The Medical Uses of Atomic Energy

by ROBLEY D. EVANS

1

FOR twelve years now, nuclear physicists have been able to produce in their laboratories a slow release of usable amounts of atomic energy, by transmuting stable atoms of the ordinary chemical elements into artificially radioactive forms of the same or different elements. The atom-smashing experiments of the physicists, carried out in many laboratories throughout the world in a coöperative quest for a better understanding of nature, have produced a new scientific tool, artificial radioactivity, which already has found wide applications in all fields of science and technology.

Biologists and physicians quickly saw that many of their unsolved problems might yield to attack with this new tool. Physicists took time out from their studies of fundamental problems in nuclear physics to collaborate with workers in the life sciences in basic studies of the process of living. In the hands of these teams of scientific investigators in the physical and biological sciences, the use of artificial radioactiv - ity has resulted in a series of medical discoveries and in the development of new therapeutic techniques which have saved thousands of lives.

The use of atomic energy did not interest statesmen or Congressional committees in the 1930’s, when these discoveries were being made. But the sober truth is that through medical advances alone, atomic energy has already saved more lives than were snuffed out at Hiroshima and Nagasaki.

We must understand something of the nature of the atom before we can understand the use it will have, say, in medical research. In modern scientific activities, only the engineer deals with objects whose dimensions can be readily appreciated by the human mind. The height of a man, the length of a bridge, the weight of a turbine, or the speed of a motorcar are all magnitudes that we can appreciate readily through our five fundamental senses.

This domain lies midway between those with which the astronomer and the nuclear physicist must deal. On the one hand, the astronomer is concerned with distances and masses and times so vast that we cannot appreciate their size, as compared with the experiences of everyday life. At the opposite end of the scale, in the domain of the atomic and nuclear physicists, the dimensions are so minute as to challenge comprehension.

Being small, atoms are also numerous. A glass of water contains about 20 million million million million atoms. If we could increase the size of each atom in a glass of water until each atom became the size of a grain of sand, say one millimeter in diameter, then the atoms from a glass of water, if they were spread over the entire ocean and land surface of the earth, would cover the earth to a depth of over 300 feet.

Atoms are mainly empty space. Each atom of any chemical element consists of a small, dense, positively charged nucleus surrounded at relatively large distances by a small number of electrons, more or less as our sun is surrounded by its planets. And each of these sub-atomic particles, the nucleus and its attendant electrons, has only about 1/100,000 the diameter of the atom. Only the very outermost electrons are involved in ordinary chemical and biochemical reactions. The inner electrons, as well as the atomic nucleus, remain relatively unaware of the chemical or biochemical activity of the outer, or valence, electrons of the atom — during even the most violent explosions of the non-atomic variety.

An explosion represents a sudden release of energy, which the physicist defines as the capacity for doing work. Every day, each of us makes use of many forms of energy. The group of devices and accessories which is the modern automobile is a striking example of the conversion and use of many forms of energy. Chemical energy in the gasoline changes through combustion in the cylinders to thermal energy. The pistons convert this energy of heat into mechanical energy, which drives the car along the road and runs the generator to produce electrical energy. The electrical energy changes to luminous energy in the lights, acoustical energy in the radio, mechanical energy in the windshield wiper or fan, and chemical energy in the storage battery.

There are still other forms of energy, one of which is mass itself. A mass of 454 grams is attracted toward the earth by gravity with the force of one pound. Mass is the fundamental property of weighable material. Over forty years ago Einstein explained theoretically the quantitative equivalence of mass and other forms of energy. Mass represents the most highly concentrated form of energy known. If we could convert one pound of matter— that is, 454 grams of mass — completely into electrical energy, we should obtain by this conversion 12 billion kilowatt-hours of electrical energy, which is more than the total monthly output of the entire United States electrical power industry in 1939. This is more than a million times the amount of energy or work which can be obtained by burning a pound of some such fuel as gasoline or coal.

The conversion of mass into mechanical or kinetic energy, and the reverse process of the conversion of various forms of energy into mass, have been routine procedures in the laboratories of nuclear physicists for decades. We do not know how to convert all of a given mass into other forms of energy. The best reactions result in only a slight reduction of the mass of the starting material.

