Letters to Peter

Linus and Peter Pauling at Warwick Castle, England. 1948.

Linus and Peter Pauling at Warwick Castle, England. 1948.

“You know how children are threatened ‘You had better be good or the bad ogre will come get you.’ Well, for more than a year, Francis and others have been saying to the nucleic acid people at King’s ‘You had better work hard or Pauling will get interested in nucleic acids.’”

Peter Pauling. Letter to Linus Pauling, January 13, 1953.

Normally, when Linus Pauling became interested in something, he would dive headlong into it. Hours and hours of his time, over weekdays and weekends, would be committed to research in pursuit of fleshing out every last useful detail. This arduous process is best illustrated by his work on the nature of the chemical bond, work which would later win him a Nobel Prize in Chemistry.

Pauling’s experience with DNA, however, was not an example of this typical approach.

First, it should be noted that Pauling did not have years to spend working on DNA. Its importance was fully realized in the summer of 1952, less than a year before Watson and Crick elucidated its structure, and although Pauling actually began studying nucleic acids as early as 1933, he wasn’t able, or willing, to spend a significant amount of time on a molecule that was perceived to be relatively unimportant.

Even after learning of the importance of DNA, Pauling still didn’t make time for it. As emphasized in earlier posts on Linus Pauling and DNA, Pauling remained very much preoccupied with his work on the nature of proteins.

An examination of Pauling’s correspondence with his son Peter – a man uniquely positioned in the middle of the DNA story – reveals that other matters, many of them trivial, also took precedence over Pauling’s pursuit of the structure of DNA.

In the fall of 1952, Peter Pauling, an aspiring crystallographer and the second oldest of the four Pauling children, began his graduate studies at the University of Cambridge. Coincidentally, James Watson and Francis Crick were also at Cambridge at this time, and not long after his arrival, Peter had met them, become an office-mate, and was spending off-hours time with the duo.

Because Linus Pauling and the Watson-Crick tandem were both attempting to solve the structure of DNA, Peter’s arrival at Cambridge gave his father an excellent opportunity to keep tabs on the work being done by his competitors in England. A close examination of the voluminous father-son correspondence from this era suggests, however, that DNA was far from a pressing topic in Pasadena.

Also, as to your curtains: will you check the dimensions and let us know. You say in your letter two windows 6’ 6” high, 50” and 37” wide respectively, in other words four curtains each 48” wide. Mama thinks that you probably mean four curtains each 36” wide. It would be hard to get the wider material.

Also, would you write us as to the exact points between which the vertical dimensions are measured. What is the distance from, say, the top of the window frame (or some other exactly specified locus) to the floor, and also to the bottom of the window frame? Mama thinks that probably the curtains should reach all the way to the floor, but in any case they should extend from the top of the window frame to the bottom of the window frame (if you have window frames), or from a point a little below the opening at the bottom. She suggests that one of your old curtains might serve for one of the windows, and that she would then have to make only a pair for the larger window.

I sympathize with you about the bed. I remember sleeping on a bed which had a two by four across under my ear; it was not very comfortable.

-Linus Pauling, letter to Peter Pauling, October 22, 1952.

Linus first wrote to Peter in England on October 22, 1952. By this time, the elder Pauling was well aware of the importance of DNA, but had not yet devised a structure. Watson and Crick, on the other hand, had developed a structure for DNA a year earlier. Although their model turned out to be incorrect, the two men continued their work with nucleic acids. Clearly, for Watson and Crick, DNA was becoming extremely important. For Pauling this did not appear to be the case – although Watson and Crick were both mentioned in this first letter, DNA was not.

As it turns out, other subjects – including, but not limited to, curtains for Peter’s new apartment, recent travels and upcoming travel plans, finances, and, of course, cars – were much more prevalent than was DNA in the Paulings’ early correspondence.

As time went on, nucleic acids naturally became a slightly larger topic, though never did they assume center stage. Take, for example, this letter sent from Linus to Peter on February 4, 1953. By the time of its authoring, Linus Pauling had completely developed his structure, and had also sent off his manuscript for publication, a development which merited one paragraph worth of description. The rest of the letter is used to discuss, in great detail, Pauling’s plans to travel to England and also his keen interest in purchasing a new Riley from the U.K.-based International Motors. (Being something of a family obsession, cars were a very popular subject in many of the letters between Linus and Peter.)

In another letter from Pauling to Peter written on March 10, 1953, DNA plays a much larger role. This time, about half of the three-page document is dedicated to discussing various aspects DNA; the remainder focuses on travel plans and automobiles.

Peter Pauling, December 1954.

Peter Pauling, December 1954.

The other letters follow this same trend. Clearly, Linus and Peter’s lengthy discussions on subjects such as cars, traveling, curtains, and other aspects of science suggest that Pauling wasn’t interested in DNA on the level of certain other scientific pursuits.

