University of Bristol: Professor Herbert “Freddie” Gutfreund, Emeritus Professor of Biochemistry, died in March 2021. Professor Stephen Halford FRS offers this appreciation.

Freddie Gutfreund – few used his birth name Herbert – joined the then newly established Department (now School) of Biochemistry in 1965. He remained one of the most distinguished members of this University through to his retirement in 1986, and he retained an emeritus presence within the Department for several years thereafter.

Prior to 1964, the University of Bristol lacked a Department of Biochemistry and its courses in Biological Chemistry had been run by the Department of Physiology. The University did however need a Department of Biochemistry to validate the construction of its new building for the School of Medical Sciences on University Walk. Professor Philip Randle FRS was appointed in 1964 to establish the Department. He recruited Freddie Gutfreund the following year. Freddie established the Molecular Enzymology Unit, located in a separate building in the Inner Court Laboratories (now part of Earth Sciences). The current strength of Biochemistry in Bristol can be traced back to its founding members in the 1960s: among others, Philip Randle, mammalian metabolism; Freddie Gutfreund, molecular enzymology and biophysics; Brian Chappell, bioenergetics; Peter Garland, lipid biochemistry; and Herman Watson, protein structures.

Freddie did however have an unorthodox career before arriving in Bristol, so much so that if someone with his academic qualifications were now to apply for a University post, it is unlikely that they would be shortlisted! Freddie passed only two exams in his life: his high school diploma in Vienna (equivalent to the old 11+ exam) and his PhD in Physics from the University of Cambridge, and nothing in between. No O-level/GCSEs; no A-levels; no BSc; nor an MSc. As a teenager in Vienna in 1938, Freddie realized that the Nazi invasion of Austria ended any hopes for a true education in his home country and any prospects for independent research. But his prospects for emigration from Austria were bleak until he noted that a scheme being run by the YMCA, “British Boys for British Farms”, was accepting candidates from Europe due to the lack of British applicants for farm work (little has changed in the past 80 years!) Freddie thus spent his first three years in the UK working as a dairyman, mostly in Westmorland.

Having touched his toes into pure research as a schoolboy in Austria, working whenever he could in a laboratory focused on colloid chemistry, and having been inspired by visits to the Kendal public library, Freddie made countless applications to research laboratories in his vicinity. He was eventually taken on as a junior technician, otherwise known as a “bottle-washer”, in the Department of Pathology at the University of Liverpool. Freddie’s experimental skills in the analysis of protein samples soon became noted by his supervisor, who suggested to colleagues in the neighboring Biochemistry Department that they too might like to make use of Freddie’s skills. His work whilst still a junior lab technician led to his first publication [Gutfreund, H. (1943) An improved method for the fractionation of protein mixtures by electrophoresis. Biochem J. 37, 186-9.] Freddie’s final paper for the Biochemical Journal was in 1989, some 46 years after his first, leading to an award from the Biochemical Society for the longest period of contributions to the journal. A Biochemistry colleague in Liverpool then recommended Freddie to Professor Chibnall who was at Imperial College at that time, but who one year later was to take up the Chair of Biochemistry at the University of Cambridge. Chibnall however stipulated that his new research assistant be allowed to register for a research degree in Cambridge.

Freddie Gutfreund spent the next 13 years of his life based in Cambridge, from his arrival as a PhD student in 1943 to his departure as a senior scientist in 1956, albeit not always in the same Department. His PhD work was in biophysics, on the reversible dissociation of proteins under the direction of Gilbert Adair (of the famous equation for cooperative binding). But his primary contacts at that time included Fred Sanger and Peter Mitchell, both subsequent Nobel laureates. Sanger gave him the basis of protein chemistry to compliment Freddie’s own work on protein dynamics while Mitchell would go on to have a major impact on Freddie’s future home in Bristol: Mitchell’s chemiosmotic theory, highly controversial at the time, was largely validated by experimental work by Brian Chappell. Freddie’s interests in Physics and Physical Chemistry led him in the 1950s to seek out members of the Department of Physics in Cambridge located in the Cavendish laboratory. These included individuals who would proceed to establish the renowned Laboratory of Molecular Biology in Cambridge: Francis Crick, Max Perutz, Fred Sanger, Hugh Huxley and many others. Freddie fell into the habit of lunching every day with Francis Crick and his colleague Jim Watson at the Eagle pub, just round the corner from the Cavendish. Freddie was actually there when Crick burst into the pub to announce that he had solved the secret of life. He also took the famous photograph of Francis Crick and Jim Watson walking alongside King’s College Chapel that appears in many textbooks.

