Archive for October, 2015

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.

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Siphons in reaction networks

October 8, 2015

The concept of a siphon is one which I have been more or less aware of for quite a long time. Unfortunately I never had the impression that I had understood it completely. Given the fact that it came up a lot in discussions I was involved in and talks I heard last week I thought that the time had come to make the effort to do so. It is of relevance for demonstrating the property of persistence in reaction networks. This is the property that the \omega-limit points of a positive solution are themselves positive. For a bounded solution this is the same as saying that the infima of all concentrations at late times are positive. The most helpful reference I have found for these topics is a paper of Angeli, de Leenheer and Sontag in a proceedings volume edited by Queinnec et. al.

There are two ways of formulating the definition of a siphon. The first is more algebraic, the second more geometric. In the first the siphon is defined to be a set Z of species with the property that whenever one of the species in Z occurs on the right hand side of a reaction one of the species in Z occurs on the left hand side. Geometrically we replace Z by the set L_Z of points of the non-negative orthant which are common zeroes of the elements of Z, thought of as linear functions on the species space. The defining property of a siphon is that L_Z is invariant under the (forward in time) flow of the dynamical system describing the evolution of the concentrations. Another way of looking at the situation is as follows. Consider a point of L_Z. The right hand side of the evolution equations of one of the concentrations belonging to Z is a sum of positive and negative terms. The negative terms automatically vanish on L_Z and the siphon condition is what is needed to ensure that the positive terms also vanish there. Sometimes minimal siphons are considered. It is important to realize that in this case Z is minimal. Correspondingly L_Z is maximal. The convention is that the empty set is excluded as a choice for Z and correspondingly the whole non-negative orthant as a choice for L_Z. What is allowed is to choose Z to be the whole of the species space which means that L_Z is the origin. Of course whether this choice actually defines a siphon depends on the particular dynamical system being considered.

If x_* is an \omega-limit point of a positive solution but is not itself positive then the set of concentrations which are zero at that point is a siphon. In particular stationary solutions on the boundary are contained in siphons. It is remarked by Shiu and Sturmfels (Bull. Math. Biol. 72, 1448) that for a network with only one linkage class if a siphon contains one stationary solution it consists entirely of stationary solutions. To see this let x_* be a stationary solution in the siphon Z. There must be some complex y belonging to the network which contains an element of Z. If y' is another complex then there is a directed path from y' to y. We can follow this path backwards from y and conclude successively that each complex encountered contains an element of Z. Thus y' contains an element of Z and since y' was arbitrary all complexes have this property. This means that all complexes vanish at x_* so that x_* is a stationary solution.

Siphons can sometimes be used to prove persistence. Suppose that Z is a siphon for a certain network so that the points of Z are potential \omega-limit points of solutions of the ODE system corresponding to this network. Suppose further that A is a conserved quantity for the system which is a linear combination of the coordinates with positive coefficents. For a positive solution the quantity A has a positive constant value along the solution and hence also has the same value at any of its \omega-limit points. It follows that if A vanishes on Z then no \omega-limit point of that solution belongs to Z. If it is possible to find a conserved quantity A of this type for each siphon of a given system (possibly different conserved quantities for different siphons) then persistence is proved. For example this strategy is used in the paper of Angeli et al. to prove persistence for the dual futile cycle. The concept of persistence is an important one when thinking about the general properties of reaction networks. The persistence conjecture says that any weakly reversible reaction network with mass action kinetics is persistent (possibly with the additional assumption that all solutions are bounded). In his talk last week Craciun mentioned that he is working on proving this conjecture. If true it implies the global attractor conjecture. It also implies a statement claimed in a preprint of Deng et. al. (arXiv:1111.2386) that a weakly reversible network has a positive stationary solution in any stoichiometric compatobility class. This result has never been published and there seems to be some doubt as to whether the proof is correct.

Trip to the US

October 5, 2015

Last week I visited a few places in the US. My first stop was Morgantown, West Virginia where my host was Casian Pantea. There I had a lot of discussions with Casian and Carsten Conradi on chemical reaction network theory. This synergized well with the work I have recently been doing preparing a lecture course on that subject which I will be giving in the next semester. I gave a talk on MAPK and got some feedback on that. It rained a lot and there was not much opportunity to do anything except work. One day on the way to dinner while it was relatively dry I saw a Cardinal and I fortunately did have my binoculars with me. On Wednesday afternoon I travelled to New Brunswick and spent most of Thursday talking to Eduardo Sontag at Rutgers. It was a great pleasure to talk to an excellent mathematician who also knows a lot about immunology. He and I have a lot of common interests which is in part due to the fact that I was inspired by several of his papers during the time I was getting into mathematical biology. I also had the opportunity to meet Evgeni Nikolaev who told me a variety of interesting things. They concerned bifurcation theory in general, its applications to the kinds of biological models I am interested in and his successes in applying mathematical models to understanding concrete problems in biomedical research such as the processes taking place in tuberculosis. My personal dream is to see a real coming together of mathematics and immunology and that I have the chance to make a contribution to that process.

On Friday I flew to Chicago in order to attend an AMS sectional meeting. I had been in Chicago once before but that is many years ago now. I do remember being impressed by how much Lake Michigan looks like the sea, I suppose due to the structure of the waves. This impression was even stronger this time since there were strong winds whipping up the waves. Loyola University, the site of the meeting, is right beside the lake and it felt like home for me due to the combination of wind, waves and gulls. The majority of those were Ring-Billed Gulls which made it clear which side of the Atlantic I was on. There were also some Herring Gulls and although they might have been split from those on the other side of the Atlantic by the taxonomists I did not notice any difference. It was the first time I had been at an AMS sectional meeting and my impression was that the parallel sessions were very parallel, in other words in no danger of meeting. Most of the people in our session were people I knew from the conferences I attended in Charlotte and in Copenhagen although I did make a couple of new acquaintances, improving my coverage of the reaction network community.

In a previous post I mentioned Gheorghe Craciun’s ideas about giving the deficiency of a reaction network a geometric interpretation, following a talk of his in Copenhagen. Although I asked him questions about this on that occasion I did not completely understand the idea. Correspondingly my discussion of the point here in my blog was quite incomplete. Now I talked to him again and I believe I have finally got the point. Consider first a network with a single linkage class. The complexes of the network define points in the species space whose coordinates are the stoichiometric coefficients. The reactions define oriented segments joining the educt complex to the product complex of each reaction. The stoichiometric subspace is the vector space spanned by the differences of the complexes. It can also be considered as a translate of the affine subspace spanned by the complexes themselves. This makes it clear that its dimension s is at most n-1, where n is the number of complexes. The number s is the rank of the stoichiometric matrix. The deficiency is n-1-s. At the same time s\le m. If there are several linkage classes then the whole space has dimension at most n-l, where l is the number of linkage classes. The deficiency is n-l-s. If the spaces corresponding to the individual linkage classes have the maximal dimension allowed by the number of complexes in that class and these spaces are linearly independent then the deficiency is zero. Thus we see that the deficiency is the extent to which the complexes fail to be in general position. If the species and the number of complexes have been fixed then deficiency zero is seen to be a generic condition. On the other hand fixing the species and adding more complexes will destroy the deficiency zero condition since then we are in the case n-l>m so that the possibility of general position is excluded. The advantage of having this geometric picture is that it can often be used to read off the deficiency directly from the network. It might also be used to aid in constructing networks with a desired deficiency.