Archive for the ‘life’ Category

Visit to Aachen

September 13, 2018

In the past few days I was in Aachen. I had only been there once before, which was for a job interview. It was just before Christmas. I only remember that it was dark, that there was a big Christmas market which I had trouble navigating through and that the building of the RWTH where the job was was large and imposing. This time the visit was more relaxed. I was there for a small meeting organized by Sebastian Walcher centred around the topic of singular perturbation theory and with an emphasis on models coming from biology.

I visited the cathedral of which a major part is older than all comparable buildings in northern Europe (eighth century). Even for someone with such rudimentary knowledge of architecture as myself it did appear very different from other cathedrals, with an oriental look. If I had been asked beforehand to imagine what the church of Charlemagne might look like I would never have guessed anything like the reality.

I gave a talk about my work with Juliette Hell about the existence of periodic solutions of the MAP kinase cascade. The emphasis was not only on the proof of this one result but also on explaining some general techniques with the help of this particular example. A theme running through this meeting was how, given a system of ODE depending on parameters, it is possible to find a small parameter \epsilon such that the limit \epsilon\to 0, while singular, nevertheless has some nice properties. In particular the aim is to obtain a limiting system with less equations and less parameters. Then we would like to lift some features of the dynamics of the limiting system to the full system. One talk, which I would like to mention, was by Satya Samal of the Joint Research Centre for Computational Biomedicine on tropical geometry. This is a term which I have often heard without understanding what it means intrinsically or how it can be applied to the study of chemical reaction networks. A lot of what was in the introduction of the talk can also be found in a paper by Radulescu et al. (Math. Modelling of Natural Phenomena, 10, 124). There was one thing in the talk which I found enlightening, which is not in the paper and which I have not seen elsewhere. I will try to explain it now. In this tropical business an algebra is introduced with ‘funny’ definitions of addition and multiplication for real numbers. It seems that often the formal properties of these operations are explained and then the calculations start. This is perhaps satisfactory for people with a strong affinity for algebra. I would like something more, an intuitive explanation of where these things come from. Let us consider multiplication first. If I start with two real numbers a and b, multiply them with \log\epsilon and exponentiate, giving the powers of \epsilon with these exponents, then multiply the results and finally take the logarithm and divide by \log\epsilon I get the sum a+b. This should explain why the tropical equivalent of the product is the sum. Now let us consider the sum. I start with numbers a and b, take powers of a quantity \epsilon with these exponents as before, then sum the results and take the logarithm. Thus we get \log (\epsilon^a+\epsilon^b). Now we need an extra step, namely to take the limit \epsilon\to 0. If b>a then the second term is negligible with respect to the first for \epsilon small and the limit is a\log\epsilon. If a>b then the limit is b\log\epsilon. Thus after dividing by \log\epsilon I get \min\{a,b\}. This quantity is the tropical equivalent of the sum. I expect that this discussion might need some improvement but it does show on some level where the ‘funny’ operations come from. It also has the following intuitive interpretation related to asymptotic expansions. If I have two functions whose leading order contributions in the limit \epsilon\to 0 are given by the powers a and b then the leading order of the product is the power given by the tropical product of a and b while the leading order of the sum is the power given by the tropical sum of a and b.

The technique of matched asymptotic expansions has always seemed to me like black magic or, to use a different metaphor, tight-rope walking without a safety net. At some point I guessed that there might be a connection between (at least some instances of) this technique and geometric singular perturbation theory. I asked Walcher about this and he made an interesting suggestion. He proposed that what is being calculated in leading order is the point at which a solution of a slow-fast system hits the critical manifold (asymptotically) thus providing an initial condition for the slow system. I must try to investigate this idea more carefully.

Advertisements

Visit to Boston

August 5, 2018

At the moment I am visiting Boston for the first time in my life. On Thursday I gave a talk at Harvard Medical School, at the invitation of Jeremy Gunawardena. The fact was not lost on me that this address was a quite exceptional one among the long list of places where I have given talks in my life. The subject of my talk was T cell signalling and, in particular, my work on this with Eduardo Sontag. I had a look around in the surrounding area and was impressed to see the variety of prestigious medical institutions which I knew by reputation, such as the Boston Children’s Hospital, The Dana-Farber Cancer Center and the Brigham and Women’s Hospital. I was happy how many pedestrians there were, indicating that at least in Boston the pedestrian is not an endangered species.

