‘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.

Harald zur Hausen and the human papilloma virus

September 27, 2014

I just finished reading the autobiography ‘Gegen Krebs’ [Against Cancer] by Harald zur Hausen. I am not aware that this book has been translated into English. Perhaps it should rather be called a semi-autobiography since zur Hausen wrote it together with the journalist Katja Reuter. If I had made scientific discoveries as important as those of zur Hausen, and if I decided to write a book about it, the last thing I would do would be to write it with someone else. He made a different choice and the book also includes reminiscences by colleagues, even by some with whom he had controversies and who have a very different view of what happened. I have the impression that the amount of material on conflicts with colleagues is rather large compared to the amount of science. I think that many successful scientists tend to selectively forget the conflicts, even if these have taken place, and concentrate more on the substance of their work. Thus I ask myself if this slant in the book comes directly from zur Hausen, or if it comes from his coauthor, or if he himself really tended to get into conflicts more often than other comparable figures. In any case, this aspect tended to make me enjoy the book less than, for instance, the book of Blumberg I read recently.

Let me now come to the central theme of the book. Harald zur Hausen discovered that a type of viruses causing warts, the human papilloma virus (HPV), also cause the majority of cases of cervical cancer. He was also involved in the development of the vaccine against these viruses which can be seen as the second major cancer vaccine, following the vaccine against hepatitis B. For this work he got a Nobel prize in 2008. He pursued the idea that this class of viruses could cause cervical cancer single-mindedly for a long time while few people believed it could be true. The picture in the book is that while there were a number of people thinking about a viral cause for the disease they were fixated either on herpes viruses or retroviruses. Herpes viruses were popular in this context because the first human virus known to be associated with cancer was the Epstein-Barr virus (EBV) related to Burkitt’s lymphoma and EBV is a herpes virus. Early in his career zur Hausen worked in the laboratory of Werner and Gertrude Henle in Philadelphia. I studied (among other things) zoology in my first year at university and part of that, which appealed to me, was learning about anatomical structures and their names. From that time I remember the ‘loop of Henle’, a structure in the kidney. The Henle of the loop, Jakob Henle, was the grandfather of Werner. As I learned from a footnote in Blumberg’s book, the elder Henle was also the mentor of Robert Koch. Incidentally, Blumberg worked in Philadelphia starting in 1964 while zur Hausen went there in 1966. I did not notice any personal cross references between the two men in their books.

It seems that Gertrude Henle ruled with a strong hand. Once when a laboratory technician was ill for a few days she put on so much pressure that the young woman came into the lab one day just to show how ill she was. She did look convincingly ill and while she was there a blood sample was taken. This turned out to be a stroke of luck. Everyone in the lab had been tested for EBV as part of the research being done there and the technician was one of the few who had tested negative. After her illness she tested positive. In this way it was discovered that glandular fever, the illness she had, is caused by EBV. At that point it is natural to ask why EBV causes a relatively harmless disease in developed countries and cancer in parts of Africa. I have not gone into the background of this but I read that the areas where Burkitt’s lymphoma occurs tend to coincide with areas where malaria is endemic, suggesting a possible connection between the two.

One of the key insights which led to progress in the research on HPV was the recognition that this was not just one virus but a large family of related viruses. Those which turned out to be the biggest cause of cervical cancer are numbers 16 and 18. (After some initial arguments the viruses were named in the order of their discovery.) To obtain this insight it was necessary to have sufficiently good techniques for analysing DNA. The book gives a clear idea of how the progress in understanding in this field was intimately linked to the development of new techniques in molecular biology.

