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Reinhart Heinrich (1946–2006)

This page contains an obituary of Reinhart Heinrich and some personal reminiscences of him, for publication in the special issue of the Journal of Theoretical Biology in his memory.

Contents

Obituary

Reinhart Heinrich (1946–2006)*

by Athel Cornish-Bowden (CNRS, Marseilles)

It falls to few of us to found a new subject of research, and to fewer still to do so on the basis of work done at the beginning of a career. Reinhart Heinrich, whose sudden death on 23rd October 2006 deprived biochemistry of one of its most original thinkers, was one of these few: metabolic control analysis derives in part from work that he did with Tom Rapoport while working in the group of Samuel Rapoport in Berlin, and in part from studies carried out independently at about the same time by Henrik Kacser and Jim Burns in Edinburgh. He was thus one of the founding fathers of systems biology, a subject that has grown in the past few years from almost nothing to become a major sub-discipline of biochemistry. He remained fully active as one of the leaders in this field right up until the end of his life. This description may give the impression of someone who devoted the whole of his research career to a single topic, but that would be very misleading.

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It is a measure of the originality of the revolution brought about by the Berlin and Edinburgh groups that for the first decade it had essentially no impact on biochemistry. Reinhart’s first papers were published in 1974, at the height of the enthusiasm for the classical picture of metabolic regulation, and his ideas seemed (wrongly, as we now realize) to contradict everything that had been learned in the previous ten years about cooperativity, allosteric interactions, feedback inhibition at the first committed step and so forth. Biochemists were not ready for Reinhart’s ideas, and the simplest response seemed to be to ignore them. The citation record makes it very clear that that is what happened: in the first eight years after publication his principal paper was cited about ten times, a total that would be substantially lower if it were not for references from others in East Germany. In the three years from 1978 to 1980 it was cited just once, and seemed well on the way to oblivion; yet in 2006 alone it was cited about 30 times, and it has been consistently cited around 20 or more times in every year from 1985 onwards. There can be few papers that are cited 20 times as often after 30 years as they were in their early years. For those who think that the impact factor is the only thing that matters this would appear to be a failed piece of research, but for those with a less simple-minded view of the impact of research the interpretation must very different.

Reinhart’s investigation of the quantitative nature of metabolic control was part of a broader project studied in the Berlin group, the efforts to understand erythrocyte metabolism in sufficient detail to permit computer models to predict its behaviour accurately. This was far from being a purely academic project, as it sprang directly from efforts to lengthen the usable life of blood for transfusion; it required a great deal of experimental work to characterize the kinetics of all the enzymes in sufficient detail, but it also required careful analysis of how to integrate all the information to understand how they would behave as a system, and not just as individual purified enzymes in a spectrophotometer. The simple-minded idea of the rate-limiting step was almost universally accepted at the time, but it was not enough, and Reinhart and Tom Rapoport showed how to deal with the whole matter quantitatively. At the same time, in another paper that has become less well known, but which also represented an important step in our understanding, they discussed how the cross-over theorem, useful and valid when used properly, was coming to be widely misused. Thanks in large part to the efforts of the Berlin group the erythrocyte has become one of the systems in biochemistry that is most thoroughly understood in quantitative detail.

Reinhart’s PhD studies in solid-state physics at Dresden served him well when he later came to apply the ideas of physics and mathematics to biochemical systems. He was interested not only in whole systems but also in dissecting the kinetic properties of individual enzymes in great detail, and in understanding the thermodynamic profiles of pathways: why, for example, do we find two ATP-consuming steps near the beginning of the glycolytic pathway, and the ATP-producing steps near the end? Would it work just as well if the different kinds of chemical steps occurred in a different order? Is there an optimizing principle involved, and if so, what is it?

