The young German researcher’s accomplishment that night, in Marshall Nirenberg’s laboratory at the National Institutes of Health in Maryland, was to crack the genetic code, and open the road to the marvels of modern genetics. Scientists had known for a decade that our genes were made of DNA – deoxyribonucleic acid – and that this DNA produced proteins. But they remained perplexed as to how the system actually worked. DNA was a boring molecule, composed of only four components, or “bases” – adenine, thymine, cytosine and guanine, normally abbreviated to A, T, C and G. No one could understand how such a simple structure could produce the complex proteins that make up life.
That enigma was resolved in 1953, in two scientific articles by James Watson and Francis Crick of the University of Cambridge. First, they suggested that the DNA molecule was composed of two parallel spirals that were mirror images of each other, with the sequence of bases on one spiral being matched by the sequence on the other – the double helix. Then, five weeks later, they boldly stated that “the precise sequence of the bases is the code which carries the genetical information”. They argued that the DNA molecule contained a code that told the cell what protein to make.
Immediately, the physicist George Gamow suggested that the code must use sequences of three “letters” or bases. Given that there were 20 amino acids, a two-base code would not work (there are only 16 possible two-letter combinations of the four bases). A three-base code would produce 64 possible combinations – easily enough to encode the 20 amino acids.
But this was still just a theory – and obtaining proof turned out to be remarkably difficult. For a start, scientists began to suspect that another molecule, RNA, was involved in producing proteins. RNA was just like DNA, except that it was only a single helix and the T was replaced by a U, uracil.
Crick, along with most scientists, thought that the best way of cracking the code would be to mutate viruses and then swap the mutated bits around until the relationship between DNA, RNA and proteins eventually became clear. Marshall Nirenberg, however, had a very different approach. Although he had an MSc in the biology of caddis flies, he had turned his attention to biochemistry and in 1959, aged 32, had decided to study how DNA encodes proteins.
This was a bold move: some of the world’s top scientists had been hammering away at the problem without getting very far, despite massive funding. Nirenberg was not a molecular biologist, had no publishing record in the field, and worked in a backwater laboratory.
Whatever the New Yorker lacked in resources, however, he made up in ingenuity. If he could get protein synthesis to occur in a test tube, he reasoned, he could find out how it worked. This proved exceptionally tricky, but in August 1960, Nirenberg recruited Matthaei to his laboratory. Over the next nine months, the German’s meticulous technical skills helped get the system going.
How did it work? First, the two men took the bits of a cell that were involved in protein synthesis and energy production, and then added various enzymes and trace elements at just the right concentrations. Into this delicate mix they poured RNA and radioactive amino acids, so they could detect the protein that was synthesised as a result.
Nirenberg had some artificial RNA that was composed of just one base – uracil – repeated over and over. The “code” on this molecule therefore read “UUUUUUUU” (or “poly-U”). By putting this into the test tube and seeing what protein came out, Nirenberg and Matthaei would be able to read the first word in the genetic code. The advantage of this approach was that it did not matter whether the individual “words” in the code – the instructions to produce a particular protein – used sets of two, three, four or more bases. Since the poly-U RNA molecule was very long, the system would be able to make sense of the message it contained.
By May 20, Nirenberg and Matthaei had used this technique to produce a radioactive protein but, frustratingly, they could not be sure of which amino acids the protein was made. In other words, the code was still unbroken. With Nirenberg away in California, Matthaei carried out crucial experiments, eliminating the alternatives until it came down to one final experiment, in the early hours, that would settle the matter.
Read more at The Telegraph
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