A working definition of life, … could [be] in terms of a large molecule made up of carbon compounds that can replicate, or make copies of itself, and metabolize food and energy…: macromolecule, metabolism, replication.

It is now widely realized that nearly all the “classical” problems of molecular biology have either been solved or will be solved in the next decade. The entry of large numbers of American and other biochemists into the field will ensure that all the chemical details of replication and transcription will be elucidated. Because of this, I have long felt that the future of molecular biology lies in the extension of research to other fields of biology, notably development and the nervous system.

Natural selection based on the differential multiplication of variant types cannot exist before there is material capable of replicating itself and its own variations, that is, before the origination of specifically genetic material or gene-material.

The discovery of reverse transcriptase was sobering for me: a momentous secret of nature, mine for the taking, had eluded me. But I was also exhilarated because reverse transcriptase offered new handles on the replication of retroviruses, handles that I seized and deployed with a vengeance.

The fundamental biological variant is DNA. That is why Mendel's definition of the gene as the unvarying bearer of hereditary traits, its chemical identification by Avery (confirmed by Hershey), and the elucidation by Watson and Crick of the structural basis of its replicative invariance, are without any doubt the most important discoveries ever made in biology. To this must be added the theory of natural selection, whose certainty and full significance were established only by those later theories.

The possibility that the infective agent may not contain nucleic acid and consist only of a peptide or peptide-polysaccharide complex which has replication properties within susceptible cells is intriguing. If peptides, short-chain proteins, or peptide/fatty-acid/ polysaccharide complexes activate nucleic-acid template activity in the host genes to produce identical infective particles, this would invalidate the accepted dogma of present-day molecular biology in which D.N.A. and R.N.A. templates control all biological activity.

The way a child discovers the world constantly replicates the way science began. You start to notice what’s around you, and you get very curious about how things work. How things interrelate. It’s as simple as seeing a bug that intrigues you. You want to know where it goes at night; who its friends are; what it eats.

We do not know of any enzymes or other chemical defined organic substances having specifically acting auto-catalytic properties such as to enable them to construct replicas of themselves. Neither was there a general principle known that would result in pattern-copying; if there were, the basis of life would be easier to come by. Moreover, there was no evidence to show that the enzymes were not products of hereditary determiners or genes, rather than these genes themselves, and they might even be products removed by several or many steps from the genes, just as many other known substances in the cell must be. However, the determiners or genes themselves must conduct, or at least guide, their own replication, so as to lead to the formation of genes just like themselves, in such wise that even their own mutations become .incorporated in the replicas. And this would probably take place by some kind of copying of pattern similar to that postulated by Troland for the enzymes, but requiring some distinctive chemical structure to make it possible. By virtue of this ability of theirs to replicate, these genes–or, if you prefer, genetic material–contained in the nuclear chromosomes and in whatever other portion of the cell manifests this property, such as the chloroplastids of plants, must form the basis of all the complexities of living matter that have arisen subsequent to their own appearance on the scene, in the whole course of biological evolution. That is, this genetic material must underlie all evolution based on mutation and selective multiplication.

We knew that DNA was important. We knew it was an important molecule. And we knew that its shape was likely to be important. But we didn’t realise I think just how important it would be. Put in other words, we didn’t realise that the shape would give us a clue to the replication mechanism. And this turned out to be really an unexpected dividend from finding out what the shape was.

We should like to propose instead that the specificity of DNA self replication is accomplished without recourse to specific protein synthesis and that each of our complementary DNA chains serves as a template or mould for the formation onto itself of a new companion chain.
[Co-author with Francis Crick]