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Lasker Luminaries

Marshall Nirenberg: Vignettes

Nirenberg and NIH

  • The stimulating atmosphere at NIH and the camaraderie and support of his fellow researchers there, helped Nirenberg in his efforts to crack the genetic code.

The Race to "Crack the Genetic Code"

  • Marshall Nirenberg, as a biochemist, was a virtual unknown in the inner circles of molecular biology. His success in breaking the genetic code took the scientific world by complete surprise.

Cracking the Genetic Code—The Science

  • Here's a glimpse at the basics—the science behind Nirenberg's work in cracking the genetic code.

The Fifth International Congress of Biochemistry--Nirenberg's Moscow Announcement

  • In 1961, Marshall Nirenberg unveiled his stunning discovery in Moscow, setting off a worldwide race to determine the rest of the genetic code, and ushering in a new era for Soviet molecular biologists.

A Breakthrough Technique Revealed - Sixth International Congress of Biochemistry- 1964

  • Deciphering the rest of the genetic code proceeded slowly until the development of a sophisticated new laboratory technique by Nirenberg and a research fellow named Philip Leder.

 



Nirenberg and NIH

"…it lifts the heart to look closely at one institution created by the United States Government which has been achieving, since its outset, one spectacular, stunning success after another."--Lewis Thomas, foreword to NIH: An Account of Research in Its Laboratories and Clinics, DeWitt Stetten, Jr., Editor

Marshall Nirenberg arrived at NIH in 1957 during the institution's "golden years" of expansion. From its beginnings as the one-room Hygienic Laboratory in the late 19th century, to an $840 million enterprise by the late 1950s, NIH saw the country through anthrax outbreaks, catastrophic influenza epidemics, and emerging health issues of the World War II period. In addition to its active role in responding to public health needs, NIH was evolving into a superb training ground for biomedical research, attracting bright, young investigators into its labs--many going on to assume scientific leadership positions outside the walls of NIH. Today, 75 buildings on 300 acres in Bethesda are home to NIH, which now has an annual budget of more than $20 billion.

NIH scientists are relatively free from the administrative and teaching obligations of their academically based peers and are not involved in grant-writing, all of which allows them more time to focus on their research. The atmosphere at NIH in the early years of Marshall Nirenberg's tenure was especially conducive to cross-pollination of ideas between disciplines.

"…perhaps it was just that NIH was smaller then, but geneticists and biochemists, crystallographers and physical chemists, endocrinologists and microbiologists were not only talking to one another, they were tennis partners and friends."--Robert Martin quote in NIH: An Account of Research in Its Laboratories and Clinics, DeWitt Stetten, Jr., Editor

Strongly influenced by a course on phage genetics and ideas represented in the book, The Chemical Basis of Heredity--which has been called the "New Testament" for the second generation of molecular biologists--Nirenberg's interest in molecular biology developed early in his NIH career.

Nirenberg faced stiff competition in the race to determine the genetic code. But with the technical assistance from other NIH scientists in "a remarkable esprit de corps and round-the-clock collaboration," he and his collaborator, J. Heinrich Matthaei, succeeded.

"Nirenberg has never failed to acknowledge great gratitude for this support. And he has observed that he ‘discovered to his horror that he liked to compete.'"--Who Wrote the Book of Life? A History of the Genetic Code, by Lily E. Kay

 

 

The Race to "Crack the Genetic Code"

In the years following Watson and Crick's determination of DNA's double helix structure, the quest to understand the mechanism of protein synthesis proceeded as a logical next step in labs throughout the world. One key to achieving this goal was deciphering the code contained in the sequence of nitrogenous bases within the nucleic acid structure.

In 1961 Nirenberg and Matthaei published their discovery that the base sequence UUU (uracil) coded for phenylalanine, throwing down the gauntlet to the scientific community to determine the remainder of the code. Severo Ochoa and his colleagues at New York University joined the pursuit, sparking some of the most intense competition ever in the history of science.

Many of Nirenberg's fellow researchers at National Institutes of Health (NIH) temporarily suspended their own work to lend a hand in his effort. Their cooperation has been lauded as "NIH's finest hour."

"The work that I was doing in the late ‘50's enabled me to synthesize RNA polymers for my colleague, Marshall Nirenberg down the hall, who used them to do the work that he did in deciphering the genetic code." --Maxine Singer, from interview at www.accessexcellence.com/AB/CC/singer.html

Marshall Nirenberg, as a biochemist, was a virtual unknown in the inner circles of molecular biology, and in fact had been denied attendance at a Cold Spring Harbor Laboratory symposium shortly before his "UUU" announcement in Moscow. The fact that he worked at NIH, an institution that had not yet achieved its present level of esteem, contributed to this lack of recognition. Nirenberg's success in breaking the genetic code took the scientific world by complete surprise.

"As a biochemist from the NIH, unknown or ignored by the molecular biologists attending the meetings, Nirenberg spoke to a nearly empty room. Fortunately, shortly after his talk, Francis Crick, who recognized the importance of the work, arranged for Nirenberg to present his work again, to a substantial audience." --Mahlon Hoagland, from Toward the Habit of Truth
Link here for the book on amazon.com

Matthew Meselson, when asked years later whether Nirenberg was now a "member of the club" responded, "I don't know…Anyway–sure; in a sense, he has a club of his own."

 

Cracking the Genetic Code–The Science

Understanding Nirenberg's accomplishment–cracking the genetic code–requires a basic knowledge of the biological "players" in the making of a protein and some appreciation of the scientists' tricks of the trade. Here is a start…

DNA (deoxyribonucleic acid)

DNA is located within the nucleus of each cell and contains instructions for making each of the 20,000 types of protein molecules found in the human body. When Watson and Crick elucidated the double helical structure of DNA, they set the stage for yet another challenge–to determine how DNA actually orchestrates the making of a protein.

