Eur. J. Nucl. Med. 1, 3
European Journal of N u c l e a r
10 (1976)
Medicine
© by Springer-Verlag 1976
George von Hevesy Memorial Lecture George Hevesy and His Concept of Radioactive Indicators-In Retrospect Hilde Levi August Krogh Institute, University of Copenhagen, Denmark
You all realize, of course, that the most outstanding scientific achievements of George de Hevesy and, consequently, a considerable span of his life, are closely linked to Copenhagen, more precisely to The Niels Bohr Institute, at that time called the Institute for Theoretical Physics of the University of Copenhagen. Hevesy loved Copenhagen, he married a Danish girl and, for over fifty years, he cherished his close friendship with Niels Bohr. For both men, this friendship was based on a deep appreciation of the other's personality as well as on a continuous stimulation and exchange of ideas. Both were men of great vision and broad interests, both focused on the essential aspects of the problems in which they were involved. Hevesy worked more than fifteen years here in Copenhagen, most of it in two extended periods from 1922-26 and from 1934-43, in addition to innumerable shorter visits. When he had moved his permanent residence to Stockholm after the Second World War, he remained for many years a commuter between the two cities. On one of his last visits, he sentimentally remarked that he felt like an old piece of furniture for ever belonging to the Bohr Institute. The two most outstanding achievements I alluded to are, first: Hevesy's discovery in 1922 of the missing element 72, which was named after the Latin name of Copenhagen "Hafnium"; second: the development of the tracer method or "radioactive indicators", as Hevesy called it in the early years. For this by now classical work we cannot give a narrow date. The idea of radioactive indicators was conceived around 1912, when Hevesy worked in Manchester with Rutherford. In the program notes to the Conference on Nuclear Medicine, the story is told and I shall briefly summarize its essence. Rutherford had received several hundred kilograms of pitchblende from Austria. This material contains RaD, however together with large quantities of lead, which absorbs the radiation emitted and therefore made the material almost useless. In his Nobel Lecture, Hevesy recalls: "When
I met Rutherford one day in 1911, he addressed me in his friendly and informal way, saying 'my boy, if you are worth your salt, you try to separate RaD from all that lead'." Hevesy goes on to tell how he labored in vain for almost two years but failed completely, and he continues with the words "In order to make the best of this depressing situation, I decided to use RaD as an indicator of lead." From its first application to the study of chemical and physico-chemical properties of metals, the idea grew steadily over a period of twenty years. Although, in the early twenties, Hevesy worked intensely on the isolation, purification, and identification of element 72, radioactive indicators were on his mind a n d - i n cooperation with the dermatologist Svend Lomhold of the Finsen Institute and the physicochemist I.A. Christiansen of the University-Hevesy studied the circulation of lead and bismuth in plants and animal organisms, using RaD, which is a lead isotope, and RaE, which is a bismuth isotope, as tracers. In two papers, "Recherches par une m6thode radiochimique sur la circulation du p l o m b - e t du bism u t h - d a r t s l'organisme" published in Comptes Rendus 1924, Hevesy's idea of using radioactive isotopes as tracers for the stable elements also in biological systems, found its first practical, and notably medical application. I better remind you that artificial radio-isotopes first became available in sizable amounts and on a commercial basis several years after the Second World War, that is after 1950. In the early thirties, after the discovery of induced radioactivity by the JoliotCuries, Fermi described in his frequent letters to Niels Bohr that he had produced unstable, that is radioactive isotopes in many different elements through bombardment with neutrons. This was wonderful news for Hevesy. A few years earlier, in Freiburg, he had already embarked on the application of the newly discovered heavy isotope of hydrogen, deuterium or heavy water, to the study of biological problems.
4
H. Levi: George yon Heresy Memorial Lecture
When Hevesy decided to give up his professorship in Freiburg and to return to Copenhagen by the end of 1934, he immediately launched preparations which would enable him to perform experiments on induced radioactivity. I was assigned to him as his assistant from the very start. I should therefore like to tell you about the early development of the tracer method, and especially the production of radiophosphorus at the Bohr Institute in 1935. Photo no. 1 shows NMs Bohr, James Franck, and George Hevesy on the terrace of the Bohr Institute in 1935; two of them had already received the Nobel prize, the third had a few years to wait for it. To brush up your memory, tl~e reactions taking place both in the radiation source and in the target are the following. The neutron source: ]Be + ~He ~ a62~~t -0 1n using c~-particles from radon. The target: 32c,- 1
32
16~-on --' 15P+lH.
The neutron source was a mixture of radon with beryllium powder. We made these sources ourselves.
