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  1. #31
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    Protein Dressing Room Has Electronic Walls 06/07/2006
    Properly folded proteins are essential to all of life. When a polypeptide, or chain of amino acids, emerges from the ribosome translation factory on its way to becoming a protein, it looks like a useless, shapeless piece of string. It cannot perform its function till folded into a precise, compact shape particular for its job. Some short polypeptides will spontaneously fold into their “native” state, ready for work, but many of the bigger ones need help. Fortunately, the cell provides a private dressing room called the GroEL-GroES chaperonin that not only gives them privacy, away from the bustle of colliding molecules in the cytoplasm, but actually helps them get dressed (see also 05/05/2003 entry). This chaperone or “helper” machine thus not only gets the actor ready for the stage faster, but prevents misfolding that could clutter the cell with useless or harmful aggregates of protein.
    A team from the Max Planck Institute, writing in Cell,1 investigated how the internal structure of this barrel-shaped molecular machine overcomes energy barriers to proper folding and speeds up the process ten-fold. They found that the inside walls of the GroEL barrel and the inside walls of the GroES lid contain protrusions that generate electrostatic and hydrophobic forces on the interior space. When the unfolded protein enters, therefore, it is subjected to gentle pressures that coax it to fold. These forces are nonspecific enough to work on hundreds of different substrates that use this general-purpose machine.
    Furthermore, they found that the forces change during the entry of the nascent protein. The interior is not barrel shaped when the actor approaches the door; the GroES lid, with the help of the energy molecule ATP, guides the protein in, and then the barrel pops into its shape, providing a safe haven for folding. Moreover, the electronic walls turn on to provide that gentle nudge to get the polypeptide over its energy barriers and into the right folding pathway. When the protein has properly completed its folding after about 10 seconds in the dressing room, the door opens and the protein pops out, ready for action.
    How finely tuned is this machine? The authors did some experiments on mutating the chaperone to make the barrel looser and tighter. They found that volume changes as small as 2-5% slowed down the folding considerably. The barrel volume needs to be within certain narrow limits, yet general enough to handle a variety of small, medium and large proteins.

    “The GroEL/GroES nano-cage allows a single protein molecule to fold in isolation. This reaction has been compared to spontaneous folding at infinite dilution. However, recent experimental and theoretical studies indicated that the physical environment of the chaperonin cage can alter the folding energy landscape, resulting in accelerated folding for some proteins. By performing an extensive mutational analysis of GroEL, we have identified three structural features of the chaperonin cage as major contributors to this capacity: (1) geometric confinement exerted on the folding protein inside the limited volume of the cage; (2) a mildly hydrophobic, interactive surface at the bottom of the cage; and (3) clusters of negatively charged amino acid residues exposed on the cavity wall. We suggest that these features in combination provide a physical environment that has been optimized in evolution [sic] to catalyze the structural annealing of proteins with kinetically complex folding pathways. Thus, the chaperonin system and its mutant versions may prove as useful tools in understanding how proteins navigate their energy landscape of folding.”

    --------------------------------------------------------------------------------
    1Tang et al., “Structural Features of the GroEL-GroES Nano-Cage Required for Rapid Folding of Encapsulated Protein,” Cell
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  2. #32
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    Plant Hula-Hoop Railroads Build Cell Walls 06/09/2006
    Solving a long-standing mystery about how plants build cell walls, Stanford scientists imaged molecular machines traveling along hoop-shaped rings around the inside of the cell. Publishing in Science, Paradez, Somerville and Ehrhardt proved that cellulose synthase (CESA), a machine that manufactures cellulose composed of six subunits arranged in rosettes, rides like a rail car on microtubules that encircle the inside of the plasma membrane. From there, the machine extrudes the complex molecule to the exterior, building the rigid cell wall.
    Clive Lloyd, commenting on this finding in the same issue of Science,2 seemed happily astonished, not only at the scientific achievement, but at the plants themselves:

    “In a remarkable series of biological transformations, green plants convert carbon dioxide into cellulose fibers stronger than steel. These thin threads of polymeric glucose are wrapped around growing cells, lending structural support to the plant as it extends further into the environment. The fibers are not simply secreted into the plant cell wall in a haphazard fashion but are deposited in ordered layers that still allow the cell to expand. For more than 40 years, it has been known that the alignment of these cellulose fibers (microfibrils) in the cell wall often coincides with cytoskeletal microtubules tethered to the cytoplasmic side of the plasma membrane... Despite this coincidence, there has never been direct proof that microtubules provide a guidance mechanism for the alignment of cellulose microfibrils. Now, on page 1491 of this issue, Paredez et al. (1) provide that proof.”

    Lloyd described the cell-encircling hoops as a “microtubule railroad” providing tracks for the cellulose-synthesizing machines. Apparently these tubules can reorient themselves, perhaps in hula-hoop fashion, allowing the machines to stitch cross-hatch patterns of cellulose for added strength (see 01/16/2003) for analogous process).
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    1Paradez, Somerville and Ehrhardt, “Visualization of Cellulose Synthase Demonstrates Functional Association with Microtubules,” Science, 9 June 2006: Vol. 312. no. 5779, pp. 1491 - 1495, DOI: 10.1126/science.1126551.
    2Clive Lloyd, “Microtubules Make Tracks for Cellulose,” Science, 9 June 2006: Vol. 312. no. 5779, pp. 1482 - 1483, DOI: 10.1126/science.1128903.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  3. #33
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    Eukaryote Evolution Proceeded from Complex to Simple 06/09/2006
    As if reprimanding simpletons, three scientists writing in Science1 preached that the old picture of evolution from simple to complex is simplistic. This is particularly true, they claim, for the story that eukaryotes were born from a blessed union. “Data from many sources,” they counter, “give no direct evidence that eukaryotes evolved by genome fusion between archaea and bacteria.” Further down, they remark, “Unfortunately, such a model has been tacitly favored by molecular biologists who appeared to view evolution as an irreversible march from simple prokaryotes to complex eukaryotes, from unicellular to multicellular.” The old picture harks back to obsolete views of straight-line evolution.

    “Comparative genomics and proteomics have strengthened the view that modern eukaryote and prokaryote cells have long followed separate evolutionary trajectories. Because their cells appear simpler, prokaryotes have traditionally been considered ancestors of eukaryotes. Nevertheless, comparative genomics has confirmed a lesson from paleontology: Evolution does not proceed monotonically from the simpler to the more complex. Here, we review recent data from proteomics and genome sequences suggesting that eukaryotes are a unique primordial lineage....”

