Growth Control

If life truly is an example of carbon-based nanotechnology, then we would expect life processes to be permeated with control.  In essence, life processes would constitute a cybernetic system that responds to internal and external cues.

Take the process of cell growth, where a cell simply increases its size. One might be tempted to think such a simple process would be entirely passive, such that a cell in an environment with lots of nutrients would be able to build more cell parts and thus grow, while a cell that was being starved would not be able to build more cell parts and thus fail to grow.  Simple, right?

Not really.  It turns out that the seemingly simple process of cell growth is under a very sophisticated form of control.

The key player in the control of cell growth is a protein known as TOR.  This protein is massive, approximately 2500 amino acids in length, and is found in all eukaryotes – plants, animals, fungi, and protozoa.  What does it do?

TOR activates cell growth by positively and negatively regulating several anabolic and catabolic processes, respectively, that collectively determine mass accumulation. In this context, it is important to note that cell growth refers to an increase in cell size rather than an increase in cell number that is a result of cell division. Whereas TOR is a central controller of cell growth, cyclin-dependent kinase is a central controller of cell division. Furthermore, the discovery of TOR led to a fundamental change in how we think about cell growth. It is not a spontaneous process that just happens when building blocks (nutrients) are available, but rather a highly regulated, plastic process controlled by TOR-dependent signaling pathways. The anabolic processes controlled by TOR include transcription, protein synthesis, ribosome biogenesis, nutrient transport, and mitochondrial metabolism. Conversely, TOR negatively regulates catabolic processes such as mRNA degradation, ubiquitin-dependent proteolysis, autophagy, and apoptosis.

From: Hall, MN. 2008. mTOR—What Does It Do? Transplantation Proceedings 40, S5–S8.

Here is a figure that shows some of the upstream and downstream components of the TOR circuit.

Legend and source

One way in which this circuit regulates cell growth is to monitor the AMP/ATP ratio inside the cell.  Since ATP is the so-called energy currency of the cell, when levels of ATP drop, this will be reflected as high levels of AMP (a precursor of ATP).  And it turns out there is a sensor for this called adenosine monophosphate (AMP)-dependent protein kinase (AMPK).  Basically, when AMP levels are high, AMPK is activated to attach phosphate groups to other proteins (such phosphorylation activity is one “language” used in intracellular communication).  Now, if you look at the figure above, AMPK will phosphorylate TSC2 and thereby activates TSC1–TSC2  (as shown by the arrow head) to inhibit Rheb (as shown by the bar at the end of the line) which ultimately shuts off TOR.  What’s not shown in the figure is that AMPK can also phosphorylate raptor, which will also result in the inhibition of TOR.  And once TOR is inhibited, it ceases to stimulate ribosomal activity and thus new protein synthesis is slowed.

Keep in mind that the ribosome is far removed from ATP synthesis.  Thus, this circuit allows the cell to coordinate the activity of its tens of thousands of ribosomes in response to internal energy levels.  It is a truly ingenious connection.

What’s more, this very system would help to front-load the emergence of multicellular life.  The cells of multicellular organisms must function as a team, and thus for an organ to emerge or grow, the cells would need to grow in a coordinated fashion.  If cells grew passively, this would pose a serious control problem.  But as you can see from the figure above, the TOR circuit clearly facilitates coordinated growth in that it can be easily linked to a circuit that responds to signals from extracellular signals, like insulin.

What we thus have in the TOR system is another clever control mechanism that not only fits nicely into the hypothesis of life as carbon-based nanotechnology, but also would facilitate the evolution of multicellular life.

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