CHAPTER
Medical physics - particle accelerators - the beginning
3
Abstract This chapter outlines the early development of particle accelerators with the redesign from linear accelerator to cyclotron by Ernest Lawrence with a view to reducing the size of the machines as the power increased. There are minibiographies of Ernest Lawrence and his brother John. The concept of artificial radiation is outlined and the early attempts at patient treatment are mentioned. The reasons for trying and abandoning neutron therapy are discussed, and the early use of protons is described.
Keywords particle accelerator, linear accelerator, cyclotron, radioisotopes, artificial radiation, neutron therapy, protons
1 THE AGE OF PARTICLE ACCELERATORS The events described above depended on radioactive events that occurred naturally from already radioactive substances. Further development in knowledge of atoms would be facilitated by machines that could split atoms into subatomic components, thus gaining knowledge of their structure. The earliest such machine was designed in Cambridge in the 1920s and is known as the Cockroft–Walton accelerator after the inventors (Cockroft and Walton, 1932). They generated a potential of 800 kV and used it to accelerate protons directed at a lithium target, which disintegrated the lithium nuclei into two alpha particles. What Cockroft and Walton had designed was a linear particle accelerator. Its descendants were to stimulate the active curiosity of a brilliant scientist to use a different way of accelerating particles (Parker).
2 THE ADVENT OF THE CYCLOTRON This is a story in which Scandinavians will play a central role. The year is 1930. Far from northern Europe in distant California, a strange-looking contraption has been made. The contraption was the first cyclotron. It was made from bronze and sealing Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00003-X © 2014 Elsevier B.V. All rights reserved.
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wax and was 4 in. in diameter but could accelerate hydrogen ions to 80,000 V. It costs $25 to make (Parker A). It will evolve into machines that will produce profound changes to a world, which is largely unaware of its existence. The man who made this first cyclotron was Ernest Lawrence, a 27-year-old American physicist (Fig. 1). In 1929, he read an article in German (Widerøe, 1928) by the Norwegian physicist Rolf Widerøe (1902–1996) who was much involved in the design of early linear particle accelerators. (It is rumored that Lawrence read the article to stave off boredom at a meeting.) He had a limited grasp of German so he could not read the article easily. However, he was fascinated by a diagram, which made him think that increasing the power of linear particle accelerators would eventually make them too large for convenient use in a university environment. Increasing the power of accelerators was necessary to gain a wider choice of beam energies to expand the range of experiments and the knowledge thus acquired. Motivated by this notion, a year later, he had built the contraption mentioned above and shown in Fig. 2. By bending a beam of particles around a spiral, it became unnecessary to increase the size of a particle accelerator so much as to make it unmanageable. The resulting machine was called a cyclotron. It was first produced in 1930 and he received his Nobel Prize for the invention in 1939. Lawrence’s main area of interest was the use of a particle accelerator that could fire small particles at other atoms producing changes that could help expand the knowledge of atomic structure. He was intimately involved in the Manhattan Project to
FIGURE 1 Ernest Lawrence.
2 The advent of the cyclotron
FIGURE 2 This strange-looking object is the very first cyclotron.
build the first atom bomb, and in due course, he became the person to devise an effective way of separating uranium-235 from uranium-238 (Amaldi, 2008). Lawrence went on to use cyclotrons of ever-increasing size. The first had a 27-in. magnet and the final one a 184-in. magnet. Clearly, this activity required financial support which Lawrence was expert at obtaining (Anon. The Rad Lab). The support was spread through private and public funding organizations. Lawrence encouraged the application of accelerators to clinical use as he realized it was easier to get funding for medicine rather than physics. One private individual who allocated funds to the Berkeley cyclotron was the industrialist William H. Donner (1864–1953). He established the International Cancer Research Foundation in 1932 in honor of his son who died from cancer. This institution gave grants to Berkeley establishing the Donner Radiation Laboratory under the direction of Ernest Lawrence’s brother John Lawrence, producing the seeds of what would become nuclear medicine. Loss of a loved one would seem to be a well-established motivation for the allocation of funds for medical purposes. Later on, the Rockefeller Foundation was approached for support for the building of the 184-in. cyclotron. There is a report from the foundation indicating how opinions fluctuated between those applying for a grant and those in a position to grant it. The document is a clear record of the importance of human interaction because the grant was finally accepted on the basis of the conviction of certain of the applicants and the personal relationships within the
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Rockefeller Foundation. Informal meetings were of vital importance in gaining acceptance for the project (Hinokawa). After the war, the budget and administration of the cyclotron laboratory were discussed forward and backward and ended up under political supervision via the establishment by Congress of the Atomic Energy Commission. This indicates an unusual willingness to allocate public funds for the purpose of scientific research. Since the running of the laboratory remained in the hands of the scientists, this was truly political generosity towards the uncertainties of research on an unparalleled scale (Anon. Cold War Science; Anon. Lawrence in the cold war). Since the above paragraphs emphasize how the course of human endeavor including science is shaped by the talents and personalities of individuals, short biographical notes are included.