Fig. 1. From left to right: Niels Bohr, James Franck, George Hevesy on the terrace of the Niels Bohr Institute, 1935
Beryllium was ground by hand in an agate mortar to an extremely fine powder which was then transferred to glass vials. We know today how hazardous it is to work with beryllium. Thus, we were indeed lucky to get away with this procedure. At the Radium Hospital, where a considerable quantity of radium salt was held in solution, about 500 mCi of radon gas, routinely used for cancer therapy, was pumped into the vial, which was then sealed. Hopefully, the seal was t i g h t - i t wasn't always. If the constriction of the glass vial retained a few beryllium particles, the seal would crack on cooling. Obviously, closing the vial that contained the radon-beryllium mixture with a flame was a slightly touchy manipulation, a small leak was bound to develop once in a while. The vial was placed into a metal holder on a long rod a n d - u s u a l l y by bicycle-brought from the Radium Station to the Bohr Institute. We always had a phone call when the bicycle started, so we could read or stop our instruments before the source came to the Institute and until it had been stored away into a well beneath the basement. The radon half-life being 3.8 days, our neutron sources were fairly effective for about a week or two. To produce P-32, the source was placed into the center of a 10 1 flask containing carbon disulphidestill in the well under the basement. Under optimum conditions and after about one or two weeks' irradiation with the latest and a few older sources, Hevesy could separate chemically about 1 gCi of carrier-free P-32 from the carbon disulphide. Geiger-Mtiller counters and amplifiers were not commercially available-such instrumentation was not in demand except among physicists who knew how to build them. Since I was trained as a spectroscopist and never had worked with radioactive substances until I began to assist Hevesy, I was badly in need of a teacher, and I found one in O.R.Frisch who worked at the Institute at that time. Under his direction the first counting equipment was built. The only parts we could purchase were radio tubes, for example thyrotrons and the device used by the telephone company to register the number of outgoing calls from a phone. Thus, we soldered together a simple amplifier, mounted it on a cigar box or inside the lid of a large cake box, powered it with auto batteries for the filaments and dry batteries for the anode current. For the high voltage supply we had a series of between 12 and 15 Hellesen dry batteries giving 100 V each. Fig. 2 shows some of the early models of GeigerMiiller counters built for our purpose. The very first one was a simple cylindrical tube about 10 cm long, made from 0.1 mm copper foil with a corrugated surface to increase its mechanical strength. The tube contained hydrogen at reduced pressure. The sample
H. Levi: George von Hevesy Memorial Lecture
to be measured could be placed underneath the horizontally oriented tube, or could be filled into a double cylinder made of paper, which would fit around the counter in a vertical position. When the counter had been hooked onto the amplifier, and a sample of uranium oxide was placed under it-believe it or n o t - t h e telephone register started clicking. It was, as a visiting journalist later put it, " t h e characteristic clicking of the atoms". Fig. 3 shows one of the early devices we used. They are now kept in the Technical Museum in Elsinore. I have arranged them so as to illustrate their use, but the power supplies are missing. The following photo, no. 4, illustrates some of the later, and more sophisticated models. Since we
Fig. 2. Left: the first Geiger-Mfiller counter built at the Niels Bohr Institute in 1935. Right: a thin window counter contained in a brass block, the mica window facing downward, built in 1936
Fig. 3. A 1935 model amplifier, counter, and register. The high voltage supply is missing
5
also worked with radio-sulphur which emits very soft beta particles, we had to construct a counter with a thin window. It is the brass block with a cylindrical opening across and a window covered with mica. In the middle of the row is the first bell-shaped counter built here in Copenhagen by drs. Madsen and Zerahn. It is made of glass and has a mica window. In the late thirties, the scaler was invented in England and soon a scale of eight was built at the Institute. The counters were then shielded from cosmic radiation and the amplifiers from electric noise by placing the cake box over its lid and connecting it to ground (see Fig. 5). The whole apparatus could be moved about after having been mounted on a wheel c a r t - i n c l u d i n g the 15 dry batteries which took up
6
H. Levi: George von Heresy Memorial Lecture Fig. 4. Some of the early models of GMtubes built at the Niels Bohr Institute
Fig. 5. Measuring equipment from around 1940
a lot of space. We called this contraption a "pram". Around 1938, Heresy and his coworkers had about five or six of these instruments running day and night. We began to think in terms of automatic sample changers of the merry-go-round type; the first ones were built in the forties, likewise by Madsen and Zerahn. Needless to say, we also made our sample planchets which were stamped out by hand with the help of a die. Why did we need so many counters, since the amount of P-32 at our disposal was so small? The situation had changed drastically in the course of only a few years. On his 50th birthday, in 1935, Niels Bohr was presented with 100.000 Dan. kroner, which had been raised through large and small donations from all over the country. It was a lot of money at that time. It was to be used to purchase c. 1 g of radium. The company Radium Belge was asked
to mix the radium salt with beryllium powder and, thus, the Institute came into possession of a few permanent neutron sources, besides the rapidly decaying radon-beryllium sources. Moreover, the cyclotron far superseded our radon- or radium-beryllium sources as far as isotope production was concerned. As early as 1936, Hevesy received P-32 from his friend Ernest Lawrence in Berkeley. At that time, a transatlantic shipment of radioactive material did not require formalities nor was it subject to safety precautions, as it is today. The P-32 supplies simply arrived in airmail letters. When Hevesy unwrapped the precious sniffer and dissolved the tiny quantity of a white powder, he had so many different ideas on what use to make of it, that the activity available for each experiment had to be kept very low indeed, and we became experts in measuring weak samples, for example
H. Levi: George von Hevesy Memorial Lecture
