Life and Work of Rolf Wideröe by © Pedro Waloschek, => Contents
13 How Radiation Kills Cells -
the Two-Component Theory
As I was building betatrons it was only natural that I should become more and more interested in their most important application, radiation therapy. By the 60s I was therefore concentrating almost exclusively on the biological effects of radiation, especially in cancer therapy. Until then I had been concerned only with the technology of betatrons. It was a kind of metamorphosis which seemed to me quite logical and, moreover, necessary.
In 1946, when we were designing the first betatron for BBC (the one which was later supplied to the Kantonsspital in Zurich), we already devoted some time to understand better the well known effects of radiation on air and water, especially with regard to the use of electron beams, which we wanted our machines to produce as well. We considered water as a substitute for ordinary cell tissue. This is how we came to select 31 MeV as the most favourable electron energy.
It didn't take us long to discover that both the measuring methods and the units of measurement used were not adequate for beam energies of several MeV (what is now called the `megavolt region') and that they would have to be updated. These problems became particularly acute later on, towards the end of the 50s, when we extracted high energy electrons from our machines.
Professor Hans Rudolf Schinz and I wrote several papers on this subject. He was in charge of radiation therapy at the Kantonsspital in Zurich and taught at Zurich University. It was not an easy task and sometimes we would have to dig deep into physics in order to get a clear picture of what was going on. It was also difficult to determine the correct radiation doses and we even ended up proposing new units of measurement for them. Professor Schinz performed pioneering work in this field. He made sure that several betatrons were bought in Switzerland and that a great deal of research was conducted in the field of radiation therapy. As a result of his lectures and research work, other countries also installed betatrons for their radiation therapy [Wi59].
The betatron we delivered to Professor Schinz at the Kantonsspital in Zurich was eventually replaced by a new model with higher energy. The older betatron was handed over to the Biological Institute of the University of Zurich which was then directed by Professor Hedi Fritz-Niggli. We made the necessary modifications so that the electrons could be extracted. This betatron is still in use, although Professor Fritz-Niggli retired a while ago. I went to her retirement party which was very nice and she gave a wonderful speech. She also came to my 90th birthday party at the ETH. She and I often discussed the problems of radiation-biology.
The results which were obtained after many years of work have clearly demonstrated that betatrons brought radiation therapy a substantial step forward. I would say that my words at the 1959 International Radiology Congress in Munich were appropriate for their time: "The use of anything other than betatrons for the treatment of deeply situated cancerous tumours should be forbidden by law". Of course I was speaking of X-rays and electrons of up to about 30 MeV energy. However, it took many years for these ideas to spread. Doctors are very conservative people and it is not easy to steer them away from their tried and tested methods. Naturally, there comes a time when they have to accept new findings, but it does cause certain problems for medical research. For example, when we started discussing the new methods of therapy at the Radiumspital in Oslo we were initially regarded almost as charlatans. A lot has changed since then and I would say, albeit with hindsight, that many of the methods which had been used previously caused more harm than good.
Whilst on that same 8th International Congress of Radiologists in 1959 in Munich, I described the therapy of tumours with 31MeV electrons for the first time and showed that this resulted in a better distribution of radiation dosages than was possible with X-rays. Irradiation of the affected tissue is improved whilst the rest of the body is subjected to less radiation. A few years later, at the Montreux symposium of 1964, there was extensive discussion of electron therapy and its clinical results. The data reviewed at this symposium was decisive for further development of the irradiation programmes, and it was at this congress that the way forward for high voltage therapy was clarified.
During my years at BBC I had the opportunity to reflect on the correlation of different effects in the irradiation processes. I also had to travel a lot, mainly to give lectures, and in so doing I met many interesting people who were specialised in this field. I stayed in contact with some of them for many years, and my interest grew. This is why I would now like to say something about the physical phenomena which has to be considered in this context.
When fast electrically charged particles (like electrons) penetrate water, tissue or other materials, they generally collide with electrons belonging to the `electron cloud' of molecules. Thus some of the molecules may end up with one or more electrons missing, i.e. they will have been `ionised'. This process is therefore called `ionisation' and it depends on the speed of the particles flying past. Ionisation is higher at lower speeds, which is quite comprehensible since the electrical forces of slower particles have more time to act on the molecules (and their electrons) than do faster ones.