    Out with the old, in with the new. What do they suggest to replace the old picture? Believe it or not, “sequence loss and cellular simplification.” Since these are “are common modes of evolution,” they argue that the first eukaryote was already a unique, complex creature. Like a predator or raptor, it acquired mitochondria by phagocytosis, and diversified from there.
    Their view does not prohibit increases in complexity, yet they seem eager to distance evolutionary theory from visions of progress. “Genome evolution is a two-way street,” they say; “This bidirectional sense of reversibility is important as an alternative to the view of evolution as a rigidly monotonic progression from simple to more complex states, a view with roots in the 18th-century theory of orthogenesis.” They describe several life-forms that have reduced their genomes and slimmed down to the bare minimum: parasites, symbionts, organelle genomes, and anaerobes.
    OK so far; evolution can move either toward complex or simple – but how does this explain eukaryotes (cells with nuclei and compartmentalized organelles)? Here, their explanation appears forced by the hard realities of the evidence. From the earliest possible ancestor, eukaryotes were already complex. They had introns (and complex spliceosomes, half of whose 78 proteins are unique to eukaryotes, to handle them), mitosomes, hydrogenosomes, mitochondria, nuclei, nucleoli, the Golgi apparatus, centrioles, and an endoplasmic reticulum, along with “hundreds of proteins with no orthologs evident in the genomes of prokaryotes.” (Simple Giardia, for example, has 347 eukaryote signature proteins.) Much of the article describes the unprecedented features of eukaryotes, which constitute a “unique cell type that cannot be deconstructed into features inherited directly from archaea and bacteria.”
    This calls for alternatives to “hypotheses that attribute eukaryote origins to genome fusion between archaea and bacteria” (endosymbiosis), which they claim “are surprisingly uninformative about the emergence of the cellular and genomic signatures of eukaryotes.” Recognition of these realities must be “the critical starting point” for explaining where eukaryotes came from: i.e., a “larger and more complex cell” at the beginning when the three kingdoms – bacteria, archaea and eukaryotes – diverged.
    Their picture can be summarized as follows: (1) the common ancestor was a raptor or predator on prokaryote mitochondria. (2) Cellular crowding and compartmentalization led to more efficient molecular interactions. (3) Extensive genome reduction followed. Darwin, of course, grins in the background; “This abbreviated account of genome reduction illustrates the Darwinian view of evolution as a reversible process in the sense that ‘eyes can be acquired and eyes can be lost’” (because of the two-way street of natural selection). Even Darwin would have agreed that “selection gives, and selection takes.” They concur with essential evolutionary doctrine without hesitation: “Genomes evolve continuously through the interplay of unceasing mutation, unremitting competition, and ever-changing environments.” Darwinism is safe, therefore; so now, let’s picture the new emerging story for the 21st century:

    “For the reasons outlined above, we favor the idea that the host that acquired the mitochondrial endosymbiont was a unicellular eukaryote predator, a raptor. The emergence of unicellular raptors would have had a major ecological impact on the evolution of the gentler descendants of the common ancestor. These may have responded with several adaptive strategies: They might outproduce the raptors by rapid growth or hide from raptors by adapting to extreme environments. Thus, the hypothetical eukaryote raptors may have driven the evolution of their autotrophic, heterotrophic, and saprotrophic cousins in a reductive mode that put a premium on the relatively fast-growing, streamlined cell types we call prokaryotes.”

    One problem. How this complex, predatory cell with most of its unique parts “emerged” is anyone’s guess. So get busy, everyone: “This scenario, which is not contradicted by new data derived from comparative genomics and proteomics, is a suitable starting point for future work.”
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    1Kurland, Collins and Penny, “Genomics and the Irreducible Nature of Eukaryote Cells,” Science, 19 May 2006: Vol. 312. no. 5776, pp. 1011 - 1014, DOI: 10.1126/science.1121674.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  4. #34
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    Rubisco “Highly Tuned” for Fixing Atmospheric Carbon 06/22/2006
    Rubisco sounds like a brand of cracker or something, but it’s actually an air cleaner your life depends on. It’s an enzyme that fixes atmospheric carbon for use by photosynthetic microbes and plants. In doing so, it sweeps the planet of excess carbon dioxide – the greenhouse gas implicated in discussions of global warming – making it a politically important molecule as well the most economically important enzyme on earth. Rubisco is the most common enzyme in the world, too; every person on earth benefits from his or her own 12 to 25 pounds of these molecular machines, which process 15% of the total pool of atmospheric carbon per year. For a long time, biochemists thought this enzyme was slow and inefficient. That view is changing. Rubisco now appears to be perfectly optimized for its job.
    Rubisco’s cute name is a handy anagram for the clumsier appellation ribulose bisphosphate carboxylase. Tcherkez et al. first broke the paradigmatic logjam about this enzyme’s purported inefficiency with an article in PNAS,1 titled, “Despite slow catalysis and confused substrate specificity, all ribulose bisphosphate carboxylases may be nearly perfectly optimized.” Howard Griffiths commented this week in Nature2 about this paper and the new findings about its optimization. Though his article referred to evolution seven times, and only mentioned design twice, the latter word seemed the most valuable player.
    There are four classes of Rubisco, some more efficient at fixing carbon than others. Its reputation as a slow enzyme (2-8 catalytic events per second) may be unfair. Carbon dioxide in gaseous form has to compete for access to the active site against the much more abundant and lighter oxygen. Griffiths shows what a difficult job this molecule has to perform; no wonder it leaks somewhat. But, as he explains, even the leaks are accommodated:

    “It is curious that Rubisco should fix CO2 at all, as there is 25 times more O2 than CO2 in solution at 25°C, and a 500-fold difference between them in gaseous form. Yet only 25% of reactions are oxygenase events at this temperature, and carbon intermediates ‘lost’ to the carbon fixation reactions by oxygenase action are metabolized and partly recovered by the so-called photorespiratory pathway. Catalysis begins with activation of Rubisco by the enzyme Rubisco activase, when first CO2 and then a magnesium ion bind to the active site. The substrate, ribulose bisphosphate, then reacts with these to form an enediol intermediate, which engages with either another CO2 or an O2 molecule, either of which must diffuse down a solvent channel to reach the active site.”

    This is a harder job than designing a funnel that will pass only tennis balls, when there are 500 times more ping-pong balls trying to get through. Not only is Rubisco good at getting the best mileage from a sloppy process, it may actually turn the inefficiency to advantage. Griffiths started by claiming, “evolution has made the best of a bad job,” but ended by saying that the enzyme’s reputation as “intransigent and inefficient” is a lie. Why? It now appears that “Rubisco is well adapted to substrate availability in contrasting habitats.” This means its inefficiency is really disguised adaptability.
    Experimenters thought they could “improve” on Rubisco by mutating it. They found that their slight alterations to the reactivity of the enediol intermediate drastically favored the less-desirable oxygenase reaction. This only served to underscore the contortions the molecule must undergo to optimize the carboxylase reaction:

    “Such observations provided the key to the idea that in the active site the enediol must be contorted to allow CO2 to attack more readily despite the availability of O2 molecules. The more the enediol mimics the carboxylate end-product, Tcherkez et al. conclude, the more difficult it is for the enzyme to free the intermediate from the active site when the reaction is completed. When the specificity factor and selectivity for CO2 are high, the impact on associated kinetic properties is greatest: kcat [i.e., the rate of enzyme catalytic events per second] becomes slower.
    So, rather than being inefficient, Rubisco has become highly tuned to match substrate availability.”

    Another finding about the inner workings of Rubisco bears on dating methods and climate models. Scientists have known that Rubisco favors the lighter, faster-moving carbon isotope 12C over 13C. By measuring the ratio of these stable isotopes in organic deposits, paleoclimatologists have inferred global carbon dioxide abundances and temperatures (knowing that Rubisco processes the isotopes differently). That assumption may be dubious:

    “Several other correlates are also explained by this relationship. For instance, Rubisco discriminates more against 13C than against 12C, the two naturally occurring stable isotopes in CO2. But when the specificity factor is high, the 13C reaction intermediate binds more tightly, and so carbon isotope discrimination is higher (that is, less 13C is incorporated); in consequence, the carbon-isotope signals used to reconstruct past climates should perhaps now be re-examined. In contrast, higher ambient temperatures (30-40 °C) reduce the stability of the enediol, and Rubisco oxygenase activity and photorespiration rate increase.”

