Franklin M. Harold

Frank Harold was an exceptional biochemist who championed the theory of chemiosmosis, mentored a diverse group of postdoctoral scientists, and sought to understand the essence of life by probing the secrets of cells. As a scholar of biochemistry and physiology, as well as human history and philosophy, he was unmatched in the breadth of his interests. With infectious enthusiasm for the pursuit of new ways to examine longstanding questions in biology, Frank implored his postdocs to spend as much time thinking about experiments as doing them.

Arriving in New York City as an emigree from Europe, Frank studied at The City College in the 1940s. Like many scientists of his generation, he was inspired by What Is Life?, the little gem published by Erwin Schrodinger in 1944. Schrodinger’s evocation of the importance of physics and chemistry in biology became a guiding principle for Frank, whose early investigations concerned the cycling of metabolites in bacteria. As his research progressed, Frank recognized that the classical view of the cell as a bag of chemical reactions controlled by diffusion was ripe for an update. This rejuvenation came from the revolutionary theory of chemiosmosis proposed by Peter Mitchell in the 1960s. Mitchell envisaged the cell as a more organized energetic structure that controlled its chemistry by moving ions across membranes. This was a game-changer for biology, explaining how ATP synthesis was driven by the flux of protons through the membranes of mitochondria and chloroplasts, as well as the membranes of bacteria from which they evolved.

Many biochemists dismissed Mitchell’s ideas as sophistry of little practical value, sometimes because they could not understand what he was proposing. Frank was more inquisitive, spending hours with his slide rule, as he put it, deriving Mitchell’s equations for himself, until “one day the light went on. It was almost a physical sensation of enlightenment, a little ‘satori,’ and one of the most exhilarating experiences science has to offer.”[1] Bioenergetics was born. Frank wrote a series of articles that translated Mitchell’s impenetrable papers into something more palatable for mere mortals—many of whom considered Mitchell a madman. Frank became Mitchell’s bulldog, standing in for him at meetings. Through his papers and presentations, Frank played a crucial role in the acceptance of chemiosmosis and the award of Mitchell’s Nobel Prize in 1978.

In the 1980s, Frank began to extend the lessons of chemiosmosis to the study of morphogenesis and became fascinated by patterns of proton efflux and influx around cells. These ion currents are associated with patterns of growth, suggesting that they might guide the shaping of the cell by telling it where to expand. Maps of these ion currents were created with a peculiar piece of laboratory instrumentation called the vibrating probe, which revealed halos of ions around cells that resembled the shape and polarization of a magnetic field. Frank adopted water molds as experimental subjects for this work. The filamentous cells of these microbes extrude protons from their tips, which was consistent with a causal relationship between ion currents and growth. By the time I joined Frank’s research group in Denver in the late 1980s, the laboratory was a jungle of dangling cables, with micromanipulators set on steel tables with cushioned tops to limit vibration and Faraday cages to exclude extraneous electrical interference with the recordings of ion currents. In the end, the work on ion currents fizzled out when the consensus was reached that the proton fluxes had more to do with the nutrient absorption by these organisms than their development. On a more positive note, the study of ion currents led to a wealth of studies on cellular development in organisms that have proven less amenable to genetic manipulation. This is important, because it added the kind of depth imagined by Schrodinger to the study of water molds and aquatic fungi, brown algae, pollen tubes, mosses. There is, after all, more to life than E. coli and yeast.    

Frank met his wife, Ruth, at Berkeley in the 1950s, and they went on to collaborate as scientific partners for the next 40 years. Ruth worked alongside the postdocs in the lab and added to the sense that we were part of a noble pursuit of the secrets of nature. Frank and Ruth spent the greater part of their careers at the National Jewish Hospital for Respiratory Medicine in Denver, Colorado, before a late move to Colorado State University in Fort Collins. Frank and Ruth were avid hikers and cross-country skiers, and embarked on adventurous mountain treks in the Himalayas, India, the Middle East, and Central Asia. They spent a sabbatical year in Iran in 1969/70, taking their 7-year-old daughter, Stephanie, and assumed the role of cultural ambassadors more than working scientists. Back in Colorado they were generous and caring mentors. Frank’s signal fault was his driving. I recall a terrifying trip into the Rocky Mountains where Frank mistook a freeway exit and we found ourselves bouncing over the ruts in a ploughed farm field.        

Besides his immense contributions to biochemistry and cellular physiology, Frank was a gifted writer. His 1988 book, The Vital Force, remains the best popular writing on bioenergetics and captures the essence of the electrified cell as a device for harvesting and transducing energy.[2] Schrodinger’s question, What is life?, leads to a second fundamental question: How did life come about? This was Frank’s retirement project, which led him to an immense amount of reading and synthesis, correspondence with researchers on abiogenesis, and a trio of books [3-5]. He did not solve the question, of course, but perhaps he helped to frame it more clearly. In one of our late conversations, we discussed his feeling that our attempts to understand cell origins is hampered by a fundamental missing link. He could not give this cryptic element a name, but he left us with the tantalizing possibility that it lies within our grasp if we think about experiments as much as we do them. He wrote, “What I have done . . . is to make a constructive contribution to the global conversation of science and to gain some measure of insight into that great mystery, the origin of life . . . The way of science is for the best of our achievements to endure in substance but lose their individuality, like raindrops falling into a pond. So let it be.”[1]

Nicholas P. Money, Miami University, Oxford, Ohio, USA

Sources: [1] Harold, F. M, To Make the World Intelligible: A Scientist’s Journey (Victoria, BC: FriesenPress, 2016); [2] Harold, F. M., The Vital Force: A Study of Bioenergetics (New York: W. H. Freeman, 1986): [3] Harold, F. M., The Way of the Cell: Molecules, Organisms, and the Order of Life (New York: Oxford University Press, 2003); [4] Harold, F. M., In Search of Cell History: The Evolution of Life’s Building Blocks (‎Chicago, IL: University of Chicago Press, 2014); [5] Harold, F. M., On Life: Cells, Genes, and the Evolution of Complexity (New York: Oxford University Press, 2021).