Even in the A-bomb those atoms which go through fission lose only one tenth of one per cent of their original mass. Most nuclear reactions which involve the interconversion of mass energy and other forms of energy manage to change the mass of the reacting component by less than one part in a thousand. The reason is that the atoms involved are never totally destroyed, but are only changed to other slightly lighter atoms or fragments, and the reduction in mass is but a minute fraction of the total mass originally present. Even the energy liberated in ordinary chemical reactions, such as the burning of gasoline, comes ultimately from a slight loss of mass of the total reacting components. The change of mass into energy is only about one-billionth as great in chemical reactions as it is in nuclear reactions.

In chemistry, an element is defined as a substance which cannot be decomposed by ordinary chemical processes into a simpler chemical substance. Common and well-known chemical elements are such materials as hydrogen, oxygen, phosphorus, iron, gold, radium, and uranium. In 1940 there were 92 known chemical elements. Two additional synthetic chemical elements, neptunium and plutonium, have been produced since then by the nuclear transmutation of uranium.

The simplest atom in nature is that of ordinary hydrogen, whose nucleus consists of a single “ proton ” (a particle carrying a positive charge) and which has but one atomic electron (a negatively charged particle). The next atom in the series is that of heavy hydrogen, whose nucleus contains one proton and one neutron (neutral particle). In heavy hydrogen too there is but one atomic electron; hence the chemical properties are those of hydrogen, although the chemical atomic weight is about twice that of ordinary hydrogen.

Since the chemical properties of the various elements are dictated by the number and configuration of the electrons, these two types of hydrogen atoms will behave identically. They are therefore called “isotopes”; that is, they have the “same place” in the Mendéleeff Periodic Table of the Chemical Elements. Some elements have only one stable isotope, while others, such as tin, have as many as ten stable isotopes.

The most complicated nucleus known in nature is the heavy and more common form of uranium. This nucleus contains 92 protons; hence uranium has an atomic number of 92 and the neutral uranium atom contains 92 electrons. This nucleus also contains 146 neutrons, making a total of 238 particles in the nucleus; hence the atomic weight of the common form of uranium is 238 — an atomic weight which, since August 6, has become familiar to readers of newspapers.

2

URANIUM, like several other heavy elements, such as thorium and radium, is not a completely stable nuclear configuration, possibly because of its excessive weight and complexity. It can become more nearly stable by splitting off from itself and expelling a nuclear fragment called an alpha particle. This effort toward stabilization constitutes the alpha-ray radioactivity of heavy elements, and the swiftly moving alpha ray has great usefulness as an atomic bullet in nuclear transmutation experiments. When an alpha particle splits off and is expelled from its nucleus, careful measurement discloses that the mass of the products of the disintegration is smaller than the mass of the uranium atom. This reduction in mass appears quantitatively as the kinetic energy — the energy of motion — of the expelled alpha particles.

Some other heavy nuclei exhibit other types of nuclear transformation in their efforts to become more stable. Thus the form of lead known as radium-D, which is a decay product of radium and is found in all uranium ores, emits beta rays. In such cases one of the neutrons in the nucleus changes into a proton. This transformation, if it were all that happened, would result in the appearance of a new unit positive charge on the nucleus.

But the conservation laws of physics preclude the possibility of the creation of electrical charge of one sign only, and permit only the simultaneous appearance of equal and opposite amounts of electrical charge. Consequently, when the neutron changes into a proton, we must expect that at the same time one unit of negative electrical charge — that is, an atomic electron — will be created. The excess nuclear energy which originally induced this transformation to take place is now given to the electron, which is expelled from the nucleus and from the atom with a relatively large kinetic energy of motion. Here again, the total mass of the products is less than that of the original atom, and the difference appears as kinetic energy of the fragment.

Some nuclei, after undergoing a primary radioactive transformation, release still further amounts of nuclear energy through the emission of electromagnetic radiation, similar in fundamental character to light and X-rays. These are known as gamma rays.

In a naturally radioactive element like radium there is going on continuously, and at a rate which man cannot alter, a slow conversion of mass to kinetic energy of motion of the disintegration particles and to gamma rays. These atomic “bullets” are emitted at a tremendous velocity and are destructive to any atom through which they pass.