    Those considerations aside, Griffiths is most interested in two things: how this enzyme evolved, and whether we can improve on it. If we can raise its carboxylation efficiency, we might be able to increase crop yields. So far, genetic engineers have not succeeded.3
    As for the evolution of Rubisco, he mentions three oddball cases but fails to explain exactly how they became optimized for their particular circumstances – only that they are optimized. Yet their abilities seem rather remarkable. For instance, though the “least efficient” forms of Rubisco reside in microbes living in anaerobic sediments, where oxygen competition is not a problem, “One bacterium can express all three catalytically active forms (I, II and III), and switches between them depending on environmental conditions.” In another real-world case, “some higher plants and photosynthetic microorganisms have developed mechanisms to suppress oxygenase activity: CO2-concentrating mechanisms are induced either biophysically or biochemically.” In another example, “Rubisco has not been characterized in the so-called CAM plants, which use a form of photosynthesis (crassulacean acid metabolism) adapted for arid conditions.” These plants, including cacti and several unrelated species scattered throughout the plant kingdom, have other mechanisms for dealing with their extreme environments. In every mention of evolution, therefore, Griffiths assumed it rather than explaining it: viz., “The systematic evolution of enzyme kinetic properties seems to have occurred in Rubisco from different organisms, suggesting that Rubisco is well adapted to substrate availability in contrasting habitats.”
    So, can we improve on it? If so, given all the praise for what evolution accomplished, Griffiths seems oblivious to the implications of his own concluding sentence:

    “Other research avenues include manipulating the various components of Rubisco and cell-specific targeting of chimaeric Rubiscos. Potential pitfalls here are that the modified Rubisco would not only have to be incorporated and assembled by crop plants, but any improved performance would have to be retained by the plants. Finally, one suggestion is that we should engineer plants that can express two types of Rubisco – each with kinetic properties to take advantage of the degree of shading within a crop canopy. Such rational design would not only offer practical opportunities for the future, but also finally give the lie to the idea that Rubisco is intransigent and inefficient.”

    What, students, is a synonym for “rational design”?
    --------------------------------------------------------------------------------
    1Tcherkez et al., “Despite slow catalysis and confused substrate specificity, all ribulose bisphosphate carboxylases may be nearly perfectly optimized,” Proceedings of the National Academy of Sciences USA, published online before print April 26, 2006, 10.1073/pnas.0600605103 PNAS | May 9, 2006 | vol. 103 | no. 19 | 7246-7251.
    2Howard Griffiths, “Plant biology: Designs on Rubisco,” Nature 441, 940-941 (22 June 2006) | doi:10.1038/441940a; Published online 21 June 2006.
    3If and when they do, the benefit would be tuned for humans and their livestock, not necessarily for the ecology or atmosphere.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  5. #35
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    Cell Untangles Its Own DNA 07/17/2006
    DNA is packed like spaghetti in a basketball (07/28/2004), but must constantly be accessed by transcribers, duplicators and other molecular machines. Scientists at the Karolinska Institute, according to EurekAlert, have found a complex of protein machines that know how to untangle DNA. Machines that can keep DNA from separating too early (cohesins) and keep DNA coils compact (condensins) have been studied extensively, but these scientists looked more at another mechanism. When they artificially perturbed DNA strands, the machines went to work fixing the damage:

    “The research group has studied the third, less well understood, protein complex, known as the Smc5/6 complex. This protein complex was found to bind to locations on the DNA strand that the researchers had artificially damaged, suggesting that it is directly involved in the repair process. Moreover, the Smc5/6 complex also seems to be required for the disentanglement of undamaged chromosomes before cell division. If these tangles, which are a natural consequence of the DNA copying process, are left unresolved the chromosomes cannot be separated and sent to the two nascent daughter cells. Like in the repair process, the Smc5/6 complex appears to resolve these intertwines by direct interaction with the DNA molecules, but this process is differently regulated as compared to the function in repair.”

    The press release starts with a “wow” factoid: “Every second, the cells constituting our bodies are replaced through cell division. An adult human consists of about 50,000 billion cells, 1% of which die and are replaced by cell division every day.” Machines like the Smc5/6 complex are essential to maintaining our genomic integrity.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  6. #36
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    Cell Backup Systems Challenge Evolution, Show Design Principles 07/21/2006
    Has an intelligent design paper been published in the Proceedings of the National Academy of Sciences?1 Read the abstract and decide whether this research supports Darwinism or design:

    “Functional redundancies, generated by gene duplications, are highly widespread throughout all known genomes. One consequence of these redundancies is a tremendous increase to the robustness of organisms to mutations and other stresses. Yet, this very robustness also renders redundancy evolutionarily unstable, and it is, thus, predicted to have only a transient lifetime. In contrast, numerous reports describe instances of functional overlaps that have been conserved throughout extended evolutionary periods. More interestingly, many such backed-up genes were shown to be transcriptionally responsive to the intactness of their redundant partner and are up-regulated if the latter is mutationally inactivated. By manual inspection of the literature, we have compiled a list of such “responsive backup circuits” in a diverse list of species. Reviewing these responsive backup circuits, we extract recurring principles characterizing their regulation. We then apply modeling approaches to explore further their dynamic properties. Our results demonstrate that responsive backup circuits may function as ideal devices for filtering nongenetic noise from transcriptional pathways and obtaining regulatory precision. We thus challenge the view that such redundancies are simply leftovers of ancient duplications and suggest they are an additional component to the sophisticated machinery of cellular regulation. In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.”

    The three authors, all from the Weizmann Institute in Rehovot, Israel, speak freely of the evolution of this phenomenon in their paper; they also, interestingly, refer to design and design principles just as often:

    “In particular, we suggest the existence of regulatory designs that exploit redundancy to achieve functionalities such as control of noise in gene expression or extreme flexibility in gene regulation. In this respect, we suggest that compensation for gene loss is merely a side effect of sophisticated design principles using functional redundancy.
    Clues for regulatory designs controlling redundancy were obtained first in a recent study...”

    They call these cases of functional redundancy responsive backup circuits (RBCs). Interestingly, they found some cases where one RBC is regulated by another RBC. Though often the two backup copies were differently regulated, they could become coregulated under certain environmental conditions. The team also found that some of these functionally redundant genes are found all the way from yeast to mammals; this is sometimes called “evolutionary conservation” but actually describes stasis, not evolution.
    The authors do not deny that these backup systems evolved somehow: “For a single cell, the ability to quickly and efficiently respond to fluctuating environments is crucial and offers an obvious evolutionary advantage,” they postulate, suggesting that accidental duplication of genes was co-opted for this purpose. They do not get into any details of how this might have happened, however, and their analysis seems more interested on the complexity and design benefit of the systems.
    Their criteria for functional backups were stated thus: “Two lines of evidence could indicate a function’s direct benefit from existing redundancy: first is the evolutionary conservation of the functional overlap, and second is a nontrivial regulatory design that utilizes it.” How many such systems exist in nature they could not say, because there have not been enough studies. Many functionally equivalent copies of enzymes (isozymes) are known. The genes that produce them are often regulated by different pathways. Under stress, however, some can become coregulated to provide robustness against environmental irregularities or damaging mutations.

