Remembering Roger Cooke (1940 – 2024)

Roger Cooke – a cherished colleague and professor at UCSF known for his outstanding insight into the biophysics and physiology of motor proteins, his kindness, awesome teaching, and his warm, positive sense of humor – died on August 1, 2024.

Roger was born on February 22, 1940 in Ann Arbor Michigan, and grew up in Lexington, Kentucky. He obtained his Bachelor of Science degree in physics at the Massachusetts Institute of Technology in 1962 and PhD in physics in 1967 from the University of Illinois in Urbana. He came to UCSF in 1968 for a postdoctoral position in Manuel Morales’s laboratory where he studied muscle contraction using fluorescence and electron paramagnetic resonance spectroscopy. He was soon appointed to the faculty in the Department of Biochemistry and Biophysics in 1971. Roger had an outstanding career as one of the primary contributors to understanding the fundamental mechanism of motor proteins, dynamical mechanism of structural elements, kinetics, thermodynamics, and structure. He worked from his office on the fourth floor of Genentech Hall until the final days of his declining health. To quote Nariman Naber, his long-time associate in his laboratory, “Roger had a special place in my heart - my favorite person ever. It was so hard to see his health deteriorating slowly over the last few years. His body failed him, but his mind was still functioning.” He loved not only the scientific questions he so keenly addressed, but the colleagues who worked with him and around him. They published 38 papers together over 34 years.

For many at UCSF, he is a loved, highly respected, admired central figure in elaborating the fundamentals of contractile mechanisms, and a wonderful, always positive colleague. As a teacher, he was keenly sensitive to responding to scholarship in research. He taught in the biophysics graduate program, always enlightening understanding of the fundamental basis for life at the level of molecular structures and particularly the dynamics of moving parts of protein machinery.

Roger pioneered the now-textbook versions of what we know of the mechanisms of muscle contraction. He elaborated the role of myosin light chains, their dynamical aspects defined by Electron Paramagnetic Resonance (EPR) spectroscopy, to focus on key questions about the mechanisms of regulating muscle contraction. Using structure, fluorescent labels and spin label probes, Roger, in collaboration with David Thomas, made landmark discoveries in motor proteins that showed that force generation in myosin did not proceed according to the dogma of the 1970s in which the entire myosin head group attached to and rotated on actin filaments. Instead, his data along with data from other investigators showed that a major part of the head was fixed on actin, and only the lever arm portion rotates (BJ 1980). Now well established in the field, this was a critical development that defined the current “lever-arm mechanisms” in myosin and its associated light chains.

With kinesins, the engines that transport “cargo” inside of cells along “microtubules,” Roger made a key contribution with Ron Vale, showing that the mechanism of force generation involved binding of the so-called neck region of the “motor domain” of ATP bound kinesin to the microtubule, and its release after ATP hydrolysis as the essence of the progressive motor function. Roger showed that a similar “switch region” was found in both kinesins and myosin, that couple the energy source, binding release, and hydrolysis ATP in both cases to the stepwise movement. Roger’s spin probe experiments helped to define the first structures of kinesins, carried out in collaboration with Robert Fletterick and Vale (Nature 1999) and made important contributions in the screening and development of ligands that lead to the crystal structures of the motor domain of NCD, a kinesin-related motor with reversed polarity of movement (Nature 2002).

Some of Roger's most notable scientific achievements came after his official retirement in 2009 when he started working at the lab bench. In 2009 with the help of a few remaining people in the lab, he discovered a new state of skeletal muscle myosin, which has a very slow ATPase turnover, called the super-relaxed state (SRX). The SRX is in equilibrium with a disordered relaxed state of myosin, called the DRX which has a higher ATPase activity. SRX was visualized by performing single nucleotide turnovers in skinned muscle fibers using a fluorescent analogue of ATP (mant-ATP) and chasing with ATP. The observations of the metabolic rate of relaxed in vivo skeletal muscle indicate that the SRX is the physiologically dominant state, leading to the energy economy of relaxed muscle. The exciting aspect of the SRX is that manipulating it can provide more effective therapies for obesity and Type 2 diabetes. Due to the importance of this state, Roger developed fluorescent probes that can be used to monitor the population of the SRX to find compounds that can alter the population of this state in skeletal muscle to treat human diseases. Screening more than 2000 compounds identified one compound “piperine,” an alkaloid found in black pepper that destabilized the SRX in fast-twitch muscle myosin and increased the ATPase activity of relaxed fibers. This opened a new field in the study of striated muscle (PNAS 2016).

