Archive for the ‘diseases’ Category

NFκB

May 1, 2016

NF\kappaB is a transcription factor, i.e. a protein which can bind to DNA and cause a particular gene to be read more or less often. This means that more or less of a certain protein is produced and this changes the behaviour of the cell. The full name of this transcription factor is ‘nuclear factor, \kappa-light chain enhancer of B cells’. The term ‘nuclear factor’ is clear. The substance is a transcription factor and to bind to DNA it has to enter the nucleus. NF\kappaB is found in a wide variety of different cells and its association with B cells is purely historical. It was found in the lab of David Baltimore during studies of the way in which B cells are activated. It remains to explain the \kappa. B cells produce antibodies each of which consists of two symmetrical halves. Each half consists of a light and a heavy chain. The light chain comes in two variants called \kappa and \lambda. The choice which of these a cell uses seems to be fairly random. The work in the Baltimore lab had found out that NF\kappaB could skew the ratio. I found a video by Baltimore from 2001 about NF\kappaB. This is probably quite out of date by now but it contained one thing which I found interesting. Under certain circumstances it can happen that a constant stimulus causing activation of NF\kappaB leads to oscillations in the concentration. In the video the speaker mentions ‘odd oscillations’ and comments ‘but that’s for mathematicians to enjoy themselves’. It seems that he did not believe these oscillations to be biologically important. There are reasons to believe that they might be important and I will try to explain why. At the very least it will allow me to enjoy myself.

Let me explain the usual story about how NF\kappaB is activated. There are lots of animated videos on Youtube illustrating this but I prefer a description in words. Normally NF\kappaB is found in the cytosol bound to an inhibitor I\kappaB. Under certain circumstances a complex of proteins called IKK forms. The last K stands for kinase and IKK phosphorylates I\kappaB. This causes I\kappaB to be ubiquinated and thus marked for degradation (cf. the discussion of ubiquitin here). When it has been destroyed NF\kappaB is liberated, moves to the nucleus and binds to DNA. What are the circumstances mentioned above? There are many alternatives. For instance TNF\alpha binds to its receptor, or something stimulates a toll-like receptor. The details are not important here. What is important is that there are many different signals which can lead to the activation of NF\kappaB. What genes does NF\kappaB bind to when it is activated? Here again there are many possibilities. Thus there is a kind of bow tie configuration where there are many inputs and many outputs which are connected to a single channel of communication. So how is it possible to arrange that when one input is applied, e.g. TNF\alpha the right genes are switched on while another input activates other genes through the same mediator NF\kappaB? One possibility is cross-talk, i.e. that this signalling pathway interacts with others. If this cannot account for all the specificity then the remaining possibility is that information is encoded in the signal passing through NF\kappaB itself. For example, one stimulus could produce a constant response while another causes an oscillatory one. Or two stimuli could cause oscillatory responses with different frequencies. Evidently the presence of oscillations in the concentration of NF\kappaB presents an opportunity for encoding more information than would otherwise be possible. To what extent this really happens is something where I do not have an overview at the moment. I want to learn more. In any case, oscillations have been observed in the NF\kappaB system. The primary thing which has been observed to oscillate is the concentration of NF\kappaB in the nucleus. This oscillation is a consequence of the movement of the protein between the cytosol and the nucleus. There are various mathematical models for describing these oscillations. As usual in modelling phenomena in cell biology there are models which are very big and complicated. I find it particularly interesting when some of the observations can be explained by a simple model. This is the case for NF\kappaB where a three-dimensional model and an explanation of its relations to the more complicated models can be found in a paper by Krishna, Jensen and Sneppen (PNAS 103, 10840). In the three-dimensional model the unknowns are the concentrations of NF\kappaB in the nucleus, I\kappaB in the cytoplasm and mRNA coding for I\kappaB. The oscillations in normal cells are damped but sustained oscillations can be seen in mutated cells or corresponding models.

