## Models for photosynthesis, part 2

May 22, 2015

In my previous post on this subject I discussed the question of the status of the variables in the Poolman model of photosynthesis and in the end I was convinced that I had understood which concentrations are to be considered as dynamical unknowns and which as constants. The Poolman model is a modified version of the Pettersson model and the corresponding questions about the nature of the variables have the same answers in both cases. What I am calling the Pettersson model was introduced in a paper of Pettersson and Ryde-Pettersson (Eur. J. Biochem 175, 661) and there the description of the variables and the equations is rather complete and comprehensible. Now I will go on to consider the second question raised in the previous post, namely what the evolution equations are. The evolution equations in the Poolman model are modifications of those in the Pettersson model and are described relative to those in the original paper on the former model. For this reason I will start by describing the equations for the Pettersson model. As a preparation for that I will treat a side issue. In a reaction network a reaction whose rate depends only on the concentrations of the substances consumed in the reaction is sometimes called NAC (for non-autocatalytic). For instance this terminology is used in the paper of Kaltenbach quoted in the previous post. The opposite of NAC is the case where the reaction rate is modulated by the concentrations of other substances, such as activators or inhibitors.

The unknowns in the Pettersson model are concentrations of substances in the stroma of the chloroplast. The substances involved are 15 carbohydrates bearing one or more phosphate groups, inorganic phosphate and ATP, thus 17 variables in total. In addition to ordinary reactions between these substances there are transport processes in which sugar phosphates are moved from the stroma to the cytosol in exchange for inorganic phosphate. For brevity I will also refer to these as reactions. The total amount of phosphate in the stroma is conserved and this leads to a conservation law for the system of equations, a fact explicitly mentioned in the paper. On the basis of experimental data some of the reactions are classified as fast and it is assumed that they are already at equilibrium. They are also assumed to be NAC and to have mass-action kinetics. This defines a set of algebraic equations. These are to be used to reduce the 17 evolution equations which are in principle there to five equations for certain linear combinations of the variables. The details of how this is done are described in the paper. I will now summarize how this works. The time derivatives of the 16 variables other than inorganic phosphate are given in terms of linear combinations of 17 reaction rates. Nine of these reaction rates, which are not NAC, are given explicitly. The others have to be treated using the 11 algebraic equations coming from the fast reactions. The right hand sides $F_i$ of the five evolution equations mentioned already are linear combinations of those reaction rates which are given explicitly. These must be expressed in terms of the quantities whose time derivatives are on the left hand side of these equations, using the algebraic equations coming from the fast reactions and the conservation equation for the total amount of phosphate. In fact all unknowns can be expressed in terms of the concentrations of RuBP, DHAP, F6P, Ru5P and ATP. Call these quantities $s_i$. Thus if the time derivatives of the $s_i$ can be expressed in terms of the $F_i$ we are done. It is shown in the appendix to the paper how a linear combination of the time derivatives of the $s_i$ with coefficients only depending on the $s_i$ is equal to $F_i$. Moreover it is stated that the time derivatives of the $s_i$ can be expressed in terms of these linear combinations.

Consider now the Poolman model. One way in which it differs from the Pettersson model is that starch degradation is included. The other is that while the kinetics for the ‘slow reactions’ (i.e. those which are not classified as fast in the Pettersson model) are left unchanged, the equilibrium assumption for the fast reactions is dropped. Instead the fast reactions are treated as reversible with mass action kinetics. In the thesis of Sergio Grimbs (Towards structure and dynamics of metabolic networks, Potsdam 2009) there is some discussion of the models of Poolman and Pettersson. It is investigated whether information about multistability in these models can be obtained using ideas coming from chemical reaction network theory. Since the results from CRNT considered require mass action kinetics it is implicit in the thesis that the systems are being considered which are obtained by applying mass action to all reactions in the networks for the Poolman and Pettersson models. These systems are therefore strictly speaking different from those of Pettersson and Poolman. In any case it turned out that these tools were not useful in this example since the simplest results did not apply and for the more complicated computer-assisted ones the systems were too large.