When zur Hausen won the Nobel prize it seemed that the German press and parts of the medical establishment had nothing better to do than to attack him, instead of celebrating his success. From the beginning it was suggested that he only got the prize because a member of the prize committee was on the board of one of the companies producing the vaccine and so would have a personal advantage from the publicity. It was also suggested that the vaccine was ineffective and/or dangerous. (The latter point actually led to a decrease in the number of people getting vaccinated and so, presumably, will mean that in the future many women will get a cancer that could have been prevented.) I do not believe that there was any justification for any of the criticism. So why did it happen? The explanation which occurs to me is the (latent or openly expressed) negative attitudes to science and technology which seem rather widespread in the German press and in German society. I find this surprising for a country which has contributed so much to science and technology and derives so much economic benefit from it.

After finishing the book I decided to try to get a small personal impression of Harald zur Hausen by watching the video of his Nobel lecture. It is untypical for such a lecture in that it contains relatively little about the work the prize was given for and instead concentrates on future research directions. According to the book zur Hausen’s co-laureate Luc Montagnier was suprised by that. The subject is zur Hausen’s lasting theme, the relation between infection and cancer. I found a lot of interesting ideas in it which were new to me. I mention just one. It is well known that there are statistics relating to a possible increase in the incidence of leukemia near nuclear power plants. Whether or not you find this data a convincing argument that there is an increased incidence it is fairly certain that you will link the increase in leukemia in this case (if any) to the effects of radiation. I was no exception to the tendency to make this connection. In his talk zur Hausen says that there are similar statistics showing an increase in leukemia near oil drilling platforms. So how does that fit together? If you cannot think of an answer and you would like to know then watch the video!

My connection to literature

September 23, 2014

When I was at school I had mixed feelings about the English class. One of the things we had to do was to write essays, which was enjoyable for me. Another was to study Shakespeare plays and I got nothing positive out of that. The teacher once asked in class who did not like Shakespeare. I was the one who was brave enough to stand up and say that I did not like it. I am sure I was not the only one who thought so. More generally I had no interest in ‘literature’. The person I have to thank for changing that is Vivia Leslie, my English teacher in my last year at school. In that year each of us was supposed to choose an author and read some of their books and write about them. At that time my main fictional reading was science fiction and so I wanted to choose a writer of that kind, such as Isaac Asimov. Mrs Leslie was rightly not prepared to allow that and in the end the compromise we found was Aldous Huxley. After all, ‘Brave New World’ is a kind of science fiction. When I then came to read other novels of Huxley it was strange at first and difficult to appreciate. With time this changed and Huxley became the first ‘serious author’ who I liked. In the following years I read more or less all of his novels and became a fan. One thing led to another and at the end of my time in school I was reading a lot of classical literature. When I went to university I had much better access to books and I spent a lot of my time reading the classics.

The one modern foreign language I studied at school was French and I liked that a lot. The system was that at the age of sixteen everyone chose between sciences and languages. I could not give up science and so I had to give up French after four years. At least officially. In my fifth and last year of secondary school I used to spend my lunch breaks with two girls, Ingrid and Joy, who were still studying French. Since I had been relatively far advanced I could help them with their homework and this naturally caused me to continue learning some more French. Apart from an intrinsic appreciation for the beauty of the French language which I already had then the association with spending time with two attractive girls certainly increased my interest further. After I went to university I started reading French literature and getting more and more into that. The culmination of this was ‘A la recherche du temps perdu’ and since then Proust has always been the author I appreciate most. Over the years I read the whole novel twice and parts of it more often. I would like to read it again but at some time (a long time ago now) I decided to put that off until my retirement.

