Remembering Barbara Low

Barbara Low in California, 1947. Credit: Low estate.

Barbara Low, a former research fellow for Linus Pauling and an esteemed scientist, died earlier this year at the age of 98. Low spent most of her career as a researcher and professor at Columbia University’s Vageos College of Physicians and Surgeons. She is perhaps best known for her work with protein structures, particularly her work on the structure of penicillin and her discovery of the pi-helix.

Barbara Wharton Rogers was born in Lancaster, England on March 23, 1920 (she married in 1950 and changed her name thereafter). After receiving her B.A. from Somerville College – an Oxford women’s college – in 1942, she went on to earn an M.A. and D. Phil. from Oxford University. As a component of her education, Low learned the techniques of x-ray crystallography, a field within the chemical sciences that was emerging for women. A major reason for this trend was the fact that one of the leading crystallographers of the era, Oxford professor Dorothy Crowfoot Hodgkin, was banned from teaching to men, so instead she taught crystallography to women at Somerville.

Low was one of Hodgkin’s star pupils, and after Low received her B.A. in chemistry, Hodgkin became Low’s advisor for her graduate studies. It was during these years that Hodgkin and Low determined the structure of penicillin using x-ray crystallography. In 1964, Hodgkin was awarded the Nobel Prize in chemistry for her work determining the structures of various important biochemical substances, penicillin certainly among them.

Molecular model of Penicillin by Dorothy Hodgkin, c.1945. Credit: Luke Hodgkin

While she was working on her doctorate, Low spent a year at the California Institute of Technology as a research fellow, supervised by Linus Pauling. This was the start of what would become a fruitful and mutual working relationship between Pauling and Low. After leaving Caltech and graduating from Oxford, Low took a position as a research associate, and later as assistant professor of physical chemistry, at Harvard University. As her career advanced, Low kept in touch with Pauling and this connection proved beneficial on more than one occasion.

In the early 1950s, Low began to apply x-ray crystallographic techniques to a study of the structure of insulin. She did so during a period of much debate within the scientific community about the structure of various proteins. Pauling famously solved a piece of this puzzle in April 1951 when he published, “The structure of proteins: Two hydrogen-bonded helical configurations of the polypeptide chain” with collaborators Robert Corey and Herman Branson. In this paper, Pauling described for the first time the alpha helical structure of many proteins, a watershed moment that ushered in a whole new era of understanding across the discipline.

Barbara Low was, of course, also working on the structure of proteins, and she became particularly inspired to investigate the connection between structure and function after attending a lecture that Pauling gave at the Massachusetts Institute of Technology in March 1951. Low believed, as did Pauling, that the configuration of the folding of the protein was of more importance to its function than was the molecular make-up itself. Determined to apply this belief to her work on the structure of insulin, Low wrote several letters to Pauling asking him to verify the bond angle distances for the proteins about which he had lectured. Pauling gladly supplied Low with the requested data, even noting that he had double-checked the calculations as he was writing her back. Pauling also helped Low to secure scientific models for the structures that he had described.

Pi-helix diagram published by Low and Grenville-Wells, 1953

These data and models proved vital to one of Low’s most famous discoveries: the pi-helix. Like the alpha-helix, the pi-helix is a type of structure found in some proteins, though one that was not published by Pauling as part of his alpha-helix investigations. This failure may have been due to the pi-helix’ small size, which at the time of its discovery led some researchers to believe it to be an infrequent and rare structure. More modern day findings indicate however that the pi-helix is much more common than previously thought; present in about 15% of protein structures all told.

Low wrote about her discovery to Pauling shortly after the news was made public and received a mixed reply from her former mentor. At the beginning of his response, Pauling suggested that the pi-helix was most likely something that he “too ran across a while back” but acknowledged that Low’s structure was not “intermediate between the alpha helix and the gamma helix,” and thus both novel and genuine. The letter concludes with an admission from Pauling that his researchers may have “overlooked it” in their previous work.

Pauling’s hedging congratulations in this instance did not seem to negatively impact the duo’s relationship, and throughout their correspondence one intuits that the colleagues remained on friendly terms throughout the years. In many letters to Pauling, Low often concluded by giving her regards to Ava Helen. Low also developed a love for the comic Li’l Abner by way of Pauling, who had introduced her to the satirical strip at a dinner party in the early 1950s.

Pauling and Low were also, at times, involved in one another’s careers. When Pauling was denied a passport to travel to the Royal Society Meeting to attend the Protein Symposium in 1952, Low wrote to express her “shock” and to express how “shaken” she was that he had been treated this way. For his part, Pauling helped Low to secure grants and funding through multiple letters of support.

Pauling also provided assistance to Low as her research position at Harvard came to an end in June 1956 by putting her in contact with colleagues Detlev Bronk of Johns Hopkins University, John Kirkwood of Yale University, and DeWitt Stetten at the National Institute of Arthritis. While it is unclear how influential these contacts may have been in Low’s gaining her eventual position at Columbia, it is certainly worth noting that Stetten had recently left Columbia after having served there for nine years as an instructor of biochemistry.

However it came to pass, Low started at Columbia in 1956 as an assistant professor and was promoted to professor in 1966. She formally retired from Columbia in 1990, but stayed on as a lecturer until 2013. Like Pauling, Low was active both socially and politically, devoting significant time and energy to affirmative action activities at her institution. She passed away on January 10, 2019 at her home in the Bronx, New York.

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.