On Friday I gave a talk on T cell activation at Northeastern University at the invitation of Eduardo Sontag. This is an institution which has recently jumped up in the rankings by cutting its student numbers drastically and increasing its fees correspondingly. The basic subject of the talk was the same as on Thursday but it was modified in order to try to cater for a different audience. The talk on Friday included more mathematics (since I expected that on average the Friday audience would have a stronger mathematical background than that on Thursday) and more biology (since on Thursday I left out more of the biology which I assumed would be known to most of the audience). There were two other talks by Michael Margaliot and Yoram Zarai. They were on the subject of certain models for the way that ribosomes are allocated to mRNA. A key idea is that many ribosomes moving along an RNA molecule could get into traffic jams. Indeed there is a close relation between these and models for traffic jams in the literal sense. The question is then how the machinery of the cell should be organized to avoid such traffic jams. Typical mathematical techniques which were applied in the work explained in the talk were theorems about monotone systems of ODE (or corresponding control systems) satisfying some extra conditions leading to a simplification of their dynamics.

Today, Saturday, I spent most of the day walking around in Boston and Cambridge. In the morning it rained quite a bit but with an umbrella that was no problem. I was blissfully unaware of the fact that there had been a tornado warning and I also only heard later that a tornado did today hit a place not too far from Boston. In Cambridge I observed a turkey sitting on the pavement and looking into a shop window as if it was considering what it might buy. After a while it crossed the road and seemed to be well-educated since it was very careful to stay on the zebra crossing. By chance and without expecting anything special I happened to enter the palatial Boston Public Library. Later in the afternoon I was on the waterfront near the aquarium and the pleasant experience of sitting by the sea was heightened by the fact that the gull on top of the lamppost was a Ring-Billed Gull, a treat for my European eyes. I also spontaneously decided to take a boat trip around the harbour. In coming to Boston I had no special expectations about the city itself. Despite my short and superficial acquaintance with the place I can say that it has gained a secure place on my personal list of the most attractive cities I know.

ECMTB 2018 in Lisbon

July 24, 2018

I am attending a meeting of the ESMTB in Lisbon. I am happy that the temperatures are very moderate, much more moderate than those at home in Mainz. The highest temperatures I encountered so far were due to body heat, for the following reason. The first two sessions on reaction networks were in rooms much too small for the number of participants with people sitting on extra chairs brought in from outside, windowsills and the floor, as available. This caused a rise in temperature despite the open windows. In any case, the size of those audiences is a good sign for the field.

The first plenary talk, by Samuel Kou, was about something called Google Flu Trends. The idea of this initiative, which started in 2008, was to predict the development of epidemics such as influenza by using data on the number of Google searches for phrases related to cases of flu. The idea is that between the time someone goes to the doctor because they are suffering from an infectious disease and the time data finally come together on a national level there can be a lag of about two weeks, even in countries like the US with a highly developed reporting system. Thus the hope was that using data on Google searches could enable predictions two weeks earlier than other methods. The first test of this system looked very successful and obtained a lot of positive media coverage. After about a year the predictions started to be very wrong (perhaps due to the swine flu prevalent at that time being atypical). After modifications were made to the method the predictions were even further off and in the opposite direction. Then there was a lot of negative media coverage. Google did not make the raw data available in order to allow experts to look into what had gone wrong. However a paper published in Nature revealed some things. The number of search terms used was optimized and showed a clear local maximum. The search terms were not made public but one striking jump in the distribution was revealed to be a search term related to the Oscar ceremony. It was later suggested that what the analysis was predicting was not the incidence of flu but the beginning of winter. The mathematics used in the analysis was made public and was extremely elementary, although that by itself is not necessarily a bad thing. The group which Kou belonged to was able to make a low-grade reconstruction of the raw data using the freely available Google services called Google Trends and Google Correlate. They could then apply sophisticated statistical techniques to this data, creating a model called ARGO which performed a lot better than Google Flu Trends. Later Google stopped publishing their own analyses and made at least part of their data available to external researchers.