In the Pettersson paper the results of computations of steady states are presented and a comparison with published experimental results looks good in a graph presented there. So whay can we not conclude that the problem of modelling the dynamics of the Calvin cycle was pretty well solved in 1988? The paper contains no details on how the simulations were done and so it is problematic to repeat them. Jablonsky et. al. set up simulations of this model on their own and found results very different from those reported in the original paper. In this context the advantage of the Poolman model is that it has been put into the BioModels database so that the basic data is available to anyone with the necessary experience in doing simulations for biochemical models. Forgetting the issue of the reliability of their simulations, what did Petterson and Ryde-Pettersson find? They saw that depending on the external concentration of inorganic phosphate there is either no positive stationary solution (for high values of this parameter) or two (for low values) with a bifurcation in between. When there are two stationary solutions one is stable and one unstable. It looks like there is a fold bifurcation. There is a trivial stationary solution with all sugar concentrations zero for all values of the parameter. When the external phosphate concentration tends to zero the two positive stationary solutions coalesce with the trivial one. The absence of positive stationary solutions for high phosphate concentrations is suggested to be related to the concept of ‘overload breakdown’. This means that sugars are being exported so fast that the production from the Calvin cycle cannot keep up and the whole system breaks down. It would be nice to have an analytical proof of the existence of a fold bifurcation for the Pettersson model but that is probably very difficult to get.

## Models for photosynthesis

May 15, 2015

Photosynthesis is a process of central importance in biology. There is a large literature on modelling this process. One step is to identify networks of chemical reactions involved. Another is to derive mathematical models (usually systems of ODE) from these networks. Here when I say ‘model’ I mean ‘mathematical model’ and not the underlying network. In a paper by Jablonsky et. al. (BMC Systems Biology 5: 185) existing models are surveyed and a number or errors and inconsistencies in the literature are pointed out. This reminded me of the fact that a widespread problem in the biological literature is that the huge amount of data being generated these days contains very many errors. Here I want to discuss some issues related to this, concentrating on models for the Calvin cycle of photosynthesis and, in particular, on what I will call the Poolman model.

A point which might seem obvious and trivial to the mathematician is that a description of a mathematical model (I consider here only ODE models) should contain a clear answer to the following two questions. 1) What are the unknowns? 2) What are the evolution equations? One source of ambiguity involved in the first question is the impossibility of modelling everything. It is usually unreasonable to model a whole organism although this has been tried for some simple ones. Even if it were possible, the organism is in interaction with other organisms and its environment and these things cannot also be included. In practise it is necessary to fix a boundary of the system we want to consider and cut there. One way of handling the substances outside the cut in a mathematical model is to set their concentrations to constant values, thus implicitly assuming that to a good approximation these are not affected by the dynamics within the system. Let us call these external species and the substances whose dynamics is included in the model internal species. Thus part of answering question 1) is to decide on which species are to be treated as internal. In this post I will confine myself to discussing question 1), leaving question 2) for a later date.

Suppose we want to answer question 1) for a model in the literature. What are potential difficulties? In biological papers the equations (and even the full list of unknowns) are often banished to the supplementary material. In addition to being less easy to access and often less easy to read (due to typographical inferiority) than the main text I have the feeling that this supplementary material is often subjected to less scrutiny by the referees and by the authors, so that errors or incompleteness can occur more easily. Sometimes this information is only contained in some files intended to be read by a computer rather than a human being and it may be necessary to have, or be able to use, special software in order to read them in any reasonable way. Most of these difficulties are not absolute in nature. It is just that the mathematician embarking on such a process should ideally be aware of some of the challenges awaiting him in advance.

