This page contains the reminiscences of Henrik Kacser that appeared as pp. 201–207 of the Special Issue of the Journal of Theoretical Biology 182 (1996) in his memory.
I met Henrik Kacser in Chile in 1984. There I got in touch
with his fascinating ideas about metabolism for the first time. His lectures
were very appealing: intuition as much as possible, rigour as much as necessary,
the emphasis on the wood
and not on the trees
. He was accessible to everyone
willing to ask questions or to know more about it, there were no barriers around
him. Three years afterwards, when I was awarded a research fellowship I had no
doubts with whom I wanted to work.
Science with Henrik was exciting. In the long term, far-reaching goals; in the everyday work, brainstorms, discussions, and the unexpected. When a breakthrough was close one could feel the adrenalin flowing through his veins; the advice of his doctor not to smoke was completely forgotten. Clear communication of results was as important as good ideas, and he could write a paper in a week with a brilliant outcome. However, he was never in a hurry to publish. If he was not persuaded to accelerate the process, the period from the emergence of the idea to the submission of the manuscript could be three or four years.
Henrik was a man of vast interests: literature, languages, sports, art... In all of them, his sharp aesthetic sense was never absent. In particular, he had an exquisite taste for art.
In the laboratory, he was not only the head of the group but the father of a family. He was always concerned with the well-being of the others, anticipating their needs. Naturally, he was an excellent host and to be in his house was to feel at home.
Henrik Kacser leaves us a treasure of deep scientific thinking, humanism and unforgettable memories.
I met Henrik for the first time in September 1982,
during a meeting of the Biochemical Society in Aberdeen, only some weeks after
I had arrived to live in England and to marry Athel. I remember this meeting
very well, because Henrik introduced me to two very important subjects. First
of all to control analysis, of course, and second, but no less important, to
malt whiskies. At that time I was working on hexokinase D (glucokinase
) and
the first words that I ever exchanged with Henrik were about this enzyme; he
banned the expression key enzyme
from my vocabulary. A couple of years ago
while I was writing my book about glucokinase
I often remembered this conversation.
The other thing that I have to thank Henrik is that it was him who, profiting
from the fact that one of the social events of the meeting in Aberdeen was a
whisky-tasting, made me try the famous Glenfiddich, Glenmorangie, Laphroaig and
others while Athel, following the English tradition, preferred to stick to beer.
During that meeting in Aberdeen I had the opportunity to interact a considerable amount with Henrik, as both he and Athel were speakers at the same symposium, and we had often meals together. Henrik greatly impressed mewith his fine sense of humour and his very sharp intellect. This first encounter was rounded off by the visit to his house, at the end of the meeting, as we gave Henrik a lift to Edinburgh and we enjoyed the warm hospitality of Elaine, his wife. That day, Henrik decided to give me a drive through Edinburgh and the four of us went in his car. Coming from Chile, where the traffic rules are not taken very seriously, I was quite happy sitting in the front enjoying the beauties of Edinburgh that Henrik, a very good guide, was pointing out to me. It was only after a while that I realized that Elaine and Athel, sitting in the back, were biting their nails a little, with the nervousness expected in respectable English people at the lightness with which Henrik, who like me had no British genes, but just the passport, was following the rules.
After this encounter, I met Henrik and Elaine on several other occasions. Because of the importance of metabolic control analysis as an emerging frame for the experimentalist to take into account, we suggested to Hermann Niemeyer, my former Professor in Chile, to invite Henrik to participate in a post-graduate course that he was organizing and in which we were also participating. As a result we had the pleasure of having Henrik and Elaine visit us in Chile, in Santiago, and spending some time together in July and August 1984. He also came to visit us in Marseilles, as he had many points of contact with Athel, who went to see him to Edinburgh on various occasions.
More than once, the telephone rang late at night at our home, making me rush
to it in the fear of bad news from the other side of the Atlantic, only to discover
with pleasure that it was Henrik wanting to talk to Athel. Often he wanted to
find out if he was the anonymous referee
that has said unreasonable
things
about his paper, or to try to guess together who else it might be and discuss
how to argue back. I normally followed these conversations as an spectator, although
sometimes I became an unwitting participant. For example, one night after dinner
Athel set me a problem to solve and I did it; only some time afterwards did I
learn that the speed with which I solved it there and then served as an argument
for Athel to tell Henrik that the point that he was making in a submitted paper
was to obvious to deserve publication. I don’t think that either Henrik or I
were very happy about this opinion, but we laughed and finally the paper got
accepted. (It had other merits and the problem as a whole was more complex than
the one I solved).