3 ERNEST ORLANDO LAWRENCE (1901–1958): AN OUTLINE Ernest Orlando Lawrence (Fig. 1) was born in Canton, South Dakota, on August 8, 1901, to Gustavus and Gunda Lawrence, both were the children of Norwegian immigrants and both were teachers. Gustavus was also an inspector of schools. Gustavus’ father Ole Hundale Lawrence was a school teacher who came from Telemark, the home of Norwegian skiing. Gudrun’s father came from Lom in Oppland County, in the Central Massif in Norway, between Oslo and Trondheim. Forty-eight percent of all mountains in Norway more than 2000 m high are in Lom commune. His name was Erik Jacobsen and he was a farmer in both Norway and the United States. Thus, the Scandinavian connection was still very close. Lawrence underwent a conventional education locally. According to his mother, he was “born grown up.” She also described him thus: “Ernest was always of a happy disposition and life to him seemed to be one thrill after another, but he was also always persistent and insistent!” His best friend growing up was Merle Tuve, who would also go on to become a highly accomplished nuclear physicist. The two boys constructed a very early short-wave radio transmitting station. Lawrence would later apply his short-wave radio experiences to the acceleration of protons (Amaldi, 2008). In 1922, he started as a medical student at the University of Minnesota but switched to physics and acquired a master’s degree in that subject in 1923. He followed his mentor William Swann from Minnesota to Chicago and then to Yale. There, he acquired a PhD on the photoelectric effect in 1925. In 1928, he moved to the University of California (Berkeley) and 2 years later became the university’s youngest full professor. He stayed there with wartime intermissions for the rest of his life. He married once in 1932 his wife Molly and he had 6 children. He was unusually well respected by his team of associates. One of whom, Luis Alvarez, himself a Nobel Prize winner wrote “For those who had the good fortune to be close to him both personally and scientifically he will always seem a giant among men.” Nonetheless, he suffered from ulcerative colitis that finally killed him and the rigidly
4 John Hundale Lawrence (1903–1991): an outline
systematic, serious workaholic personality he exhibited was in keeping with that illness. He sacked twice one of his associates for less than optimal routines but then allowed him back into the fold. This was Robert R. Wilson of whom more later. He was also rigidly correct with regard to financial rewards arising out of his inventions. He patented the cyclotron but never asked for royalties (Hinokawa). He invented the calutron isotope separator for separating uranium-235 from uranium-238 for the manufacture of atom bombs. He assigned the patent rights to the US government for one dollar (Kovarick and Neuzil). Thus, while he would seem to have been something of a martinet, he generated much respect and affection. Part of this paradox may be the result of his being intellectually generous and always willing to argue and accept that he might be in error. He was an unusual, complex, but exceedingly talented person.
4 JOHN HUNDALE LAWRENCE (1903–1991): AN OUTLINE Although Ernest Lawrence was the more famous, his younger brother John Hundale Lawrence (Fig. 3) is of more relevance to the matters under advisement here. He was born on 7 January 1904, just 2½ years younger than his elder brother. He recounts how he lived in a secure home where discipline was by example. His father Gustavus was a gifted classicist and, while religious, was not fanatical. A drink was permitted on occasion. His father was also mindful of the politics of the day. His mother was a
FIGURE 3 John Lawrence.
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mathematician and was the motivator for John and Lawrence to succeed in life. However, neither parent helped with homework. Another influence in his young life was the family doctor who was instrumental in getting him interested in medicine, and he maintained that his interest in a career in medicine arose during childhood and never left him. He tells that his first 2 years at the university was not successful, involving basketball and a girlfriend. Thereafter, he buckled down and set his sights on Harvard Medical School, which was considered the best. This was a fateful decision because there he met of all people Harvey Cushing. Cushing was the world’s leading neurosurgeon having virtually founded the specialty (Fig. 4). His prestige was based on drive, intellect, and a formidable surgical technique. In any medical activity during his lifetime, his support would have been of considerable value. Cushing showed a personal interest in John Lawrence. In his fourth year as a student, Cushing persuaded him to do an internship in his laboratory. When he asked Cushing what he was to do about his MD qualification, Cushing told him “I’ll take care of that.” So he did not finish his fourth year but he got his MD. He wrote a couple of papers with Cushing, and when the internship was over, he told Cushing he was quite sure he did not want to do surgery. Cushing arranged a medical residency at the University of Rochester without Lawrence having to endure a medical internship. After a year,
FIGURE 4 Harvey Cushing, the father of modern neurosurgery.