What is the function of NF\kappaB? The short answer is that it has many. On a broad level of description it plays a central role in the phenomenon of inflammation. In particular it leads to production of the cytokine IL-17 which in turn, among other things, stimulates the production of anti-microbial peptides. When these things are absent it leads to a serious immunodeficiency. In one variant of this there is a mutation in the gene coding for NEMO, which is one of the proteins making up IKK. A complete absence of NEMO is fatal before birth but people with a less severe mutation in the gene do occur. There are symptoms due to things which took place during the development of the embryo and also immunological problems, such as the inability to deal with certain bacteria. The gene for NEMO is on the X chromosome so that this disease is usually limited to boys. More details can be found in the book of Geha and Notarangelo mentioned in  a previous post.

The German Dr. House

January 14, 2016

The central figure in the American TV series Dr. House is a doctor who is brilliant in the diagnosis of unusual medical conditions but personally very difficult. When I first saw this series I found the character so unpleasant that I did not want to watch the programme. However in the course of time I got drawn in to watching it by the interest of the medical content. While some aspects of this series are quite exaggerated and far from reality the medical parts are very accurate and well researched. As I learned yesterday even details seen there like the numbers on heart monitors accurately reflect the situation being portrayed. I have this information from a lecture I attended yesterday at the Medizinische Gesellschaft Mainz [Mainz Medical Society]. The speaker was Professor Jürgen Schäfer, a man who has become known in the media as the German Dr. House. I am pleased to report that I detected no trace of the social incompetence of Dr. House in Dr. Schäfer.

Jürgen Schäfer is trained as a cardiologist. He and his wife, who is a gastroenterologist, got so interested by the series Dr. House that they would spend time discussing the details of the diagnoses and researching the background after they has seen each programme. Then Schäfer had the idea that he could use Dr. House in his lectures at the University of Marburg. The first obstacle was to know if he could legally make use of this material. After a casual conversation with one of his patients who is a lawyer he contacted the necessary people and signed a suitable contract. At this time his project attracted considerable attention in the media even before it had started. In the lectures he analyses the cases occurring in the series. The students are encouraged to develop their own diagnoses in dialogue with the professor. These lectures are held in the evenings and are very popular with the students. In the evaluations the highest score was obtained for the statement that ‘the lectures are a lot of fun’.

This is only the start of the story. During a consultation in one of the episodes of Dr. House he suddenly makes a deep cut with a scalpel in the body of the patient (one of the melodramatic elements), opens the wound and shows that the flesh inside is black. The diagnosis is cobalt poisoning. After seeing this it occurred to Dr. Schäfer that this diagnosis might also apply to one of his own patients and this turned out to be true. In addition to serious heart problems this patient was becoming blind and deaf. He had had a hip joint replacement with an implant made of a ceramic material. At some point this became damaged and was replaced. In order to try to avoid the implant breaking again the new one was made of metal. The old implant fragmented and left splitters in the body. These had acted like sandpaper on the new joint and at the time of removal it had been reduced to 70% of its original size by this process. As a result large quantities of cobalt was released, resulting in the poisoning. The speaker showed a picture of the operation of another of his patients with a similar problem where the wound could be seen to be filled with a black oily liquid. Together with colleagues Schäfer published an account of this case in The Lancet with the title ‘Cobalt intoxication diagnosed with the help of Dr. House’. Not all his coauthors were happy with this title but Schäfer wanted to acknowledge his debt to the series. At the same time it was a great piece of advertizing for him which lead to a lot of attention in the international media.

Due to his growing fame Schäfer started to get a lot of letters from patients with mysterious illnesses. This was more than he could handle. He informed the administration of the university clinic where he worked that he was going to start sending back letters of this type unopened, since he just did not have the time to cope with them. To his surprise they wanted him to continue with this work and arranged from him to be relieved from other duties. They set up a new institute for him called Zentrum für unerkannte Krankheiten [centre for unrecognized diseases]. This was perhaps particularly surprising since this is a privately funded clinic and the work of this institute costs money rather than making money. The techniques used there include toxicological and genomic analyses.

