# Selection of the week

Songs of a Wayfarer by Gustav Mahler, sung by mezzo soprano Sarah Connolly with the BBC Symphony Orchestra.

# Talk at Michigan

I gave a talk in the Department of Computational Medicine and Bioinformatics at the University of Michigan yesterday. The video of the talk is here.  The talk is similar to the one I gave at the SMB annual meeting this summer.  My slides can be found here.

# Selection of the week

Bela Bartok’s Romanian Folk Dances played by the Sydney Camerata Chamber Orchestra.

# The philosophy of Thomas the Tank Engine

My toddler loves to watch the television show Thomas and Friends based on the The Railway Series books by the Rev. Wilbert Audry. The show tells the story of sentient trains on a mythical island off the British coast called Sodor. Each episode is a morality play where one of the trains causes some problem because of a character flaw like arrogance or vanity that eventually comes to the attention of the avuncular head of the railroad, Sr. Topham Hatt (called The Fat Controller in the UK). He mildly chastises the train, who becomes aware of his foolishness (it’s almost always a he) and remedies the situation.

While I think the show has some educational value for small children, it also brings up some interesting ethical and metaphysical questions that could be very relevant for our near future. For one, although the trains are sentient and seem to have full control over their actions, some of them also have human drivers. What are these drivers doing? Are they simply observers or are they complicit in the ill-judged actions of the trains? Should they be held responsible for the mistakes of the train? Who has true control, the driver or the train? Can one over-ride the other? These questions will be on everyone’s minds when the first self-driving cars hit the mass market in a few years.

An even more relevant ethical dilemma regards the place the trains have in society. Are they employees or indentured servants of the railroad company? Are they free to leave the railroad if they want? Do they own possessions? When the trains break down they are taken to the steam works, which is run by a train named Victor. However, humans effect the repairs. Do they take orders from Victor? Presumably, the humans get paid and are free to change jobs so is this a situation where free beings are supervised by slaves?

The highest praise a train can receive from Sir Topham Hatt is that he or she was “very useful.” This is not something one would say to a human employee in a modern corporation. You might say you were very helpful or that your action was very useful but it sounds dehumanizing to say “you are useful.” Thus, Sir Topham Hatt at least, does not seem to consider the trains to be humans. Perhaps, he considers them to be more like domesticated animals. However, these are animals that clearly have aspirations, goals, and feelings of self-worth. It seems to me that they should be afforded the full rights of any other citizen of Sodor. As machines become more and more integrated into our lives, it may well be useful to probe the philosophical quandaries of Thomas and Friends.

# Selection of the week

Igor Stravinsky’s ballet Le sacre du printemps (The Rite of Spring), Part 1 with the San Francisco Symphony conducted by Michael Tilson Thomas. This piece ushered in the modern age. It cause minor rioting when first performed in Paris in 1913 but now is considered one of the masterpieces of the 20th century.

# R vs Matlab

It has now been almost half a year since I switched from Matlab to open source software and I’ve been amazed at how easy the transition has been. I had planned to replace Matlab with Python, Julia, and R but I have found that R and Julia have been sufficient for my requirements. Maxima is also more than adequate to replace Mathematica. I have become particularly attached to R especially after I started to use R Studio as the interface. I had only used R before as just a statistics tool but it really is a complete programming platform like Matlab. It has very nice graphics capabilities and I find the language very nice to program in. I really like its use of lists where I can pile sets of any type and any size into one object. I also like how R Studio can save your work into Projects, which keeps the whole environment and history in one place. I can then switch between multiple projects and everything comes back. The only thing I miss from Matlab is the command completion history feature, where I could easily find a previous command by just typing the first few letters. Also, I haven’t quite figured out how to output R data into a text file seamlessly yet. I seem to always get extraneous row or column information. I use Julia when I want to write a code that needs to loop fast but for everything else I’ve been reaching for R.

# Selection of the week

For Good Friday, here is the famous aria Erbarme dich from Johann Sebastian Bach’s St. Matthew Passion, with mezzosoprano Marianna Pizzolato.

If you have three spare hours, I would listen to the whole thing.  You should do this at least once in your life.