At university I was a member of the Creative Writing Group. I wrote some poetry and short pieces of prose but nothing has remained of that. It was a chance to meet interesting people. For certain periods Bernard MacLaverty was writer in residence and part of the duties associated with that was to take part in the Creative Writing Group and give the students advice. I remember him arriving to meet us for the first time with a bottle of Scotch whisky as a present. Among the members of the group were Alison Smith and Alison Lumsden (commonly referred to by us as Ali Smith and Ali Lum). I recently saw that Alison Lumsden has gone back to Aberdeen University (where we studied) as professor of English. As for Ali Smith, she was clearly the most talented writer in the group and later she became a successful novelist. I last saw her quite a few years ago at a reading she gave in Berlin. Perhaps I will write something about my impressions of her novels in a later post. I recently remembered a story associated to another member of the group, Colin Donati. I was once visiting him in his flat in Aberdeen and I found a single loose page of a novel lying on the floor. Of course I was curious to read it and see if I could identify the author. It was not something I had read before but I thought I recognized the style as that of one of my favourite authors. Despite that I would not have been certain if it had not been for one specific subject mentioned on the page which appeared to me conclusive: rooks. These birds occur in several places in the writings of Virginia Woolf (the errant page was from her novel ‘Jacob’s room’), notably in ‘To the Lighthouse’. At the moment I am living in a small furnished flat until our house is built and the final move to Mainz can take place. Near that flat there is a roost of Jackdaws and Rooks and I enjoy hearing them through the open window in the evenings. It occurres to me that I will probably miss those pleasant companions when I move to the house.

These days I do not find much time for reading novels. The last one I can remember reading which I really liked is ‘Ungeduld des Herzens’ by Stefan Zweig. That was about a year ago. Perhaps I should take some time again for reading beyond the confines of science.

The existence proof for Hopf bifurcations

September 22, 2014

In a Hopf bifurcation a pair of complex conjugate eigenvalues of the linearization of a dynamical system \dot x=f(x,\alpha) at a stationary point pass through the imaginary axis. This has been discussed in a previous post. Often textbook results (e.g. Theorem 3.3 in Kuznetsov’s book) concentrate on the generic case where two additional conditions are satisfied. One of these is that the first Lyapunov coefficient is non-vanishing. The other is that the eigenvalues pass through the imaginary axis with non-zero velocity. The existence of periodic solutions can be obtained if only the second of these conditions are satisfied. This was already included in the original paper of Hopf in 1942. Hopf states his results only in the case of analytic systems but this should perhaps be seen as a historical accident. A similar result holds with mucher weaker regularity assumptions. It is proved under the assumption of C^2 dependence on x and C^1 dependence on \alpha in Hale’s book on ordinary differential equations. This has consequences for the case where the second genericity assumption is not satisfied. Let \lambda be an eigenvalue which passes through the imaginary axis for \alpha=0 and suppose that the derivatives of {{\rm Re}\lambda} with respect to \alpha vanish up to order 2k for an integer k but that the derivative of order 2k+1 does not vanish. Then it is possible to replace \alpha by \alpha^{2k+1} as parameter and after this change the second genericity assumption is satisfied. Even if the original right hand side was analytic in \alpha the transformed right hand side is in general not C^2. It is, however, C^1 and so the version of the theorem in Hale’s book applies to give the existence of periodic solutions. This theorem applies to a two-dimensional system but it then also evidently applies in general by a centre manifold reduction.

The theorem is proved as follows. The problem is transformed to polar coordinates (\rho,\theta) and then \rho is written as a function of \theta. In this way a non-autonomous scalar equation with 2\pi-periodic coefficients is obtained and the aim is to find a 2\pi-periodic solution. The first step is to reformulate the task as a fixed-point problem with the property that if a fixed point is periodic it will be a solution of the original problem. Then it is shown using the Banach fixed point theorem(in a minor variant of the local existence theorem for ODE using Picard iteration) that there always exists a fixed point depending on a certain new parameter. This fixed point is only periodic if the result of substituting it into the right hand side of the original equation has mean value zero. This condition can be written as G(\alpha,a)=0. Applying the implicit function theorem to G shows the existence of a solution of G(\alpha(a),a)=0 for a small. This completes the proof.

Summing up, there are two types of theorem about Hopf bifurcation, a ‘coarse’ theorem of the type just sketched with weak hypotheses and a weak but still very interesting conclusion and a ‘fine’ theorem which gives stronger conclusions but needs a stronger hypothesis (non-vanishing of the Lyapunov coefficient and its sign). In his original paper Hopf proved both types. Are there also ‘rough’ versions of theorems about other bifurcations?

