February 2012

A 'mad race to the finish'

A conversation with Philip Leder on the genetic code experiments that he began 50 years ago


Philip Leder in 2002 in his laboratory at Harvard Medical School with then-graduate student Benjamin Leader. Photo courtesy of Steve Gilbert.

In 1961, Marshall W. Nirenberg of the National Institutes of Health and his postdoctoral associate, Heinrich Matthaei, shot to fame for “breaking the genetic code.” Their work launched the era of genomics, leading to the Human Genome Project, whole-genome sequencing and personalized medicine.

In the now-famous polyU experiment, Nirenberg and Matthaei showed that a synthetic RNA made of only uracils coded for the amino acid phenylalanine (1). But the polyU experiment was just the beginning. Scientists still had to work out how many bases were in a codon and which codon corresponded to which amino acid.

In 1962, a year after the polyU experiment, Philip Leder joined Nirenberg’s laboratory as a research associate. He used artificial RNA sequences of three nucleotides in cell-free systems as an assay for the genetic code. The fragments were long enough to let ribosomes bind with the complementary aminoacyl-tRNA molecule and still be detectable. Leder and other members of Nirenberg’s laboratory radioactively labeled one amino acid at a time in a mixture of the 20 amino acids and put the mixture through a filter. The filter let unbound aminoacyl-tRNAs pass through but caught the ribosomes. The sample in the filter was then tested for radioactivity. If radioactivity was present, then the labeled aminoacyl-tRNA matched the codon in the oligonucleotide; the sequence of bases in the codon was the code for amino acid carried by the tRNA.

With this assay, Nirenberg’s group deciphered most of the codons by 1966. In 1968, Nirenberg shared the Nobel Prize in physiology or medicine with Robert W. Holley and Har Gobind Khorana for deciphering the genetic code.

Subsequently, Leder’s career led to understanding the genetic underpinnings of the immune system and cancer. His work garnered him, among other things, the Lasker Award and the National Medal of Science. One of his seminal contributions was the introduction of oncogenes into laboratory mice to make transgenic animals. Leder recently retired from Harvard Medical School.

Leder spoke with ASBMB Today to reflect on the experiments he embarked on 50 years ago. Below are edited excerpts from the interview.

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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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