Many decades ago, it was discovered that these radiations are more destructive to organic tissue of rapid growth, such as cancer tissue, than they are to normal tissue. On this basis, radium and other radioactive substances found an early and continuing use in the therapy of malignancies. The energy which is used to destroy the cancer tissue is strictly atomic energy released by the slow conversion of a small fraction of the nuclear mass into kinetic energy of the disintegration radiations.

Various electrical instruments have been developed which can count one by one the disintegration particles from a group of radioactive atoms. Measurement is possible because the swift motion of the disintegration particle through air or other gases smashes a number of atoms of the gas into a free electron and a positively charged atomic residue, or ion. The presence of these electrified particles makes the gas a conductor of electricity. Sensitive electronic instruments, such as the Geiger-Müller counter, can therefore report the presence of the particles, as electrical pulses in the output circuit of an electronic amplifier.

The detection instruments now in use provide a previously undreamed-of sensitivity in the determination of minute quantities of chemical substances which happen to be radioactive, because they permit the counting of atoms individually, instead of requiring, as in the case of weighing with a chemical balance, the accumulation of millions of billions of atoms to obtain a minimum weighable quantity.

3

AS FAR back as 1913 Georg von Hevesy and Fritz Paneth found that the chemical properties of the radioactive substance radium-D were identical with those of lead. Moreover, when a small amount of radium-D was mixed with a sample of lead, it was impossible by any chemical means to separate the two. Historically, this was one of the earliest proofs of the existence of isotopes, for radium-D is simply a beta-ray-emitting heavy radioactive isotope of lead.

The inability of these workers to separat e radium-D from lead was a small but important scientific advance. It was like so many other small advances along the frontiers of fundamental science, which when taken together represent the advancing wave of our understanding and conquest of nature.

It occurred to these workers that a small amount of radium-D could be added to lead, and that subsequently the highly sensitive radioactive determination of radium-D could be used as a quantitative measure of the amount of the lead sample present even after elaborate chemical or biological reactions had taken place. They performed, then, the first deliberately planned experiment using a radioactive “tracer,” and subsequently they and their students used the method of radioactive tracers in studies of the biochemistry of lead, the mechanism of chemical reactions, the properties of colloids, surface adsorption, and many other matters.

There are 39 naturally occurring radioactive isotopes of the elements having atomic numbers between 81 and 92, and all these isotopes are found in minerals containing the parent radioactive substances uranium and thorium. Stable isotopes, however, are possessed by only three of these chemical elements: those with atomic numbers 81, 82, and 83, which are the chemical elements thallium, lead, and bismuth.

For this reason the practical use of the method of radioactive tracers was at first limited to those fields of science and those problems in which thallium, bismuth, and lead were concerned — either directly, or indirectly in combination with other chemical elements which would react with them. Although this was a severe limitation, many important investigations were carried out with minute, unweighable amounts of these elements.

Twelve years ago, in the early part of 1934, Irène Curie and Frédéric Joliot announced their accidental discovery of the artificial production, through nuclear reactions induced by alpha-ray bombardment, of radioactive isotopes of three light elements — nitrogen, silicon, and phosphorus. By this time the cyclotron had been developed into a powerful and fairly reliable machine. Using the cyclotron and other atom-smashing instruments, physicists found in a few years that all the chemical elements could be transmuted, and that radioactive isotopes of all the chemical elements could be artificially produced. By 1940 there were known some 370 radioactive isotopes of the 83 stable chemical elements.

In the production of nearly half of these isotopes, the cyclotron remains the most prolific production machine. More than 200 of the 370 known radioactive isotopes can be produced by neutron bombardment of stable chemical elements. The greatest yields of radioactive materials involving these elements are obtained through the use of the uranium piles developed in the atomic bomb projects.