Both Athel and I had a great admiration for Henrik, and because of this it was with a great pleasure that we both accepted Jean-Pierre Mazat’s invitation to participate in the honour that the University of Bordeaux II paid to Henrik in May 1993, in nominating him Doctor Honoris Causa. The paper on channelling that I presented on that paper may not have had his complete agreement, but he was very happy that we were there and said so several times.
Not long after this meeting, he and Elaine came to Nice on holiday and invited us for lunch there. The five of us had a lovely time together, and Elaine took a very nice picture of our daughter Isadora with her head looking out from a fairy-tale house. The wandering through antiquarian and art shops was, of course part, of the activities of that day. That was the last time that I saw Henrik.
My resarch interests are not and have been not as close as Athel’s are to Henrik’s, but progressively his ideas have infiltrated me. If I were have to say in a sentence what is what appreciated the most in him I would say that it was his originality, the importance that he gave to ideas and his efforts to address fundamental questions. In these lines I have wanted to bring back the memory not of the father of control theory (or control analysis as he preferred to call it) — there are others better qualified to do this — but of the friend that we all miss.
I met Henrik Kacser for the first time in Bordeaux
in 1987, at the wonderful meeting that Jean-Pierre Mazat organized there. As
a newcomer to the world of Metabolic Control Analysis that I had just discovered
a year earlier, I was fascinated there by Kacser’s presentation on Control Analysis
and its consequences for genetic dominance. I have since had the opportunity
to listen his presentations at several meetings and I have been always captivated
by his ability to present complex ideas in a easy and attractive manner. Later
I also became interested in Biochemical System Analysis and I have collaborated
with Dr. Savageau and his coworkers. My ideas about similarities and differences
between the two approaches and their usefulness in metabolic studies have been
always different from those of Dr Kacser, but this was not an obstacle to starting
a fruitful scientific collaboration in the field of metabolic transit time just
before his death. I consider myself fortunate to have had the opportunity to
collaborate with him, and I have been impressed by his rigour, even in the most
minor detail. Those of us involved in this collaboration with him tended to say
This time we don’t have to be worried about any referee’s criticisms: after
dealing with Kacser’s continuous criticisms and suggestions for improvement
it is difficult to imagine that there can be any minor errors in any formula!
.
I admired Dr. Kacser not only for his ideas and results but mainly his ability to present the mathematics underlying the quantitative description of metabolic systems in a simple and attractive manner. This has made it possible that nowadays many experimentalists are applying control analysis, convinced that their subject could advance more rapidly with more attention to theoretical ideas.
In the late seventies I was a young lecturer finding
my way into teaching metabolism and its regulation. I was dissatisfied with the
superficial way textbooks treated the behaviour of biochemical pathways, but
I was far too ignorant to figure out exactly what worried me. In my search for
more information I discovered Kacser and Burns’s treatment of flux control; for
me this was, as for so many others, the start of an exciting intellectual adventure.
While planning my first sabbatical in 1985 I asked my geneticist neighbour, who
had got to know Henrik (or Henry, as some of his colleagues called him) while
studying in Edinburgh, to enquire about the possibility of my spending some time
in his lab. Henrik’s reply, as always, was to the point: Let Hofmeyr come
.
So, on the basis of this terse invitation, my wife and I arrived in Edinburgh
to find in Henrik and Elaine the most charming and congenial hosts imaginable.
Within a day I was initiated into the two main activities of the West building:
furious argumentation in front of the blackboard in the tea-room and the unique
game of Thunderball played during lunchtimes on the grass path outside. I had
fortunately immersed myself in control analysis during the previous six months
in Athel Cornish-Bowden’s lab, because I was confronted simultaneously with Henrik’s
critical and penetrating mind and Enrique Meléndez-Hevia’s wonderful brand
of English. I had studied moiety-conserved cycles for a few months, so imagine
my dismay when Henrik told me that they do not exist. This started a three-month
argument that led to Henrik being convinced and our joint paper on the control
analysis of moiety-conserved cycles. My stay with Henrik also started a friendship
that could fortunately be renewed on numerous subsequent occasions. The science
was uppermost, but I shall never forget Henrik lovingly handling and talking
about his exquisite collection of Asian statuettes, or, Henrik roasting green
peppers the Eastern European way in Hans and Anneke Westerhoff’s gas oven in
Bethesda, while I struggled to prepare a South African bobotie with American
ingredients. With Henrik’s death I lost my intellectual father, but his scientific
legacy will remain a treasure-house of ideas and insights for the rest of my
life.
