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.

Edward Crellin Pauling, 1937-1997

Crellin Pauling, 1991.

[Ed Note: June 4, 2012 marks what would have been the 75th birthday of Crellin Pauling, the youngest of Linus and Ava Helen Pauling’s four children.  In commemoration, we present today the first installment of a two part biography exploring Crellin’s life and work.]

A kind and gentle man, Crellin Pauling was also a talented and well-liked teacher and researcher who enjoyed a long scientific career. Always interested in people, he would often interact with those he didn’t know, sharing his sense of humor while learning something interesting about those with whom he interacted. He was more than a scientist, husband, father, teacher and youngest son of Linus Pauling. He held a passion for life that was evident through his numerous hobbies, including traveling, fishing, sailing, gardening, cars and airplanes. His eldest daughter, Cheryl, describes him as being “just a wonderful person.”

Crellin’s career was evenly divided between two productive tenures as a professor at the University of California, Riverside and San Francisco State University. Crellin’s teaching focus was on microbiology and genetics, usually to upper division or graduate students, and later he moved into an administrative role. In the laboratory he was supported by a full-time technician and a rotation of graduate assistants.

Most of his research focused on DNA repair and replication, which was a huge interest of his. Perhaps most notably, he discovered the first DNA ligase mutant, a temperature-sensitive variant of E. coli. His first paper on the topic was co-authored with his technician, Lyla Hamm, and published in 1969; several other contributions followed.

Crellin Pauling with a friend, 1940.

Born on June 4, 1937 at Huntington Memorial Hospital in Pasadena, California, Edward Crellin Pauling – named after a steel magnate who donated the funds for Caltech’s Crellin Laboratory for research in organic chemistry – joined older siblings Linus Jr., Peter and Linda. Several anecdotes from his childhood, as recorded by his mother, suggest that Crellin possessed a nimble mind from a young age. In November 1945, Ava Helen noted this interaction with her eight-year old son:

On Saturday, November 10, at the dinner table, I said to Crellin, ‘If we had a circle 10 inches in diameter, that is 10 inches across, what would be its circumference, that is, how long would a string have to be to go clear around the circle?’

In perhaps a minute Crellin said, ‘I think it would be 32 inches.’ I said, ‘That’s pretty good, how did you decide that it would be 32 inches?’ Crellin said, ‘Well, its 10 inches across and it would take about three of those to go around – that would be 30 inches – and then a little more would make 32 inches.’

Crellin attended Polytechnic Elementary and Junior High School in Pasadena from 1943 to 1950. One of his fondest memories of his childhood was getting to ride to school with his dad every morning, a chance to spend some quality time with his busy father. Crellin received satisfactory grades, often scoring a little low in English and penmanship, with highest marks in history. His sixth grade teacher wrote, “Crellin is a pleasant, helpful member of the group. He should get better results in arithmetic. The homework in this subject is often carelessly done. He understands the processes and can quickly raise the grades with more careful work.” In 1949, he received a certificate of honor from the school for his accomplishments in choral music.

Peter, Linda and Crellin Pauling, 1946.

In 1950 Crellin was sent to the Chadwick Boarding School in Palos Verdes, California and it is through his notes to home that we are able to trace the development of his personality. In the letters that he sent, usually to his mother, Crellin discussed a series of roommate changes, his classes, his enjoyment of baseball and basketball, girls that he fancied, and ideas for Christmas presents, always signing his name either “Crellie” or “Crelly” with multiple X’s and O’s.

As he moved into adolescence he developed a deep love of cars, often reminding his parents to have their own vehicles regularly inspected and to get frequent oil changes. In one letter to his mom, he wrote, “English makes a little better sense, but not much. This letter will be very short, because I must be doing some studying. I think I will go into art and model cars in clay.”

Crellin on the Queen Mary, headed to England, 1948.

Although the letters to his parents did not betray a high level of unhappiness, others recall that Crellin hated boarding school. In the words of Crellin’s widow, Kay,

He felt like when Linda went off to Reed [College in Portland, Oregon] that he was the only child left at home and his parents didn’t want to deal with him so they put him in boarding school so his mother could be free to travel as much as she wanted to with Daddy. He finally talked them into letting him come back home and he graduated from high school in Pasadena.

Indeed, Crellin was twelve years younger than his oldest brother Linus Jr. and five years younger than his closest sibling Linda. As a result, a sense of isolation brought about by his age permeated many of Crellin’s feelings about his childhood.

The Pauling family in Sweden for the Nobel Chemistry Prize ceremony, 1954. Crellin stands second from left.

