Embryology and the Organization of DNA in Higher Organisms, 1966-1976

"This is an historic occasion," declared Francis Crick on June 2, 1966, in his opening remarks to the annual conference of molecular biologists at Cold Spring Harbor Laboratory on Long Island. "There have been many meetings," he explained, "about the genetic code during the past ten or twelve years but this is the first important one to be held since the code became known." Major questions about the genetic code remained to be answered: scientists had not yet determined the base sequence of any gene, nor had they looked closely at the site of protein synthesis, the ribosome, or at the important role of enzymes in DNA replication, repair, and control. Nonetheless, with the identification of the codons for all twenty amino acids, most of the basic concepts of molecular biology had been affirmed and its classical era, as Crick would later call it, had reached its apogee. Due in significant measure to Crick's work, molecular biology had established an intellectual dominance similar to that of theoretical physics during the first half of the twentieth century.

Crick remained as busy as ever, involved in several lines of research and much in demand as a speaker, commentator, and sounding board for scientists throughout the world. Indeed, for various periods during the 1960s and early 1970s, he became so burdened with work that he turned down all invitations to travel and lecture. He sometimes used a pre-printed postcard, reproduced in this exhibit, on which he checked off one of seventeen kinds of solicitation (to lecture, heal a disease, accept an honorary degree) that he routinely declined because they infringed on his time to think.

Crick's final contribution to the understanding of how deoxyribonucleic acid (DNA) controlled protein synthesis, made also in 1966, was his "wobble" hypothesis. This was a proposition concerning how a triplet of bases on a transfer ribonucleic acid (tRNA), the anticodon, recognized and bound to the codon on the messenger RNA, the complementary triplet that coded for the respective tRNA and the amino acid it carried during protein synthesis. Crick suggested that while the first two bases of the codon and of the anticodon formed standard complementary base pairs according to the pairing rule propounded by him and Watson in their original DNA model, there might be some degree of variance, or wobble, in the pairing of the third bases, allowing, for example, a pairing between uracil (which takes the place of thymine in RNA) and adenine as well as between uracil and guanine. Such variance would help explain why the genetic code was degenerate, that is, why almost all amino acids are specified by more than one codon.

From 1966 on, Crick's main scientific concern was to understand how genes controlled the processes of cell division, cell differentiation, and organ growth, that is, to merge genetics and embryology or, as it is generally called today, developmental biology. Gene replication, action, and control had been studied nearly exclusively in microorganisms such as molds, bacteria, and bacterial viruses. Very little was known about the organization of DNA on chromosomes or about the action of genes in more complex organisms. Experimental studies of how the genetic instructions in the fertilized egg are transcribed in the process of cell division and cell specialization, and how these instructions interact with environmental factors to form the growing organism, promised not only to enhance scientists' understanding of the basic processes of life, but to reveal the molecular pathways of human scourges like cancer, neurological diseases, and organ failure.

During the late 1960s and early 1970s, Crick drew on Sydney Brenner's innovative experimental work on the life cycle of the nematode Caenorhabditus elegans, a self-fertilizing earth worm made up of about a thousand cells, to develop theories about the organization of chromosomes and about genetic control of an organism's development. As a result of his preoccupation with chromosome structure Crick became interested in the histones, simple proteins that are associated with DNA in the chromosomes of higher organisms, and that Crick thought played an important role in gene replication. Histones and DNA are components of chromatin, the name given to the chromosomal material when extracted from the cell nucleus. Discovering the structure of chromatin and of nucleosomes, assemblies of histones and short stretches of chromosomal DNA that appear like beads on a string under the electron microscope, was the focus of Crick's colleagues at the Laboratory of Molecular Biology in Cambridge, Aaron Klug and Roger Kornberg. Crick followed their work closely, and in discussion with them brought to bear his unmatched ability to perceive the central problem at hand through layers of conflicting experimental data, as can be seen in his correspondence with Klug from the 1970s.

Crick suspected that a key feature of development were gradients, postulated factors that might explain why cells, when looked at in a sheet of cells, seemed to know their position within the sheet and to interact with other cells according to their relative position. He assumed that gradients denoted regular changes in the concentration and electrical charge of chemicals within a sheet of cells, but he was unable to work out the biochemistry of such gradients--what molecules formed them and how--and abandoned this field after some time.

Genetic research advanced greatly during the 1970s with the introduction of recombinant DNA, genetic engineering, rapid DNA sequencing, and monoclonal antibodies used in experimental chemotherapy. Crick was not directly involved in the development of these new research and therapeutic techniques, but paid close attention to them. At the same time, scientists were making discoveries that questioned some of the assumptions he and Watson had made in their original theory of genetic transfer. One example was the discovery of "introns," sequences of DNA found on the chromosomes of higher organisms which interrupt those stretches of DNA that code for a polypeptide chain, the so-called exons. Introns are eliminated in the assembly of messenger RNA by splicing. Watson and Crick's theory had posited that coding sequences were continuous; now it turned out that in higher organisms with large amounts of DNA, the introns were often longer than the meaningful sequences, the exons. In fact, researchers found that as much as ninety percent of the human genome (the complete chromosomal gene complement of an individual) was made up of "junk DNA" without apparent function.

Crick was intrigued by these findings, and tried to make sense of them in an article on "selfish" DNA co-authored with his former Cavendish colleague Leslie Orgel. In the article, the two suggested that nonsense sequences originated as DNA parasites, traveled along the chromosomes, and left copies of themselves embedded in the host DNA. These copies were rendered meaningless over time through random mutation and were subsequently eliminated by the host cell, a process repeated many times over the course of evolution. Whether this hypothesis is true remains to be seen.

At various points during the late 1960s and 1970s, researchers questioned whether Watson and Crick's model of the double helix was correct at all, asserting, variously, that for mathematical reasons the two strands of DNA must be straight rather than twisted around one-another to allow unwinding and replication, and that the X-ray evidence could accommodate base pairings other than A=T and C=G. Jerry Donohue, the physical chemist who in 1953 had given Watson crucial information regarding the proper chemical structure of the DNA bases, was one such critic. In 1979, Crick responded to his critics in a review article entitled "Is DNA Really a Double Helix?" In his article he cited mounting scientific evidence for the validity of his and Watson's original model, evidence that has only grown since.