Henrik Kacser FRSE (22 September 1918 – 13 March 1995) was a biochemist and geneticist. Henrik's achievements have been recognised by his election to the Royal Society of Edinburgh in 1990, by an Honorary Doctorate of the University of Bordeaux II in 1993.
Henrik (or Henrick) Kacser was born in Câmpina, Romania, in 1918 of Austro-Hungarian parents who later moved to Berlin where Henrik went to school. Before the World War II, he move to Belfast, Northern Ireland, where he did his undergraduate and postgraduate work at the Queen's University of Belfast. There he studied chemistry, specialising in physical chemistry as a postgraduate student. He went to Edinburgh in 1952 as a Nuttfield Fellow under a scheme to introduce physical scientists into biology. This was to become the start of his work as a geneticist/biochemist. He got the Diploma of Animal Genetics, and in 1955 he became appointed lecturer in the department of Genetics at the University of Edinburgh.
Areas of research
In most of his research his original training physical chemistry is quite evident as he focused mainly on the physical/chemical aspects of biology. Much of his early work includes work on practical chemistry, kinetics of enzyme reactions and very little on genetics. His work falls into four distinct categories: 1. building a foundation in physical chemistry; 2. development of metabolic control analysis; 3. consolidation and 4. expansion. Only in the third phase of his career his expertise in genetics came to light when he set out to find experimental models to demonstrate the correctness of his paper on metabolic control analysis.
The control of flux
The control of flux (Kacser & Burns, 1973) was a landmark paper for both Kacser and Jim Burns describing how the rates of metabolic pathways were affected by changes in the amounts or activities of pathway enzymes (See Metabolic Control Analysis). In it they show that the expectation that a metabolic pathway will be controlled by a single pacemaker reaction is a fallacy, and most of the experimental criteria used in the supposed identification of such steps are misleading. Instead, varying amounts of control can be distributed over the enzymes of the pathway, but this is a property of the metabolic system as a whole and cannot be predicted from the characteristics of the enzymes in isolation.
The molecular basis of dominance
The molecular basis of dominance (Kacser & Burns, 1981) is the companion paper to "The control of flux" and reveals the full meaning of its footnote "the implication of this for the problem of dominance and its evolution will be dealt with in a separate publication". The connection was that if the flux–enzyme relationship is quasi-hyperbolic, and if, for most enzymes, the wild-type diploid level of enzyme activity occurs where the curve is levelling out, then a heterozygote of the wild-type with a null mutant will have half the enzyme activity but will not exhibit a noticeably reduced flux. Therefore the wild type appears dominant and the mutant recessive because of the system characteristics of a metabolic pathway.
Kacser's most important work was published in 1973. Written with J.A. Burns it was called the “Control of Flux” paper. By the mid-1980s the central ideas of metabolic control analysis laid out in this paper were becoming far more widely accepted. Further experimental methods based on the theories laid out in the paper were used to help in the understanding of metabolic regulation and molecular evolution, and to show how metabolic control analysis could be applied to problems in medicine and biotechnology. Another paper published in 1984 showed how the idea of evolution by natural selection could be applied in a constructive way to provide models for the evolution of enzyme catalysis.
Other papers include:
- Responses of metabolic systems to large changes in enzyme activities and effectors: 1. The linear treatment of unbranched chains (Small & Kacser, 1993a)
- Responses of metabolic systems to large changes in enzyme activities and effectors: 2. The linear treatment of branched chains (Small & Kacser, 1993b)
- A universal method for achieving increases in metabolite production (Kacser & Acerenza, 1993)
- Control analysis of time-dependent metabolic systems. (Acerenza, Sauro and Kacser, 1989)
These papers, in collaboration with Rankin Small and Luis Acerenza, have shown that the prospects for achieving large increases in flux by changing the activity of a single enzyme are poor but a coordinated set of changes, designed by their "Universal Method" could make large changes without catastrophic perturbations of the rest of metabolism.
Biochemical interest in the ideas expressed in "The control of flux" started to grow in the 1980s, particularly with its experimental applications in Amsterdam to oxidative phosphorylation, urea synthesis and gluconeogenesis. At this time, because the theory of Kacser and Burns and the simultaneous but independent work carried out by Reinhart Heinrich and Tom Rapoport in Berlin were compatible, a common terminology and set of symbols was agreed for the new field of Metabolic Control Analysis.
Upon retirement from lecturing in 1988 he became a Fellow of the University of Edinburgh. Kacser was an active geneticist/biochemist right up until his death. At the time of his death, Henrik still ran an active laboratory, had two large grants supporting his work and continued to produce original scientific ideas. He was elected to the Fellowship of The Royal Society of Edinburgh in 1990 and in 1993 he received an honorary doctorate from the University of Bordeaux.
- In 1955 Henrik Kacser was offered a lecturer position in the department of genetics. Before that he had just finished his Diploma of Animal Genetics. At the time he has no offer for work. One day he was walking down the corridor in the department and Conrad Hal Waddington passed him in the opposite direction. Waddington stopped, turned, lowered his pipe and asked Henrik what he was going to do now that he'd finished his Diploma. Henrik said he had no plans as yet. Waddington replied, well why not stay here? And that is how Henrik became a lecturer in the department of genetics (Sauro, personal communication).
- Henrik's work on the control of flux and the hypothesis that the rate-limiting step was an erroneous concept started as a result of an observation of a mutant Aspergillus strain. He observed that a particular enzyme in one of the amino acid biosynthesis pathways had lost 95% of its activity and yet the phenotype appeared unchanged. It was this observation that prompted Henirk to realize that phenotypes are most likely determined by the network in which the enzyme belongs as it is the enzyme itself (Sauro, personal communication).
- "The control of flux".
- "The molecular basis of dominance".
- "Responses of metabolic systems to large changes in enzyme activities and effectors: 1. The linear treatment of unbranched chains".
- "Responses of metabolic systems to large changes in enzyme activities and effectors: 2. The linear treatment of branched chains".
- "A universal method for achieving increases in metabolite production".
- "Control analysis of time-dependent metabolic systems". PMID 2626059.