    “The model that emerges is that although many isozymes are specialized for different environmental regimes, alarm signals induced by particular stress stimuli may call for their synergistic coexpression. Here, RBCs provide functional specialization together with extreme flexibility in gene control that could be activated when sufficient stress has been applied. For example, in yeast, glucose serves as a regulatory input for alternating between aerobic and anaerobic growth. Its presence is detected by two separate and independent signaling pathways, one probing intracellular glucose concentrations and the other probing extracellular concentrations.”

    They searched the literature and found several interesting ones that are described in detail in the paper. “In all these cases, the common denominator is that one of the two duplicates is under repression in wild type and that that repression is relieved upon its partner’s mutation.”
    This raises an interesting question – one that could have been asked by someone in the intelligent design movement. They even answer a possible objection with a design principle:

    “The extent to which genomic functional redundancies have influenced the way we think about biology can be appreciated simply by inspecting the vast number of times the word “redundancy” is specifically referred to in the biomedical literature (Fig. 5, which is published as supporting information on the PNAS web site). Particularly interesting is the abundance with which it is addressed in studies of developmental biology (Fig. 5). In fact, it is here that concepts such as “genetic buffering” and “canalization” first had been suggested. Furthermore, the robustness of the developmental phenotypes such as body morphologies and patterning have been repeatedly demonstrated. So the question is, are these redundancies simply leftovers of ancient duplications, or are they an additional component to the sophisticated machinery of cellular regulation?
    In criticism, one may argue that many of the reported redundancies do not actually represent functionally equivalent genes but rather reflect only partial functional overlap. In fact, knockout phenotypes have been described for a number of developmental genes that have redundant partners. For these reasons, it has been suggested to define redundancy as a measure of correlated, rather than degenerate, gene functions. Although these facts may suggest that redundancies have not evolved for the sake of buffering mutations, it has, in our opinion, little relevance to the question of whether they serve a functional role. The interesting question is, then, can such a functional role for the duplicated state be inferred from the way the two genes are regulated?”

    Along that line, they found that the amount of upregulation of one gene was often dependent on the regulation of the other. This suggested to them that the sum of the expression of the two copies is nearly constant as a buffer against noise in the system. When one line gets noisy, due to a mutation, the other responds with more signal. They call this “dosage-dependent linear response.” In some cases during development, the responsive overlap decreases as the organism grows. In short, “The abundance of redundancies occurring in genes related to developmental processes, and their functional role as master regulators (Fig. 5) may be taken to suggest their utilization in either the flexibility or robustness of regulatory control.”
    Some examples they give are even more complex. RBCs may also be implicated in the resistance of some organisms to multiple drugs. In some cases, each isoform can compensate equally for the other; in others, one of the forms is the main (the controller) and the other acts as the backup (the responder), only coming into play when the primary goes sour. “One of the most profound and insightful of these recurring regulatory themes,” they exclaim, “is that, although both genes are capable of some functional compensation, disruption of the responder produces a significantly less deleterious phenotype than disruption of the controller”. In evolutionary terms, why would the backup copy be better?

    “A simple potential interpretation may suggest that although the controller is the key player performing some essential biological role, the responder is merely a less efficient substitute. Yet, accepting the notion that redundancy could not have evolved for the sake of buffering mutations, this interpretation still is severely lacking.
    A different, and more biologically reasonable, hypothesis accounting these asymmetries is that one of the functions of the responder is to buffer dosage fluctuations of the controller. This buffering capacity requires a functional overlap that also manifests itself in compensations against the more rare event of gene loss. Other models accounting for this assymetry are discussed further in this work, but our main point of argument is that this complex regulation of functionally redundant, yet evolutionarily conserved genes, strongly indicates utilization of redundancy.”

    Their next subsection is called “Regulatory Designs.” What emerges from their discussion of how each gene can regulate its partner is a complex picture: in one case, “redundancy is embedded within a more complex interaction network that includes a unidirectional responsive circuit in which the controller (dlx3) also represses its own transcription, whereas the responder (dlx7) is a positive autoregulator.” More examples like this are described. They predicted, and found, that RBCs could also regulate “downstream processes from variation and fluctuations arising from nongenetic noise.” The net result is that by using these functional backup systems, the organism has more robustness against perturbations, yet more flexibility in a dynamic environment.
    What is the fruit of this research? Why should scientists look for these “regulatory designs” in the cell? They offer an intriguing example. It is known that one form of human muscular dystrophy occurs when a member of an RBC suffers a mutation. Studies of this pair in mice, however, shows that the other member can respond by upregulating its expression. It is thought a similar response might occur in humans. “Inspired by the compensatory effect demonstrated by this RBC in mice, its artificial induction in humans by means of gene therapy has been suggested. Although such modalities have not yet been realized, they suggest a fruitful possibility.”
    --------------------------------------------------------------------------------
    1Kafri, Levy and Pilpel, “The regulatory utilization of genetic redundancy through responsive backup circuits,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0604883103, published online before print July 21, 2006
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  7. #37
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    Self-Correcting RNA: Is It a Missing Link? 07/28/2006
    A team of Russian scientists at Rutgers discovered a remarkable phenomenon: RNA that proofreads itself during its own synthesis. The work was reported in Science1: “We show that during transcription elongation, the hydrolytic reaction stimulated by misincorporated nucleotides proofreads most of the misincorporation events and thus serves as an intrinsic mechanism of transcription fidelity.” It has already been known that DNA transcription and translation includes a whole suite of error-correcting mechanisms, but this is the first instance of RNA self-correction.
    The researchers did not comment on the evolution of this capability except to state that it “is likely evolutionarily conserved” (i.e., unevolved in all living organisms), and that in an RNA-protein world, a “proofreading and repair mechanism similar to the one described here could have allowed a large RNA genome of the last common universal ancestor to exist.” This is because without an accurate proofreading mechanism even in an RNA world, duplication fidelity would have been too low for evolution: “the relatively low fidelity of RNAP-catalyzed synthesis could not have been sufficient for stable maintenance of large RNA genomes in the absence of cleavage factors.”
    Patrick Cramer (Gene Center Munich), however, writing in the same issue of Science,2 launched their final, speculative paragraph into a story of how this RNA must be a missing link. Starting with the admission that “Precision can be vital,” Cramer immediately invoked the E word: “cells have evolved processes for proofreading and correction to shut down the propagation of errors” in the DNA-to-protein pathway. Referring to the work by Zenkin et al., he said, “This finding helps to explain the fidelity of gene transcription and suggests that self-correcting RNA was the genetic material during early evolution.”
    But how, exactly, could that have come about? In his missing-link story, notice how many times Cramer used speculation words like could, probably and suggests compared to the hard requirements of reality:

    “The discovery of self-correcting RNA transcripts suggests a previously missing link in molecular evolution. One prerequisite of an early RNA world (devoid of DNA) is that RNA-based genomes were stable. Genome stability required a mechanism for RNA replication and error correction during replication, which could have been similar to the newly described RNA proofreading mechanism described by Zenkin et al. If self-correcting replicating RNAs coexisted with an RNA-based protein synthesis activity, then an early RNA-based replicase could have been replaced by a protein-based RNA replicase. This ancient protein-based RNA replicase could have evolved to accept DNA as a template, instead of RNA, allowing the transition from RNA to DNA genomes. In this scenario, the resulting DNA-dependent RNA polymerase retained the ancient RNA-based RNA proofreading mechanism.
    Whereas an understanding of RNA proofreading is only now emerging, DNA proofreading had long been characterized. DNA polymerases cleave misincorporated nucleotides from the growing DNA chain, but the cleavage activity resides in a protein domain distinct from the domain for synthesis. The spatial separation of the two activities probably allowed optimization of two dedicated active sites during evolution, whereas RNA polymerase retained a single tunable active site. This could explain how some DNA polymerases achieve very high fidelity, which is required for efficient error correction during replication of large DNA genomes.”