Another interesting aspect of the correspondence between Linus and Peter Pauling is the opportunity that it provides for tracking the evolution of the consensus response to Pauling’s structure.

As might be expected, Peter’s reaction stayed upbeat throughout all of their letters. However, as time progressed, it is clear that Peter became less-confident that his father had solved DNA. For example, in a few of the earlier letters, Peter mentions that Watson and Crick earlier devised and discarded a structure similar to the Pauling-Corey triple helix, but that the opinion at the Cavendish Laboratory is that Pauling’s structure is a good one, albeit “pretty tight.”

From that point on though, Peter begins talking less about Pauling’s structure, and more about work being done by Watson, Crick, and Rosalind Franklin. One might deduce that, although Peter didn’t specifically issue a disagreement with his father’s structure, he did develop a certain degree of skepticism as time progressed. Peter also does not often mention other opinions of his father’s structure, most likely because, upon further examination, it was not well-received by the English contingent.

Peter Pauling Discusses His Father’s Strengths and Personality

For more information on DNA, please visit the Race for DNA website. For more information on Linus Pauling, check out the Linus Pauling Online portal.

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Chargaff’s Rules

Erwin Chargaff, 1930.

Erwin Chargaff, 1930.

“We have created a mechanism that makes it practically impossible for a real genius to appear. In my own field the biochemist Fritz Lipmann or the much-maligned Linus Pauling were very talented people. But generally, geniuses everywhere seem to have died out by 1914. Today, most are mediocrities blown up by the winds of the time.”

-Erwin Chargaff, 1985.

Erwin Chargaff, (1905-2002) a biochemist born in Austria, became interested in DNA earlier than most. In the 1930s, while he was working with the bacteria Rickettsi, he became aware of nucleic acids, and decided to educate himself about them.

In 1944, after Oswald Avery published his paper detailing the transforming principle of the Pneumococcus bacteria, Chargaff decided to devote his laboratory almost entirely to the chemistry of nucleic acids. Experimenting with these delicate substances was not an easy task, but eventually a chromatographic technique was developed that would allow for the separation and analysis of the base rings in DNA. This work would later lead to the development of Chargaff’s Rules, the topic of today’s post.

The guanine-cytosine base pair.

The guanine-cytosine base pair.

DNA has two main structural components – a backbone made up of sugar and phosphate groups, and a series of bases found in the middle of the molecule. There are four different bases found in DNA: Adenine (A), Cytosine (C), Guanine (G), and Thymine (T). These four bases can be divided into two categories, pyrimidines and purines. The pyrimidine bases, Cytosine and Thymine, contain only one ring, while the purine bases, Guanine and Adenine, contain two rings. In the DNA structure, the bases pair complementarily, meaning that a purine base will bind with a pyrimidine base. More specifically, Adenine binds with Thymine and Cytosine binds with Guanine.

The adenine-thymine base pair.

The adenine-thymine base pair.

Although this information is now considered fundamental biology, it wasn’t fully understood until after Watson and Crick discovered the structure of DNA in 1953. However, Chargaff’s research in the late 1940s had suggested that the four bases paired in the manner described above.

When Chargaff first decided to devote his laboratory to nucleic acids, he allowed a postdoctoral student named Ernst Vischer to choose his research program from a list of suggested topics. Vischer decided to analyze the purines and pyrimidines in nucleic acids, and went to work developing the chromatographic technique so crucial to isolating the bases. Although his technique was rather crude, it did the trick and Vischer achieved great success. The results of the base analysis showed that the amounts of Adenine and Thymine were about equal, and also that the amounts of Guanine and Cytosine were about equal. Eventually, Chargaff came to the conclusion that in a single molecule of DNA, Guanine/Cytosine = Adenine/Thymine = 1. This concept would later become known as Chargaff’s Rules.

Chargaff’s Rules were officially announced in a lecture delivered in June of 1949 and were first published in May of 1950. However, Linus Pauling had heard about the ratios much earlier – straight from Chargaff in late 1947, while traveling to England for his six-month stay as a professor at Oxford University. Pauling, who considered the trip by ship across the Atlantic Ocean with his family to be a vacation, did not pay attention to what Chargaff told him.

Crellin Pauling, the youngest child of Linus and Ava Helen Pauling, mentioned the remarkable background to the incident in a speech given during a symposium to celebrate Pauling’s life that was held here at Oregon State University in 1995.

Crellin Pauling on “The DNA Story: A Missed Opportunity.”

[Click here to view the rest of Crellin’s talk]

Over time Chargaff mentioned his work to individuals beyond Pauling. In the spring of 1952, Chargaff met James Watson and Francis Crick.  A prickly character, it is clear that Chargaff didn’t think much of the duo. In his truly remarkable autobiography Heraclitean Fire: Sketches from a Life before Nature, Chargaff calls Watson and Crick “a variety act” and further describes them as:

One 35 years old (Crick), with the looks of a fading racing tout. . .an incessant falsetto, with occasional nuggets gleaming in the turbid stream of prattle. The other (Watson), quite undeveloped. . .a grin, more sly than sheepish. . .a gawky young figure.