Roger extended the research to cardiac muscle, finding that the cardiac super relaxed state has different properties than the skeletal. In skeletal fibers it modulates the resting metabolic rate, in cardiac fibers it modulates the output of the active state. In cardiac cells, the SRX is involved in modulating the contractility of the myocardium. Agents that alter the stability of the SRX in cardiac cells could be used to modulate the contractility of the myocardium providing effective treatment strategies for many cardiac disorders including heart failure, and cardiomyopathies. This research was in collaboration with Cris Dos Remedios’ laboratory. In collaboration with Jim Spudich’s laboratory and with MyoKardia, small molecules which can stabilize the super-relaxed state leading to a reduction in the contractility of the cardiac tissue were discovered. These molecules are now in clinical trials for the treatment of hypertrophic cardiomyopathies (PNAS 2018).

In 2018, Roger showed how piperine acts to alter the conformation of two regulatory light chains. To do this he used a construct consisting of 2 regulatory light chains (RLC) along with the fragment of the heavy chain to which they bind, and a portion of the coiled-coil rod sufficient to form a dimer. Together, these form a mini-fragment of myosin he termed the regulatory domain (Arch.B.B 2018). This was in collaboration with Alla Kostyukova’s laboratory and opened up a new area in the regulation of striated muscle.

A longtime collaborator with Roger was the late Edward Pate. Their collaboration on many projects endured for 36 years and resulted in more than 55 publications that focused on the nucleotide binding site and effects of ATP hydrolysis on cross bridges in muscle.

In the lab, Roger was famous for what he called “Barn Yard Engineering.” He used to build his own equipment, saving the lab thousands of dollars. On one occasion, the lab needed to conduct an EPR experiment on fibers at lower temperatures, which required a cooling system. Bruker quoted the lab a price tag of $17,000. Roger walked to the hardware store down the street, bought a few items, ordered one other item, and assembled a cooling system that cost the lab only $265. Roger was versatile, resourceful, and accomplished – a true jack-of-all-trades whose talents influenced and enhanced the work of many labs.

For over 50 years, Roger was a key figure in, and regular contributor to, the Biophysical Society. He attended the annual meeting every year and was an elected Fellow of the Society. Roger was the organizer of the annual meeting of the Society in 1988, and served as a member of the Council for three years. He was a central key figure in one of the core areas of the society, the “contractility” sub-group section, of which he was sometimes chair. He was also the keynote speaker at the Motility subgroup of the Biophysical Society in 2008 and the Plenary Lecture, Myofilament Meeting in Madison, Wisconsin in 2014. These accolades recognized his key discoveries in how contractile proteins work.

Roger was an avid sports enthusiast throughout his life. He was a competitive swimmer, diver for abalone, a surfer, skier, rock climber and an avid sailor who berthed his sailboat close to the UCSF Mission Bay campus in San Francisco. Roger would take any opportunity to entertain everyone on his boat and share his love of sailing with them. His work-life balance was impressive and set an inspirational standard for all those who knew him.

Reflecting comments of colleagues in the Biochemistry & Biophysics department, Geeta Narlikar recalls “Roger was not just a creative biophysicist and fabulous collaborator. He was multidimensional: captain of his sailboat, ocean swimmer, car builder, and overall, a gem of a person. He will be dearly missed.” Jeremy Reiter recalls, “Probably my favorite scientific tale of his was about a long-lived super-relaxed state of tarantula myosin (“the super-duper relaxed state”). He was characteristically pithy about the tribulations of collecting tarantulas at night with a flashlight. He was characteristically insightful about the potential energy-saving advantages that evolution of this form of myosin might have imparted to tarantulas."

We were so fortunate to have such a wonderful, considerate, and supportive colleague on the faculty of our department, always with keen insights, a sensitive and great sense of humor, and positive energy that endear him to colleagues across the world of science. He is so greatly missed and loved in so many ways.

Our deepest sympathies go to Greta Alexander, his dearly loved wife, children Dylan and Robin, brothers Stuart and Randy and their families, stepchildren David and Gia, granddaughter Chloe, and to all of the science family and friends who loved him.

On October 4, 2024, over 130 people from UCSF and other institutions around the world came together for a symposium honoring Roger’s life and legacy. Recordings of the talks can be viewed here and a book of tributes can be found here.

Rest in peace, Roger.