16 R. n. MOLE 



change happens then the thing really gets under way. This doubly-altered cell doesn't 

 stay latent because if so it would make nonsense of all their age-specific mortality rate 

 distributions. Once the second change happens the cell has some reason for undergoing 

 cell division and turnmg into a real tumour. This means, then, that when an individual 

 is exposed to radiation some cells which have previously suffered the first change may 

 suffer the second change. Then you are going to get the risk of cancer or leukaemia 

 occurring in the next few years, but once those cells are exhausted there won't be any 

 further increased risk above the normal for the age of the individual concerned. 

 botblat: Your data, I think from Japan, show an increase in ageing. 

 mole: In Japan the data are remarkably consistent with the idea that radiation affects a 

 special kind of cell and that there are more of these to affect the older you are. However, 

 in Japan, the incidence of leukaemia in people under the age of 20, the proportional 

 increase, has been greater than in people who are older, but I don't know myself just 

 how to interpret that. 



MULLER: As I understand it, what you call the second kind of change cannot occur 

 unless the first kind has already occurred, not merely that the second kind must occur 

 also. In other words, this couldn't be the type of genetic change which would remain 

 latent until the first kind of change had occurred. 

 mole: I agree, the two incidents have to occur in the right order. 



MULLER: But have you also considered the other possibility of each event being necessary 

 regardless of the other? 



MOLE: If you do that, then it doesn't allow you to fit the observed change of age-specific 

 mortality with age for different kinds of cancer. You've got to have some kind of direc- 

 tional effect to allow for the increase with age. 



berenblum: I would just like to say that there seems to me an inconsistency in this kind 

 of reasoning becaiise it presupposes that aU the progeny of any one cell continue to be 

 present later on to undergo the second change. This situation, in fact does not exist; 

 if it did then neoplasia would be the normality. What in fact occurs, statistically speak- 

 ing, is as foUows. The number of stem-cells — that is, cells capable of progressive division 

 — is statistically more or less constant throughout life. This is what is meant by normalit3% 

 and is true whether for skin or for haemaopoietic tissue or for anything else. But, for the 

 number to remain constant statistically speaking 50% of the progeny must die and only 

 one remains as the stem-cell for the next generation. If this goes on like this under normal 

 conditions then the final progeny of stem-cells capable of acting as stem-cells is still the 

 same as originally. Therefore the chances of this cell undergomg a second change is 

 theoretically no greater than before. I think this ought to be kept in mind in tliis kind of 

 reasoning. 



MOLE: Well, I've got two things to say about that: first of aU I think that neoplasia is 

 normal. One-fifth of us is going to die of it. Secondly, I think this argument of constancy 

 of stem-ceU number is not necessarily applicable. All the hypothesis proposes is that once 

 altered stem-cells have a particular selective advantage; they are still capable of acting 

 as stem-cells and producing cells which have a normal physiological function. As the 

 altered stem-cells increase m number, the number of unaltered stem-cells correspondingly 

 diminishes. 



berenblum: I said that under normal conditions the number of stem-cells that exists in 

 the body for any particular system of cells is more or less constant. In a tumour it is not 

 constant, and that is the difference. 



mole: Yes, but the hypothesis deals with events before there is a tumour. This hjrpothe- 

 tical first change is not supposed to produce a recognizable tumour in any sense of the 

 word at all, it merely provides a reservoir of cells which can undergo a second change. 