How does this look in the case of the Poolman model? It was first published in a journal in a paper of Poolman, Fell and Thomas (J. Exp. Botany, 51, 319). The reaction network is specified by Fig. 1 of the paper. This makes most of the unknowns clear but leaves the following cases where something more needs to be said. Firstly, it is natural to take the concentration of ADP to be defined implicitly through the concentration of ATP and the conservation of the total amount of adenosine phosphates. Secondly, it is explictly stated that the concentrations of NADP and NADPH are taken to be constant so that these are clearly external species. Presumably the concentration of inorganic phosphate in the stroma is also taken to be constant, so that this is also an external variable, although I did not find an explicit statement to this effect in the paper. The one remaining possible ambiguity involves starch – is it an internal or an external species in this model? I was not able to find anything directly addressing this point in the paper. On the other hand the paper does refer to the thesis of Poolman and some internet resources for further information. In the main body of the thesis I found no explicit resolution of the question of external phosphate but there it does seem that this quantity is treated as an external parameter. The question of starch is particularly important since this is a major change in the Poolman model compared to the earlier Pettersson model on which it is based and since Jablonsky et. al. claim that there is an error in the equation describing this step. It is stated in the thesis that ‘a meaningful concentration cannot be assigned to’ … ‘the starch substrate’ which seems to support my impression that the concentration of starch is an external species. Finally a clear answer confirming my suppositions above can be found in Appendix A of the thesis which describes the computer implementation. There we find a list of variables and constants and the latter are distinguished by being preceded by a dollar sign. So is there an error in the equation for starch degradation used in the Poolman model? My impression is that there is not, in the sense that the desired assumptions have been implemented successfully. The fact that Jablonsky et. al. get the absurd result of negative starch concentrations is because they compute an evolution for starch which is an external variable in the Poolman model. What could be criticised in the Poolman model is that the amount of starch in the chloroplast varies a lot over the course of the day. Thus a model with starch as an external variable could only be expected to give a good approximation to reality on timescales much shorter than one day.

## The species-reaction graph

May 14, 2015

In the study of chemical reaction networks important features of the networks are often summarised in certain graphs. Probably that most frequently used is the species graph (or interaction graph), which I discussed in a previous post. The vertices are the species taking part in the network and the edges are related to the non-zero entries of the Jacobian matrix of the vector field defining the dynamics. Since the Jacobian matrix depends in general on the concentrations at which it is evaluated there is a graph (the local graph) for each set of values of the concentrations. Sometimes a global graph is defined as the union of the local graphs. A sign can be attached to each edge of the local graph according to the sign of the corresponding partial derivative. In the case, which does occur quite frequently in practise, that the signs of the partial derivatives are independent of the concentrations the distinction between local and global graphs is not necessary. In the general case a variant of the species graph has been defined by Kaltenbach (arXiv:1210.0320). In that case there is a directed edge from vertex $i$ to vertex $j$ if there is any set of concentrations for which the corresponding partial derivative is non-zero and instead of being labelled with a sign the edge is labelled with a function, namely the partial derivative itself.

Another more complicated graph is the species-reaction graph or directed species-reaction graph (DSR graph). As explained in detail by Kaltenbach the definition (and the name of the object) are not consistent in the literature. The species-reaction graph was introduced in a paper of Craciun and Feinberg (SIAM J. Appl. Math. 66, 1321). In a parallel development which started earlier Mincheva and Roussel (J. Math. Biol. 55, 61) developed results using this type of graph based on ideas of Ivanova which were little known in the West and for which published proofs were not available. In the sense used by Kaltenbach the DSR graph is an object closely related to his version of the interaction graph. It is a bipartite graph (i.e. there are two different types of vertices and each edge connects a vertex of one type with a vertex of the other). In the DSR graph the species define vertices of one type and the reactions the vertices of the other type. There is a directed edge from species $i$ to reaction $j$ if species $i$ is present on the LHS of reaction $j$. There is a directed edge from reaction $i$ to species $j$ if the net production of species $j$ in reaction $i$ is non-zero. The first type of edge is labelled by the partial derivative of flux $j$ with respect to species $i$. The second type is labelled by the corresponding stoichiometric coefficient. The DSR graph determines the interaction graph. The paper of Soliman I mentioned in a recent post uses the DSR graph in the sense of Kaltenbach.

A type of species-reaction graph has been used in quite a different way by Angeli, de Leenheer and Sontag to obtain conditions for the montonicity of the equations for a network written in reaction coordinates.

