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compilerbitchOn my walk into Mountain View this evening, I picked up a copy of the US edition of New Scientist. On page 14, 3rd July 2004 issue, the article Embryonic stem cells 'should be dead' jogged a memory of an excellent conversation early this year, when ![[livejournal.com profile]](https://www.dreamwidth.org/img/external/lj-userinfo.gif)
doseybat and I visited livredor in Dundee.
We were chatting about an old idea of mine about modelling dependencies between genes (I'll spare you the details of that, because it's actually not directly relevant). Anyway,livredor was describing some of the characteristics of P53, which somehow seems to know when a cell is trying to behave like more than one cell line at once, triggering apoptosis. The interesting thing was that there seemed to be no direct connection between P53 and what it was sensing, because it appeared somehow to 'know' that something was wrong, despite many, many possible triggers. I started asking naive questions, working from a computer science/information theory point of view, just to try to understand what was going on. What I didn't know at the time was that a large proportion of signals within cells operate in pairs; i.e. one protein for 'on', and a different protein for 'off'. Apparently, in a normal cell, you never typically see both molecules present at the same time, just one or the other. And, these signals form networks that are at least to a point (to my engineer's eyes, at least) somewhat analogous to signals in networks of digital logic gates. Interestingly, this exact same 'dual rail', one signal for on, another separate signal for off, principle is actually commonly used in the design of asynchronous digital circuits. I mentioned that I'd recently been to a workshop presentation, where dual rail signalling had been modified to use 'both on' to represent an error state, that (so it turns out) naturally propagates around the circuit if you happen to use the default (obvious) designs for and, or and not elements.
It occurred to me that if you built a digital circuit from dual rail logic with several, distinct operating modes, each selected by a separate dual-rail input (i.e. several such inputs, with exactly one input active at any time), then heavily optimised the logic to remove gates that would only be necessary to arbitrate cases where multiple modes might be simultaneously active, you might have something analogous to what goes on inside a cell after it has been specialised. It is the nature of genetic algorithms to optimise anything you throw at them, so in a case where all normally functioning cells only ever have one mode operational at any time, it would be very likely indeed that evolution would knock out unnecessary 'logic'. OK, so what would happen if, say, two mode select inputs are simultaneously active? Well, in the case of dual rail digital logic, without the extra hardware necessary to handle these cases, you'd get a (probably large) number of cases where both rails are turned on simultaneously. I wondered if cells might do this, and if P53 might pick up on that somehow. Anyway,livredor pointed out that there is a membrane through which these signalling molecules pass, with 'on' signals passing in the opposite directions to 'off' signals. Hmm, I thought. Then she pointed out that if you block the channels in that membrane (she mentioned a recently discovered drug that did just that), you turn on P53, and hence the demise of the cell, rather extremely. Smoking gun, thought I.
Anyway, I didn't really think much more about this until I saw the article in New Sci today. Apparently, in stem cells (which are basically cells where pretty much all modes are turned on at once, until they specialise), contrary to expectations, all the usual things that turn on programmed cell death are present big time, but the cells don't die. This is really fascinating, because if my theory is correct, if all the modes are simulataneously active in a cell, as with a stem cell, you will inevitably get exactly the behaviour that was reported.
I suppose I'm mostly posting this as a prod tolivredor -- I really am fascinated to know whether this hunch is right. It feels right from an engineering point of view, but, of course, someone will have to prove that it is true by inventive labwork, which is (realistically) well outside my sphere.
doseybat and I visited livredor in Dundee.We were chatting about an old idea of mine about modelling dependencies between genes (I'll spare you the details of that, because it's actually not directly relevant). Anyway,
livredor was describing some of the characteristics of P53, which somehow seems to know when a cell is trying to behave like more than one cell line at once, triggering apoptosis. The interesting thing was that there seemed to be no direct connection between P53 and what it was sensing, because it appeared somehow to 'know' that something was wrong, despite many, many possible triggers. I started asking naive questions, working from a computer science/information theory point of view, just to try to understand what was going on. What I didn't know at the time was that a large proportion of signals within cells operate in pairs; i.e. one protein for 'on', and a different protein for 'off'. Apparently, in a normal cell, you never typically see both molecules present at the same time, just one or the other. And, these signals form networks that are at least to a point (to my engineer's eyes, at least) somewhat analogous to signals in networks of digital logic gates. Interestingly, this exact same 'dual rail', one signal for on, another separate signal for off, principle is actually commonly used in the design of asynchronous digital circuits. I mentioned that I'd recently been to a workshop presentation, where dual rail signalling had been modified to use 'both on' to represent an error state, that (so it turns out) naturally propagates around the circuit if you happen to use the default (obvious) designs for and, or and not elements.It occurred to me that if you built a digital circuit from dual rail logic with several, distinct operating modes, each selected by a separate dual-rail input (i.e. several such inputs, with exactly one input active at any time), then heavily optimised the logic to remove gates that would only be necessary to arbitrate cases where multiple modes might be simultaneously active, you might have something analogous to what goes on inside a cell after it has been specialised. It is the nature of genetic algorithms to optimise anything you throw at them, so in a case where all normally functioning cells only ever have one mode operational at any time, it would be very likely indeed that evolution would knock out unnecessary 'logic'. OK, so what would happen if, say, two mode select inputs are simultaneously active? Well, in the case of dual rail digital logic, without the extra hardware necessary to handle these cases, you'd get a (probably large) number of cases where both rails are turned on simultaneously. I wondered if cells might do this, and if P53 might pick up on that somehow. Anyway,
livredor pointed out that there is a membrane through which these signalling molecules pass, with 'on' signals passing in the opposite directions to 'off' signals. Hmm, I thought. Then she pointed out that if you block the channels in that membrane (she mentioned a recently discovered drug that did just that), you turn on P53, and hence the demise of the cell, rather extremely. Smoking gun, thought I.Anyway, I didn't really think much more about this until I saw the article in New Sci today. Apparently, in stem cells (which are basically cells where pretty much all modes are turned on at once, until they specialise), contrary to expectations, all the usual things that turn on programmed cell death are present big time, but the cells don't die. This is really fascinating, because if my theory is correct, if all the modes are simulataneously active in a cell, as with a stem cell, you will inevitably get exactly the behaviour that was reported.