Biochemists know Reinhart Heinrich for his brilliant research career, and for his book The Regulation of Cellular Processes, which he wrote with Stefan Schuster. However, this is to know only half of the story: he also published a novel, Jenseits von Babel; he was fluent in Russian (as well, of course, as English and German) and spoke a passable Georgian; he was an accomplished musician. Just two weeks before his sudden death he was participating in the Systems Biology congress in Japan, as full of life s always, and discussing his plans for future research. His current studies of the chemical logic of metabolic networks, their modular structure, their robustness and potential for expansion during evolution, were far from complete, and leave much for his colleagues to develop.

He is survived by his wife Nana, his daughter Lisa and his son Lukas.

Personal reminiscences

The first time I met Reinhart Heinrich...

by Jean-Pierre Mazat (Université de Bordeaux II)

The first time I met Reinhart Heinrich was in 1974 at the 9th FEBS meeting held in Budapest. It was my first congress. There I discovered many famous modellers: Jens Reich, Evgeny Sel’kov, Benno Hess, and probably many others. Reinhart was there as well, but I had a better meeting with him one week later during the FEBS Advanced Course on Mathematical Models of Metabolic Regulation in Dobogókö (Hungary). Together with Tom and Sam Rapoport he presented the theory of metabolic control analysis they had just developed with the parameters called control strength, which would later become control coefficients. I must confess that I did not understand at that time the originality or the importance of this work, because I was, like many other biochemists, immersed in the study of the kinetics and regulation of allosteric enzymes. Only later, while working on the control of oxidative phosphorylation, did I feel the need for a more global approach. After reading the paper of Bert Groen et al. in 1982 and the simultaneous papers of the Magdeburg group, I realized the importance of control coefficients, and of the fact that the control of a pathway is usually distributed. Several others became aware of the importance of the theory and, for this reason, Athel Cornish-Bowden and María Luz Cárdenas organized their famous meeting in Il Ciocco (Italy) in April 1989, where I met Reinhart again after a lapse of 15 years. Afterwards we visited Pisa and Florence, and I remember that we talked in a café about the Berlin wall: Reinhart told us that it would remain for several decades more, but a few months later it disappeared. That was the only time I caught Reinhart out. The same year he organized a meeting in Holzhau (Germany), which, as it turned out, took place just one week after the wall fell. I remember this strange fin de regne atmosphere. On our return to Berlin, where Nana and he welcomed nearly all the Holzhau meeting in his house, he led me to the U-Bahn station near his lab where he heard the sounds from the subway that was forbidden for East German people; he was also happy to drive me through the way in the no man’s land in front of the wall.

After that time, we met many times in Berlin, in meetings or in Bordeaux, where Reinhart was invited professor and became Doctor Honoris causa of our University. It was an exceptional collaboration, quiet, confident and strengthened by post-docs (Ronny and Stefan Schuster) and the exchange of many students until now. He had a simple vision of modelling, with some common-sense rules. For instance, when the Km of an enzyme is not known just take the cellular concentration as Km. One of our last discussions concerned the modelling of a simplified version of the Krebs cycle done by one of his students in our lab. He told me that he did one such a modelling when he was as a post-doc in Pushchino and soon after he sent me the paper that we analyse further in this issue of the Journal of Theoretical Biology. Several times I was tempted to call or to e-mail him in order to get some explanation of the paper.

We miss not only his scientific ability but also, and above all, his friendship, his kindness and his sense of humour.

Memories of Reinhart Heinrich

by Enrique Meléndez-Hevia (Universidad de La Laguna)

I first met Reinhart at the symposium that Athel Cornish-Bowden organised at Il Ciocco in April 1989 that brought together numerous researchers interested in the control and design of metabolism. We connected immediately, because we had many things in common and were so like-minded.

After much discussion of the evolution and optimisation of metabolism, our first work was on the optimisation of glycolysis. Paco Montero had the first important idea that the aim of evolution was to maximize the flux of ATP production, and this has been instrumental for all subsequent work in the field.

