November 30, 2006 | David F. Coppedge

The Nature of Cellular Tech

For molecule-size entities working in the dark, cellular machines seem pretty clever.  Here are some tricks they perform day and night to keep life functioning, described this month in Nature and PNAS.  Cell biology is sounding more and more like a mixture of Popular Mechanics and Wired.

  1. Energy balancing act:  Cells have to use oxygen without being burned by it.  In Nature 11/09,1 Toren Finkel described the delicate way mitochondria deal with their explosive fuel without polluting their environment. 

    Much like any factory producing widgets, mitochondria consume carbon-based fuels.  Their product is ATP, the energy currency of the cell.  Nonetheless, just like factory smokestacks, mitochondria also release potentially harmful by-products into their environment.  For mitochondria, these toxins come in the form of reactive oxygen species (ROS) that include superoxide and hydrogen peroxide.  In turn, these oxidants can interact with other radical species or with transition metals to produce by-products that are even more damaging.  To combat ROS production, the cell has evolved a number of sophisticated antioxidant defences, including enzymes such as superoxide dismutase to scavenge superoxide, as well as catalase and glutathione peroxidase to degrade hydrogen peroxide.

    Finkel did not explain how these sophisticated mechanisms might have evolved, except to assert that mitochondria are “tiny and evolutionarily ancient energy-producing organelles.”  He did consider a claim that they contain a “design flaw” because they leak measurable amounts of reactive oxygen species.  Is this a bug or a feature?

    If ROS synthesis is so bad, and a molecular solution so apparently straightforward, why has this ‘design flaw’ not been eradicated during the billions of years of evolution?  There are many possible answers, but one is that the notion that ROS from the mitochondria are solely harmful could be incorrect.  Indeed, substantial evidence exists that ROS generated in the cytoplasm could have vital signalling functions, and this might also be true for oxidants derived from mitochondria.

    On closer inspection, then, it appears that “a homeostatic loop exists between mitochondria and ROS and that this loop is, at least in part, orchestrated by PGC-1alpha.”  This, in turn, stimulates the production of more oxidant-sweeping molecular machines.

  2. Codes within codes:  Helen Pearson wrote a thought-provoking article in Nature 11/16 entitled “Genetic information; Codes and enigmas.”2  The idea is that there is “more than one way to read a stretch of DNA.”  Biologists have been searching for hidden meanings in the repetitive and non-coding regions and are turning up codes within the genetic code that affect regulation and expression of genes.  The way that DNA is packaged around nucleosomes appears an integral part of the message system.  As to how these codes allegedly evolved, she simply asserted that it did, and personified evolution as a designing hand:

    This elegance is surely the handiwork of evolution – and if the way in which that hand had worked to solve these problems were clearer, the simultaneous decoding of all the messages involved might become easierPerhaps ancestral organisms had simpler sequence patterns that evolution has optimized, taking advantage of its degeneracy to layer in additional information that helped organisms acquire extra complexity.  Hanspeter Herzel, who specializes in statistical analyses of DNA at Humboldt University, Berlin, speculates that the space constraints of the cell may have favoured the development of nucleosomes that wound up unruly DNA – and that their existence then encouraged the evolution of a nucleosome code in the sequence because this lowered the energetic cost of coiling up DNA.  But as yet such ideas, and any help they might offer, remain tentative.  “We don’t really have a phylogeny of these signals,” he says.

    Next, Pearson considered that some of the stretches of apparently meaningless code have no biological function at all: they are just there.  This approach, though, she finds distasteful: “But to some people the thought of order with no meaning is an affront.  To such minds, the idea of teasing out nature’s secrets with little more than mathematical cunning and processing power will never lose its allure.”  Stay tuned.