Another plenary talk, by Eörs Szathmáry, was about relationships between learning processes in the brain and evolution. I only understood a limited amount of the content but I nevertheless enjoyed the presentation, which combined a wide variety of different ideas. One specific point I did pick up concerns the Darwin finches. The speaker explained that the molecular (genetic) basis of the different beak shapes of these birds is now understood. This evolution takes place in a three-parameter space and it was indicated how this kind of space can be established. A similar process has been modelled in the case of RNA by Uri Alon. In the talk there was a nice partially implicit joke. One of the speaker’s main collaborators in this work is called Watson and he hinted at the idea of himself as Sherlock Holmes. Apart from the content I found the delivery of the talk very accomplished. I found it good in a way I cannot make precise.

Macronectes giganteus

April 15, 2018

Southern Giant Petrel

This blog is named after the Storm Petrel, Hydrobates pelagicus. It is a small bird, looking superficially like a swallow, and with a wingspan of less than 20 centimetres and a weight of about 30 grams. Looking back to my recent trip to South America, I see that the bird which made the biggest impression on me was a relative of the title species, the Southern Giant Petrel, Macronectes giganteus. It is on quite a different scale, with a wingspan of about two metres and a weight of about 5 kilograms. Thus it approaches the size of one of the smaller species of albatross. In form it looks a bit like a giant version of the Fulmar. The first ones I saw were in the harbour of Ushuaia. I then saw many more in flight during the cruise on the Beagle Channel. Before the trip I was not informed about how to distinguish Macronectes giganteus from the very similar Northern Giant Petrel, Macronectes halli. Fortunately for me, Eva was very active with her camera and took a photograph (see above) of an individual in Ushuaia which shows what I later learned to be a characteristic feature of M. giganteus, namely the fact that the tip of the bill is green. There does exist a light morph which is mainly white but we did not see any of those.

I will now mention something else which is related to the trip to South America. Someone in our group mentioned that Stefan Zweig has written a book about Magellan and since I admire Zweig’s writing I decided to read it. I remember that when I was at school we learned about Henry the Navigator and the other Portuguese explorers who found the sea route to India. At that time I had no interest in such things but now I enjoyed being reminded of this. When reading the part related to South America I had a much closer relationship to it having been in that region myself. If I could return to Punta Arenas I would look at the replica of the ship ‘Victoria’, the only ship of Magellan’s fleet which got back to Spain, with other eyes. What was the importance of Magellan’s voyage? It probably had much less economic influence than expected. It did have an important influence on ideas. The one part was that it gave a concrete demonstration that the world is round. A more subtle but fundamental point was the fact that the travellers discovered that they had lost a day although they had kept time very carefully. This led to lively discussions among the scholars in Europe.

Trip to Ushuaia, Part 2

February 26, 2018

The reason for visiting El Calafate was its proximity to the glacier Perito Moreno. In the garden of our hotel there was a Buff-Necked Ibis, an attractive species which we saw repeatedly during the rest of our trip. Perito Moreno has interesting dynamical properties. I wonder if it has ever been modelled mathematically? Let me describe the process. The glacier comes from a peninsula and its lower end enters a lake, the Lago Argentino. It then proceeds until it has crossed the lake, which is quite narrow at that point. When it has reached the other side it separates one arm of the lake from the main part. The lake has an outflow but none in the smaller separated part. Thus the water level in the separated part rises compared to that in the main part. At the moment the difference in the levels is about thirty meters. This results in flooding of the surrounding land. We visited one farm there where an important part of the grazing land has already been submerged. The process just described leads to the water exterting a strong force on the glacier. This pressure is first released to a limited extent when water starts to flow under the glacier. This flow increases in intensity and produces a kind of arch which is flows under. Pieces of ice break off the arch successively, making it higher and higher. Eventually, about three days after the water has first penetrated the ice the arch is so narrow and high it collapses and then the obstruction has been removed. We are back at the starting point of the process. All this could be seen in a video in the glacier museum. The next breakthrough of the water is expected within the next few months but nobody knows exactly when it will happen.