I saw that Reinhart’s theory of the optimization of enzyme kinetic parameters was very important, but hard for students. I wondered whether it could be presented with a simplified example limited to the essential facts. I proposed it to Reinhart, and, although he was not sure that it could be done, we ploughed ahead anyway. It proved not to be as easy as I had hoped, but also not as difficult as he had thought, and when he saw the finished paper, he spontaneously exclaimed that he could finally explain the theory to his students!

Reinhart had one of most lucid minds I have ever known; he could understand difficult new concepts at first sight, although he also said that he needed time to understand them well and to be able to discuss them, and that he needed to see them in mathematical formulas to believe them, which was not always easy for me. He was an indefatigable and persistent worker, and he was always calm. I never saw him anxious or agitated, never seeming to worry about things others might anguish over, able to bear any setback without getting upset, and knowing how to accomplish everything before deadlines.

Reinhart was very serious in his work and in his life, but he was a very amusing, delightful person, always a smile on his face. His sense of humour was characteristic, and we both liked telling jokes. He was a recognised literary author, and his enthusiasm for music was another point of empathy between us. He played the violin and I have heard him movingly play fragments of concertos by Beethoven, Mendelssohn and Bach.

In April 2000, Reinhart secured lodging for me in the lovely house for at Humboldt University, where María Rosa, my wife, came to spend a few delightful days with me, and spent time talking with Nana, Reinhart’s wife. We spent a couple of days in Dresden at Reinhart's mother's home and heard the concert in Dresden Cathedral for Bach's St. Matthew's Passion, which Reinhart loved and liked to play on his violin. This was a sensational performance, but there was no applause at the end, because, as he explained to us, there is never applause in a church in Germany. There are some things about Germans that are hard for Spanish people to understand!

Reinhart was always worried about world peace. He was very sensitive to human suffering, was especially troubled about the state of Georgia, Nana's native country, and was a regular contributor to reconstruct the Dresden Cathedral.

The social, political and economic changes in Germany greatly excited Reinhart. He saw his Institute grow and secured a spacious place for himself and his group to work, where he kept a poster of La Laguna University as well as the typical satellite photograph of the Canary Islands that I had given to him. We worked together several weeks every year in Berlin and Tenerife.

When Reinhart died I was lecturing on some of his scientific contributions. When the next day, after I had learned of the tragic news, I had to continue, I showed my students a slide with a picture of him with some of his mathematical formulas and told them of his death. Then I could hardly contain my tears.

My laboratory notebooks and files are full of memories of Reinhart, which I keep as valuable treasures. When a close friend and colleague dies, one thinks of the common projects that never will be realized together, and this deepens the sadness of a very personal loss. One thinks of how much richer life has been because of his friendship, and laments the new, even greater things that might have been.

Now that Reinhart is not with us, we who have worked with him have to shoulder the main task of every responsible scientist, one that every scientist hopes that others will do: continue with his research, working along the lines that he helped formulate. We must ensure that his scientific school and the lines of research that he initiated will not be lost; we must make an exceptional effort for an exceptional man. Our pain is that he cannot be here to share these next steps.

Reinhart Heinrich — An Unassuming Intellectual Giant

by Tom Rapoport (Harvard Medical School)

It is a difficult task to write in memoriam of my best friend, Reinhart Heinrich. We collaborated together for thirty-six years and were connected in many avenues besides science. His untimely death is a terrible loss for the entire scientific community, but particularly for me. In this short article, I cannot do full justice to Reinhart’s life, but I will try to illustrate what a special person he was.

Reinhart was born in Dresden in 1946, but he spent his first years in Kuibishev, Russia. His father was a professor of applied mathematics and belonged to the group of East German scientists who were recruited by Russia to help build its aviation industry. Reinhart’s family only returned to East Germany in the early 1950s. Reinhart studied in Dresden and got his PhD in solid-state physics. He was only twenty-five years old when he graduated, an early testament to his exceptional talents.

