A young man in a lab coat and plastic gloves holds up a glass tube in a laboratory.

Deciphering the Genetic Code: A 50 Year Anniversary

By Christie Moffatt

A young man in a lab coat and plastic gloves holds up a glass tube in a laboratory.
Marshall Nirenberg in the lab, ca. 1962
Profiles in Science

Fifty years ago, on January 18, 1965, Dr. Marshall W. Nirenberg (1927–2010) completed his first summary of the genetic code—one of the most significant documents in the history of twentieth-century science—a painstaking, handwritten chart of the discovery of how sequences of DNA, known as “triplets,” direct the assembly of amino acids into the structural and functional proteins essential to life.  The chart is included in the Marshall W. Nirenberg Papers, held at the National Library of Medicine. Preserving this genetic code chart has been an important and exciting challenge for NLM conservators, as they study the best way to store this important document written on multiple sheets of paper in pencil, India ink, and multiple ball-point pen inks, and held together with adhesive tape.

The data provided in this summary was compiled beginning in 1961 after Dr. Nirenberg presented, in a now-famous speech given to  a small group of about 30 scientists at the International Congress of Biochemistry in Moscow, the results of his “poly-U experiments” conducted with post-doctoral researcher J. Heinrich Matthaei.  Francis Crick, who was in attendance at the Moscow meeting, had heard that Nirenberg and Matthaei had found a clue that might unravel one of the central mysteries of molecular genetics. Crick arranged to have the young scientist deliver his paper again, this time to the assembled body of about a thousand people. Many scientists–especially the 1959 Nobel Laureate Severo Ochoa–were eager to take it to the next level. Thus began a research race with some of the world’s most famous (and well-funded) molecular geneticists. Over the course of the next five years, Nirenberg worked steadily with a team of about twenty postdoctoral researchers and laboratory technicians, including Norma Heaton, who remained a member of Nirenberg’s team at the National Heart, Blood, and Lung Institute for forty years. Dr. DeWitt “Hans” Stetten, former director of the National Institute of General Medical Sciences, called this period of time “the finest hour of the NIH.”

In 2006, Dr. Nirenberg provided a description of this first summary chart:

“The DNA that we inherit from our parents contains the information that is needed to make the more than 100,000 kinds of proteins that are the molecular machinery of the body. DNA consists of four kinds of [nucleotides represented by the] letters, T, C, A and G, in long sequences. DNA is transcribed to RNA that also consists of long sequences of four letters, U, C, A, and G. The sequence of letters in RNA determines the sequence of amino acids in proteins. There are 64 kinds of 3 letter words or triplets in RNA. When we deciphered the genetic code, we determined the sequence of letters in each RNA triplet that corresponds to each kind of amino acid in protein. All forms of life on this planet use the same genetic code, although small differences in the code have been found in some organisms.

This is the first summary of the genetic code that I made on Jan. 18, 1965, when we had deciphered more than half of the code. The columns on the left and right of the chart are the 64 RNA triplets. The row across the top, ALA, ARG, ASP, etc., are the 20 amino acids. The numbers in the chart correspond to the amount of radioactive aminoacyl-tRNA that bound to a triplet on ribosomes. The second column on the right hand side contains the tentative amino acid-triplet assignments that we made at that time. Some of the tentative assignments were changed when we obtained more data, and all of the assignments that we published were correct.”

A large paper chart constructed of serveral pages taped together, handwritten in several colors of ink.
Nirenberg’s handwritten genetic code chart, 1965.

 

Throughout 1965, there would be several versions of the chart created to incorporate new findings from the many experiments conducted during this intense period of discovery. A second and last summary of the code was prepared at Dr. Nirenberg’s request by his technician, Norma Heaton, in late 1965 or early 1966, when almost all of the 64 codons had been deciphered. In an oral history interview from 2010 Norma Heaton remembers:

A young woman in a white lab coat.
Norma Heaton, ca. 1964
Courtesy Norma Heaton

“I do not even know if the term spreadsheet had been invented then. It got to the point where we knew we needed to have some sort of means of seeing it all in one big picture. So I taped data paper together and drew the columns and rows with a pen and ruler…

One of my memories…is that I can remember being in the room, and Mert Bernfield and Edward M. Scolnick—Ed went on to be vice president of Merck.…They were both kind of, I don’t want to say loud, but they were not quiet, soft-spoken people. One of my memories is, they would hang over the [experiment], and they would have the tape and they would say, “Which one is this? Which one is this?” Then you would hear this shout, like, “Oh, we discovered a new one.””

Dr. Nirenberg would go on to win the Nobel Prize in Physiology or Medicine in 1968 for this work, sharing the award with Robert W. Holley of Cornell University and Har Gobind Khorana of the University of Wisconsin at Madison “for their interpretation of the genetic code and its function in protein synthesis.” He began donating his papers to NLM in 1999, and since then nearly 500 selections from the Marshall Nirenberg Papers have been digitized and made available on NLM’s Profiles in Science.   Visitors can access archival materials related to the code, including pages from Dr. Nirenberg’s laboratory notebooks, photographs of Dr. Nirenberg in his laboratory, correspondence with other scientists working on the code, such as Francis Crick, and the full 2010 oral history interview with Norma Heaton, in which she recalls the technical challenges of the research, and more broadly, what it was like to work in Dr. Nirenberg’s laboratory during this time.

A group of people pose in a hallway.
The staff of Nirenberg’s lab celebrating his Nobel Prize.
From left to right: Norma Zabriskie Heaton, Ed Scolnick, Mike Wilcox, Marshall Nirenberg, Theresa Caryk, Ty Jaouni (hidden), Wynn Russner (partially hidden), Darlene Levenson, Greg Milman, Frank Portugal.
Courtesy Marshall Nirenberg

On March 17, 2015 at 1:00, NLM will host a special two-hour program, “A Tribute to Marshall Nirenberg.” The program marks the 50th anniversary of Nirenberg’s Genetic Code Charts—groundbreaking scientific documents now held in NLM’s historical collections. Marshall Nirenberg’s Nobel Prize medal and certificate, newly given to NLM through the generous donation of his wife, Dr. Myrna Weissman, will be on display. Dr. Frank Portugal, author of The Least Likely Man: Marshall Nirenberg and the Discovery of the Genetic Code (MIT Press), and Dr. David Serlin, historian and curator of NLM’s Profiles in Science site on the Marshall Nirenberg Papers, will speak at the event. For more information and directions please visit our 2015 lectures page. Subsequent NIH events will be announced soon.

This article is part of a series that commemorates the 50th anniversary of the Genetic Code Charts. Stay tuned throughout the year to learn more about Marshall Nirenberg and these ground breaking documents.

Christie in the NLM HMD reading room.Christie Moffatt is Manager of the Digital Manuscripts Program in the History of Medicine Division at the National Library of Medicine and Chair of the NLM Web Collecting and Archiving Working Group.

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