Welcome,
dear reader. This is the start of a short series of blog posts aimed at
providing some insight into the process of development of a computational model
of a cell. The type of the model we’ll focus at is one which simulates the
development of ionic concentrations and behavior of ionic currents and fluxes
over time (probably most relevant for excitable cells such as cardiomyocytes or
neurons). I'm hoping that tips and observations in this series will be of use to graduate students and researchers who are interested in computer simulations.
While the posts are about the development of human ventricular cardiomyocyte model ToR-ORd (https://elifesciences.org/articles/48890), I mostly try to focus on general observations (usually those I wish I knew about when I started). I decided to write up the topics in the form of blog, given that scientific publications tend to have a somewhat rigid format, and tend to focus at what is done, how, and what it means, rather than at discussions of the author’s motivation for taking a particular route during the research process (which is what I’ll do here). Also, and that is something that brings me much pain, most journals directly discourage the use of footnotes [1], which often leads to omission of interesting, if not critical information, as not everything is well-suited for Supplementary materials/appendices. This series is essentially a big bag of footnotes to our paper.
While the posts are about the development of human ventricular cardiomyocyte model ToR-ORd (https://elifesciences.org/articles/48890), I mostly try to focus on general observations (usually those I wish I knew about when I started). I decided to write up the topics in the form of blog, given that scientific publications tend to have a somewhat rigid format, and tend to focus at what is done, how, and what it means, rather than at discussions of the author’s motivation for taking a particular route during the research process (which is what I’ll do here). Also, and that is something that brings me much pain, most journals directly discourage the use of footnotes [1], which often leads to omission of interesting, if not critical information, as not everything is well-suited for Supplementary materials/appendices. This series is essentially a big bag of footnotes to our paper.
It must be
said that making a model is hard, lengthy, and may end up as unrewarding. When
talking to the author of one very popular model at a conference, upon telling
him I wanted to do some work on model development, he gave me a stare of cosmic
horror, and a really good advice – “don’t do it”. How many times I wished I
have heeded his word…
Anyway,
assuming the image of impending Doom has not scared you, the structure of the
series is as follows:
- Part 1 is a short overview of some points to consider when formulating the criteria the model should fulfill in the first place.
- Part 2 is about general approaches to achieving the criteria – manual and automated searching strategies, and what are their respective [dis]advantages.
- Part 3 is about the automated searching strategy I found most useful: the genetic algorithm and its multicriterial variant. This is a mixture of introduction to the methodology and practical notes on using it.
- Part 4 is a concrete example of mechanistically-guided manual change to the model, going over the somewhat twisty road of finding out that we need to replace the model of IKr.
- Part 5 is another example of the mechanistically-guided change; this time it’s about the changes to the ionic driving force and activation curve for L-type calcium current.
- Part 6 is about mechanistically-guided change to SR release formulation (Jrel), where I failed to reach a satisfactory outcome, and on the art of giving up at the right moment.
- Part 7 consists of concluding remarks.
[1] "I want translations
papers with copious footnotes, footnotes reaching up like skyscrapers to the
top of this or that page so as to leave only the gleam of one textual line
between commentary and eternity." - Nabokov
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