2 cpm alternately with a background of 5 cpm, for hours, sometimes for days. Meanwhile, a cyclotron was being built at the Bohr Institute and, in 1939, Copenhagen produced P-32 became available in larger quantities. Also shortlived isotopes, for example Na-24 and K-42, could be produced and for the first time used by Heresy in his biological studies. The great impact of radioactive indicators on biological and medical research was recognized by Niels Bohr, Heresy, and August Krogh, the physiologist, from the very start. As early as 1935, they approached the Rockefeller Foundation to obtain support for what they termed "physico-biological experiments" with artificially produced radioisotopes. Bohr's genuine interest in biology, in the interrelationship between the world of physics and the life sciences, has been a tremendous stimulus, and has speeded and carried forward a development which proved to be of the greatest benefit to both fields. A year later, in 1936, in view of the possibility for what appeared as an abundant production of radio-isotopes in Lawfence's cyclotron, Bohr, Krogh and Heresy convinced the Rockefeller Foundation, whose primary interest at that time was in the life sciences, that the cyclotron was indispensable for the production of isotopes, which in turn would benefit biological research. The Rockefeller Foundation thus contributed to the construction of the cyclotron and supported the isotope research of Heresy and Krogh, and later of H.H. Ussing and his associates. After the war, the center of "physico-biological experiments" moved from the Bohr Institute into the biological environment where it rightly belonged. Heresy was not a skilful experimentalist and he did not particularly like manual work in the laboratory. Whenever he grew impatient for results or he felt he should visit and encourage us, he would enter the laboratory and immediately start fiddling with the counters, causing more disturbance than he anticipated. If he handled glassware, he often broke it and sometimes hurt himself rather badly. He would then rush to the emergency ward of the Rigshospital, where he was well known, to be treated. I remember that Heresy once broke a Kjeldahl flask containing boiling sulphuric acid which splashed over his arm and injured him quite seriously. When he came back from the hospital with his arm all bandaged, he was rather pale and in pain. His secretary suggested that he go home and get some rest, but Hevesy's laconic answer was "Do you think it hurts less when I go home?", and he disappeared into his study. Heresy had a vivid imagination, a legendary memory, and irresistable enthusiasm. He was in touch with practically every professor working in the sciences at this university, and he gradually captured
7
most of them by his incitation and convincing arguments. He was an excellent salesman of his own ideas, which very soon penetrated many fields other than his own. It is interesting to note that Hevesy's ventures into biology as the most obvious field of application of radioactive indicators began in collaboration with medical people: with Lomholt in 1923, and again in 1935 in his pioneer work using P-32 carried out together with the head surgeon of the Finsen Hospital, Ole Chievitz. I vividly recall that rats and mice were injected with P-32 and Heresy brought back samples of excreta, blood and various organs, samples of a kind never before seen at the Bohr Institute. He taught me the art of wet combustion and of phosphorus analysis, and we developed a technique of sample preparation for the counter. However, very soon these activities could no longer satisfy Hevesy's appetite for new ventures and therefore he established himself in a number of institutes all over the city. In the laboratories of August Krogh, Einar Lundsgaard, Kaj Linderstrom-Lang, and several others, he initiated experimental work with P-32. However, all the samples were measured
Fig. 6. Automatic sample changer in front, lead shielded G M counter and sample holder in the rear. On top : 6 registers recording counts from the six samples on the rotating disk. Built around 1949
8
with the counting equipment built at the Bohr Institute, since counters were not to be found anywhere else. In consequence, Hevesy constantly traveled all over town, sometimes by tram, but as a rule on his bicycle. He had a special mode of shuffling his bike under his body rather than mounting it as other people do. And when it rained, he unfolded his umbrella and pedaled undisturbed through the city. Before I conclude this retrospect of the early development of the indicator method and turn to the early applications of radioactive indicators, I should like to illustrate very briefly how, during and shortly after the Second World War, the instrumentation developed, thus paving the way for commercial production of tracer equipment. Figs. 6 and 7 shown rather advanced sets built between 1946 and 1949. The batteries have disappeared and the power supply is taken from the plug in the wall. A metal case houses the amplifier and scaler, the lead shield for the counter and the sample holder look almost commercial. Fig. 8 is a picture of the first amplifier and scaler built commercially in this country according to our specifications. This machine contains two scales of eight, which could be combined to a scale of 64 and allowed us to count samples that were much hotter than the GM tube could digest. We are now on the way to meet the challenge of the post-war period. In our time, the pace of scientific and technological advance is so fast that the origin and the step-bystep development of ideas and methods very soon become part of history. In the opinion of many, a study of historical developments is of no interest; instead, one rushes on to ever more sophisticated
H. Levi: George von Heresy Memorial Lecture
gadgets which are postulated to make scientific work better and easier. I do not share this view and therefore choose to show with a few examples what happened in the early years of the tracer method and how simple, almost primitive were the means, by which Hevesy gained a wealth of new insight. Hevesy started, as you know, with the studies of phosphorus metabolism in animals and plants, and he observed what he interpreted as the dynamic equilibrium prevailing in these organisms. Together with Ole Chievitz he submitted a Letter to the Editor of Nature in 1935, in which he says: "The results strongly support the view that the formation of the bones is a dynamic process, the bones continuously taking up phosphorus atoms which are partly or wholly lost again and are replaced by other phosphorus atoms. In the case of an adult rat, about 50% of the phosphorus atoms deposited in the skeleton were removed in the course of 20 days." The editor laconically remarked in his comments, which are printed a few pages further on: "The authors further believe that the formation of the bone is a dynamic process, involving continuous loss and replacement." Obviously, he was not convinced and wanted to place himself at some distance from such untraditional thinking. A couple of months later, on December 9, 1935, Hevesy together with Linderstrom-Lang and C. Olsen from the Carlsberg Laboratory published similar investigations into maize plants and, linking these new results to those obtained in 1924, he says: "The fact that the easy exchangeability already found for lead which is only incidentally present in plant tissues has also been ascertained for phosphorus, one of the chief
Fig. 7. Measuring equipment from around 1949
H. Levi: George yon Hevesy Memorial Lecture
9
Fig. 8. Scaler consisting of two "scales of eight" built commercially in Copenhagen, 1950