In 1983 we were checking the effect of increasing the
activity of some enzymes on the total glycolytic flux of a soluble extract from
rat liver. We hoped to demonstrate the regulatory power of each enzyme by adding
a large quantity of it to the mixture to see how the output flux was increased.
We were surprised to see that hexokinase and phosphofructokinase could both independently
enhance the lactate flux; each of them separately showed the typical rate-limiting
behaviour of textbooks. Afterwards I looked for the reason for this double activation
that contradicted the dogma of the rate-limiting step as a single enzyme controlling
all flux of the pathway. My first step was, of course, to look for an explanation
in the literature. I knew the 1973 paper of Kacser and Burns on flux control;
I had had it for years, though I had not read it carefully. I then found their
1979 paper on molecular democracy, and studied both carefully. I thought that
our in vitro system could be a good tool to check control theory experimentally,
especially as at that time there was very little experimental work on the theory.
The idea was to repeat our experiments to see the role of each enzyme on the
total flux, adding small quantities in separate experiments, i.e. titrating the
system with each enzyme.
Unfortunately an important scientific discovery sometimes has to wait a long time to be acknowledged. Even in 1983, ten years after that first paper by Kacser and Burns, very few groups were working on metabolic control theory. Ten years of solitude, waiting to be read, understood, and applied by other researchers... I wrote my first letter to Kacser in April 1984, telling him our first experimental results on enzyme titration; they were not yet definitive, and we had to make some changes in our experimental protocol following the suggestions he made. Kacser replied quickly to that letter — he had always quick reflexes — encouraging me to continue with the research. Later, after many letters had been exchanged, I had the opportunity to go to Edinburgh in July 1985, and I spent a week staying at Kacser’s home. It was a very nice week, with a lot of control theory to learn, experimental results to discuss, and scarcely any time to see just a little of the beautiful city of Edinburgh. Our paper was published in the Biochemical Journal some months later.
In April 1987 the Kacsers stayed ten days in Tenerife at my home, so that we could work on our second subject, the control of transition time, and we were able to show them some of the beauties of Tenerife. This work was finished two years later, during my second stay in Edinburgh, also at Kacser’s home, and it was published the following year. In 1987 I had written a review on control theory and its application to metabolism for the Spanish Journal Anales de Química. It contained 102 references, of which about 50 dealt directly with control theory, but many were reviews (about 20 different reviews on that subject in the previous five years!), but few papers with original results; at that time there were fewer than ten different groups in the world working on metabolic control. Just two years later, in 1989, the workshop on Control of metabolic processes, organized by Athel Cornish-Bowden at Il Ciocco (Italy), brought 63 people together; the book of proceedings has 36 papers, most of them dealing with different aspects of control theory, and about 20 different groups from around the world met at Il Ciocco. The number of active groups has now increased tenfold. Those ten years of solitude were followed by an explosion of the impact of the first work, and a big radiation of the theory.
Henrik Kacser’s contribution to biochemistry has been great, and his control
theory has taught all of us more about the way cells work. His work promoted
an important advance in studies of metabolic regulation, one of the most critical
fields in biochemical research today. However, I consider that his most important
contribution was to enlarge the theoretical framework of biochemistry. In the
seventies it was becoming too empirical, and most work on metabolic regulation
lacked a theoretical support. Many biochemists worked in the belief that no theory
was necessary to know how the cell controls its metabolism, but Kacser demonstrated
that biochemistry needed a mathematical framework to be rigorous, and he implanted
a quantitative mentality in many biochemists. He was first of all a scientist
who never submitted to the constraints of the classic and old-fashioned borders
between the different fields of science, such as genetics, biochemistry or mathematics.
Science was for him just one, and any speciality was always welcome for him if
it could supply an useful way to reach an answer. As a person of an open mind
and great culture, he was always ready to study any new approach, and to learn
new things from colleagues. He also dominated the art of communication and was
also unique in popularizing science — a task that may be more difficult than
to create it. All of us have enjoyed reading his papers: they remain fresh as
scientific literature, and one can be sure that they will be read by future generations
with the same enthusiasm.
