Honesty is the best policy

December 10, 2016

Yesterday I did the following thought experiment. I imagined a situation where someone asked me two questions, saying that I should answer spontaneously without thinking too long. The first question was ‘Are you happy with your life?’ and the second ‘Are you happy with the society around you?’ My answer to the first question was ‘yes’ and to the second ‘no’. I then started thinking about the cause of the discrepancy between these two answers. I came to the conclusion that it has a lot to do with the concept of ‘honesty’. I believe in and live according to the phrase in the title of this post, ‘honesty is the best policy’ while I feel that in the society around me lies have a huge influence. It is also worth remarking that lies are not the only kind of dishonesty.

If I am honest what is the reason? One important influence is my upbringing. I grew up in a family which was very attached to telling the truth. Here the influence of my mother was particularly strong. What influenced me was not so much what she said on the subject as the example of how she behaved. My mother’s attachment to honesty had a lot to do with her attachment to religion. I did not inherit her religion, becoming an atheist in my teens. I also did not inherit her moral convictions but I did inherit certain patterns of moral behaviour. One thing that stops me telling lies is simply that I find it very unpleasant due to childhood conditioning. Since truth plays a central role in mathematics it is perhaps natural that mathematicians should tend to be truthful, also in everyday life. It might also conversely be the case that among people who go into academia those with a specially strong attachment to truth might tend to go in the direction of mathematics.

Probably the main motivation for lying is the hope to gain some advantage by doing so. This may be short-sighted if despite a short-term profit the net long-term payment is negative. The idea that this is often the case is one motivation for me not to lie. Another is the fact that lies require management in order to profit from them. It is necessary to remember the lies you told so as not to betray yourself and it is also necessary to remember the corresponding true version. A lot of profitable lies require a lot of management and this is stress which I like to avoid. More thoughts in similar directions can be found on this web page
http://www.becomingminimalist.com/why-honesty-is-the-best-policy-for-simplicity/

What types of dishonesty in society bother me? One is political correctness. It means sanctions againt telling the truth, or just speaking plainly rather than in euphemisms, in many situations. There are some cases where there may be good reasons for measures like this but I think that in the majority of cases there are no good reasons. They are based on arbitrary conventions or at best on misguided ideas of well-meaning people. I prefer to speak openly but I often avoid doing so and simply keep quiet in order to avoid problems. I would prefer if this was not so often necessary. A related topic is that of reference letters. When I write references for people applying for academic jobs I generally feel free to tell the truth. For jobs outside academia things are very different. There telling the truth might easily lead to disaster since open criticism is often effectively forbidden. Instead it is necessary to write in code and even then the information which might be helpful for the employer, or for the applicant, might not get through. In other situations it is necessary to be careful when criticising people but it is wrong not to criticise. Constructive criticism can be good. I am happy when I receive constructive criticism although it may be unpleasant at the moment it arrives. I believe that it is also important to make statements in certain situations like ‘in my opinion person X is better than person Y at doing task Z’. This is not a comparison of the value of the two people in general but just in the context of a particular ability.

One other theme I want to mention is marriage, because my marriage is one of the things in my life which contributes most to my happiness. When I use the word ‘marriage’ here I mean it to denote a long-term romantic relationship, not only one which is recognised legally by a piece of paper. I have been married in the latter sense for eight years but the underlying relationship goes back sixteen years. I would not dare to write here about individual marriages (apart from my own) but I will say something about averages. It seems that with time marriages in our society become less and less stable and last for shorter times. I believe in marriage in the old-fashioned sense of ’till death do us part’ and I think it is very unfortunate for many people that they have replaced this by a sequence of shorter-term relationships accompanied by difficult separations. The relation of this topic to that of honesty is as follows. I think that separations often result from the fact that the people involved are pursuing short term gains at the expense of the partner. Then the short-term gains turn into long-term losses. In a talk I heard recently the speaker voiced the opinion that the kind of degradation of marriage (or of love) I have been talking about is due to the fact that many people going into relationships have not had the experience of good marriages in their childhood. I had the advantage of growing up in surroundings where this type of relationship was widespread and I had very direct experience of how it was in the case of my own parents.

Photorespiration and RuBisCO

November 29, 2016

The enzyme at the centre of the fixation of carbon in photosynthesis (which is the ultimate source of our food) is RuBisCO (Ribulose Bisphosphate Carboxylase Oxygenase). It is sometimes called the ‘lazy enzyme’ because it works so slowly. This is unjust since the process is so difficult that RuBisCO is the only enzyme that can do it. So it is like the situation of a strong man who is the only one who can carry very heavy rocks and who is called lazy because it takes him so long to move the rocks. The name already indicates that this enzyme catalyses two different reactions with the same substrate, ribulose bisphosphate. So it might also be claimed that it does not concentrate well. Instead of spending all its time on the useful process of carboxylation it apparently wastes a lot of time on the hobby of oxygenation. Carboxylation produces two molecules of phosphoglycerate (PGA) by combining a molecule of carbon dioxide with one of ribulose bisphosphate. In the oxygenation reaction only one molecule of PGA is produced together with one of phosphoglycolate. At least superficially the latter substance is not only useless but actual causes the cell a lot of trouble getting rid of it. I have not seen a definitive explanation about what purpose this process, photorespiration, might serve. One idea is that it might act as a safety valve. A too large input of energy to the photosynthesis system might damage it and photorespiration can be used to dissipate this energy in a relatively harmless way when necessary. The relative rates of the two reactions are influenced by the concentration of carbon dioxide and for normal atmospheric concentrations the relative rate of photorespiration is quite high.