constituents of plants, indicates that we have to do with a general property of plant constitution." Another example of Hevesy's successful efforts to introduce isotopic indicators into different fields is, as you know, his work on blood volume determinations. As already mentioned, Hevesy used heavy water to measure water turnover and total body water in animal organisms, and for a number of years, this method was widely applied also in humans. When sufficient quantities of P-32 became available thanks to Ernest Lawrence, a new variation on the isotope dilution principle could be developed. Hevesy labeled red blood corpuscles in vitro with P-32 and re-injected them into the organism. From the dilution o f the active corpuscles with inactive ones in a blood sample drawn after the re-injection, he could calculate the total blood volume. He knew that this method is of considerable interest to the clinician. Some years later, other radio-isotopes were considered to be more suitable for the purpose and Hevesy continued to contribute to the improvement of,his original technique. I want to take the time for one more example, namely Hevesy's observation that the synthesis of nucleic acid takes place in tissue where cells are proliferating. I mention these studies not to provide documentation for the broadness of his interests or the boldness of his thinking, rather because this example provides evidence of the fact that some of the important topics still in the center of research today were tackeled by Hevesy 35 years ago. At that time, the list of isotopes and labeled compounds available was very, very short indeed, and the equipment did not cost 100,000 k r o n e r . -
Hevesy came to his conclusion concerning the formation of nucleic acid through a careful analysis of the specific activities of different phosphorus compounds in muscle, liver, and brain. Also this paper appeared in Nature. In the meantime, the editor had learnt that the Letters Hevesy sent him were well worth publishing. This one, on the "Turnover rate of nucleic acid", appeared on April 6, 1940. It was in print only six weeks after it had been submitted, and just a few days before the German occupation of Denmark. This event seriously impeded Hevesy's activities and interrupted his international contacts. Hevesy came to Sweden at the end of 1943. During his later years, Hevesy's interest turned to radiobiology and cancer research, topics much more familiar to this audience. He lived to see the early phases of nuclear medicine, and it must have been a great satisfaction to him that radio-isotopes in addition to being a widely used and indispensable research tool in many fields also would play an increasingly important role in diagnosis and treatment of disease. When I was invited to give the Hevesy Memorial Lecture in Copenhagen, I felt that radioactive indicators should be the central topic of my talk, not only because I have had the good fortune to take part in this epoch-making development, but likewise because only few eye-witnesses are left to recall the history of radioactive indicators. A retrospect of the tracer method is intimately interwoven with a retrospect of a great and most remarkable personality. Hevesy was an ideal boss to work with. Intellectually, because he was constantly
10
overflowing with ideas and p l a n s - there never was a dull moment. Personally, he was extremely amiable and polite, and he would never lose his temper or even complain when something went wrong. In his attitude towards people, he was truly aristocratic in the sense that he would meet his subordinates and his colleagues or friends with the same courtesy and readiness to help. He was possessed by his scientific ideas which dominated his thinking so much that he did not have time for other activities. However, his love for nature was great and he liked to go for long hikes, often together with one of his coworkers, so he could talk shop at the same time. Hevesy's productivity was enormous. In the period between 1912 and 1963, that is in the course of 50 years, he published close to 400 papers, several books and reviews', in five languages. A propos languages, he spoke them all fluently, even elegantly, with his typical accent, as if he had a mixture of all these languages to start from and then brought to the surface of his memory what was needed to meet any given situation. He also spoke Skandinavian in a manner that bridged the differences between the tongues. Most of his acquaintances were amused, a few were irritated or at times bewildered. He wrote practically everything by h a n d - t h e typewriter was used only in the very last years of his life - and he had an extensive correspondence. Very little of it is preserved, because Hevesy would read a letter as it came in, answer it immediately by hand, tear the letter up, and throw it away. There are only few exceptions to this rule, such as the letters from Rutherford and Niels Bohr. His legendary memory enabled him for years to recall almost everything he ever read, and he likewise remembered observations or measurements he did not understand when they were made. But at the same time, he was extremely absent-minded. His concentration on the problems that occupied his mind made him forget everything else, especially his appointments with his dentist or with guests he had invited to his home. Hevesy frequently dashing out of the laboratory in enormous haste, leaving behind one of his galoshes, would indicate that he suddenly realized he had forgotten something, and he would shout to us that he'll be back shortly. On such an occasion, one of the most popular Hevesy slogans was coined. He was running down the stairs real fast and shouted to his coworker: "Herr Hahn, Herr Hahn, you are lucky, you have your rabbits, I must go home to my family!" 1 For a complete list of Hevesy's publications, see Nuclear Physics A 98 (1967), No. 1.
H. Levi: George yon Heresy Memorial Lecture
You must not misinterpret this story; Hevesy adored his family, he was just a little envious that Herr Hahn was able to stay in the laboratory all night. The Hevesys were very hospitable. However, being invited there for tea or dinner and not finding anybody at home is an experience most of his friends share. For Hevesy, even pleasant company must not last too long. One night, I was among the guests when he called for his daughter Jenny at about 9.30 p.m. and asked her, please, to shut off the central heating in his bedroom. Turning to his guests with a friendly smile, he said: "You know, I always turn off the heat half an hour before ! go to bed." In the early years of the tracer method, as Hevesy expanded his activities, some of his colleagues blamed him for not knowing enough about the complexity of the problems in which he became involved, and this criticism may sometimes have been justified. But Hevesy was not really interested in details, he focused on the essential points and particularly attacked problems which, in principle, had only become accessible through the use of radio-isotopes, for example certain types of exchange reactions, permeability studies, transport of ions and molecules, and dynamic equilibria. Hevesy's approach to such problems can only be called visionary. Often, he was so sure of the outcome of an experiment that the draft of the paper was written before he had seen the experimental result. For all these achievements he was honored with numerous degrees, medals, memberships in learned societies, and prizes. The greatest distinctions bestowed on him, many people think, were the Nobel Prize in 1944 and the Atoms for Peace Award in 1959. He himself says what pleased him most was to be elected a foreign member of the Royal Society of London and to receive this Society's Copley medal. I could go on speaking about Hevesy for hours. He was unique. His scientific achievements are contained in the literature and thus available to everybody. To those who knew him, his personality is unforgettable. Hevesy did not have much sense of humor, but because of his very special bearing, he gave rise to many quite surprising situations. He himself did not think they were at all funny. Nevertheless, he supplied his friends and colleagues with the material for innumerable delightful stories and anecdotes. Maybe, when I have retired, I shall have the time to write a few more of them down.