I first met Henrik Kacser and metabolic control analysis
at a special meeting in Elbingerode in the mid-1980s and was impressed very much
by both of them. At that time I was interested in the enzyme-enzyme interactions
and metabolic channelling and had already published papers on these subjects.
It was clear that macromolecular associations can influence both the local
and system
properties. I learned these two key phrases at the Elbingerode meeting
as the basis of Kacser’s analysis (a term he preferred over theory
). At that
time I understood only the basic concept of MCA, and I thought it would be very
useful to connect the interaction and channelling problems to control analysis.
What I learned at that meeting was it is not a problem, the mechanism does not
matter, the conversion of intermediates by enzymes can be considered as a black
box
.
After the meeting of Elbingerode I met Henrik on several other occasions and was delighted that he had become interested in the channelling problem. He visited me a couple of times in Budapest and I visited him in Edinburgh. I especially enjoyed visiting his wonderful house and the lovely hospitality of his wife, Elaine. During these occasions we worked on how the association of enzyme pairs inducing changes in the kinetic parameters of the individual enzymes affects the formulations and theorems of control analysis. I still preserve the papers that document our discussions: his explanations of the details of his analysis and my explanations of the structural prerequisite and functional consequences of intermediate channelling effects. The accompanying scheme in Henrik’s hand illustrate our discussions of the meaning of channelling and the first attempts to formulate the matrix that included enzyme-enzyme interactions. In fact, the key recognition at that time was that small changes in the enzyme activity are not necessarily equal to the changes in enzyme concentration simply because the enzymes are not independent entities.
Somewhat later in 1990 Henrik and his co-workers published two consecutive papers in Eur. J. Biochem. In these papers a new elasticity coefficient is defined, π, which quantifies the effects of homologous and heterologous enzyme interactions. He referred to our experiments that provided experimental data for the existence of metabolite channelling and used these data to test his extended analysis. These papers did not solve the original problem on enzyme-enzyme interactions and control analysis, yet they are extremely important since many scientists were stimulated by the new concept. Although the data accumulated by mainly theoretical works contribute significantly to the understanding of the channelling effect on metabolic pathways, however, no control approach has been evaluated which analyses systematically the control properties of channelled systems and, more important, no approach has been suggested which can predict whether the channelling mechanism acts in a metabolic pathway under in vivo conditions. The reason is partly that it is still not clear how to define the appropriate control coefficients, nor how to take into consideration the alterations of kinetic properties of enzymes induced by enzyme associations when the mechanism of intermediate transfer is analysed in complex biological systems. Nevertheless, Henrik made enormous contributions in an effort to solve this complex and important problem and all of us working on this area have benefited from his presentations. Henrik Kacser was cheerful and gentlemanly in his discussions with his critics; in addition, he was Hungarian.
I first met Henrik at a Biochemical Society Meeting at
Trinity College, Dublin in 1986. I had gone to the meeting specifically to introduce
myself to him and to seek his help and advice. My interest in the role of mitochondrial
3-hydroxy-3-methylglutaryl-CoA synthase in the control of hepatic ketogenesis
convinced me that the popular view expressed in the literature at that time,
of a single rate-limiting step
(overt carnitine palmitoyltransferase) of the
pathway, was inadequate. I was looking for ways of showing that control over
ketogenic flux was shared and that the control structure of the pathway might
change with changes in metabolic state. I had discovered Henrik’s early papers
and realized that metabolic control analysis could help me answer the questions
I was asking. I decided to approach Henrik himself after his lecture and to ask
him if he would be willing to test my understanding of control analysis and to
discuss the potential theoretical problems involved in its experimental application
to the particular pathway.
Having found the courage to approach him I was amazed by his enthusiastic response to my requests. Henrik made the time to discuss my ideas with me, probably to the annoyance of others at the meeting who were waiting to speak with him and he invited me to Edinburgh to continue the conversation. On that occasion I spent three days with Henrik when he gave me his undivided attention, having first swept all his incoming mail into the wastepaper basket, declaring that if anything was sufficiently important he would be approached a second time! When I expressed my apprehension about my ability to master control analysis, arising from my unusual background for biochemistry (as a former student of fine arts not maths or science!) he dismissed it and reassured me that my training as a schoolteacher and an artist as well as a biochemist ought to make me uniquely capable of teaching and converting others. Not only did he go through all the theory with me, with the vigour and energy of a child, but he was also the perfect host. He drove me around the city and made me welcome in his beautiful home where he wined and dined me in the company of his wife.