From El Calafate we travelled overland and crossed the border into Chile.We had hardly crossed the border when we saw our first Andean Condor. This part of Chile has no road connection within the country to the rest of Chile. All necessary goods are imported by ship and the prices are correspondingly high. We were first in Puerto Natales. There it was convenient to observe the local ducks and cormorants along the waterfront. There is a statue of a giant sloth, a creature whose remains were found in a cave in the region. We travelled to the Torres del Paine, a spectacular mountain range. What you can see there is heavily dependent on the weather and we were quite lucky. Only the very top of the largest of the three ‘Cuernos’ (horns) refused to emerge from the clouds as long as we were there. What sounded like thunder turned out to be an avalanche. From Puerto Natales we travelled to Punta Arenas on the Strait of Magellan. There we visited some reconstructions of famous naval vessels. There is the Beagle, with which Darwin travelled, one of the ships of the expedition of Magellan himself and the modified lifeboat with which Shackleton sailed from Elephant Island to South Georgia and thus saved the lives of the members of his expedition. The text of the famous advertisement with which Shackleton recruited men for this expedition is reproduced there. According to Wikipedia the story of this advertisement is apocryphal but the text is so delicious that I cannot resist repoducing it here: ‘Men wanted for hazardous journey. Low wages, bitter cold, long hours of complete darkness. Safe return doubtful. Honour and recognition in event of success’.

From Punta Arenas we flew to Puerto Montt and travelled from there to Puerto Vargas. Here the attraction was the volcano Osorno. This time our luck with the weather seemed to be at an end. Our guide explained in a quite amusing manner how if the weather had been different the wall of cloud which we saw in a certain direction would have been replaced by a view of the beautiful volcano. In fact it turned out that there was a small window before breakfast the next day where the volcano could be seen from the hotel. The last step of the journey was a flight to Santiago. The city did not make a very good impression at first sight. Compared with Buenos Aires all the signs seemed to be reversed. Later we learned that the city is divided very strictly along economic lines. The rich upper part of the city looks quite different to the rest. We learned about the story of Chile as a model system for testing neoliberal theories. Just now the Chileans, who used to be considered as very backward are proud to be doing better (economically) than their neighbours, the Argentinians. We also had the opportunity to learn from our guides about the politics of Allende and Pinochet, in particular that Pinochet still enjoys considerable popularity in Chile.

We flew back from Santiago to Frankfurt via Madrid, our heads full of many images of Argentina, Chile, their people and their natural environment.

Trip to Ushuaia

February 25, 2018

Eva and I have just come back from a trip to Argentina and Chile. I had been in Argentina twice before, for conferences. The country made a positive impression on me but I did not have time to see very much. At that time I thought I should come back to see more. Now I have finally got around to doing so. The trip could have ended almost before it started since we almost missed our flight. I usually leave plenty of time when travelling to the airport and this was no exception. The ICE which we intended to take to travel from Mainz to Frankfurt airport was cancelled, without a explanation being offered. We then got into the regional train which was the next possibility. It just sat there instead of leaving. Then there was an announcement to say that because of a problem with points it would take a different route and, in particular, would not stop at Frankfurt airport. Our only hope was to travel to the main station in Frankfurt and then back to the airport. The situation seemed chaotic due the problem with the points already mentioned and the fact that there were people on the tracks somewhere. Even the ticket collector on the train did not seem to be able to give us a reasonable suggestion. Eventually we got to the airport and after running throught the airport and jumping a few queues we did get to our flight. We would have preferred a less stressful start to our journey. We flew via Sao Paulo to Buenos Aires and joined the group there. (This was an organized group trip).

The first time I visited Argentina I also flew to Buenos Aires but I saw almost nothing of the city. I just took a taxi from the international airport to the domestic one and my memory was that it drove around the periphery. Looking at how the airports lie this impression was probably mistaken. During my first trip I had a few hours to wait for my continuing flight to Cordoba and I was able to watch the for me exotic gulls, since the airport is close to the water. This time we were warned on arrival about the dangers of the city and how to behave so as to avoid them. We actually had no problems although we did not pay that much attention to security issues. One member of the group was attacked in the middle of the day close to our hotel. A man jumped on his back and tried to steal his watch. I do not think the watch was of particular value but the thief could not know that. Two brave women came and intervened and the thief ran away without the watch. The victim was left with some nasty-looking bruises on his arm but there was no further damage.

