An Era of Discovery in Protein Structure

Linus and Ava Helen Pauling, Oxford, 1948.

[The Paulings in England: Part 4 of 5]

Though metals were consuming a good portion of his time during his fellowship at Oxford, Linus Pauling’s other projects never strayed far from his thoughts.  High on the list were the mysteries of proteins, whose structures and functions were slowly starting to be unraveled.

Pauling’s interest in proteins was spurred in the mid-1930s when the Rockefeller Foundation began to look most favorably upon the chemistry of life when deciding where their grant money would go. Early on, Pauling set out to tackle hemoglobin and though his affair with the molecule lasted for the remainder of life, Pauling certainly didn’t limit himself to the study of just one protein.

At a time when most were looking at proteins from the top down, trying to sort out the complicated data produced by an x-ray diffraction photograph of an entire protein, Pauling was working from the bottom up, in the process determining the structures of individual amino acids – the building blocks of proteins.

A specific protein that kept coming back into view over the years was keratin. In the 1930s, the English scientist William Astbury had studied the structure of wool, which along with hair, horn, and fingernail is made up primarily of this enigmatic protein, keratin. Astbury proposed that the structure was akin to a flat, kinked ribbon, but Pauling disagreed. “I knew that what Astbury had said wasn’t right,” Pauling recalled, “because our studies of simple molecules had given us enough knowledge about bond lengths and bond angles and hydrogen-bond formation to show that what he said wasn’t right. But I didn’t know what was right.” Pauling attempted to construct a model at the time, but could not match his structure to the measurements dictated by Astbury’s blurry x-ray diffraction images. Pauling wrote the project off as a failure and continued pursuing other interests.

In 1945 Pauling found himself seated next to Harvard medical Professor William B. Castle on a railroad journey from Denver to Chicago. Castle was a physician working on the nature of sickle cell anemia and the conversation that he shared with Pauling planted a seed in Pauling’s mind about the cause of this debilitating disease.

In the bodies of those suffering from sickle cell anemia, red blood cells assume a sickled shape when they are in the deoxygenated venous system but retain their normal flattened disk shape in the oxygen-rich arterial system. Noting this, Pauling suggested that perhaps the source of the problem could be a defect in the oxygen-carrying protein itself: hemoglobin.

Amidst his travels in Europe, Pauling continued to act on this idea as maestro from afar, directing the scientists in his Caltech laboratory to continue searching for differences in the hemoglobin of normal and sickled cells. In the meantime, he sought out and communicated new ideas gleaned from meetings such as the Barcroft Memorial Conference on Hemoglobin, held at Cambridge in June 1948. Pauling’s research team, in particular Harvey Itano and S. Jonathan Singer, were able to show experimentally that his hunch had been right, and less than a year after his return to Pasadena a paper was published that established sickle cell anemia as the first illness to be revealed as a truly molecular disease.

Linus and Peter Pauling at the model Bourton-on-the-water, England. 1948.

While in England, Pauling had occasion to interact closely with a number of scientific greats.  Among these were his close friend Dorothy Crowfoot Hodgkin, who is credited as a pioneer in the development of protein crystallography and was the winner of the 1964 Nobel Prize for Chemistry.  Likewise, Pauling conversed with Max Perutz, a protege of Sir William Lawrence Bragg‘s at the Cavendish Laboratory at Cambridge, who would go on to discover the structure of hemoglobin and receive the Nobel Prize for Chemistry in 1962.  While fruitful in many respects, these interactions served to increase Pauling’s feelings of urgency as concerned the race to determine the structure of proteins.

Bragg shared the 1915 Nobel Prize in Physics with his father for their early development of X-ray crystallography, and though there existed a long-standing scientific rivalry between Pauling’s and Bragg’s laboratories, it wasn’t until Pauling saw, with his own eyes, the work that was being done that he admitted he was “beginning to feel a bit uncomfortable about the English competition.” As he wrote to his colleague Edward Hughes back at Caltech

It has been a good experience for me to look over the x-ray laboratory at Cambridge. They have about five times as great an outfit as ours, that is, with facilities for taking nearly 30 x-ray pictures at the same time. I think that we should expand our x-ray lab without delay.

