Harden McConnell, distinguished chemistry professor at Stanford, dies

Harden M. McConnell, Stanford professor emeritus of chemistry, died at his home in Atherton, Calif., on Oct. 8 after a long illness. He was 87.

McConnell was one of the leading physical and biophysical chemists of the last half-century, contributing pioneering approaches and incisive results in diverse areas ranging from fundamentals of magnetic resonance to cell membrane biophysics and immunology.

Many of the discoveries and techniques attributed to his work have become fundamental parts of chemistry education.

“Harden McConnell was a brilliant scientist – he was simply smarter than all of us,” said Steven Boxer, the Camille and Henry Dreyfus Professor in Chemistry. “He could see into the heart of a problem so quickly that it was breathtaking. In fact, it was a bit terrifying. He was a gentle soul, but had zero interest in sloppy thinking or side issues; his work was always highly focused. Very few scientists have such breadth in both theory and experiment or have worked in and impacted so many fields.”

During the past year, at the urging of former students, he assembled a remarkable personal history that summarizes key steps, turning points in his scientific career and a comprehensive bibliography, which can be found at www.hardenmcconnell.org.

McConnell, who had been the Robert Eckles Swain Professor of Chemistry, is survived by his widow and soulmate, Sophia, sons Hunter and Trevor, daughter Jane, daughter-in-law Oksana and one granddaughter.

Private funeral services have been held; a memorial celebration of his remarkable achievements is being planned.

Early foundational work

Harden Marsden McConnell was born July 18, 1927, in Richmond, Va. He completed his bachelor’s degree in 1947 from George Washington University, and went on to study under the heroes of those scientific fields that would eventually influence his career. He earned his doctorate in chemistry from the California Institute of Technology in 1951, where he worked with Norman Davidson, a molecular biologist who was well known for advancing genome research.

This was followed by a two-year postdoctoral fellowship at the University of Chicago under the guidance of Robert Mulliken, a physicist and chemist who developed ways to compute the structure of molecules.

McConnell’s early work was concerned with both theoretical and experimental studies of charge transfer processes, by which electrons move within or between molecules. He then moved to Shell Development Company in Emeryville, Calif., at the time a basic research center with one of the first commercial nuclear magnetic resonance (NMR) spectrometers, where he initiated fundamental studies of NMR spectra and spectral line shapes. He then joined the faculty of Caltech in 1956, where he flourished prior to becoming a professor at Stanford in 1964.

McConnell’s work in the 1950s and ’60s was primarily concerned with testing and defining fundamental concepts of the electronic structure of molecules. Pioneering and often conflicting work by his long-time mentor at Caltech, Linus Pauling, and his postdoctoral advisor, Mulliken, had established differing approximate quantum mechanical descriptions of how electrons are distributed in molecules to create chemical bonds, concepts that are now commonly taught to freshman chemistry students.

At the time, there were few definitive tests of these models, and McConnell realized that electron spin resonance (ESR) spectra could provide the missing link. This required both theoretical development and experiments, a powerful combination that characterized his work throughout his career. The results, known as the McConnell relations, provide fundamental insights into the origins of long-range interactions between electrons and nuclei in molecules.

Related work formed the basis for understanding long-distance electron transfer reactions, and he published a series of foundational papers on excited states in solids and the origins of ferromagnetism. Each of these topics developed into fields pursued by his former students and others throughout the world.

Cell research on The Farm

Around the time McConnell moved to Stanford, he began work with small, stable organic free radicals – molecules with an unpaired electron. Through this work, he developed the “spin label” technique, where the free radical, with its unpaired electron spin, is attached to a target molecule to make a very sensitive probe for the local structure and dynamics of the molecule. This proved to be especially useful for probing motions in macromolecular systems – such as proteins and nucleic acids – making it possible to observe, for example, the conformational changes in hemoglobin upon oxygenation.

The spin label technique also made it possible to study the structure and dynamics of cell membranes, notably the lipid bilayer. The result was a series of classic papers by McConnell and his graduate students Wayne Hubbell and Roger Kornberg and postdoctoral fellow Joachim Seelig – all now renowned scientists in their own right. This work revealed that the membrane is essentially a two-dimensional fluid, and provided a measurement of the “flip-flop” of lipids between bilayer leaflets which proved to be quite slow. Both results are now essential features of our understanding of biological membrane dynamics.

McConnell became fascinated by interactions that lead to separation among specific lipid species, in particular those involving cholesterol. This led to major work on the phase behavior of lipid molecules at the air-water interface, the shapes and manipulation of phase-separated domains, ideas concerning the activity of cholesterol in membranes and cholesterol homeostasis. He continued to publish deeply insightful papers in this area until the time of his death.

In parallel, he became interested in fundamental questions of immunology, because the key players are membrane-associated proteins. He developed a simple platform for creating planar bilayers on glass supports – known as a solid supported bilayer – that can be used to display components of the immune system so that scientists can directly observe their properties and their interactions with cells that recognize these components. This platform has been widely adopted in many laboratories for investigating many membrane-related systems.

His lab was largely self-contained, and he collaborated with only a few groups, including those of Mark Davis, W.E. Moerner and Boxer. “He had many incredibly talented graduate students and postdoctoral fellows, a large fraction of whom have gone on to distinguished scientific careers,” Boxer said. “These co-workers were intensely loyal to him and he had a huge impact on their scientific interests and style.”

“Harden always impressed me with the depth of his insight and with his ability to provide a thoughtful calculation of the basic physical effect at hand, efforts he pursued for many years after ‘retirement’,” said Moerner, the Harry S. Mosher Professor of Chemistry and this year’s Nobel laureate in chemistry. “He was truly inspiring and scholarly; I can only say that it was a pure joy to collaborate with this giant of physical chemistry.”

McConnell was widely recognized for his achievements with awards at the highest level, including the Wolf Prize (1984), the U.S. National Academy of Sciences Award in the Chemical Sciences (1988), the National Medal of Science (1989) and the Welch Award in Chemistry (2002), among many others. He was elected to the National Academy of Sciences in 1965.