6 First cyclotron-related patient treatment
Lawrence found Rochester rather provincial so he moved to Yale. Cushing retired from Harvard at the age of 65 and came to Yale as professor of the history of medicine but still had patients including patients with Cushing’s disease. Lawrence became deeply involved in their management, thus stimulating an interest in endocrinology. At that time, Cushing’s disease was treated with radiation. Later, when John Lawrence was a senior medical resident, the closeness of his personal relationship with Cushing was shown by his being allocated to care for the old man when he was a patient in the hospital, a most unusual arrangement. Around this time, Cushing met Ernest Lawrence and under discussions stated of artificial radiation “This is going to be as important, if not more important, as Pasteur and bacteriology.” Cushing was close enough to Ernest Lawrence to help him prepare his first commencement address. Cushing advised John Lawrence to become involved with radiation in Berkeley and was instrumental in persuading him to move to California. He quotes Cushing as saying “You are pioneering in a very exciting new field, which will have a tremendous impact in medicine. Go to it” (Hughes, 1979–1980).
5 ARTIFICIAL RADIATION In the early 1930s, there was much anxiety related to radiation because the “radium girls” case had been settled only a few years earlier in 1928 (Shank). This was the case that ended with considerable compensation to women who had painted radium onto the dials of watches and suffered various forms of radiotoxicity as a result. The right of individual employees to sue an employer for labor abuse was established by this case. John Lawrence started using the cyclotron to make radioactive isotopes by firing a particles at substances. This was a continuation of the methodology in use prior to the invention of accelerators, when a particles produced by spontaneous radioactive breakdown were the only heavy particles available. With the isotopes, he was using artificial radiation. He was insistent that while a particles were used to produce the isotopes, these were not themselves a emitters. Since there was no substance involved that could be permanently deposited in bone or other tissues, there was no risk. He also mentioned later that over 20 years, he saw no such delayed complications.
6 FIRST CYCLOTRON-RELATED PATIENT TREATMENT The first clinical application of the cyclotron was treatment with radioactive isotopes. The first patient treated with a radioisotope had chronic lymphatic leukemia and on Christmas Eve 1936 received phosphorus-32. The patient was still alive in 1979 at the age of 74 and Lawrence was immensely proud of this success (Ouellette). The use of the cyclotron in nuclear medicine in the first few years
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was limited to the production of isotopes. These were used in physiological studies, diagnostic studies, and, as indicated above, medical therapy. Lawrence published a monograph on this topic in 1950 having delivered the material in 1949 as a lecture to the New York Academy of Medicine (Lawrence, 1950).
7 PRINCIPLES OF EARLY MEDICAL APPLICATIONS OF THE CYCLOTRON: NEUTRONS However, while the cyclotron could make isotopes, it could also make high-energy radiation beams. Nonetheless, it took a while for these beams to be used in therapy. At the time, radiotherapy was fairly primitive. One radiation beam technique that was in current use, as mentioned above, was the management of Cushing’s disease with X-rays: that is, with photons. Cushing did not operate upon these patients (Hughes, 1979–1980). It should be remembered that there were no clinical X-ray LINACs in the mid- to late 1930s, but there were X-ray generators with a low beam energy by modern standards, being somewhere between 150 and 200 keV up to 2 MeV, compared with the 10 MeV used today. Neutrons are transiently important in this account as they were the first particles to be used for therapy. This followed some experiments on mice with tumors in the 1930s. Using whole-body neutron radiation, it was shown that cancer cells were killed at a lower dose than that that killed the mice. This is the reverse of what would be expected, since the tumor cells are hypoxic and would be expected to be radioresistant. However, nobody was aware at that time that for densely ionizing radiations like neutrons, oxygenation has either no or a much reduced effect on radiosensitivity. Indeed, there was not yet general awareness of the oxygen effect. While it had been recorded in the German literature from the early 1920s, it did not permeate to the English language literature until a decade or so later (Hall and Giaccia, 2012). The neutron therapy was managed by a colleague of John Lawrence, a distinguished radiotherapist called Robert Stone. The therapy was carried out for a while but it had a high complication rate. Then, the war came and the treatments were stopped. In retrospect, it was considered that the dose had been far too high, based on ignorance of the associated phenomena at the time (Asimov, 1991; Hughes, 1979–1980). The relative biological effect of neutrons was notably higher than that of photons, which was positive. However, there were many problems with neutron therapy since the particles cannot be directed and collimated like charged particles and spread in every direction. Thus, a differential dose between tumor and tissue based on selective geometry would be nigh on impossible to achieve, and therapeutic success would be based on differential radiosensitivity between the tissues and the tumor. After the war in 1948, in a Janeway lecture, Dr. Stone recommended that neutron therapy should be discontinued and not restarted (Hughes, 1979–1980).
