Pauling Predicts the Process of Gene Replication

A segment of the original Watson and Crick DNA model. 1953.

“…I realized that I myself might discover something new about the nature of the world, have some new ideas that contributed to better understanding of the universe. For seventy years the motive to obtain greater understanding has dominated my life.”

-Linus Pauling. “The Nature of Life, Including My Life. Chapter 1 – How I developed an Interest in the Question of the Nature of Life.” May 5, 1992.

On May 28, 1948, Linus Pauling gave the 21st Sir Jesse Boot Foundation Lecture at the University of Nottingham. His talk, “Molecular Architecture and the Processes of Life,” presented many interesting examples of the important roles that certain molecules play in the human body. In so doing, Pauling discussed topics such as respiration, genetics and the immune system, and in typical Pauling fashion, displayed a knack for providing simple yet fascinating explanations of complicated subject matter. Although the entirety of his speech is interesting, Pauling’s comments concerning the gene were clearly well ahead of his time, and that is the focus of today’s post.

By 1948 it had already been suggested, through experimentation by Oswald Avery, that DNA was the genetic material. However most major scientists, including Pauling, still thought it more likely that proteins, being more complex and versatile substances than DNA, would carry the building blocks of heredity. As a result, DNA didn’t gain much importance until James Watson and Francis Crick discovered its structure in 1953. But scientists concerned themselves with trying to understand the gene long before they were aware of its place in the DNA molecule.

Pauling and two colleagues in Glasgow, Scotland, April 1948.

Included among these interested researchers was Pauling, who in his Boot Lecture predicted both the basic manner in which genes act as templates for proteins as well as the means by which gene replication might occur.

 I believe that the same process of molding of plastic materials into a configuration complementary to that of another molecule, which serves as a template, is responsible for biological specificity. I believe that genes serve as the templates on which are molded the enzymes that are responsible for the chemical characters of the organisms, and that they also serve as templates for the production of replicas of themselves.

As it turned out, Pauling’s simple statement had outlined the basics of the now familiar mechanism for the transcription of a protein from an RNA molecule. At the time of his talk, he may not have known the specific elements of the procedure, but the bulk of his prediction was more or less spot-on.

So an impressive start, but Pauling wasn’t done there. Continuing, he commented on how he imagined the gene might replicate itself.

The detailed mechanism by means of which a gene or a virus molecule produces replicas of itself is not yet known. In general the use of a gene or virus as a template would lead to the formation of a molecule not with identical structure but with complementary structure. It might happen, of course, that a molecule could be at the same time identical with and complementary to the template on which it is molded. However, this case seems to me to be too unlikely to be valid in general, except in the following way. If the structure that serves as a template (the gene or virus molecule) consists of, say, two parts, which are themselves complementary in structure, then each of these parts can serve as the mold for the production of a replica of the other part, and a complex of two complementary parts thus can serve as the mold for the production of duplicates of itself.

Again, Pauling hit the nail right on the head. We are now aware that DNA replication occurs precisely in this manner, and the fact that he was able to logically deduce the essentials of the mechanism without knowing the site or the structure of the gene is rather remarkable.

To read Pauling’s entire speech, click this link. For more information on Linus Pauling ranging from his attempts at elucidating the structure of DNA to his prolific peace work, please visit the Linus Pauling Online portal.


James F. Crow, 1916-2012

James F. Crow. (Credit: Millard Susman)

Professor Crow ran his laboratory on the principles of bringing smart people together to pursue their passions and encouraging interaction, mutual respect and support, constructive criticism, and the free sharing of ideas and resources. There were no formal group meetings or reports, as there was so much daily interaction that group meetings would have been superfluous. He would advise, suggest, and encourage, but never direct or cajole. The standard of mutual respect was set by Professor Crow himself and extended not only to members of the lab but also to everyone in the field. I never heard him utter an unkind word about anyone. He also treated everyone in the lab as a colleague. One day he came to me and said, ‘Dan, there’s a matter on which I’d like your advice.’ He must have seen how flattered I was at being asked because he quickly added, ‘That doesn’t mean I’ll take it. It only means I want to hear it.’

