May 30, 2007 | David F. Coppedge

Molecular Motors Move You

The realization that cells are filled with molecules that move like machines fascinates many people.  Students who grew up thinking of chemistry as bouncing molecules that did little more than link up and separate have a whole new paradigm to consider: molecules that walk, fold and unfold, spin and operate like ratchets, robots, wrenches and motors.  Here are a few recent developments in the world of molecular machines:

  1. Brownian walk:  Researchers in Science1 reported that myosin, a molecular “walking” motor used in muscle, harnesses the random force of Brownian motion to keep on track.  Brownian motion is the random shuddering action of small molecules due to thermal motion in the environment.  Like sails in the wind, myosin motors are built in such a way that they can make use of the vector component corresponding to the direction they need to go.  “The leading neck swings unidirectionally forward, whereas the trailing neck, once lifted, undergoes extensive Brownian rotation in all directions before landing on a site ahead of the leading head,” said Shiroguchi and Kinosita.  “The neck-neck joint is essentially free, and the neck motion supports a mechanism where the active swing of the leading neck biases the random motion of the lifted head to let it eventually land on a forward site.”  This way they get a push for free.  The authors did not discuss how this mechanism might have evolved.
  2. Gut-level machinery:  Speaking of myosin, did you know it aids digestion?  Your digestive tract is lined with microvilli, tiny projections that vastly increase the surface area of the intestinal membrane that absorbs nutrients.  Now, scientists have found there’s a lot more going on in the tips of these projections.  Science Daily reported on work at Vanderbilt that showed myosin is concentrated in the tips and appears actively involved in shedding membrane material at the tips.  This process of vesicle formation and detachment may inject metabolic enzymes into the passing food material, as well as protect the lining of the intestine from invaders.  It’s all done with motors: myosin 1a, “a protein with the potential to generate force and move cargo around in cells.”  Matthew Tyska figured that there must be a reason these force-generating motors are concentrated in the microvilli, and sure enough, he found them at work: “It’s a little machine that can shed membrane from the tips,” he said.  This could give a whole new dimension to the term bowel movement.  Now his group is seeing if a similar mechanism operates in other cellular projections, like the hair cells of the inner ear.  See also EurekAlert.
  3. Clockworks:  A paper in Nature discussed the latest research into the molecular mechanisms behind biological clocks.2  There is not one clock molecule involved, but a host of proteins that form feedback loops in cycles that express and repress certain genes in response to environmental cues.  One of the proteins is even nicknamed CLOCK.  The article payed particular attention to PGC-1-alpha, a protein that appears intimately linked to both the circadian rhythm and metabolism, affecting the production of glucose, fatty acids and haem (iron-containing molecules).  Many questions remain, however.  This is clearly a work in progress.
  4. Splice and dice:  Another paper in Nature used the word “machinery” six times, speaking of the spliceosome.3  “A complex macromolecular machinery in the nucleus of eukaryotic cells is responsible for pre-mRNA splicing,” said Blencowe and Khanna.  They described how alternative splicing “is a remarkably efficient mechanism for a cell to increase the structural and functional diversity of its proteins, and it plays many roles in gene regulation” (see 05/20/2007).  The way alternative splicing is controlled is by RNA “riboswitches,” including messenger-RNA transcripts that can regulate their own expression with feedback and feed-forward loops.  These riboswitches can actually change shape in response to cues, and the shape determines how the gene will be expressed.  The authors used the word switch 18 times.
        Earlier, riboswitches were thought to exist only in bacteria and fungi, but now it appears they may be common in higher animals and in plants.  The authors speculated about evolution’s place in this: “It seems plausible that splicing-regulatory riboswitches represent a system that has evolved to coordinately regulate multiple genes in the same biochemical pathway using feedback and, in some cases, feed-forward mechanisms,” they asserted.  “Presumably, the rapid kinetics and energy-saving advantages afforded by bypassing protein-mediated regulation explain why riboswitch aptamers have persisted during evolution and function at many levels of regulation of gene expression.”  Yet this seems to assume what needs to be proved.  They used the presence of these switches, and the advantages they appear to confer, as evidence they evolved, yet provided no details on how that could have occurred by natural selection.  By contrast, the evidence they did provide shows the opposite of evolution: between very distant organisms, like fungi and higher plants, the genes involved are “evolutionarily conserved” (i.e., unevolved).
  5. Machine language:  Two scientists publishing in PNAS sounded like factory planners, but were talking about cells.4  “Experimental and theoretical studies of proteins, acting as motors, ion pumps, or channels, and enzymes, show that their operation involves functional conformational motions,” they said.  A few sentences later, the machine talk continued: “Generally, a machine is a mechanical device that performs ordered internal motions that are robust against external perturbations.”  They were discussing how molecular machines in the cell, particularly myosin and ATP synthase, are examples of such robustness.  “In conclusion,” they said in the final discussion section, “we have shown that motor proteins possess unique dynamical properties, intrinsically related to their functioning as machines.”  This recalls a line Scott Minnich said in the film Unlocking the Mystery of Life: “It’s not convenient that we give them these [machine] names; it’s truly their function.”
        Part of the title read, “design principles of molecular machines.”  Yet the authors attributed this design to undirected chance processes of evolution in this statement: “Actual proteins with specific architectures allowing robust machine operation may have developed through a natural biological evolution, with the selection favoring such special dynamical properties.”  They ran a simulation of an “evolutionary computer optimization process” and achieved a “artificial elastic network architectures possessing machine-like properties,” but this statement blurs the line between intelligently-selected outcomes and chance.