Received November 25, 1975
European Journal of N u c l e a r
10 (1976)
Medicine
© by Springer-Verlag 1976
George von Hevesy Memorial Lecture George Hevesy and His Concept of Radioactive Indicators-In Retrospect Hilde Levi August Krogh Institute, University of Copenhagen, Denmark
You all realize, of course, that the most outstanding scientific achievements of George de Hevesy and, consequently, a considerable span of his life, are closely linked to Copenhagen, more precisely to The Niels Bohr Institute, at that time called the Institute for Theoretical Physics of the University of Copenhagen. Hevesy loved Copenhagen, he married a Danish girl and, for over fifty years, he cherished his close friendship with Niels Bohr. For both men, this friendship was based on a deep appreciation of the other's personality as well as on a continuous stimulation and exchange of ideas. Both were men of great vision and broad interests, both focused on the essential aspects of the problems in which they were involved. Hevesy worked more than fifteen years here in Copenhagen, most of it in two extended periods from 1922-26 and from 1934-43, in addition to innumerable shorter visits. When he had moved his permanent residence to Stockholm after the Second World War, he remained for many years a commuter between the two cities. On one of his last visits, he sentimentally remarked that he felt like an old piece of furniture for ever belonging to the Bohr Institute. The two most outstanding achievements I alluded to are, first: Hevesy's discovery in 1922 of the missing element 72, which was named after the Latin name of Copenhagen "Hafnium"; second: the development of the tracer method or "radioactive indicators", as Hevesy called it in the early years. For this by now classical work we cannot give a narrow date. The idea of radioactive indicators was conceived around 1912, when Hevesy worked in Manchester with Rutherford. In the program notes to the Conference on Nuclear Medicine, the story is told and I shall briefly summarize its essence. Rutherford had received several hundred kilograms of pitchblende from Austria. This material contains RaD, however together with large quantities of lead, which absorbs the radiation emitted and therefore made the material almost useless. In his Nobel Lecture, Hevesy recalls: "When
I met Rutherford one day in 1911, he addressed me in his friendly and informal way, saying 'my boy, if you are worth your salt, you try to separate RaD from all that lead'." Hevesy goes on to tell how he labored in vain for almost two years but failed completely, and he continues with the words "In order to make the best of this depressing situation, I decided to use RaD as an indicator of lead." From its first application to the study of chemical and physico-chemical properties of metals, the idea grew steadily over a period of twenty years. Although, in the early twenties, Hevesy worked intensely on the isolation, purification, and identification of element 72, radioactive indicators were on his mind a n d - i n cooperation with the dermatologist Svend Lomhold of the Finsen Institute and the physicochemist I.A. Christiansen of the University-Hevesy studied the circulation of lead and bismuth in plants and animal organisms, using RaD, which is a lead isotope, and RaE, which is a bismuth isotope, as tracers. In two papers, "Recherches par une m6thode radiochimique sur la circulation du p l o m b - e t du bism u t h - d a r t s l'organisme" published in Comptes Rendus 1924, Hevesy's idea of using radioactive isotopes as tracers for the stable elements also in biological systems, found its first practical, and notably medical application. I better remind you that artificial radio-isotopes first became available in sizable amounts and on a commercial basis several years after the Second World War, that is after 1950. In the early thirties, after the discovery of induced radioactivity by the JoliotCuries, Fermi described in his frequent letters to Niels Bohr that he had produced unstable, that is radioactive isotopes in many different elements through bombardment with neutrons. This was wonderful news for Hevesy. A few years earlier, in Freiburg, he had already embarked on the application of the newly discovered heavy isotope of hydrogen, deuterium or heavy water, to the study of biological problems.
4
H. Levi: George yon Heresy Memorial Lecture
When Hevesy decided to give up his professorship in Freiburg and to return to Copenhagen by the end of 1934, he immediately launched preparations which would enable him to perform experiments on induced radioactivity. I was assigned to him as his assistant from the very start. I should therefore like to tell you about the early development of the tracer method, and especially the production of radiophosphorus at the Bohr Institute in 1935. Photo no. 1 shows NMs Bohr, James Franck, and George Hevesy on the terrace of the Bohr Institute in 1935; two of them had already received the Nobel prize, the third had a few years to wait for it. To brush up your memory, tl~e reactions taking place both in the radiation source and in the target are the following. The neutron source: ]Be + ~He ~ a62~~t -0 1n using c~-particles from radon. The target: 32c,- 1
32
16~-on --' 15P+lH.
The neutron source was a mixture of radon with beryllium powder. We made these sources ourselves.
