February 2012

A 'mad race to the finish'

 

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Marshall Nirenberg (seated) with Heinrich Matthaei. The duo performed the first experiment that started the race to crack the genetic code. Photo courtesy of National Institutes of Health/Department of Health and Human Services.

What prompted you to join Nirenberg’s laboratory in 1962?
It’s an interesting story and says something about the history of the time. I graduated from medical school and was training to do primary care in internal medicine. In those days, anybody who was a physician got drafted. It was just about that simple. The Berlin Wall had gone up. People in the political and military circles were anticipating difficulties [during the Cold War], so that resulted in drafting all eligible physicians. I got drafted, so I applied for a position in the Public Health Service, which supplied physicians and scientists to the National Institutes of Health in Bethesda.

A friend at NIH told me that I ought to meet Marshall Nirenberg because he was doing interesting experiments with the genetic code. Frankly, I didn’t know anything about the genetic code. But I went to see Marshall, and he explained to me what he was doing and its importance. It was the most fascinating thing I’d ever heard. Marshall was quite a young guy at the time – I think in his late 20s or early 30s – and conveyed a lot of enthusiasm and excitement.

What was going on at the time with the genetic code?
There was a mad race to the finish. We were competing with a large biochemical laboratory in New York University run by Nobel laureate Severo Ochoa. It was quite a horse race. The polyU experiment which Marshall and Matthaei did was essential to the beginning of the process. The race was a lot of fun to watch up close.

How did the polyU experiment set the stage for your experiments?
By the time I arrived in the laboratory, the polyU experiment had been done. It had elucidated the fact that some sequence of uridylic acid resides constituted phenylalanine. But it didn’t tell us what, for example, UCU coded for or what were the other codons. It didn’t even tell us how many bases were actually needed in a codon. There was a lot of speculation. But that was the problem I worked on.

What did the assay that you and your colleagues in Nirenberg’s laboratory designed reveal?
By purification and enzymatic degradation techniques, we were able to develop very short oligoribonucleotide sequences and show that the code was triplet code. Two Us didn’t induce the binding of phenylalanine-tRNA to ribosomes. But three nucleotides set up in a row did, in fact, induce the binding of phenylalanine. So from that we knew, for example, that the code word for phenylalanine was a series of 3 Us.

I had noticed in a scientific magazine that a company in Germany was selling diribonucleotides. I bought all 16 diribonucleotides, which all had known sequences. I then systematically added a base to each of them to make triplets. [Ochoa’s] large group in New York was very good and had developed an enzyme called polynucleotide phosphorylase. I used that enzyme to synthesize the oligoribonucleotides. I developed an array of what ultimately became 64 triplets. Most of them encoded an amino acid except, of course, the termination codons.

What was the atmosphere like?
I couldn’t sleep for days at a time because of the excitement! I must admit it was very competitive; there’s no question about that. I would go to bed thinking about the next day’s experiments and then jump out of bed in the morning and rush to the laboratory. I stayed late at night. It was a lot of work but the intellectual excitement was enormous.

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This is a typically erudite and eloquent series of reflections by Phil Leder, a scientist of tremendous talent and accomplishment. However, in setting up the interview Rajendrani Mukhopadhyay might have inadvertently given some readers the impression that the number of nucleotides in the codon was unknown in 1962. The triplet nature of the genetic code had been discovered by Francis Crick and Sydney Brenner a year earlier (in the only hands-on bench science Crick ever did, and an intellectual achievement far greater than getting the double helix with Jim Watson). Phil Leder's catalytic role in the early coding race was to develop a beautiful assay system that accelerated getting most of the codons beyond that for phenylalanine, a gigantic step and one that took Nirenberg to Stockholm. Thoru Pederson UMass Medical School

 

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