As soon as radioactive isotopes of elements having physiological importance, such as carbon, phosphorus, sulphur, iron, iodine, and others, became available, medical men were quick to join with their physicist colleagues in putting the exquisitely sensitive methods of radioactive tracers to work in the solution of a wide variety of mysteries in the physiology and pathology of plants and animals. The great merit in the use of radioactive tracers is that it literally provides a way of marking a few atoms and of following these atoms as they proceed through even the most complicated metabolic processes in either diseased or normal organisms. At last we could distinguish between, for example, atoms of phosphorus in the enamel of a rat’s incisors, which had been there for months, and atoms of phosphorus which the animal had drunk in its milk at a particular meal very recently.

In the method of radioactive tracers a new analytical tool of unparalleled sensitivity became available to medical men. The method is to be classed with other analytical techniques now widely used by workers in all fields, but coming originally as by-products of fundamental research in physics. These have included such well-known devices as the analytical balance, the microscope, the X-ray, the spectograph, the electron microscope, and others.

Once it has been produced, each of the man-made radioactive isotopes — like those that occur in nature — disintegrates with a rapidity which is determined solely by its own internal constitution. This rapidity of disintegration is not altered by any chemical or physical processes to which the isotope may later be subjected. Some radioactive isotopes have extremely long lifetimes, requiring a span of a thousand years for the disintegration of half the atoms produced. Others have “half periods” of a few years or days or hours. Still others have half periods of only a few seconds, and are of interest only to physicists, because their half periods are too short to permit them to be used in protracted tracer experiments. Happily, most chemical elements have at least one radioactive isotope with a reasonably long half period.

4

DURING the war one group of American physicists and several groups of the biochemists, hematologists, and physicians working in medical centers throughout the United States and Canada were teamed together in a successful attack, by the method of radioactive tracers, on the problem of preserving whole blood for long periods and under such conditions that it could withstand the rigors of air shipment to our distant battlefronts.

When the war began, many blood banks were in operation in which human blood could be stored for periods up to five days and then transfused safely into the sick or injured. In the treatment of certain battle casualties and in the prevention or management of some cases of shock, transfusions with whole blood were required. It was undesirable to obtain this blood by bleeding of reserve troops, especially in the Pacific theater, for a variety of reasons, including the possible transmission of tropical diseases, such as undetected malaria. The armed forces called for a blood preservative solution which could be added to freshly drawn whole blood and which would keep it in excellent condition for a minimum of twenty-one days.

The crucial test of a satisfactorily preserved blood is that the transfused red cells remain in circulation in the recipient’s blood stream so that they can transport oxygen to the tissues. In testing a sample of preserved blood it was necessary to distinguish between the recipient’s own red cells and the red cells which he had received by transfusion. A method of marking without injury to the stored red cells was therefore required. Radioactive isotopes of iron were used for this purpose.

The process was this: a small fraction of manganese was transmuted into a radioactive isotope of iron, which has a half period of about five years. The bombarded manganese target was turned over to the chemists in the radioactive scientific team. Mixing a few milligrams of ordinary iron with the dissolved manganese target, they then separated chemically a small quantity of iron tagged with the radioactive isotope of iron.

It must be emphasized that the radioactive tracer atom behaves normally and is chemically identical with all other atoms of the same element until the radioactive transition occurs. The radioactive isotopes are actually spies which go around unrecognized in the company of normal atoms of the same chemical type and at a later time reveal in detail the movements of the normal atoms which they accompany. _

Having obtained a few milligrams of iron tagged with the radioactive isotopic tracer, the chemists then synthesized this iron into ferric ammonium citrate. After sterilization, the ferric ammonium citrate was turned over to the medical members of the scientific team, who made intravenous injections of small quantities of it in the volunteer human subjects who were subsequently to act as blood donors. These donors utilized the iron received by injection in the formation of hemoglobin, which they incorporated into the new red cells entering their circulating blood. In this way the donors’ red cells became tagged by the radioactive iron atoms in the hemoglobin molecules of the red cells.

The donors then gave the standard 500 cubic centimeters of blood, and to this blood was added one of the many chemical preservative solutions whose merits were being studied. After storage at a predetermined temperature and for a specified time, this blood was transfused in a human recipient. Beginning immediately after the transfusion, small samples of the recipient’s blood were taken at regular intervals. These blood samples were then measured for radioactive iron, using highly sensitive Geiger-Müller counters to measure the radiation emitted.