# New paper on gene repression

CC Chow, KK Finn, GB Storchan, X Lu, X Sheng, SS Simons Jr., Kinetically-Defined Component Actions in Gene Repression. PLoS Comp Bio. 11:e1004122, (2015)

Abstract

Gene repression by transcription factors, and glucocorticoid receptors (GR) in particular, is a critical, but poorly understood, physiological response. Among the many unresolved questions is the difference between GR regulated induction and repression, and whether transcription cofactor action is the same in both. Because activity classifications based on changes in gene product level are mechanistically uninformative, we present a theory for gene repression in which the mechanisms of factor action are defined kinetically and are consistent for both gene repression and induction. The theory is generally applicable and amenable to predictions if the dose-response curve for gene repression is non-cooperative with a unit Hill coefficient, which is observed for GR-regulated repression of AP1LUC reporter induction by phorbol myristate acetate. The theory predicts the mechanism of GR and cofactors, and where they act with respect to each other, based on how each cofactor alters the plots of various kinetic parameters vs. cofactor. We show that the kinetically-defined mechanism of action of each of four factors (reporter gene, p160 coactivator TIF2, and two pharmaceuticals [NU6027 and phenanthroline]) is the same in GR-regulated repression and induction. What differs is the position of GR action. This insight should simplify clinical efforts to differentially modulate factor actions in gene induction vs. gene repression.

Author Summary

While the initial steps in steroid-regulated gene induction and repression are known to be identical, the same cannot be said of cofactors that modulate steroid-regulated gene activity. We describe the conditions under which a theoretical model for gene repression reveals the kinetically-defined mechanism and relative position of cofactor action. This theory has been validated by experimental results with glucocorticoid receptors. The mode and position of action of four factors is qualitatively identical in gene repression to that previously found in gene induction. What changes is the position of GR action. Therefore, we predict that the same kinetically-defined mechanism usually will be utilized by cofactors in both induction and repression pathways. This insight and simplification should facilitate clinical efforts to maximize desired outcomes in gene induction or repression.

I am so happy that this paper is finally published.  It was a two-year ordeal from the time I had the idea of what to do until it finally came out. This is the second leg of the three-legged stool for a theory of steroid-regulated gene expression. The first was developing the theory for gene induction (e.g. see here) that started over ten years ago when Stoney and I first talked about trying to understand his data and really took off when Karen Ong turned her summer internship into a two-year baccalaureate fellowship. She’s now finishing up the PhD part of her MD-PhD at the Courant Institute at NYU.

In the first leg, we showed that if the dose-response curve for steroid-regulated gene induction (i.e. gene product as a function of ligand concentration), had the form  $a x/ (c+x)$, (which has been variously called noncooperative, Michaelis-Menten function, Hill function with Hill coefficient equal to 1, hyperbolic, first order Hill dose response curve, to give a few), then the dose-response could be written down in closed form.  The theory considers gene induction to be a sequence of complex forming reactions $Y_{i-1} + X_{i} \leftrightarrow Y_i$ for $i = 1, 2, ..., n$, and the dose-response is given by $[Y_n]$ as a function of $[Y_0]$, which in general is a very high order polynomial which is not Michaelis-Menten. However,  when some biophysically plausible conditions on the parameters are met, the polynomial can be represented by the group of lower triangular matrices and can be solved exactly.  We can then use the formulae to make predictions for the mechanisms of various transcription factors.

However, steroids also repress genes and interestingly enough the repression curve is also noncooperative and is given by the linear fractional function $a + bx/(1 + c x)$. The question then was how does this work. I was puzzled for a while on how to solve this but then thought that if we believe that the transcription machinery after initiation is mostly conserved then the induction theory we had previously derived should still be in place. What is different is that in repression instead of steroids initiating the cascade, there was some other agonist and steroid repressed this. In our induction theory, we included the effects of activators and inhibitors from enzyme kinetics, which we called accelerators and decelerators to avoid confusing with previously used terms. Because of the group property of the reactions, basically any function you are interested in has linear-fractional form. I thus postulated that steroids, after binding to a nuclear steroid receptor, acts like a decelerator. I then had to work out all the possible cases for where the decelerator could act and the large number of them made the calculations rather tedious. As a result, I made lots of mistakes initially and the theory just wouldn’t fit the data. I finally had a breakthrough in the fall of 2013 when I was in Taiwan for a workshop and everything started to come together. It then took another six months to work out the details and write the paper, which was then followed by several back and forth’s with the referees, a major rewriting and a final acceptance a few months ago. In the process of working on this paper, I discovered a lot of properties about the induction system that I didn’t realize. I still didn’t believe it was finished until I saw it posted on the PLoS Comp Bio website this week.

I’m currently putting on the finishing touches for revisions on the third leg of the stool now. We have even reunited the band and convinced Karen to take some time away from her thesis to help finish it. This paper is about how partial agonists or antagonists like tamoxifen work, which could have implications for drug development and avoiding side effects. Steroids are not the only ligand that can activate a steroid-regulated gene. The steroid cream that you use for rashes consists of a highly potent steroid agonist. There are also molecules that block or impede the action of steroids by binding to steroid receptors and these are called partial agonists, antagonists or antisteroids. However, steroid receptors are widely expressed and that is why when you take them they can have severe side effects. Hence, it would be nice to be able to control where they act and by how much. This third leg paper is the theory behind how to do this.