Our impression of Buenos Aires was of a beautiful city with a very pleasant atmosphere. It must be said that the days we were there were holidays, so that we experienced the city in a much more relaxed mode than it would be in on a working day. We discovered that there is a very nice nature reserve within easy walking distance of the city. My experience travelling with groups which are not specialised on birds is that if you go anywhere which might be good for birds you see so little that it is frustrating. The present trip was an exception to this rule. In the reserve area near Buenos Aires one of the most prominent species was the Jacana, whch was numerous. Some other prominent sightings were Roseate Spoonbill, Black-Necked Swan (which we later also saw in many other places), Red-Crested Cardinal and a Hummingbird of an undetermined species. From our guides we learned a bit about the complicated subject of Argentinian politics. One story which stuck in my mind and which I reproduce here without further comment is the following. There was a time when many Argentinians were protesting about the meat prices being too high. The Kirchners banned the export of beef. The result was a situation of overproduction which did lead to a decrease in the prices. This led in turn to many producers going out of business or drastically cutting their stocks. The final results were then shortages (beef had to be imported to Argentina from Uruguay!) and that a key national industry had been damaged in a major and probably irreparable way.

After a couple of days in Buenos Aires we flew to Trelew and spent some time exploring the Valdes peninsula, staying in Puerto Madryn. We learned what dry pampa looks like, a brown very dry landscape which in that area forms huge monotone expanses. At that stage I did not find the landscape attractive although other variants we saw in other areas later looked better. We were able to see some of the standard wildlife: sea elephants, sea lions and a huge colony of Magellanic Penguins. The temperature was around 30 degrees (I mean Celcius, not Fahrenheit) and the penguins were suffering a lot from the heat. I was pleasantly suprised to get a close view of an armadillo. The towns in this area was established by settlers from Wales, which explains the curious names. I would be interested to read about the adventures of these pioneers.

After this we flew to the town mentioned in the title of this post, Ushuaia. Before the trip I felt that Ushuaia was more like a mythical place than a real one. But now I have been there. Because of a last-minute change of plane schedule we had less time in Ushuaia than planned. Despite this we were able to take a trip on the Beagle channel with a catamaran in the late afternoon. The weather was excellent. For me this was the highlight of the whole trip. In the town itself we saw Dolphin Gulls and the first Giant Petrels. We visited some seabird islands with breeding colonies of terns and cormorants. We even landed on one island where there were Great Skuas flying around. In one place I saw a couple of Sheathbills on the beach. What was special is that we came to one place where there was a big concentration of fish. There was a corresponding concentration of seabirds, including several Albatrosses. Afterwards one Black-Browed Albatross followed the ship for quite a long time. At 22.00 we caught a flight to El Calafate.

SMB conference in Utah

July 21, 2017

I have just attended the annual meeting of the Society for Mathematical Biology in Salt Lake City. Before reporting on my experiences there I will start with an apparently unrelated subject. I studied and did my PhD at the University of Aberdeen and I am very satisfied with the quality of the mathematical education I received there. There was one direction in mathematics in which I did not get as much training as I later needed, namely analysis and partial differential equations. This was not the fault of the lecturers, who had enough expertise and enthusiasm for teaching these things. It was the fault of the students. Since it was a small department the students chose which advanced courses were to be offered from a list of suggestions. Most of the students (all of them except me?) did not like analysis and so most of the advanced courses with a significant analysis content were not chosen. By the time I got my first postdoc position I had become convinced that in the area I was working in the research based on differential geometry was a region which was overgrazed and the thing to do was to apply PDE. Fortunately the members of the group of Jürgen Ehlers which I joined were of the same opinion. The first paper I wrote after I got there was on a parabolic PDE, the Robinson-Trautman equation. I had to educate myself for this from books and one of the sources which was most helpful was a book by Avner Friedman. Here is the connection to the conference. Avner Friedman, now 84 but very lively, gave a talk. Mathematically the subject was free boundary value problems for reaction-diffusion-advection equations, Friedman’s classic area. More importantly, these PDE problems came from the modelling of combination therapies for cancer. The type of therapies being discussed included antibodies to CTLA-4 and PD-1 and Raf inhibitors, subjects I have discussed at various places in this blog. I was impressed by how much at home Friedman seemed to be with these biological and medical themes. This is maybe not so surprising in view of the fact that he did found the Institute for Mathematical Biosciences in Ohio and was its director from 2002 to 2008. More generally I was positively impressed by the extent to which the talks I heard at this conference showed a real engagement with themes in biology and medicine and evidence of a lot of cooperations with biologists and clinicians. There were also quite a number of people there employed at hospitals and with medical training. As an example I mention Gary An from the University of Chicago who is trained as a surgeon and whose thoughtful comments about the relations between mathematics, biology and medicine I found very enlightening. There was a considerable thematic overlap with the conference on cancer immunotherapy I went to recently.