The discussion up to now has been appropriate for what is called C_3 photosynthesis. The name comes from the fact that the first molecule to be produced is the three-carbon molecule PGA. There is an alternative called C_4 photosynthesis. This also contributes to food production, even to the food I eat. My generic breakfast is cornflakes and the most economically important plant which uses C_4 photosynthesis is maize. In this process carbon dioxide is used to make malate. Malate is not directly useful but is an intermediate. It is transported to an internal compartment (bundle-sheath cells) where it releases carbon dioxide. The result is an increased concentration of carbon dioxide and RuBisCO, which is waiting there, is pushed towards doing more carboxylation at the expense of oxygenation. Since the C_4 process leads to greater crop yields under certain conditions there is a project to genetically engineer rice so as to produce a C_4 variant. There is third type of photosynthesis , CAM photosynthesis for crassulacean acid metabolism. It is used, for instance by pineapples. There are similarities with C_4 with the difference that while in C_4 carbon dioxide is harvested in one place and released in another in CAM it is harvested at one time (during the night) and released at another (during the day).

The importance of dendritic cells

October 30, 2016

I just realized that something I wrote in a previous post does not make logical sense. This was not just due to a gap in my exposition but to a gap in my understanding. I now want to correct it. A good source for the correct story is a video by Ira Mellman of Genentech. I first recall some standard things about antigen presentation. In this process peptides are presented on the surface of cells with MHC molecules which are of two types I and II. MHC Class I molecules are found on essentially all cells and can present proteins coming from viruses infecting the cell concerned. MHC Class II molecules are found only on special cells called professional antigen presenting cells. These are macrophages, T cells and dendritic cells. The champions in antigen presentations are the dendritic cells and those are the ones I will be talking about here. In order for a T cell to be activated it needs two signals. The first comes through the T cell receptor interacting with the peptide-MHC complex on an APC. The second comes from CD28 on the T cell surface interacting with B7.1 and B7.2 on the APC.

Consider now an ordinary cell, not an APC, which is infected with a virus. This could, for instance be an epithelial cell infected with a influenza virus. This cell will present peptides derived from the virus with MHC Class I molecules. These can be recognized by activated {\rm CD8}^+ T cells which can then kill the epithelial cell and put an end to the viral reproduction in that cell. The way I put it in the previous post it looked like the T cell could be activated by the antigen presented on the target cell with the help of CD28 stimulation. The problem is that the cell presenting the antigen in this case is an amateur. It has no B7.1 or B7.2 and so cannot signal through CD28. The real story is more complicated. The fact is that dendritic cells can also present antigen on MHC Class I, including peptides which are external to their own function. A possible mechanism explained in the video of Mellman (I do not know if it is certain whether this is the mechanism, or whether it is the only one) is that a cell infected by a virus is ingested by a dendritic cell by phagocytosis, so that proteins which were outside the dendritic cell are now inside and can be brought into the pathway of MHC Class I presentation. This process is known as cross presentation. Dendritic cells also have tools of the innate immune system, such as toll-like receptors, at their disposal. When they recognise the presence of a virus by these means they upregulate B7.1 and B7.2 and are then in a position to activate {\rm CD8}^+ T cells. Note that in this case the virus will be inside the dendritic cell but not infecting it. There are viruses which use dendritic cells for their own purposes, reproducing there or hitching a lift to the lymph nodes where they can infect their favourite cells. An example is HIV. The main receptor used by this virus to enter the cells is CD4 and this is present not only on T cells but also on dendritic cells. Another interesting side issue is that dendritic cells can not only activate T cells but also influence the differentiation of these cells into various different types. The reason is that the detection instruments of the dendritic cell not only recognise that a pathogen is there but can also classify it to some extent (Mellman talks about a bar code). Based on this information the dendritic cell secretes various cytokines which influence the differentiation process. For instance they can influence whether a T-helper cell becomes of type Th1 or Th2. This is related to work which I did quite a long time ago on an ODE system modelling the interactions of T cells and macrophages. In view of what I just said it ḿight be interesting to study an inhomogeneous version of this system. The idea is to include an external input of cytokines coming from dendritic cells. In fact the unknowns in the system are not the concentrations of cytokines but the populations of cells. Thus it would be appropriate to introduce an inhomogeneous contribution into the terms describing the production of different types of cells.