Following high school, Crellin followed his sister’s example and began studies at Reed College in Portland, Oregon, where he intended to major in chemistry, but ended up graduating with a degree in biology. At Reed, Crellin generally enjoyed himself a great deal, reading books about chemistry and physics, while diving into courses in mathematics and genetics. Crellin was also active in theater, most notably playing a role in “The Mikado,” a comic opera set in Japan. Throughout his first couple of years, he hinted at the possibility of changing his major to philosophy or another discipline in the liberal arts because he no longer felt interested in chemistry, intending instead to go to medical school after graduation. In the end he stayed in the sciences, a decision that surely pleased his parents.

Having settled on a course of study, Crellin also began spending a great deal of time with one of his classmates, Lucy Neilan Mills, an art major. Lucy, who was from Evanston, Illinois, was a talented artist and knitter who enjoyed pottery, cooking and playing the piano. Crellin hoped that his parents would like her as she “approached his ideals quite nicely.” Shortly after telling his mother that he was in love with Lucy, the couple were married at Lucy’s grandmother’s house in Oswego, Oregon on November 21, 1956. The ceremony included forty of the couple’s closest friends, although Crellin was upset that his parents were not able to attend. The two were in love and looked forward to buying a house together and starting a family.

Lucy Neilan Mills and Crellin Pauling on their wedding day, 1956.

A short time later, Crellin and Lucy’s first child, Cheryl, was born. Still undergraduates, the young parents moved into an apartment on SE Clinton Street in Portland, while Lucy took a French literature course and Crellin took plant evolution, animal physiology and humanities classes. Crellin seemed to be thrilled with fatherhood, telling his parents all about Cheryl and mentioning that, “she is growing day by day. She has suddenly decided that she likes to sleep twelve hours a night.” In his letters Crellin recounted Cheryl being able to flip herself over from tummy to back and becoming quite vocal by cooing, which was a hit around school. “We are very proud of her and are very happy to have her,” he wrote.

By the end of his junior year, Crellin had passed his exams and chosen his thesis mentor, Dr. Gwilliam, who was an invertebrate zoologist. Crellin decided that he was interested in two fields, physiology and invertebrates, specifically marine zoology. At this time, he considered graduate school at either Berkeley or the University of Washington and looked forward to spending the summer in Pasadena, where Lucy would be able to take piano lessons and he could land an enjoyable summer job working with one of his favorite immunologists.

A few months later, on October 28, 1958, the couple’s second child, Kirstin, was born, joining older sister Cheryl, who was now learning how to hold her own spoon and cup and was almost potty-trained. Crellin graduated from Reed in 1959 and then the family moved to Seattle, as he had decided on the University of Washington for graduate school.

Crellin Pauling with his mother, Pasadena, 1950s.

Crellin remained in regular contact with his parents during the family’s time in Seattle, telling them all about how school was going and how well their apartment was shaping up. He also wrote frequently to his brother Peter, who was in London. Crellin and Lucy attended a Unitarian church and he was happy as a graduate student, enjoying the fact that a few of his friends from Reed had also decided to attend UW. In his correspondence he often pondered scientific topics, noting in one letter to his parents,

There certainly are some interesting questions to think about. The present idea of a chromosome is that it consists of a protein backbone with the DNA as little side chains. The question of separation of the two strands of DNA is interesting; I wonder if the segment completely uncoils, or if there is some process of breakdown and reformation.

As his studies advanced he felt ever more confident in his decision to come to UW, remarking in particular that the courses were of “quite good caliber.” And as always, the updates to home included details on life and family: plans for Christmas break in Pasadena, excitement in seeing Kirstin starting to talk, a recent sailing trip on Lake Washington. As the end of 1959 approached, Crellin was busy preparing for finals and discussing research topics with Dr. Motulsky, while Lucy took care of the children and sewed Christmas presents.

Cheryl Pauling, age 4 months, doing some exploring. 1957.

Crellin loved being a father, speaking often and affectionately about his children. Kay Pauling recalled, “I have never known a man who loved and devoted his time to his kids as much as Crellin did.” In a typical letter to his parents, Crellin wrote, “Our kids are growing by leaps and bounds. Kirstin sprouted a couple of teeth the other day and Cheryl is a real rambunctious little rascal, full of spirits. I am still amazed at the completeness of her vocabulary, and of her ability to form sentences.”

The family expanded on December 31, 1960 when Edward Crellin Pauling, Jr. was born, a boy described by his father as having bright blues eyes and being, “very handsome and very, very good.” He didn’t cry much as a baby and his sisters were keenly interested in him, always wanting to hold him. Crellin loved watching the children ride their trikes and was impressed with how Cheryl seemed to be developing a “quite sensitive nature with regard to music.” He was likewise enthralled with living in Seattle and was excited to someday start a vegetable garden and have a lawn to mow. As summer 1961 approached, the family made plans to go on a picnic for Cheryl’s birthday and Crellin said that she would be “tinkled pink” if her grandparents could come.