SIAM Conference on the Life Sciences in Charlotte

August 7, 2014

This week I have been attending the SIAM Conference on the Life Sciences in Charlotte. Here I want to mention some highlights from my personal point of view. First I will mention some of the plenary talks. John Rinzel talked about mathematical modelling of certain perceptual phenomena. We are all familiar with the face-vase picture which switches repeatedly between two forms. I had never considered the question of trying to predict how often the picture switches. Rinzel presented models for this and for other related auditory phenomena which he demonstrated in the lecture. I find it remarkable that such apparently subjective phenomena can be brought into such close connection with precise mathematical models. Kristin Swanson talked about her work on modelling the brain cancer known as glioma and its various deadly forms. I had heard her talk on the same theme at the meeting of the Society for Mathematical Biology in Dundee in 2003. Of course there has been a lot of progress since then. This was long before I started this blog but if the blog had existed I would certainly have written about the topic. I will not try to resurrect the old stories from that distant epoch. Instead I will just say that Kristin is heavily involved in using computer simulations to optimize the treatment (surgery, radiotherapy, chemotherapy) of individual patients. One of the main points in her talk this week is that it seems to be possible to divide patients into two broad categories (with nodular or diffuse growth of the tumour) and that this alone may have important implications for therapeutic decisions. Oliver Jensen talked about a multiscale model for predicting plant growth, for instance the way in which a root manages to sense gravity and move downwards. This involves some very sophisticated continuum mechanics which the speaker illustrated by everyday examples in a very effective and sometimes humorous way. The talk was both impressive and entertaining. Norman Mazer talked about the different kinds of cholesterol (LDL, HDL etc.). According to what he said lowering LDL levels is an effective means for avoiding risks of cardiovascular illness but the alternative strategy of raising HDL levels has not been successful. He explained how mathematical modelling can throw light on this phenomenon. My understanding is that the link between high HDL level and lower cardiovascular risks is a correlation and not a sign of a causal influence of HDL level on risk factors. The last talk was by James Collins, a pioneer of synthetic biology. The talk was full of good material, both mathematical and non-mathematical. Maybe I should invest some time into learning about that field.

There was one very interesting subject which was not the subject of a talk at the conference (at least not of one I heard – it was briefly referred to in the talk of Collins mentioned above) but was a subject of conversation. It is a paper called ‘Paradoxical Results in Perturbation-Based Signaling Network Reconstruction’ by Sudhakaran Prabakaran, Jeremy Gunawardena and Eduardo Sontag which appeared in Biophys. J. 106, 2720. It suggests that the ways in which biologists deduce the influence of substances on each other on the basis of experiments are quite problematic. The mathematical content of the paper is rather elementary but its consequences for the way in which theoretical ideas are applied in biology may be considerable. The system studied in the paper is an in vitro reconstruction of part of the MAP kinase cascade and so not so far from some of my research.

Among the parallel sessions those which were most relevant for me were one entitled ‘Algebra in the Life Sciences’ and organized by Elisenda Feliu, Nicolette Meshkat and Carsten Wiuf and one called ‘Developments in the Mathematics of Biochemical Reaction Networks’ organized by Casian Pantea and Maya Mincheva. My talk was in the second of these. These sessions were very valuable for me since they allowed me to meet a considerable number of people working in areas close to my own research interests, including several whose papers were well known to me but whom I had never met. I think that this will bring me to a new level in my work in mathematical biology due to the various interactions which took place. I will not discuss the contents of individual talks here. It is rather the case that what I learned form them will flow into my research effort and hence indirectly influence future posts in this blog. I feel that this conference has gained me entrance into a (for me) new research community which could be the natural habitat for my future research. I am very happy about that. The whole conference was an enjoyable and stimulating experience for me. I noticed no jet lag at all but I must be suffering from a lack of sleep due to the fact that the many things going on here just did not leave me the eight hours of sleep per night I am used to.