  3. Enzyme ballet:  Proteins and enzymes often work in complexes.  How do the parts dance without stepping on each other’s toes?  How do they get together on a crowded, active dance floor?  Two biologists considered this problem in the same 11/16 issue of Nature.3  Pick your favorite analogy; choreography or electrical engineering:

    Living cells, particularly during growth and proliferation, need regulatory processes of great sensitivity and high specificity.  To achieve this, signal-to-noise ratios must be high when information is received and transmitted between the cell surface, the cytoplasm and the nucleus.  Just like electrical and engineering control systems, living cells have complex signalling pathways that are moderated by feedback mechanisms.  It is becoming increasingly clear that most switches, transducers and adaptors in living systems are created by the assembly and disassembly of multi-component complexes of proteins, nucleic acids and other molecules….
        How do the molecular assemblies in cells achieve the required sensitivity and specificity?  Efficient signal transduction must maintain fidelity and decrease noise while amplifying the signal.  So the solution cannot be explained in terms of tightly bound, enduring molecular complexes, because the signals could not then be turned off.  Rather, it seems to lie in first assembling weak binary complexes, and then using cooperative interactions to produce multi-component complexes in which the weak interactions are replaced by much stronger and more specific interactions.
        Although weak, nonspecific, transient complexes could give rise to a noisy system, such ‘encounter complexes’ might be exploited so that interaction partners do not have to be found afresh in the busy milieu of the cell, thus increasing the rate of formation of specific binary and higher-order complexes.  Essentially, the partners bump into one another and are held loosely, allowing them time to become reorientated and repositioned on the surface or to adjust their shape to fit together more tightly.  Recent studies are beginning to describe the dynamics of the assembly processes and to show that nonspecific, transient collisions play an important role in macromolecular associations.

    How this is accomplished is discussed in more detail in the paper.  Sounds a bit like electrical robots in a random dance that, on average, brings partners together with the right chemistry such that they get a brief charge out of the bond before trying other players.

  4. Trigger finger:  There’s a chaperone in some bacteria called “trigger factor.”  This machine was discussed by Ada Yonah in Nature 11/23,4 summarizing a couple of papers in the issue.  He pictured it like a clamshell that attaches to the exit tunnel of the ribosome.  As a nascent polypeptide emerges, there is a risk that the hydrophobic amino acid residues, like magnets, will stick to the wrong stuff in the cell and create a tangled mess.  The trigger-factor clamshell forms a shelter around the exit tunnel, watching for these hydrophobic residues.  When one pops out, it gloms onto it and lets go of the ribosome, protecting it from the intercellular medium, until the polypeptide can fold properly into its finished shape.  The next trigger-factor chaperone takes its place on the exit tunnel for the next hydrophobic residue.  When folding proceeds, the clamshell opens up and goes back to the exit tunnel to look for more.  There’s an excess of trigger factor chaperones at all times.  “This means that there is a continuous supply of trigger factor to protect a nascent chain,” Yonah explains.
  5. Not a simple needle prick:  Two biologists described the “needle-nosed pump” known as Type-3 Secretion System (T3SS) in the Nov 30 issue of Nature.5  Though this machine, composed of 20 protein parts, shares some components with the famous bacterial flagellum, the authors did not dwell on this relationship but explained what else is known so far about T3SS.  For one thing, it is much more complex than previously realized.  Though it resembles somewhat a hypodermic syringe, the protein cargo it delivers is not just a needle prick into the host.  A complex delivery channel is assembled at the tip.  Moreover, assembly of the basal body and needle complex follows elaborate feedback mechanisms; the length of the needle complex is specifically controlled by either a “measuring cup” in the C-ring basal complex, or a “molecular ruler” in the channel or some other control method, such that the tip does not grow too long or too short.  The machine also has to be built to the right diameter such that the substrate protein can pass through.
        The T3SS is implicated in many pathogenic bacteria, like Yersinia pestis, bubonic plague.  Bacteria seem able to mimic the function of host proteins with substrates that function similarly without sequence similarity.  Though the authors attribute this to “convergent evolution,” they open the possibility that the needle shots these bacteria give to eukaryotic cells can be beneficial.  Why would bacteria mimic the legitimate proteins in a host?  The authors say, “this strategy seems appropriate to have been adapted by bacteria that have type III secretion systems as a central element for the establishment of a close functional interface that is often symbiotic in nature.
        Much remains to be learned about T3SS.  The authors seem genuinely excited about the potential for understanding disease transmission and bacterial-eukaryote interactions through the continued elaboration of these molecular mechanisms.  The 3-D diagrams look like something manufactured in a machine shop.  The authors seem to think machine language is the appropriate code for describing them; they called these things “machines” 42 times.  Let their ending paragraph express their enthusiasm:

    The discovery of type III secretion machines has arguably been one of the most significant discoveries in bacterial pathogenesis of the past few years.  The widespread distribution of such a macromolecular machine and its use in rather diverse biological contexts is a testament to the success of the evolutionary forces working to shape the complex functional interface between pathogenic or symbiotic bacteria and their eukaryotic hosts.  Its central role in the interaction of many pathogenic bacteria opens up the possibility of developing new anti-infective strategies.  In addition, a detailed understanding of these machines is allowing them to be harnessed to deliver heterologous proteins for therapeutic or vaccine purposes.  The past few years have seen a rather remarkable increase in the understanding of these machines.  There is no doubt that the importance and intrinsic beauty of these fascinating machines will continue to attract the attention of scientists and therefore progress is likely to continue at an even faster pace.

  6. Centriole olé:  Tiny devices called centrioles are vital to all life, because they duplicate each cell division and are intimately involved in it: “Centrioles are necessary for flagella and cilia formation, cytokinesis, cell-cycle control and centrosome organization/spindle assembly,” wrote 5 biologists in Nature 11/30.6  How the little machines duplicate themselves has been unclear.  “Here we show using electron tomography of staged C. elegans [roundworm] one-cell embryos that daughter centriole assembly begins with the formation and elongation of a central tube followed by the peripheral assembly of nine singlet microtubules,” they announced.  Various other proteins trigger, regulate, signal and terminate the process.
         Their models of the centrioles resemble cylinders lined by equally-spaced rods on the outside.  The shape can be discerned in the photographs.  “The structure of centrioles is conserved [i.e., unevolved] from ancient eukaryotes to mammals,” they noted, saying also at the end of the paper, “It is therefore likely that some of the assembly intermediates uncovered here in C. elegans are conserved in mammals and other eukaryotes.”
        As they reproduce, the daughter centrioles grow at a perpendicular angle to the mother.  How this all happens is mysterious, but you can watch movies of these geometric structures emerging out of the cell matrix in the supplementary materials of the paper.  The authors superimpose models of the centrioles to aid the visualization of a mechanical process just now coming into focus.  To watch machinery 400 billionths of a meter in size assembling itself in a living cell is a harbinger of exciting days ahead for cell biology.  For more on the lab roundworm C. elegans, visit our 06/25/2006 entry, and try counting the number of times “information” is used.
  7. Spectacrobatics:  Three scientists from U of Maryland, publishing in PNAS7, employed a dramatic word rarely seen in a scientific paper while trying to figure out the interactions of another famous chaperone, the GroES-GroEL complex.  They described a particular flip of a helix in the enzymes as “spectacular.”  They used the word not only in the abstract but in the body of the paper, and added a synonym for emphasis.  A coordinated switch between a network of salt-bridges in the enzyme produced what they called a “dramatic” outside-in movement.  Must be quite a show.  Now playing in a cell inside you.
  8. Dynein truckers:  In the film Unlocking the Mystery of Life, Michael Behe spoke of molecular trucks that carry cargo from one end of the cell to the other.  One of these trucks has a motor called dynein.  To show that Behe was not exaggerating, read a press release on EurekAlert.  It tells how a team of scientists U of North Carolina School of Medicine tried to figure out the power stroke of these little engines.  In describing the way the enzyme exerts mechanical force by converting chemical energy (in the form of ATP) into mechanical energy, they also used the transportation metaphor.  The article says, “the dynein puzzle is similar to figuring out how auto engines make cars move.”  One of the researchers continued, “You have an engine up front that burns gas, but we didn’t know how the wheels are made to move.”
        What’s interesting is that the gas tank is quite a ways from the wheels; that means that the chemical energy must be transmitted over a substantial distance from where the power stroke actually occurs (if you consider a few nanometers a substantial distance).  The truck is a speedster, too: “We saw it could allow a very rapid transduction of chemical energy into mechanical energy,” he said.  That’s good, because there’s nanotons of work for a trucker in Cellville.  “Conversion to mechanical energy allows dynein to transport cellular structures such as mitochondria that perform specific jobs such as energy generation, protein production and cell maintenance.  Dynein also helps force apart chromosomes during cell division.”  So the truck has as a good winch, too.
        These results were published in PNAS.8  Search on dynein above for more facts about these heavy lifters of the cell world, especially 02/25/2003 and 02/13/2003.  Also interesting are the entries from 12/02/2004 and 04/13/2005.  But then, 07/12/2004 might just blow you away.

