December 28, 2011 | David F. Coppedge

Cells Optimize Their Tasks

The key to design in manufacturing is optimization – hitting the “sweet spot” between competing interests.  It’s not always possible to have all the elements of a product be ideal.  A laptop computer, for instance, can’t have an extra-large monitor and simultaneously have long battery life and compact design.  A muscle car cannot be expected to have the best gas mileage.  In the heyday of “faster, better, cheaper” spacecraft, engineers often joked, “pick any two.”  In the same way, living cells have to optimize their operations.  A couple of recent papers explore how they find that sweet spot.

Efficiency vs accuracy:  A paper in PNAS reported, “Genetic code translation displays a linear trade-off between efficiency and accuracy of tRNA selection.”1  Johansson, Zhang and Ehrenberg found “a simple, linear trade-off between efficiency of cognate codon reading and accuracy of tRNA selection.  The maximal accuracy was highest for the second codon position and lowest for the third.”  At the start of the paper, they acknowledged the competing forces: “Translation of the ancient and universal genetic code into protein on ribosomes requires precise mRNA decoding by aminoacyl-tRNAs (aa-tRNAs) and rapid formation of nascent peptide chains.”  A cell needs speed and accuracy.  How does it find the sweet spot between them, given that there are limitations of space and time?  In the transfer-RNA (tRNA) case, the matching (anticodon) end has to find the right (cognate) codon end within time constraints.  The authors state, “Codon reading by aa-tRNAs ultimately relies on the specificity of cognate in relation to noncognate codon–anticodon interactions, but two ribosome-dependent specificity enhancements greatly improve mRNA decoding.

Ribosome animation, courtesy of Illustra Media.

That’s right; there are two downstream proofreading mechanisms to make sure the matching was done right: “the ribosome enhances the accuracy of codon reading by a twostep mechanism in which initial codon selection by a tRNA is followed by a proofreading step.”  Amazing.  In short, speed is achieved by the tRNA matching up initially with its cognate, but mechanisms in the ribosome during translation clean up any mistakes.  The authors looked for optimization here.  They explored the “maximal possible discrimination between a cognate and a noncognate codon–anticodon interaction: the ‘d value’,” and came up with some tentative numbers that will require further elaboration.  In conclusion, they ascribed the remarkable optimization to evolution: “Finally, we propose that quantitative estimates of the d values of the genetic code in conjunction with the remarkably simple efficiency-accuracy trade-off revealed by the present experiments will clarify how the accuracy in living cells has been evolutionarily tuned for maximal fitness of growing bacteria.”

A stitch in time:  As the time-worn proverb attests, you can avoid nine stitches later by doing one stitch at the right time.  Ask the “DNA mismatch repair” team, known as MMR.  According to PhysOrg, in eukaryotic cells, “DNA mismatch repair happens only during a brief window of opportunity.”  Work at UC San Diego showed that “newly replicated DNA produces a temporary signal for 10 to 15 minutes after replication which helps identify it as new – and thus a potential subject for MMR.”  This means that the MMR team gets notified early on when a DNA strand has been copied, so that mistakes can be repaired when they are fresh – a stitch in time that might avoid catastrophe later, like cancer or programmed cell death.  “How eukaryotes identify the newly synthesized strand of DNA is a mystery that has persisted for at least 30 years,” said Christopher Putnam at UC San Diego. “These findings really change our ideas of how MMR works.”

It’s a cinch:  Watching cell division through a high-school light microscope is like watching a football game from a blimp.  There’s so much more going on down there.  One of the critical components of cell division is the “contractile ring,” a protein structure that forms around the center of the dividing cell that virtually cinches down the midpoint (the cleavage furrow), something like a cable tie wrapped around a balloon, forcing it into two lobes.  Ann Miller [U of Michigan] described the construction and function of the contractile ring in Current Biology.2  Like the MMR example mentioned above, the contractile ring has to get formed at the right time, and has limited time to complete its function.  If you care about preventing birth defects and tumors, you’ll be glad the cell takes great pains to get it right:

The formation of the contractile ring must be regulated with spatial and temporal precision to ensure that the cleavage furrow is positioned properly and the chromosomes and organelles are distributed equally to each daughter cell. Successful execution of cytokinesis is necessary during development as well as for maintenance of adult tissues.

Asked how the cell positions the contractile ring properly, Miller said, “the cell ingeniously uses the microtubules of the mitotic spindle to perform both the physical separation of the chromosomes and the specification of the contractile ring.”  She lists a whole squad of proteins and complexes that get involved.  But what if the ring starts forming too soon?  No worries: “The temporal control of contractile ring assembly is regulated by mitotic kinases to ensure that the contractile ring is initiated only after anaphase onset once the chromosomes have separated.”

The view from the blimp is too crude.  You have to get down and dirty to understand the game.  At the level of cellular machines, how does the ring cinch down the middle of the cell?  According to the “purse-string model,” there are teams of molecular winches, myosin-2 motors, that generate force by walking along two microtubule strands in opposite directions.  Actually, Miller explains, the picture is even more complicated. “Studies in mammalian cells and yeast suggest that the contractile ring is a dynamic structure in which F-actin and myosin-2 are continuously assembled and turned over.”  Not only is the contractile ring progressively disassembled as it constricts, it “may be organized in discrete contractile modules that are arrayed in series around the ring such that cells with a larger circumference have more contractile modules, and thus the rate of constriction is proportional to the initial circumference of the ring.”  Much remains to be learned about this amazing process.

1. Johansson, Zhang and Ehrenberg, “Genetic code translation displays a linear trade-off between efficiency and accuracy of tRNA selection,” PNAS December 21, 2011, doi: 10.1073/pnas.1116480109.

2. Anne L. Miller, “Quick Guide: The contractile ring,” Current Biology Volume 21, Issue 24, R976-R978, 20 December 2011, doi:10.1016/j.cub.2011.10.044.

These are wonderful discoveries coming to light, using ordinary observational science.  As Johansson et al. showed the evolution-talk is non-essential to the science.  It is stated as an object of faith.  Darwin’s theory neither predicted nor explained the discoveries, and is actually an impediment to further understanding.  It takes intelligent design, not undirected processes, to optimize a system.

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