8 Principles of early medical applications of the cyclotron: protons
8 PRINCIPLES OF EARLY MEDICAL APPLICATIONS OF THE CYCLOTRON: PROTONS In 1946, 2 years before Stone’s Janeway lecture, a different approach had been suggested by Robert Wilson (1914–2000). In 1946, he published a paper on the advantages of using high-energy (fast) protons as a radiation therapy tool (Wilson, 1946). He used the phrase narrow beams in his paper, maybe for the first time. He also described the very important way in which a proton beam continued without spreading until it reached the end of its path (Ouellette). Robert Wilson was a high profile figure who had a difficult time at the Berkeley Laboratory. He was twice sacked by Ernest Lawrence for errors arising from a cavalier attitude (Weart). He twice returned. He was a genuine horse riding cowboy. It is reasonable to assume his very American rather physical attitude to life was at odds with the introspective, obsessional martinet that Lawrence was. However, he also wrote that Lawrence had a big heart. After working in Berkeley, he was chosen to head up the new Fermilab to which he contributed sculptures. When being considered for the appointment, he said he wanted to do research not administration, and when Fermi tried to persuade him otherwise, he responded that Fermi would not have accepted the job and he was following in the master’s footsteps. Fermi replied “It’s something you have to earn, and you’re not Fermi yet.” During a senate hearing where there was an attempt to reduce government spending on large physics facilities, he was asked if a cyclotron had any value with respect to the security of the country. He replied no. The senator asked him “It has no value in this respect?” to which he replied “It has only to do with the respect with which we regard one another, the dignity of man, our love of culture. It has to do with: Are we good painters, good sculptors, great poets? I mean all the things we really venerate in our country and are patriotic about. It has nothing to do directly with defending our country except to make it worth defending” (Lawrence, 1950). A talented, articulate but opinionated man! Wilson was interested in a special property of particle beams, which differs from photon beams. Photon beams have no actual mass and move at the speed of light never slowing down, though they can disappear on absorption. Particle radiation consists of particles with mass. Thus, they can and do slow down. With charged particles, the beam traverses the tissue with relatively little transmission of energy to the tissues (a low linear energy transfer), but at a given distance depending on the speed and nature of the particle, they decelerate over a limited very clearly defined region, depositing most of their contained energy. This phenomenon is called the Bragg peak after its discoverers William Henry Bragg (1862–1942) and his son William Lawrence Bragg (1880–1971) (Figs. 5 and 6). Wilson’s work stimulated the Berkeley team to use protons to treat diseases within the head but not initially in the way he suggested. How the beams were used is considered in the next chapter.
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FIGURE 5 William Henry Bragg (father) and William Lawrence Bragg (son). The only father and son to win the same Nobel Prize.
FIGURE 6 Robert Wilson, physicist, cowboy, and sculptor. Suggested the Bragg Peak could be used for therapy.
References
REFERENCES Amaldi, U., Amaldi, U., 2008. History of hadrontherapy in the world and Italian developments. Riv. Med. 14 (1), 7–22. Anon. Cold War Science. AIP Center for History of Physics. Retrieved http://www.aip.org/ history/lawrence/cws.htm. Anon. Lawrence in the cold war. AIP Center for History of Physics. Retrieved from http:// www.aip.org/history/lawrence/lcw.htm. Anon. The Rad Lab. AIP Center for History of Physics. Retrieved from https://www.aip.org/ history/lawrence/radlab.htm. Asimov, I., 1991. Atom: Journey Across the Subatomic Cosmos. Truman Talley Books, New York. Cockroft, J.D., Walton, E.T.S., Cockroft, J.D., Walton, E.T.S., 1932. Artificial production of fast protons. Nature 129, 242. Hall, E.J., Giaccia, A.J., 2012. Chapter 6 ‘Oxygen Effect and Reoxygenation’ in Radiobiology for the Radiologist. Lippincott Williams & Wilkins, New York, pp. 86–103. Hinokawa, S. The Rockefeller Foundation’s decision-making process in funding the 184-inch cyclotron (translated Sugihara B). Retrieved from http://www.rockarch.org/publications/ resrep/hinokawa.pdf. Hughes, S.S., 1979–1980. John H. Lawrence: an interview. The Bancroft Library, University of California, Berkeley. Kovarick, W., Neuzil, M. Environment history timeline: radium girls. Retrieved from http:// 66.147.244.135/enviror4/people/radiumgirls. Lawrence, J.H., 1950. The clinical use of radioactive isotopes. Bull. N. Y. Acad. Med. 26 (10), 639–669. Ouellette, J. Cocktail Party Physics: Robert Wilson, the gun-toting physicist who helped give us the particle accelerator. Retrieved from http://io9.com/5843998/robert-wilsonthe-gun+toting-physicist-who-helped-give-us-the-particle-accelerator. Parker, A. Remembering E.O. Lawrence. Science and technology review. Retrieved from https://www.llnl.gov/str/October01/Lawrence.html. Shank, C.V. Ernest Orlando Lawrence. The Man, his lab, his legacy. Retrieved from http:// www.lbl.gov/Science-Articles/Archive/lawrence-legacy.html. Weart, S. Oral history transcript—Dr. Robert R. Wilson. Niels Bohr Library & Archives. Retrieved from http://www.aip.org/history/ohilist/4972.html. ¨ ber Ein Neues Prinzip Zur Herstellung Hoher Spannungen” Arch. Widerøe, R., 1928. U ¨ bertrag. 21 (4), 387–405. Elektron. U Wilson, R.R., 1946. Radiological use of fast protons. Radiology 47 (5), 487–491.
