Under lid

That’s it, dear readers. I can’t thank enough the people who contributed to this project and helped shape T-World into its final form. It was wonderful to work on this with a range of very different people, addressing different aspects of the model development and presentation, from support in formulating details of calcium handling, conceptualizing new components, to demonstrating applicability to interesting and relevant tasks. I’ve been going through memories of different stages of the project, and the project wouldn’t be the same without you all! I am also very grateful to the Wellcome Trust, whose fellowship gave me the freedom to focus properly on the later stages of development and bring the work to completion. At the same time, this project has made me think a bit about how we support the development of substantial computational methodologies. My experience with T-World was ultimately a positive one, but it also highlighted how difficult this kind of work can be to carry ou...

 At one point, I noticed how EADs are quite a bit harder to evoke in the Shannon-Bers model than in ToR-ORd. I.e., when I ported key currents (I CaL , I NaL , I Kr , I Ks ) to the newly created model built closer to the Bers/Grandi framework, it would still not generate EADs as readily in the right conditions as models like ToR-ORd. The difference was not huge, but it was noticeable. In a separate investigation, when I was trying to build an understanding of differences in each current in either framework, I noticed how relatively different is the voltage-dependence – near-linear in ToR-ORd, but sublinear in the Shannon model. And there I had a spark of thinking that clarified why the Shannon-like models could be naturally less prone to EAD formation, arising from the sodium-potassium pump differences. Let’s go over this in more detail. Below is shown a comparison of the linear voltage-dependence used in T-World, versus the sublinear voltage-dependence of the sodium-potassium pum...

The model of I CaL that we had in ToR-ORd (based on the ORd formulation) had clear strengths, enabling nice early afterdepolarisations (EADs), for example. However, I also felt it had aspects I didn’t like that much. One is that the refractoriness under repeated activation was not that strong (and if made stronger, EADs would be lost). A second aspect was that the model produces slightly heavy-tailed current profile, which could probably inactivate more. One side-effect of this is that the current would produce nontrivial depolarizing current throughout the plateau, requiring quite a strong I Kb to offset this and maintain good AP shape. Again, if the model was just reparametrized to be leaner, EADs would be lost. I therefore wanted a leaner-profile model that would be even more in line with data on refractoriness. Having worked a bit with the 8-state cube model used e.g. in the Heijman-Rudy canine model, I thought it would be a very nice starting point. And in many ways, it was. I...

 To address the issue of timing of calcium rise in the junctional dyad, I first tried to just facilitate the calcium-sensitivity of release. Nope, again too fidgety and prone to spontaneous release when pushing the sensitivity too far. I then had an idea I was slightly proud of – that was after I had the bucket size insight. I thought – ok, let’s split the dyad into an “inner dyad”, which is even smaller, and where I CaL and RyR meet, and an “outer dyad”, where e.g. the Na-Ca exchanger could reside. In this way, we would have even tighter coupling with a smaller bucket, and thus faster dynamics. Going over papers on dyad sizes and counts, a back-of-an-envelope calculation revealed we can push the inner dyad size down quite a bit. This has worked really well for a lot of aspects, we had nice calcium dynamics, alternans, DADs, all looked pink and rosy. Except then I realised that the model had massive issue with the release being far too refractory. I tried to address it, but coul...

  Looking over the field, I clearly saw the pattern of different families of computer models being used for different tasks, being good for different things. The two families that would come up the most would be the “Rudy family” from the group of Yoram Rudy (e.g. Luo-Rudy, Hund-Rudy, O’Hara-Rudy, Heijman-Rudy) and the “Bers/Grandi family” (Shannon-Bers, Grandi-Bers, Morotti-Grandi). Our prior model ToR-ORd that we developed in the Rodriguez group would belong to the Rudy family with regards to its philosophy. (Please don’t read too much into the naming of the families – I needed a short and memorable naming, and I used PI’s names as they’re the closest unifying factors to the models; it is definitely not intended to take credit from other authors) . Both families of models are used for a range of tasks, but in general, one would see Rudy models used more for studies on electrophysiology, response to drugs, and early-afterdepolarization-driven arrhythmia, whereas the Bers/Grandi ...

 It is an unfortunate fact that this project went on for quite long. One could trace the roots to what I described in my ToR-ORd blog on RyRs and calcium handling , saying how we could not achieve everything we wanted. I hate to be beaten by a mystery and of course wanted to revisit this problem if I could (except within few weeks of finalizing ToR-ORd, while the arguably healthier mindset of “I’ll never make another model” lasted). The blog was published in Dec 2019, and the first unsuccessful forays into more realistic calcium handling we have taken might have even taken place in 2018. (I’m not the worst in this in our household though, my wife’s major project – and amazing success – took 8 years to finish) The scale of development was simply on another level compared to the prior ToR-ORd. There were many more and larger conceptual decisions, more situations of “OK, I have NO idea what to do about this”. For each development step (testing a new idea, running a genetic algorith...

 Welcome again after a few years, dear readers. Much has happened since the last posting – I went to Davis (CA) and back to Oxford, I have two children, wrote a book on statistics with Prof. David Eisner, and recently, a new model was born too, the T-World ( Paper 1 , Paper 2   ). I thought I’d revisit several points in this blog, that will complement the paper and share a bit of background of its creation, without any need for salesmanship. Specifically, I’ll address the following: 1)       “ You claim high generality of the model – but who cares? ” I found it so interesting that most people respond to the high generality of T-World with “obviously, this is what we always wanted”, but a nontrivial number of people also didn’t find it that important at the first sight. Let’s go over some reasons why I think it matters deeply. 2)       “ Why did you guys take so long? ” Yes, it took ages. I’m sorry, I’m the first to have wished it wa...