Tuesday, August 10, 2010

Complexity made simply--and reversals, too

A pair of encouraging gene-manipulation stories were reported in the New York Times on Friday (the graphic is from the story).  Essentially, two groups have found ways to de-differentiate specialized cells so that they become able to go down developmental pathways their cellular ancestors did early in the individual's life (or, perhaps, new paths that that cell lineage never took).

Producing various sorts of 'stem' cells is a major goal of modern medicine.  In principle, it will allow the regeneration or even cloning of a patient's damaged organs, with cells from the same individual.  Unlike other therapies, this will not generally lead to tissue rejection (which usually is only of foreign cells), nor will it require removing something, like a ligament, from elsewhere in the patient, to use as a replacement ligament elsewhere in the body.

The problem is that most cells in an adult are fully committed to their current function.  They are functioning stomach, lung, or muscle cells.  As mature differentiated cells they can't do other things, because those require a different set of genes to be activated (or inactivated).  For a muscle cell to be used in lungs its gene expression would have to be that of a cell that lungs use, and that often means of a cell earlier in lung development than the type of cell the therapist needs.

Most vertebrate tissues are made of a series of partly committed stem cells--say, cells in the blood-cell, or lung, or intestinal lineage--that when called upon will differentiate into final functional cells of that organ, known as terminally differentiated cells.  The latter typically can no longer divide.

If organ-specific stem cells can be made more generic, behaving like cells early in the embryonic lineage, or if organ-specific differentiated cells can be made more like that organ's stem cells, then transplanting healthy cells from a patient back into the patient could regenerate healthy tissue to replace damaged tissue.

The studies reported did that in two different contexts.  While still experimental, they're another example of the productive road developmental-genetic research is making possible.  What one group of  investigators did was block the expression of tumor-suppressor genes, which freed the cells to begin to divide.

Finding the right combination of genes to suppress was a critical step in the new research. One of the two tumor suppressor genes is an ancient gene, known as Rb, which is naturally inactivated in newts and fish when they start regenerating tissue. Mammals possess both the Rb gene and a backup, called the Arf gene, which will close down a cancer-prone cell if Rb fails to do so.
The Stanford team found that newts did not have the Arf backup gene, which mammals must have acquired after their lineage diverged from that of amphibians. This suggests that the backup system “evolved at the expense of regeneration,” the Stanford researchers in Friday’s issue of Cell Stem Cell.
The Stanford team shut off both Rb and Arf with a chemical called silencing-RNA and found the mouse muscle cells started dividing. When injected into a mouse’s leg, the cells fused into the existing muscle fibers, just as they are meant to.

The second group of investigators has found a way to transform heart fibroblast cells in a mouse into heart muscle cells, the cells that a heart attack destroys, bypassing the embryonic stem cell stage.

Both of these methods for reprogramming cells reflects something important about life and it was a major topic of the book after which our blog is named.  What it shows is that complex, differentiated tissue is produced by processes of gene expression and response--signaling in generic terms.   Because signaling is a hierarchical process in which response to one signal leads to subsequent signals and response by and between cells, a few changes in signal timing or intensity can lead to complex changes in cell behavior.  Since cells in a tissue communicate to affect their differentiation, simple processes can have what appear to be complex effects:  Complexity made simply.

Understanding this (we think) greatly helps account for the ability of evolution to generate 'complex' traits, the polygenic nature of such traits which might seem antithetical to simplicity, and the  misrepresentation or culpable misunderstanding of the evolution of complexity by the 'Intelligent Design' people.

A few changes in a few processes can make substantial changes in a trait, or evolve some new trait.  Yet many genes are involved in signaling, so that their individual variation can yield trait variation, the kind of small variation GWAS (genomewide association studies) are picking up.  But over long time periods, increasingly complex, integrated traits can arise.

Since signaling interactions are the essence of life, there is every reason to hope that signal manipulation can be a major productive goal of modern medicine, especially regenerative medicine but probably much beyond.  The current articles show steps along that path.

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