In late 1971 we were involved in a study of the interaction of radiation
with matter and were trying to use measurements of radiation
fluorescence in biological molecules to indicate how radiation affected
living cells. It soon became apparent that we were working in the dark;
the doses we used to get a significant signal were too large to be of
interest for radiation biology and although the DNA molecule appeared to
be the most likely target molecule we did not know which sort of events
and which sort oflesions were the most important. We decided to alter
our approach to see if we could find any consistent mathematical order
in the radiobiological dose relationships. We found that cell survival
curves could be very usefully described by a linear-quadratic dose
relationship and very soon came to the somewhat premature but, as it
turned out, most effective conclusion that the induction of DNA double
strand breaks should be linear-quadratic. In deciding that the DNA
double strand break was the crucial and all-important lesion we were
able to associate the mathematical analysis with the biology of the cell
and were able to relate known properties of the DNA molecule to known
radiobiological effects. On the other hand, we were restricted and
brought, from an abstract two-hit lesion which could have any property
one wished, down to earth, to a defined moleccular structure of
nanometer dimensions and well-known functions and properties.