    Of course, being only a “scenario” for how proofreading “could” have evolved, Cramer offered no evidence, lab or otherwise, for such a self-correcting RNA “missing link.” For a discussion of problems with the RNA-world scenario, see the 07/11/2002 entry.
    --------------------------------------------------------------------------------
    1Zenkin, Yuzenkova and Severinov, “Transcript-Assisted Transcriptional Proofreading,” Science, 28 July 2006: Vol. 313. no. 5786, pp. 518 - 520, DOI: 10.1126/science.1127422.
    2Patrick Cramer, “Perspectives: Molecular Biology: Self-Correcting Messages,” Science, 28 July 2006: Vol. 313. no. 5786, pp. 447 - 448, DOI: 10.1126/science.1131205.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  8. #38
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    Bacteria Rule the World – Benevolently 08/02/2006
    We should love bacteria, not annihilate them. Bacteria are our friends, according to Dianne K. Newman of Caltech:1

    “As a microbiologist, I’m appalled when I go to buy soap or dishwashing detergent, because these days it’s hard to find anything that doesn’t say ‘antibacterial’ on it.... It’s a commonly held fallacy that all bacteria are germs, but it’s been estimated that out of more than 30 million microbial species, only 70 are known to be pathogens. That’s a trivial number. The vast majority are actually doing remarkable things, both for the quality of our life and for the quality of the planet.”

    We couldn’t annihilate them, anyway, if we wanted to. They are the most widespread and hardiest organisms on earth. Maybe you heard on the news today that there are more bacteria on your cell phone than on a toilet seat. Better to get used to it; they’re everywhere.
    The realization that bacteria rule the world began when Leeuwenhoek found more organisms on his teeth than men in a kingdom. Newman continues:

    “Leeuwenhoek underestimated. Not only do they exceed the number of men and women in a kingdom, they go far beyond that. We have anywhere from 5 million to 50 million bacteria per square inch on our teeth, and over 700 microbial species living in our mouths. Most of them are aiding us in our digestion—as are the 300 billion bacteria living in each gram of our colon. The palms of our hands have between 5,000 and 50,000 organisms per square inch, although that’s nothing compared to the skin of our groin and armpit areas, which as at least 5 million per square inch.
    The grand total per person is about 70 trillion (70 x 10exp12), so we’re really walking vats of bacteria. There are 10 times the number of microbial cells in an adult body than there are human cells, and the gut microbiome alone is estimated to contain more than a hundred times the number of genes that we have in our own genome—so there’s a remarkable amount of metabolic diversity living within us. We shouldn’t be alarmed by this, however, because most of these bacteria are our friends.”

    If you are sufficiently grossed out by the revelation that you are a zoo, consider that the animals in a zoo represent just a tiny fraction of life on earth:

    “As well as living on and within animals, microbes live in plants, oceans, rivers, lakes, aquatic sediments, soils, subsoils, and air. The total number of microbes on the planet has been estimated at 5 x 10exp30, which is an enormous number. If they were all lined up end to end in a chain, it would stretch to the sun and back 200 x 10exp12 times.

    A related article on BBC News noted the remarkable diversity of microbes. “One litre of seawater can contain more than 20,000 different types of bacteria,” the article begins, suggesting that microbial diversity is much greater than imagined.
    Most of Dianne Newman’s delightful article is concerned with her Caltech team’s research into the amazing metabolic properties of certain bacteria that can live on rust as well as oxygen. She talks about bacteria that can generate light, orient by magnetic fields, and help larger organisms in numerous ways. Her colorful prose, unfortunately, is marred here and there by evolutionary stories that qualify for Stupid Evolution Quote of the Week:

    • They invented oxygenic photosynthesis...
    • Over the course of time, these types of cyanobacteria became engulfed by other organisms that then evolved into plants...
    • ...the chloroplast, is nothing more than an ancient cyanobacterium.
    • Moreover, we can only breathe this oxygen because our mitochondria—the little organelles in our cells that produce energy—are vestigial microorganisms descended from another ancient bacterium.
    • Microbes are very, very old. They’ve been on our planet for at least 3.8 billion years, appearing just 800 million years after the planet formed. for the first 1.6 billion years or so of their existence, they had the place to themselves, and it was only after the oxygenation of the air and oceans by the cyanobacteria that the forerunners of plants and animals came along.
    • The reason we find microbes almost everywhere we look is because, over the billions of years of Earth’s history they’ve been around, they’ve figured out how to be fantastic chemists.

    Perhaps this is one of the reasons that Kansas school board member Connie Morris, who was just voted out of office (see yesterday’s entry), often described evolution as “a nice bedtime story.”
    --------------------------------------------------------------------------------
    1Dianne K. Newman, “Bacteria Are Beautiful,” Caltech Engineering & Science (LXIX:2), Aug. 2006, pp. 8-15.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  9. #39
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    How Useful Is Evolutionary Theory to Biology? 08/04/2006
    A favorite quote by evolutionists is the line by Theodosius Dobzhansky, “Nothing in biology makes sense except in the light of evolution.” Why, then, do so many biological papers fail to mention evolution at all? Indeed, many employ design language, sometimes with a sense of awe. Here are more recent examples in which the E word was missing (or inconsequential) in the glare of amazement over complex design:

    Charged with pain: Wounds generate electric fields that guide repair crews to the site. Science Now got a charge out of this: “Talk about healing energy,” reporter Laura Blackburn challenged the faith healers. “Every wound, from the tiniest scratch to the nastiest gash, generates an electric field that pulls in cells that help repair the damage.”

    Rotary switch: A team publishing in PNAS1 discussed the ID Movement’s favorite biological toy, the bacterial flagellum. They considered the switching mechanism that allows the propeller to go into reverse. Their paper sounds like something out of Popular Mechanics: “Structure of FliM provides insight into assembly of the switch complex in the bacterial flagella motor.”

    Checkpoint, no Charlie: M. Andrew Hoyt appreciates even more the way the cell uses checkpoints to make sure division occurs without error. In Science2 he examined a new answer to how the cell switches this control on and off:

    “Paradoxically, the mechanism responsible for separation of the chromosomes at anaphase itself creates chromosome attachments that the checkpoint would normally recognize in metaphase as improper. Yet, the cell cycle proceeds naturally unimpeded; these improper chromosome attachments fail to activate the cycle-blocking activity of the spindle checkpoint after anaphase onset. From a clever series of experiments reported on page 680 of this issue by Palframan et al., we now know why. In anaphase cells, the actions of the spindle checkpoint are extinguished by the very same protein complex that previously was the target of its anaphase-inhibitory activity.”