He further notes that:

I never met two men who knew so little and aspired to so much. They told me they wanted to construct a helix, a polynucleotide to rival Pauling’s helix. They talked so much about ‘pitch’ that I remember I wrote it down afterwards, ‘Two pitchmen in search of a helix.’

[More samples from Chargaff’s acid pen are available here]

Regardless of what he thought of them, Chargaff still mentioned his work to Watson and Crick. The information, although published almost two years earlier, seemed to be new to the pair.

Though Chargaff himself didn’t speculate much on his rules, and Pauling completely ignored them, they did prove to be extremely useful to Watson and Crick. With this new knowledge, the feedback they had received from Rosalind Franklin and Maurice Wilkins, and data obtained through their own research, Watson and Crick were soon able to correctly deduce the structure of DNA.

For more information on DNA, please visit the Race for DNA website, or check out the other posts in the DNA series. For more information on Linus Pauling, visit the Linus Pauling Online portal.

The Passport Imbroglio

Ava Helen and Linus Pauling's passport photo. 1953.

Ava Helen and Linus Pauling's passport photo. 1953.

A quick glance at the “Today in Linus Pauling” widget found at the top of the left sidebar of the Pauling Blog gives an excellent representation of the span and influence of Linus Pauling’s career. Rarely does a day go by where he didn’t write at least one manuscript or give a speech at a university or some other institution. Most days, readers will also note that he won some sort of award – including, of course, his two Nobel Prizes in chemistry and peace. Basically, Pauling’s career fits very well with the old cliché that anything can be done if the mind is simply set on it.

However, if one looks closely enough, a few failures can still be picked out of Pauling’s illustrious career. One of these failures is undoubtedly his attempt at determining the correct primary structure of DNA. Pauling first started working with DNA in the early 1950s, right around the time when his scientific career was reaching its peak. During this time, Pauling’s pursuits had also taken a controversial political shift – work which caused him to be denied a passport for a short period of time. This passport denial, because it is believed by many to be the reason why Pauling was beaten to the structure of DNA, is the topic of today’s post.

Near the end of 1951, Pauling received an invitation to attend a meeting of the Royal Society in England; a meeting that was specially designed for him to address questions about his protein structures. The meeting was scheduled for May 1, 1952, and promised to give Pauling an opportunity to visit King’s College in London, where he knew Maurice Wilkins had some excellent X-ray patterns of DNA.

However, when Pauling sent in his passport renewal application in January 1952, he was upset but unsurprised to find it denied by Ruth B. Shipley, the head of the State Department’s passport division. Shipley didn’t give Pauling a good reason for the denial, stating only that “the Department is of the opinion that your proposed travel would not be in the best interests of the United States.” Reading between the lines, Pauling’s liberal views had clearly earned him the label of “possible Communist,” and Shipley, who was a fervent anti-Communist, had the authority to deny passports at her discretion.

Video Link: Pauling discusses his reaction to the refusal of his passport.

Fortunately for Pauling, the delay caused by the situation was not a long one. In the summer of 1952, he sent in another passport application. Again, Shipley immediately denied it, but her decision was overruled – after much deliberation – by higher-level employees of the State Department. Eventually, Pauling was notified that he would be granted a limited passport to travel for a short period of time in England and France if he agreed to sign an affidavit stating that he wasn’t a Communist. Surprised and pleased by the news, Pauling immediately agreed and received his new passport within days.

Thus equipped with the necessary papers, Pauling traveled to England, where he stayed for a month. He visited the same places and talked with the same people that he would have earlier in the year, but he did not visit King’s College to view Wilkins’ X-ray data. As it turns out, Pauling wasn’t even thinking about DNA during his time in England.

After England, Pauling traveled to France, where he learned of the results of the Hershey-Chase blender experiment:  DNA was in fact the site of the gene, not proteins, as Pauling had believed. Upon learning of the keen importance of DNA, he decided that he would solve the structure of the molecule.

However, when he returned to Caltech in September of 1952, he continued to work almost exclusively with proteins. It wasn’t until November that Pauling would finally take a serious stab at the structure of DNA. And, as has been well-documented, even with his excellent knowledge of structural chemistry, Pauling’s data – presented in the form of blurry X-ray patterns created by William T. Astbury – was insufficient. He ended up creating a model that was nearly identical to one Watson and Crick had made over a year earlier. Of course, Pauling soon learned that his structure was incorrect, and before he could make another attempt, Watson and Crick had solved DNA.

The importance of Pauling’s passport imbroglio is, as it turns out, counter to the popular mythology of the DNA story. Although the denial of Pauling’s passport caused minor delays in his travels, it surely did not keep him from determining the structure of DNA. Even if he had traveled to England as originally planned, it is unlikely that he would have visited Wilkins to view his X-ray data. Pauling, even after finding out that DNA was extremely important, made no effort to obtain better data, nor did he even work specifically with DNA for quite some time. One is forced to conclude then, that the reason that Linus Pauling was not able to solve DNA is that he never really put his mind to the matter, not because of a pesky passport denial that delayed his travels a mere ten weeks.