Modern cancer therapies

October 28, 2016

I find the subject of cancer therapies fascinating. My particular interest is in the possibility of obtaining new insights by modelling and what role mathematics can play in this endeavour. I have heard many talks related to these subjects, both live and online. I was stimulated to write this post by a video of Martin McMahon, then at UCSF. It made me want to systematize some of the knowledge I have obtained from that video (which is already a few years old) and from other sources. First I should fix my terminology. I use the term ‘modern cancer therapies’ to distinguish a certain group of treatments from what I will call ‘classical cancer therapies’. The latter are still of central importance today and the characteristic feature of those I am calling ‘modern’ here is that they have only been developed in the last few years. I start by reviewing the ‘classical therapies’, surgery, radiotherapy and chemotherapy. Surgery can be very successful when it works. The aim is to remove all the cancerous cells. There is a tension between removing too little (so that a few malignant cells could remain and restart the tumour) and too much (which could mean too much damage to healthy tissues). A particularly difficult case is that of the glioma where it is impossible to determine the extent of the tumour by imaging techniques alone. An alternative to this is provided by the work of Kristin Swanson, which I mentioned in a previous post. She has developed techniques of using a mathematical model of the tumour (with reaction-diffusion equations) to predict the extent of the tumour. The results of a simulation, specific to a particular patient, is given to the surgeon to guide his work. In the case of radiotherapy radiation is used to kill cancer cells while trying to avoid killing too many healthy cells. A problematic aspect is that the cells are killed by damaging their DNA and this kind of damage may lead to the development of new cancers. In chemotherapy a chemical substance (poison) is used with the same basic aim as in radiotherapy. The substance is chosen to have the greatest effect on cells which divide frequently. This is the case with cancer cells but unfortunately they are not the only ones. A problem with radiotherapy and chemotherapy is their poor specificity.

Now I come to the ‘modern’ therapies. One class of substances used is that of kinase inhibitors. The underlying idea is as follows. Whether cells divide or not is controlled by a signal transduction network, a complicated set of chemical reactions in the cell. In the course of time mutations can accumulate in a cell and when enough relevant mutations are present the transduction network is disrupted. The cell is instructed to divide under circumstances under which it would normally not do so. The cells dividing in an uncontrolled way constitute cancer. The signals in this type of network are often passed on by phosphorylation, the attachment of phosphate groups to certain proteins. The enzymes which catalyse the process of phosphorylation are called kinases. A typical problem then is that due to a mutation a kinase is active all the time and not just when it should be. A switch which activates the signalling network is stuck in the ‘on’ position. This can in principal be changed by blocking the kinase so that it can no longer send its signals. An early and successful example of this is the kinase inhibitor imatinib which was developed as therapy for chronic myelogenous leukemia (CML). It seems that this drug can even cure CML in many cases, in the sense that after a time (two years) no mutated cells can be detected and the disease does not come back if the treatment is stopped. McMahon talks about this while being understandibly cautious about using the word cure in the context of any type of cancer. One general point about the ‘modern’ therapies is that they do not work for a wide range of cancers or even for the majority of patients with a given type of cancer. It is rather the case that cancer can be divided into more and more subtypes by analysing it with molecular methods and the therapy only works in a very specific class of patients, having a specific mutation. I have said something about another treatment using a kinase, Vemurafenib in a previous post. An unfortunate aspect of the therapies using kinase inhibitors is that while they provide spectacular short-term successes their effects often do not last more than a few months due to the development of resistance. A second mutation can rewire the network and overcome the blockade. (Might mathematical models be used to understand better which types of rewiring are relevant?) The picture of this I had, which now appears to me to be wrong, was that after a while on the drug a new mutation appears which gives the resistance. The picture I got from McMahon’s video was a different one. It seems that the mutations which might lead to resistance are often there before treatment begins. They were in Darwinian competition with other cells without the second mutation which were fitter. The treatment causes the fitness of the cells without the second mutation to decrease sharply. This removes the competition and allows the population of resistant cells to increase.

Another drug mentioned by McMahon is herceptin. This is used to treat breast cancer patients with a mutation in a particular receptor. The drug is an antibody and binds to the receptor. As far as I can see it is not known why the binding of the antibody has a therapeutic effect but there is one idea on this which I find attractive. This is that the antibodies attract immune cells which kill the cell carrying the mutation. This gives me a perfect transition to a discussion of a class of therapies which started to become successful and popular very recently and go under the name of cancer immunotherapy, since they are based on the idea of persuading immune cells to attack cancer cells. I have already discussed one way of doing this, using antibodies to increase the activities of T cells, in a previous post. Rather than saying more about that I want to go on to the topic of genetically modified T cells, which was also mentioned briefly here.

I do not know enough to be able to give a broad review of cellular immunotherapy for cancer treatment and so I will concentrate on making some comments based on a video on this subject by Stephan Grupp. He is talking about the therapy of acute lymphocytic leukemia (ALL). In particular he is concerned with B cell leukemia. The idea is to make artificial T cells which recognise the surface molecule CD19 characteristic of B cells. T cells are taken from the patient and modified to express a chimeric T cell receptor (CAR). The CAR is made of an external part coming from an antibody fused to an internal part including a CD3 \zeta-chain and a costimulatory molecule such as CD28. (Grupp prefers a different costimulatory molecule.) The cells are activated and caused to proliferate in vitro and then injected back into the patient. In many cases they are successful in killing the B cells of the patient and producing a lasting remission. It should be noted that most of the patients are small children and that most cases can be treated very effectively with classical chemotherapy. The children being treated with immunotherapy are the ‘worst cases’. The first patient treated by Grupp with this method was a seven year old girl and the treatment was finally very successful. Nevertheless it did at first almost kill her and this is not the only case. The problem was a cytokine release syndrome with extremely high levels of IL-6. Fortunately this was discovered just in time and she was treated with an antibody to IL-6 which not only existed but was approved for the treatment of children (with other diseases). It very quickly solved the problem. One issue which remains to be mentioned is that when the treatment is successful the T cells are so effective that the patient is left without B cells. Hence as long as the treatment continues immunoglobulin replacement therapy is necessary. Thus the issue arises whether this can be a final treatment or whether it should be seen a preparation for a bone marrow transplant. As a side issue from this story I wonder if modelling could bring some more insight for the IL-6 problem. Grupp uses some network language in talking about it, saying that the problem is a ‘simple feedback loop’. After I had written this I discovered a preprint on BioRxiv doing mathematical modelling of CAR T cell therapy of B-ALL and promising to do more in the future. It is an ODE model where there is no explicit inclusion of IL-6 but rather a generic inflammation variable.

