Turned up to eleven: Fair and Balanced

Monday, July 15, 2002

Genetics, Mathematical Limits to Understanding, and Engineering the Future (II)

I want to continue down this path just a bit further, to hopefully guide my readers a bit more into how a "working scientist" looks at the world. As I noted in the comments section of the post below, my description of the Three Body Problem may have been a bit glib, but the point boils down to this; a model is useful if it predicts the future behavior of a system, and predicts the outcome of perturbation to the system. Systems that we have been studying for 500 years (such as the planets), are still mathematically intractable to a certain degree, and a model of the system in the aforementioned sense is beyond the limits of continuumcalculus (note to the math geeks out there; this formulation allows for discrete time step simulations, ala numerical methods systems). In essence the conjecture that I mean to flesh out in this and possibly future posts is the notion that predicting the outcome of genetic engineering in the manner that Godless Capitalist and his pals at Gene Expression have suggested is beyond the capabilities of present day mathematics, and will require a great deal of innovation at the theoretical level before it can be attempted. (as has been mentioned here previously, in silico modeling of bacteria is being attempted; the project is called E-Cell, and is worth a look. A thorough investigation of it will help you understand the hopes and pitfalls of this approach, I think)

In order to understand the analogy of the "Three-Body Problem", it is helpful to recall how, in general, gene expression works. For generic GeneX, encoded in the DNA, several factors are involved; The assembly of the RNA polymerase holoenzyme, and the alteration of the three dimensional structure of the DNA by transcription factors, allowing for the enzyme complex to bind to the operator/promoter site. All of that gibberish, which is essentially true in all forms of life from bacteria to humans, means that many factors are involved in the transcription of a single gene (transcription is the production of RNA from the gene, which is made of DNA). In "higher" organisms, this process is followed by splicing, in which non-protein coding regions of the mRNA (m stands for "messenger") are removed, and then all organisms take the final mRNA product and process it through a ribosome to produce a protein. This is essentially the Central Dogma of Molecular Biology, (DNA to RNA to Protein), and it is the fundamental picture of how genes are expressed.

Lets go back to the beginning of that paragraph. As I mentioned, there are several factors involved in the initiation of gene expression. This fundamentally means that if we make a simplified, dynamical model of this system, it has several inputs, and one output (the polypeptide product). We can ask, in turn, where do the several factors involved come from? The transcription initiation factors are proteins, that are necessary for the process to start. Since they are proteins, they in turn are under the same fundamental control system (with different factors controlling their expression). What we can see here is the beginning of an event cascade, in which the alteration of a single gene product (say, a transcription factor) can affect the expression of many genes. Not only that, but there are many different ways in which these alterations can occur. This is getting a bit complicated, so I will give a specific example in the next post.

I will leave you with the following analogy that give a tiny taste of what biological complexity is like;

Suppose that it is a warm summer day, and you realize, looking out your window, that the grass is getting a bit long (no fair guessing what i did this weekend!). So you decide, I am going to flip a coin, and if it is heads, I will mow the lawn. If it is tails, I won't. It turns up tails, so you decide not to mow your lawn. Unbeknownst to you, the head of your homeowner's association is walking by your house that afternoon, and he sees that you haven't mowed your lawn for a while, and he gets ticked off, so he sends you a letter, saying "Cut your lawn or we will throw you out!". Of course, the letter is not really a big deal, and you were going to cut the lawn the next day anyway (which you do). A week goes by, and it is time for the annual homeowner's association meeting, when everyone gets together to discuss plans for fixing up or changing the community. At the meeting, you suggest that the pothole on 6th avenue is really bad, and we should really fix it. The assoc. head says "You can't even keep your lawn mowed, what do you know about it¡± Everyone has a good laugh, and ignores you completely. The following week, the head of the association is driving along 6th ave, hits the pothole, swerves out of control, and slams into the side of a house. All because the coin came up tails! (I am being facetious, of course; many other things happened, but if the coin had come up heads, it would have been completely different) A biological example of this "cascade" effect will follow...