Frank Bruggeman wrote:
> Lately I have been wondering whether metabolic control analysis as developed
> originally by Kascer & Burns and Heinrich & Rapoport is a genuine theory or
> not. Personally I think a theory should be falsifiable in the Popper sense.
> I'm quite convinced that metabolic control analysis is not falsifiable since
> it holds for any (nonlinear) dynamical system under steady state conditions
> (all theorems can be obtained from implicit differentiation of N*V=0).
>> An example:
> Let's say that according to MCA the flux control coefficient of succinate
> dehydrogenase on TCA flux =0.21 (obtained with a mathematical model
> consisting of detailed enzyme kinetics (obtained from in vitro rate kinetic
> measurements)). But when measured it turmed out to be 0.8. Does this flasify
> MCA? No. It falsifies only the mathematical model!
>> Therefore I'm inclined to think that MCA is not a theory but a tool and
> therefore its MCA and not MCT.
>> Can anybody think of a way to falsify MCA?
> Can anybody make an argument why MCA is a theory even though not
> falsifiable?
> Are there examples of similar theories?
As I understand it Popper's ideas were related to theories based on real-world
observation. So, in developing a general theory to explain and predict the
behaviour of metabolism based on rate-limiting steps, we could reasonably
propose the hypothesis that (e.g.) PFK is the rate limiting step for
glycolysis. This is reasonable in the sense that we can, potentially, modify
systems and make observations that might disprove it: we could treat cells with
an inhibitor, and observe no change. However, from Popper's point of view, if
we did get a change in glycolitic flux by modulating PFK, this wouldn't prove
it to be rate limiting, because, (e.g.) of some other modes of action of the
inhibitor. According to Popper, theories can never be proved by observation of
data, we can only fail to disprove.
None of the above applies to the mathematical theorems of MCA. Summation,
Connectivity, and the rest are implicit in the definition of elasticities and
control coefficients. Any observation that appeared to violate these would
serve to highlight flaws in the experimental methodology, not the theorems.
I think.
Regards
Mark
Mark Poolman
Post Doctoral Researcher
Metabolic Control Analysis Group
Oxford Brookes University