The degree of radioactivity of the recipient’s circulating blood gave a direct measure of the survival of the transfused red cells in his circulating blood stream. The National Standard of a satisfactory transfusion, as established for this work, is that 70 per cent of the transfused red cells shall remain in the recipient’s circulation for at least forty-eight hours after the transfusion. Actually it was found that those red cells which had been damaged by storage or shipment were withdrawn from the recipient’s circulating blood in the first two hours or so after the transfusion.

These methods served to screen out many preservatives which proved to be inferior, and led to the selection of a preservative known as ACD-1, which much more than meets the military requirements.

5

JUST at the time when the war was closing down fundamental research, another group of scientists were concluding the preliminary parts of a study of carbohydrate metabolism. Carbohydrates are thought to enter the blood as simple sugars, and any surplus is converted and stored in the liver as the animal starch glycogen. This glycogen provides a reserve supply of food which may be called on between meals, when the glycogen is changed back to blood sugar as needed. In the process, liver enzymes and insulin from the pancreas play important roles.

Sodium lactate in which particular carbon atoms had been tagged by using radioactive carbon atoms to synthesize the lactate was administered to a series of animals. Information on the details of the chemical reactions leading to the formation of liver glycogen as a result of the administration of this tagged lactate was sought by radioactive analysis of the new glycogen appearing in the livers of the experimental animals. The situation was found to be vastly more complicated than had been believed previously. In fact, it could be shown that a large proportion of the carbon atoms in the newly formed glycogen were actually from carbon dioxide being carried by the blood stream to the lungs for exhalation.

These and many other metabolic experiments have recently disclosed an extremely general, rapid, and widespread turnover and interchange among the molecules in the living body. Enzymatic equilibrium or steady-state reactions occur everywhere all of the time in the body. The isotopic tracers provide a unique method for investigating a normal animal or organism under equilibrium conditions. Calorie balance and nitrogen balance can be maintained rigorously during the entire course of the investigation.

That this procedure is a great step forward can be appreciated when we realize that our previous knowledge of intermediary metabolism had to come mostly from experiments performed under abnormal conditions. It was necessary to use organisms which were sick or poisoned, or from which certain tissues or organs had been removed. Abnormal or unnatural compounds had to be administered, or diets employed that were unduly enriched or impoverished in the test substances. It is small wonder that the results of such experiments were necessarily fragmentary and often incompatible with one another.

The entire field of physiology and biochemistry is being re-examined with the powerful aid of the method of radioactive tracers. In many cases the new results already obtained are contrary to previously accepted points of view. These new results serve to clear away much deadwood and to give valid reasons for discarding many alternative or conflicting interpretations of old observations. The new results are establishing a firm basis on which biochemical and physiological knowledge can be rapidly and consistently enlarged.

Vitamin B1 has been synthesized, using radioactive sulphur, and studies of its storage, utilization, and excretion have shown that 10 per cent of the vitamin Bi in the human body is destroyed every twenty-four hours. Based on such definite evidence, dosage intervals and levels in human nutrition can be made on a much more scientific basis.

The thyroid gland plays a fundamental role in the regulation of growth and of body heat. Its principal hormonal secretion, thyroxin, is rich in iodine. The metabolism of this compound, which appears to be of basic importance in the proper functioning of the thyroid, has been studied in several laboratories over a period of years with the aid of radioactive iodine. The conversion of inorganic iodine into di-iodotyrosine in the thyroid gland and the subsequent formation of thyroxin from this chemical have been traced in quantitative detail in both normal and diseased thyroid glands.

Both normal and diseased thyroid glands take up iodine from the blood stream within a few minutes after administration, but the uptake is much greater in the case of an overactive, toxic, or hyperplastic gland. Both normal and hyperplastic thyroid glands take up a larger fraction of any single dose of iodine if the size of the dose is small. In patients with toxic goiter, the thyroid gland may take up as much as 80 per cent of a single orally administered dose of sodium iodide if the total amount of iodine in the dose is one milligram or less.

When X-rays are used for radiation therapy, the X-rays knock individual electrons from some of the atoms in the irradiated tissue and project these electrons forward with high velocity. These high-velocity electrons then interact with a large number of other atoms in neighboring tissue cells to produce effects which are highly damaging or lethal to the cells traversed by the secondary electrons. This is the essence of the physical phenomena involved in the therapeutic use of X-rays.