-Daniel Hartl.

James Crow, Professor Emeritus of Genetics at the University of Wisconsin-Madison, enjoyed a successful scientific career that spanned some seventy years. Crow was most widely recognized and honored for his research in the field of population genetics. With Motoo Kimura, Crow co-authored a book titled, An Introduction to Population Genetics Theory (1970), which focused on the mathematical basis of population genetics and which is now considered a classic of the field.

Born on January 18, 1916 in Phoenixville, Pennsylvania, Crow was exposed to the importance of education early on, as his father was a teacher at Ursinus College and later at Friends University in Witchita, Kansas, which Crow attended. Throughout his schooling, Crow enjoyed physics and chemistry, and ended up double majoring in chemistry and biology. In 1941 he earned his doctorate degree in genetics at the University of Texas-Austin, where he also played viola in the student orchestra. This is also where he met his wife, Ann, who was a clarinetist.

Crow next spent seven years at Dartmouth before moving to the University of Wisconsin, where he remained for the rest of his life. Crow’s collaborator Kimura joined Crow’s lab at Wisconsin in 1961, where he spent the next two years working on important problems like the fixation probability of a newly occurring mutation and the “infinite alleles model.”

(Credit: W. Hoffmann)

Over the course of his career, Crow witnessed the discovery of the structure of DNA, the rise of computer technology, cloning and the sequencing of the complete human genome. He stayed current with scientific several fields and was always curious about new research and findings. He became a respected leader in his field and served on a genetics committee set up by the National Academy of Sciences to assess mutational damage in those exposed to radiation from the atomic weapons dropped on Hiroshima and Nagasaki. He also developed the concept of genetic load, a measure of how fitness may be reduced by selection, and applied it to the rate at which natural selection would remove deleterious mutations from a population.

Remembered for his ability to explain concepts in ways that others could understand, Crow was described as a “brilliant mind and a fabulous storyteller.” His writings on genetics gained international traction and are now commonly referred to as “Crow’s Notes.” During his career, genetics was a growing and changing field; when asked by his students to give them a hint about questions that might be posed on their exams, Crow would often reply, “the questions are the same every year but the answers are different.”

I have never met Professor Crow, but I myself have developed a strong feeling about his ability and reliability from reading his papers.

-Linus Pauling

Known for being social and maintaining a positive outlook on life, Crow enjoyed parties and other avenues that afforded him the opportunity to influence fellow scientists. (One such avenue was his work with the journal Genetics, for which he edited the “Perspectives” section from 1987 until 2008, where he published scientific anecdotes from major scientists in the field of genetics.) One of the scientists influenced by his work was Linus Pauling, who often referenced Crow’s research in his own writings and speeches.

One notable example came about in 1962, when Pauling began writing “Fallout,” a piece discussing nuclear weapons tests that he hoped to publish in The Saturday Evening Post.  As he was developing his text that February, Pauling wrote to Crow, asking if he would be willing to rewrite any sections that he felt might need it and to advise him on any other aspects that needed to be revised or omitted. Crow responded with a three page handwritten letter, providing only minor mark-ups on the actual text, but adding several comments regarding word choice, making sure that Pauling felt no pressure to credit him for the revisions. “Your article fills the bill,” he noted, “I see no need for me to write anything additional.”

Crow did, however, include a quote of his own that he said was published in one of his public affairs pamphlets.  It read,

The harm from fallout is spread over space and time so thinly that the increased risk to any individual is too small to measure, but if all the damaged individuals could be identified and brought into one place at one time it would be regarded by everyone as a major catastrophe.

He concluded his letter by inviting Pauling to visit his lab in Madison, Wisconsin.

Later that year, in an article titled “Genetic Effects of Weapons Test,” published in December in the Bulletin of the Atomic Scientists, Pauling once again referenced Crow’s research on exposure to radiation and its deleterious effects on children. This research led Pauling to look into the possibility that carbon-14, a by-product produced by neutron irradiation of nitrogen-14 during nuclear weapons tests, could do extensive genetic and somatic damage. Based on estimates for radiation dosages published by Crow, Pauling determined that one’s exposure to carbon-14 over the entire lifetime of the isotope is actually four times higher than what had normally been assumed for worldwide radioactive fallout.