Ionisation processes literally `put the brakes on' and eventually stop electrically charged particles. Towards the end of their path, the number of remaining ionised molecules increases sharply because the particles travel at slower speed by then. The result is therefore an increasingly dense `track' of ionised molecules which is left behind by each charged particle at the end of its journey.
However, at the higher energies which we are considering here, an electron (of a molecule) may also receive quite a lot of energy when it is hit, which would cause it to travel a certain distance itself, triggering further ionisation processes. These electrons are called `delta electrons'. As ionisation greatly increases at the end of the tracks, delta electrons contribute a great deal to the total ionisation effect. And ionisation is the most important factor involved in killing cells. I shall have more to say on this later, especially on the theories developed by myself and others.
First of all though, I must explain a few things about the physical processes which occur when X-rays penetrate matter. Xrays consist of nothing more than high energy light-particles or `photons'. These can ionise molecules too, by hitting one of their electrons and thus throwing it out of its orbit. At higher energies this is a relatively rare process during which X-ray photons lose a lot of energy and are strongly deviated or even absorbed. Most high energy X-ray photons penetrate through the irradiated body without any interaction. X-ray images are produced by the different rate at which collision processes occur in various substances, which corresponds to different absorptions. Single X-ray photons therefore do not leave a `track', as would electrically charged particles like electrons.
We end up with rather a complicated picture when we look at the effects of various types of radiation. I have illustrated the most important fact in Fig 13.1 - it is taken from one of my publications on this subject [Wi62].
The top part (a) shows the effect of X-rays produced by a (low energy) 100,000 volts machine on air or water. Ionisation is strongest on the surface and decreases as the X-rays penetrate deeper - the photons are gradually `absorbed'. A tumour located deep inside the tissue could barely be reached. The surface is subjected to a great deal of radiation and may even suffer burning.
In the centre (b), I show what happens when X-rays of a 30 MeV betatron are used. The radiation is very `hard', that is, it can penetrate thick layers of matter. Such X-ray photons eventually hit electrons, which can receive a high amount of energy and therefore behave like delta electrons: At the end of their path they cause a lot of ionisation. The radiation effect on the surface is not very strong, which is important, for example, in order to avoid skin damage to the patient.
And finally, at the bottom of the picture (c), I show how 30 MeV electrons penetrate matter. They ionise on their way (because they are electrically charged), and in doing so lose energy in small stages. In some stronger collisions they also produce delta rays which cause additional ionisation effects. However, the important fact is that the electrons have a limited and defined average range (ionisation and the corresponding energy loss is a statistical process and therefore the `range' is subject to fluctuations). The region in which most of the electrons `stop' (where the ionisation effects are strongest) can be determined quite accurately from the energy of the penetrating electrons. The effect on the surface is moderate.
Ionisation of molecules in living cells can have grave, even irreparable consequences. In this context, cancer cells are much more sensitive than healthy cells. Also, healthy cells are better equipped to repair themselves than are cancer cells. This fact is fundamental to the whole of radiation therapy. For example, when a DNA molecule is broken in two places, the almost inevitable result is the death of the cell. During irradiation with alpha rays (for example from radium or other naturally radioactive substances) which have an extremely strong ionising effect, this tends to be the case. Alpha rays are helium nuclei with an electric charge of 2, which move at relatively low velocity and therefore have a correspondingly strong ionising effect on molecules. This is known as the `alpha effect' - even when it is caused by other types of radiation.
When electrons are used for irradiation, in general just minor, more or less reparable damage occurs to the cells. Only in the worst cases does it lead to the death of a cell. This is called the `beta effect', named after the `beta-rays' of radioactive substances which consist of fast electrons.
With regard to the cells which survive following irradiation it is possible to state a formula which I proposed in September 1965 in Rome, unaware of the fact that the same had already been published by M.A.Bender and P.C.Gooch in 1962 [Be62]. I didn't find out about this until 1968. I explained further details and gave references in an article for the periodical `Strahlentherapie und Onkologie' [Wi90]. The formula is now known as the Bender-Gooch-Wideröe or B.G.W. formula. It provides the probability of survival S of cells following irradiation with a dose D and is made up of two factors, one for the alpha effect and the other for the beta effect of radiation:
whereby Salpha and Sbeta are precisely defined functions of the dose D. This might also take into consideration the repopulation effects and properties of various cell types as indicated in Fig. 13.2. This description of the alpha and beta effects of radiation is called the `two component theory'. It was first formulated by P. Howard-Flanders in 1958 (although without the B.G.W. formula), but received little attention at the time.