Fig. 1. From left to right: Niels Bohr, James Franck, George Hevesy on the terrace of the Niels Bohr Institute, 1935
Beryllium was ground by hand in an agate mortar to an extremely fine powder which was then transferred to glass vials. We know today how hazardous it is to work with beryllium. Thus, we were indeed lucky to get away with this procedure. At the Radium Hospital, where a considerable quantity of radium salt was held in solution, about 500 mCi of radon gas, routinely used for cancer therapy, was pumped into the vial, which was then sealed. Hopefully, the seal was t i g h t - i t wasn't always. If the constriction of the glass vial retained a few beryllium particles, the seal would crack on cooling. Obviously, closing the vial that contained the radon-beryllium mixture with a flame was a slightly touchy manipulation, a small leak was bound to develop once in a while. The vial was placed into a metal holder on a long rod a n d - u s u a l l y by bicycle-brought from the Radium Station to the Bohr Institute. We always had a phone call when the bicycle started, so we could read or stop our instruments before the source came to the Institute and until it had been stored away into a well beneath the basement. The radon half-life being 3.8 days, our neutron sources were fairly effective for about a week or two. To produce P-32, the source was placed into the center of a 10 1 flask containing carbon disulphidestill in the well under the basement. Under optimum conditions and after about one or two weeks' irradiation with the latest and a few older sources, Hevesy could separate chemically about 1 gCi of carrier-free P-32 from the carbon disulphide. Geiger-Mtiller counters and amplifiers were not commercially available-such instrumentation was not in demand except among physicists who knew how to build them. Since I was trained as a spectroscopist and never had worked with radioactive substances until I began to assist Hevesy, I was badly in need of a teacher, and I found one in O.R.Frisch who worked at the Institute at that time. Under his direction the first counting equipment was built. The only parts we could purchase were radio tubes, for example thyrotrons and the device used by the telephone company to register the number of outgoing calls from a phone. Thus, we soldered together a simple amplifier, mounted it on a cigar box or inside the lid of a large cake box, powered it with auto batteries for the filaments and dry batteries for the anode current. For the high voltage supply we had a series of between 12 and 15 Hellesen dry batteries giving 100 V each. Fig. 2 shows some of the early models of GeigerMiiller counters built for our purpose. The very first one was a simple cylindrical tube about 10 cm long, made from 0.1 mm copper foil with a corrugated surface to increase its mechanical strength. The tube contained hydrogen at reduced pressure. The sample
H. Levi: George von Hevesy Memorial Lecture
to be measured could be placed underneath the horizontally oriented tube, or could be filled into a double cylinder made of paper, which would fit around the counter in a vertical position. When the counter had been hooked onto the amplifier, and a sample of uranium oxide was placed under it-believe it or n o t - t h e telephone register started clicking. It was, as a visiting journalist later put it, " t h e characteristic clicking of the atoms". Fig. 3 shows one of the early devices we used. They are now kept in the Technical Museum in Elsinore. I have arranged them so as to illustrate their use, but the power supplies are missing. The following photo, no. 4, illustrates some of the later, and more sophisticated models. Since we
Fig. 2. Left: the first Geiger-Mfiller counter built at the Niels Bohr Institute in 1935. Right: a thin window counter contained in a brass block, the mica window facing downward, built in 1936
Fig. 3. A 1935 model amplifier, counter, and register. The high voltage supply is missing
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also worked with radio-sulphur which emits very soft beta particles, we had to construct a counter with a thin window. It is the brass block with a cylindrical opening across and a window covered with mica. In the middle of the row is the first bell-shaped counter built here in Copenhagen by drs. Madsen and Zerahn. It is made of glass and has a mica window. In the late thirties, the scaler was invented in England and soon a scale of eight was built at the Institute. The counters were then shielded from cosmic radiation and the amplifiers from electric noise by placing the cake box over its lid and connecting it to ground (see Fig. 5). The whole apparatus could be moved about after having been mounted on a wheel c a r t - i n c l u d i n g the 15 dry batteries which took up
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H. Levi: George von Heresy Memorial Lecture Fig. 4. Some of the early models of GMtubes built at the Niels Bohr Institute
Fig. 5. Measuring equipment from around 1940
a lot of space. We called this contraption a "pram". Around 1938, Heresy and his coworkers had about five or six of these instruments running day and night. We began to think in terms of automatic sample changers of the merry-go-round type; the first ones were built in the forties, likewise by Madsen and Zerahn. Needless to say, we also made our sample planchets which were stamped out by hand with the help of a die. Why did we need so many counters, since the amount of P-32 at our disposal was so small? The situation had changed drastically in the course of only a few years. On his 50th birthday, in 1935, Niels Bohr was presented with 100.000 Dan. kroner, which had been raised through large and small donations from all over the country. It was a lot of money at that time. It was to be used to purchase c. 1 g of radium. The company Radium Belge was asked
to mix the radium salt with beryllium powder and, thus, the Institute came into possession of a few permanent neutron sources, besides the rapidly decaying radon-beryllium sources. Moreover, the cyclotron far superseded our radon- or radium-beryllium sources as far as isotope production was concerned. As early as 1936, Hevesy received P-32 from his friend Ernest Lawrence in Berkeley. At that time, a transatlantic shipment of radioactive material did not require formalities nor was it subject to safety precautions, as it is today. The P-32 supplies simply arrived in airmail letters. When Hevesy unwrapped the precious sniffer and dissolved the tiny quantity of a white powder, he had so many different ideas on what use to make of it, that the activity available for each experiment had to be kept very low indeed, and we became experts in measuring weak samples, for example
H. Levi: George von Hevesy Memorial Lecture