Now Subgroups are being set up within the Society to concentrate on particular subjects. One of these, the Immunobiology and Infection Subgroup had its inaugural meeting this week and of course I went. There I and a number of other people learned a basic immunological fact which we found very surprising. It is well known that the thymus decreases in size with age so that presumably our capacity to produce new T cells is constantly decreasing. The obvious assumption, which I had made, is that this is a fairly passive process related to the fact that many systems in our bodies run down with age. We learned from Johnna Barnaby that the situation may be very different. It may be that the decrease in the size of the thymus is due to active repression by sexual hormones. She is involved in work on therapy for prostate cancer and said that it has been found that in men with prostate cancer who are getting drugs to reduce their testosterone levels it is seen that their thymus increases in size.

There were some recurrent themes at the conference. One was oncolytic viruses. These are genetically engineered viruses intended to destroy cancer cells. In modelling these it is common to use extensions of the fundamental model of virus dynamics which is very familiar to me. For instance Dominik Wodarz talked about some ODE models for oncolytic viruses in vitro where the inclusion of interferon production in the model leads to bistability. (In reponse to a question from me he said that it is a theorem that without the interferon bistability is impossible.) I was pleased to see how, more generally, a lot of people were using small ODE models making real contact to applications. Another recurrent theme was that there are two broad classes of macrophages which may be favourable or unfavourable to tumour growth. I should find out more about that. Naveen Vaidya talked about the idea that macrophages in the brain may be a refuge for HIV. Actually, even after talking to him I am not sure if it should not rather be microglia than macrophages. James Moore talked about the question of how T cells are eliminated in the thymus or become Tregs. His talk was more mathematical than biological but it has underlined once again that I want to understand more about positive and negative selection in the thymus and the related production of Tregs.

On a quite different subject there were two plenary talks related to coral reefs. A theme which is common in the media is that of the damage to coral due to climate change. Of course this is dominated by politics and usually not accompanied by any scientific information on what is going on. The talk of Marissa Blaskett was an excellent antidote to this kind of thing and now I have really understood something about the subject. The other talk, by Mimi Koehl, was less about the reefs themselves but about the way in which the larvae of snails which graze on the coral colonize the reef. I found the presentation very impressive because it started with a subject which seemed impossibly complicated and showed how scientific investigation, in particular mathematical modelling, can lead to understanding. The subject was the interaction of microscopic swimming organisms with the highly turbulent flow of sea water around the reefs. Investigating this involved among other things the following. Measuring the turbulent flow around the reef using Doppler velocimetry. Reconstructing this flow in a wave tunnel containing an artificial reef in order to study the small-scale structure of the transport of chemical substances by the flow. Going out and checking the results by following dye put into the actual reef. And many other things. Last but not least there was the mathematical modelling. The speaker is a biologist and she framed her talk by slides showing how many (most?) biologists hate mathematical modelling and how she loves it.

Conference on mathematical analysis of biological interaction networks at BIRS

June 9, 2017

I have previously written a post concerning a meeting at the Banff International Research Station (BIRS). This week I am at BIRS again. Among the topics of the talks were stochastic chemical reaction networks, using reaction networks in cells as computers and the area of most direct relevance to me, multiple steady states and their stability in deterministic CRN. Among the most popular examples occurring in the talks in the latter area were the multiple futile cycle, the MAPK cascade and the EnvZ/OmpR system. In addition to the talks there was a type of event which I had never experienced before called breakout sessions. There the participants split into groups to discuss different topics. The group I joined was concerned with oscillations in phosphorylation cycles.

In the standard dual futile cycle we have a substrate which can be phosphorylated up to two times by a kinase and dephosphorylated again by a phosphatase. It is assumed that the (de-)phosphorylation is distributive (the number of phosphate groups changes by one each time a substrate binds to an enzyme) and sequential (the phosphate groups are added in one order and removed in the reverse order). A well-known alternative to this is processive (de-)phosphorylation where the number of phosphate groups changes by two in one encounter between a substrate and an enzyme. It is known that the double phosphorylation system with distributive and sequential phosphorylation admits reaction constants for which there are three steady states, two of which are stable. (From now on I only consider sequential phosphorylation here.) By contrast the corresponding system with processive phophorylation always has a unique steady state. Through the talk of Anne Shiu here I became aware of the following facts. In a paper by Suwanmajo and Krishnan (J. R. Soc. Interface 12:20141405) it is stated that in a mixed model with distributive phosphorylation and processive dephosphorylation periodic solutions occur as a result of a Hopf bifurcation. The paper does not present an analytical proof of this assertion.