This realization prompted Pauling to get researchers in his lab started on work with insulin – an arduous and complicated process that required sample purification and crystallization prior to x-ray investigation. In relaying research findings from English scientists working on insulin to his partners back in Pasadena, Pauling intimated that

It is clear that there is already considerable progress made on the job of a complete structure determination of insulin. However, there is still a very great deal of work that remains to be done, and I do not think that it is assured that the British school will finish the job. I believe that this is the problem that we should begin to work on, with as much vigor as possible, under our insulin project.

Little did Pauling know that, while laying in bed, using little more than a piece of paper, a pen and a slide rule, he would soon make a major breakthrough in protein chemistry on his own.

Dorothy Hodgkin and Ava Helen Pauling

Ivan Zupec, Dorothy Hodgkin, Linus and Ava Helen Pauling, 1977.

[Part 2 of 2]

Amidst the huge number of Linus Pauling’s publications, speeches, personal books, and letters held in the Pauling collection, you will also find a section dedicated to Ava Helen Pauling. Although much smaller in size than her husband’s treasure trove, the series still contains a sizable number of items documenting Ava Helen’s own pursuits as a peace activist of some renown. Within her correspondence section, one finds the subject matter for part two of our post on Dorothy Crowfoot Hodgkin. Today, we’ll be discussing Hodgkin’s friendship with Ava Helen.

Dorothy Crowfoot Hodgkin was a prominent X-ray crystallographer and a long-time friend of both Linus and Ava Helen Pauling.  Although Linus Pauling and Hodgkin may have initially been drawn together because of their shared interest in chemistry, they quickly became friends – a relationship which spilled over to include both of their spouses.

Correspondence specifically between Ava Helen and Hodgkin is sporadic, but does demonstrate very well the friendship that they fostered. For example, in a letter written to Ava Helen on December 27, 1957, Hodgkin writes:

It is lovely indeed to have the memory of our time spent with you. It seemed almost a miracle that Thomas [Hodgkin - Dorothy's husband] and I should come together to visit you. I think your home is one of the most beautiful places I know in the world in every sort of way. And we do thank you more than I can properly say for having us and looking after us and cooking and washing and all the things I feel that I ought to be doing for you and not the other way around.

Similarly, Ava Helen immensely enjoyed the time that she and Linus spent with Dorothy and Thomas. On September 23, 1960, in noting Dorothy’s appointment as the first Wolfson Research Professor of the Royal Society, Ava Helen writes:

It gave me great happiness to write on this envelope this lovely address. I have regretted that I did not have time to congratulate you properly in London. We are always so filled with joy at seeing you and Thomas that we forget to say all of these proper and expected things.

At times, Ava Helen and Hodgkin discussed more serious matters in their lives. In the same September 23 letter, Ava Helen talks about Linus’ experience with the Internal Security Subcommittee of the U.S. Senate.

It is no light matter to be cited for contempt by the Senate and many lives have ruined in just this way. You must know, too, that there are a good number of people in prison right now in the United States for the exact reasons that they were citing Linus, namely, the refusal to produce names. The First Amendment protects people in this regard and it is absolutely against our Constitution to ask for these names and to put people in prison when they refuse to divulge them. But, nevertheless, this goes on all the time.

The correspondence between Ava Helen Pauling and Dorothy Hodgkin continued up until Ava Helen succumbed to cancer in 1981. Afterward, Hodgkin wrote a heartfelt letter to Linus Pauling, in remembrance of her friend.

I walk about this lovely garden thinking about you and her and your life together, always in such beautiful places too.  Pasadena where first we met, the Ranch, Portola Valley. In the early days, at Oxford.  She was so troubled about your health and then, so much involved with you in efforts for world peace.  I cannot think of her as old, she seemed so bright a spirit, so courageous to the end.  I think of her when last I spoke on the telephone to her, saying ‘I am quite well.’

Yesterday marked the centenary anniversary of Dorothy Crowfoot Hodgkin’s birth. Read more about her relationship with the Paulings in this post.

Dorothy Crowfoot Hodgkin, 1910-1994

Linus Pauling and Dorothy Hodgkin, 1957.

[Part 1 of 2]

On May 12, 1910, Dorothy Crowfoot Hodgkin – a renowned X-ray crystallographer and long-time friend of both Linus and Ava Helen Pauling – was born in Cairo, Egypt. In honor of the hundredth anniversary of her birth, today’s and Thursday’s posts will be devoted to the discussion of not only Hodgkin’s life and extensive contributions to the scientific community, but also her friendship to the Pauling family.