In the beginning was the worm

September 29, 2016

In a previous post I mentioned the book by Andrew Brown whose title I have used here. I came across it in a second hand bookshop in Berkeley when I was spending time at MSRI in 2009. I read it with pleasure then and now I have read it again. It contains the story of how the worm Caenorhabditis elegans became an important model organism. This came about because Sydney Brenner deliberately searched for an organism with favourable properties and promoted it very effectively once he had found it. It is transparent so that it is possible to see what is going on inside it and it is easy to keep in the lab and reproduces fast enough in order to allow genetic research to be done rapidly. The organism sought was supposed to have a suitable sexual system. C. elegans is normally hermaphrodite but does also have males and so it is acceptable from that point of view. One further important fact about C. elegans is that it has a nervous system, albeit a relatively simple one. (More precisely, it has two nervous systems but I have not looked into the details of that issue.) Brenner was looking to understand how genetics determines behaviour and C. elegans gave him an opportunity to make an attack on this problem in two steps. First understand how to get from genes to neurons and then understand how to get from neurons to behaviour. C. elegans has a total of 302 neurons. It has 959 cells in total, not including eggs and sperm. Among the remarkable things known about the worm are the complete developmental history of each of its cells and the wiring diagram of its neurons. There are about 6400 synapses but the exact number, unlike the number of cells or neurons, is dependent on the individual. For orientation note that C. elegans is a eukaryotic organism (in contrast to phages or E. coli) which is multicellular (in contrast to Saccharomyces cerevisiae) and it is an animal (in contrast to Arabidopsis thaliana). Otherwise, among the class of model organisms, it is as simple and fast reproducing as possible. In particular it is simpler than Drosophila, which was traditionally the favourite multicellular model organism of the geneticists.

In this blog I have previously mentioned Sydney Brenner and expressed my admiration for him. I have twice met him personally when he was giving talks in Berlin and I have also watched a number of videos of him which are available on the web and read various texts he has written. In this way I have experienced a little of the magnetism which allowed him to inspire gifted and risk-taking young scientists to work on the worm. Brenner spent 20 years at the Laboratory of Molecular Biology in Cambridge, a large part of it as director of that organization. In the pioneering days of molecular biology the lab was producing Nobel prizes in series. He had to wait until 2002 for his own Nobel prize (for physiology or medicine), shared with John Sulston and Robert Horvitz. In his Nobel speech Brenner said that he felt there was a fourth prizewinner, C. elegans, which, however, did not get a share of the money. My other favourite quote from that speech is his description of the (then) present state of molecular biology, ‘drowning in a sea of data, starving for knowledge’. Since then that problem has only got worse.

Now I will collect some ‘firsts’ associated with C. elegans. It was the first multicellular organism to have its whole genome sequenced, in 1998. This can also be seen as the point of departure for the human genome project. Here the worm people overtook the drosophilists and the Drosophila genome was only finished in 2000. Sulston played a central role in the public project to sequence the human genome and the struggle with the commercial project of Craig Venter. It was only the link between the worm genome project and the human one which allowed enough money to be raised to finish the worm sequence. According to the book Sulston was more interested in the worm project since he wanted to properly finish what he had started. Martin Chalfie, coming from the worm community introduced GFP (green fluorescent protein) into molecular biology. He first expressed it in E. coli and C. elegans. He got a Nobel prize for that in 2008. microRNA (miRNA) was first found in C. elegans. It is the basis of RNA interference (RNAi), also first found in C. elegans. This earned a Nobel prize in 2006. The genetics of the process of apoptosis (programmed cell death) was understood by studying C. elegans. When Sulston was investigated the cell lineage he saw that certain cells had to die as part of the developmental process. Exactly 131 cells die during this process.

To conclude I mention a couple of features of C. elegans going beyond the time covered by the book. I asked myself what we can learn about the immune system from C. elegans. Presumably every living organism needs an immune system to survive in a hostile environment. The adaptive immune system in the form known in humans only exists in vertebrates and hence, in particular, not in the worm. Some related comments can be found here. It seems that C. elegans has no adaptive immune system at all but it does have innate immunity. It has cells called coelomocytes which have at least some resemblance to immune cells. It has six of them in total. Compare this with more than 10^9 immune cells per litre in our blood. C. elegans eats bacteria. These days the human gut flora is a fashionable topic. A couple of weeks ago I heard a talk by Giulia Enders, the author of the book ‘Darm mit Charme’ which sold a million copies in 2014. I had bought and read the book and found it interesting although I was not really enthusiastic about it. Now TV advertising includes products aimed at the gut flora of cats. So what about C. elegans? Does it have an interesting gut flora? The answer seems to be yes. See for instance the 2013 article ‘Worms need microbes too’ in EMBO Mol. Med. 5, 1300.