Here is another example from the lecture. Schäfer’s institute uses large scale DNA analysis to screen for a broad range of parasites in patients with unclear symptoms. In one patient they found DNA of the parasite causing schistosomiasis. This disease is usually got by bathing in infected water in tropical or subtropical areas. The patient tested negatively for the parasite and had never been to a place where this disease occurs. The mystery was cleared up due to the help of a vet of Egyptian origin. He was familiar with schistosomiasis and due to his experience with large animals he was not afraid of analysing very large stool samples. He succeeded in finding eggs of the parasite in the patient’s stool. The diffculty was that the numbers of eggs were very low and that for certain reasons they were difficult to recognise in this case, except by an expert. The patient was treated for schistosomiasis as soon as the genetic results were available but it was very satisfying to have a confirmation by more classical techniques. The mystery of how the patient got infected was solved as follows. As a hobby he kept lots of fish and he imported these from tropical regions. The infection presumably came from the water in his aquarium. We see that in the modern world it is easy to import tropical diseases by express delivery after placing an order in the internet

I do not want to end before mentioning that Schäfer said something nice about how mathematicians can help medical doctors. He had a patient who is a mathematics professor and had the following problem. From time to time he would collapse and was temporarily paralysed although fully conscious. A possible explanation for this would have been an excessively high level of sodium in the body. On the other hand measurements showed that the concentration of sodium in his blood was normal, even after an attack. The patient then did a calculation (just simple arithmetic). On the basis of known data he worked out the amount of sodium and potassium in different types of food and noted a correlation between negative effects of a food on his health and the ratio of the sodium to potassium concentrations. This supported the hypothesis of sodium as a cause and encouraged the doctors to look more deeply into the matter. It turned out that in this type of disease the sodium is concentrated near the cell membrane and cannot be seen in the blood. A genetic analysis revealed that the patient had a mutation in a little-known sodium channel.

I think that this lecture was very entertaining for the audience, including my wife and myself. However this is not just entertainment. With his institute Schäfer is providing essential help for many people in very difficult situations. He has files of over 4000 patients. This kind of work requires a high investment in time and money which is not possible for a usual university clinic, not to mention an ordinary GP. It is nevertheless the case that Schäfer is developing resources which could be used more widely, such as standard protocols for assessing patients of this type. As he emphasized, while by definition a rare disease only effects a small number of patients the collection of all rare diseases together affects a large number of people. If more money was invested in this kind of research it could result in  a net saving for the health system since it would reduce the number of people running from one doctor to another since they do not have a diagnosis.

David Vetter, the bubble boy

October 17, 2015

T cells are a class of white blood cells without which a human being usually cannot survive. An exception to this was David Vetter, a boy who lived 12 years without T cells. This was only possible because he lived all this time in a sterile environment, a plastic bubble. For this reason he became known as the bubble boy. The disease which he suffered from is called SCID, severe combined immunodeficiency, and it corresponds to having no T cells. The most common form of this is due to a mutation on the X chromosome and as a result it usually affects males. The effects set in a few months after birth. The mutation leads to a lack of the \gamma chain of the IL-2 receptor. In fact this chain occurs in several cytokine receptors and is therefore called the ‘common chain’. Probably the key to the negative effects caused by its lack in SCID patients is the resulting lack of the receptor for IL-7, which is important for T cell development. SCID patients have a normal number of B cells but very few antibodies due to the lack of support by helper T cells. Thus in the end they lack both the immunity usually provided by T cells and that usually provided by B cells. This is the reason for the description ‘combined immunodeficiency’. I got the information on this theme which follows mainly from two sources. The first is a documentary film ‘Bodyshock – The Boy in the Bubble’ about David Vetter produced by Channel 4 and available on Youtube. (There are also less serious films on this subject, including one featuring John Travolta.) The second is the chapter on X-linked SCID in the book ‘Case Studies in Immunology’ by Raif Geha and Luigi Notarangelo. I find this book a wonderful resource for learning about immunology. It links general theory to the case history of specific patients.