 

 

Baruch Blumberg and Hepatitis B

August 6, 2014

This year, at my own suggestion, I got the book ‘Hepatitis B. The hunt for a killer virus.’ by Baruch Blumberg as a birthday present. Blumberg was the central figure in the discovery of the hepatitis B virus and was rewarded for his achievements by a Nobel prize in 1976. The principal content of the book is an account of the story leading up to the discovery. In fact the subtitle is a bit misleading since Blumberg was not hunting for a virus when he started the research which eventually led to it being found. He was interested in polymorphisms, differences in humans (and animals) which lead them to have different susceptibilities to certain diseases. Nowadays this would be done by comparing genes but at that time, before the modern developments in molecular biology, it was necessary to compare proteins. This was done by observing that antibodies in the blood of some individuals reacted with proteins in the blood of others. This is a mild version of what happens when someone gets a transfusion with an incompatible blood group.

Blumberg did a lot of work with blood coming from people living in unusual or extreme conditions. For this he travelled to exotic places such as Suriname, northern Alaska and remote parts of Nigeria. He seems to have had a great appetite for exciting travel and a corresponding dose of courage. He has plenty of adventures to relate. The second protein he found he names the ‘Australia antigen’ since it was common among aborigines. A good source of antibodies was the blood of people who had had many blood transfusions since their immune systems had been confronted with many antigens. In particular they often carried the Australia antigen.

Pursuing the nature of the Australia antigen led  to the realization that it was part of the hepatitis B virus, a virus which causes liver disease and can be spread by blood contact, in particular blood transfusions. The transfusion recipients had become infected with hepatitis B and had produced antibodies to it. Hepatitis B was the first hepatitis virus to be discovered and so why is it labelled ‘B’? In fact people had noticed cases of hepatitis after tranfusions and suspected two viruses, ‘A’ transmitted by contaminated food or water and ‘B’ transmitted by blood contact. There were researchers who had been ‘hunting’ intensively for these viruses and many of them were understandibly not happy when an outsider beat them to it.

For many years Blumberg worked at the Fox Chase Cancer Center in Philadelphia. It was generously funded and the fact that his research had little obvious relation to cancer was not a problem. Once the director of the institute warned that a serious funding cut might be coming. This led Blumberg and colleagues to the idea of developing a vaccine against hepatitis B as a way of making money. Just as Blumberg had not been a virologist when he discovered the virus he was not an expert on vaccines when he developed the vaccine. At that time the need for a vaccine did not seem so urgent since hepatitis B was known as an acute disease which was rarely life-threatening. Later the vaccine acquired a very different significance. There are very many chronic carriers (hundreds of millions worldwide) and a significant proportion of these develop liver cancer after many years. Thus, surprisingly, the hepatitis B vaccine has attained the status of an ‘anti-cancer vaccine’ and has had a huge medical impact.

This book has a very different flavour from the book of Francois Jacob I wrote about in a previous post. Blumberg gives the impression of being a highly cultured person but more than that of an adventurer and man of action. (Along the way he was Master of Balliol College Oxford and director of the NASA Astrobiology Institute.) Jacob also had enough adventures but appears to belong to a more intellectual type, concentrating more on his inner life. In his book Blumberg does not reveal too much which is really personal and always maintains a certain distance to the reader.

 

 

Breaking waves in Madrid

July 19, 2014

Last week I was at the 10th AIMS Conference on Dynamical Systems, Differential Equations and Applications in Madrid. It was very large, with more than 2700 participants and countless parallel sessions. This kind of situation necessarily generates a somewhat hectic atmosphere and I do not really like going to that type of conference. I have heard the same thing from many other paople. There is nevertheless an advantage, namely the possibility of meeting many people. To do this effectively it is necessary to proceed systematically since it is easy to go for days without seeing a particular person of interest. This aspect was of particular importance for me since I am still at a relatively early stage in the process of entering the field of mathematical biology and I have few contacts there in comparison to my old field of mathematical relativity. In any case, the conference allowed me to meet a lot of interesting people and learn a lot of interesting things.