In 1960, experiments were already being conducted using various types of radiation on human kidney cells. These experiments proved that alpha and beta effects were independent of each other (G. W. Barendsen [Ba60]). Later on I pointed out that delta electrons (and even further generations of electrons) hitting the cells have to be taken into account additionally.
That is how we finally arrived at a pretty useful picture of the various effects which have to be considered when calculating irradiations. Clinical investigations had also shown that tumour cells react far more sensitively to beta radiation than do normal cells, and this is the main reason for electron therapy providing better results than therapy with radiation containing higher alpha components.
At a meeting of the German Radiology Association - it may have been 1951 in Baden-Baden - I was introduced to Professor Werner Schumacher. After 1960 we met more frequently in Berlin. He was the senior physician in charge of radiation therapy at the Rudolf-Virchow hospital in West Berlin. We had supplied them with a BBC betatron which was inaugurated at the end of November 1961. It was the first betatron with a `magnetic lens' and was replaced in 1972 by a 45 MeV Asclepitron. When Schumacher retired in April 1986 I went along to his leaving party and stayed in his house in Berlin. He is at present recovering from a serious traffic accident in September 1993.
Professor Schumacher searched for and tested new and better patient irradiation programmes which were specially adapted for electron therapy of deep-lying lung tumours - his speciality. He dared do many things which other doctors were much less willing to attempt. I worked closely with Schumacher and tried to calculate and explain his results with the help of the two component theory. Our aim was to optimise the electron programmes and to propose a suitable theory. Schumacher irradiated many thousands of patients and gained a great experience in doing so.
In the beginning Schumacher applied single doses which were a little too high (this was between 1962 and 1966) and this put too much stress on the arterial systems. The recovery periods between radiation sessions had to be correspondingly increased. However, when he started to use single doses of electrons which were approximately twice or three times as high as those used by other radiologists, he appeared to have found the optimal dosage distribution. Of course, the dose had to be varied slightly according to the size and type of the tumour - brain tumours received a little more, others perhaps a little less.
In the end Schumacher got far better results than those achieved with traditional radiation programmes. The patients' survival chances were much improved. His experiences went on to be of great use to other doctors (see i.e. [Sch72]).
However, there is a particular difficulty which I shall now recount. Some tumour cells do not have a good supply of oxygen. These so called `anoxic' cells are much more resistant to radiation than those with a good supply of oxygen and they are not easy to kill. This causes one of the most difficult problems encountered in tumour therapy.
The situation is not entirely without hope however, since radiation changes the supply of oxygen to the tissue. Cells which previously had too little oxygen, start to take in more and can thus be killed during the subsequent radiation session. However, this causes a considerable uncertainty factor which affects both calculation and therapy.
It was a great step forward then, when, in the period between 1973 and 1986, Professor Wolfgang Pohlit discovered a new way to improve the killing of tumour cells and in particular those with an inadequate supply of oxygen [Pu82]. Pohlit's weapon was to treat the patient with 2-deoxy-D-glucose (2-DG). This substance is so similar to ordinary glucose that the tumour cells (especially those which lack oxygen) absorb it. However, the 2DG blocks the glucose and therefore undermines the energy sources of the oxygen deficient cells and so they die off quite quickly. 2-DG does not appear to have any harmful effects, and the first clinical tests proved positive. I believe that this removed a major uncertainty in radiation therapy and I would count it amongst the greatest advances of recent times.
But let's get back to Schumacher's radiation therapy in Berlin. The fact that he was able to use higher single doses with electrons is easily explained. Electrons have the lowest alpha effect of all types of radiation. Consequently the total radiation effect at the usual dose values is correspondingly low. It is therefore necessary to apply higher single doses in order to achieve the same radiation effect. At the same time this avoids killing normal cells with alpha effects. The optimal single dosages and radiation programmes which Schumacher arrived at could probably be improved upon by means of Pohlit's 2-DG therapy.