David Vetter had an older brother who also suffered from SCID and died of infection very young. Thus his parents and their doctors were warned. The brother was given a bone marrow transplant from his sister, who had the necessary tissue compatibility. Unfortunately this did not save him, presumably because he had already been exposed to too many infections by the time it was carried out. The parents decided to have another child, knowing that if it was a boy the chances of another case of SCID were 50%. Their doctors had a hope of being able to save the life of such a child by isolating him and then giving him a bone marrow transplant before he had been exposed to infections. The parents very soon had another child, it was a boy, he had SCID. The child was put into a sterile plastic bubble immediately after birth. Unfortunately it turned out that the planned bone marrow donor, David’s sister, was not a good match for him. It was necessary to wait and hope for an alternative donor. This hope was not fulfilled and David had to stay in the bubble. This had not been planned and it must be asked whether the doctors involved had really thought through what would happen if the optimal variant they had thought of did not work out.

At one point David started making punctures in his bubble as a way of attracting attention. Then it was explained to him what his situation was and why he must not damage the bubble. Later there was a kind of space suit produced for him by NASA which allowed him to move around outside his home. He only used it six times since he was too afraid there could be an accident. His physical health was good but understandably his psychological situation was difficult. New ideas in the practise of bone marrow transplantation indicated that it might be possible to use donors with a lesser degree of compatibility. On this basis David was given a transplant with his sister as the donor. It was not noticed that her bone marrow was infected with Epstein-Barr virus. As a result David got Burkitt’s lymphoma, a type of cancer which can be caused by that virus. (Compare what I wrote about this role of EBV here.) He died a few months after the operation, at the age of 12. Since that time treatment techniques have improved. The patient whose case is described in the book of Geha and Notarangelo had a successful bone marrow transplant (with his mother as donor). Unfortunately his lack of antibodies was not cured but this can be controlled with injections of immunoglobulin once every three weeks.

Immunotherapy for cancer

September 20, 2015

A promising innovative approach to cancer therapy is to try to persuade the immune system to attack cancer cells effectively. The immune system does kill cancer cells and presumably removes many tumours which we never suspect we had. At the same time established tumours are able to successfully resist this type of attack in many cases. The idea of taking advantage of the immune system in this way is an old one but it took a long time before it became successful enough to reach the stage of an approved drug. This goal was achieved with the approval of ipilimumab for the treatment of melanoma by the FDA in 2011. This drug is a monoclonal antibody which binds the molecule CTLA4 occurring on the surface of T cells.

To explain the background to this treatment I first recall some facts about T cells. T cells are white blood cells which recognize foreign substances (antigens) in the body. The antigen binds to a molecule called the T cell receptor on the surface of the cell and this gives the T cell an activation signal. Since an inappropriate activation of the immune system could be very harmful there are built-in safety mechanisms. In order to be effective the primary activation signal has to be delivered together with a kind of certificate that action is really necessary. This is a second signal which is given via another surface molecule on the T cell, CD28. The T cell receptor only binds to an antigen when the latter is presented on the surface of another cell (an antigen-presenting cell, APC) in a groove within another molecule, an MHC molecule (major histocompatibility complex). On the surface of the APC there are under appropriate circumstances other molecules called B7.1 and B7.2 which can bind to CD28 and give the second signal. Once this has happened the activated T cell takes appropriate action. What this is depends on the type of T cell involved but for a cytotoxic T cell (one which carries the surface molecule CD8) it means that the T cell kills cells presenting the antigen. If the cell was a virus-infected cell and the antigen is derived from the virus then this is exactly what is desired. Coming back to the safety mechanisms, it is not only important that the T cell is not erroneously switched on. It is also important that when it is switched on in a justified case it should also be switched off after a certain time. Having it switched on for an unlimited time would never be justified. This is where CTLA4 comes in. This protein can bind to B7.1 and B7.2 and in fact does so more strongly than CD28. Thus it can crowd out CD28 and switch off the second signal. By binding to CTLA4 the antibody in ipilimumab stops it from binding to B7.1 and B7.2, thus leaving the activated T cell switched on. In some cases cancer cells present unusual antigens and become a target for T cells. The killing of these cells can be increased by CTLA4 via the mechanism just explained. At this point I should say that it may not be quite clear whether this is really the mechanism of action of CTLA4 in causing tumours to shrink. Alternative possibilities are mentioned in the Wikipedia article on CTLA4.