I suppose I'm mostly posting this as a prod to
livredor -- I really am fascinated to know whether this hunch is right. It feels right from an engineering point of view, but, of course, someone will have to prove that it is true by inventive labwork, which is (realistically) well outside my sphere.
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(no subject)
Date: 2004-07-10 11:23 am (UTC)I haven't forgotten this conversation at all, I've been thinking about it lots and racking my brains to try and see if I can incorporate it into my thesis. Thanks so much for posting about it!
stem cells
Date: 2004-07-10 11:27 am (UTC)pedantic information points
Date: 2004-07-10 11:45 am (UTC)Re: stem cells
Date: 2004-07-13 05:20 am (UTC)neonate
Date: 2004-07-13 06:07 am (UTC)Re: neonate
Date: 2004-07-13 06:51 am (UTC)Why are the cell types are 'supposedly identical'. Is it a general assumption, or do they behave identically under a large range of conditions? How is the level of identity practically determined?
Sorry about all the questions.
I believe we've met, by the way.
:-)
Re: neonate
Date: 2004-07-13 08:28 am (UTC)Well, they're supposed to be identical in that they are the same cell type: skin fibroblasts. Fibroblasts are the type that cells default to if they don't have any reason to be any particular kind of cell. They are mature cells, not stem cells, but they're still pretty general. Anyone who has ever worked with cells knows that no two cells are actually identical, even if they come from the same clone (let alone the same cell type or the same individual). But embryonic and neonatal fibroblasts could be expected to be identical within reasonable practical limits. And I said supposedly because the fact that they have entirely different responses to some drugs means that they're obviously not in fact identical, by definition.
Is it a general assumption, or do they behave identically under a large range of conditions? How is the level of identity practically determined?
It's a general assumption. Biologists are on the whole interested in bulk properties of cells, not in the variations between individual cells.
After all, I'm looking for a medicine that will cure everybody with a particular type of cancer, not one that will have unpredictable effects depending exactly what cells are in the tumour. Now, that's the ideal; real cancer medicines do in fact vary quite a bit in their effectiveness, and that's one of the things that my lab are trying to improve.
There are people who study in detail the differences between foetal and post-birth cells. It's not my job though; from my point of view it's a minor practical nuisance to be worked round (by making sure I always source the cells in the same way). But if you think about Dolly the sheep, what was exciting about that was not the cloning per se; that's been possible for about half a century, but the fact that she was cloned from an adult cell. Why the surprisingly large differences should exist is something that the scientific community is still learning about, I think. But it may well be related to some of the stuff Sarah is postulating in her original post.
Sorry about all the questions.
Not at all! I really like answering questions about my work. Cos I think it's really exciting (well, I would, really!) and it's not something that the general public know about, even those who have a reasonable level of scientific education.
I believe we've met, by the way.
We have indeed met. When I saw your comment, my reaction was, oh, Sarah has commented on my post, I'd better answer her. I didn't think I needed to discuss who you were or introduce myself. I'm sorry if this was an oversight.
Re: neonate
Date: 2004-07-14 02:40 pm (UTC)I remember the first time she mentioned the germ of that idea to me. At the time, I'd recently read a book by Eric Laithwaite in which he hinted at some mystic meta-thing that allows ants to perform complicated group activities. It seemed at the time that he was overlooking the possibility of a quite sophisticated degree of communication via the medium of chemical messages, allowing ants to act as a sort of primitive, distributed computer.
(I like Eric Laithwaite. He's bosey.)
Then Sarah started thinking about dependency graphs of developmental triggers orchestrating the development of complex animals, and I think we talked about the relevance of this to the posited, speculative, but fun idea of the distributed ant computer.
> Cos I think it's really exciting (well, I would, really!)
I think it's really exciting, too.
> who you were or introduce myself. I'm sorry if this
Sorry, I'm actually rather shy.
:)
However, thrusting my inadequacies aside for the moment - may I friend you?
(no subject)
Date: 2004-07-14 03:39 pm (UTC)Ooh, cute concept. I think complexity is very often a better explanation than mysticism for hard to explain phenomena, but it's even better if you can propose a plausible mechanism!
Sorry, I'm actually rather shy. :)
Fair nuff. I'm totally the opposite of shy, so apologies if I end up not reading you correctly because of this.
However, thrusting my inadequacies aside for the moment - may I friend you?
Oh, absolutely, I'm most flattered. (In general I don't mind who friends me, but it's particularly pleasing when it's someone I know is cool.) I shan't be offended if you decide my journal isn't that interesting after all, either. May I friend you back or would that bother you? (I very rarely lock entries except when I'm talking about other people's health issues, so you're not missing much either way.)
(no subject)
Date: 2004-07-14 03:49 pm (UTC)