Archive for the ‘diseases’ Category

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.

IPEX and CD25

December 20, 2011

In a recent post I wrote about some ideas of Kendall Smith and his role in discovering the cytokine IL-2. On 8th December I heard him give a talk in which he presented various ideas about IL-2, its receptor and Tregs. I discussed some aspects of IL-2 in the last post. When mutant mice are engineered which cannot produce IL-2 they show a strange combination of symptoms which combine immunodeficiency (a reduced capability of the immune system to fight pathogens) and autoimmune disease (an inappropriate reaction of the immune system to host tissues). This probably has to do with the fact that IL-2 is important for the production of both effector T cells and Tregs, which act in opposite directions. Similar phenomena are seen in the disease of humans called IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome). It is often attributed to a lack of the transcription factor Foxp3 which is of central importance for the function of Tregs. The gene for Foxp3 is on the X chromosome and this explains the way IPEX is inherited and the term X-linked in its name. However, as pointed out by Smith in his talk, one third of patients diagnosed with IPEX have no mutation in the Foxp3 gene. In this context he referred to a paper of Caudy et al. (J. Allergy Clin. Immunol. 119, 482). What is shown in this paper is that there is a different possible cause of IPEX-like symptoms, namely mutations in the gene for CD25, a surface molecule associated to Tregs.

The paper concerns a patient (an eight year old boy) who had suffered a horrific combination of diseases. It was found that he had mutations in both copies of the CD25 gene. The mutation in one copy came from the mother and was a frame shift due to an insertion. In other words, there is a extra base in the DNA which makes the part of the gene after it look like nonsense when it is being transcribed. The mutation in the other copy came from the father and consisted of one base being exchanged. This happed to cause a stop codon so that reading stopped at that point. The combination of these circumstances meant that the boy could not produce CD25 and this was the presumed cause of his disease. His Foxp3 gene was normal. On the other hand other IPEX patients can produce CD25. Thus there appear to be two diseases with related symptoms. The gene coding for CD25 is on chromosome 10, not the X chromosome. This is why two mutations are necessary to produce CD25 deficiency.

What is the connection to IL-2? The IL-2 receptor, which was also discovered by Kendall Smith and his collaborators, consists of three chains called \alpha, \beta and \gamma. The second and third are always present on the surface of T cells but the first is only present in variable amounts. In fact the \alpha chain of the IL-2 receptor is nothing other than CD25. The \beta and \gamma chains together allow for some IL-2 signalling but strong signalling in response to normal concentrations of IL-2 is only possible with the help of the \alpha chain. In this case it is not only the case that the receptor signals when IL-2 is bound to it. Binding also causes the receptor to be taken into the interior of the cell and destroyed. This process is an important part of the dynamics associated to IL-2. The \gamma chain of the IL-2 receptor also forms part of the receptor for many other cytokines, for instance IL-4. The gene for this receptor is on the X chromosome. When it cannot be produced due to a mutation this leads to a disease called X-linked severe combined immunodeficiency (SCID). In this case the immune system does not function since so much of its signalling system has been disrupted. This is also known as the ‘bubble boy disease’ since children affected by it have to live in a sterile environment.

Shifting attention towards Tregs

December 3, 2011

Yesterday I heard a talk by Abul Abbas where two of the main themes were regulatory T cells (Tregs) and interleukin 2. Correctly functioning immunity is the result of a balance between effector cells and Tregs and he emphasized that in trying to develop therapies it might be more valuable to concentrate on influencing the regulatory side. He described a mouse model which he has developed for studying autoimmune disease. One criterion in developing this model was that it should concern the target tissue where an antigen is expressed and not the lymphoid tissue. Another is that the target tissue should be easily accessible for doing experiments in vivo. For this reason he chose the skin. In this transgenic model antigen expression can be turned on and off by feeding the mice with doxycyclin. When the antigen is turned on an autoimmune disease results. If it is turned off the mice recover. If it is turned on again the mice get sick again but much less than the first time. This is reminiscent of ordinary immunity which is due to memory effector cells. In this case it seems that there are memory Tregs. This suggests the idea that a possible cause of autoimmune disease in humans could be a lack of memory Tregs.

When IL-2 was first discovered it was known for causing T cells to proliferate and thus strengthening the immune response. More recently it has been found that eliminating IL-2 does not necessarily act in an immunosuppressive way. Apparently it can be replaced by something else in driving the proliferation of effector T cells. On the other hand it also drives the proliferation of Tregs and Abbas argued that this is its most essential function. In that case it cannot be replaced.

The lecturer made a number of interesting comments about themes such as immunology, therapies for immune disorders and cancer, clinical trials etc. I did not note them down and I cannot reproduce them here. Nevertheless I have the impression that a learned of lot of things which I might profit from in the future.


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