For more information on Linus Pauling’s DNA pursuits, please visit the website Linus Pauling and the Race for DNA: A Documentary History. For other information on Pauling, check out the Linus Pauling Online portal.

The X-Ray Crystallography that Propelled the Race for DNA: Astbury’s Pictures vs. Franklin’s Photo 51

Rosalind Franklin, March 1956

Rosalind Franklin, March 1956

During their so-called race to discover the structure of DNA, Linus Pauling and the unlikely pair of James Watson and Francis Crick utilized remarkably similar approaches in attempting to solve the riddle of the genetic material. In fact, one of the main tactics used by Watson and Crick was to approach the problem in the same manner that they assumed Pauling would. Although Pauling and Watson and Crick did, at one point, come up with nearly identical, yet incorrect, structures, it was Watson and Crick who would eventually solve DNA. Why then, if the pair were thinking like Pauling, were they able to beat him to the structure?

Although there were a variety of reasons behind Watson and Crick’s success, a good portion of it can be attributed to the relative superiority of resources available to them. Watson and Crick obviously had each other to keep themselves in check, but they also benefited from other voices of criticism such as Rosalind Franklin, Maurice Wilkins, and later Jerry Donohue. Linus Pauling also shared his ideas with his colleagues, but none of them were very familiar with DNA, and therefore couldn’t offer much feedback. (And they were largely ignored even when they did offer criticisms of Pauling’s structure.)

Another vital resource available to Watson and Crick was an excellent X-ray crystallography pattern, the famous photo 51, taken by Rosalind Franklin. Although, in all likelihood, Pauling could have also viewed Franklin’s photographs had he tried, he settled on using blurry patterns published by William T. Astbury several years before Franklin’s superior images. These X-ray photographs are the main topic of today’s post. In particular, the factors accounting for the difference in quality between Franklin’s and Astbury’s patterns will be discussed. Before delving into this subject, however, a brief overview of X-ray crystallography is necessary.

William T. Astbury, ca. 1950s.

William T. Astbury, ca. 1950s.

X-ray crystallography, also sometimes known as X-ray diffraction, is used to determine the arrangement of atoms within a crystalline molecule. It is a rather complicated procedure, and the photos taken in the process can be interpreted only by a person with significant training. The steps to obtaining these photos are as follows.

First, an adequate crystal must be obtained. This is a very difficult step because the crystal must be large enough to observe and also sufficiently uniform. If it does not meet these specifications, errors – such as blurriness – will occur, often rendering the resulting crystallographic patterns useless, at least for purposes of determining atomic arrangement.

After an adequate crystalline specimen is obtained, a beam of X-rays is shined through it. When the beam strikes the electron clouds of the atoms in the crystal, it is scattered. These scattered beams can then be observed on a screen placed behind the crystal. Based on the angles and intensities of the scattered beams, a crystallographer can create a three dimensional picture of the electron density of the crystal.

Finally, from the electron density information, the mean positions of the atoms within a crystal can be determined, and the structure of the molecule can be considered “solved.” That said, just one image is not nearly enough to determine the structure of an entire crystal. Therefore, the crystal must be rotated stepwise through angles up to and even slightly beyond 180 degrees, depending on the specimen. Patterns are required at each step, and complete data sets may contain hundreds of photos.

Clearly, because the process of X-ray crystallography is so cumbersome, there are many opportunities for mistakes that may have led to the poor quality of Astbury’s photographs. However, Astbury’s techniques seem to have been excellent. He was a very experienced crystallographer, and had achieved great success in his earlier work with X-ray diffraction on substances such as keratin.

As it turns out, Astbury’s photos were of poor quality because of the DNA sample he was using. In the early 1950s, Rosalind Franklin had discovered that DNA came in two forms – a dry condensed form and a wet extended form. Astbury’s DNA sample was well prepared from calf thymus, but it contained a mixture of the two forms. This turned out to be the major reason why Astbury’s photographs were so blurry

Astbury's images, 1947. Plate 2.

Astbury's images, 1947. Plate 2.

It is important to note that, even if Astbury had known he was using a poor crystalline sample of DNA, he probably still wouldn’t have been able to compete with the quality of Franklin’s photos. In 1950, three years after Astbury’s images were published, Maurice Wilkins developed a way to obtain much better X-ray patterns of DNA through the use of a solution of sodium thymonucleate. This solution is highly viscous, and Wilkins found that thin strands could be drawn out by gently dipping a glass stirring rod into a sample and slowly pulling it out. These thin strands were pure DNA, and Wilkins was able to get excellent X-ray patterns from them.

