Sunday, January 21, 2007

Is Systems Biology Teaching Us Anything New?

What I find most exciting about basic molecular biology today is the prospect of building a quantitative understanding of how a cell works. Many other scientists are excited about this as well, leading to the current popularity of what's being called 'systems biology.' The idea is that maybe we can understand the design principles behind a cellular process - how the behavior of a cell emerges from all of those detailed physical interactions among proteins, nucleic acids and other components of the cell. If that sounds vague to you, well, that's because it is vague. It's a nice sentiment, but I think biologists still have a hard time defining just what it is we want to learn.

Think of this problem from a historical perspective: biology has several profound organizing theories that have been fantastically useful as explanations for what happens in biological systems. As the geneticist Dobzhansky famously put it, nothing in biology makes sense except in the light of evolution. The same thing holds true for genetics (you don't have adaptive evolution if you don't have genes encoding traits that are passed on from one generation to the next), biochemistry (all organisms are made of molecules that obey the laws of physics and chemistry - not some mysterious substance that transcends physical laws), and molecular biology (DNA makes RNA makes Protein). Each of these theories has been successful by those criteria that define a good scientific theory; for example, they have explained previously mysterious phenomena, they have predicted completely new phenomena that have since been verified, and they have opened up huge new avenues of research. Each one of these theories has changed the way the entire community of biologists operates.

Will systems biology do that? I hope so, but I don't know. It hasn't yet. Let's take the cell division cycle, for example, since it's a process that's near and dear to my heart. It's also a process that is crucial for understanding human disease, notably cancer. How can systems biology help us understand the cell cycle? How can it help us understand and cure cancer?

A recent paper in Nature, from Michael Laub's lab, reports the identification of an "integrated genetic circuit." This is a very nice paper, with a clear set of experiments, that identifies certain interactions among key cell cycle proteins that control division in the bacterium Caulobacter crescentus. The interactions identified in this research explain how it is that a key cell cycle regulator protein, called CtrA, is cyclically switched on and off during the various stages of the cell cycle.

The authors aren't claiming that they are producing a quantitative model, but they use the language of systems biology, notably by calling their set of novel interactions an "integrated genetic circuit." So what then is a non-integrated genetic circuit? How does a biological integrated circuit relate to the integrated circuit used in electronics?

Ultimately, this study, and many others like it, are largely filling in the molecular details of a specific process, something molecular biologists have been doing for decades. Feedback loops and regulatory interactions are valuable, but not new. In some cases, we are getting enough detailed data to build some primitive computer models, but these models are largely descriptive - reproducing what extensive experimental work has already shown.

So is systems biology ever going to amount to something like the paradigm-shifting initiation of molecular biology in the 50's and 60's? Are there any Really Big Questions left in biology, or are we now just finding better, faster ways to fill in the details? I think there are big questions left, but they're still poorly defined and often lost in the flood of genomic research. One telling gap in our knowledge is the origin of living cells from nonliving systems - we can't build a cell from scratch. We don't have the theoretical tools to understand, rigorously, how the first cells could have arisen from available components on the early earth, for example. This suggests that there is more we need to understand about how physical systems can cohere together to produce something that can adapt to its environment and reproduce. Not just molecular details, but new concepts of how physical systems organize themselves.

For now I'm just raising questions, but in future posts I'll discuss how we might go about finding some answers.

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