2 cpm alternately with a background of 5 cpm, for hours, sometimes for days. Meanwhile, a cyclotron was being built at the Bohr Institute and, in 1939, Copenhagen produced P-32 became available in larger quantities. Also shortlived isotopes, for example Na-24 and K-42, could be produced and for the first time used by Heresy in his biological studies. The great impact of radioactive indicators on biological and medical research was recognized by Niels Bohr, Heresy, and August Krogh, the physiologist, from the very start. As early as 1935, they approached the Rockefeller Foundation to obtain support for what they termed "physico-biological experiments" with artificially produced radioisotopes. Bohr's genuine interest in biology, in the interrelationship between the world of physics and the life sciences, has been a tremendous stimulus, and has speeded and carried forward a development which proved to be of the greatest benefit to both fields. A year later, in 1936, in view of the possibility for what appeared as an abundant production of radio-isotopes in Lawfence's cyclotron, Bohr, Krogh and Heresy convinced the Rockefeller Foundation, whose primary interest at that time was in the life sciences, that the cyclotron was indispensable for the production of isotopes, which in turn would benefit biological research. The Rockefeller Foundation thus contributed to the construction of the cyclotron and supported the isotope research of Heresy and Krogh, and later of H.H. Ussing and his associates. After the war, the center of "physico-biological experiments" moved from the Bohr Institute into the biological environment where it rightly belonged. Heresy was not a skilful experimentalist and he did not particularly like manual work in the laboratory. Whenever he grew impatient for results or he felt he should visit and encourage us, he would enter the laboratory and immediately start fiddling with the counters, causing more disturbance than he anticipated. If he handled glassware, he often broke it and sometimes hurt himself rather badly. He would then rush to the emergency ward of the Rigshospital, where he was well known, to be treated. I remember that Heresy once broke a Kjeldahl flask containing boiling sulphuric acid which splashed over his arm and injured him quite seriously. When he came back from the hospital with his arm all bandaged, he was rather pale and in pain. His secretary suggested that he go home and get some rest, but Hevesy's laconic answer was "Do you think it hurts less when I go home?", and he disappeared into his study. Heresy had a vivid imagination, a legendary memory, and irresistable enthusiasm. He was in touch with practically every professor working in the sciences at this university, and he gradually captured
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most of them by his incitation and convincing arguments. He was an excellent salesman of his own ideas, which very soon penetrated many fields other than his own. It is interesting to note that Hevesy's ventures into biology as the most obvious field of application of radioactive indicators began in collaboration with medical people: with Lomholt in 1923, and again in 1935 in his pioneer work using P-32 carried out together with the head surgeon of the Finsen Hospital, Ole Chievitz. I vividly recall that rats and mice were injected with P-32 and Heresy brought back samples of excreta, blood and various organs, samples of a kind never before seen at the Bohr Institute. He taught me the art of wet combustion and of phosphorus analysis, and we developed a technique of sample preparation for the counter. However, very soon these activities could no longer satisfy Hevesy's appetite for new ventures and therefore he established himself in a number of institutes all over the city. In the laboratories of August Krogh, Einar Lundsgaard, Kaj Linderstrom-Lang, and several others, he initiated experimental work with P-32. However, all the samples were measured
Fig. 6. Automatic sample changer in front, lead shielded G M counter and sample holder in the rear. On top : 6 registers recording counts from the six samples on the rotating disk. Built around 1949
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with the counting equipment built at the Bohr Institute, since counters were not to be found anywhere else. In consequence, Hevesy constantly traveled all over town, sometimes by tram, but as a rule on his bicycle. He had a special mode of shuffling his bike under his body rather than mounting it as other people do. And when it rained, he unfolded his umbrella and pedaled undisturbed through the city. Before I conclude this retrospect of the early development of the indicator method and turn to the early applications of radioactive indicators, I should like to illustrate very briefly how, during and shortly after the Second World War, the instrumentation developed, thus paving the way for commercial production of tracer equipment. Figs. 6 and 7 shown rather advanced sets built between 1946 and 1949. The batteries have disappeared and the power supply is taken from the plug in the wall. A metal case houses the amplifier and scaler, the lead shield for the counter and the sample holder look almost commercial. Fig. 8 is a picture of the first amplifier and scaler built commercially in this country according to our specifications. This machine contains two scales of eight, which could be combined to a scale of 64 and allowed us to count samples that were much hotter than the GM tube could digest. We are now on the way to meet the challenge of the post-war period. In our time, the pace of scientific and technological advance is so fast that the origin and the step-bystep development of ideas and methods very soon become part of history. In the opinion of many, a study of historical developments is of no interest; instead, one rushes on to ever more sophisticated
H. Levi: George von Heresy Memorial Lecture
gadgets which are postulated to make scientific work better and easier. I do not share this view and therefore choose to show with a few examples what happened in the early years of the tracer method and how simple, almost primitive were the means, by which Hevesy gained a wealth of new insight. Hevesy started, as you know, with the studies of phosphorus metabolism in animals and plants, and he observed what he interpreted as the dynamic equilibrium prevailing in these organisms. Together with Ole Chievitz he submitted a Letter to the Editor of Nature in 1935, in which he says: "The results strongly support the view that the formation of the bones is a dynamic process, the bones continuously taking up phosphorus atoms which are partly or wholly lost again and are replaced by other phosphorus atoms. In the case of an adult rat, about 50% of the phosphorus atoms deposited in the skeleton were removed in the course of 20 days." The editor laconically remarked in his comments, which are printed a few pages further on: "The authors further believe that the formation of the bone is a dynamic process, involving continuous loss and replacement." Obviously, he was not convinced and wanted to place himself at some distance from such untraditional thinking. A couple of months later, on December 9, 1935, Hevesy together with Linderstrom-Lang and C. Olsen from the Carlsberg Laboratory published similar investigations into maize plants and, linking these new results to those obtained in 1924, he says: "The fact that the easy exchangeability already found for lead which is only incidentally present in plant tissues has also been ascertained for phosphorus, one of the chief
Fig. 7. Measuring equipment from around 1949
H. Levi: George yon Hevesy Memorial Lecture
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Fig. 8. Scaler consisting of two "scales of eight" built commercially in Copenhagen, 1950