Pauling family picnic, 1950s.

In an oral history interview conducted many years later, Cheryl reflected on her childhood with her dad by reminiscing about sitting on her father’s lap while he played solitaire and taking family trips to the Pauling home at Deer Flat Ranch. She also noted her father’s capacity for innovative thinking:

He was really crafty in a way I didn’t realize until later, as I look back. I remember one time when we went to the ranch he made kites for us out of balsa wood, string and newspapers. And when I was really little, I remember he used to make Christmas ornaments – at least for more than one year he made Christmas ornaments with toothpicks by gluing tissue paper on them and getting tetrahedral shapes and things like that.

Deer Flat Ranch, where Linus and Ava Helen lived, was full of great memories, especially for the grandchildren, because they could have picnics on the beach, it had a long and steep driveway that was perfect for running down, there were cows to ponder and, of course, plenty of family. Cheryl recalled that the ranch, “was always special, because we were always going to see either Grandmamma or the cousins, so aside from the fact that the ranch was a beautiful place to be, it was always fun. There were always other family members there that we were looking forward to seeing.” Crellin loved being at the ranch and was always busy with a project, using the chainsaw and doing anything hands-on, only rarely sitting around reading or studying.

Crellin Pauling speaking at his father’s sixtieth birthday celebration, 1961.

By 1963 Crellin had progressed in his studies at UW and was looking toward the future and his next pursuits. He considered taking a jobs in New Zealand and Hawaii, but decided instead to opt for a two-year post-doctoral opportunity at Stanford, working on DNA repair with Professor Phil Hanawalt.

But before Stanford, Crellin needed to complete his doctoral dissertation, which was titled “The Specificity of Thymineless Mutagenesis,” a project that involved spectroscopic analysis of E. coli samples. He was heavily invested in this work, writing that

the past six months have been the most productive in my career in terms of results per unit experiment. I am feeling pretty good, actually. I have lots of ideas, and plenty of things to do after I get out. I’m kind of anxious to get out, although I’m not particularly anxious to leave Seattle.

By the end of his time at Washington, Crellin was still greatly enamored with his children, mentioning in a letter that he was looking forward to buying Crellin Jr. a go-kart, for the enjoyment of them both. More than anything, Crellin looked forward to getting his degree and starting something new, although he knew he was going to miss the Pacific Northwest.

The Watson and Crick Structure of DNA

Francis Crick and James Watson, walking along 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.

The Fraser Structure of DNA

Today, the DNA series is continued with a post discussing a mostly correct structure that almost emerged from King’s College in the early 1950s. Although Maurice Wilkins, Rosalind Franklin, and Bruce Fraser each contributed information for the structure, it was Fraser that actually put the pieces together and built a model. Therefore, today’s post will focus on Fraser, a lesser-known player in the DNA story.

Robert Donald Bruce Fraser was born on August 14, 1924 in Ickenham, England. In 1943, he received his first of many degrees – an intermediate Bachelors of Science from Birkbeck College in London. Fraser returned to academics after a stint with the Royal Air Force that lasted from 1943 to 1946. In 1948, he received a Bachelors of Science in Physics and Math from King’s College in London. After receiving this degree, Fraser remained at King’s College for quite some time. He held a Medical Research Council Studentship position for approximately three years and received his Ph.D. in Biophysics in 1951.

During his Ph.D. candidacy, Fraser utilized infrared methods to study DNA samples prepared by his wife, Mary Fraser. The duo used the data gathered from this research to establish the idea that the large base groups in DNA sit perpendicular to the molecular axis – information that was soon published (“Physical Studies of Nucleic Acid: Evidence on the Structure of Deoxyribonucleic Acid from Measurements with Polarized Infra-Red Radiation” by Mary J. Fraser & Robert D.B. Fraser in Nature 167. Link not available).

Although DNA had yet to become a particularly important molecule in terms of research, Fraser was not the only person at King’s College working with it. Maurice Wilkins and Rosalind Franklin were also studying DNA, but neither was inclined to make a model based on their data. In fact, Franklin was strongly against model-building until the structure was completely understood.

Despite this, Fraser decided to try his hand at building a model based on both his own research as well as the research of Wilkins and Franklin. Before beginning, he discussed the molecule with both his soon-to-be famous colleagues. More specifically, he asked how many chains each thought a molecule of DNA would contain. Both said three, based on two pieces of information: a) the measurements and density for water content suggested more than one chain, and b)  two chains wouldn’t seem to fill enough space. Using this information, Fraser began to work on his model.