    Hoyt did also speak of “conserved” (i.e., unevolved) proteins of the spindle checkpoint, but had no other references to evolution.
    Stretchy Clots: Another paper in Science3 examined the properties of fibrin, one of the principle ingredients in blood clots, and found that they have “extraordinary extensibility and elasticity.”

    “Blood clots perform an essential mechanical task, yet the mechanical behavior of fibrin fibers, which form the structural framework of a clot, is largely unknown. By using combined atomic force-fluorescence microscopy, we determined the elastic limit and extensibility of individual fibers. Fibrin fibers can be strained 180% (2.8-fold extension) without sustaining permanent lengthening, and they can be strained up to 525% (average 330%) before rupturing. This is the largest extensibility observed for protein fibers. The data imply that fibrin monomers must be able to undergo sizeable, reversible structural changes and that deformations in clots can be accommodated by individual fiber stretching.”

    Readers of the primary intelligent design book Darwin’s Black Box might remember the blood clotting system as one example Michael Behe used of irreducible complexity.

    When evolution is mentioned in papers dealing with complex, interacting systems in biology, the references often seem imprecise and incidental to the work that went into the research, as if tacked on as an afterthought. For instance, R. John Ellis, writing in Nature July 27,4 described the details of the protein-folding chaperone complex, Gro-EL and Gro-ES. After describing in some detail the specifications of these versatile molecular machines, noting that “both the size and surface charge of the cage are optimized to speed up the folding of several different types of chain,” he referred to evolution on only two places, both speculative, and both personifying natural selection as the wizard of technology:

    “The size and surface properties of the cage represent an evolutionary compromise that helps the bacterial cell to produce functional proteins fast enough to survive in a competitive microbial world.....
    It is a testament to the ingenuity of natural selection that the chaperonin cage not only combats aggregation caused by crowding outside the cage but also uses crowding to accelerate protein folding inside the cage. Nanoengineers trying to improve the yield of therapeutic proteins could profit from studying the tricks of the chaperonin nanocage.”

    Go figure.
    --------------------------------------------------------------------------------
    1Park et al., “Structure of FliM provides insight into assembly of the switch complex in the bacterial flagella motor,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0602811103, published online before print August 1, 2006.
    2Palframan et al., “Anaphase Inactivation of the Spindle Checkpoint,” Science, 4 August 2006: Vol. 313. no. 5787, pp. 680 - 684, DOI: 10.1126/science.1127205.
    3Liu et al., “Fibrin Fibers Have Extraordinary Extensibility and Elasticity,” Science, August 2006: Vol. 313. no. 5787, p. 634, DOI: 10.1126/science.1127317.
    4R. John Ellis, “Protein folding: Inside the cage,” Nature 442, 360-362(27 July 2006) | doi:10.1038/442360a; Published online 26 July 2006.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  10. #40
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    Another Flagellum Excites Scientists 09/01/2006
    “The bacterial flagellar motor excites considerable interest because of the ordered expression of its genes, its regulated self-assembly, the complex interactions of its many proteins, and its startling mechanical abilities,” begins a paper in Nature by three Caltech scientists.1 They performed electron cryotomography imaging on the flagella of Triponema primita, a different critter with a different model from the flagellum found in E. coli, the favorite toy of microbiologists (with an outboard motor that is an icon of the intelligent design movement). Treponema is a little spirochete that lives in the hindgut of termites. It has two flagella, one at each end, that apparently rotate on its inside and make the organism gyrate rather than swim through liquid.
    The Caltech team got good images of the stator for the first time. Their exterior and cross-section illustrations show a multi-part circular structure with 16-fold symmetry and complex contours, with rings and other parts of unknown function. This particular motor apparently operates in low gear. It is larger than the E. coli or Salmonella flagella and apparently runs at much higher torque.

    “These differences have important implications for current models of the functional and architectural relationships of the components. Whereas the Salmonella motor spins just the flagellum, because Treponema flagella are periplasmic, it is thought that they cause the whole cell to gyrate. Thus, each rotation may be much slower and require greater torque. The unusually large stud ring, C ring and rotor in Treponema may serve to increase torque by increasing the length of the effective lever arm through which each stator stud acts. These larger rings may also accommodate more stator studs and FliG molecules around the ring, in effect ‘gearing down’ the Treponema motor so that the passage of each proton across the membrane produces a smaller angular rotation.”

    The paper includes a link to an animation video that shows the motor in operation from different angles. The authors talk a lot about machine specs, but don’t mention anything about evolution.
    --------------------------------------------------------------------------------
    1Murphy, Leadbetter and Jensen, “In situ structure of the complete Treponema primitia flagellar motor,” Nature 442, 1062-1064(31 August 2006) | doi:10.1038/nature05015.

    [b]Yoke Up Those Bacteria [/i] 09/06/2006
    My, how history repeats itself – often in unexpected ways. In ancient times, our ancestors got the heavy work done by hitching oxen, horses or slaves (like Samson, see pictures 1 and 2) to a harness and making them turn a grinding wheel. The same principle is now on the cutting edge of modern applied biological engineering – only now, the movement is measured in micrometers, and the beasts of burden are bacteria. Scientists in Japan, publishing in PNAS,1 have successfully hitched their harnesses to multi-legged crawlers named Mycoplasma mobile and made them turn a gear 20 micrometers wide, many times their size.
    In the contraption rigged by Hiratsuka et al., the bacteria walk inside a circular track, pushing a six-petal rotor made of silicon dioxide above them. The inventors (slavedrivers?) developed a surface that would ensure the majority of the cell “microtransporters” would move in one direction with the right amount of friction. The cooperative workers achieved forces of 2 to 5 x 10exp-16 newton-meters, with rotation rates of 1.5 to 2.6 rpm. “To the best of our knowledge,” they boasted with some merit, “a micromechanical device that integrates inorganic materials with living bacteria has not succeeded until this study.” (They did, however, reference the PNAS research reported in our 08/19/2005 entry, “Saddle Up Your Algae.”)
    The inventors didn’t mention evolution once in their paper. Instead, they spoke in glowing terms about their little microscopic oxen and marveled at their technology. First, they scanned the arena of biological micro-machinery with the delight of a gadget freak:

    “Nature provides numerous examples of nanometer-scale molecular machines. In particular, motor proteins, which efficiently convert chemical energy into mechanical work, are fascinating examples of functional nanodevices derived from living systems. The molecular mechanism underlying the function of these motors has long been a major focus of biophysical research, and the information emerging from those studies should greatly aid in the design and fabrication of novel synthetic micro/nanomotors....
    Turning an eye to higher-order biological structures reveals many examples of excellent mechanical devices, including bacterial and eukaryotic flagella and muscle sarcomeres. These motile units are tens of nanometers to several micrometers in size and consist of multiprotein complexes built up with atomic accuracy through the self-assembly and self-organization of protein molecules within cells. In general, these devices work far more efficiently and intelligently than the isolated proteins but, because the principles and mechanisms of self-assembly are only vaguely understood, we are currently unable to assemble higher order motile units from the isolated component proteins outside the cells. Consequently, research aimed at developing hybrid devices using biological motile units is rare at present.”

