stuart_a_kauffman's picture
Professor of Biological Sciences, Physics, Astronomy, University of Calgary; Author, Reinventing the Sacred
Systems Medicine

Systems Medicine is emerging, a new holistic view of the organism, and the integrated molecules, cells, tissues, and organs that comprise that organism living in its world. We are heritors of over forty years of wonderful molecular biology, which was, however, somewhat over-confident of a molecular reductionism that failed to integrate the pieces. 

Within each cell is a vast genetic regulatory system coordinating the activities of thousands of genes, that is, which genes are transcribed when and where, along with new knowledge about epigenetic factors such as histone modifications. These comprise a complex nonlinear dynamical system whose coordinated behaviors, coupled with the physics and chemistry of molecules and structures within and between cells, and the environment, mediate ontogeny and disease.

It is now becoming known that some of these genetic factors form auto-regulatory feedback loops, which are likely to underlie alternative dynamical “attractors,” or stable alternative patterns of gene expression, underlying different cell types. The idea of cell types as alternative attractors goes back to Nobel laureates Jacob and Monod in 1963. If cell types are such attractors, each drains a “basin of attraction” in its state space. Then cell differentiation is a flow among attractors induced by signals or noise, or “bifurcations” to new attractors as parameters change. Not only cells, but tissues and organs may be nonlinear dynamical systems with attractors linked hierarchically in unknown ways.

This fine, if yet early, holistic dynamical picture leaves out the myriad biological functions of these variables. We need a very enhanced physiology of the total organism in its world. We live in environments. Odd chemicals can switch an antenna to a leg in genetically normal developing fruit flies. What of the thousands of new chemicals unleashed into the atmosphere?

How can we control and try to “treat” such complex systems? Think of a spring bed mattress, with linked springs all wiggling. Now, would you try to control the wiggling springs by throwing a small pillow on one spring? Not often, unless its unique product directly mediated a disease. You would try to subtly alter the wiggling of the springs to get the coordinated behavior that you want. The same applies to us as patients with vastly complex nonlinear systems underlying health and disease. We need to begin carefully to move toward combinatorial therapies, our multiple pillows, a move that is gradually happening. This move may require new testing procedures beyond our current gold standard of randomized clinical trials which really only work well if the many factors involved each affects the “phenotype” independently. This is rare in biology where causality is multiple and interwoven, with feedback loops in complex networks with complex topology and “logic.”  

But there is hope:

We can empirically climb “clinical “fitness landscapes,” each described with many variables, where peaks represent good treatments by one or many variables, from one or a set of drugs to environmental factors. In fact, almost anecdotal evidence, a kind of “learning by doing,” can search such rugged clinical landscapes. More, Bayesian and other models of the underlying multi-causal mechanisms can guide our empirical search.

It is a time of hope as we step towards a holistic view of the organism in its world.