The first plenary talk, by Charles Fefferman, was on a subject related to a topic I was interested in many years ago. I learned that a lot has happened since I last thought about this. The attempt to model a body of fluid with a free surface leads to considerable mathematical difficulties. When I started working on dynamical models for this kind of situation few people seemed to be interested in proving theorems on the subject. The source of my interest in the subject was the influence of Jürgen Ehlers, who always had a clear vision of what were the important problems. In this way I found myself in the position of a pioneer in a certain research area. Being in that situation has the advantage of not being troubled by strong competition. On the other hand it can also mean that whatever you achieve can be largely ignored and it is not the best way to get wide recognition. Often finishing mathematical research directions gets more credit than starting them. This could no doubt be compensated by suitable advertizing but that was never my strong point. This is a configuration which I have often found myself in and in fact, comparing advantages and disadvantages, I do not feel I need to change it. Coming back to the fluids with free surface, this is now a hot topic and played a prominent role at the conference. When I was working on this the issue of local existence in the case of inviscid fluids was still open. A key step was the work of Sijue Wu on water waves. I learned from the talk of Fefferman that this has been extended in the meantime to global existence for small data. The question which is now the focus of interest is formation of singularities (i.e. breakdown of classical solutions) for large data. Instead of considering the breaking of one wave the idea is to consider two waves which are approaching each other while turning over until they meet. There are already analytical results on parts on this process by Fefferman and collaborators and they plan to extend this to a more global picture by using a computer-assisted proof. Another plenary was by Ingrid Daubechies, who talked about applications of image processing to art history. I must admit that beforehand the theme did not appear very attractive to me but in fact the talk was very entertaining and I am glad I went to hear it.

I gave a talk on my recent work with Juliette Hell on the MAPK cascade in a session organized by Bernold Fiedler and Atsushi Mochizuki. I found the session very interesting and the highlight for me was Mochizuki’s talk on his work with Fiedler. The subject is how much information can be obtained about a network of chemical reactions by observing a few nodes, i.e. by observing a few concentrations. What I find particularly interesting are the direct connections to biological problems. Applied to the gene regulatory network of an ascidian (sea squirt) this theoretical approach suggests that the network known from experimental observations is incomplete and motivates searching for the missing links experimentally. Among the many other talks I heard at the conference, one which I found particularly impressive concerned the analysis of successive MRT pictures of patients with metastases in the lung. The speaker was using numerical simulations with these pictures as input to provide the surgeon with indications which of the many lesions present was likely to develop in a dangerous way and should therefore be removed. One point raised in the talk is that it is not really clear what information about the tissue is really contained in an MRT picture and that this could be an interesting mathematical problem in itself. In fact there was an encouragingly (from my point of view) large number of sessions and other individual talks at the conference on subjects related to mathematical biology.

The conference took place on the campus of the Universidad Autonoma somewhat outside the city. A bonus for me was hearing and seeing my first bee-eater for many years. It was quite far away (flying high) but it gave me real pleasure. I was grateful that the temperatures during the week were very moderate, so that I could enjoy walking through the streets of Madrid in the evening without feeling disturbed by heat or excessive sun.

Itk and T cell signalling

June 18, 2014

I have spent a lot of time thinking about signalling pathways involved in the activation of T cells and ways in which mathematical modelling could help to understand them better. In the recent past I had not found much time to read about the biological background in this area. Last weekend I started doing this again. In this context I remembered that Al Singer told me that Itk was an interesting target for modelling. At that time I knew nothing about Itk and only now have I come back to that, reading a review article by Andreotti et. al. in Cold Spring Harbor Perspectives in Biology, 2010. Before I say more about that I will collect some more general remarks.

