DNA -- Then, Now and in the Future

Matthew Meselson
Harvard University
Cambridge Massachusetts

Before 1953 the question “What is Life” was as philosophical as it was scientific. But then, all at once, it could be seen how life works in terms of molecular structure and molecular interactions, at least in plausible outline.

The double-strand molecular structure of DNA and the proposals for how it might replicate and mutate proposed by James Watson and Francis Crick in two papers in Nature that year were seen by some as too simple to be right, for is biology not immensely complicated? By others the structure was seen as too beautifully simple to be wrong. But it was only a model.  It could be built as a satisfactory structure with molecular scale-models, a structure consistent with diverse physical and chemical evidence, although not actually proven by the X-ray diffraction pattern. The fact that the separate chains wind around a common axis, “plectonemically”, was not proven until 1978.

It was the immensely attractive way in which the structure could explain fundamental life processes that from the start argued most strongly for its correctness: how the structure could code for protein, how it could replicate, and how mutations could result from chemically plausible mis-pairing of the component pyrimidines and purines.  In addition to all that, it was the directly visualizable demonstration in 1958 that, as had been predicted in the second of the two Nature papers,  DNA replicates semi-conservatively, each parental chain becoming associated with a newly synthesized chain, that dispelled remaining doubt, as Watson wrote at the time. 

For the following decade or so, the WC structure took over the agenda of much of molecular biological research. Simply looking at the structure suggested detailed ways in which it might replicate, mutate, code for protein, and fold into chromosomes. Experiments were based on such suggestions from the molecule itself.  When has just looking at a lipid molecule or even a protein ever told the experimenter what to do?

With the development of increasingly powerful methods for determining DNA sequence, there have come immense advances in fields as diverse as medical genetics and patterns of ancient human migration.  And with the recent advent of simple methods for precise alteration of DNA sequence in living cells we can foresee a time when we humans will, for better or worse, guide our own  evolution  by deliberate modification of germline DNA.  The prospect of human intervention in human evolution, even if only theoretical now, raises the questions of what in our genetic make-up must not be lost.  Certainly the answer is that, while possibly introducing beneficial enhancements into the genome, we must avoid losing essential human attributes. It would probably be generally agreed that the most essential of these is our humanity itself. Yet how is that to be defined? And if defined, how to determine its genetic basis, for surely our most valued human attributes, or more precisely, the potential for their expression is coded in our genomes.