Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid

The Discovery of the DNA Double Helix

Molecular structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid by James D. Watson and Francis H. Crick. Nature 171, 737–738 (1953).

Impact

This article is a “pearl” because it is short and contains the answer to a fundamental mystery about living organisms. That mystery was how it is possible for genetic instructions to be held inside organisms and passed from generation to generation.

The article had extra impact because it surprised many biologists who did not suspect that this answer would be as easy to obtain as it was. The structure itself explains why the discovery was easy; the structure is simple and consequently, how the structure produces its function is easy to understand. That Watson and Crick were able to solve this mystery as quickly as they did is an example of prepared investigators being in the right place at the right time and working tirelessly to find the answer. The article is also symbolic of a transition between two ages:

1. what might be called the Classical Age of Biology and
2. the Age of Molecular Biology.

File:Mendel.png

Figure 1. The Classical Age of Biology came before tools were available to study the molecules in living organisms. Gregor Mendel working in his garden on the inheritance of physical characteristics of pea plants (such as flower color) discovered the rules of genetic inheritance.

Some consequences for us, here in the Age of Molecular Biology, that arise out of the revolution in biology that can be traced back to Watson and Crick’s 1953 article: pre-natal screening for disease genes, identification of the remains of 9/11 disaster victims by DNA testing, genetically engineered foods, the rational design of treatments for diseases like AIDS, releasing wrongly-convicted people from death row by DNA testing of physical evidence.

The Nature of the Discovery

Watson and Crick’s 1953 article contains the answer to a fundamental mystery about living organisms, but exactly what was the nature of their discovery?

Some scientific discoveries provide answers to mysteries that are revealed to be mysteries only by an earlier chain of scientific investigations. For example, the idea of a black hole is entirely outside of every day human experience. In contrast, the Sun has always been part of human experience and it was natural for people to wonder about the physical composition of the Sun, its origin and its ultimate fate. For a large part of human history it seemed an unavoidable part of human existence that we were so dependent on the Sun yet cut off from discovering exactly what the Sun is. The science of astronomy was eventually able to reveal that the Sun is a typical star: a gravitationally confined fusion reaction. When it became possible to characterize many stars with a wide range of masses, it became possible to develop the idea of a black hole and to find ways of detecting them.

Figure 2. Diagramatic representation of the key structural features of the DNA double helix.

The title “Molecular structure of Nucleic Acids; A Structure for Deoxyribose Nucleic Acid” may suggest that Watson and Crick’s discovery was similar in nature to the discovery of black holes. By the sound of it, surely “Deoxyribose Nucleic Acid” is not the stuff of every day human experience. It is true that the existence of nucleic acids was only revealed by analysis of the chemical components of living cells, so DNA was just as hidden from human experience as were black holes. However, DNA is not nearly as remote from human experience as are black holes. Humans are readily aware of the fact that offspring resemble their parents. It is the means by which such genetic instructions are stored inside organisms and passed from generation to generation that is hidden from view. What is hidden in the technical jargon of the title is that it is Watson and Crick’s discovery of the chemical structure of DNA that finally revealed how genetic instructions are stored inside organisms and passed from generation to generation.

Origins of Molecular Biology

The application of physics and chemistry to biological problems led to development of molecular biology. Not all biology that concerns molecules falls into the category that is labelled "molecular biology". Molecular biology is particularly concerned with the flow and consequences of biological information at the level of genes and proteins. Discovery of the DNA double helix made clear that genes are functionally defined parts of DNA molecules and that there must be a way for cells to make use of their DNA genes in order to make proteins.

Linus Pauling was a chemist who was very influential in developing an understanding of the structure of biological molecules. In 1951, Pauling published the structure of the alpha helix, a fundamentally important structural component of proteins. Early in 1953 Pauling published an incorrect triple helix model of DNA. Both Crick, and particularly Watson, felt that they were racing against Pauling to discover the structure of DNA.

Max Delbrück was a physicist who recognized some of the biological implications of quantum physics. Delbruck's thinking about the physical basis of life stimulated Erwin Schrödinger to write the highly influential book, What Is Life?. Schrödinger's book was an important influence on Francis Crick, James D. Watson and Maurice Wilkins who won a Nobel prize for the discovery of the DNA double helix. Delbruck's efforts to promote the "Phage Group" (exploring genetics by way of the viruses that infect bacteria) was important in the early development of molecular biology in general and the development of Watson's scientific interests in particular.

DNA Structure and Function

It is not always the case that the structure of a molecule is easy to relate to its function. What makes the structure of DNA so obviously related to its function was described modestly at the end of the article, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

Figure 3. DNA replication. The two base-pair complementary chains of the DNA molecule allow for replication of the genetic instructions.

