Marie Curie Individual Fellowships: be in touch!

The deadline for Marie Curie Individual Fellowships is 11th September. We would be very interested to hear from anyone interested in putting in an application with us to work in our labs, particularly in the areas of Bioinformatics / Computational Biology / Mathematical Modelling applied to pathogenic microbes (E. coli or other pathogens).

Details can be found on the EU Horizon 2020 web site.

If you would like to apply with us, the University of Nottingham has excellent professional writing support, with success rate considerably higher than the European average.

 

New publication: AtMYB93 is a novel negative regulator of lateral root development in Arabidopsis

Thanks to Juliet Coates, we have a new publication:

Gibbs, D. J., Voß, U., Harding, S. A., Fannon, J., Moody, L. A., Yamada, E., Swarup, K., Nibau, C., Bassel, G. W., Choudhary, A., Lavenus, J., Bradshaw, S. J., Stekel, D. J., Bennett, M. J. and Coates, J. C. 2014. AtMYB93 is a novel negative regulator of lateral root development in Arabidopsis. New Phytologist. doi: 10.1111/nph.12879.

Summary

  • Plant root system plasticity is critical for survival in changing environmental conditions. One important aspect of root architecture is lateral root development, a complex process regulated by hormone, environmental and protein signalling pathways.
  • Here we show, using molecular genetic approaches, that the MYB transcription factor AtMYB93 is a novel negative regulator of lateral root development in Arabidopsis.
  • We identify AtMYB93 as an interaction partner of the lateral-root-promoting ARABIDILLO proteins. Atmyb93 mutants have faster lateral root developmental progression and enhanced lateral root densities, while AtMYB93-overexpressing lines display the opposite phenotype. AtMYB93 is expressed strongly, specifically and transiently in the endodermal cells overlying early lateral root primordia and is additionally induced by auxin in the basal meristem of the primary root. Furthermore, Atmyb93 mutant lateral root development is insensitive to auxin, indicating that AtMYB93 is required for normal auxin responses during lateral root development.
  • We propose that AtMYB93 is part of a novel auxin-induced negative feedback loop stimulated in a select few endodermal cells early during lateral root development, ensuring that lateral roots only develop when absolutely required. Putative AtMYB93 homologues are detected throughout flowering plants and represent promising targets for manipulating root systems in diverse crop species.

And it has even made BBSRC headlines.

To be fair, most credit goes to Juliet and to Dan Gibbs, who have been working on this project for many years. My contribution is fairly minor: I am responsible for the p-values in the manuscript! One of the referees was unhappy that some of the claims lacked statistical backing (which is fair enough – I would have made the same point as a referee) so I ran some likelihood ratio tests with simulated data in order to ensure that all claims had statistical backing. I’m really pleased for Juliet and Dan, because I know how much they have put into this paper.

 

Some personal reflections on D-Day and both World Wars

Today is the 70th anniversary of D-Day. Just as poignantly, we approach the 100th anniversary of the start of World War 1. Like many people, I find myself thinking about what these world wars mean to me. This is my lab blog, where I write about science, or things pertaining to science. In this post I try to reflect my thoughts on the wars through three facets of my identity: as English, as Jewish and as a Scientist.

The trench warfare of WW1 have always had a particular horror to them: the battles of the Somme and Passchendaele,have somehow gained a reputation as being the worst warfare in human history. A pointless bloodiness, incompetent generals and terrible human sacrifice. Growing up in England, it has always been the “British” experience that I have learned, and along with that, a palpable sense of “relief” when it comes to the stories of “winning” that war.

But it really is not as simple as that. My family history is actually from the “other” side. My four grandparents were all born between 1910 and 1915 and so were all small children during WW1. My great-grandparents would have been young adults, and probably most of my great-great-grandparents would have experienced WW1 too. All of my family lived in the Central Powers: my father’s parents in Austria and my mother’s parents in Hungary. Indeed, my paternal grandfather was born en-route from Western Ukraine (where the Stekel name originates) to Vienna, as they fled the Russian invasion (a somewhat poignant 100 years ago given the current situation). I don’t know if any of my great-grandparents served in WW1 – it is entirely possible – certainly their families would have suffered greatly as a consequence of the war – indeed, as a consequence of British actions, that, at least in the stories I have grown up with, I “support”.

So much as I honour the sacrifice of the people of WW1, it also seems somewhat absurd to talk of “sides”. For different reasons, I stand on both sides on that war, and in the end, for the young men in the mud and blood of Passchendaele, the suffering was the same whether they were British or German. With the benefit of hindsight, it just all seems like a terrible tragedy and waste.