Speaking of Wired, the pop-technology website actually posted a story recently called “Mother Nature’s Nanotech.”  Click here to see examples of cells that “will work for food.”  Why reinvent the wheel?  “Nature has everything nailed down already.  Single-celled organisms are everywhere, and some slave-driving scientists have figured out that if you hitch ’em to microdevices and nanocargo, these bugs can be dragooned into doing all kinds of work.  It’s time to domesticate the microworld.  Mush, you Escherichia coli! Mush!”  (See 09/06/2006).

1Toren Finkel, “Cell biology: A clean energy programme,” Nature 444, 151-152 (9 November 2006) | doi:10.1038/444151a.
2Helen Pearson, “Genetic information: Codes and enigmas,” Nature 444, 259-261 (16 November 2006) | doi:10.1038/444259a.
3Tom L. Blundell and Juan Fernandez-Recio, “Cell biology: Brief encounters bolster contacts,” Nature 444, 279-280 (16 November 2006) | doi:10.1038/nature05306.
4Ada Yonah, “Molecular biology: Triggering positive competition,” Nature 444, 435-436 (23 November 2006) | doi:10.1038/444435a.
5Jorge E. Galan and Hans Wolf-Watz, “Protein delivery into eukaryotic cells by type III secretion machines,” Nature 444, 567-573 (30 November 2006) | doi:10.1038/nature05272.
6Pelletier et al, “Centriole assembly in Caenorhabditis elegans,” Nature 444, 619-623 (30 November 2006) | doi:10.1038/nature05318.
7Hyeon, Lorimer and Thirumalai, “Dynamics of allosteric transitions in GroEL,” Proceedings of the National Academy of Sciences USA, published online before print November 29, 2006, 10.1073/pnas.0608759103.
8Serohijos et al, “A structural model reveals energy transduction in dynein,” Proceedings of the National Academy of Sciences USA, published online before print November 22, 2006, 10.1073/pnas.0602867103.

Need we say more?  You see the contrast between the exciting scientific work of investigating a world of technology at the limits of our grasp, alongside evolutionary speculations that are just plain silly.  “This elegance is surely the handiwork of evolution,” Pearson says, after describing a coded information and communication system more sophisticated than any software design we know.  Such pop-evo lingo contributes nothing to the science of these reports.  It’s just added after the fact, like trying to attach a sticky-note to a fountain, and does nothing but pollute it.
    This morning on the radio, atheists Lawrence Krauss and Sam Harris were claiming that ”People of Faith” who dare to believe “irrational” religious claims and deny evolution are dangerous and making America lose its edge in the scientific world.  They urged people to trust their minds to the pronouncements of “science” which is based on “evidence” (revealing their ignorance of philosophy of science, that they would still embrace logical positivism).  A scientist called in and said his faith was supported by evidence, not just faith.  Another caller rightly noted how many times scientists have changed their views, and how many scientists did great work because of their religion.  It’s the evolutionists who push their own faith in spite of the evidence, she said.  She ended her concise and intelligently-worded comeback by saying she didn’t have enough faith to be an atheist.  Nowhere is blind faith more exposed than in these articles, and many more like them reported in these pages, where high technology is simply assumed to arise by evolution, without any logic, reason or evidence to support it.
    Kudos to the researchers who are continuing to uncover these marvels.  Take the Darwinspeak out and you will do better.  The People of Froth need to understand that the age of biological machines will not endure simplistic Darwinian explanations any longer.  People sense the tension between the discoveries about biological machinery and the generalities in evolutionary tall tales.  Facts have stretched Darwinian faith to the breaking point.  The abrupt appearance of high technology in the simplest of organisms is not “evolutionary conservation,” it is creation.  The widespread incidence of similar technologies between disparate groups is not “convergent evolution,” it is common design.  When all the evolutionists can do is make religious arguments and get emotional, you know the Age of Darwin is over.  Welcome to the Information Age.  To be on the cutting edge, earn your degree at Celltech U (06/25/2006).

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