“Machine” language is quite common in the scientific literature.  One often finds matter-of-fact discussion of proteins and enzymes as machines.  They use energy and perform physical work according to tight specifications.  The evolutionary conundrum is: how could functioning machines arise from non-functional matter in motion?  Authors of scientific papers typically either ignore the question, or assume evolution did the design work.
    A more fruitful approach was offered by a biophysicist who wrote Nature last week, suggesting that we “Look at biological systems through an engineer’s eye.5  R. S. Eisenberg said that when approaching a black box, whether an amplifier in a sound system or an unknown mechanism in a living cell, we should identify the inputs and outputs, the power supply and the device equation.  Looking at biological devices with the eyes of an engineer, he said, can lead to fruitful experiments:

Complex systems – for example, with many internal nonlinear connections like the integrated circuit modules of digital computers or, perhaps, the central nervous system – may not be easily analysed as devices, no matter how many experimental data are available.  But it seems clear, at least to a physiologist, that productive research is catalysed by assuming that most biological systems are devices.  Thinking today of your biological preparation as a device tells you what experiments to do tomorrow.
    Asking the questions in this way leads to the design of useful experiments that may eventually lead to the device description or equation, if it exists.  If no device description emerges after extensive investigation of a biological system, one can look for other, more subtle descriptions of nature’s machines.

An intelligent design scientist might feel vindicated.  No evolutionary theorizing is needed in this approach.  Assuming design in the device, and asking engineering questions, can stimulate a fruitful experimental program.

1Shiroguchi and Kinosita, “Myosin V Walks by Lever Action and Brownian Motion,” Science, 25 May 2007: Vol. 316. no. 5828, pp. 1208-1212, DOI: 10.1126/science.1140468.
2Grimaldi and Sassone-Corsi, “Circadian rhythms: Metabolic clockwork,” Nature 447, 386-387 (24 May 2007) | doi:10.1038/447386a.
3Blencowe and Khanna, “Molecular biology: RNA in control,” Nature 47, 391-393 (24 May 2007) | doi:10.1038/447391a.
4Togashi and Mikhailov, “Nonlinear relaxation dynamics in elastic networks and design principles of molecular machines,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0702950104, published online before print May 16, 2007.
5R. S. Eisenberg, “Look at biological systems through an engineer’s eye,” Correspondence, Nature 447, 376 (24 May 2007) | doi:10.1038/447376a.

These papers speak for themselves.  Was anybody impressed by the evolutionary storytelling?  Was it useful?  Did it contribute to understanding in any way?  How about, on the other hand, the machine language?  Can you talk machine language without assuming intelligent design?  Where do you think science is headed?  Bye-bye, Charlie.

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