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Medical physics - particle accelerators - the beginning
3
Abstract This chapter outlines the early development of particle accelerators with the redesign from linear accelerator to cyclotron by Ernest Lawrence with a view to reducing the size of the machines as the power increased. There are minibiographies of Ernest Lawrence and his brother John. The concept of artificial radiation is outlined and the early attempts at patient treatment are mentioned. The reasons for trying and abandoning neutron therapy are discussed, and the early use of protons is described.
Keywords particle accelerator, linear accelerator, cyclotron, radioisotopes, artificial radiation, neutron therapy, protons
1 THE AGE OF PARTICLE ACCELERATORS The events described above depended on radioactive events that occurred naturally from already radioactive substances. Further development in knowledge of atoms would be facilitated by machines that could split atoms into subatomic components, thus gaining knowledge of their structure. The earliest such machine was designed in Cambridge in the 1920s and is known as the Cockroft–Walton accelerator after the inventors (Cockroft and Walton, 1932). They generated a potential of 800 kV and used it to accelerate protons directed at a lithium target, which disintegrated the lithium nuclei into two alpha particles. What Cockroft and Walton had designed was a linear particle accelerator. Its descendants were to stimulate the active curiosity of a brilliant scientist to use a different way of accelerating particles (Parker).
2 THE ADVENT OF THE CYCLOTRON This is a story in which Scandinavians will play a central role. The year is 1930. Far from northern Europe in distant California, a strange-looking contraption has been made. The contraption was the first cyclotron. It was made from bronze and sealing Progress in Brain Research, Volume 215, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63520-4.00003-X © 2014 Elsevier B.V. All rights reserved.
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wax and was 4 in. in diameter but could accelerate hydrogen ions to 80,000 V. It costs $25 to make (Parker A). It will evolve into machines that will produce profound changes to a world, which is largely unaware of its existence. The man who made this first cyclotron was Ernest Lawrence, a 27-year-old American physicist (Fig. 1). In 1929, he read an article in German (Widerøe, 1928) by the Norwegian physicist Rolf Widerøe (1902–1996) who was much involved in the design of early linear particle accelerators. (It is rumored that Lawrence read the article to stave off boredom at a meeting.) He had a limited grasp of German so he could not read the article easily. However, he was fascinated by a diagram, which made him think that increasing the power of linear particle accelerators would eventually make them too large for convenient use in a university environment. Increasing the power of accelerators was necessary to gain a wider choice of beam energies to expand the range of experiments and the knowledge thus acquired. Motivated by this notion, a year later, he had built the contraption mentioned above and shown in Fig. 2. By bending a beam of particles around a spiral, it became unnecessary to increase the size of a particle accelerator so much as to make it unmanageable. The resulting machine was called a cyclotron. It was first produced in 1930 and he received his Nobel Prize for the invention in 1939. Lawrence’s main area of interest was the use of a particle accelerator that could fire small particles at other atoms producing changes that could help expand the knowledge of atomic structure. He was intimately involved in the Manhattan Project to
FIGURE 1 Ernest Lawrence.
2 The advent of the cyclotron
FIGURE 2 This strange-looking object is the very first cyclotron.
build the first atom bomb, and in due course, he became the person to devise an effective way of separating uranium-235 from uranium-238 (Amaldi, 2008). Lawrence went on to use cyclotrons of ever-increasing size. The first had a 27-in. magnet and the final one a 184-in. magnet. Clearly, this activity required financial support which Lawrence was expert at obtaining (Anon. The Rad Lab). The support was spread through private and public funding organizations. Lawrence encouraged the application of accelerators to clinical use as he realized it was easier to get funding for medicine rather than physics. One private individual who allocated funds to the Berkeley cyclotron was the industrialist William H. Donner (1864–1953). He established the International Cancer Research Foundation in 1932 in honor of his son who died from cancer. This institution gave grants to Berkeley establishing the Donner Radiation Laboratory under the direction of Ernest Lawrence’s brother John Lawrence, producing the seeds of what would become nuclear medicine. Loss of a loved one would seem to be a well-established motivation for the allocation of funds for medical purposes. Later on, the Rockefeller Foundation was approached for support for the building of the 184-in. cyclotron. There is a report from the foundation indicating how opinions fluctuated between those applying for a grant and those in a position to grant it. The document is a clear record of the importance of human interaction because the grant was finally accepted on the basis of the conviction of certain of the applicants and the personal relationships within the
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Rockefeller Foundation. Informal meetings were of vital importance in gaining acceptance for the project (Hinokawa). After the war, the budget and administration of the cyclotron laboratory were discussed forward and backward and ended up under political supervision via the establishment by Congress of the Atomic Energy Commission. This indicates an unusual willingness to allocate public funds for the purpose of scientific research. Since the running of the laboratory remained in the hands of the scientists, this was truly political generosity towards the uncertainties of research on an unparalleled scale (Anon. Cold War Science; Anon. Lawrence in the cold war). Since the above paragraphs emphasize how the course of human endeavor including science is shaped by the talents and personalities of individuals, short biographical notes are included.