## Proof of the global attractor conjecture

May 14, 2015

In a previous post I discussed the global attractor conjecture which concerns the asymptotic behaviour of solutions of the mass action equations describing weakly reversible chemical reaction networks of deficiency zero (or more generally complex balanced systems). Systems of the latter class are sometimes called toric dynamical systems because of relations to the theory of toric varieties in algebraic geometry. I just saw a paper by Gheorghe Craciun which he put on ArXiv last January (arxiv.org/pdf/1501.0286) where he proves this conjecture, thus solving a problem which has been open for more than 40 years. The result says that for reaction networks of this class the long-time behaviour is very simple. For given values of the conserved quantities there is exactly one positive stationary solution and all other solutions converge to it. What needs to be done beyond the classical results on this problem is to show that a positive solution can have no $\omega$-limit points where some concentration vanishes. This property is sometimes known as persistence.

A central concept used in the proof of the result is that of a toric differential inclusion. This says that the time rate of change of the concentrations is contained in a special type of subset. The paper contains a lot of intricate geometric constructions. These are explained consecutively in dimensions one, two, three and four in the paper. This should hopefully provide a good ladder to understanding.

## Arrival in Bretzenheim

May 1, 2015

Since I moved to Mainz two years ago my wife has remained in Berlin and we have been searching for a suitable place to live in Mainz or its surroundings. The original plan was to buy a piece of land on which we could build a house. This turned out to be much more difficult than we expected. The only land within our financial horizons was in small villages with almost no infrastructure or had other major disadvantages from our point of view. Eventually, after wasting a lot of time and effort, we stopped searching in the surroundings and looked for something in Mainz itself. Of course this was not easy but eventually we decided to buy a house (still to be built) within a small housing scheme in the district of Mainz called Bretzenheim. There is very little land available in Mainz and the scheme where we will be living is an example of the way in which the few remaining open spaces are being filled up, driven by the high property prices. The house was finished in March and I moved in on a provisional basis on 1st April, giving up my appartment, exactly two years after starting my job in Mainz. (Goodbye Jackdaws! The first birds I saw in what will be our garden were a Carrion Crow, which I am not taking as a bad omen, and a Black Redstart.) Our belongings left Berlin on 16th April and arrived in Mainz on 17th. Eva came to Mainz definitively on the 16th. So now there can be no doubt that a new era has begun for us.

The new house is conveniently situated. From there I can walk to the mathematics institute in 20 minutes and to the main train station in half an hour. It is near the end of a tram line coming from the station. Very close to where the houses have been built a Merovingian grave was found. When the garden centre a little further up the hill was being built the grave of a Merovingian warrior was found who had been buried with his horse. It is just as well for us that the archeologists did not dig too deep or we might have had to wait a long time before we could move in. Whenever you dig a hole in Mainz you are in danger of encountering a distant past and potential problems with the archeology department of the city. To show what can happen I will give an example. In the district of Gonsenheim there is a small stream, the Gonsbach. At some time when progress was fashionable the winding stream was straightened. Later an EU directive came into force which said that streams like this which had been straightened had to be made winding again, for ecological reasons, within a certain number of years. By now the deadline has been reached, or almost reached for the Gonsbach, and the city has started measures to attempt to comply with the directive. They started to dig and found … a Roman settlement. The work had to be stopped, for archeological reasons. So now, as far as I know, the archeological and ecological regulations and the city officials representing them are in deadlock.

Since I am British it is a curiosity for me that one suggested origin of the name Bretzenheim is that it is named after the Britons. It has been suggested that it could be identified with a certain vicus Brittaniae where the Roman Emperor Severus Alexander was murdered in the year 235. The evidence for this seems limited and an alternative hypothesis says that it was named after a locally important man called Bretzo. I cannot imagine what the Britons would have been doing there. Another theory is that the emperor was murdered in Britain and not in Mainz.