Models for photosynthesis, part 4

September 19, 2016

In previous posts in this series I introduced some models for the Calvin cycle of photosynthesis and mentioned some open questions concerning them. I have now written a paper where on the one hand I survey a number of mathematical models for the Calvin cycle and the relations between them and on the other hand I am able to provide answers to some of the open questions. One question was that of the definition of the Pettersson model. As I indicated previously this was not clear from the literature. My answer to the question is that this system should be treated as a system of DAE (differential-algebraic equations). In other words it can be written as a set of ODE \dot x=f(x,y) coupled to a set of algebraic equations g(x,y)=0. In general it is not clear that this type of system is locally well-posed. In other words, given a pair (x_0,y_0) with g(x_0,y_0)=0 it is not clear whether there is a solution (x(t),y(t)) of the system, local in time, with x(0)=x_0 and y(0)=y_0. Of course if the partial derivative of g with repect to y is invertible it follows by the implicit function theorem that g(x,y)=0 is locally equivalent to a relation y=h(x) and the original system is equivalent to \dot x=f(x,h(x)). Then local well-posedness is clear. The calculations in the 1988 paper of Pettersson and Ryde-Pettersson indicate that this should be true for the Pettersson model but there are details missing in the paper and I have not (yet) been able to supply these. The conservative strategy is then to stick to the DAE picture. Then we do not have a basis for studying the dynamics but at least we have a well-defined system of equations and it is meaningful to discuss its steady states.

I was able to prove that there are parameter values for which the Pettersson model has at least two distinct positive steady states. In doing this I was helped by an earlier (1987) paper of Pettersson and Ryde-Pettersson. The idea is to shut off the process of storage as starch so as to get a subnetwork. If two steady states can be obtained for this modified system we may be able to get steady states for the original system using the implicit function theorem. There are some more complications but the a key step in the proof is the one just described. So how do we get steady states for the modified system? The idea is to solve many of the equations explicitly so that the problem reduces to a single equation for one unknown, the concentration of DHAP. (When applying the implicit function theorem we have to use a system of two equations for two unknowns.) In the end we are left with a quadratic equation and we can arrange for the coefficients in that equation to have convenient properties by choosing the parameters in the dynamical system suitably. This approach can be put in a wider context using the concept of stoichiometric generators but the proof is not logically dependent on using the theory of those objects.

Having got some information about the Pettersson model we may ask what happens when we go over to the Poolman model. The Poolman model is a system of ODE from the start and so we do not have any conceptual problems in that case. The method of construction of steady states can be adapted rather easily so as to apply to the system of DAE related to the Poolman model (let us call it the reduced Poolman model since it can be expressed as a singular limit of the Poolman model). The result is that there are parameter values for which the reduced Poolman model has at least three steady states. Whether the Poolman model itself can have three steady states is not yet clear since it is not clear whether the transverse eigenvalues (in the sense of GSPT) are all non-zero.

By analogy with known facts the following intuitive picture can be developed. Note, however, that this intuition has not yet been confirmed by proofs. In the picture one of the positive steady states of the Pettersson model is stable and the other unstable. Steady states on the boundary where some concentrations are zero are stable. Under the perturbation from the Pettersson model to the reduced Poolman model an additional stable positive steady state bifurcates from the boundary and joins the other two. This picture may be an oversimplification but I hope that it contains some grain of truth.

A visit to Iceland

September 4, 2016

I just returned from 10 days as a tourist in Iceland. It was not my first time there. Years ago I went on a cruise which included two stops in Iceland, one in Reykjavik and one in Akureyri. In each case there was a short bus tour to see some typical sights – a waterfall, a geysir and a volcanic region with bubbling mud and hot springs. This time I had a chance to see a lot more. I enjoyed the cruise a lot but I had the impression that the majority of the people on the ship were very bored. The main antidote to the boredom offered was lots of food. One day I got up from the dinner table and went on deck. There had been no indication that there might be something interesting to see. When I opened the door I was confronted with a beautifully conical volcano covered with ice, Snaefellsjökull. (I will come back to the interesting issue of Icelandic pronuciation later.) This was one of my strongest impressions from the whole cruise. The volcano is at the end of a long peninsula to the north of Reykjavik. This time I learned that this volcano is the esoteric centre of Iceland and that it was the starting point of Jules Verne’s Journey to the Centre of the Earth. This was not really a point on the programme of the tour this time but it was clearly visible with binoculars from the hotel in Rekjavik where we spent the last two nights. I had one view of it which was monochrome due to the light conditions but where the sharp edges of the crater stood our clearly.