Before long, Wilkins had also acquired better equipment and had also hired Rosalind Franklin to run it. Franklin, essentially working independently, used the same basic technique developed by Wilkins. She did, however, add several of her own smaller experimental refinements, which made the photographs even better. Eventually, she developed photo 51, which would later be shown to Watson and Crick. The rest, as they say, is history.

Rosalind Franklin and William Astbury were both excellent crystallographers, but Franklin’s experience with DNA gave her a clear advantage when working with the molecule. Her brilliant X-ray patterns would later prove to be a major determining factor in the “race for DNA”. For more information on DNA, please visit the Race for DNA website. For much more on Linus Pauling, check out the Linus Pauling Online portal.

Oswald Avery’s Pneumococcus Experiments: Forerunner of the DNA Story

Portrait of Oswald T. Avery, ca. 1940s.

Portrait of Oswald T. Avery, ca. 1940s.

DNA, although now known to be extremely important, was overlooked for quite some time. Until early 1953, around when the Watson and Crick structure of DNA was published, most major scientists thought that proteins, rather than DNA, were probably the site of the gene.

In the early 1940s however, experiments performed by Oswald T. Avery and his colleagues at the Rockefeller Institute for Medical Research made a strong argument for DNA as the source of the genetic material. Unfortunately, for many years not much attention was paid to Avery’s work.

Streptococcus pneumoniae, also called pneumococcus, was the subject of Avery’s experiment. This bacterium causes a variety of diseases, including pneumonia and peritonitis. The organism can be found in two forms, smooth (S) and rough (R) which are designated as such simply because of their appearance when viewed microscopically. The smooth appearance is a result of the formation of a polysaccharide capsule that encases the bacterial cell. This capsule protects the cell from immunological defenses, which makes the S form virulent. The R form, on the other hand, is mutated so that it does not synthesize the enzyme that creates the polysaccharide capsule, and is therefore not virulent.

The pneucmococcus bacteria can be further characterized into types, which are designated by roman numerals. Although an S form bacterial cell can be experimentally changed to an R form (and vice versa) provided the cell is not too far degraded, change of type never suddenly occurs. For example, a type III S cell can be converted to a type III R cell, but a type II cell will never spontaneously convert to a type III cell.

Although a spontaneous change of type is not possible, a specific experiment had been done showing that a transformation of type can be induced. This experiment was first performed by injecting a live culture of the Type II R form into mice along with a dead culture of the Type III S form. Theoretically, none of the mice should have died because they hadn’t been exposed to a virulent form of the bacteria. However, many of the mice did actually die, and living Type III S form bacteria was extracted from their blood. Later, the same experiment was accomplished by growing the bacteria in a glass dish rather than in mice.

Understandably, this transformation from a non-virulent bacteria to a virulent bacteria was troubling to the medical community. Although some scientists may have been concerned with the mechanism of transformation, Oswald Avery was more concerned with the identity of the agent performing the transformation. He went to work on devising an experiment that would allow him to isolate the transforming agent from the rest of the bacterial cell. Although DNA extraction is now considered a simple process, it was just beginning to emerge during the time when Avery began his work. The fact that Avery did not know that the transforming agent was in fact DNA complicated matters even further.

Nevertheless, after years of hard work, Avery and his colleagues were able to develop an experiment that effectively isolated the transforming agent from the bacterial cells. Type III S form bacteria were grown in large vats of broth made from beef hearts. The bacteria was then killed, and washed with brine in order to remove the polysaccharide capsule and whatever protein would come off in the process. The remainder of the bacteria was then precipitated in pure grain alcohol. After this, the precipitate was washed with chloroform and subjected to a digestive enzyme, both of which functioned to remove the remaining protein. Finally, after no trace of protein was evident, pure grain alcohol was once again added, which allowed the transforming agent to be separated. The process was long and difficult, and in the end only yielded approximately ten to twenty-five milligrams of the agent per seventy-five liters of culture.

Transformation of pneumococcal types, from Avery's 1944 paper.

Transformation of pneumococcal types, from Avery's 1944 paper.

After obtaining enough of the active transforming agent to conduct his tests, Avery and his colleagues set out to show exactly what the substance was. First, standard qualitative tests for proteins were performed, which came back negative. Qualitative tests for DNA, however, were strongly positive. Chemical analysis of the substance also showed that the ratio of nitrogen atoms to phosphorous atoms was approximately 1.67 to 1. This number is very close to the DNA ratio, and would have been different had there been a significant amount of protein present.

Next, tests with digestive enzymes were performed. The addition of enzymes that digest proteins and RNA left the agent intact, while enzymes that digest DNA completely destroyed the substance.

Finally, immunological tests involving centrifugation and electrophoresis were performed, which also showed that proteins and polysaccharides weren’t present, but that DNA was.