The structure came together very quickly. It was a rather simple model that consisted of a helical shape with three chains, the phosphate groups on the outside of the molecule, and the base groups stacked in the center. As it would turn out, this model correctly predicted almost all of the key features of DNA – the only fault was the three chain property, something that was becoming a common error.

Although Fraser created an excellent model, it did not receive any credit. As a result of Wilkins’ and Franklin’s views on model building, the structure was not to be published. After completing his doctorate work in 1952, Fraser left London and took a position as the chief of the protein chemistry division for the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Melbourne, Australia.

However, this move did not put Fraser completely out of the DNA picture. In 1953, James Watson and Francis Crick were preparing to publish their structure. Wilkins, upon seeing their model, decided that Fraser should have the opportunity to publish his model before Watson and Crick’s was released. Furthermore, Wilkins wanted credit for his significant work with DNA.

Accordingly, Wilkins contacted Fraser in Australia and asked him to quickly write up his structure for an article in Nature that would be accompanied by a short note from Wilkins. Fraser complied and frantically authored a brief paper titled “The Structure of Deoxyribose Nucleic Acid.” This work took Fraser the entirety of one night, and the next morning he cabled it off to London – a rather expensive process.

Unfortunately, despite Fraser’s hard work, he was once again disappointed.

Upon the arrival of the document in London, Francis Crick decided that it should not be published. Instead, he told Wilkins that Fraser would be acknowledged by him and Watson in their article (“Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid“) and that they would state that Fraser’s paper was “in the press”. In reality, the paper was not in the press and it would, in fact, never be published.

For more information on R.D.B. Fraser’s work, visit the website Linus Pauling and the Race for DNA, available at the Linus Pauling Online portal.

The Race for DNA: The Ronwin Structure

This post marks the beginning of an extensive series of posts on DNA. The first four posts in the series will cover structures of DNA proposed by various individuals, including one by Linus Pauling, as well as the correct structure discovered by James Watson and Francis Crick. Today, an early structure proposed by Edward Ronwin will be discussed.

Until the 1950s, DNA was not considered to be an important molecule. At that time, it was known that genes were located in chromosomes, structures made up of nucleic acids and proteins that can be found in the nucleus of cells. The nucleic acids, one of which is DNA, were not thought to be the carrier of genetic information, and therefore didn’t garner much interest from scientists. Even Linus Pauling favored the more complicated and abundant proteins as the site of the gene. However, there was still some research being done on DNA.

In November of 1951, the Journal of the American Chemical Society published a paper entitled “A Phospho-tri-anhydride Formula for Nucleic Acids.” This article was written by Edward Ronwin and outlined a possible structure of DNA.

At this time, it was known that DNA was made up of four nucleotides. These nucleotides were understood to each consist of a sugar attached to a phosphate group and to a large flat ring structure called a base. However, it wasn’t known how these nucleotides bonded together to form large molecules. In his structure, Ronwin proposed that the phosphate groups were placed down the middle of the molecule with the large bases sticking out to the sides. According to x-ray data gathered by William Astbury, this was a definite possibility. It also made the molecule much easier to manipulate.

Diagram of the Ronwin structure for the nucleic acids. November 1951.

Diagram of the Ronwin structure for the nucleic acids. November 1951.

Unfortunately, not everything about Ronwin’s structure made sense. Linus Pauling was quick to point out, through a letter to the Journal of the American Chemical Society, that the Ronwin molecule contained a structure for which no theoretical precedent existed. He added that in normal phosphorous compounds, the phosphorous atom is bonded to four oxygen atoms. However, in Ronwin’s molecule, the phosphorous atom is bonded to five oxygen atoms. Therefore, Pauling concluded, there was no significant evidence for such an extraordinary structure and that Ronwin’s idea deserved no serious consideration.

Not long after his letter appeared, Ronwin responded to Pauling and pointed out the existence of four synthesized phosphorous compounds with five oxygen atoms bonded to the phosphorous atom. This information forced Pauling to retract his earlier statement about precedence, but did not otherwise change his opinion of Ronwin’s work. He quickly drew attention to the fact that these compounds decompose rapidly in the presence of water, a prevalent substance in DNA.

All in all, Pauling was rather offended by Ronwin’s proposition. He noted in a May 1952 letter to John F. Tinker the extreme ease with which a scientist in the field of molecular biology could hypothesize structures, and that no reputable worker in the field would do so without significant supporting evidence.

Although Ronwin’s structure had a variety of faults, it appeared to spark some interest in DNA, at least for Pauling. Before long, other structures would begin to appear, and the race for DNA would be well on its way.

Check back on Thursday for the next post in the DNA series. For more information about DNA, please visit the website Linus Pauling and the Race for DNA:  A Documentary History, available at the Linus Pauling Online Portal.