## Systems and synthetic biology in Strasbourg

March 26, 2015

This past week I was at a conference entitled ‘Advances in Systems and Synthetic Biology’ in Strasbourg. The first talk was by Albert Goldbeter and anyone who has read many of the posts on my blog will realize that I went there with high expectations. I was not disappointed. It was a broad talk with the main examples being glycolysis, circadian rhythms and the cell cycle. A lot of the things he talked about were already rather familiar. It was nevertheless rewarding to hear the inside story. There were also enough themes in the talk which were quite new to me. For instance he mentioned that oscillations have been observed in red blood cells, where transcription is ruled out. I enjoyed listening to him, perhaps even more than I did reading his book. Another talk on Monday was by Jacques Demongeot. I am sure that he is a brilliant, versatile and highly knowledgeable person. Unfortunately he made no concessions in his talk for the benefit of non-experts. He jumped into the talk without saying where it was going and I did not have the background knowledge to be able to supply that information on my own. I felt as if I was flattened by a blast wave of information and unfortunately I understood essentially nothing.

The first talk on Tuesday was by Nicolas Le Novère and it had to do with engineering-type approaches to molecular biology. This is very far from my world but gave me some fascinating glimpses as to how this kind of thing works. Incidentally, I found out that Le Novère has a blog with a number of contributions which I found enlightening. The next talk was by François Fages and was focussed on computer science issues. It nevertheless contained more than one aspect which I found very interesting. At this point I should give some background. There are influential ideas on the relation of feedback loops to the qualitative behaviour of the solutions of dynamical systems due to René Thomas. They have been developed over many years by several people and a number of them are at this conference (El Houssine Snoussi, Marcelle Kaufman, Jacques Demongeot) and today I attended a tutorial held by Gilles Bernot on related themes. The basic idea is ‘positive feedback loops are necessary for bistability, negative feedback loops for periodic solutions’. I will not get into this more deeply here but I will just mention that some of the conjectures of Thomas have been made into theorems over the years. For instance a rather definitive version of the result on multistability was proved by Christophe Soulé. In his talk Fages mentioned a recent generalization of this result due to Sylvain Soliman. In the past I had the suspicion that the interest of the conjectures of Thomas was severely limited by the fact that the hypotheses rule out certain configurations which are very widespread in reaction networks of practical importance. It seemed to me that Fages made exactly this point and was saying that the improved results of Soliman overcome this difficulty. I must go into the matter in more detail as soon as I have time. Another point mentioned in the talk was an automated way to find siphons. This is a concept in reaction networks which I should know more about and I have the impression that in a couple of cases I have discovered these objects in examples without realizing that they were instances of this general concept.

On Wednesday there was an extended presentation by Oliver Ebenhöh. One speaker had cancelled and Oliver extended his presentation to fill the resulting extra time. I felt that listening to the presentation was time well spent and I did not feel my attention waning. He explained many things related to plant science and, in particular, the use of starch by plants. One key topic was the way in which a particular enzyme acts on chains of glucose monomers (generalization of maltose, which is the case of two units). It creates a kind of maximal entropy distribution of different lengths. The talk presented both a theoretical analysis and precise experimental results. The theoretical part involved an application of elementary thermodynamic ideas. I liked this and it brought me to a realization about my relation to physics. In the past I have been exposed to too much theoretical physics of a very pure kind, remote from applications to phenomena close to everyday life. It was refreshing to see basic physical ideas being applied in a down to earth way to the analysis of real experiments, in this case in biology.

In his talk on Thursday Joel Bader talked about his work on engineering yeast in such a way as to find out which combinations of genes are essential for survival. The aim is to look for a kind of minimal genome within yeast. One of the techniques of gathering information is to do a random recombination using a Cre-Lox system and looking to see which of the mutants produced are viable. The analysis of these experiments leads to consideration of self-avoiding or non-self-avoiding random walks and at this point I had a strange feeling of deja vu. A few weeks ago I gave a talk in the Hausdorff colloquium in Bonn. In this event two speakers are invited on one afternoon and their themes are not necessarily correlated. On the day I was there the other speaker was Hugo Duminil-Copin and he was talking about self-avoiding random walks, a topic which I knew very little about. Now I was faced with (at least superficially) similar ideas in the context of DNA recombination. At the end of his talk Bader spent a few minutes on a quite different topic, namely bistability in the state of M. tuberculosis. I would have liked to have heard more about that. He is collaborating on this together with Denise Kirschner whose work on modelling tuberculosis I have discussed in a previous post.