But the beta rays given off by radioactive isotopes are also high-speed electrons. Physically, they are indistinguishable from the secondary electrons produced by X-rays. Therefore the beta rays of radioactive isotopes could be used for therapeutic purposes provided that they were present in sufficiently great numbers to produce a radiation effect. Through the use of the cyclotron and the uranium pile developed for use in the A-bomb, sufficiently strong sources of radioactive isotopes can now be obtained.

In the case of toxic goiter in human beings, as I have said, a small, orally administered dose of iodine is rapidly concentrated in the thyroid gland alone. By using an accurately controlled amount of a radioactive isotope of iodine, it is possible then to deliver to the thyroid gland an amount of radiation which is equivalent to X-ray therapy.

Indeed, a much larger radiation dose can be readily administered in this manner than is possible with X-rays. When X-rays are used in treating the thyroid gland, these rays must pass through the skin and overlying tissue and nerves before reaching the thyroid, and the thyroid dosage often has to be limited in order to avoid doing irreparable damage to the overlying tissues. But radioactive iodine supplies the radiation from within the thyroid gland itself and produces substantially no effects in the surrounding tissues. Although the work is still in an experimental stage, encouraging results have been obtained in two medical clinics using radioactive iodine as the only therapeutic measure in the treatment of toxic goiter.

Through the use of radioactive phosphorus it was found some years ago that an administered dose of phosphorus is initially concentrated in the bloodproducing centers. This discovery has formed the basis for the treatment of certain blood dyscrasias, notably the leukemias, and polycythemia vera. A large number of cases have been treated in many medical centers throughout the United States, and the results so far obtained indicate that radioactive phosphorus therapy is the only known satisfactory cure for polycythemia vera. No permanent cure is known for the leukemias, although several modes of treatment produce improvement. Among these is radioactive phosphorus, which is judged to be at least as effective as any other known therapy.

6

THE therapeutic application of radioactive isotopes is a broad field for future research. Its only requirement is that some molecule be found which the body will concentrate in the diseased tissues needing radiation. It is then only necessary to synthesize this molecule, using a sufficiently strong sample of radioactive isotope. Naturally the quest for a desirable molecule is best carried on by using radioactive isotopes in the more minute amounts characteristic of tracer applications.

In all these therapeutic applications it is evident that the radiant energy actually used on the tissues is the kinetic energy of the disintegration particles from radioactive atoms. In many instances this atomic energy was stored in the atoms of the radioactive isotope as a result of the nuclear bombardment by which the material was produced. This mass energy is then converted at the time of the radioactive disintegration into useful radiant energy.

There is no question that the slow release of atomic energy in radioactive isotopes will have many and varied applications in medical research and in the treatment of disease. Fundamental investigations are needed in nutritional studies, in the behavior and improvement of drugs, in the mode of operation of various types of anesthetics, in the growth and treatment of malignancies, and in the mode of transmission of insect-borne diseases.

The wide need for adequate supplies of radioactive isotopes of the various chemical elements will quickly stimulate their industrial production. These materials ought to be commercially available to all types of laboratories in the near future. The specialized types of detection devices are beginning to be produced commercially by several competent electronic manufacturing concerns. This equipment should be sufficiently reliable to permit its being successfully operated by technicians and others having a minimal experience in the intricacies of the electronic circuits involved. It should be possible to bring these instruments to nearly the same state of universal usefulness as a household radio.

The problem of personnel is at the moment more difficult. So far, the most fruitful applications of these new techniques have been the results of teamwork between physicists and other scientists. There is need for a number of hybrid Ph.D.’s who can bridge the gap between physics and the other scientific fields and whose breadth of knowledge fits them to act as key men in the coöperative research teams of the present and future. At the moment such people are rare, and their scarcity is one of the educational deficits which our country has accumulated through its failure during the war years to permit the continuance of the scientific training of talented young men and women. The new tool of nuclear energy lies ready at hand for the infinite uses of peace, but the workmen have lost irreplaceable time through the stupidities of war.