Once Avery was satisfied with the results of his tests, he began writing a manuscript that explained the experiment. In January of 1944 “Studies on the Chemical Nature of the Substance Inducing Transformation of Pneumococcal Types” by Oswald T. Avery, Colin M. MacLeod, and Maclyn McCarty was published. Although it may seem that Avery and his colleagues had proven that DNA was the site of the gene, this was not entirely the case. There was still a possibility that, as Avery puts it in the manuscript, “the biological activity of the substance described is not an inherent property of the nucleic acid but is due to minute amounts of some other substance adsorbed to it or so intimately associated with it as to escape detection. . .”

Avery was clearly being very cautious in his conclusions, never stating that he was certain that DNA was the transforming agent. It is possible that his cautiousness with the matter contributed to his lack of attention received. However, there were other reasons why Avery wasn’t given serious attention. As James Watson later stated in 1983:

Both Francis and I had no doubts that DNA was the gene. But most people did. And again, you might say, ‘Why didn’t Avery get the Nobel Prize?’ Because most people didn’t take him seriously. Because you could always argue that his observations were limited to bacteria, or that [the transformation of pneumococcus that he described was caused by] a protein resistant to proteases and that the DNA was just scaffolding.

Although Avery’s manuscript may not have been received with high praise at the time of its publication, it is now considered to be a very thorough account of an expertly accomplished experiment. For more information on DNA, please visit the Race for DNA website. For information on Linus Pauling, a major player in the DNA story, visit the Linus Pauling Online portal.

The Watson and Crick Structure of DNA

Francis Crick and James Watson, walking along the the Backs, Cambridge, England. 1953.

Today, our series on models of DNA is concluded with a discussion of the correct structure determined by James Watson and Francis Crick. Although they made an unlikely pair, the two men succeeded where one of the era’s leading scientists – Linus Pauling – failed, and in the process they unraveled the secrets of what may be the most important molecule in human history.

In the fall of 1951, James Watson was studying microbial metabolism and nucleic acid biochemistry as a postdoctoral fellow in Europe. It didn’t take long for him to tire of these subjects and to begin looking for more inspiring research. He became interested in DNA upon seeing some x-ray photos developed by Maurice Wilkins. He then tried to talk his way into Wilkins’ lab at King’s College, but was denied and ended up studying protein x-ray diffraction in the Cavendish Laboratory at Cambridge University. Here he was assigned space in an office to be shared with an older graduate student named Francis Crick, a crystallographer. At the time, Crick was studying under Max Perutz, and was also becoming bored with his research. Watson and Crick hit it off immediately and before long, Watson’s interest in DNA had worn off on Crick. Although neither of them were experts in structural chemistry, they decided to attempt to solve the structure of DNA. As Watson put it, their planned method of attack would be to “imitate Linus Pauling and beat him at his own game.”

The pair’s first attempt at the structure in the fall of 1951 was very quick, and also unsuccessful. Interestingly, however, it was quite similar to Linus Pauling and Robert Corey‘s own attempt about a year later. Watson and Crick came up with a three stranded helix, with the base rings located on the outside of the molecule and the phosphate groups found on the inside. This left them with the problem of fitting so many negatively charged phosphates into the core without the molecule blowing itself apart. In order to solve this problem, they turned to Pauling’s own The Nature of the Chemical Bond. They were looking for positive ions that would fit into the core of DNA, therefore canceling the negative charge. They found magnesium and calcium to be possibilities, but there was no significant evidence that these ions were in DNA. However, there was no evidence against it either, so they ran with the idea.

Watson and Crick assumed – as would Pauling in his later attempt – that the finer details would fall into place. Overjoyed at solving DNA so quickly, they invited Wilkins and his assistant, Rosalind Franklin, to have a look at their structure. Expecting praise, they were undoubtedly surprised when Franklin verbally destroyed their work. She told them that any positive ions found in the core would be surrounded by water, which would render them neutral and unable to cancel out the negative phosphate charges. She also noted that DNA soaks up a large amount of water, which indicates that the phosphate groups are on the outside of the molecule. All in all, Franklin had no positive feedback for Watson and Crick.  And she was, at it turned out, correct. After the visit, Watson and Crick attempted to persuade Wilkins and Franklin to collaborate with them on another attempt at the structure of DNA, but their offer was declined.

Diagram of the double-helix structure of DNA. August 1968.

When Sir William Lawrence Bragg, the head of the Cavendish laboratory, heard about Watson and Crick’s failure, he quickly sent them back to other projects. Almost a year passed with Watson and Crick accomplishing no significant work on DNA. Although they weren’t building models, DNA was still at the front of their minds and they were gathering information at every opportunity. In the fall of 1952, Peter Pauling, the second eldest of Linus and Ava Helen Pauling’s four children, arrived at Cambridge to work as a graduate student. Jerry Donohue, another colleague of Pauling’s from Caltech, also arrived at the same time and was assigned to share an office with Watson and Crick. As a result, Peter also fell in with the group. Therefore, as the quest for DNA progressed, Linus Pauling was provided with a general idea of Watson and Crick’s work with DNA through contact with Peter. However, the opposite also proved true.