World War 2 might seem more “obvious”, especially given the Jewish dimension. My father’s parents fled Vienna to England in 1938, while my maternal grandmother was one of the few members of my mother’s family to survive Auschwitz. D-Day really did save my family, and when I read posts from friends about their grandparents actions on D-Day, I feel a profound sense of gratitude. Indeed, today, when our nearly 3-year-old daughter saw a D-Day veteran on TV, I said to her “that man and others like him rescued my grandmother from a bad place, and we wouldn’t be here if it weren’t for him.” So, born in England, to Jewish family, a double dose of fighting against the Nazis.

But there is complexity here too. My maternal grandfather served in WW2. He fought for Hungary, who were allied with Germany, against the Russians. He was captured early in the war, and spent most of the war in prisoner of war camp in Siberia (more on that later). So, technically, he was on the “other side” too. And this is it. It was a world war, not just a war between England and Germany, and so for people whose family histories are international, things become less clear-cut.

There is a lot I could write about my family history in WW2, but I don’t want to dwell on it, because I want to turn back to science. Scientists, and scientific discoveries, have played a role in warfare throughout history. There were many contributions of scientists and mathematicians to the two world wars. But there is one that, for a number of reasons, I feel a particular connection with, and that is the development of the atomic bomb.

Studying mathematics and theoretical physics as a teenager and young adult, we idolized the physicists of the first half of the 20th century. It was a golden age, and these people revealed how matter works, how atoms works, and came up with the great theories: relativity, radioactivity, quantum mechanics and so forth. There is almost a sense of teleology in the collection of physicists at Los Alamos who invented the nuclear bomb. And, like my father’s family, many of these physicists where themselves Jewish people who had fled the Nazis. It becomes even more personal because twenty years ago I spent a summer working at the Los Alamos National Laboratory. It was civilian work (like most of the work there), in my case mathematical models of HIV infection. I was part of the lab, and the Jewish community there, and met many truly wonderful people. So I have a first-hand personal connection to Los Alamos.

And here lies the problem. Because “we” – the people I identify with on all fronts (British – or Allies really, Jewish and Scientist) – invented the most terrible weapon in human history – and “my side” used this weapon against the civilian population of Japan. Twice. There is a totally different relationship to an atrocity where one associates as victim/survivor (i.e. the holocaust) to where one associates as perpetrator (i.e. Hiroshima and Nagasaki). The former – however horrible – is in some ways “easy” because one has a sense of “moral right” on one’s side. The latter is much harder to face – especially if you do not want to descend into any kind of apologism.

Four years ago I received a research grant to work with Japanese colleagues, and this has led to several wonderful visits. My travel in Japan was restricted to places relevant to work. However, having worked in Los Alamos, I feel a strong need to go to at least one of these cities and to leave some mark of peace, although I have not yet had that opportunity. We are so privileged to live in a different world now – and we do have former generations to thank for that. I have only known peace with Germany and Japan. And one of the greatest things about working in research science is just how international it is. We coalesce around research interests and meet and work with colleagues from around the world. National boundaries are irrelevant: we are united by a passion for science and discovery (truly, really, this is not hyperbole). So I have met many wonderful people from all sorts of countries – including of course Germany and Japan, as well as more modern day “enemy” countries – Syria, Iraq, Iran or whomever are portrayed as the current “bad guys”. When you meet amazing people from around the world you realize just how ridiculous and petty nationalism (and especially ethnocentric nationalism) is – even if its consequences in warfare are appalling.

So at this one hundredth anniversary I wish to send a message of peace and brotherhood to all my friends and colleagues – whether from the old “enemy” countries or the new ones. Sadly, there are still wars in this world. There is still ethnic nationalism, and here in Britain, and indeed across Europe, people’s memories are short, and we are witnessing a rise in support for nationalist political parties.

But our shared humanity is stronger – must be stronger. For human suffering is the same. Whichever trench are in, the fear, blood and mud are the same. The flesh that burned in Auschwitz or Hiroshima is the same flesh. All we can do is celebrate each other, celebrate the peace that we have. As a scientist, I publish research papers, and it is particularly in the names of my co-authors that I feel a strong sense of shared humanity that transcends national boundaries. In those research papers, my name, from Jewish Western Ukraine, joins names from America, Australia, Austria, Belgium, Bosnia, China, Egypt, England, Germany, Holland, India, Iran, Israel, Italy, Japan, Mexico, Pakistan, Poland, Russia, Sri Lanka and Wales.