It is a well-known open question, whether there are periodic solutions in the case that the modificiations are all distributive. It has been claimed in a paper of Errami et. al. (J. Comp. Phys. 291, 279) that a Hopf bifurcation had been discovered in this system but the claim seems to be unjustified. In our breakout sessions we looked at whether oscillations might be exported from the mixed model to the purely distributive model. We did not get any definitive results yet. There were also discussions on effective ways of detecting Hopf bifurcations, for instance by using Hurwitz determinants. It is well-known that oscillations in the purely distributive model, if they exist, do not persist in the Michaelis-Menten limit. I learned from Anne Shiu that it is similarly the case that the oscillations in the mixed model are absent from the Michaelis-Menten system. This result came out of some undergraduate research she supervised. Apart from these specific things I learned a lot just from being in the environment of these CRN people.

Yesterday was a free afternoon and I went out to look for some birds. I saw a few things which were of interest to me, one of which was a singing Tennessee warbler. This species has a special significance for me for the following reason. Many years ago when I still lived in Orkney I got an early-morning phone call from Eric Meek, the RSPB representative. He regularly checked a walled garden at Graemeshall for migrants. On that day he believed he had found a rarity and wanted my help in identifying it and, if possible, catching it. We did catch it and it turned out to be a Tennessee warbler, the third ever recorded in Britain. That was big excitement for us. I had not seen Eric for many years and I was sad to learn now that he died a few months ago at a relatively young age. The name of this bird misled me into thinking that it was at home in the southern US. In fact the name just came from the fact that the first one to be described was found in Tennessee, a migrant. The breeding range is much further north, especially in Canada. Thus it is quite appropriate that I should meet it here.

Becoming a German citizen

May 24, 2017

I first moved to Germany in 1987 and I have spent most of the time since then here. The total time I have spent elsewhere since my first arrival in Germany does not add up to more than two years. There is every reason to expect I will spend the rest of my life here. I am married to a German, I have a job here I like and a house. I could have applied for German citizenship a long time ago but I never bothered. Being an EU citizen living in Germany I had almost almost all privileges of a native. The only exception is that I could not vote except in local elections but since I am not a very political person that was not a big issue for me. It was also the case that for a long time I might have moved to another country. For instance I applied for a job in Vienna a few years ago and I might well have taken it if it had been offered to me. Now the chances of my moving are very small and so there is no strong argument left against becoming a German citizen.

What is more important is that there are now arguments in favour of doing so. With the EU showing signs of a possible disintegration the chance that I could lose the privileges I have here as an EU citizen is not so small that it should be neglected. The referendum in which the Scots voted on the possibility of leaving the UK was the concrete motivation for my decision to start the application process. Scotland stayed in the UK but then the Brexit confirmed that I had made the right decision. At the moment there is no problem with keeping British citizenship when obtaining German citizenship and I am doing so. This may change sometime, meaning that I will have to give up my British citizenship to keep the German one, but I see this as of minor importance.

As prerequisites for my application I had to do a number of things. Of course it was necessary to submit a number of documents but I have the feeling that the amount of effort was less than when obtaining the documents needed to get married here. I had to take an examination concerning my knowledge of the German language, spoken and written. It was far below my actual level of German and so from that point of view it was a triviality. It was just a case of investing a bit of time and money. I also had to do a kind of general knowledge test on Germany and on the state where I live. This was also easy in the sense that the questions were not only rather simple for anyone who has lived in the country for some time but they are also taken from a list which can be seen in advance. Again it just meant an investment of time and money. At least I did learn a few facts about Germany which I did not know before. In my case these things were just formalities but I think it does make sense that they exist. It is important to ensure that other applicants with a background quite different from mine have at least a minimal knowledge of the language and the country before they are accepted.