This meeting had the advantages of relatively small conferences (in this case of the order of 50 participants) and has served the purpose of opening new perspectives for me.

## Harald zur Hausen, colon cancer and MS

December 5, 2014

Having recently written about Harald zur Hausen I now had the opportunity to see him live since he gave a talk in Mainz today. On main theme of his talk was colon cancer. He discussed the different frequencies of this disease in different countries and how this is changing in time. The disease is increasing in Europe and decreasing in the US. He suggested that the latter is due to the increasing success of colonoscopy is identifying and removing pre-cancerous states. There has been a particularly strong increase in Japan and Korea which correlates with a much increased consumption of red meat. Places where this disease is relatively rare, despite considerable meat consumption, are Bolivia and Mongolia. One popular theory about the link between meat consumption and colon cancer is that the process of cooking at high temperatures produces carcinogens. A problem with this theory is that cooking chicken and fish at high temperatures produces the same carcinogens and that there is no corresponding correlation with colon cancer in that case. Thus there is no specificity of red meat. Zur Hausen’s suggestion is that the thing that favours the development of colon cancer is a combination of two factors. One of them is the carcinogens just mentioned but the other is specific to red meat. In fact the study of the geographical distribution suggests that it is even more specific than that. It is specific to cattle and even to the subtype of cattle common in Europe. The types of cattle or related animals in Bolivia and Mongolia do not have the same effect. The idea is that the causative agent could be a virus which is present just in that type of cattle prevalent in the ‘western’ countries. No specific virus has been incriminated but zur Hausen and his collaborators have isolated a lot of candidates from cattle. If this idea is correct then the highest danger would come from raw or lightly cooked meat and this is indeed popular in Japan and Korea.

Another main theme, which was quite unexpected for me, was MS. Here there is also a suggestion of a cattle connection. The idea is that consumption of cows milk at a young age and in particular consumption of non-pasteurized milk may carry a risk for getting MS. The model, at present rather speculative, is that there could be an interaction between some factor present in cows milk and some kind of virus, for instance EBV. Implication of virus infections in general and EBV in particular in causing MS is not new but here it is integrated into a more complicated suggestion. One problem with linking EBV and MS is that such a high percentage of the population has been affected with EBV. I cannot judge how solid these ideas about colon cancer and MS are but they are certainly interesting and original.

## ‘There but for the’ by Ali Smith

November 13, 2014

In a previous post I said that I might write something about my impressions of Ali Smith’s novels. Since I just finished reading ‘There but for the’ I thought that this was a good opportunity to do so. The other novels of hers which I have read (both a very long time ago) are ‘Like’ and ‘Hotel World’. I liked the first of these a lot and the second less. I no longer have many concrete memories of the contents of these books and I just want to mention one thing which sticks in my mind from ‘Like’. I am telling this story from memory and I did not go back to check the details. In one episode a young girl growing up in Scotland is alone at home when a woman comes to the door. This woman is of the exotic type called ‘English’. The girl asks her if she would like tea, according to the usual code of hospitality in that social context, which is the one I grew up in. The woman asks her what kinds of tea she has. This confuses the girl completely and would have confused me just as much in the same situation. For us drinking tea was very important and tea was tea. We knew nothing about herbal tea, fruit tea, green tea or special kinds of black tea. I only encountered Earl Grey, for example, as a student. In this context I remember one other experience I had while I was at university. I used to spend the summer holidays with my family. In general our dinner at home, the main meal of the day, always included potatoes. These potatoes grew on our farm and I was involved with planting and picking them as well as eating them. (I mentioned in a previous post how this encouraged my interest in metaphysics.) My grandmother, who lived with the family, loved eating potatoes, in particular potato soup, and towards the end of her life she sometimes said that that she would be quite happy to eat nothing else. The specific memory I wanted to mention is a comment she made on the eccentric habits I had picked up at university. She said, in the context of potatoes, ‘O, Alan he eats rice and pasta and ‘yin dirt’ (standard English translation ‘that rubbish’).