One attraction of Iceland for me was the bird life. It seems that the country has claimed exclusive rights on the puffin. The numerous tourist shops in Reykjavik are called ‘puffin shops’ due to the number of representations of that bird they sell. I also saw puffin offered as one of the constituents of a special menu also including whale and horse meat. We spent one night in Vik and I discovered two stranded fulmars on a grass area not far from the hotel. These birds can only take off from an elevated starting point like a cliff or from water. If one lands on a flat area some distance from the sea then it is doomed unless it gets help. I rescued two of them by carrying them (ten minutes walk including crossing a road with significant traffic) to the sea. Since there had not been a big storm I suppose they had come down during their first flight after leaving the nest. (There were fulmars nesting on inland cliffs on the other side of the hotel from the sea.) Fortunately I still knew how to catch them and pick them up without hurting them or being the victim of their defence mechanism of spitting foul-smelling oil when feeling threatened. I enjoyed seeing a few glaucous gulls in the harbour in Reykjavik on the last day. Probably the last time I saw any was on the cruise I already mentioned. It was also nice to see and hear many whimbrels. The first one already welcomed me at the airport when I arrived.

I felt at home in the natural surroundings in Iceland and after a few days I thought of one explanation. There are very few trees in Iceland and this is just as it is in Orkney where I grew up. The first time I was on the mainland of Scotland when I was four years old I said ‘I don’t like this place – you can’t see anything for trees’. There are many areas in Iceland where there is only sand, rocks, water and ice. I had the impression of seeing what the Earth is really like, without the veil of green which we usually see. I also got an impression of what it is really like to live next to a volcano. I was in a museum close to (and devoted to) Eyafjallajökull, the infamous producer of ash with the complicated name. I learned that one US journalist just called it E15, due to the number of letters. There was a film showing in the museum explaining what people living near the volcano experienced at the time of the last eruption. Coming back to the name, the pronunciation of Icelandic does seems to be a difficult question but also an interesting one. I would like to spend some time understanding it better. There are nice videos on the pronuciation of Eyafjallajökull here and here. The final double l is the really tricky point. There are points of similarity between the Icelandic language and the dialect I grew up with. This is due to the influence of an extinct language called Norn which was spoken on Orkney and Shetland in past centuries and which is related to (Old) Icelandic. For instance the oystercatcher is called tjaldur in Icelandic and chaldro in our dialect.

I also had some culinary experiences. At breakfast in the hotels there was always a bottle of cod liver oil on the table. I remember this liquid from my childhood as a threat used on young children. ‘If you do not behave yourself I will give you a spoonfull of cod liver oil.’ Due to persistent encouragement from Eva I tried a little and found it not as bad as I expected. Our guide also gave us some pieces of Greenland shark to try. He gave  us a warning about the taste and some of the alcholic drink called the black death to wash it down with. It tastes of nothing at first but chewing leads to a strong taste reminiscent of urine. In fact the flesh of the shark is poisonous due to its content of trimethylamine N-oxide. In Iceland it is treated by first burying it for several weeks and then drying it to get rid of the poison. The result is considered a delicacy. The Greenland shark is interesting because of the fact that it was recently discovered that it can live to be four hundred years old, only becoming sexually mature when it is 150. I want to read more about it.

As a final comment on Iceland: the weather was much better than we expected!

ECMTB 2016 in Nottingham

July 17, 2016

This past week I attended a conference of the ESMTB and the SMB in Nottingham. My accomodation was in a hall of residence on the campus and my plan was to take a tram from the train station. When I arrived it turned out that the trams were not running. I did not find out the exact reason but it seemed that it was a problem which would not be solved quickly. Instead of finding out what bus I should take and where I should take it from I checked out the possibility of walking. As it turned out it was neither unreasonably far nor complicated. Thus, following my vocation as pedestrian, I walked there.

Among the plenary talks at the conference was one by Hisashi Ohtsuki on the evolution of social norms. Although I am a great believer in the application of mathematics to many real world problems I do become a bit sceptical when the area of application goes in the direction of sociology or psychology. Accordingly I went to the talk with rather negative expectations but I was pleasantly surprised. The speaker explained how he has been able to apply evolutionary game theory to obtain insights into the evolution of cooperation in human societies under the influence of indirect reciprocity. This means that instead of the simple direct pattern ‘A helps B and thus motivates B to help A’ we have ‘C sees A helping B and hence decides to help A’ and variations on that pattern. The central idea of the work is to compare many different strategies in the context of a mathematical model and thus obtain ideas about what are the important mechanisms at work. My impression was that this is a case where mathematics has generated helpful ideas in understanding the phenomenon and that there remain a lot of interesting things to be done in that direction. It also made me reflect on my own personal strategies when interacting with other people. Apart from the interesting content the talk was also made more interesting by the speaker’s entertaining accounts of experiments which have been done to compare with the results of the modelling. During the talk the speaker mentioned self-referentially that the fact of his standing in front of us giving the talk was an example of the process of the formation of a reputation being described in the talk. As far as I am concerned he succeeded in creating a positive reputation both for himself and for his field.

Apart from this the other plenary talk which I found most interesting was by Johan van de Koppel. He was talking about pattern formation in ecology and, in particular, about his own work on pattern formation in mussel beds. A talk which I liked much less was that of Adelia Sequeira and it is perhaps interesting to ask why. She was talking about modelling of atherosclerosis. She made the valid point near the beginning of her lecture that while heart disease is a health problem of comparable importance to cancer in the developed world the latter theme was represented much more strongly than the former at the conference. For me cancer is simply much more interesting than heart disease and this point of view is maybe more widespread. What could be the reason? One possibility is that the study of cancer involves many more conceptual aspects than that of heart disease and that this is attractive for mathematicians. Another could be that I am a lot more afraid of being diagnosed with cancer some day than of being diagnosed with heart disease although the latter may be no less probable and not less deadly if it happens. To come back to the talk I found that the material was too abundant and too technical and that many ideas were used without really being introduced. The consequence of these factors was that I lost interest and had difficulty not falling asleep.