constituents of plants, indicates that we have to do with a general property of plant constitution." Another example of Hevesy's successful efforts to introduce isotopic indicators into different fields is, as you know, his work on blood volume determinations. As already mentioned, Hevesy used heavy water to measure water turnover and total body water in animal organisms, and for a number of years, this method was widely applied also in humans. When sufficient quantities of P-32 became available thanks to Ernest Lawrence, a new variation on the isotope dilution principle could be developed. Hevesy labeled red blood corpuscles in vitro with P-32 and re-injected them into the organism. From the dilution o f the active corpuscles with inactive ones in a blood sample drawn after the re-injection, he could calculate the total blood volume. He knew that this method is of considerable interest to the clinician. Some years later, other radio-isotopes were considered to be more suitable for the purpose and Hevesy continued to contribute to the improvement of,his original technique. I want to take the time for one more example, namely Hevesy's observation that the synthesis of nucleic acid takes place in tissue where cells are proliferating. I mention these studies not to provide documentation for the broadness of his interests or the boldness of his thinking, rather because this example provides evidence of the fact that some of the important topics still in the center of research today were tackeled by Hevesy 35 years ago. At that time, the list of isotopes and labeled compounds available was very, very short indeed, and the equipment did not cost 100,000 k r o n e r . -
Hevesy came to his conclusion concerning the formation of nucleic acid through a careful analysis of the specific activities of different phosphorus compounds in muscle, liver, and brain. Also this paper appeared in Nature. In the meantime, the editor had learnt that the Letters Hevesy sent him were well worth publishing. This one, on the "Turnover rate of nucleic acid", appeared on April 6, 1940. It was in print only six weeks after it had been submitted, and just a few days before the German occupation of Denmark. This event seriously impeded Hevesy's activities and interrupted his international contacts. Hevesy came to Sweden at the end of 1943. During his later years, Hevesy's interest turned to radiobiology and cancer research, topics much more familiar to this audience. He lived to see the early phases of nuclear medicine, and it must have been a great satisfaction to him that radio-isotopes in addition to being a widely used and indispensable research tool in many fields also would play an increasingly important role in diagnosis and treatment of disease. When I was invited to give the Hevesy Memorial Lecture in Copenhagen, I felt that radioactive indicators should be the central topic of my talk, not only because I have had the good fortune to take part in this epoch-making development, but likewise because only few eye-witnesses are left to recall the history of radioactive indicators. A retrospect of the tracer method is intimately interwoven with a retrospect of a great and most remarkable personality. Hevesy was an ideal boss to work with. Intellectually, because he was constantly
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overflowing with ideas and p l a n s - there never was a dull moment. Personally, he was extremely amiable and polite, and he would never lose his temper or even complain when something went wrong. In his attitude towards people, he was truly aristocratic in the sense that he would meet his subordinates and his colleagues or friends with the same courtesy and readiness to help. He was possessed by his scientific ideas which dominated his thinking so much that he did not have time for other activities. However, his love for nature was great and he liked to go for long hikes, often together with one of his coworkers, so he could talk shop at the same time. Hevesy's productivity was enormous. In the period between 1912 and 1963, that is in the course of 50 years, he published close to 400 papers, several books and reviews', in five languages. A propos languages, he spoke them all fluently, even elegantly, with his typical accent, as if he had a mixture of all these languages to start from and then brought to the surface of his memory what was needed to meet any given situation. He also spoke Skandinavian in a manner that bridged the differences between the tongues. Most of his acquaintances were amused, a few were irritated or at times bewildered. He wrote practically everything by h a n d - t h e typewriter was used only in the very last years of his life - and he had an extensive correspondence. Very little of it is preserved, because Hevesy would read a letter as it came in, answer it immediately by hand, tear the letter up, and throw it away. There are only few exceptions to this rule, such as the letters from Rutherford and Niels Bohr. His legendary memory enabled him for years to recall almost everything he ever read, and he likewise remembered observations or measurements he did not understand when they were made. But at the same time, he was extremely absent-minded. His concentration on the problems that occupied his mind made him forget everything else, especially his appointments with his dentist or with guests he had invited to his home. Hevesy frequently dashing out of the laboratory in enormous haste, leaving behind one of his galoshes, would indicate that he suddenly realized he had forgotten something, and he would shout to us that he'll be back shortly. On such an occasion, one of the most popular Hevesy slogans was coined. He was running down the stairs real fast and shouted to his coworker: "Herr Hahn, Herr Hahn, you are lucky, you have your rabbits, I must go home to my family!" 1 For a complete list of Hevesy's publications, see Nuclear Physics A 98 (1967), No. 1.
H. Levi: George yon Heresy Memorial Lecture
You must not misinterpret this story; Hevesy adored his family, he was just a little envious that Herr Hahn was able to stay in the laboratory all night. The Hevesys were very hospitable. However, being invited there for tea or dinner and not finding anybody at home is an experience most of his friends share. For Hevesy, even pleasant company must not last too long. One night, I was among the guests when he called for his daughter Jenny at about 9.30 p.m. and asked her, please, to shut off the central heating in his bedroom. Turning to his guests with a friendly smile, he said: "You know, I always turn off the heat half an hour before ! go to bed." In the early years of the tracer method, as Hevesy expanded his activities, some of his colleagues blamed him for not knowing enough about the complexity of the problems in which he became involved, and this criticism may sometimes have been justified. But Hevesy was not really interested in details, he focused on the essential points and particularly attacked problems which, in principle, had only become accessible through the use of radio-isotopes, for example certain types of exchange reactions, permeability studies, transport of ions and molecules, and dynamic equilibria. Hevesy's approach to such problems can only be called visionary. Often, he was so sure of the outcome of an experiment that the draft of the paper was written before he had seen the experimental result. For all these achievements he was honored with numerous degrees, medals, memberships in learned societies, and prizes. The greatest distinctions bestowed on him, many people think, were the Nobel Prize in 1944 and the Atoms for Peace Award in 1959. He himself says what pleased him most was to be elected a foreign member of the Royal Society of London and to receive this Society's Copley medal. I could go on speaking about Hevesy for hours. He was unique. His scientific achievements are contained in the literature and thus available to everybody. To those who knew him, his personality is unforgettable. Hevesy did not have much sense of humor, but because of his very special bearing, he gave rise to many quite surprising situations. He himself did not think they were at all funny. Nevertheless, he supplied his friends and colleagues with the material for innumerable delightful stories and anecdotes. Maybe, when I have retired, I shall have the time to write a few more of them down.
Received November 25, 1975
