While the use of IC50’s is a huge problem in the biological sciences, Academia, Industry and Regulatory bodies have good reason to avoid the established field of enzyme kinetics. As I said in the last post, the problem with IC50 values is that they strip away or obscure finer details of molecular interactions producing an artificial wall on the amount of information we can obtain from biological systems.  However, the perception is that modern enzyme kinetic drug studies do not provide a significant improvement in our understanding relative to the increase in resources that are required to do the studies.

 As such its easy to see why funding and biological research interest have shifted towards molecular biology and genomics. With these trends, the slow death of enzyme kinetics shouldn't really be a concern for anyone as the over-complexity of the discipline turns out to be just a mess based on misunderstanding.

Yup that's right, I have good news for all the biologists/biochemist that have had to suffer through that page or two devoted to enzyme inhibition in your textbook, you can put a big black X there or better yet rip it out because it is wrong.    

But how could that be? Well, those equations were developed around 100 years ago, but guess what, they are even acknowledged to be wrong by most enzyme kineticists.  

Here is how a reviewer of one of my publications summed it up:

“It is widely accepted that the standard model is in many ways inadequate. However, the standard model has held sway for so long because it is simple, easily understood, very widely applicable and leads to a level of understanding which can be used predictively.” (personally I can’t see where we could go wrong by embracing the flat world theory as well)

This statement is supported by the opinion I got from the askacademia form on reddit which equates the equations found in these textbooks as 

“reductionist formula to introduce the basics of enzyme kinetics to novices. In most cases, i.e., first university year students, it serves it's designated purpose.” (glad to know the students are getting their monies worth)

But that is hardly supported by the use of these reductionist equations in top journals.  Maybe someone should let The Journal of Medicinal Chemistry know they are publishing well known erroneous information only intended to placate the uninitiated or maybe I missunderstood the comment and most researchers are also included in the “most cases” generalization.

But aside from that how did the field of enzyme kinetics become such a terrible mess?  

Well, when the initial equation were first developed, they were based on chemical reaction theories. For example, if you start with a reactant and it undergoes a chemical reaction to produce a product the reaction can be schematized in the form of A goes to B with a nice arrow in between them.  This method of conceptualizing reactions was quickly adopted to analyze how drugs inhibit the activity of enzymes.  

Using this methodology the basic theoretical mechanistic inhibition equations that have successfully placated undergraduate students for so long were derived (competitive, non-competitive, mixed non-competitive and if you want to stretch it uncompetitive inhibition). However when enzyme kineticists started to use these equations, it was quickly realized that they didn't work very well and rather than examine the assumptions they were based on (because how could something derived from chemistry and math go wrong) they decided to build on top of them.  

So from the initially defined equations sprang partial forms to account for things that were missing, such as partial competitive inhibition and partial non-competitive inhibition. When these new equations were found to be wanting, the process was repeated, to the point where we are at today, in which individual groups working on these complex models  don’t even bother to consult prior literature preferring to derive equations from scratch based on the hubris that their equations are mechanistic so infallible.

A prime example of this is Segels book, republished by Wiley as a Classic in 1993, Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems.  A book that has been suggested to be a definitive work on enzyme kinetics by some and completely useless by others (check the reviews on amazon, where the reviews "Enzyme Kinetics Bible"and "This book is bad, a perfect trap for naïve and incompetent"sit side by side).  

So while the fields of biology and psychology were using statistics to examine their methods attempting to reduce over-fitting, improve and simplify their models,(Burnham and Anderson provide an interesting account of this in their book Model selection and multimodel inference: a practical information-theoretic approach) enzyme kineticists already entrenched in theoretical mechanistic derivations continued to build more diversity and complexity into their models.  

The degree of complexity produced seemed to suggest that drugs did not follow the general principles that govern the interactions of all molecules... And as complexity increased the tendency of groups to compare models with each other decreased leading to the almost purely theoretical derivation of equations without the pesky need to comprehensively explain or validate these models using real data, a point raised in a review of Segels book shortly after it was released (Gutfreund 1975). But the fact that no data mares the pages of this theoretical mechanistic maze shouldn't really be a problem since they are only theories.

So with the incomprehensible over-complexity of the field, I can’t really blame regulatory bodies for accepting IC50’s as a sufficient way of characterizing drug interactions.  

I’m actually much more in favor of using IC50s to describe drug interaction, than the theoretical mechanistic mess that is enzyme kinetics.  IC50s work on the premise that drugs obey the same universal mass action principle used to define all molecular interactions, while modern enzyme kinetic mechanistic theories do not. 

As stated above, the basic models of inhibition are wrong and that's where this sandcastle of theoretical mechanistic equations starts.  

But I guess that can wait for the next post.

Front page image: The Culture of Biochemistry