Tuesday, May 11, 2010

Every organism is unique, but we all become unique in the same way

We've just run across a 2004 Nature paper by André Pires-daSilva and Ralf Sommer about the evolution of signaling in animal development. This paper, of which we were not aware but should have been, is highly related to some main themes of our book The Mermaid's Tale, which deals with fundamental aspects of how life works including, but not focused on, how it evolved.

The authors write that only seven signaling pathways are responsible for most of the cell-cell interactions that control the development of a single cell into the organism it becomes. They are used repeatedly at every stage of development, and have been co-opted through evolutionary time in the development of new morphological traits and systems.

After millions of years of evolution, signalling pathways have evolved into complex networks of interactions. Surprisingly, genetic and biochemical studies revealed that only a few classes of signalling pathways are sufficient to pattern a wide variety of cells, tissues and morphologies. The specificity of these pathways is based on the history of the cell (referred to as the 'cell's competence'), the intensity of the signal and the cross-regulatory interactions with other signalling cascades.
These ubiquitous pathways are the Hedgehog, Wnt, transforming growth factor-beta, receptor tyrosine kinase, Notch, JAK/STAT and nuclear hormone pathways. How can the wide diversity of life around us be produced by so few ways for cells to communicate with each other?

Given the flexibility of signalling pathways, research in the past decade has concentrated on the question of how specificity is achieved in any signalling response. There is now clear evidence that the specificity of cellular responses can be achieved by at least five mechanisms, which in some cases act in combination, highlighting the network properties of signalling pathways in living cells.
First, the same receptor can activate different intracellular transducers in different tissues.
Second, differences in the kinetics of the ligand or receptor might generate distinct cellular outcomes.
Third, combinatorial activation by signalling pathways might result in the regulation of specific genes. Several signalling pathways can be integrated either at signalling proteins or at enhancers of target genes.
Fourth, cells that express distinct transcription factors might respond differently when exposed to the same signals.
Fifth, compartmentalization of the signal in the cell can contribute to specificity. The recruitment of components into protein complexes prevents cross signalling between unrelated signalling molecules or targets multifunctional molecules to specific functions.
The idea that a handful of networks can be responsible for most of the cellular 'decision-making' that is development is a beautiful example of core principles of life that we write about. The different ways that cells respond, the different developmental cascades that can be triggered by the same signaling networks, the interaction of different signaling pathways to trigger specific responses, and so forth all demonstrate the importance of modularity, signaling, contingency, sequestration and chance over and over again. How the components of these signaling pathways have evolved -- co-evolved -- is not yet well-understood, but it has to be that the interactions are tolerant of imprecision, and indeed, that tolerance (variation in the affinity of receptor/ligand binding) has been built into the system and leads to the evolutionary novelty.

The keys to this are partial sequestration of components of an organism so that local cells in different parts of the plant or animal can behave in different ways, so they can sense and respond to their environment (by signalling), and the arbitrary combinatorial codes by which signalling systems -- like the ones discussed in the 2004 paper -- work. That the same systems can produce diverse organisms reflects the logic of development, that is, the relational principles by which life is organized. Notch signaling is about the code specified by Notch, its receptor and related proteins, in combination with other such systems--and not by any particular property of the Notch proteins per se.

Every organism is unique, but we all become unique in the same way. It is basically the open-ended use of these very simple processes involving a limited number of components that enables this essentially unlimited diversity of living Nature.

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