When Pauling and Corey submitted their manuscript on the structure of DNA in the last few days of 1952, Peter passed on to Watson and Crick the news that his father had solved DNA. Although the two men were crestfallen by this information, they decided to soldier on with their own program of research, figuring that if they published something at the same time Pauling that did, they might at least be able to share some of the credit.

Around this time, the pair added an important piece of information that they had learned from Erwin Chargaff, a biochemist. He had told them that the four different base rings in DNA appeared to be found in pairs. That is, one base ring is found in the same relative amounts as another. This first correlation constitutes one pair, and the remaining two bases make up the other pair. Interestingly enough, Chargaff had also told Pauling this same thing in 1947. However, Pauling had found him to be annoying and, as a result, disregarded his tip. Chargaff’s information did, however, prove to be crucial for Watson and Crick, who were slowly piecing together the basics of the DNA structure.

When Watson and Crick finally received Pauling’s manuscript via Peter in early-February 1953, they were surprised – not to mention elated – to see a structure very similar to their own first attempt. Bragg, a long time competitor of Pauling’s, was so pleased to see Pauling’s unsatisfactory work that he allowed Watson and Crick to return to DNA full time. The pair wasted no time, and had soon spread the news about Pauling’s model to all of Cambridge. Watson even told Wilkins about the manuscript, and was rewarded with the permission to view Franklin’s most recent DNA x-ray patterns. These beautifully-clear photos immediately confirmed Watson’s suspicion that DNA was a helix, adding yet another piece of important information.

Based on all of the information that they had gathered, Watson and Crick began rapidly building models. One model, which Watson called “a very pretty model,” contained the wrong structures for two base rings. Fortunately, Donohue, who was an excellent structural chemist, set them right. After his correction, Watson and Crick noticed that hydrogen bonds would form naturally between the base pairs. This explained Chargaff’s findings, and also showed the potential for replication of the molecule. The rest of the model came together quickly, and Watson and Crick began to write up their structure.

Eventually, Linus Pauling began to catch wind of the recent work that Watson and Crick had been doing with DNA. His first actual glimpse of their work came in March 1953 when Watson sent a letter to Max Delbrück, a colleague of Pauling’s, that included a brief description and rough sketches of the structure. Although Watson had asked Delbrück not to show the letter to Pauling, Delbrück could not resist. Pauling marveled at the simplicity and functionality of the structure, but still retained confidence in his own structure. Only a few days later, Pauling received an advance copy of the Watson and Crick manuscript, but he was still not convinced they had solved DNA. In April, Pauling finally traveled to England, and only after seeing the model in person and comparing it to Franklin’s DNA photographs was he certain that Watson and Crick had solved the structure of DNA.

On April 25, 1953, Watson and Crick’s article, “A Structure for DNA” was published in Nature. James Watson, Francis Crick, and Maurice Wilkins would go on to share the Nobel Prize in Physiology or Medicine for 1962 “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material.” Unfortunately, Rosalind Franklin died of cancer at age 37 and, for many years, was given only minor credit for her considerable contributions related to the discovery of the DNA structure.

For more information on Watson and Crick and DNA, please visit the website Linus Pauling and the Race for DNA: A Documentary History. For more information on Linus Pauling and his research, visit the Linus Pauling Online Portal.

The Pauling-Corey Structure of DNA

Today, the structure of DNA series is continued with the model proposed by Linus Pauling and Robert Corey in 1953. As a result of insufficient data and an overloaded research schedule, Pauling’s structure turned out to be incorrect. However, it is interesting to see the ways in which one of the world’s leading scientists went wrong with his approach to the structure of this hugely-important molecule.

Linus Pauling played around with nucleic acids as early as 1933 when he hypothesized a structure for guanine, a base ring. In the summer of 1951, he again became interested in DNA when he heard that Maurice Wilkins at King’s College had developed a few good photographs of nucleic acids. Unfortunately for Pauling, Wilkins was unwilling to share his research. In November of that same year, a structure of nucleic acids was proposed and then published by Edward Ronwin. Pauling could tell almost immediately that Ronwin’s structure wasn’t correct, but it did contain a few good ideas that got him thinking about other possible structures. Pauling hypothesized that DNA was likely helical in shape, with the large base groups facing out and the phosphate groups stacked in the core. At this juncture, however, Pauling was again distracted by other research and let the project drop.

Until 1953 nucleic acids weren’t considered to be very important. At the time, proteins, rather than DNA, were considered by most scientists to be the carriers of genetic material. Partly because of this, Pauling’s attention was focused on proteins, not DNA. In May of 1952, Pauling was scheduled to attend a special meeting of the Royal Society where he would address questions pertaining to his protein structures. This trip would also give him an opportunity to discuss DNA with Rosalind Franklin, who was Maurice Wilkins’ assistant. She had recently developed an especially clear photograph of DNA which likely would have saved Pauling from making some key mistakes when determining the structure of DNA.