3 ERNEST ORLANDO LAWRENCE (1901–1958): AN OUTLINE Ernest Orlando Lawrence (Fig. 1) was born in Canton, South Dakota, on August 8, 1901, to Gustavus and Gunda Lawrence, both were the children of Norwegian immigrants and both were teachers. Gustavus was also an inspector of schools. Gustavus’ father Ole Hundale Lawrence was a school teacher who came from Telemark, the home of Norwegian skiing. Gudrun’s father came from Lom in Oppland County, in the Central Massif in Norway, between Oslo and Trondheim. Forty-eight percent of all mountains in Norway more than 2000 m high are in Lom commune. His name was Erik Jacobsen and he was a farmer in both Norway and the United States. Thus, the Scandinavian connection was still very close. Lawrence underwent a conventional education locally. According to his mother, he was “born grown up.” She also described him thus: “Ernest was always of a happy disposition and life to him seemed to be one thrill after another, but he was also always persistent and insistent!” His best friend growing up was Merle Tuve, who would also go on to become a highly accomplished nuclear physicist. The two boys constructed a very early short-wave radio transmitting station. Lawrence would later apply his short-wave radio experiences to the acceleration of protons (Amaldi, 2008). In 1922, he started as a medical student at the University of Minnesota but switched to physics and acquired a master’s degree in that subject in 1923. He followed his mentor William Swann from Minnesota to Chicago and then to Yale. There, he acquired a PhD on the photoelectric effect in 1925. In 1928, he moved to the University of California (Berkeley) and 2 years later became the university’s youngest full professor. He stayed there with wartime intermissions for the rest of his life. He married once in 1932 his wife Molly and he had 6 children. He was unusually well respected by his team of associates. One of whom, Luis Alvarez, himself a Nobel Prize winner wrote “For those who had the good fortune to be close to him both personally and scientifically he will always seem a giant among men.” Nonetheless, he suffered from ulcerative colitis that finally killed him and the rigidly
4 John Hundale Lawrence (1903–1991): an outline
systematic, serious workaholic personality he exhibited was in keeping with that illness. He sacked twice one of his associates for less than optimal routines but then allowed him back into the fold. This was Robert R. Wilson of whom more later. He was also rigidly correct with regard to financial rewards arising out of his inventions. He patented the cyclotron but never asked for royalties (Hinokawa). He invented the calutron isotope separator for separating uranium-235 from uranium-238 for the manufacture of atom bombs. He assigned the patent rights to the US government for one dollar (Kovarick and Neuzil). Thus, while he would seem to have been something of a martinet, he generated much respect and affection. Part of this paradox may be the result of his being intellectually generous and always willing to argue and accept that he might be in error. He was an unusual, complex, but exceedingly talented person.
4 JOHN HUNDALE LAWRENCE (1903–1991): AN OUTLINE Although Ernest Lawrence was the more famous, his younger brother John Hundale Lawrence (Fig. 3) is of more relevance to the matters under advisement here. He was born on 7 January 1904, just 2½ years younger than his elder brother. He recounts how he lived in a secure home where discipline was by example. His father Gustavus was a gifted classicist and, while religious, was not fanatical. A drink was permitted on occasion. His father was also mindful of the politics of the day. His mother was a
FIGURE 3 John Lawrence.
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mathematician and was the motivator for John and Lawrence to succeed in life. However, neither parent helped with homework. Another influence in his young life was the family doctor who was instrumental in getting him interested in medicine, and he maintained that his interest in a career in medicine arose during childhood and never left him. He tells that his first 2 years at the university was not successful, involving basketball and a girlfriend. Thereafter, he buckled down and set his sights on Harvard Medical School, which was considered the best. This was a fateful decision because there he met of all people Harvey Cushing. Cushing was the world’s leading neurosurgeon having virtually founded the specialty (Fig. 4). His prestige was based on drive, intellect, and a formidable surgical technique. In any medical activity during his lifetime, his support would have been of considerable value. Cushing showed a personal interest in John Lawrence. In his fourth year as a student, Cushing persuaded him to do an internship in his laboratory. When he asked Cushing what he was to do about his MD qualification, Cushing told him “I’ll take care of that.” So he did not finish his fourth year but he got his MD. He wrote a couple of papers with Cushing, and when the internship was over, he told Cushing he was quite sure he did not want to do surgery. Cushing arranged a medical residency at the University of Rochester without Lawrence having to endure a medical internship. After a year,
FIGURE 4 Harvey Cushing, the father of modern neurosurgery.