In the case of the parallel talks there were seventeen sessions in parallel and I generally decided to go to whole sessions rather than trying to go to individual talks. I will make some remarks about some of the things I heard there. I found the first session I went to, on tumour-immune dynamics, rather disappointing but the last talk in the session, by Shalla Hanson was a notable exception. The subject was CAR T-cells and what mathematical modelling might contribute to improving therapy. I found both the content and the presentation excellent. The presentation packed in a lot of material but rather than being overwhelmed I found myself waiting eagerly for what would come next. During the talk I thought of a couple of questions which I might ask at the end but they were answered in due course during the lecture. It is a quality I admire in a speaker to be able to anticipate the questions which the audience may ask and answer them. I see this less as a matter of understanding the psychology of the audience (which can sometimes be important) and rather of really having got to the heart of the subject being described. There was a session on mathematical pharmacology which I found interesting, in particular the talks of Tom Snowden on systems pharmacology and that of Wilhelm Huisinga on multidrug therapies for HIV. In a session on mathematical and systems immunology Grant Lythe discussed the fascinating question of how to estimate the number of T cell clones in the body and what mathematics can contribute to this beyond just analysing the data statistically. I enjoyed the session on virus dynamics, particularly a talk by Harel Dahari on hepatitis C. In particular he told a story in which he was involved in curing one exceptional HCV patient with a one-off therapy using a substance called silibinin and real-time mathematical modelling.

I myself gave a talk about dinosaurs. Since this is work which is at a relatively early stage I will leave describing more details of it in this blog to a later date.

An eternal pedestrian

June 13, 2016

I am presently visiting Japan. My host is Atsushi Mochizuki who leads the Theoretical Biology Laboratory at RIKEN in Wako near Tokyo. RIKEN is a research organisation which was founded in 1917 using the Kaiser-Wilhelm-Gesellschaft as a model. Thus it is a kind of Japanese analogue of the Max Planck Society which is the direct descendant of the Kaiser-Wilhelm-Gesellschaft. I had only been in Japan once before and looking at my records I see that that was in August 2005. At that time I attended a conference in Sendai, a place which I had never heard of before I went there. Since then it has become sadly famous in connection with the damage it suffered from the tsunami which also caused the Fukushima nuclear disaster. At least I had even then previously heard of Tohoku University which is located in the city.

Yesterday, sitting by the river in Wako, I was feeling quite meditative. I was in an area where motor vehicles are not permitted. There were not many people around but most of those who were there were on bikes. I started thinking of how this is typical of what I have experienced in many places I have been. On a walk along the Rhine in Mainz or in the surrounding countryside most of the people you see are on bikes. Copenhagen is completely dominated by bikes. In the US cars dominate. For instance when I was in Miami for a conference and was staying at the Biltmore Hotel I had to walk quite a distance to get dinner for an affordable price. In general the only people I met walking on the streets there were other conference participants. When I visited the University of California at Santa Barbara bikes were not the thing on the campus but it was typical to see students with skateboards. Summing up, I have frequently had the experience that as a pedestrian I was an exception. It seems that for normal people just putting one foot in front of the other is not the thing to do. They need some device such as a car, a bike or a skateboard to accompany them. I, on the other hand, am an eternal pedestrian. I like to walk places whenever I can. I walk twenty minutes to work each day and twenty minutes back. I find that a good way of framing the day. When I lived in Berlin there was a long period when I had a one-way travelling time of 90 minutes by train. I am glad to have that behind me. I did not consciously plan being so near to work in Mainz but I am glad it happened. Of course being a pedestrian has its limits – I could not have come to Japan on foot.

My pedestrian nature is not limited to the literal interpretation of the term. I am also an intellectual pedestrian. An example of this is described in my post on low throughput biology. Interestingly this post has got a lot of hits, more than twice as many as any other post on my blog. This is related to the theme of simple and complex models in biology. Through the talks I have given recently in Copenhagen, Berlin and here in Japan and resulting discussions with different people I have become of conscious of how this is a recurring theme in those parts of mathematical biology which I find interesting. The pedestrian may not get as far as others but he often sees more in the places he does reach. He may also get to places that others do not. Travelling fast along the road may cause you to overlook a valuable shortcut. Or you may go a long way in the wrong direction and need a lot of time to come back. Within mathematics one aspect of being a pedestrian is calculating things by hand as far as possible and using computers as a last resort. This reminds me of a story about the physicist John Wheeler who had a picture of a computer on the wall in his office which he called ‘the big computer’. When he wanted to solve a difficult problem he would think about how he would programme it on the computer and when he had done that thoroughly he had understood the problem so well that he no longer needed the computer. Thus the fact that the computer did not exist except on paper was not a disadvantage.

This is the direction I want to (continue to) go. The challenges along the road are to achieve something essential and to make clear to others, who may be sceptical, that I have done so.

