Molecular structure of Nucleic Acids

The Molecular structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid was an article published by James D. Watson and Francis Crick in the scientific journal Nature in its 171th volume on page 737-738 (dated April 25, 1953). It was the first publication which described the discovery of the double helix structure of DNA. This discovery had a major impact on genetics in particular and biology in general.

Impact
This article is often termed a "pearl" of science because it is short and contains the answer to a fundamental mystery about living organisms. This mystery involved the question concerning how it was possible that genetic instructions were held inside organisms and how they were 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 of what might be called the "classical age" of biology and a second "age" of molecular biology.

Some consequences for humanity due to the dominance of molecular biology 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, genetically engineered foods, the rational design of treatments for diseases like AIDS, and the use of information obtained by DNA testing as evidence in criminal court.

The nature of the discovery
Watson and Crick’s 1953 article contains the answer to a fundamental mystery about living organisms. The nature of their discovery was distinctive and in some ways surprising.

The title Molecular structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid may suggest that Watson and Crick’s discovery is not relevant 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 through heredity. 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.”

The “specific pairing” is a key feature of the Watson and Crick model of DNA, the pairing of nucleotide subunits. 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 hydrogen bonded A, T, G, and C components. Each strand could then be used as a template for assembly of a new base-pair complementary strand.

Future considerations
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 was one of the more prominent biology articles of the twentieth century.

Controversy
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 usually 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 together all of the scattered fragments of information 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 from the King's College researchers.

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. These reports were not widely circulated, but 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 take part in molecular model building and so missed the chance to explore the structural implications of her own crystallographic results.

It is questioned whether Crick's boss, Max Perutz acted unethically by allowing Crick access to the MRC report. Perutz 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.

Books about the discovery of the double-helical structure of DNA

 * Horace Freeland Judson, "The Eighth Day of Creation. Makers of the Revolution in Biology"; Simon and Schuster, ©1979.; ISBN 0671225405
 * Brenda Maddox, Rosalind Franklin: The Dark Lady of DNA, 2002. ISBN 0-06-018406-8.


 * Robert Olby; The Path to The Double Helix: Discovery of DNA; first published in 0ctober 1974 by MacMillan, with foreword by Francis Crick; ISBN 0486681173 ; revised in 1994, with a 9 page postscript.


 * James D. Watson; The Double Helix: A Personal Account of the Discovery of the Structure of DNA, Atheneum, 1980, ISBN 0-689-70602-2 (first published in 1968) is a very readable first hand account of the research by Crick and Watson.


 * Maurice Wilkins; The Third Man of the Double Helix: The Autobiography of Maurice Wilkins (2003) ISBN 0-19-860665-6.

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.

Molecular structure of Nucleic Acids 核酸分子結構