It was not at all easy to overcome the orthodoxy of some of the surgeons in this field. I can clearly remember what took place at the Radiumspital in Oslo. I had recommended that Dr.Rennäs, who worked there, should visit Schumacher and had arranged an appointment. When the time came, Dr.Rennäs wrote to me (he has since passed away) that his director had strictly forbidden him to go to Berlin and visit Schumacher. The traditionally orientated senior surgeon was obviously somewhat fearful of the newer methods.
Metastasis is still a major problem for radiation therapy. Many experiments have been conducted using poisonous substances to kill cells, but the results have been more than merely doubtful. New ways are now being tried, such as utilising the immune system to dissolve tumours.
See Box 14: The Success of the Megavolt Therapy
I met a very interesting man at the Radiation Research Congress in Evian, I think it was in 1970. This was Dr. Lionel Cohen. I had the opportunity to have some longer talks with him during two subsequent visits to Johannesburg in South Africa where he was leading radiation therapy in a big hospital. We stayed in contact for many years. Cohen is an excellent radiologist and has had many good ideas. He moved on to Chicago (USA) and has since retired.
Cohen had confirmed the correctness of Schumacher's programmes for electron therapy with higher single doses and increased recovery periods. He seemed to place particular importance on the fact that tumour cells mend at a much slower rate and much less successfully following beta damage than do normal, damaged cells. The same applies to the repopulation of dead tissue. However, this subject has not been deeply investigated so far. Cohen recognized the decisive importance of the parameters in the B.G.W. formula and set everything on deriving these from the practice of radiation therapy. He soon extended the two component theory by a third component; a very interesting development. He took into consideration the destroyed cell tissue and was thereby able to come up with even better programmes for irradiation. This difficult task could only be possible with the help of computers and he developed the required software which he described, together with his methods, in a book published in 1983 [Co83].
I also had a very good relationship with the chief surgeon of a hospital in Beijing where we had installed a BBC betatron. I had to go to China two times to give lectures. Of course, during these lectures I explained precisely how a betatron is made up and how it works. On a subsequent visit I discovered that the Chinese had built their own betatron in the meantime, which complied exactly with the contents of my lectures. It worked rather well too, except that they were not able to extract the electrons, something which was possible with our betatron.
In many cases, electron therapy has proven to be an improvement on X-ray therapy. The `magnetic lens' for electrons mentioned earlier, which we developed at BBC, also came to be applied. It was made up of rotating permanent magnets which bent the electron beam and thus steered it towards the object to be irradiated from continually changing directions. This distributes the stress on the tissue layers above even more advantageously. Use of the `lens' was essential to gain full profit from extracting the electrons from the betatrons.
When I first started working in this field nobody really knew anything precise about the primary physical effects of radiation. Nowadays we know, for instance, that the secondary electrons, the delta electrons, have a major role to play. The next effect which should be investigated is purely biological: the effects of delta electrons on enzymes, and in particular, on the DNA molecule.
And with this we have come directly to the big question: How are cancer cells created? We believe today that we know something about this. They come about by means of certain enzyme mutations. But the problems and the possibilities are various and the scientists are still a long way from concluding their research.
Naturally there are many more details on which I would like to expand, but I think it may be better to stop here. For further questions on cancer therapy and the application of betatrons I would like to refer to the many articles I have written on the subject (see i.e. [Wi90]).
My occupation with the uses of the betatron, especially in the field of medicine, required me to pay many visits to the institutes and hospitals to which we had supplied our machines. Of course, I also attended at as many conferences and congresses on the subject as I could to keep myself well informed of the latest developments. The list of my trips after 1947 is very long and quite interesting. I always wrote down the purpose for which I was making a trip (a conference or perhaps a lecture - sometimes it was several lectures), and the names of the most important people I met there. This helps to refresh many memories, for instance the two beautiful dresses I brought my wife from Beijing and my visits to the Krüger animal park in South Africa.
And last but not least, I became the recipient of many
honours as a result of my work in the field of radiation biology. In fact,
they were more numerous than for my developments and ideas
on particle accelerators. This may have a lot to do with the lectures
I gave all around and with many articles which I published
on radiation therapy.