RNA (ribonucleic acid)

The "information of life" flows in only one direction; that is, from DNA to RNA to protein. In a process known as "transcription," the DNA helix unwinds and a new molecule, messenger RNA (mRNA), is made from the exposed DNA template. The mRNA travels outside the cell nucleus to the "protein factory," or ribosome, located in the cytoplasm where it interacts with small adaptor or transfer RNA (tRNA) molecules that carry amino acids for protein synthesis. Transfer RNA molecules recognize the 3-letter nucleotide sequence that corresponds with a particular amino acid, and attach it during the process known as translation.

 

Nirenberg and Matthaei discovered the first of these 3-letter nucleotide sequences (codons) when they determined that three uracil nucleotides, notated as "UUU", resulted in the incorporation of the amino acid, phenylalanine. Their experiments involved incubating RNA samples with a "soup"(cell-free extract) of bacterial ribosomes, enzymes, ATP (an energy source), tRNA, and amino acids tagged with carbon-14 for later detection.

They were successful when, by chance, they added synthetic RNA composed of a long chain of uracil molecules (polyuridylic acid). In response, the ribosomes produced a long chain of the amino acid phenylalanine, creating, in effect, the synthetic protein polyphenylalanine!

The concept of using RNAs of predetermined sequence, such as the artificial UUU molecule, suddenly opened up a whole new method for deciphering the genetic code. Scientists in labs throughout the world joined the race to uncover the rest of the genetic code.

 

The Fifth International Congress of Biochemistry--Nirenberg's Moscow Announcement

"We are coming to the end of an era in molecular biology. If the DNA structure was the end of the beginning, the discovery of Nirenberg and Matthaei is the beginning of the end." --quote by Francis Crick, in his 1962 Nobel address, Who Wrote the Book of Life? A History of the Genetic Code link here to the book on amazon.com by Lily Kay

Less than a decade after Stalin's death and concurrent with Khrushchev's construction of the Berlin Wall, Moscow hosted The Fifth International Congress of Biochemistry in 1961, the site of Marshall Nirenberg's startling scientific announcement. Several thousand participants from all over the world arrived that summer, to learn, to share, and to sample the flavor of Soviet science, which was surprisingly still under the influence…some would say corruption…of Lysenkoism.

"The assertion that there is, in an organism, some minute particles, genes, responsible for the transmission of heredity traits is pure fantasy without any basis in science." --quote by Isaak Izrailevich Prezent, Lysenko theorist, The Eighth Day of Creation, link here to the book on amazon.com by Horace Freelance Judson

Trofim Denisovich Lysenko's followers opposed molecular biology and held to the anti-Mendelian notion called Lamarckism–the refuted belief that characteristics gained by interaction with one's environment could be passed on through heredity. Under Lysenko's power, dissident scientists, among them Zhores Alexandrovich Medvedev, author of a book about the horrors of science under Lysenko, had even been confined to insane asylums as punishment for expressing their views.

"It was only eight or ten years later, when I read Medvedev's book about Lysenko, that I realized how perfectly frightful the conditions for research were for them then." --quote by Max Perutz, The Eighth Day of Creation

The Fifth International Congress of Biochemistry highlighted the scientific advances of the West–Nirenberg's cracking of the genetic code, for one--in a way that could not be ignored, providing Soviet scientists who opposed it a new foothold in their struggle against Lysenkoist dogma.

"And because of DNA and all of its consequences that were becoming clear then, and that the congress made us realize, molecular biologists in the Soviet Union started to be the first group to do battle against Lysenko. [The Soviet molecular biologists] used the opportunity of the Biochemical Congress to make quite clear their disagreement with Lysenko and with his whole biology." --quote by Medvedev, The Eighth Day of Creation

 

A Breakthrough Technique Revealed

Sixth International Congress of Biochemistry- 1964

When Marshall Nirenberg made his understated announcement of cracking the genetic code at the Fifth International Congress of Biochemistry in 1961, it meant that for the first time the composition of base pairs coding for one particular amino acid was known. What had yet to be revealed, however, was the recipe of nucleotides required for each of the other 19 amino acids--the specific nucleotide sequence--and whether any "overlaps" or redundancies existed. The "door" to the genetic code was ajar--but not fully open.

Technological limitations plagued the researchers who sought these answers. The development of a novel "triplet binding assay" by Nirenberg and a research fellow named Philip Leder, proved to be a stunning breakthrough. They made the announcement at the Sixth International Congress of Biochemistry in 1964.

"I began to talk to Marshall, who was young and enthusiastic, and…I became very excited about the work that he was doing…I almost immediately decided that this was the fellow I really would like to spend my time with." --Quote by Philip Leder from A Century of DNA by Portugal and Cohen link here to the book on amazon.com

With emerging scientific knowledge as their foundation, Leder and Nirenberg, using special filter paper, found a way to analyze the ribosome, nucleotide triplet, and tRNA/amino acid complexes involved in protein synthesis.

"I walked into [Nirenberg's] little office, I was scarcely able to contain myself, and I asked him how long he thought an oligonucleotide had to be in order to get recognition… ‘Would you believe six, would you believe five, would you believe three?'…And he nearly jumped out of his skin."--Quote by Philip Leder from A Century of DNA by Portugal and Cohen

Leder's development of a more sophisticated apparatus based on the filtering technique streamlined the process, and all 64 codons (base triplets) were determined within five years of Nirenberg's initial publication.