After his PhD he became interested in applying physics to biology, likely influenced by Nobel Prize laureate Manfred Eigen, whom he heard speak at meetings at the Leopoldina Academy. In 1971, he made a trip to Berlin to look for a job and bumped into my father, Samuel Rapoport, then head of the Biochemical Institute at Humboldt University. My father had recognized the need to introduce theory into biology and was delighted to have such a great applicant. He immediately offered Reinhart a position. I was then a graduate student at the same institute and met Reinhart only a little later. My thesis project was in enzymology, but Reinhart and I began to talk about metabolic systems and hit it off right from the beginning. Prodded by my father, we began to develop a concept that would describe in quantitative terms the importance of an enzyme for the overall flux through a metabolic pathway. We also wanted to have similar quantitative terms for the regulation of the metabolite concentrations in a pathway. Our key was to introduce dimensionless quantities that expressed the relative change of the flux or metabolite concentration upon a relative change of the rate of a given metabolic step. Simple summation theorems and analytical expressions for linear metabolic chains could be derived. The results showed that previous concepts, such as the crossover theorem, were theoretically flawed or incomplete. In addition, the new theory showed that enzymes that are at the beginning of a pathway tend to dominate flux control, and those that operate close to equilibrium cannot have a major effect. We also applied the concept to a real metabolic system, the glycolytic pathway in red blood cells. Although the model was rather simple, it led to provocative conclusions, such as the one that indicated that hexokinase and phosphofructokinase acted as the main flux controllers. Perhaps most importantly, the application of the theory to a realistic system appealed to a broader biochemical community.

An initial account of our work was published in 1973 in Acta Biol. Med. Ger., but the full story appeared in 1974 in three consecutive papers in the European Journal of Biochemistry. The submission process was an adventure in itself. I remember that we submitted a huge package of paper: three copies of each manuscript. We did not have Xerox machines, so we were left with using an alcohol-based East German copying procedure. The package smelled as if it came straight out of a distillery. Another problem was that the ink tended to fade with time. And the reviewing process indeed took time! When we finally received the reports, the major reviewer was extremely negative. Fortunately for us, the editor-in-chief, Claude Liébecq, found out that this reviewer had never written a positive report about any paper, and thus dismissed his negative opinion. When the paper was finally accepted, we received desperate letters from the copy editors, not only because the papers contained formulas that were uncommon in a biochemical journal, but also because they could hardly read the faint letters. Despite all of these hurdles, the papers were a great success. The main paper is still both Reinhart’s and my most cited paper. While normally the citation of a paper shows a bell curve with time, this one continues to be quoted. The concept is now known as metabolic control theory, and was independently developed by Henrik Kacser and James A Burns in Edinburgh, UK. The first time we presented the control theory in public was at a meeting in Oberhof, East Germany, organized by Horst Frunder. We each gave a talk, and it was the first in English for both of us. I remember that we practiced the introductory sentence for hours, trying to correctly pronounce gluconeogenesis and glycogenolysis. David Garfinkel, a pioneer in the application of computers in biology, was the chairman of the session and his compliments were a huge encouragement for us. But the response was not always as positive; when we presented our work at a meeting in Dobogoko, Hungary, another pioneer, Joseph Higgins, declared that he had done everything before and that there was little new in the theory.

The mathematical modeling work led Reinhart and myself to a joint Habilitation or Doktor B, the second degree that one needs in Germany for an eventual professorship. In 1979 we wrote and defended this thesis as a team, a curious sight indeed for the East German science system. Shortly after the defense, our paths separated: Reinhart moved to the Biophysical Institute at the Humboldt University, while I moved to the Academy of Sciences and concentrated on experimental work.