6 First cyclotron-related patient treatment
Lawrence found Rochester rather provincial so he moved to Yale. Cushing retired from Harvard at the age of 65 and came to Yale as professor of the history of medicine but still had patients including patients with Cushing’s disease. Lawrence became deeply involved in their management, thus stimulating an interest in endocrinology. At that time, Cushing’s disease was treated with radiation. Later, when John Lawrence was a senior medical resident, the closeness of his personal relationship with Cushing was shown by his being allocated to care for the old man when he was a patient in the hospital, a most unusual arrangement. Around this time, Cushing met Ernest Lawrence and under discussions stated of artificial radiation “This is going to be as important, if not more important, as Pasteur and bacteriology.” Cushing was close enough to Ernest Lawrence to help him prepare his first commencement address. Cushing advised John Lawrence to become involved with radiation in Berkeley and was instrumental in persuading him to move to California. He quotes Cushing as saying “You are pioneering in a very exciting new field, which will have a tremendous impact in medicine. Go to it” (Hughes, 1979–1980).
5 ARTIFICIAL RADIATION In the early 1930s, there was much anxiety related to radiation because the “radium girls” case had been settled only a few years earlier in 1928 (Shank). This was the case that ended with considerable compensation to women who had painted radium onto the dials of watches and suffered various forms of radiotoxicity as a result. The right of individual employees to sue an employer for labor abuse was established by this case. John Lawrence started using the cyclotron to make radioactive isotopes by firing a particles at substances. This was a continuation of the methodology in use prior to the invention of accelerators, when a particles produced by spontaneous radioactive breakdown were the only heavy particles available. With the isotopes, he was using artificial radiation. He was insistent that while a particles were used to produce the isotopes, these were not themselves a emitters. Since there was no substance involved that could be permanently deposited in bone or other tissues, there was no risk. He also mentioned later that over 20 years, he saw no such delayed complications.
6 FIRST CYCLOTRON-RELATED PATIENT TREATMENT The first clinical application of the cyclotron was treatment with radioactive isotopes. The first patient treated with a radioisotope had chronic lymphatic leukemia and on Christmas Eve 1936 received phosphorus-32. The patient was still alive in 1979 at the age of 74 and Lawrence was immensely proud of this success (Ouellette). The use of the cyclotron in nuclear medicine in the first few years
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was limited to the production of isotopes. These were used in physiological studies, diagnostic studies, and, as indicated above, medical therapy. Lawrence published a monograph on this topic in 1950 having delivered the material in 1949 as a lecture to the New York Academy of Medicine (Lawrence, 1950).
7 PRINCIPLES OF EARLY MEDICAL APPLICATIONS OF THE CYCLOTRON: NEUTRONS However, while the cyclotron could make isotopes, it could also make high-energy radiation beams. Nonetheless, it took a while for these beams to be used in therapy. At the time, radiotherapy was fairly primitive. One radiation beam technique that was in current use, as mentioned above, was the management of Cushing’s disease with X-rays: that is, with photons. Cushing did not operate upon these patients (Hughes, 1979–1980). It should be remembered that there were no clinical X-ray LINACs in the mid- to late 1930s, but there were X-ray generators with a low beam energy by modern standards, being somewhere between 150 and 200 keV up to 2 MeV, compared with the 10 MeV used today. Neutrons are transiently important in this account as they were the first particles to be used for therapy. This followed some experiments on mice with tumors in the 1930s. Using whole-body neutron radiation, it was shown that cancer cells were killed at a lower dose than that that killed the mice. This is the reverse of what would be expected, since the tumor cells are hypoxic and would be expected to be radioresistant. However, nobody was aware at that time that for densely ionizing radiations like neutrons, oxygenation has either no or a much reduced effect on radiosensitivity. Indeed, there was not yet general awareness of the oxygen effect. While it had been recorded in the German literature from the early 1920s, it did not permeate to the English language literature until a decade or so later (Hall and Giaccia, 2012). The neutron therapy was managed by a colleague of John Lawrence, a distinguished radiotherapist called Robert Stone. The therapy was carried out for a while but it had a high complication rate. Then, the war came and the treatments were stopped. In retrospect, it was considered that the dose had been far too high, based on ignorance of the associated phenomena at the time (Asimov, 1991; Hughes, 1979–1980). The relative biological effect of neutrons was notably higher than that of photons, which was positive. However, there were many problems with neutron therapy since the particles cannot be directed and collimated like charged particles and spread in every direction. Thus, a differential dose between tumor and tissue based on selective geometry would be nigh on impossible to achieve, and therapeutic success would be based on differential radiosensitivity between the tissues and the tumor. After the war in 1948, in a Janeway lecture, Dr. Stone recommended that neutron therapy should be discontinued and not restarted (Hughes, 1979–1980).
