Henrik Kacser (1918–1995):
an Annotated Bibliography
Introduction
Henrik
Kacser’s bibliography gives the
lie to some myths of modern science, in particular the belief that to become
the recognized leader of one’s field one must publish a great many papers, appearing
regularly over one’s career, and constituting a coherent whole. Some also believe
that to make a significant contribution one must publish one’s major ideas early
in life, with everything that follows just consolidation. However, it is difficult
to relate much in Henrik Kacser’s work published before 1957 with the ideas for
which he is best known; moreover, as illustrated in Fig. 1, his career was astonishingly
late to develop, and even at its end his total number of publications was less
than some scientists produce in a year. Anyone assessing Henrik Kacser in 1970
by the sort of criteria that have become commonplace would find it hard to avoid
concluding that his research career was over, and that the best use of his talents
would be to administer car parking at Edinburgh University. Perhaps, indeed,
this was exactly the assessment that was made.
Fig. 1. Published work, 1949-1995. The
continuous line shows the cumulative totals.
Yet 1970 was mid-way between the first suggestions of
what we now call metabolic control analysis (Kacser & Burns,
1968) and its triumphant unveiling in the classic paper The control of
flux (Kacser & Burns, 1973). Far from being over, his
work was just beginning; far from declining, his output accelerated after the
middle 1980s.
There is another surprise in the early work of Henrik Kacser for those of
us who thought of him, as to some degree he did himself, as a classical geneticist
turned biochemist: his early papers include work in practical chemistry, the
kinetics of enzyme reactions, and very little genetics. His expertise in genetics
becomes evident only in the third phase of his career, when he set out to find
experimental models to demonstrate the correctness of his views on metabolic
control.
In general, his publications fall fairly naturally into four phases: 1,
building a foundation in physical chemistry; 2, development
of metabolic control analysis; 3, consolidation; 4,
expansion. The borderline between the third and fourth phases is perhaps
arbitrary, but can be justified as the moment when the main points of metabolic
control analysis were widely accepted and it was time to fill in the details
and show how it could be applied.
1. Early Work in Chemistry: from the Inorganic World to Proteins
(1949-1957)
The initial phase of Henrik Kacser’s career reflects his undergraduate
training in chemistry and postgraduate research in physical chemistry. A good
understanding of physical chemistry, especially thermodynamics and kinetics,
laid the foundation for clear thinking about biological control later on, but
there is little suggestion of the interest in metabolic control that came to
dominate the later part of his career, despite a steady trend from pure chemistry
at the beginning to the chemistry of living systems at the end. Nonetheless,
the closing words of his discussion of gene structure (Kacser, 1956) foreshadow
ideas familiar to the modern reader: The evidence that the plant viruses contain
ribose nucleic acid only (where one definitely does not find base pairs) should
serve as a reminder that genetic mechanisms should not be looked for in the properties
of particular substances but in the way the whole system is organized.
In this
paper, and the earlier one on aconitase kinetics (Kacser, 1952), Kacser’s readiness
to draw attention to flaws in arguments advanced by such figures as Crick, Delbrück
and Lynen should perhaps have warned contemporary readers that they were not
dealing with a scientist who would always be willing to remain on the sidelines.
- KACSER, H. & UBBELOHDE, A. R. (1949). A thermostatically controlled micro-polarimeter tube.
J. Soc. Chem. Ind.
68, 135-138
- KACSER, H. & UBBELOHDE, A. R. (1949). Thermodynamic conditions for the retention
of solvents by crystals: the system brucine/benzene.
Nature
164, 445-446.
- KACSER, H. & UBBELOHDE, A. R. (1950). Thermodynamic factors in stereospecific
processes.
J. Chem. Soc.
2152-2158.
- KACSER, H. (1950). The purification of brucine.
J. Chem. Soc.
2908.
- KACSER, H. (1952). The specificity and kinetics of aconitase.
Biochim. Biophys. Acta
9, 406-415.
- KACSER, H. (1952). The probability factor in bimolecular reactions. I. Uncomplicated
ion-dipole systems.
J. Phys. Chem.
56, 1101-1106.
- KACSER, H. (1955). The cortical changes on fertilization of the sea-urchin
egg.
J. Exp. Biol.
32, 451-467.
- KACSER, H. (1956). Molecular organization of genetic material.