Although Dorothy Crowfoot was born in Egypt, her parents were English and she spent most of her childhood in the United Kingdom. When World War I began in 1914, she and her two sisters were taken to England, where they lived for a time with their grandparents. After the war, Dorothy’s mother, who had moved to Sudan from Cairo with her husband in 1916, decided to return to England to be with her daughters. In 1920 the family moved to Beccles, England, and in 1921 Crowfoot entered the Sir John Leman Grammar School. During her time there, her interest in science grew immensely.

In 1928, after spending a year studying Latin and botany, Dorothy began to focus on chemistry at Oxford’s Somerville College, where she quickly became interested in X-ray crystallography. In 1932 Crowfoot left Oxford for Cambridge to work under J.D. Bernal. Two years later she returned to Oxford and after another two years of study was appointed a research fellow there, a position that she held until 1977.  During her time at Oxford, Dorothy supervised the work of many students, including a young Clara Brink, whose papers now reside in the Oregon State University Libraries Special Collections.

In 1937 Crowfoot married Thomas Hodgkin, with whom she had three children.

Throughout her lengthy scientific career, Hodgkin worked with great success on a wide variety of research projects pertaining to molecules such as sterols, vitamin B12 and insulin. She participated in the 1946 meetings that led to the formation of the International Union for Crystallography, and also became a member of various academies and societies, including the Royal Society and the American Academy of Arts and Sciences.

In 1964 Dorothy Crowfoot Hodgkin received her highest decoration: the Nobel Prize in Chemistry “for her determinations by X-ray techniques of the structures of important biochemical substances.” She also received the Order of Merit, the Lenin Peace Prize – for which she was nominated by Linus Pauling – the Copley Medal, and many other awards for her extensive research.

The first mention of Dorothy Hodgkin in the Pauling Papers appears in correspondence dated to 1947. In it, Pauling writes to Dr. H. Marshall Chadwell of the Rockefeller Foundation, asking for advice about Hodgkin, who will be coming to the U.S. in the fall on a grant from the Rockefeller Foundation. Pauling states that he has “known her work very well, and for a long time, and I have been looking forward to meeting her.” Not long after, Pauling and Hodgkin did meet, and they soon began personally exchanging letters. This process lasted essentially for the rest of their lives, and allows for direct observation of their developing friendship.

Letter from Pauling to Hodgkin, October 7, 1953.

Although much of the correspondence between Hodgkin and Pauling relates to research, they often discuss more personal matters. Alongside the numerous letters on Hodgkin’s work pertaining to Vitamin B12 and Pauling’s research on proteins, there are many letters discussing subjects such as health issues – not only their own but also those of their spouses – Pauling’s experience of being trapped on a cliff, and various travel plans – many of which set up visits to each other.

One specific letter of interest from Pauling to Hodgkin is dated September 14, 1955, in which Pauling writes

to congratulate you on the wonderful job that you have done on Vitamin B12. I find it hard to believe, although very satisfying, that the methods of x-ray crystallography can be used so effectively on such a complex molecule.

Hodgkin had begun work with the Vitamin B12 molecule in 1948.

Another interesting letter from Pauling to Hodgkin illustrates the extent to which the scientific viewpoint permeated Pauling’s thinking on a whole host of matters. In his letter dated January 27, 1959, Pauling thanks Hodgkin for a book that she had sent to him – Christopher Hill’s Puritanism and Revolution – and notes that “I have written to Christopher that I think that mad hatters are mad because of mercury poison – felt is made by treating the hair with mercuric nitrate. His chapter 11 is about a mad hatter.”

One last letter of note is written by Hodgkin on October 14, 1974, in which she informs Pauling that she “should be very happy indeed to be an Associate of the Linus Pauling Institute of Science and Medicine.” In this same letter, Vitamin B12 makes another appearance, demonstrating the longevity of her work with the molecule. This time, Hodgkin sends a stereo print of her structure of the Vitamin B12 coenzyme, which she calls “the most important naturally occurring form of the vitamin.”

Hodgkin and Pauling, 1986.

Unfortunately, not every letter between Pauling and Hodgkin comes under happy circumstances. On December 15, 1981, Hodgkin writes to Pauling to mourn the death of Ava Helen, which had occurred on December 7. Some six months later, on June 4, 1982, Pauling writes to Hodgkin in order to express his sympathy after hearing that her husband Thomas had died.