Reinhart’s subsequent work with a growing group of students attests to his broad interests. Among his most visible achievements are papers about the optimality of metabolic systems. In what respect have metabolic systems been optimized during evolution? Interestingly, he and his students discovered that there is no unique optimal solution, and that the one chosen by evolution is just one of several possibilities. Nevertheless, some general conclusions could be derived; for example, regardless of whether the optimization criterion was maximum flux or minimal enzyme concentration, the Michaelis constants tended to match the substrate concentrations. Reinhart also studied how many pathways one can construct from a given number of metabolites, and which compounds can give rise to the largest number of different metabolites. In addition to his theoretical studies, he was always interested in the modeling of specific experimental systems. Reinhart’s major belief was that a model should always be adopted to the biological problem and must be relevant to the experimentalists. He was not keen on simply using theories that were borrowed from other fields, such as applying models of electric conductance networks to metabolic systems.

Over the years, I repeatedly collaborated with Reinhart, often on projects originating from my experimental work. We developed a model for the function of the signal recognition particle in the targeting of proteins to the translocon of the endoplasmic reticulum (ER) membrane, and we generated a Brownian ratcheting model for post- translational protein transport across the ER membrane. Almost thirty years after developing the metabolic control theory, we tried to establish a similar theory for signal transduction pathways. Again, we introduced key parameters, but now to describe time- dependent changes. As with the metabolic control theory, we were able to derive analytical expressions for simple cases. In our final project, we found an explanation for how distinct membrane-bound compartments can be generated, despite the fact that these compartments are connected by bidirectional vesicle transport. According to Reinhart, this was the hardest project he had ever tackled, and indeed it took him three sabbaticals in Boston to solve the problem. His death interrupted the continuation of this work, our attempts to understand how the Golgi compartment is generated.

I consider myself extremely fortunate that I met and collaborated with Reinhart. In a way, we were the perfect team: he was the actual theoretician, while I usually suggested a project and tried to extract a biological conclusion. I have some mathematical background from attending a special high school, and while this was no match to Reinhart’s mathematical prowess, it allowed me to appreciate the beauty and elegance of his theoretical work. Reinhart had an amazing talent to convert a biological problem presented to him into a mathematical formalism. I have never seen anyone more innovative and intelligent. He always wanted to know deeply about the biology; often it was only after trying to explain things to him that it would dawn on me that much was unknown about the system in question.

Reinhart was a remarkable person in many other ways. He was a true Renaissance man, well versed in literature, history, geography, and science in general. While he was working on the metabolic control theory, he published a booklet of poems. In my mind, these are excellent poems: melancholic, humorous, and with a lot of fantasy. Even more impressively, he wrote a novel (Jenseits von Babel (Beyond Babylon)), a philosophical and biographical book for which he received the Brigitte Reimann prize, the highest award of the East German Writer Association. He played the violin, and once in Hungary we were able to persuade him to play with a gypsy band. His humor and charm were contagious, and despite his amazing intellect, he was extremely unassuming and understated. We had the most wonderful time together when he came in 2000 for a sabbatical with his family. His wife Nana, who is from Georgia of the former Soviet Union, immediately rounded up all Georgians in Boston- mostly consisting of a delightful group of women- and they hosted parties every evening in their apartment. What a crowd of people, a veritable Babylonian mix of languages, with warm hospitality, joint singing, cooking, and joyful laughter! But any description of Reinhart woud be incomplete without mentioning his love for his children Lisi and Lukas. Lisi had him wrapped around her little finger, and Lukas’ choice to study physics made him very proud.

This special edition of the Journal of Theoretical Biology attests to Reinhart’s international reputation. He had friends in many different countries. Often he would spend weeks or even months in a different laboratory, while other times he would visit several continents within a week. He worked hard- perhaps too hard- but through his dedication he trained a whole generation of students, becoming the father of the Berlin School of Theoretical Biophysics. He organized the Hiddensee meetings (at a scenic island in the Baltic sea), which trained countless modelers, and his book with his former student Stefan Schuster is now a classic in theoretical biophysics. He received an honorary degree from the University of Bordeaux. Reinhart Heinrich will be remembered as a founder and pioneer of the now so popular field of systems biology, as a true intellectual giant, whose breadth of scientific vision was only matched by his zest for life and his affection for his colleagues, friends, and family.