Science
124, 151-154. [Forward] [Quotations]
2. The Birth of Metabolic Control Analysis (1957-1973)
Henrik Kacser’s first exposition of the idea that understanding systems required
a systemic treatment (Kacser, 1957b) came in a 60-page invited appendix to a
book. So it must have been evident to his colleagues from his conversation and
spoken criticisms of the ideas that were then current that he was interested
in systems, even if the bibliography before 1957 contains little suggestion of
this. The first steps towards metabolic control analysis came in 1967 (Kacser
& Burns, 1967), unless we read more into note 16 of Kacser
(1956) than he probably intended; but it had to wait six years (of apparent silence!)
before the appearance of what has come to be universally regarded as the classic
paper (Kacser & Burns, 1973) that opened up the whole field. This paper has recently
been updated and re-published (Kacser et al., 1995).
The other papers of this section have received little attention in recent
years, but two in particular (Kacser, 1957b, 1960) were influential in establishing
the important idea that biological organization could be understood in terms
of chemical kinetics. Peacocke (1983) discussed this in his
book, in a passage that will be reproduced in the special
issue of the Journal of Theoretical Biology in honour of Henrik Kacser
(Peacocke, 1996). Kacser (1960) himself described one of these
papers very briefly, and therefore very inaccurately,
as the interpretation
of biology in terms of chemistry
, a description that may well apply to the whole
of his work.
- BEALE, G. H. & KACSER, H. (1957) Studies on the antigens of Paramecium
aurelia with the aid of fluorescent antibodies.
J. Gen. Microbiol.
17, 68-74.
- KACSER, H. (1957a) The heat inactivation and serum neutralization sites
of bacteriophage T2.
Proc. Roy. Phys. Soc. Edinburgh
26, 1-6.
- KACSER, H. (1957b). Some physico-chemical aspects of
biological organisation. Appendix to The strategy of the genes by C. H.
Waddington, pp. 191-249. George Allen and Unwin, London. [Quotations]
- KACSER, H. (1960). Kinetic models of development and heredity.
Symp. Soc. Exp. Biol.
14, 13-27. [Quotations]
- KACSER, H. (1963). The kinetic structure of organisms,
in Biological organization at the cellular and supercellular level (Harris,
R. J. C., ed.), pp. 25-41, Academic Press, New York and London [Forward]
[Quotations]
- BURNS, J. A., CURTIS, C. F. & KACSER, H. (1965). A method for the production
of a desired buffer gradient and its use for the chromatographic separation of
argininosuccinate.
J. Chromatog.
20, 310-318.
- KACSER, H. & BURNS, J. A. (1968). Causality, complexity
and computers, in Quantitative biology of metabolism (Locker, A., ed.),
pp. 11-23, Springer Verlag, Berlin [Back]
- KACSER, H., BULFIELD, G. & WALLACE, M. E. (1973). Histidinaemic mutant in
the mouse.
Nature
244, 77-79.
- KACSER, H. & BURNS, J. A. (1973). The control of flux.
Symp. Soc. Exp. Biol.
27, 65-104. [Back]
[Forward] [Updated in 1995]
3. Consolidation (1974-1983)
Fig. 2. Citations to Kacser & Burns (1973). The data are
derived from the Science Citation Index, the value for
1995 being obtained by scaling up the value for January–September 1995.
The continuous line shows the cumulative totals.
The control of flux (Kacser & Burns, 1973) is a
model of coherent argument and clear exposition, and is now generally regarded
as the starting point, though as it happens experimental evidence that some enzymes
have extremely low flux control coefficients had been published some ten years
earlier (Kacser, 1963). The appearance of an independent study
leading to similar conclusions (Heinrich & Rapoport, 1974)
should have convinced the sceptics of the general correctness of the ideas in
the 1973 paper. It is remarkable, therefore, how much of the subsequent decade
passed before it became widely known and accepted (see Fig. 2), and how much
effort needed to be put into providing experimental evidence (e.g. Barthelmess
et al., 1974; Flint et al., 1980), and recasting the same material
in a popular
form (Kacser & Burns, 1979). In 1980 the main ideas had scarcely
begun to penetrate the general biochemical consciousness, and the field was still
largely confined to its originators.
Within this group of papers mention must be made of the analysis of dominance
and recessivity (Kacser & Burns, 1981), which resolved a puzzle that had existed
for more than a century. This paper will be discussed by Porteous
(1996) in the special issue of the Journal
of Theoretical Biology in honour of Henrik Kacser. Useful background information
about the origins of the ideas of dominance and recessivity may be found in the
MendelWeb.
- BULFIELD, G. & KACSER, H. (1974) Histidinaemia in man and mouse.
Arch. Dis. Childh.
49, 545-552.
- BARTHELMESS, I. B., CURTIS, C. F. & KACSER, H. (1974). Control of the flux
to arginine in Neurospora crassa: de-repression of the last three enzymes
of the arginine pathway.