After all these things had been completed and I had submitted everything it took about a year before I heard that the application had been successful. This time is typical here in Mainz – I do not know how it is elsewhere in Germany – and it results from the huge backlog of files. People are queueing up to become German citizens, attracted by the prospect of a strong economy and a stable political system. Yesterday I was invited to an event where the citizenship of the latest group of candidates was bestowed in a ceremony presided over by the mayor. There were about 60 new citizens there from a wide variety of countries. The most frequent nationality by a small margin was Turkish, followed by people from other middle eastern countries such as Iraq and Iran. There were also other people from the EU with the most frequent nationality in that case being British. My general feeling was one of being slightly uneasy that I was engaged in a futile game of changing horses. It is sad that the most civilised countries in the world are so much affected by divisive tendencies instead of uniting to meet the threats confronting them from outside.

Herbal medicine and its dangers

December 18, 2016

I recently heard a talk by Thomas Efferth of the Institute for Pharmacology of the University of Mainz on herbal medicine. There is a common point of view that substances derived from plants are harmless and good while the chemical drugs of standard medicine are evil. The speaker emphasized that plants have good reasons for not being good to those who eat them. They do not have immune systems of the type we do and they cannot run away and so it is natural that they use poisons to defend themselves. Herbal medicines are effective in some cases but they need to be subject to controls as much as do substances obtained by artificial chemical means. In the talk a number of examples of the dangers of ‘natural’ medicines were presented and I will write about some of them here.

The first example is that of Aristolochia. This a large genus of plants, some of which are poisonous. One of these, Aristolochia clematitis, has been extensively used in herbal medicine. It was used extensively in the west in ancient times and is used in traditional Chinese medicine until today. In the talk the story was told of an incident which happened in Belgium. There was a product sold as a means of losing weight which contained a Chinese plant. It sold so well that the manufacturer’s supplies of the plant were running out. When more was ordered a fateful mistake took place. There are two plants which have the same name in China. The one is that which was originally contained in the weight-loss product. The other is the poisonous Aristolochia fangchi and it was the one which was delivered. This led to more than 100 cases of kidney failure in the people using the product. Another way in which plants can be dangerous is as weeds in crop fields. In the Balkans contamination of grain with Aristolochia clematitis led to a kidney disease called Balkan nephropathy, with 35000 recorded cases. The substance, aristolochic acid, which is responsible for the kidney toxicity is also known to be a strong carcinogen. Interestingly, this substance is not poisonous for everyone and its bad effects depend a lot on the variability in liver enzymes among individuals.

A class of substances used by many plants to protect themselves against insects are the pyrrolizidine alkaloids. These substances are hepatotoxic and carcinogenic. They may move through the food chain being found, for instance, in honey. It has been noted that there may be risks associated to the amount of these substances contained in medicinal herbs used both in the West and in China. It was mentioned in the talk that drinking too much of certain types of herbal tea may be damaging to health. The problem is usually not the plants that are the main components of the teas but other plants which may be harvested with them in small quantities. There is at least one exception to this, namely coltsfoot (Tussilago farfara). In one case the death of an infant due to liver disease is believed to be due to the mother drinking this type of tea during pregnancy. After that the sale of coltsfoot was banned in Germany.

There were some remarks in the talk on heavy metals which I found quite suprising. One concerned ayurvedic medicine which has an aura of being gentle and harmless. In fact in many of these substances certain heavy metals are added delibrately (lead, mercury and arsenic). According to Wikipedia more than 80 cases of lead poisoning due to ayurvedic ‘medicines’ have been recorded. Another remark was that there can be significant concentrations of heavy metals in tobacco smoke. The negative health effects of smoking are sufficiently well known but this aspect was new to me.

Another theme in the talk was interactions between herbal medicines and normal drugs. Apparently it is often the case that patients who use herbal remedies are afraid to mention this to their doctors since they think this may spoil the relationship to their practitioner. Then it can happen that a doctor is suprised by the fact that a drug he prescribes is not working as expected. Little does he know that the patient is secretly taking a ‘natural’ drug in parallel. An example is St. John’s wort which is sometimes taken as a remedy for depression. It may work and it has no direct negative effects but it can be problematic because it reduces the effects of other drugs taken at the same time, e.g. the contraceptive pill. It changes the activity of liver enzymes and causes them to eliminate other drugs from the body faster than would normally happen, thus causing an effective reduction of the dose.

We are surrounded by poisonous plants. I was always sceptical of the positive effects of ‘natural’, plant-derived medicines. Now I have realised how seriously the dangers of these substances should be taken.