It is clear from Pauling’s papers that he learned a lot from James Crow’s extensive research on genetics and on the effects of radiation. The two also shared a taste for public service, as Crow chaired various civic organizations while staying engaged in his studies for the remainder of his life. Crow died of congestive heart failure on January 4, 2012, aged 95, at his home in Madison. He spoke frequently with his colleagues until the end.

Pauling’s Methodology: Electrophoresis

Diagram of a Tiselius electrophoresis apparatus.

Diagram of a Tiselius electrophoresis apparatus.

[Electrophoresis image extracted from the published version of Arne Tiselius’ Nobel lecture, December 13, 1948.  A digitized version of this lecture is available here courtesy of the Nobel Museum.]

The item of $7,500 for apparatus, supplies, animals would permit us to use the large number of animals required for some of our projected researches, and should permit also the construction of a Tiselius apparatus for the electrophoretic separation of antibody fractions by the suggested method of combination with charged haptens, and for other investigations.
– Linus Pauling, budget request letter to Warren Weaver. January 2, 1941.

Though, by the late 1930s, X-ray crystallography had become important to Linus Pauling’s research on the structure of complex organic proteins, the newly developed technique of electrophoresis eventually became the technology that defined his work on sickle cell anemia.  Indeed, Pauling was one of the first in a generation of scientists to effectively use the technique of electrophoresis to explain a biological phenomenon.

Lying at the core of Pauling’s interest in sickle cell disease was this question: What really made normal hemoglobin and the hemoglobin from someone suffering from sickle cell anemia different? Though Pauling and his fellow researchers theorized that the answer lay in differences between the structures of the hemoglobin molecules themselves, and also figured that magnetic properties somehow played a role, they had yet to find or develop a method suitable for testing their ideas.

As it turned out, Pauling and his colleagues had to do both: they found and they developed.

The Pauling group seized upon the new technique of electrophoresis but manipulated it considerably to fit their own research agenda. Pauling attributed the idea of using electrophoresis in the first place to one of his graduate students, Harvey Itano. Later Pauling and Itano sought advice, assistance and collaboration with others who were also using the technique, including Karl Landsteiner and Arne Tiselius, both accomplished researchers and close colleagues of Pauling’s. After the construction at Caltech of an electrophoretic machine, Stanley Swingle, a general chemistry instructor at the Institute, developed a number of mechanical improvements while Harvey Itano and Seymour Jonathon Singer conducted research using the apparatus.

After much trial and error, electrophoresis emerged as one of the more important experimental methods used to determine the difference in electrical charge between normal hemoglobin and sickle cell hemoglobin.

Listen:  Pauling discusses the evolution of electrophoresis work at Caltech

The results of Pauling’s electrophoretic experiments, reported in his group’s groundbreaking 1949 paper, “Sickle Cell Anemia, a Molecular Disease,” promoted the argument that sickle cell anemia was not only a pathology resultant of differential protein folding patterns, but that it was also inherited in a simple Mendelian pattern. In other words, sickle cell anemia was both ‘molecular’ and ‘genetic,’ and by seeing it as such, Pauling suggested certain therapies that directly addressed both the structural and the genetic components of the disease.

Even as late as the 1960s Pauling was still looking for ways to use electrophoresis in his research. He mentions, in a handwritten note, that of the ‘likely developments’ in biology, control of molecular and genetic diseases could possibly be obtained through the “electrophoresis of sperm.”

(Though the idea may sound strange today, Pauling was an advocate for the controversial notion of positive eugenics — that is the planned and controlled production of healthy offspring, primarily through genetic counseling. We’ll talk more about this component of Pauling’s thinking in a later post.)

In more ways than one, electrophoresis was a new technology that required the coordinated effort of a number of trained individuals. Though it took several years to fine-tune both the method and the instruments, the results were well worth the wait.

To learn more about Linus Pauling’s use of electrophoresis, please visit the website It’s in the Blood!  A Documentary History of Linus Pauling, Hemoglobin and Sickle Cell Anemia.