J. Mol. Biol.
87, 303-316
- BULFIELD, G. & KACSER, H. (1975). Histamine and histidine levels in the brain
of the histidinaemic mutant mouse.
J. Neurochem.
24, 403-405.
- KACSER, H. (1976) The proper solutions of Kacser’s developmental model.
J. theor. Biol.
63, 239-241.
- BURNS, J. A. & KACSER, H. (1977) Allosteric repression: an analysis.
J. theor. Biol.
68, 199-213.
- KACSER, H., MYA, K. M., DUNKER, M., WRIGHT, A. F., BULFIELD, G., McLAREN,
A. & LYON, M. F. (1977) Maternal histidine metabolism and its effect on foetal
development in the mouse.
Nature
265, 262-266.
- BULFIELD, G., MOORE, E. A. & KACSER, H. (1978). Genetic variation in activity
of the enzymes of glycolysis and gluconeogenesis between inbred strains of mice.
Genetics
89, 551-561.
- KACSER, H., BULFIELD, G. & WRIGHT, A. F. (1979). The biochemistry and genetics
of histidinaemia in the mouse, in Models for the study of inborn errors of
metabolism (Hommes, F. A., ed.), pp. 33-43, Elsevier, Amsterdam.
- KACSER, H., MYA, K. M. & BULFIELD, G. (1979). Endogenous teratogenesis in
maternal histidinaemia, in Models for the study of inborn errors of metabolism
(Hommes, F. A., ed.), pp. 43-53, Elsevier, Amsterdam.
- KACSER, H. & BURNS, J. A. (1979). Molecular democracy: who shares the controls?
Biochem. Soc. Trans.
7, 1149-1161.
- FLINT, H. J., PORTEOUS, D. J. & KACSER, H. (1980). Control of flux in the
arginine pathway of Neurospora crassa. The flux from citrulline to arginine.
Biochem. J.
190, 1-15.
- KACSER, H. & BURNS, J. A. (1981). The molecular basis of dominance.
Genetics
97, 639-666.
- WRIGHT, A. F., BULFIELD, G., ARFIN, S. H. & KACSER, H. (1982). Comparison
of the properties of histidine ammonia-lyase in normal and histidinaemic mutant
mice.
Biochem. Genet.
20, 245-263.
- FLINT, H. J., TATESON, R. W., BARTHELMESS, I. B., PORTEOUS, D. J., DONACHIE,
W. D. & KACSER, H. (1981). Control of flux in the arginine pathway of Neurospora
crassa. Modulations of enzyme activity and concentration.
Biochem. J.
200, 231-246.
- KACSER, H. (1983). The control of enzyme systems in vivo. Elasticity analysis
of the steady state.
Biochem. Soc. Trans.
11, 35-40.
- MIDDLETON, R. J. & KACSER, H. (1983). Enzyme variation, metabolic flux and
fitness: alcohol dehydrogenase in D. melanogaster.
Genetics
105,
633-650.
4. Expansion (1984-1995)
By the mid 1980s the central ideas of metabolic control analysis were becoming
far more widely accepted, and more groups started to enter the field each year.
It was time to expand it, by developing new and more powerful experimental methods
for studying real systems, to remove some of the limitations that were present
in the first analyses, to improve our understanding metabolic regulation and
molecular evolution, and to show how metabolic control analysis could be applied
to problems of medicine and biotechnology. Henrik Kacser played a major role
in most of these aspects, and as his accelerating rate of publication in the
last years of his life shows, his interest not only remained active but even
increased. It is altogether characteristic of him that his last paper to appear
during his lifetime should be about the future development of his subject (Kacser,
1995), but equally characteristic that it was not his last paper: at the time
of his death he was almost ready to submit a stimulating and original paper on
a topic he had not dealt with previously. This (Kacser & Small, 1996) will appear
in the special issue of the Journal of Theoretical
Biology in his memory.
The first paper in this section (Kacser & Beeby, 1984) requires special mention,
as it has received much less attention than its importance and originality merit.
Its outstanding achievement was to show how the idea of evolution by natural
selection, the central theme of all biology, could be applied in a constructive
and usable way to provide models for the evolution of enzyme catalysis. This
will be discussed by Schuster (1996) in his contribution to
the special issue of the Journal of Theoretical
Biology.
- KACSER, H. & BEEBY, R. (1984). Evolution of catalytic proteins: on the origin
of enzyme species by means of natural selection.
J. Mol. Evol.
20,
38-51.
- FLINT, H. J., DIBLE, S. & KACSER, H. (1985). Derepression of enzyme synthesis
is response to arginine limitation in Neurospora crassa.