The signalling network involved in the activation of T cells is very complex but over time I have become increasingly familiar with it. I want to review now some of the typical features to be found in this and related networks. Phosphorylation and dephosphorylation play a very important role. Phosphate groups can be added to or removed from many proteins, replacing (in animals) the hydroxyl groups in the side chains of the amino acids serine, threonine and tyrosine. The enzymes which add and remove these groups are the kinases and phosphatases, respectively. Often the effect of (de-)phosphorylation is to switch the kinase or phosphatase activity of the protein on or off. This kind of process has been studied from a mathematical point of view relatively frequently, with the MAPK cascade being a popular example. Another phenomenon which is controlled by phosphorylation is the binding of one protein to another, for instance via SH2 domains. An example involved in T cell activation is the binding of ZAP-70 to the \zeta-chain associated to the T cell receptor. This binding means that certain proteins are brought into proximity with each other and are more likely to interact. Another type of players are linker or adaptor proteins which seem to have the main (or exclusive?) function of organising proteins spatially. One of these I was aware of is LAT (linker of activated T cells). While reading the Itk paper I came across Slp76, which did not strike me as familiar. Another element of signalling pathways is when one protein cleaves another. This is for instance a widespread mechanism in the complement system.

Now back to Itk (IL2-inducible T cell kinase). It is a kinase and belongs to a family called the Tec kinases. Another member of the family which is more prominent medically is Btk, which is important for the function of B cells. Mutations in Btk cause the immunodeficiency disease X-linked agammaglobulinemia. This is the subject of the first chapter of the fascinating book ‘Case studies in Immunology’ by Geha and Notarangelo. As the name suggests this gene is on the X chromosome and correspondingly the disease mainly affects males. In some work I did I looked at the pathway leading to the transcription factor NFAT. However I only looked at the more downstream part of the pathway. This is related to the fact that in experimental work the more upstream part is often bypassed by the use of ionomycin. This substance causes a calcium influx into the cytosol which triggers the lower part of the pathway. In the natural situation the calcium influx is caused by {\rm IP}_3 binding to receptors on the endoplasmic reticulum. The {\rm IP}_3 comes from the cleavage of {\rm PIP}_2 by {\rm PLC}\gamma. This I knew before, but what comes before that? In fact {\rm PLC}\gamma is activated through phosphorylation by Itk and Itk is activated through phosphorylation by Lck, a protein I was very familar with due to some of its other effects in T cell activation.

It seems that in knockout mice which lack Itk T cell development is still possible but the immune system is seriously compromised. Effects can be seen in the differentiation of T-helper cells into the types Th1, Th2 and Th17. The problems are less in the case of Th1 responses because Itk can be replaced by another Tec kinase called Rlk. In the case of Th2 responses this does not work and the secretion of the typical Th2 cytokine IL4 is seriuously affected. The Th17 cells are in an intermediate position, with IL17A being affected but IL17F not. Itk also has important effects during the maturation of T cells. Despite the many roles of Itk there are few cases known where mutations in the corresponding genes leads to medical problems in humans. This kind of mutation is a unique opportunity to learn about the role of various substances in humans, where direct experiments are not possible.

In a 2009 paper of Huck et. al. (J. Exp. Med. 119, 1350) the case of two sisters who suffered from serious problems with immunity is described. In particular they had strong infections with Epstein-Barr virus which could not be overcome despite intensive treatment. They also has an excess of B cells. The older sister died at the age of ten. The younger sister was even more severely affected and stem cell transplantation was attempted when she was six years old. Unfortunately she did not survive that. After extensive investigations it was discovered that both sisters were homozygous for the same mutation in the gene for Itk and that was the source of their problems. Their medical history offers clues to what Itk does in humans. The gene is on chromosome 5 and thus it is natural that its mutations are much more rarely discovered than those of Btk. The mutation must occur in both copies of the gene in order to have a serious effect and this can happen just as easily in females as in males.


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