    How about the machines employed by their chosen beast of burden? The praise service continues:

    “Mycoplasma mobile, a species of gliding bacteria, is another example of a higher-order unit (cells in this case) with superb motility. M. mobile has a pear-shaped cell body ~ 1 micrometer in length and moves continuously over solid surfaces at speeds up to 2-5 micrometers per second. The mechanism by which it glides remains unknown, although a mechanical walking model that makes use of the rod-like structures protruding from the cell surface has been proposed. Although three proteins have been identified as essential for gliding, we speculate that this motile system may need a dozen additional proteins, including various cytoskeletal proteins.”

    So why reinvent the wheel? Why go to all the trouble to invent walking nanorobots, when bacteria have it all figured out? The inventors list other reasons for enlisting biological beasts of burden instead of trying to start from scratch:

    “As a result, it is currently impractical, if not impossible, to reconstitute fully functional motile units from the isolated proteins of M. mobile in vitro. For that reason, we have been attempting to construct micromechanical devices using intact M. mobile cells instead of the isolated proteins. A key benefit of this approach is that hybrid devices into which living cells are integrated enable us to take advantage of preassembled excellent motor units that have the potential for self-repair or self-reproduction when damaged.”

    So there you go: spare parts and repairs come included with the package. Oxen must be fed, however, and they didn’t talk about that (cf. Solomon). Someone else may have to invent the nanomanger.
    --------------------------------------------------------------------------------
    1Hiratsuka et al., “Applied Biological Sciences: A microrotary motor powered by bacteria,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0604122103, published online before print September 1, 2006.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  11. #41
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    Flagellar Swimmers Attain Mechanical Nirvana 09/06/2006
    Those little germs that scientists love, E. coli – you know, the ones with the flagella that intelligent-design folk get all excited about – well, they move through the water pretty efficiently with those high-tech outboard motors of theirs. Some Pennsylvania physicists reporting in PNAS1 measured the “swimming efficiency of bacterium Escherichia coli” and concluded, “The propulsive efficiency, defined as the ratio of the propulsive power output to the rotary power input provided by the motors, is found to be ~ 2%, which is consistent with the efficiency predicted theoretically for a rigid helical coil.” An engineer can’t get much more efficient than that, in other words, even in theory. Later in the paper, they summarized, “The measured [epsilon: i.e., propulsive efficiency] is close to the maximum efficiency for the given size of the cell body and the shape of the flagellar bundle.”
    That efficiency rating is the overall measurement for the package. Many bacteria have multiple flagella, however, and ascertaining the individual contributions of each component, and the subtle hydrodynamic interactions between them, is a difficult task. They did, however, assess the length of the flagellum as a factor in the optimal performance, and concluded that “flagella are as long as required to maximize its propulsive efficiency.”2
    They measured the swimming efficiency by capturing single bacteria in “optical tweezers” and putting them into a measured rate of flow. The work was edited by Howard Berg of Harvard, a pioneer of flagellum research (see his 1999 article on Physics Today).

    --------------------------------------------------------------------------------
    1Chattopadhyay, Moldovan, Yeung and Wu, “Swimming efficiency of bacterium Escherichia coli,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0602043103, published online before print September 5, 2006.
    2For a dazzling animation showing how the flagellum tip is constructed, see the video link from our 11/02/2005 entry. Fast-forward to 18:20. How does it know when to stop growing? There must be feedback from the growing tip to the control mechanism in the cell body.

    Another Rotary Machine Found in Bacteria 09/13/2006
    A molecular “garbage disposer” in the cell membrane bearing some resemblance to the rotating motor ATP synthase has been described in Nature.1 This machine, called AcrB, expels toxins from the cytoplasm through the cell membrane to the outside. Like ATP synthase, it has three active sites at one end where the binding occurs, and it operates on proton motive force; but unlike the former, it performs “functional rotation” instead of mechanical rotation.
    Murukami et al., a team of five in Japan, described the machine in the 14 Sept issue of Nature.1 Here is a simplified picture of how it works. Picture a pie with three slices and follow a toxin from the inside of the cell, through the AcrB disposer, to the outside. One of the slices has a port open and ready for use; we follow the molecule inside as it gets dragged in because of the proton flow. A trap door lets us into the first chamber then snaps shut. Inside, we are squeezed into another chamber, then into a tunnel, then handed off to a membrane protein that ejects us out to the exterior environment. The squeezing occurred because the neighboring pie slice opened its port when ours closed. When the third slice opened in turn, we were ejected into the tunnel. In this “functional rotation” model of the action, each of the three segments cycles through three states, and affects the state of the neighboring segment. The result is a continuous garbage-disposer like operation that sucks in the toxins, binds them, and ejects them out. Apparently each segment can handle a wide variety of substrates, and adjacent segments might be working on different molecules simultaneously.
    There’s one bad side effect of this technology for us humans. For doctors trying to administer chemotherapeutic drugs or antibacterial agents, the bacteria put up a challenge; they can be ejecting the drugs as fast as the doctor administers them. This is one way bacteria gain immunity to drugs. Finding ways to disable these “ubiquitous membrane proteins” may be easier now that we know how they work. This particular machine operates in the lab bacterium E. coli, but there are other types of these “multi-drug transporters” (MDTs) in other organisms that work in other ways. In the same issue of Nature,2 two Swiss researchers described a different MDT in S. aureus called Sav1866. Instead of proton motive force, this member of the ABC family of MDTs uses ATP to twist the toxin out of the membrane.
    In the case of the rotary machine AcrB, both the research team and commentator Shimon Schuldiner (Hebrew U) couldn’t help but notice the resemblance to ATP synthase. AcrB lacks the mechanical rotation of the gamma subunit, and seems to lack the rotating carousel driven by protons, but it does have three active sites that appear to operate in turn like a rotary engine. Schuldiner did not explain any details of a relationship, but speculated that AcrB might be a missing link of sorts: “It is possible that this is a remnant of the evolutionary process that led to the development of true rotary molecular machines.” Other than that, and an offhand remark earlier in the commentary that “MDTs have evolved into many different forms to act on a wide range of xenobiotics” [i.e., alien molecules], the only other reference to evolution in any of these three papers was a speculation about Sav1866 by Dawson and Locher. Noting the functional similarity but distinctly different architecture between Sav1866 and another member of the ABC family of MDTs, “the bacterial lipid flippase MsbA” in Salmonella, they cannot see an evolutionary relationship between them: “The observed architectures of MsbA and Sav1866 remain incompatible, even when considering that the proteins may have been trapped in distinct states,” they note. So what is the answer? How did these structurally different yet functionally similar machines originate? They leave it at, “the differences—if real—would indicate a convergent evolution of the two proteins.”

