Franklin M. Harold

A Lifetime of Science

I am a biochemist by formal training, but a physiologist/cell biologist by outlook: it is the living system as a whole that fascinates me, not its molecular parts. For the past fifty years my professional life has turned on research in microbial physiology, passing through several consecutive phases.

Inorganic Polyphosphate

Between 1958 and 1963 Ruth and I used mutants to explore the metabolism and function of polyphosphates, which are abundant in many microorganisms. This phase concluded with the formulation of a polyphosphate cycle, and a major review of the field (Harold, 1966).

Energy Coupling by Ion Currents

When it became clear that polyphosphates are not an essential feature of life, my interests shifted to the transport of inorganic ions across the plasma membrane of bacteria. This line of inquiry blossomed in 1967, when I became convinced that Peter Mitchell’s chemiosmotic theory supplied a comprehensive framework for all of bioenergetics, including active transport across membranes. At that time few understood Mitchell’s ideas, and fewer still took them seriously. The new paradigm put me outside the main stream of biochemistry, but at the leading edge of a revolution in bioenergetics. Several excellent postdocs joined the lab: Karlheinz Altendorf, Evert Bakker, Don Heefner, Hajime Hirata, Hiroshi Kobayashi, Yoshimi Kakinuma, Milka Pavlasova, and Jennifer Van Brunt. During the next two decades our studies helped to clarify the metabolic effects of ionophores; to document that the F₁F_o-ATPase is a proton pump; to develop methods for measuring membrane potential and pH gradients; and to demonstrate that endogenous as well as artificial ion gradients drive active transport and flagellar rotation. They also led to the discovery of several novel ATPases responsible for the accumulation of K⁺ and the extrusion of Na⁺ and Ca²⁺ ions.

The realization that a circulation of protons across the plasma membrane underlies energy transduction and the performance of work gave rise to a series of literature reviews, designed to explain and expound the chemiosmotic viewpoint (Harold 1972, 1974, 1977, 1978, 1996). I would like to believe that these articles, coupled with our experimental work, paved the way for the general acceptance of the theory, signaled by the award of the Nobel Prize to Mitchell in 1978. These efforts culminated in a book that surveyed bioenergetics as a whole; “The Vital Force: A Study of Bioenergetics” was published by W.H. Freeman in 1986.

Transcellular Electric Currents

By 1980, research on the genesis and functions of ion currents had come to focus on transcellular currents. The pioneering researches of Lionel Jaffe had shown that many eukaryotic organisms and cells drive electric currents through themselves and suggested that these currents may be involved in the localization of growth and development. Minuscule currents can be monitored in the external medium by an ultra-sensitive voltmeter called a vibrating probe.

In collaboration with a professional electrophysiologist, John H. Caldwell, I embarked on a systematic study of currents generated by filamentous fungi, especially the water mold Achlya bisexualis. We were again fortunate in our postdocs: Chung-Won Cho, Neil Gow, Darryl Kropf, Jan Schmid, Willie Schreurs, Yuko Takeuchi and later Nicholas Money made the work possible. We demonstrated that the hyphae drive a spatially extended circulation of protons: protons are expelled from the hyphal trunk by a proton-translocating ATPase, and return into the apical region by symport with amino acids. The current imposes a substantial electric field across the cytoplasm, with the apex positive. Nevertheless, detailed studies convinced us that transcellular electric currents are not the cause of polarized growth, but rather a consequence of the spatial separation of transport systems brought about by that mode of enlargement (Harold, 1985; Harold and Caldwell, 1990).

Apical Growth of Fungal Hyphae

Over time, my interests have shifted from the molecular level to the organismal, from mechanisms of transport and energy coupling to growth and morphogenesis. The final phase of my career as an experimental scientist focused on efforts to understand how hyphae organize themselves to carry out apical growth, particularly the role of turgor as driving force and the cytoskeleton as the instrument of localized secretion.

The larger purpose was always to use apical growth as a paradigm for cell growth in general, and thereby gain a little more insight into the abiding mystery of biological organization. This effort produced another crop of reviews (Harold, 1990, 1995, 1997, 2002, 2005), and eventually another book: “The Way of the Cell: Molecules, Organisms and the Order of Life”, published by Oxford University Press in 2001.

A Taste for Synthesis, and for Travel

Early on I recognized that I am less interested in the facts of life than in their meaning. Synthesis requires wide reading, reflection and eventually writing; general articles and especially books are still the best vehicle for this purpose, and these have occupied much of my personal attention over the past thirty years.

Once again, I find myself well outside the main stream. Biology today is dominated by the outlook of molecular reductionism, intensely focused on the structures and interactions of biological molecules, with the genome as the center of command and control. The reductionist approach has generated profound insight into the chemical basis of life, but fails to illuminate the higher levels of order: growth and development of cells and organisms, development, behavior, even evolution.

Organized complexity calls for a different mindset, one that puts cells rather than genes in the center. Living things are dynamic systems made up of innumerable molecules that draw matter and energy into themselves, maintain their identity despite turnover, and reproduce their own kind. All their mechanisms are molecular, but it is spatial and structural organization that brings molecules to life. This is the theme explored in several articles (Harold, 1990, 1995, 2001, 2005), and especially in The Way of the Cell. My efforts to persuade others have not been noticeably successful, but I persist in the belief that if you keep reiterating the obvious, common sense will eventually prevail. A third book, on cell evolution, has just been published (In Search of Cell History: The Evolution of Life’s Building Blocks; University of Chicago Press, 2014).

The academic life, while immensely rewarding, is apt to be devoid of incident. Ruth and I have satisfied the craving for adventure and travel by taking sabbaticals whenever possible (In Iran on a Fulbright lectureship, in Canberra, Australia, and twice in Aberdeen, Scotland), and by extensive travel. Over the years we have hiked widely in the mountains of the western US and Canada; come to know Europe and the Mediterranean basin; trekked repeatedly in the High Himalayas; wandered up and down the Indian subcontinent and the Middle East, from Morocco to Afghanistan; and followed the Silk Road from China to Constantinople. The years have slowed us down, but have not quite stopped us yet.