Hodgkin’s leading work in the field of X-ray crystallography made her one of the most decorated and successful scientists of the twentieth century, as well as a pioneering example of the role that women could play in the laboratory. Although a deep interest in science may have initially introduced Hodgkin and Pauling, our brief look at the correspondence between the two shows that their professional relationship quickly evolved into a long-lasting friendship.

Dorothy Crowfoot Hodgkin died on July 29, 1994, twenty-one days before Linus Pauling.

Check back on Thursday for our post on Hodgkin and Ava Helen Pauling, and make sure to visit the Linus Pauling Online portal for more information on Linus Pauling.

David and Clara Shoemaker

David and Clara Shoemaker working in an x-ray laboratory at Oregon State University, 1983.

Husband and wife crystallographers David and Clara Shoemaker were, in many respects, an unlikely couple.

David Shoemaker was born on May 12, 1920 in the tiny town of Kooskia, Idaho. Clara Brink was born on June 20, 1921 in Rolde, Holland. Both moved through their primary studies in orderly fashion and progressed to undergraduate work in chemistry – David at Reed College in Portland, Oregon, Clara at the University of Leiden.

In 1942 David received his bachelor’s degree from Reed and moved directly to the California Institute of Technology. Working under Linus Pauling, David quickly established himself as a promising doctoral candidate. His research was initially divided between Pauling’s expansive program of scientific war work and, later, a series of crystallographic investigations. While in Pasadena, David determined the structure of sixteen molecules, most notable among them threonine, an amino acid.

Upon receiving his Ph. D. in 1947, David – with the assistance of Pauling – was subsequently named a Guggenheim fellow, studying at both Oxford and the Institute for Theoretical Physics in Copenhagen. Aged 27, he was among the youngest of his era to receive a Guggenheim Fellowship.

Group photo of participants at the Conference on Current Problems of Physics. Copenhagen, Denmark. September 1947. Niels Bohr sits in the front row, far left. David Shoemaker is seated in the second row, fourth from right.

Clara’s path through graduate studies was somewhat less smooth. She completed her undergraduate work at the University of Leiden in 1941, shortly before the Nazi occupation of the Netherlands and the subsequent closing of the university. Despite the turbulence of World War II, Clara was able to commence her graduate studies through the University of Utrecht, though much of her coursework was self-taught, conducted in her parents’ home. Despite these handicaps, Clara completed her doctoral examinations on time, in 1946, after which point she assumed an assistantship at the University of Utrecht and learned the techniques of x-ray crystallography, commuting one day per week to Amsterdam to study under the renowned crystallographer Caroline MacGillavry.

The years immediately following the close of hostilities were fruitful ones for both David and Clara. Having returned home from his Guggenheim trip, David was named a Senior Research Fellow at Caltech, where he solved the difficult structure of DL-serine and began the research program that came to define much of his (and Clara’s) career – a broad series of investigations into the structures of complex transition-metal phases. In the meantime, Clara became a full-time crystallographer, first studying crystal structures of monovalent ions at the University of Leiden and later working for one year at Oxford, where she conducted research on the crystal structure of vitamin B12 under Dorothy Hodgkin, the 1964 Nobel laureate in Chemistry.

In 1951 David was hired away from Caltech by the Massachusetts Institute of Technology, where he began investigating zeolite structures as an Assistant Professor. Two years later, dissatisfied with the working environment at the University of Leiden, Clara took a one-year leave of absence to work on transition metals at M.I.T. Her laboratory in Cambridge was run by David Shoemaker.

In 1954 David renewed Clara’s leave of absence for an additional year and by 1955 it was clear that Clara would not be returning to Europe – on August 5th, the couple was married. Shortly thereafter Clara transferred to Harvard Medical School to work under the biochemist Barbara W. Low. One year later, Clara gave birth to the couple’s only son. While caring for the newborn Robert, Clara worked from home on the International Tables of Crystallography.

The Shoemakers enjoyed a productive tenure at M. I. T. – David was promoted to full professor, began a lengthy service on the U. S. National Committee for Crystallography (including a three-year term as President) and published widely, including a textbook titled Experiments in Physical Chemistry, which would eventually run through six editions.

