David Davies: Structural biologist and mentor

David Davies (Fig. 1) was not, initially, a macromolecular crystallographer and neither was he enthusiastic about the prospects of using crystallography to determine the structures of proteins. During the time that he was a student at Oxford, determining the crystal structures of small molecules, he attended a meeting in Cambridge at which Max Perutz discussed his X‐ray studies of hemoglobin crystals. On the drive back to Oxford, David and his fellow students discussed the presentation. As David would recall later, it was the consensus of the group that “If only Max Perutz was a bit smarter he would realize what a waste of time it is to work on crystal structures of large molecules.”

Figure 1.

David Davies, left, with the author. Jerusalem, 1980.

Notwithstanding these early reservations, David was soon to change his mind, and was, in fact, a participant in the determination by Kendrew's group of the first high‐resolution crystal structure of any protein.1

David spent two years as a postdoc with Linus Pauling working on structures such as parabanic acid which provided the geometry of the structures of the amino acids, the essential basis for Pauling's prior proposals for the structures of the α‐helix and β‐sheet. David's structures set the standard for accuracy, in part because they were among the first to use full three‐dimensional X‐ray data sets, and also because they pioneered the use of the newly‐available computers to facilitate structure refinement.2

On subsequently moving to the NIH, David's initial focus was on oligonucleotide structures related to DNA. Together with Gary Felsenfeld, he discovered the structure of the DNA triple helix, the implications of which only became apparent much later.3 Gary and David had first met in the Pauling laboratory and were to become lifetime friends and colleagues.

I first met David during the time that I was a postdoc in David Blow's group at the MRC working on the structure of α‐chymotrypsin. I was also very pleased to accept David's invitation to join his group at the NIH beginning in 1967.

By the end of 1966, while I was still in David Blow's group, we obtained high‐resolution electron density maps for α‐chymotrypsin but were unable to interpret them. After I had left, data for another heavy‐atom derivative were included, which permitted David Blow to determine the structure. David was, however, not fully confident of his interpretation, and suggested to David Davies that I might independently interpret the map at the NIH. It is indicative of David Davies' generosity that he immediately agreed to this proposal. For me, it was an unparalleled opportunity to gain experience in the interpretation of electron density maps.

During the time that I was in David's group, he became interested in immunoglobulins, for which essentially no structural information was available. David asked his colleagues at the NIH to alert him to any potential leads. Bill Terry came back with information regarding a patient in Minnesota who had in his serum large amounts of a cryoglobulin, i.e. an immunoglobulin‐like protein which precipitates on cooling. To prevent this protein from precipitating in the capillaries of the patient during cold weather, the serum was removed, chilled to remove the cryoglobulin, and then returned to the patient. In this case, however, the cryoglobulin precipitated as “rock candy.” David confirmed that yes, indeed, he would be very interested to examine this “rock candy.”

Within a couple of days, a number of vials arrived, all with clear solutions, but no rock candy. On checking, David was informed that he needed to put these vials of clear liquid into the refrigerator overnight and to check the following morning. Sure enough, the vials contained an abundance of beautiful crystals which seemed admirable for X‐ray study. The only problem, however, was that the temperature of the crystals needed to be maintained just above freezing. To resolve this problem, we moved an entire rotating anode generator into a cold room, together with a precession camera. Within a few days we had very promising X‐ray photographs (Fig. 2 of Reference 4).4 (After a week or so, however, the viscosity of the grease in the precession camera increased to the point that the camera froze up and refused to operate.)

An unexpected bonus of these early crystals was that they showed immediately that the immunoglobulin molecule had twofold symmetry, consistent with molecular weight and sequence information. Also, the now well‐known Y‐shaped structure of the immunoglobulin molecules could be seen directly in the crystals in beautiful electron micrographs taken subsequently by David's collaborator, Lou Labaw [Figs. 1(D) and 2(C) of Reference 5].5 Subsequently, David was to become a world leader in the immunoglobulin field.

David's subsequent accomplishments are well known and do not need elaboration—the structure of tryptophan synthetase,6 the structure of the HIV‐1 integrase,7 and structures of the Toll‐like receptors,8 among others.

He was elected early to the U.S. National Academy of Sciences and the American Academy of Arts and Sciences. Notwithstanding these and other accolades, David always remained remarkably humble. He could not have been more generous as a role‐model and mentor. When I arrived from England via Australia to join his group, David and his first wife, Cynthia, insisted that our family stay with them until we found a place to live. Indeed, it was in their home, and with David's encouragement, that our baby daughter first began to walk.

David encouraged the establishment of a series of other outstanding structural biology groups at the NIH, including NMR and crystallography, and facilitated this by relinquishing some of his own space.

Late in his career he was singularly pleased when the NIH recognized his extraordinary contributions by allocating him a personal, named, parking space. At the same time, he seemed almost embarrassed that he had been singled out for such a unique distinction.

The field of structural biology has been singularly fortunate to be established by a group of individuals who were not only extraordinary scientists but also exemplary human beings. Lawrence Bragg, Desmond Bernal, Linus Pauling, Dorothy Hodgkin, and Max Perutz come to mind. David Davies was one of that group.

David, who died at the age of 89, is survived by his wife Monica, two daughters, Helen and Sally, and a very large group of postdocs, lab members, colleagues, and collaborators who had the extraordinary good fortune of benefiting from his friendship, his wise counsel, and his example. His personal memoir,9 “A Quiet Life with Proteins” is highly recommended.

BRIAN W. MATTHEWS
1229 University of Oregon, Institute of Molecular Biology, Eugene, Oregon 97403‐1229