My final story is a myth I have created. My mother’s father was captured early in WW2, and spent most of it in prisoner of war camp in Siberia. On my first visit to Japan, one of my colleagues (friend really) took me for a trip around Kyoto. At the end of the day, we dropped into his grandparents’ flat, where his pregnant wife was resting. His grandparents insisted in inviting me in. It was wonderful – actually probably the best experience of Japan I had. Their flat was traditionally Japanese – we sat on tatami mats, to a backdrop of calligraphic wall hangings, and my friend’s wife served us perfectly made green tea in porcelain cups on low tables, and, where I sat, I had a view of a photograph of the grandfather as a young man in his uniform, complete with Samurai sword. His grandfather told me (in Japanese) how he spent most of the war in prisoner of war camp in Siberia. I thought about my own grandfather whose war was also spent in Siberia. In truth, our grandfathers probably never met, and even if they had, they could not have conversed. But in my head, my story, is that they did meet. One cold winter’s morning, after several hours of hard labour, they sat together on a fallen tree and shared a contraband cigarette: the only shared language they could have was that moment of rest and enjoyment of the cigarette. My Japanese friend and I are writing a research paper together. We each have two young daughters of very similar ages. What can war or enmity possibly mean?

New Publication: Computational Prediction of Domain-domain Interactions: Factor-graph Based Modelling and Inference

This is very much Mudassar’s paper – a review of work he has done prior to being in my lab. Full credit (and congratulations) goes to Mudassar. That said, we very much appreciate Charlie’s editorial input that really helped improve the final version.

 

Iqbal, M., Hodgman, T.C. and Stekel, D.J. 2014. Computational prediction of domain-domain interactions: factor-graph based modelling and inference. Current Chemical Biology 7:234-240.

Abstract

Proteins interact with each other to perform an array of cellular functions. A systems-level knowledge of protein interaction networks, as well as the underlying domain-domain interactions, constitutes a major goal in systems biology. In this mini-review, we discuss some background to the problem of inference of domain-domain interactions and briefly discuss some relevant computational and statistical approaches. Specifically, we review our earlier work in which we formulate this problem using a graphical model combined with inference of domain-interaction probabilities using powerful statistical inference methods, namely belief propagation. The inferred interactions can be used for analysing network data, and, by looking at the specificity of protein-protein interactions, they can also be used to predict novel protein interactions within and across orthologous species.

Writing an equation in concrete: is this the cure for cancer?

Stekels_R_Blog

We are having a new downstairs bathroom fitted, and, with a freshly screeded concrete floor, I decided to inscribe the equation of the R statistic from Stekel, Git and Falciani 2000. This is the second time I have inscribed an equation somewhere unusual: the first time being the T-cell recirculation equation from Stekel 1997 in the snow at Annapurna Base Camp – more on that story later. The R statistic equation will soon be covered by some nice new cushioned floor, and will remain covered for many years.

When the bathroom fitter saw it he was somewhat bemused: he was more used to seeing people’s names in such situations! Interestingly, he asked “Is this the cure for cancer?”. I said, well, not exactly, but it can be used to compare cancer cells with healthy cells to find genes that could help with a cure. He and his colleague looked suitably impressed! Actually, I wrote this equation because I now recognize that this equation is, so far, my most impactful piece of original research. According to Google Scholar, that paper has now been cited 247 times; only my book has been cited more often. Funnily enough, although the original application was in cancer, the most prominent citations are mostly in plant and crop science, where the use of EST libraries has been particularly valuable.

Of course, now EST libraries are rarely used, and next generation sequencing has taken their place. This R statistic isn’t really appropriate for NGS gene expression comparison: the statistic is derived on the basis of Poisson distribution of sequence counts, which is not the case for NGS, where the sequence counts are better described by negative binomial distributions. Estimating good parameters for negative binomials is tougher, and several groups have written good software for comparing gene expression with NGS including DESeq and edgeR.

Nonetheless, the R statistic remains popular. The paper was not perfect (I most regret not being aware of Benjamini and Hochberg’s false discovery rate at the time), but I still think that, where the Poisson assumption is appropriate, the use of this statistic remains the best possible approach. So I am proud of my contribution and wrote the equation into the concrete.

Now to the Annapurna story. In April 2001 I went trekking in Nepal, reaching Annapurna Base Camp on a fairly classic walk. Feeling frustrated about my contributions to science while working in the pharmaceutical / biotechnology sector, I inscribed into the snow the equation from my PhD that described the interaction between recirculating T-cells and dentritic cells. At the time this was the work I was most proud of. Of course, as I have written previously, that mechanism has since been proven wrong. What is even more ironic is that I had already published the R statistic, although it had not yet received many citations. Moreover, the work for the R statistic was carried out while Francesco Falciani and I were working at Glaxo, and Yoav Git was working for an investment bank! Such is hindsight.