The “specific pairing” is a key feature of the Watson and Crick model of DNA, the pairing of nucleotide subunits^[1]. In DNA the amount of guanine is equal to cytosine and the amount of adenine is equal to thymine. The A:T and C:G pairs are structurally similar. In particular, the length of each base pair is the same and they fit equally between the two phosphate backbones (Figure 2). The base pairs are held together by hydrogen bonds, a type of chemical attraction that is easy to break and easy to reform. After realizing the structural similarity of the A:T and C:G pairs, Watson and Crick soon produced their double helix model of DNA with the hydrogen bonds at the core of the helix providing a way to unzip the two complementary strands for easy replication: the last key requirement for a likely model of the genetic molecule.

Indeed, the base-pairing did suggest a way to copy a DNA molecule. Just pull apart the two phosphate backbones, each with its covalently attached A, T, G, and C components. Each strand could then be used as a template for assembly of a new base-pair complementary strand.

Challenge for the future: The Genetic Code

When Watson and Crick produced their double helix model of DNA, it was known that most of the specialized features of the many different life forms on Earth are made possible by proteins. Structurally, proteins are long chains of amino acid subunits. In some way, the genetic molecule, DNA, had to contain instructions for how to make the thousands of proteins found in cells. From the DNA double helix model, it was clear that there must be some correspondence between the linear sequences of nucleotides in DNA molecules to the linear sequences of amino acids in proteins. The details of how sequences of DNA instruct cells to make specific proteins was worked out by molecular biologists during the period from 1953 to 1965. Francis Crick played an integral role in both the theory and experiments that led to a full understanding of the genetic code.

Consequences

Other advances in molecular biology stemming from discovery of the DNA double helix eventually led to ways to sequence genes. James Watson played an important role in getting government funding for the Human Genome Project. The ability to sequence and manipulate DNA is now central to the biotechnology industry and modern medicine. Thousands of years of anticipation, the austere beauty of the structure, and the practical implications of the DNA double helix all combined to make “Molecular structure of Nucleic Acids; A Structure for Deoxyribose Nucleic Acid” what may be the most talked about biology article of the twentieth century.

Controversy: real or imagined?

Watson and Crick based their molecular model of the DNA double helix on data that had been collected by researchers in several other laboratories. Physics has a strong traditional role for theoretical physicists who do not collect data, but in biology, it is unusually the case that a single research team will both collect structural data and produce their own theoretical interpretation of the data. However, the data that Watson and Crick used were scattered in the results from several laboratories. Watson and Crick were the first to put all of the scattered information together that were required to produce a successful molecular model of DNA.

Much of the data that were used by Crick and Watson came from unpublished work by Maurice Wilkins and Rosalind Franklin at King's College London. Key data from Wilkins and Franklin were published in two additional articles in the same issue with the article by Watson and Crick. The article by Watson and Crick did acknowledge that they had been "stimulated" by experimental results generated by Wilkins and Franklin.

In 1968, Watson published an autobiographical account of the discovery of the structure of DNA called The Double Helix. In his book, Watson stated that he and Crick had obtained some of Franklin's data from a source that she was not aware of. In particular, in late 1952, Franklin had submitted a progress report to the Medical Research Council. Watson and Crick worked in one MRC laboratory in Cambridge while Wilkins and Franklin were in another MRC laboratory in London. While these reports were not widely circulated, Crick read a copy of Franklin's research summary in early 1953. The report contained information that Watson had previously heard in November 1951 when Franklin had talked about her unpublished results during a meeting at King's College. However, at that time, Watson had no training in X-ray crystallography and did not understand what Franklin was saying about the structural symmetry of the DNA molecule. Crick correctly interpreted one of Franklin's findings as indicating that DNA was most likely a double helix with the two nucleotide chains running in opposite directions. Crick was in a unique position to make this interpretation because he had previously worked on the X-ray diffraction data for another large molecule that had the same structural symmetry as DNA. Franklin herself had failed to see the structural implications of her own crystallographic results.

Had Crick's boss, Max Perutz acted unethically by allowing Crick access to the MRC report? He felt he had not because the report was not confidential and had been designed as part of an effort to promote contact between different MRC research groups^[2].

External links

1. ^ Discover the rules of DNA base pairing with an online simulator.
2. ^ "DNA helix" by M. F. Perutz, J. T. Randall, L. Thomson, M. H. Wilkins J. D. Watson in Science (1969) Volume 164 pages 1537-1539. Template:Entrez Pubmed

• Annotated copy of the article from San Francisco's Exploratorium
• Access Excellence Classic Collection article on DNA structure.

Online versions of the article

• Online version (Original text) at nature.com
• National Library of Medicine's PDF copy in the Francis Crick Documents Collection.
• Commemorative HTML version Am J Psychiatry 160:623-624, April 2003.

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