obvious method to reconstruct the gene mutation in a different organism to study its function. By 1979, that same gene could be shuttled into bacteria, spliced into a viral vector, delivered into the genome of a mammalian cell, cloned, sequenced, and compared to the normal form.
In December 1980, in recognition of these seminal advancements in genetic technologies, the Nobel Prize in Chemistry was awarded jointly to Fred Sanger, Walter Gilbert, and Paul Berg—the readers and writers of DNA. The “arsenal of chemical manipulations [of genes],” as one science journalist put it, was now fully stocked. “Genetic engineering,” Peter Medawar, the biologist, wrote, “implies deliberate genetic change brought about by the manipulation of DNA, the vector of hereditary information. . . . Is it not a major truth of technology that anything which is in principle possible will be done . . . ? Land on the moon? Yes, assuredly. Abolish smallpox? A pleasure. Make up for deficiencies in the human genome? Mmmm, yes, though that’s more difficult and will take longer. We aren’t there yet, but we are certainly moving in the right direction.”
The technologies to manipulate, clone, and sequence genes may have been initially invented to shuttle genes between bacteria, viruses, and mammalian cells (à la Berg, Boyer, and Cohen) but the impact of these technologies reverberated broadly through organismal biology. Although the phrases gene cloning or molecular cloning were initially coined to refer to the production of identical copies of DNA (i.e., “clones”) in bacteria or viruses, they would soon become shorthand for the entire gamut of techniques that allowed biologists to extract genes from organisms, manipulate these genes in test tubes, produce gene hybrids, and propagate the genes in living organisms (you could only clone genes, after all, by using a combination of all these techniques). “By learning to manipulate genes experimentally,” Berg said, “you could learn to manipulate organisms experimentally. And by mixing and matching gene-manipulation and gene-sequencing tools, a scientist could interrogate not just genetics, but the whole universe of biology with a kind of experimental audacity that was unimaginable in the past.”
Say an immunologist was trying to solve a fundamental riddle in immunology: the mechanism by which T cells recognize and kill foreign cells in the body. For decades, it had been known that T cells sense the presence of invading cells and virus-infected cells by virtue of a sensor found on the surface of the T cell. The sensor, called the T cell receptor, is a protein made uniquely by T cells. The receptor recognizes proteins on the surface of foreign cells and binds to them. The binding, in turn, triggers a signal to kill the invading cell, and thereby acts as a defense mechanism for an organism.
But what was the nature of the T cell receptor? Biochemists had approached the problem with their typical penchant for reduction: they had obtained vats upon vats of T cells, used soaps and detergents to dissolve the cell’s components into a gray, cellular froth, then distilled the membranes and lipids away, and purified and repurified the material into smaller and smaller parts to hunt down the culprit protein. Yet the receptor protein, dissolved somewhere in that infernal soup, had remained elusive.
A gene cloner might take an alternative approach. Assume, for a moment, that the distinctive feature of the T cell receptor protein is that it is synthesized only in T cells, not in neurons, or ovaries, or liver cells. The gene for the receptor must exist in every human cell—human neurons, liver cells, and T cells have identical genomes, after all—but the RNA is made only in T cells. Could one compare the “RNA catalog” of two different cells, and thereby clone a functionally relevant gene from that catalog? The biochemist’s approach pivots on concentration: find the protein by looking where it’s most likely to be concentrated, and distill it out of the mix. The geneticist’s approach, in contrast, pivots on information: find the gene by searching for differences in “databases” created by two closely related cells and multiply the gene in bacteria via cloning. The biochemist distills forms; the gene cloner amplifies information.
In 1970, David Baltimore and Howard Temin, two virologists, made a pivotal discovery that made such comparisons possible. Working independently, Baltimore and Temin discovered an enzyme found in retroviruses that could build DNA from an RNA template. They called the enzyme reverse transcriptase—“reverse” because it inverted the normal direction of information flow: from RNA back to DNA, or from a gene’s message backward