in the Anger camera. When Gottschalk returned to the University of Chicago, he first applied the synergy of 99mTc and the gamma camera to clinical situations. The high photon flux of the shorter-lived 99mTc combined with the temporal resolution of a stationary imaging device to revolutionize the field of nuclear medicine. Most clinical nuclear medicine today revolves about the use of technetium initiated by Gottschalk.
The strength of nuclear medicine has in part derived from its diversity. In the most formative years, endocrinologists, hematologists, and surgeons were the dominant specialists involved in the clinical use of radionuclides. The multidisciplinary nature of the field soon involved radiologists, pathologists, cardiologists, general physicians, physiologists, radiochemists, radiopharmacologists, and engineers. All of these types of specialists have contributed to the advances that have been made over the years.
Perhaps this strength in diversity should be a lesson for those who currently advocate exclusivity, rather than inclusivity, in the evolution of diagnostic imaging. Generally speaking, the broader the range of backgrounds of the involved individuals, the better the collective decisions in the growth of a discipline. In seeking to apply diagnostic imaging in clinical medicine, it may be better to nurture diverse backgrounds than to fight turf battles at the intersections of career fields. Reflections on nuclear medicine have taught us that turf battles consume human resources by maintaining hostilities between disciplines while adding little value. If we want the future to reflect well on what we are doing today, perhaps we should focus our energies on how we can maximize our contribution to human welfare. Current concerns about disciplinary prerogatives can benefit from the management strategy of "co-opetition" (24). It is possible to develop a win-win strategy within and between medical specialties.
Acknowledgments
Personal written communications were provided by the following: S. James Adelstein, MD, PhD, Harvard Medical School, Boston, Mass; Frederick J. Bonte, MD, Nuclear Medicine Center, University of Texas Southwestern Medical Center, Dallas; Alexander L. Gottschalk, MD, Department of Radiology, Michigan State University, East Lansing; David E. Kuhl, MD, Division of Nuclear Medicine, University of Michigan Medical Center, Ann Arbor; John G. McAfee, MD, Consultant in Nuclear Medicine, Department of Health and Human Services and National Institutes of Health, Bethesda, Md; and Henry Wagner, MD, Divisions of Nuclear Medicine and Radiation Health Sciences, Johns Hopkins Medical Institutions, Baltimore, Md.
Footnotes
Abbreviations: NIH = National Institutes of Health UCLA = University of California, Los Angeles
References
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