8 Principles of early medical applications of the cyclotron: protons
8 PRINCIPLES OF EARLY MEDICAL APPLICATIONS OF THE CYCLOTRON: PROTONS In 1946, 2 years before Stone’s Janeway lecture, a different approach had been suggested by Robert Wilson (1914–2000). In 1946, he published a paper on the advantages of using high-energy (fast) protons as a radiation therapy tool (Wilson, 1946). He used the phrase narrow beams in his paper, maybe for the first time. He also described the very important way in which a proton beam continued without spreading until it reached the end of its path (Ouellette). Robert Wilson was a high profile figure who had a difficult time at the Berkeley Laboratory. He was twice sacked by Ernest Lawrence for errors arising from a cavalier attitude (Weart). He twice returned. He was a genuine horse riding cowboy. It is reasonable to assume his very American rather physical attitude to life was at odds with the introspective, obsessional martinet that Lawrence was. However, he also wrote that Lawrence had a big heart. After working in Berkeley, he was chosen to head up the new Fermilab to which he contributed sculptures. When being considered for the appointment, he said he wanted to do research not administration, and when Fermi tried to persuade him otherwise, he responded that Fermi would not have accepted the job and he was following in the master’s footsteps. Fermi replied “It’s something you have to earn, and you’re not Fermi yet.” During a senate hearing where there was an attempt to reduce government spending on large physics facilities, he was asked if a cyclotron had any value with respect to the security of the country. He replied no. The senator asked him “It has no value in this respect?” to which he replied “It has only to do with the respect with which we regard one another, the dignity of man, our love of culture. It has to do with: Are we good painters, good sculptors, great poets? I mean all the things we really venerate in our country and are patriotic about. It has nothing to do directly with defending our country except to make it worth defending” (Lawrence, 1950). A talented, articulate but opinionated man! Wilson was interested in a special property of particle beams, which differs from photon beams. Photon beams have no actual mass and move at the speed of light never slowing down, though they can disappear on absorption. Particle radiation consists of particles with mass. Thus, they can and do slow down. With charged particles, the beam traverses the tissue with relatively little transmission of energy to the tissues (a low linear energy transfer), but at a given distance depending on the speed and nature of the particle, they decelerate over a limited very clearly defined region, depositing most of their contained energy. This phenomenon is called the Bragg peak after its discoverers William Henry Bragg (1862–1942) and his son William Lawrence Bragg (1880–1971) (Figs. 5 and 6). Wilson’s work stimulated the Berkeley team to use protons to treat diseases within the head but not initially in the way he suggested. How the beams were used is considered in the next chapter.
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FIGURE 5 William Henry Bragg (father) and William Lawrence Bragg (son). The only father and son to win the same Nobel Prize.
FIGURE 6 Robert Wilson, physicist, cowboy, and sculptor. Suggested the Bragg Peak could be used for therapy.
References
REFERENCES Amaldi, U., Amaldi, U., 2008. History of hadrontherapy in the world and Italian developments. Riv. Med. 14 (1), 7–22. Anon. Cold War Science. AIP Center for History of Physics. Retrieved http://www.aip.org/ history/lawrence/cws.htm. Anon. Lawrence in the cold war. AIP Center for History of Physics. Retrieved from http:// www.aip.org/history/lawrence/lcw.htm. Anon. The Rad Lab. AIP Center for History of Physics. Retrieved from https://www.aip.org/ history/lawrence/radlab.htm. Asimov, I., 1991. Atom: Journey Across the Subatomic Cosmos. Truman Talley Books, New York. Cockroft, J.D., Walton, E.T.S., Cockroft, J.D., Walton, E.T.S., 1932. Artificial production of fast protons. Nature 129, 242. Hall, E.J., Giaccia, A.J., 2012. Chapter 6 ‘Oxygen Effect and Reoxygenation’ in Radiobiology for the Radiologist. Lippincott Williams & Wilkins, New York, pp. 86–103. Hinokawa, S. The Rockefeller Foundation’s decision-making process in funding the 184-inch cyclotron (translated Sugihara B). Retrieved from http://www.rockarch.org/publications/ resrep/hinokawa.pdf. Hughes, S.S., 1979–1980. John H. Lawrence: an interview. The Bancroft Library, University of California, Berkeley. Kovarick, W., Neuzil, M. Environment history timeline: radium girls. Retrieved from http:// 66.147.244.135/enviror4/people/radiumgirls. Lawrence, J.H., 1950. The clinical use of radioactive isotopes. Bull. N. Y. Acad. Med. 26 (10), 639–669. Ouellette, J. Cocktail Party Physics: Robert Wilson, the gun-toting physicist who helped give us the particle accelerator. Retrieved from http://io9.com/5843998/robert-wilsonthe-gun+toting-physicist-who-helped-give-us-the-particle-accelerator. Parker, A. Remembering E.O. Lawrence. Science and technology review. Retrieved from https://www.llnl.gov/str/October01/Lawrence.html. Shank, C.V. Ernest Orlando Lawrence. The Man, his lab, his legacy. Retrieved from http:// www.lbl.gov/Science-Articles/Archive/lawrence-legacy.html. Weart, S. Oral history transcript—Dr. Robert R. Wilson. Niels Bohr Library & Archives. Retrieved from http://www.aip.org/history/ohilist/4972.html. ¨ ber Ein Neues Prinzip Zur Herstellung Hoher Spannungen” Arch. Widerøe, R., 1928. U ¨ bertrag. 21 (4), 387–405. Elektron. U Wilson, R.R., 1946. Radiological use of fast protons. Radiology 47 (5), 487–491.
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