Harden Marsden McConnell, a “serial trailblazer” in physical chemistry and biophysics, succumbed to an aggressive cancer on 8 October 2014 in Atherton, California. Throughout his career, he defined and then spearheaded new research directions that resulted in both theoretical and experimental discoveries. Examples include establishing the McConnell equation for electron spin resonance (ESR), inventing spin labeling, and measuring fundamental parameters of lipid membranes.
Harden was born on 18 July 1927 in Richmond, Virginia. After earning his BS in chemistry from George Washington University in 1947, he completed doctoral work in chemistry in 1951 with Norman Davidson at Caltech. During his postdoctoral stint at the University of Chicago with Robert Mulliken and John Platt, he was introduced to powerful new tools of molecular orbital theory. In 1953 Harden joined Shell Oil, which owned one of the first commercial nuclear magnetic resonance (NMR) spectrometers on the West Coast. Through his groundbreaking work, he helped establish NMR as the premiere method for determining the molecular structure and dynamics of organic molecules in solution.
The impact of Harden’s work led Davidson, Verner Schomaker, and Jack Roberts to urge Linus Pauling, chair of chemistry at Caltech, to hire “the most exciting chemical physicist on the scene.” Years later, German Nobel laureate Manfred Eigen echoed those sentiments with “Das ist der beste Biophysiker, den sie drüben haben” (“that’s the best biophysicist they have over there”). Harden joined Caltech in 1956 as an assistant professor.
Harden’s seminal 1958 single-author publication “Reaction rates by nuclear magnetic resonance” showed how to modify the Bloch equations to elucidate rate processes and laid the foundation for a new field of measuring reaction rates and conformational changes. Harden’s subsequent work in the 1950s provided the foundation for nearly all ESR studies of organic paramagnetic systems: The McConnell equation, a = Qρ, relates a proton’s hyperfine splitting a to the spin density ρ in the π orbital of an adjacent carbon. Harden solved a conundrum concerning how hyperfine splitting arises in planar organic free radicals and elucidated the nature of anisotropic hyperfine interactions.
Although difficult to imagine now, the utility of molecular orbital theory was not well established in the early 1950s. Harden’s pioneering theoretical work and elegant experimental verification helped establish the emerging theory as a powerful tool for calculating the detailed electronic structure and other properties of organic molecules.
His interest then turned to the dynamics of paramagnetic spins. Harden was first to recognize that the ESR spectra of ion-radical salts based on tetracyanoquinodimethane were due to triplet excitons. He and coworkers then predicted and experimentally verified the presence of triplet excitons for Wurster’s blue perchlorate radicals. Harden’s theoretical and experimental studies greatly stimulated the field of solid-state triplet exciton research.
After Harden moved to Stanford University in 1964, he and Shun-ichi Ohnishi cleverly used DNA flowing through a capillary to demonstrate that chlorpromazine radicals intercalate between DNA base pairs. Harden then exploited the superior stability of nitroxide radicals to launch the spin-labeling technique, a now-standard way of characterizing structure and dynamics of biological molecules, particularly hemoglobin and membrane lipids.
Harden’s immense contributions to membrane biophysics can be found in most biology textbooks and include the first measurements of lateral fluidity of lipids in membranes, done with Roger Kornberg. Understanding membranes, particularly the role of cholesterol, consumed much of his later career. Harden’s 1987 paper on immiscible liquid phases in membranes inaugurated 25 years of his group’s discoveries on immiscible liquid phases in membranes and culminated in a paper, published when Harden was 85, that examined diffusion within lipid bilayers near miscibility critical points.
Harden was fearless about entering new fields. His groundbreaking application of physical chemistry tools to immunology became a major research thrust after his 1984 paper provided the first demonstration that the binding of specific peptides to major histocompatibility complex molecules in membranes is sufficient to trigger response from a T cell.
Harden’s accomplishments resulted from his drive and focus; he literally dreamt science. He attracted students and postdocs likely to appreciate his intense intellectual investment in them. To thrive in Harden’s lab meant to be flattered by remarks like, “You got suntanned. You might know that this causes cancer. It would be better for you to stay in the lab.” To the uninitiated, he seemed severe. Gordon Conferences are casual; Harden would have been the only scientist at his conference to wear a tie—if en route he had not also bought a tie for his graduate student. However, colleagues knew he had a sense of humor as deep and dry as his Beefeater martinis. His group members knew his dedication to them; Harden convinced more than one despondent student to finish a dissertation, and he wrote recommendation letters even after being informed of his terminal illness. In total, Harden advised 79 PhD students and 71 postdoctoral fellows. His account of his group’s accomplishments is at http://hardenmcconnell.org.
The urgency of time weighed on Harden throughout his life—he had a nervous habit of jingling keys during unstimulating seminars. In the end, he was right. There was not enough time. The day before he died, his characteristically terse and curious email to a former student regarding a manuscript read, “para 2 is not terrible anymore. Anything new?” We miss him profoundly.