I was born 30 October 1931 in Rye, a small town in the south-east of England. Both of my parents came from generations of small family farmers. One of my earliest childhood memories is of listening to Prime Minister Neville Chamberlain’s radio broadcast on the day war broke out in September 1939 after which I began avidly following the news on the radio that my parents allowed by my bedside. Soon after, I managed to construct a short wave radio with a purchased kit, and began listening to news broadcasts from around the globe. My fascination with radio led to a subscription to Wireless World magazine, which further encouraged my enthusiasm for science with its famously prescient 1945 article by Arthur C Clarke on the potential for radio broadcasting from geostationary satellites.
Starting in 1943, I attended Faversham Grammar School, then a state-funded school that had been originally founded by Queen Elizabeth I in 1665, where I obtained an excellent education with a strong emphasis on mathematics, physics and chemistry. Although I enjoyed maths, my real enthusiasm was for practical physics, where my liking for details encouraged me to try small changes that might improve the final accuracy of my experiments.
Following an 18-month detour performing National Service as a radar mechanic in the Royal Air Force, I entered King’s College Cambridge in 1951 to read for a degree in physics. My advisor foresaw the future expansion of biological research and recommended that I prepare myself by taking side courses in physiology and biochemistry. After graduation, I was offered a research studentship on biological applications of electron microscopy in the Cavendish lab at Cambridge. My colleagues in the EM Unit were the first real social group that I had joined since leaving home and formed my first group of scientific kindred spirits.
Upon leaving Cambridge, I obtained an electron microscopy position at Harvard University with the agreement of devoting half my time to my own research. My supervisor, George Wald, invited me to join his active lunch group, where by good fortune I met my future wife, research biochemist Barbara Hollingworth. In addition to science, Barbara and I shared interests in hiking and classical chamber music, as well as a strong belief in non-religious family bonds. We were fortunate enough to have an enduringly happy marriage, as well as a highly productive research collaboration until her death in 2013.
For 50 years, I continued working on the biomolecular mechanisms of cell motility, first at Harvard, where I discovered, named and characterised the founding member of the dynein ATPase family of motor proteins and other microtubular components in cilia and flagella. Then in 1967 we moved to the University of Hawaii’s Kewalo Marine Laboratory, where Barbara and I combined biochemical techniques with light and electron microscopy of sea urchin sperm flagella, to advance our understanding of microtubule-based motility.
By 1971, we were able to produce structurally-weakened flagella that seemed to just disappear upon exposure to ATP under a regular light microscope. I knew that dark field microscopy with a very powerful light source, such as the sun, was the way to see how the apparent “disappearance” of the flagella actually occurred. But our most powerful light source was a simple 6 volt lamp. Not to be deterred, Barbara and I returned to the lab after dark one evening to test an idea. With Barbara watching over my shoulder I was rewarded by being able to see for the first time the actual sliding apart of the weakened flagella into their component doublet microtubules in response to the addition of ATP. To a well dark-adapted eye, the faint scattered light from individual microtubules was visible even with just that 6 volt lamp. Our elation over the clarity and significance of this demonstration of ATP-dependent microtubule sliding certainly marked one of the major high points of life with dynein.
Over the next two decades, our lab continued to develop innovative techniques such as using a modified polymerase chain-reaction to determine a complete sequence for the exceptionally heavy polypeptide subunit forming a dynein motor. This opened dynein to study by molecular biological procedures in many laboratories, rapidly revealing the highly conserved structure and broad functional importance of the dynein motor family in eukaryotes.
By 2005, after I had retired from Hawaii and was working part-time at the University of California Berkeley, my lab had designed and synthesized multiple stabilized forms of dynein’s microtubule-binding domain with different binding affinities for microtubules, some of which yielded well-diffracting protein crystals. Analysis of binding affinity of the different forms, in collaboration with Ron Vale’s lab, enabled description of the sliding coiled-coil mechanism involved in modulating dynein’s affinity for microtubule binding during its mechanochemical ATPase cycle. Continuing the collaboration, X-ray analysis of the crystals enabled us to determine an atomic structure for this domain, the first functional region of the dynein motor studied at this resolution.
Given the recent discoveries of dynein’s critical importance in human health, my fifty years with it were a well spent journey.
26 September 2017 Hong Kong