There are various things which have contributed to my interest in this subject. One is lectures I heard in the series ‘Universität im Rathaus’ [University in the Town Hall] in Mainz last February. The speakers were Matthias Theobald and Ugur Sahin and the theme was personalized cancer medicine. The central theme of what they were talking about is one step beyond what I have just sketched. A weakness of the therapy using antibodies to CTLA4 or the related approach using antibodies to another molecule PD-1 is that they are unspecific. In other words they lead to an increase not only in the activity of the T cells specific to cancer cells but of all T cells which have been activated by some antigen. This means that serious side effects are very likely. An approach which is theoretically better but as yet in a relatively early stage of development is to produce T cells which are specific for antigens belonging to the tumour of a specific patient and for an MHC molecule of that patient capable of presenting that antigen. From the talk I had the impression that doing this requires a lot of input from bioinformatics but I was not able to understand what kind of input it is. I would like to know more about that. Coming back to CTLA4, I have been interested for some time in modelling the activation of T cells and in that context it would be natural to think about also modelling the deactivating effects of CTLA4 or PD-1. I do not know whether this has been tried.

Harald zur Hausen, colon cancer and MS

December 5, 2014

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

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

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!

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.

 

 

Guillain-Barré syndrome

May 9, 2013

Yesterday I went to a talk by Hans-Peter Hartung about autoimmune diseases of the peripheral nervous system. To start with he gave a summary of similarities and differences between the peripheral and central nervous systems and their relations to the immune system. Of the diseases he later discussed one which played a central role was Guillain-Barré syndrome. In fact he emphasized that this ‘syndrome’ is phenomenologically defined and consists of several diseases with different underlying mechanisms. There is one form which is sporadic in its occurrence and predominant in the western world and another which can take an epidemic form and occurs in China. At a time when medical services in China were very poor this kind of epidemic had very grave consequences. Now, however, I want to return to the ‘classical’ form of Guillain-Barré.

GBS is a disease which is fascinating for the outside observer and no doubt terrifying for the person affected by it. I first learned about it in an account – I do not remember where I read it – of the case of a German doctor. He was on holiday in Tenerife when he fell ill. He recognized the characteristic pattern of symptoms, suspected GBS and got on the first plane home. He wanted to optimize the treatment he got by going to the best medical centre he knew to get treated. The treatment was successful. In GBS the immune system attacks peripheral nerves and this leads to a rapidly progressive paralysis over the course of a few days. In a significant proportion of patients this leads to the control of the muscles responsible for breathing failing and thus to death. For this reason it it is important for the patient to quickly reach a place where the disease will be recognized and they can be put on a ventilator when needed.The disease can then also be treated by plasmapheresis or immunoglobulins. In the talk it was mentioned that in the epidemics in China it was often necessary to put patients on a manual ventilator which was operated their relatives. If this acute phase can be overcome the patient usually recovers rather completely, although some people have lasting damage. It is typical that in a single patient the disease does not recur although there are a small number of cases where there are several relapses and disability accumulates.

It has been suggested that influenza infections, or influenza vaccinations, can lead to an increased risk of developing GBS. This has been an important element of controversies surrounding vaccinations, including those against H1N1. I wrote briefly about this in a previous post. In the talk the speaker mentioned a recent Canadian study indicating a slight risk of GBS due to vaccination against influenza. Nevertheless this risk was still a lot less than that due to actually becoming infected with influenza. There has also been a German study with similar results which, however, has not yet been published. There is another kind of infection which appears to carry a much higher risk, namely that with the bacterium Campylobacter jejuni. I actually mentioned this in my previous post but had completely forgotten about it. In the talk it was pointed out that this infection is quite common while GBS is very rare. So the question arises of why GBS is not more frequent. A possible explanation is that the bacterium is rather variable. The suggested mechanism is molecular mimicry (and it seems that GBS is the first case where molecular mimicry was precisely documented). In other words, certain molecules of the bacterium are similar to molecules belonging to the nervous system. Then it happens that antibodies against the bacterium cause damage to the nerves. Depending on the variant of the bacterium this similarity of the two types of molecules is more or less strong so that the effect is more or less pronounced. There is some idea in this case what exactly the molecules are which show this similarity. They are so-called gangliosides, a type of glycolipids.