As a result of his very-public anti-war and anti-nuclear activities, Pauling’s initial request for a passport was denied, though he was granted a limited passport only ten weeks later. However, when Pauling arrived in England, he did not visit King’s College. He was preoccupied with his protein research and he assumed that Wilkins still wouldn’t be willing to share his data.

Soon after his visit to England, Pauling was granted a full passport and traveled to France. Here he was informed, through an experiment performed by Alfred Hershey and Martha Chase, that DNA was in fact the genetic master molecule. Upon learning this, Pauling decided that he would solve the structure of DNA. However, when he returned to California, he continued to work primarily with proteins. It wasn’t until November 25, 1952 that Linus Pauling would make a serious attempt at the structure of DNA.

Unfortunately, when Pauling did decide to put in some time with DNA, he still had insufficient data to correctly deduce its structure. Using only a few blurry x-ray patterns done by William Astbury in the 1930s and a photograph published by Astbury in 1947, Pauling decided that DNA was indeed a three-chain helix with the bases facing outward and the phosphates in the core.

Astbury's 1947 photographs of DNA.

Astbury's 1947 photographs of DNA.

However, it was immediately clear that making room for so many phosphates in the center of the molecule would be quite a task. Pauling spent a great deal of time manipulating his model, and eventually produced a satisfactory representation. He then asked Robert Corey, his chief assistant at Caltech, to perform detailed calculations on the proposed atomic positions. Corey’s calculations proved that, despite Pauling’s efforts, there still wasn’t enough room for all of the atoms. Pauling, refusing to consider the possibility that his structure was incorrect, resorted to further manipulation. (In fact, Pauling refused to concede even after a colleague pointed out that there was no room for sodium ions in the core of his model, a feature that is essential in the creation of sodium salts of DNA.) Convinced that the finer details would later fall into place, Pauling and Corey spent the last week of the year writing up their structure, and on the last day of 1952, they submitted “A Proposed Structure for the Nucleic Acids” to the Proceedings of the National Academy of Sciences.

Diagram of the Pauling-Corey structure for DNA, as published in PNAS.

Diagram of the Pauling-Corey structure for DNA, as published in PNAS.

The paper was uncharacteristic of Pauling. Instead of his usual confidence, he stated that the structure was “promising” but also “extraordinarily tight.” Pauling likewise noted that the model accounted only “moderately well” for the x-ray data, and that the atomic positions were “probably capable of further refinement.” As it turned out, Pauling wasn’t seeking perfection with his structure. In reality, he wanted to be the first to publish a roughly correct structure of DNA. Rather than having the final say, he wanted the first.

Once the article was published in February of 1953, it became more and more apparent that Pauling’s structure wasn’t even roughly correct. By this time, Pauling had already moved on to other projects, and was surprised at the fact that his paper was received so poorly. Once he caught wind of the talk surrounding his structure, he decided to return to the topic of DNA. Despite the negative reaction, Pauling still believed that his structure was essentially right. However, he soon received better nucleotide samples from Alex Todd, an organic chemist at Cambridge, and began a more rigorous approach to determining the structure of DNA.

Unfortunately, by this time it was too late. Upon the publication of Pauling’s unsatisfactory model, James Watson and Francis Crick were given the green light to pursue their own model of DNA. Before long, Pauling saw that the work they were doing was very promising. A few days after first seeing their structure, Pauling received an advance copy of the Watson and Crick manuscript. At this point, he still retained a fair amount of confidence in his own model, but acknowledged that there was now another possible model. In a letter to Watson and Crick written on March 27, 1953, Pauling noted

I think that it is fine that there are now two proposed structures for nucleic acid, and I am looking forward to finding out what the decision will be as to which is incorrect.

However, he had still not seen Rosalind Franklin’s data; Watson and Crick had. (Interestingly enough, Robert Corey had traveled to England in 1952 and viewed Franklin’s photographs. It is unknown whether or not he purposely failed to provide Pauling with the details of the images.)

This fact would soon change. In April of 1953, Pauling was to attend a conference on proteins in Belgium. On his way, he stopped in England to see the Watson and Crick model of DNA as well as Franklin’s photographs. After examining both, Pauling was finally convinced that his structure was wrong and that Watson and Crick had solved DNA.

Linus Pauling, although disappointed with the results, accepted his defeat graciously. He gave Watson and Crick full credit for their discovery and assisted them in tying up a few loose ends with their model. For Pauling, this event was a single failure in a sea of successes. In fact, the very next year, he would win the Nobel Prize in Chemistry – the first of his two Nobel Prizes. Despite his embarrassing mistakes, Pauling was to remain in good standing with the scientific community.

Please check back on Thursday for the conclusion of the DNA structure series – an examination of the correct structure deduced by Watson and Crick. For more information on DNA, please visit the website Linus Pauling and the Race for DNA. For more information on Linus Pauling, visit the Linus Pauling Online Portal.