Upon completion of his PhD in 1947, Freddie took up a postdoctoral position with Professor F J W Roughton who had just been appointed head of the Department of Colloid Chemistry at Cambridge. This was a pivotal moment in Freddie’s career because Roughton was the pioneer in applying rapid reaction techniques to biological systems. Roughton had broken completely new ground by using a technique called “continuous-flow” to measure the rate of oxygen binding to hemoglobin, long before anyone else had been able to make similar measurements. The application of rapid reaction techniques to biological systems became the cornerstone of Freddie’s research career, along with his continued interest in biothermodynamics. While continuous-flow is a very cumbersome technique, extremely wasteful of reagents, Freddie worked with others to streamline the technologies for rapid reaction kinetics in solution, exploiting the stopped-flow and quenched-flow techniques and the new relaxation methods such as temperature-jump and pressure-jump. He did much of this work in collaboration with others and the laboratories that Freddie spent time during the 1950s and 60s read like a Who’s Who of Biophysics: in roughly chronological order, Julian Sturtevant (Yale), Quentin Gibson (Cornell), Britton Chance (Philadelphia), Sidney Bernhard (Eugene, Oregon), Leo de Mayer and Manfred Eigen (Göttingen), John Edsall (Harvard).

Between 1956 and 1965, Freddie held a post as a research scientist at the National Institute for Dairying Research in Shinfield, then part of the University of Reading. Not that this represented a return to Freddie’s initial occupation in the UK, but rather an opportunity to continue his work on the kinetics and dynamics of protein reactions. Some very significant work arose from Freddie’s time at Shinfield, especially from a collaboration with Tom Barman in Montpellier in the south of France. Tom and Freddie pioneered the application of the quenched-flow technique to identify short-lived intermediates in enzyme reactions that did not have an optical signal. Freddie always chose collaborators in attractive locations, so he doubtless preferred the blue Mediterranean skies of Montpellier over the dull grey of Reading and thus chose to spend much of his time there. Visits to Oregon also allowed for his key collaboration with Sidney Bernhard on proteolytic enzymes. But perhaps the most important event during his time at Reading was meeting and marrying Mary in 1958, his wife to the end of his life and with whom he had three wonderful children.

From 1965, Freddie Gutfreund was to spend the rest of his career in the Department of Biochemistry in Bristol. The Molecular Enzymology Unit quickly became internationally recognised as one of the world leaders of the fields of enzymology and protein chemistry. In its initial days, the Unit benefitted enormously from two senior postdoctoral fellows, John Holbrook and David Trentham, both of whom would go on to research careers of great distinction. Holbrook remained in Bristol for all of his subsequent career, heading the Molecular Recognition Group, becoming one of the pioneers in the emerging technology of protein engineering, and later proceeding to a Deanship. Trentham started his keynote work on muscle proteins while still in Bristol and would go on to develop this field further in his subsequent posts: initially the Britton Chance chair at the University of Pennsylvania and then returning to the UK to head the Division of Physical Biochemistry at the National Institute for Medical Research in London. Another key player in the early days of the Unit was David Yates, who focused particularly on the instrumentation: he went on to run the administration of Biochemistry in Bristol. Instrumentation was central to the success of the laboratory: one of Freddie’s favorite aphorisms was “If you buy a machine, you can do the same experiment as everyone else, but if you build your own machine, you can do an experiment that no-one else can”. In recent years, the development and construction of new instrumentation based on Freddie’s designs has been advanced by Ted King at Hi-Tech Scientific (now TgK Scientific), who continues to maintain the rapid reaction equipment in Bristol still in current use by Szczelkun, Dillingham and others.

One indication of the strength of Gutfreund’s Molecular Enzymology Unit is that throughout the early 1970s one would often find in the laboratory four individuals who would proceed to be elected as Fellows of the Royal Society: Freddie himself, in 1981; then David Trentham followed by Brian Sykes and Stephen Halford. Sykes was at that time an Assistant Professor at Harvard but spent many summers in Bristol attempting to marry NMR data to rapid reaction kinetics: he now directs Canada’s National High Field NMR resource in Edmonton. Halford stayed on in Bristol for his whole research career, using the concepts he learnt in Freddie’s laboratory to analyse DNA-protein interactions with restriction enzymes. In later years, Freddie’s research interests turned to the molecular mechanisms of muscle contraction as Trentham’s research moved into this area. Mike Geeves, now Chair of Biochemistry at Kent, played a pivotal role in this development as did a new series of new associates including Ken Holmes at Heidelberg.

Even his best friends would struggle to say that Freddie Gutfreund was a gifted teacher of basic Biochemistry to undergraduates. But his educational legacy lives on and will do so for many more years. Firstly, the many PhD students and postdoctoral associates who passed through his lab learnt so much in the time they were in the lab and, as many have proceeded to their own research careers, that knowledge has been passed on to their own students and colleagues and to yet further generations. Secondly, Freddie wrote a series of monographs on enzymes and kinetic systems that have been highly influential in the development of these fields and which have stood the test of time remarkably well. His first book, An Introduction to the Study of Enzymes (Blackwell, 1965), set the tone for many subsequent years. His most recent book, Kinetics for the Life Sciences (Cambridge University Press, 1995), was published several years after his retirement. It remains to this day an invaluable source of the mathematical solutions to a whole variety of kinetic processes.

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