Obituary Bernhard Brenner

Bernhard Brenner, M.D., professor and chairman of physiology at the Medical School of Hannover, Germany, died on June 26th, 2017 after a courageous fight against cancer. He was 66. Bernhard was a scientist with a razor sharp intellect and an unyielding zeal to elucidate the mechanism of muscle contraction. He will be fondly remembered as an inspiring colleague and mentor to many.

Bernhard was born in Stuttgart, Germany. He studied Medicine at the University of Tübingen from 1969 to 1975 and received his doctoral degree in 1979. For his thesis he studied strain-induced calcium release from striated muscle sarcoplasmic reticulum with Professor Rudhard Jacob. He demonstrated independence and a talent for innovative experimental approaches early on in his career. Bernhard designed and built his own devices for measuring fast mechanical kinetics of single muscle fibers. He perfected the preparation of permeabilized single mammalian (rabbit) skeletal muscle fibers with control over the bathing medium. He discovered that repeated cycles of stretches and quick releases of a muscle fiber under fully activating conditions could keep the striation pattern stable for hours without deterioration. Later such cycles were dubbed by some colleagues as the “Brenner Cycles” and are still a standard method in muscle labs.

From 1980 to 1985 Bernhard was a visiting research associate in the laboratory of Richard Podolsky at the National Institutes of Health (NIH), USA. While at NIH, a rather close-knit and long lasting collaborative group was formed, which included Richard Podolsky, Evan Eisenberg, Joseph Chalovich, Lois Greene, Mark Schoenberg, Leepo Yu and Bernhard. The group took advantage of the fact that, for the first time, biochemical, mechanical and structural results could be obtained under the same experimental conditions. Biochemical results were previously obtained from rabbit muscle whereas mechanical and structural (X-ray diffraction) results were measured in frog muscle.

At the time the Eisenberg lab proposed the existence of weak binding states within the actomyosin ATP hydrolysis cycle. Bernhard’s high-speed mechanical and X-ray diffraction measurements provided the first evidence of these weak binding states in muscle fibers. The results indicated that tropomyosin-troponin does not block cross-bridge binding to actin in relaxed muscle, contrary to the widely accepted “steric blocking” model of muscle regulation. Further experiments showed that the specific attachment of cross-bridges to actin in the weak binding states is essential in the pathway to contraction. He showed that, rather than controlling the binding of myosin to actin, tropomyosin-troponin regulates contraction by altering the rate of cross-bridge cycling kinetics. Calcium shifts the equilibrium between the inactive and active forms of actin-tropomyosin-troponin to the active form that has rapid cycling kinetics.

The conclusion that calcium regulates cross-bridge kinetics in muscle fibers came from the experimental protocol that Bernhard used. Muscle fibers in a medium with a defined calcium concentration were subjected to a short period of unloaded shortening followed by re-stretch to isometric conditions. Bernhard showed that the rate constant of force redevelopment, k_TR, represents cross-bridge turnover kinetics. His observation that k_TR increased as the calcium-concentration (and force) were increased supported the earlier suggestion by F.J. Julian that calcium changes cross-bridge turnover kinetics in a graded way, while the number of cross-bridges involved in active cycling remains essentially constant. This “rate modulation” concept was in contrast to the “recruitment” model, where tropomyosin was thought to control the number of cycling cross-bridges without changing the turnover kinetics. Many scientists that work on skeletal or cardiac muscle still use the k_TR measurement to investigate effects on rate modulation of cross-bridge cycling.

The PNAS article that described the measurement of k_tr, is only one example of an important article in which Bernhard was the sole author; he was undeniably creative. He made lasting contributions to our understanding of the regulation of striated muscle contraction and of the changes in structure and kinetics associated with force generation of cross-bridges. His findings are reflected in modern physiology text books.

Bernhard’s ideas were sometimes counter to the prevailing thought of the muscle field but he was always ready for objective and spirited discussions. He studied the work of his peers and was able to offer insightful comments about their work. Yet, Bernhard was equally critical of the work of his students and associates. He was open to criticism and suggestions for alternative ways of thinking. Bernhard’s first priority was the truth wherever it could be found.

After returning to Germany, Bernhard completed his Habilitation in 1987 at the University of Tübingen on the molecular mechanism of muscle contraction. Bernhard’s first academic appointment was in 1988 at the University of Ulm in the Physiology department of Professor Reinhard Rüdel. In 1993 he became the Director of the Institute for Molecular and Cell Physiology, Hannover Medical School (MHH), Hannover, Germany where he served with passion even during his lengthy illness.

He continued to study mechanisms of force generation using fiber studies and in addition, in vitro single motor molecule analyses. Studies on skeletal and non-muscle myosin revealed two active site conformations of a single myosin molecule. In one conformation the myosin could complete the ATPase cycle. In the other conformation, the intact ATP dissociated. This observation should be important for head–head coordination of processive myosins. Bernhard also applied his expertise to dynein, kinesin and Tau protein.

With his life-long interest in cardiac physiology, Bernhard focused the later part of his career on studies of mutations in cardiac myosin that are related to Hypertrophic Cardiomyopathy. He and his group in Hannover made major contributions in defining the structure–function relationship of human cardiac and slow skeletal myosin. They revealed that a variable region of the myosin converter domain is a major element for tuning cross-bridge compliance. His group recently proposed a new hypothesis for the marked heterogeneity in expression of both, the fraction of mutated β-myosin heavy chain and contractile performance among individual cardiomyocytes in the myocardium of patients with Hypertrophic Cardiomyopathy. They found burst-like, stochastic on/off-switching of myosin transcription, which most likely is independent for the mutant and the wildtype MYH7-allele. The transition that Bernhard made from muscle mechanics to gene expression is emblematic of Bernhard’s drive to learn. When faced with a difficult research problem he acquired whatever skills were necessary to solve that problem.

For more than 30 years Bernhard was a passionate and popular teacher at medical school for which he received several awards. In his last years he was committed to implement a new way of teaching basic physics. He integrated physics directly into the physiology course, giving undergraduate students a much more concrete and practical understanding of the subject. Bernhard was also a highly valued and respected colleague, serving for several years as elected member of the Senate of Hannover Medical School where he fought to promote excellence in both research and academics in the preclinical institutes of the medical school. Bernhard was often critical but fair and his input was always valued.

Bernhard will be remembered as one who made his way quickly to the microphone at conferences to ask a question or to provide an insightful interpretation of data. Many students, postdoctoral fellows and colleagues were inspired by his wisdom, his critical thinking and scientific objectiveness. Bernhard Brenner will be greatly missed by his family, his students, his colleagues and his friends.