J. Gen. Microbiol.
131, 2891-2900.
- TORRES, N. V., MATEO, F., MELÉNDEZ-HEVIA, E. & KACSER, H. (1986) Kinetics
of metabolic pathways. A system in vitro to study the general control
of flux.
Biochem. J.
234, 169-174.
- STUART, F., PORTEOUS, D. J., FLINT, H. J. & KACSER, H. (1986). Control of
the arginine flux in the arginine pathway of Neurospora crassa: effects
of co-ordinate changes of enzyme concentration.
J. Gen. Microbiol.
132, 1159-1166.
- HOFMEYR, J.-H. S., KACSER, H. & VAN DER MERWE, K. (1986). Metabolic control
analysis of moiety-conserved cycles.
Eur. J. Biochem.
155, 631-641.
- KACSER, H. & PORTEOUS, J. W. (1987). Control of metabolism: what do we have
to measure?
Trends Biochem. Sci.
12, 5-14.
- KACSER, H. (1987) Regulation and control of metabolic pathways, in Physiological
models (Basin, M. J. & Prosser, J. I., eds.), pp. 1-23,
CRC Press, Boca Raton.
- KACSER, H. (1987) Control of metabolism, in The biochemistry of plants
(Davies, D. D., ed.), vol. 11, 39-66.
- KEIGHTLEY, P. D. & KACSER, H. (1987). Dominance, pleiotropy and metabolic
structure.
Genetics
117, 319-329.
- BURNS, J. E. & KACSER, H. (1987). Genetic effects on susceptibility to histidine-induced
teratogenesis in the mouse.
Genet. Res. Camb.
50, 147-153.
- KACSER, H. (1987). On parts and wholes in metabolism, in The organization
of cell metabolism (Welch, G. R. & Clegg, J. S., eds.), pp. 327-337, Plenum,
New York.
- KACSER, H. (1987) Dominance not inevitable but very likely.
J. theor. Biol.
125, 505-506.
- ACERENZA, L., SAURO, H. M. & KACSER, H. (1989). Control analysis of time-dependent
metabolic systems.
J. theor. Biol.
137, 423-444.
- KACSER, H. (1989) Quantitative variation and the control analysis of enzyme
systems, in Evolution and animal breeding (Hill, W. G. & Mackay, T. F.
C., eds.), pp. 219-226,
CAB International,
Wallingford, Oxfordshire, UK
- KACSER, H., SAURO, H. M. & ACERENZA, L. (1990) Enzyme-enzyme interactions
and control analysis. 1. The case of non-additivity: monomer-oligomer associations.
Eur. J. Biochem.
187, 481-491.
- SAURO, H. M. & KACSER, H. (1990) Enzyme-enzyme interactions and control
analysis. 2. The case of non-independence: heterologous associations.
Eur. J. Biochem.
187, 493-500.
- MELÉNDEZ-HEVIA, E., TORRES, N. V., SICILIA, J. & KACSER, H. (1990)
Control analysis of transition times in metabolic systems.
Biochem. J.
265, 195-202.
- KACSER, H., SAURO, H. M. & ACERENZA, L. (1990) Control analysis of systems
with enzyme-enzyme interactions, in Control of metabolic processes (Cornish-Bowden,
A. & Cardenas, M. L., eds.), pp. 251-257, Plenum, New York
- ACERENZA, L. & KACSER, H. (1990) Enzyme kinetics and metabolic control. A
method to test and quantify the effect of enzymic properties on metabolic variables.
Biochem. J.
269, 697-707.
- BEEBY, R. & KACSER, H. (1990) Metabolic constraints in evolution, in Organizational
constraints on the dynamics of evolution (Maynard Smith, J. & Vida, G., eds.),
pp. 1-22, Manchester University Press, Manchester.
- KACSER, H. (1991) A superior theory?
J. theor. Biol.
149, 141-144.
- NIEDERBERGER, P., PRASAD, R., MIOZZARI, G. & KACSER, H. (1992). A strategy
for increasing an in vivo flux by genetic manipulation. The tryptophan system
of yeast.
Biochem. J.
287, 473-479.
- KACSER, H. & ACERENZA, L. (1993). A universal method for achieving increases
in metabolite production.
Eur. J. Biochem.
216, 361-367.
- SMALL, J. R. & KACSER, H. (1993). Responses of metabolic system to large
changes in enzyme activities and effectors. 1. The linear treatment of unbranched
chains.
Eur. J. Biochem.
213, 613-624.
