December 2009

Retrospective: Charles Tanford (1921–2009)

In 1960, Tanford moved to a professorial chair in the department of biochemistry at Duke University Medical Center, where he remained for 28 years. He will perhaps be best remembered for his work on protein stability and the hydrophobic effect. This became central to the way in which the structure of globular proteins is perceived. He himself always emphasized the debt he owed to Kauzmann, who, if not the originator of the concept, clarified it and brought it to the attention of protein chemists. Kauzmann planted the seeds in Tanford’s mind during their conversations at Princeton, and the notion that the folded state is imposed on globular proteins by the instability of the unfolded chain in water, rather than the energy of interaction in the globule, came to him as an epiphany. It led to a series of classical studies on protein unfolding by nonaqueous solvents, and especially by urea and guanidinium chloride, and on the free energies of transfer of model hydrophobic compounds from water to such media.

Throughout this period, Tanford made forays into more functional aspects of protein chemistry. Notable among these was his work on antibodies. Rival models of immunoglobulin G were in circulation. Antibodies of this kind were known to be divalent, but the disposition of the antigen-binding sites was a matter of controversy. By a tour de force of hydrodynamic analysis and inference, Tanford and his colleagues defined the lineaments of the molecule. Moreover, they separated the light and heavy chains of an antibody, denatured, refolded and reunited them, and showed that the antigenic specificity was recovered. This eliminated in one stroke Linus Pauling’s “template” theory of antigenic specificity, which was based on transitions between conformational states of the protein.

Around this time, Tanford embarked on his last major undertaking, this time in association with Jacqueline Reynolds, a professor in the department of anatomy at Duke University. Together, they took a daring plunge into what were then the turbid waters of membrane chemistry. Membrane proteins were viewed with disgust by protein chemists, for they were generally insoluble in water, except in an indeterminate denatured condition in complexes with destructive detergents, such as sodium dodecyl sulfate, or fully unfolded in high concentrations of denaturants. Tanford and Reynolds found that the native states could be preserved in soluble complexes with benign detergents, which they carefully characterized. They devised a method of measuring the molecular weights of membrane proteins in this state by masking the detergent contribution to the buoyancy of the complex with D2O. This made it possible to determine the sizes and subunit structure of these refractory proteins by sedimentation analysis.

The contemplation of membranes and their relation to the various states of amphiphiles, such as lipids, led to the culmination of Tanford’s thinking about hydrophobicity. This he set out in a typically lucid and elegant book, encompassing the nature of detergent micelles, surface layers and membranes, “The Hydrophobic Effect: Formation of Micelles and Biological Membranes,” and in an article in Science in 1978. With the new methods they had honed, Reynolds and Tanford made a number of inroads into membrane biology: With the neurophysiologist Arthur Karlin, they studied the acetylcholine receptor and, with Walther Stoeckenius, the structure of bacteriorhodopsin. They fractionated the proteins of the red cell membrane and determined their molecular weights, and, while on sabbatical leave in Germany, they immersed themselves deeply in the action of ion pumps.

Tanford’s professional collaboration with Reynolds had long since blossomed into domestic harmony, he and his wife having divorced in 1968. In 1988, he and Jackie decided to retire. They settled in the small country town of Easingwold in Yorkshire and melted into its community. But they were far from idle, as they began a new joint career as historians of science. Tanford already had published a delightful popular book on membranes and surfaces, “Ben Franklin Stilled the Waves: An Informal History of Pouring Oil on Water with Reflections on the Ups and Downs of Scientific Life in General.” Next, there emerged a typically original joint concept: “The Scientific Traveller: A Guide to the People, Places and Institutions of Europe”— a guidebook for the scientifically inclined tourist. It was so well received that the publisher demanded, and got, a second and equally captivating volume, “A Travel Guide to Scientific Sites of the British Isles.” But the most important joint venture was still to come: “Nature’s Robots: A History of Proteins”— a work of meticulous scholarship, delivered with style, wit and a fine narrative sweep.

Hilaire Belloc, historian and poet, wrote his own epitaph:

When I am gone, I hope it may be said
His sins were scarlet, but his books were read.

Tanford, alas, is gone, but his books and his papers are indeed still read.

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