Now let me finally come to ‘There but for the’, I enjoyed reading it a lot and it had the effect of a good novel of somehow modifying my feelings and mood in everyday life. Being confronted with and made to think about certain ideas helps with getting out of certain ruts. I have to say that I cannot recommend the book as bedside reading. I found that when I read it before going to bed it had the effect that my thoughts had such a momentum that they could not easily slow down. I would not advise reading it in public either, unless you are a real extrovert. At any rate I could end up laughing so much that it would make me embarrassed to do so in public.

The book is very up to date in the sense that it features a lot of aspects of our daily life which are very new. There are some things which can creep up on us so that they become familiar without our ever really being conscious that they are there. The book helps to reveal these hidden companions. It is full of humour and wordplay, much of which I appreciated. I imagine that I also missed a lot. I have lived outside Britain and even outside English-speaking countries for many years now and this is bound to mean that various jokes and references were lost on me. Many of the things in the book could be taken as comments on society but the interesting thing is that these comments come from inside. We receive them through a portrayal of the thoughts of individual characters including a young girl (who plays a central role) and an old woman approaching death. We also receive them by hearing the conversation between very different characters and seeing the misunderstandings which limit communication between them. In the end, while I appreciated the text ‘locally’ I was left  with the feeling that I did not understand its global structure. I could see that the snake bites its tail, the end connecting to the beginning, but I felt as if I was left facing a question mark. Was this the author’s intention? Or did I miss something essential? Whatever the answers to these questions I feel that the time I spent reading the book was time well spent.

## Symposium in Mainz on controversies in biomedicine

October 26, 2014

Last Friday I attended a symposium on controversies in biomedicine at the Academy of Science and Literature in Mainz. There were a number of talks and a round table discussion at the end. The event itself was not the scene of much controversy. It seems that most of the people attending had a positive attitude to biomedical research. At least there was not much sign of the contrary in the questions after the talks. I thought that an event like this might have attracted more participants with a critical view of the subject but that does not seem to have been the case. The one vein of controversial discussion was between some journalists who had been invited for the round table (from Bavarian TV, Süddeutsche Zeitung and Frankfurter Allgemeine Zeitung) and the majority of the participants who were presumably scientific researchers in one form or another. The journalists expressed the opinion that scientists did not take part actively enough in public debates and the scientists suggested that journalists often sensationalized scientific subjects of public interest.

The first talk, by Christof von Kalle was about gene therapy. This taught me a number of things concerning this subject which I did not previously know much about. One example he discussed was that of X-linked SCID (severe combined immunodeficiency). The first choice of therapy for this fatal condition is a bone marrow transplant but this is dependent on the availability of a suitable donor. In other cases gene therapy was tried. It often cured the SCID but a high proportion of patients later got leukemia. A promoter in the inserted DNA had not only activated the gene it was supposed to but an oncogene as well. My one criticism of the talk is that the speaker packed in much too much information, sometimes flashing slides for just a couple of seconds. The next talk was by Bernhard Fleckenstein on pathogenic viruses. His main theme was biosecurity and biosafety. The first has to do with preventing voluntary misuse (such as bioterrorism) and the second with preventing accidents. I learned that this is still the subject of lively discussion. One amazing story is that there was an attempt to stop a paper written in Holland being published in the US by claiming that it was an export and that therefore an authority in Holland responsible for exports of goods had the right to forbid it. There is no doubt that experimental work on influenza viruses which are both highly virulent and highly infectious could be dangerous. However in my opinion it makes no sense to ban such research or to try to keep the results secret. This is because I think that somebody will do the research anyway, despite bans, and any important results will leak out. I think that the danger is minimized if the research is legal and open rather than illegal and secret. The next talk, by Martin Lohse, was on the necessity of animal experiments. One aspect which came out clearly was the tension between the legislation limiting research on animals and that requiring a certain amount of such research in the form of testing before a new drug can be approved.