This has reminded me of an issue which fascinated me before. Is there a simple explanation of why some autoimmune diseases show repeated relapses while others show a single episode (like typical GBS), a continuous progression or a combination of relapsing and progressive phases at different times? Has anyone collected data on these patterns over a variety of autoimmune diseases?

SMB annual meeting in Knoxville, part 2

July 27, 2012

The music did seem to have a positive effect on the synchronization of lectures. Unfortunately it was not always there – for instance it was not there before my talk – and it seems to have been getting less and less. One good thing is that the name tags, as well as showing the usual information have the first name (or nickname) printed in large letters at the top. I find that this can be very useful for recognizing people after only having met them fleetingly.

The plenary talk of Claire Tomlin yesterday was about the HER2 receptor which plays an important role in breast cancer. It is connected to transcription factors in the nucleus by a signalling network containing two main pathways. One of these includes the MAP kinase cascade while another passes through the substance Akt. Excessive activity of this type of signalling can be reduced by a drug called lapatinib, which is a tyrosine kinase inhibitor. There is, however, a problem that this beneficial effect can be neutralized after some time. The speaker described ideas for overcoming this effect based on a study of the signalling network. A result of this analysis is that, counterintuitively, combining the administration of lapatinib with another treatment which increases the concentration of Akt at a different time could lead to a more effective therapy. I did not get the details but this seems like a case where mathematical modelling could actually contribute effectively to cancer treatment by suggesting new strategies. Relations were mentioned to the pattern of hairs on the wings of Drosophila. In her research on biomedical themes she benefits from her background in control engineering and aerodynamics.

The talk of Becca Asquith which I mentioned in the last post was cancelled. Instead there was a lecture by Sandy Anderson who seems to like to cultivate the image of the hard-drinking Scotsman. He started his career in mathematical modelling and then moved a long way towards medical research, now heading a lab at the Moffit Cancer Center in Florida. The subject of his talk was the role of heterogeneity in cancer. He started by giving a view of the importance of cancer (in terms of the number of people it kills) and the trends in the numbers for the different forms. They have mostly been decreasing for many years with the notable exception of lung cancer (for well-known reasons) but the rate of decrease is not very large despite the huge amount of effort, and money, put into cancer research. He said that death in cancer usually does not result from a tumour which stays in its original site but as a result of metastasis. Thus that is the key phenomenon to be understood. This requires an understanding of many different scales and for the talk he concentrated on the cellular scale. He claimed that an important fact that cancer researchers had not taken into account sufficiently until very recently is how heterogeneous tumours are. There is a large variation in the phenotype of the individual cancer cells and the phenotypes are evolving. This evolution is strongly influenced by the environment of the tumour, for instance the structure of the surrounding extracellular matrix. Experiments done on cell cultures may give misleading results since the ‘happy’ cells in the Petri dish with all modern comforts are not under the same pressure as corresponding cells in the body. The more the external pressures are the more the dangerous cells which are going to metastasize dominate over the others. In some cases treatment can accelerate the growth of a tumour. This danger exists if the treatment is given too late. These ideas have arisen by the use of mathematical modelling. These are ‘hybrid models’ which combine discrete and continuous dynamical systems and this is a terms which I have met in several other talks at this conference. One of the conclusions of this research is that it may be a good idea to control cancer cells rather to destroy them. For the attempt to destroy cells may destroy the relatively harmless ones and unleash the dangerous one on their surroundings. Anderson’s talk conveyed the excitement of the application of mathematical modelling in cancer research at this moment and I wonder if some of the young people in the audience might have been recruited.

This afternoon I went to a session on wound healing. There was an introductory lecture by Rebecca Segal and this was helpful for me since I knew very little about the subject. Two of the things I found interesting – I was already primed for this by talking to Angela Reynolds at her poster yesterday – is that immunology (dynamics of neutrophils and macrophages) plays a big role and that ODE models can be useful. Useful means that they can help doctors make decisions how to treat wounds they are confronted with in practise.


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