- SMALL, J. R. & KACSER,
H. (1993). Responses of metabolic system to large changes in enzyme activities
and effectors. 2. The linear treatment of branched pathways and metabolite concentrations.
Assessment of the general non-linear case.
Eur. J. Biochem.
213,
625-640.
- SMALL, J. R. & KACSER, H. (1994). A method for increasing the concentration
of a specific internal metabolite in steady-state systems.
Eur. J. Biochem.
226, 649-656.
- KACSER, H., BURNS, J. A. & FELL, D. A. (1995). The control
of flux.
Biochem. Soc. Trans.
23, 341-366 (updated reprint of the
1973 article).
- KACSER, H. (1995). Recent developments beyond metabolic control analysis.
Biochem. Soc. Trans.
23, 387-391
- CASCANTE, M., E. MELÉNDEZ-HEVIA, B. KHOLODENKO, J. SICILIA & H. KACSER
(1995). Control analysis of transit time for free and enzyme-bound metabolites:
physiological and evolutionary significance of metabolic response times.
Biochem. J.
308, 895-899.
- KACSER, H. & SMALL, J. R. (1996). How many phenotypes from one genotype?
The case of prion diseases.
J. theor. Biol.
182, 209-218.
REFERENCES (NOT LISTED ABOVE)
- HEINRICH, R. & RAPOPORT, T. A. (1974) A linear steady-state
treatment of enzymatic chains. General properties, control and effector strength.
Eur. J. Biochem.
42, 89-95. [Back]
- PEACOCKE, A. R. (1983). An Introduction to the Physical
Chemistry of Biological Organization. pp. 119-124, Clarendon Press, Oxford
[Back]
- PEACOCKE, A. R. (1996). A Pioneer of the Kinetic Approach.
J. theor. Biol.
182, 219-222. [Back]
- PORTEOUS, J. W. (1996). Dominance – one hundred and fifteen
years after Mendel’s paper.
J. theor. Biol.
182, 223-232. [Back]
- SCHUSTER, S. (1996). Control analysis in terms of generalized
variables characterizing metabolic systems.
J. theor. Biol.
182,
259-268. [Back]
Some quotations
From Kacser (1956)
When one is analysing the synthesis of new genetic material, it is not helpful
to explain it in terms of the hypothetic property of a substance or body called
a self-duplicating ability
. No property of this type is known for any molecule
except the trivial one of autocatalysis, where already preexisting material is
released. The relevant phenomenon is autosynthesis which is the property of a
system...
From Kacser (1957b)
The belief that a living organism is nothing more
than a collection of substances,
albeit a very complex collection of very complex substances, is as widespread
as it is difficult to substantiate...
The problem is therefore the investigation of systems, i.e. components
related or organised in a specific way. The properties of a system are in fact
more
than (or different from) the sum of the properties of its components,
a fact often overlooked in zealous attempts to to demonstrate additivity
of
certain phenomonena. It is with these systemic properties
that we shall be
mainly concerned...
One may wonder how Mendel could have laid the foundations of genetics. Fortunately
for him and later investigators most of the effects will be eliminated by buffering
and, of the remaining, many will not be apparent by inspection. In general, many
mutations must occur which have no apparent effects...
From Kacser (1960)
An analogue is clearly an analogue of something. Billiard balls on a table may
be an analogue of gas molecules in a vessel, or they may be a source of relaxation
for tired University professors, or they may be the beginning of the ruin of
a promising student. It therefore appears that it is the use to which objects
are put that marks them out as analogues...
If our questions are then directed towards the present, we see the genes not
as dictators of every action within their realm but rather like civil servants
who work within a framework of tradition. Some of the reasons for doing things
are buried in the past. But as good servants they faithfully carry on, fitting
themselves into the conditions as they find them.
From Kacser (1963)
An organism is not simply a mixture but a system of interacting molecules. It
is therefore to these interactions that we must look for an elucidation of biological
behaviour...
The widespread phenomena of dominance, pleiotropy and epistasis in genetics and
of regulation and differentiation in embryology have shown the inadequacy of
such a view. There is, however, as yet no comprehensive scheme which links the
evidence for the unitary genetic determination of protein structure with the
bewildering array of epigenetic and metabolic consequences... Some of the conclusions
of the treatment which follows may therefore appear intuitively strange – but
so much the worse for intuition...
The existence of specific feed-back mechanisms such as inhibition and repression
in bacteria and which also may exist in other organisms, is of course additional
to the phenomena here described...
In a system with many interactions many properties arise which cannot be assigned
to any one isolable entity...
Which particular enzymes are in positions of importance may vary from organism
to organism, but it is impossible for all of them to be...