Over lunch I had some stimulating conversations with other participants. The first talk after lunch was by Jörg Michaelis on the benefit or otherwise of screening, in particular for cancer. He recounted his own experience in organizing a large study on the use of screening of small children for neuroblastoma, with negative results. He then surveyed what is known about the value of various other types of screening. In particular he stated that screening for skin cancer, as paid for by the German public health service is not justified by any scientific evidence. Nobody in the audience contradicted this. The last talk of the day, by Uwe Sonnewald was about green genetic engineering. Among other things he presented statistics on the huge difference in the level of the use of these techniques in the Americas and in Europe, particularly Germany. If the bar representing Germany had not been a different colour it would have been invisible. The meeting ended with the round table. I just want to mention one point which arose there. In a recent post I mentioned the negative attitude to science and technology, particular in the area of biomedicine, which I notice in Germany. (This was one motivation for me to attend the event I am writing about here, with the idea of collecting arguments in support of science.) Of course this was a recurrent theme in the symposium in one form or another, particularly during the round table. An idea which appeared repeatedly, implicitly or explicitly, during the day was that the troubled relationship of the Germans to this subject could have to do with thinking of the abuses carried out by certain German doctors during the time that the Nazis were in power. This is maybe an obvious point but in the discussion someone (I think it was Christof Niehrs) introduced another idea, one which was new to me. He asked if it was possible that this troubled relationship perhaps goes back much further, namely to the period of romanticism when there was a reaction in Germany against the rationalism of the Enlightenment. I found this symposium very informative and it provided me with a lot of material which I can use in the future in discussions on this type of subject.

## Thoughts on Helen Keller

October 19, 2014

I must have seen something about Helen Keller on TV when I was a child. I do not exactly remember what it was and when her name recently came into my mind I could not remember what the story was. I just knew that she had an unusual handicap. Wikipedia confirmed my vague memory that she was deaf and blind. I saw that her autobiography is available online and I started to read it. I got hooked and having been reading a bit each evening I have now finished it. Actually the text is not just the autobiography itself but also has other parts such as some of her letters and text by her teacher Anne Sullivan.

Helen Keller, born in 1880, was left deaf and blind by an illness (it does not seem to be clear what, perhaps meningitis or scarlet fever) at the age of 19 months. Being cut off to such an extent from communication she lost some of the abilities she had already acquired as a small child, although she did invent her own personal sign language. The development was only turned around by the arrival her teacher in 1887. Anne Sullivan was not happy with the way in which people exaggerated when writing about the achievements of Helen and herself. She rightly remarked that what Helen did did not require extra embroidery – the plain truth was remarkable enough. It was claimed that she (Anne) had become Helen’s teacher as a selfless act. She writes that in fact she did so because she needed the money. She had herself been blind for some time before regaining her sight. On the other hand what she did for her pupil was in the end very remarkable. The first route of communication for Helen was through her teacher spelling into her hand. Later on Helen learned to type and read Braille, to write on paper (although in the latter form she could not read what she had written) and to speak (in several languages). She got a college degree despite the special difficulties involved. For instance in mathematics, which was not her favourite subject, there were difficulties for her to be able to understand the examination questions which were presented in a special form of Braille which she was not very familiar with.

I think that the story of Helen Keller can be an inspiration for the majority of us, those who do not have to struggle with the immense difficulties she was confronted with. If we compare then we may complain less of our own problems. Of course she did have one or two advantages. Her family must have been quite well off so as to pay for personal tuition so that she was freed from certain practical difficulties. She had great intellectual gifts which could develop vigorously once a sufficiently good channel of communication to the outside world (and, very importantly, to the world of books) had been established. The prose in her autobiography is of high quality. When she is describing some experience she often describes it as if she had seen and heard everything. This makes a strange impression when you realize that this had to be reconstructed from things her teacher had communicated to her, direct sensations such as smells and vibrations and memories from things she remembered from books. She seems to have had a remarkable talent for integrating all this information. I can only suppose that this integration was done not just for her writing but to create parts of her day to day experience.

The book was published in 1903 and so only contains information about Helen Keller’s life until about the turn of the century. She lived until 1968, was later a prominent public figure and wrote many books. Perhaps in the future accounts of her later life will cross my path.