The Stability of the Genome and the Genetic Instability of Tumors

In Copenhagen, Michael Frayn dramatizes a visit made by Werner Heisenberg to Niels Bohr in 1942 [1]. The theme of the play is uncertainty and complementarity: notwithstanding the explanations of the participants, no one is really sure why Heisenberg went to Copenhagen in the midst of the war and the start of the A bomb project. But the uncertainty that revolves around the characters of Bohr and of Heisenberg also reflects on the "uncertainty principle" that Heisenberg developed along with Bohr. The concepts of "uncertainty" and "complementarity" had a profound effect on Bohr's philosophical views [2]. In particular, the thought that there are certain unknowable things in the physical world seemed to Bohr to be applicable to biology, and this viewpoint--that there might be special principles in biology, not inconsistent with the laws of physics but different--appears to have convinced many of the physicists, Schrödinger and Delbruck among them, for whom Bohr was a major influence [3].

The reminiscences of many of the important figures in the development of molecular genetics testify to the importance of the lectures by Erwin Schrödinger published in 1945 with the title What is Life? [4; see 5, 6]. Schrödinger was greatly impressed by the stability of the gene from generation to generation and by the calculations, based largely on an early paper of Delbruck's (which Schrödinger had seen in a reprint given to him by a colleague[3]), that only the release of large amounts of energy could result in mutation, presumably by providing the activation energy to move the gene from one extremely stable configuration to another equally stable mutant form. Ionizing radiation was demonstrably effective in promoting gene mutation. As Schrödinger wrote:

We are now seriously faced with the question: How can we, from the point of view of statistical physics, reconcile the facts that the gene structure seems to involve only a comparatively small number of atoms (of the order of 1000 and possibly much less) and that nevertheless it displays a most regular and lawful activity--with a durability or permanence that borders upon the miraculous. . . .

The gene [here Schrödinger is speaking of the Habsburger Lippe] has been kept at a temperature around 98°F during all that time. How are we to understand that it has remained unperturbed by the disordering tendency of the heat motion for centuries? . . .

We shall assume the structure of a gene to be that of a huge molecule, capable only of discontinuous change, which consists in a rearrangement of the atoms and leads to an isomeric molecule. The rearrangement may affect only a small region of the gene, and a vast number of different rearrangements may be possible. The energy thresholds, separating the actual configuration from any possible isomeric ones have to be high enough (compared with the average heat energy of an atom) to make the change-over a rare event. These rare events we shall identify with spontaneous mutations. . . .

From Delbruck's general picture of the hereditary substance it emerges that living matter, while not eluding the "laws of physics" as established up to date, is likely to involve "other laws of physics" hitherto unknown, which however, once they have have been revealed, will form just as integral a part of this science as the former. [4, pp. 46-47, 56, 69]

Delbruck was particularly suspicious that biochemistry would automatically provide an answer to Schrödinger's question:

Biology is a very interesting field to enter for anyone, by the vastness of its structure and the extraordinary variety of strange facts it has collected, but to the physicist it is also a depressing subject, because, insofar as physical explanations of seemingly physical phenomena go, like excitation, or chromosome movements, or replication, the analysis seems to have stalled around in a semidescriptive manner without noticeably progressing towards a radical physical explanation...