We decided that analysis of that system was not possible at that time, however, I remained faithful to the ideas of metabolic control analysis and continued to try to find a way of applying it to fatty acid oxidation and ketogenesis. Later, the birth of the top-down approach of control analysis allowed me to answer fundamental questions about control in the system. Henrik welcomed the new approach and continued to be totally supportive of all my research. Indeed, at a time when I was faltering in confidence, due to serious illness, Henrik was sensitive to this and gave me the incentive to continue by convincing me that my contribution was worthwhile.
Henrik’s view of the top-down and bottom-up approaches to metabolic control analysis, as drawn by him in a letter to Patti Quant in 1992.
The outcome of Henrik’s patient tuition and continued enthusiastic support was that I have remained a faithful evangelist of metabolic control analysis in the three universities with which I am involved.
I shall, therefore, remember Henrik both as a talented scientist, whom I admired for his clear insights and authoritative certainty and as a kind friend and sensitive human being.
I first met Henrik Kacser in 1982 when I went for an interview
as a 3rd year student in an attempt to enter the Genetics Honours class at Edinburgh
University. I remember he asked me an apparently simple question which I then
spent the next few minutes trying to answer only to discover that the question
was not as straightforward as I had thought. This was typical of Henrik’s style
of teaching, as I was later to find out, where his main challenge was to make
students think rather than just repeat text-book
knowledge. Although I did
enter the Honours class, which was organized at that time by Henrik, I managed
to miss his option
course which would have introduced me to metabolic control
analysis. I therefore managed to leave Edinburgh University blissfully unaware
of its existence.
I next met Henrik when I returned to Edinburgh University the following December.
I happened to mention at coffee time to the group that I was looking for a project
to undertake as part of my M.Sc. in Biological Computation at York University.
On hearing this, Henrik pounced on me and dragged me off to see his papers on
control analysis and suggested that I could carry out a project with him. I had
escaped
from him once, but I couldn’t do it again! Henrik was such an advocate
for control analysis that I was immediately fascinated by the subject and his
enthusiasm led me not only to an M.Sc. project but ultimately to my Ph.D. study
at Oxford Polytechnic.
Over the next few years I met Henrik at various scientific meetings around
Europe in addition to the time when he was my external examiner for my Ph.D.
thesis. I eventually returned to Edinburgh in 1990 when I accepted his offer
of a post-doctoral position in his group. The following years were a great time
to be working with Henrik. During these five years the Universal method
was
published by Henrik and Luis Acerenza, my own work with Henrik on the effect
of large changes and our work on changing metabolite concentrations was developed
and published and finally Henrik and I worked on the Prion paper, which is published
here. In addition Henrik’s experimental side took an upturn with the return of
Sheila Carmichael to work on her split
lac-operon and the start of experimentally
testing the Universal method
when Paul Hunt and Carol-Ann Middleton joined
the group. It is clear that Henrik’s enthusiasm for science never diminished
towards the end of his life. In fact, the work carried out in these last years
suggested that there would have been much more to come.
Several days after
submitting our paper for publication in this issue, I learned that Henrik Kacser
was born in Romania of a Hungarian father and Austrian mother, and lived the
first years of his life here. In the belief that the places where we are born
and spend our childhood somehow mark all our existence, I tried to find out the
exact place of Henrik’s birth, and with the great help of his friends and colleagues,
I succeeded: it was Câmpina, situated in Europe’s second oil-rich region.
One might think that with its 8000 inhabitants (as recorded in about 1925) this
small town might be one of those insignificant places that are called corners
that God has forgotten
. Is it really so? Definitely not: the wonderful landscapes,
the beautiful view of the valley of Prahova, the patriarchal life and also the
gentle people of Câmpina attracted many great personalities of the 19th
and 20th centuries. That is why Câmpina is strongly associated with the
life of Bogdan Petriceicu Hasdeu, the well-known Romanian linguist, historian
and writer, and of Nicolae Grigorescu, the greatest of Romanian painters, whose
family home is illustrated here. Now, it is certain, Câmpina will become
associated with the name of Henrik Kacser.