Overcoming complexity in biology

I've been sitting in on a short lecture series presented by Prof. John Marko here at the EPFL. The topic is on the biophysics of DNA and covers what is probably at least a 25 year span of research that has emerged on its mechanical and biochemical properties.

DNA amazes me in two different ways: relatively simple physical theories can explain /in vitro/ experiments, but establishing a complete understanding of the behavior of DNA and its associated proteins (collectively known as chromatin) /in vivo/ seems at this point almost hopeless.

So why do I think it's so difficult to establish a complete physical theory of the nucleus?

Certainly a lot of recent research has helped us to understand parts of what happens inside the nucleus. Take for example recent experiments that look at transcription factor (TF) binding and the nuclear architecture. TF binding experiments have helped us understand the mechanism of how a single transcription factor searches for a target site on a chromosome. It undergoes diffusion in the crowded nuclear environment, occasionally binding to the DNA non-specifically and sliding along it. We now know that this combined diffusion/sliding mechanism produces an optimum search strategy.

Studies of nuclear architecture attempt to understand how the long DNA polymer, which is on the order of /one meter/ long, is packaged into the nucleus, which is only about /five micrometers/ in diameter. This is nearly six orders of magnitude of compaction. Some current theories treat the DNA as a hierarchically packaged polymer or a fractal structure. Interestingly, the fractal model can explain why TF's may diffuse optimally and when crowding can hinder their search.

Both of these examples represent a generalization of one particular phenomenon that occurs inside the nucleus. And even given the enormity of these works, I think this generalization can be dubious because it may not apply to all cell types and there may be differences between cultured cells and those found in an actual organism.

The problem in capturing complete physical models of the nucleus seems to lie with the philosophy of physics itself: find the most essential parts of the system and include those in your model, discarding all irrelevant details. Unfortunately, in vitro experiments suggest that every detail seems to matter inside the nucleus. Local salt concentrations effect electrostatic interactions and entropic binding between proteins and DNA, the global nuclear architecture has an effect on single TF's diffusing inside the nucleus, there are a huge number of proteins that associate with DNA and control the conformation in toplogically associating domains. The list goes on and on.

A common theme to this list that I have described above is that phenomena at one length scale tend to have a direct impact on those at another, like the global nuclear architecture affecting a single TF trajectory. These are hallmarks of complexity: a dependence on the details of a system and multiscale behavior.

I am currently of the opinion that a complete model of the nucleus, and probably of other biological systems, must therefore necessarily abandon one important part of physical theories: reduction to the simplest possible set of parameters to describe a system. We need to incorporate all the details across all length scales to reproduce what exactly is going on.

And if classical physics falls short of this goal, what other approaches do we then require?