In 1970 David was elected President of the American Crystallography Association. That same year, the Shoemakers relocated to Oregon State University, where David had been hired to chair the Department of Chemistry. In reaction to the university’s nepotism guidelines, Clara arranged to work as Research Associate under Dr. Ken Hedberg – like David Shoemaker, a former graduate student of Linus Pauling. The arrangement lasted for several years until the university’s rules were relaxed.

Model of the crystal structure and superstructure of the K Phase, Mn77Fe4Si19. Model built by Clara B. Shoemaker, David P. Shoemaker and Ted E. Hopkins.

During his tenure as department chair, David oversaw two major building projects – the construction of a new chemistry laboratory facility and the renovation of the chemistry offices and research building. Over that same period of time, Clara trained several graduate students in techniques of x-ray crystallography, publishing papers with many of her protégés. The couple retired in 1984, though they continued to conduct important work on transition metal phases as well as the controversial topic of quasicrystals.

The Shoemakers remained close friends with Linus Pauling, though they did dispute certain of Pauling’s claims about the nature of quasicrystals. In 1995 David Shoemaker, himself in fading health, spoke of his long association with Pauling at a memorial conference organized at Oregon State University. David’s comments detailing his recollection of the discovery of the alpha-helix caused something of a stir in the audience, as the provenance of the alpha-helix work has long been a matter of some dispute.

David Shoemaker on the Discovery of the Alpha Helix

Afterward, Shoemaker offered this clarification:

My memory may have been faulty in claiming to have seen Pauling actually taping his cardboard amide linkages together to form a helix, but Professor William Lipscomb, in a talk that preceded mine, showed a drawing in Pauling’s own hand of an alpha-helix rolled out flat, showing what points the polypeptide chain joined together in the helix. The drawing was titled ‘alpha helix. First drawn March 1948. Linus Pauling.’ My visit to Oxford was from January to March 1948.

David Shoemaker died of kidney failure on August 24, 1995, some six months after the Pauling memorial conference. His wife Clara, a close friend of our department, passed away on September 30, 2009. Over the course of their professional association, David and Clara published thirty-six scientific papers together.

The David and Clara Shoemaker Papers are just one of the many collections held in the OSU Libraries Special Collections.

Linus Pauling baseball!

As the Phillies and Rays prepare for another rendition of the Fall Classic, we thought it appropriate to share with you one of our favorite pieces of video:  Linus Pauling playing beach baseball at a Caltech chemistry department picnic in 1938.

Author of more than 1,100 published articles and inarguably one of history’s great minds, Pauling’s knowledge of the strike zone was, evidently, a little less authoritative.  And while coaches around the world would surely appreciate Pauling’s hustle on the basepaths, one does fear for the safety of those enlisted to play third for any team opposing the two-time Nobel prizewinner.

The Linus Pauling baseball clip is just a small segment of “The Edward W. Hughes Tapes,” a series of home movies recorded by Hughes, for twenty-five years a colleague of Pauling’s at Caltech.  The Hughes tapes, which run to just under an hour, offer fascinating glimpses of Caltech social gatherings and Pasadena life over the course of five decades.  Along with Linus and Ava Helen Pauling, careful viewers will note the presence of multiple scientific luminaries in the films — Albert Szent-Györgyi, Dorothy Hodgkin, Jerry Donohue, James Watson and Francis Crick, to name a few.

It is worth noting that the tapes also include footage from additional baseball outings at later department picnics.  Pauling — whose general disinclination toward sports was covered here — doesn’t take part in these match-ups.  One who was a bit more interested in tossing it around the diamond was 1976 Nobel chemistry laureate William Lipscomb, who, in 1995, recounted that

[Pauling's] illness from nephritis and his frequent trips meant that we did not see him very often, but he and his family did occasionally attend the Caltech Chemists games of (intermediate) baseball in the local league.

In a footnote, Lipscomb adds a few memorable details of his time roaming the outfield with The Chemists:

Seventy-five feet between bases, softball, but hardball rules and overhand pitching from 57.5 feet. I made the local newspaper for an unassisted triple play while playing center field.

Oregon State University, of course, has become something of a baseball powerhouse, given the Beavers’ back-to-back national championships in 2006 and 2007.  Our colleagues in the University Archives have created a terrific website documenting the evolution of this program through its centenary: Oregon State Baseball: 100 Years to a National Championship, 1907-2006.