Hepatitis C

May 29, 2016

I once previously wrote something about hepatitis C in this blog which was directed to the mathematical modelling aspects. Here I want to write about the disease itself. This has been stimulated by talks I heard at a meeting of the Mainzer Medizinische Gesellschaft. The speakers were Ralf Bartenschlager from Heidelberg and and Stefan Zeuzem from Frankfurt. The first speaker is a molecular biologist who has made important contributions to the understanding of the structure and life cycle of the virus. For this work he got the 2015 Robert Koch prize together with Charles Rice from the Rockefeller University. The second speaker is a clinician.

Hepatitis C is transmitted by blood to blood contact. According to Zeuzem the main cause of the spread of this disease in developed countries is intravenous drug use. Before there was a test for the disease it was also spread via blood transfusions. (At one time the risk of infection with hepatitis due to a blood transfusion was 30%. This was mainly hepatitis B and by the time of discovery of hepatitis C, when the risk from hepatitis B had essentially been eliminated, it had dropped to 5%.) He also mentioned that there is a very high rate of infection in certain parts of Egypt due to the use of unsterilized needles in the treatment of other diseases. Someone asked how the disease could have survived before there were injections. He did not give a definitive answer but he did mention that while heterosexual contacts generally carry little risk of infection with this virus homosexual contacts between men do carry a significant risk. The disease typically becomes chronic and has few if any symptoms for many years. It does have dramatic long-term effects, namely cirrhosis and cancer of the liver. He showed statistics illustrating how public health policies have influenced the spread of the disease in different countries. The development in France has been much more favourable (with less cases) than in Germany, apparently due to a publicity campaign as a result of political motives with no direct relevance to the disease. The development in the UK has been much less favourable than it has even in Germany due an almost complete lack of publicity on the theme for a long time. The estimated number of people infected in Germany is 500000. The global number is estimated as 170 million.

There has been a dramatic improvement in the treatment of hepatitis C in the past couple of years and this was the central theme of the talks. A few years ago the situation was as follows. Drugs (a combination of ribavirin and interferon \alpha) could be used to eliminate the virus in a significant percentage of patients, particularly for some of the sub-types of the virus. The treatment lasted about a year and was accompanied by side effects that were so severe that there was a serious risk of patients breaking it off. Now the treatment only lasts a few weeks, it cures at least 95% of the patients and in many situations 99% of them. The side effects of the new treatments are moderate. There is just one problem remaining: the drugs for the best available treatment are sold for extremely high prices. The order of magnitude is 100000 euros for a treatment. Zeuzem explained various aspects of the dynamics which has led to these prices and the circumstances under which they might be reduced in the future. In general this gave a rather depressing picture of the politics of health care relating to the approval and prescription of new drugs.

Let me get back to the scientific aspects of the theme, as explained by Bartenschlager. A obvious question to ask is: if hepatitis C can essentially be cured why does HIV remain essentially incurable despite the huge amount of effort and money spent on trying to find a treatment? The simple answer seems to be that HIV can hide while HCV cannot. Both these viruses have an RNA genome. Since the copying of RNA is relatively imprecise they both have a high mutation rate. This leads to a high potential for the development of drug resistance. This problem has nevertheless been overcome for HCV. Virus particles are continually being destroyed by the immune system and for the population to survive new virus particles must be produced in huge numbers. This is done by the liver cells. This heavy burden kills the liver cells after a while but the liver is capable of regenerating, i.e, replacing these cells. The liver has an impressive capability to survive this attack but every system has its limits and eventually, after twenty or thirty years, the long-term effects already mentioned develop. An essential difference between HIV and HCV is that the RNA of HCV can be directly read by ribosomes to produce viral proteins. By contrast, the RNA of HIV is used as a template to produce DNA by the enzyme reverse transcriptase and this DNA is integrated into the DNA of the cell. This integrated DNA (known as the provirus) may remain inactive, not leading to production of protein. As long as this is the case the virus is invisible to the immune system. This is one way the virus can hide. Moreover the cell can divide producing new cells also containing the provirus. There is also another problem. The main target of HIV are the T-helper cells. However the virus can also infect other cells such as macrophages or dendritic cells and the behaviour of the virus in these other cells is different from that in T-helper cells. It is natural that a treatment should be optimized for what happens in the typical host cell and this may be much less effective in the other cell types. This means that the other cells may serve as a reservoir for the virus in situations where the population is under heavy pressure from the immune system or drug treatment. This is a second sense in which the virus can hide.

Some of the recent drugs used to treat HCV are based on ideas developed for the treatment of HIV. For instance a drug of this kind may inhibit certain of the enzymes required for the reproduction of the virus. There is one highly effective drug in the case of HCV which works in a different way. The hepatitis C virus produces one protein which has no enzymatic activity and it is at first sight hard to see what use this could be for the virus. What it in fact does is to act as a kind of docking station which organizes proteins belonging to the cell into a factory for virus production.

The hepatitis C virus is a valuable example which illustrates the relations between various aspects of medical progress: improvement in scientific understanding, exploitation of that information for drug design, political problems encountered in getting an effective drug to the patients who need it. Despite the negative features which have been mentioned it is the subject of a remarkable success story.