    --------------------------------------------------------------------------------
    1Murukami et al., “Crystal structures of a multidrug transporter reveal a functionally rotating mechanism,” Nature 443, 173-179(14 September 2006) | doi:10.1038/nature05076.
    2Dawson and Locher, “Structure of a bacterial multidrug ABC transporter,” Nature 443, 180-185(14 September 2006) | doi:10.1038/nature05155.
    3Shimon Schuldiner, “Structural biology: The ins and outs of drug transport,” Nature

    What’s Inside a Spore? Nanotechnology 09/17/2006
    The spores that are emitted from fungi and ferns are so tiny, the appear like dust in the wind. Who would have ever thought such specks could exhibit nano-technological wonders like scientists have found recently:

    • Evapo-Motors: Scientists at U of Michigan were intrigued by how ferns turn the power of evaporation into launching pads. The sporangia (spore ejectors) use a “microactuator” to eject the spores into the environment as they dry out. The team was so impressed, they said “Oh, we have to build that,” and imitated the mechanism to build microchips that open and close when wetted or dried. They think they might be able to generate electricity without batteries with this technique.
    • Info Compactor: Despite their minute size, spores must carry the entire genome of the species. A Wistar Institute press release talked about that. It’s incredible: a histone tag on the chromatin somehow signals a compaction process that reduces the already-tight fit to 5% of the original volume. All this must be done very delicately, because spores are haploid (one strand of DNA) and much more subject to disastrous breaks.

    In the second article, the researchers found that a similar compaction method works in the sperm cells of animals as diverse as fruit flies and mice. To them, this observation is “suggesting that the mechanisms governing genome compaction are evolutionarily ancient, highly conserved in species whose lineages diverged long ago.”
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  12. #42
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    Biological Nanomachines Inspire Nanotechnology 10/07/2006
    Nano, nano; we’re hearing that morkish prefix a lot these days. It means 10exp-9 of something: most often, of meters (see powers of ten). A nanometer is a billionth of a meter. This gets down into the range of protein molecules and small cellular components. A DNA molecule, for instance, is about 20 nanometers across; an ATP synthase rotary motor is about 8 x 12 nanometers, and a bacterial flagellum about 10 times larger. Now that imaging technology is reaching into realms of just a few nanometers, scientists are keen to understand nature’s engineering in hopes of doing their own.
    The premiere issue of Nature Nanotechnology made its debut this month.1 It contains a centerpiece review article by Wesley R. Browne and Ben L. Feringa entitled, “Making molecular machines work.”2 Though the article focuses on human progress and potential in the world of nanotechnology, it contains numerous ecstasies about biological machines unmade by human hands:

    • Consider a world composed of nanometre-sized factories and self-repairing molecular machines where complex and responsive processes operate under exquisite control; where translational and rotational movement is directed with precision; a nano-world fuelled by chemical and light energy. What images come to mind? The fantastical universes described in the science fiction of Asimov and his contemporaries? To a scientist, perhaps the ‘simple’ cell springs more easily to mind with its intricate arrangement of organelles and enzymatic systems fuelled by solar energy (as in photosynthetic systems) or by the chemical energy stored in the molecular bonds of nucleotide triphosphates (for example, ATP).
    • Biological motors convert chemical energy to effect stepwise linear or rotary motion, and are essential in controlling and performing a wide variety of biological functions. Linear motor proteins are central to many biological processes including muscle contraction, intracellular transport and signal transduction, and ATP synthase, a genuine molecular rotary motor, is involved in the synthesis and hydrolysis of ATP. Other fascinating examples include membrane translocation proteins, the flagella motor that enables bacterial movement and proteins that can entrap and release guests through chemomechanical motion.
    • Whereas nature is capable of maintaining and repairing damaged molecular systems, such complex repair mechanisms are beyond the capabilities of current nanotechnology.
    • In designing motors at the molecular level, random thermal brownian motion must therefore be taken into consideration. Indeed, nature uses the concept of the brownian ratchet to excellent effect in the action of linear and rotary protein motors. In contrast to ordinary motors, in which energy input induces motion, biological motors use energy to restrain brownian motion selectively. In a brownian ratchet system the random-molecular-level motion is harnessed to achieve net directional movement, and crucially the resulting biased change in the system is not reversed but progresses in a linear or rotary fashion.
    • Biosystems frequently rely on ATP as their energy source, however very few examples of artificial motors that use exothermic chemical reactions to power unidirectional rotary motion have been reported to date.
    • That biological motors perform work and are engaged in well-defined mechanical tasks such as muscle contraction or the transport of objects is apparent in all living systems.

    It is clear that the biological machines are inspiring the human drive toward exploiting the possibilities of mimicking, if not duplicating, what already exists in nature. They say in conclusion,

    “The exquisite solutions nature has found to control molecular motion, evident in the fascinating biological linear and rotary motors, has served as a major source of inspiration for scientists to conceptualize, design and build – using a bottom-up approach – entirely synthetic molecular machines. The desire, ultimately, to construct and control molecular machines, fuels one of the great endeavours of contemporary science....
    ....As complexity increases in these dynamic nanosystems, mastery of structure, function and communication across the traditional scientific boundaries will prove essential and indeed will serve to stimulate many areas of the synthetic, analytical and physical sciences. In view of the wide range of functions that biological motors play in nature and the role that macroscopic motors and machines play in daily life, the current limitation to the development and application of synthetic molecular machines and motors is perhaps only the imagination of the nanomotorists themselves.”

    --------------------------------------------------------------------------------
    1Nature Nanotechnology, Vol. 1, No. 1, October 2006.
    2Wesley R. Browne and Ben L. Feringa, “Making molecular machines work,” Nature Nanotechnology, 1, pp25-35 (2006), doi:10.1038/nnano.2006.45.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

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    Precambrian Cell Division Imaged 10/17/2006
    Embryos frozen in stone in the act of cell division were reported in Science.1 According to a press release from Virginia Tech, there are millions of fossilized embryos in the Doushantuo formation in south China, estimated to be 551 million years old, but “later stages of these animals are rare.” The EurekAlert version of this press release contains images of the embryos. A press release from Indiana University says some of the embryos have 1000 cells or more.
    With X-ray computed tomography, the researchers were able to get past taphonomic artifacts and image the actual cells. The embryos show asynchronous cell division, which means that the embryos were differentiating into more complex organisms than bacteria in strata said to be 10 million years prior to the Cambrian explosion. The original paper in Science puts the find into an evolutionary context: “Asynchronous cell division is common in modern embryos, implying that sophisticated mechanisms for differential cell division timing and embryonic cell lineage differentiation evolved before 551 million years ago.” None of the larger embryos in the 162-sample set showed differentiation into epithelial tissues, however, an observation they call “striking.” “Many of these features are compatible with metazoans, but the absence of epithelialization is consistent only with a stem-metazoan affinity for Doushantuo embryos.... Epithelialization, by whatever mechanism of gastrulation, should be underway in modern embryos with >100 cells.” Thus, they imply these represent pre-animal experiments in cell division. “The absence of this 3D hallmark of sponge- and higher-grade metazoans may indicate that they did not yet exist... the combined observations suggest that the Doushantuo embryos are probably stem-group metazoans”; i.e., organisms on the way to evolving into full-fledged multicellular animals.
    It’s hard to be sure, though, because specimens in later stages of development are lacking. Even so, these embryos have characteristics of the embryos of advanced Cambrian animals:

    “Despite hypotheses that Doushantuo embryos are unusual in comparison to most known metazoans, the patterns of cleavage and cell topology are compatible with a range of animal groups. For instance, in embryos composed of eight or more cells, the offset arrangement of successive tiers of cells, strong cell cohesion, and a stereoblastic cell topology are comparable to early cleavage embryos of many arthropod groups. Stereoblastulae are also particularly common among sponges and scyphozoan cnidarians. Doushantuo embryos composed of many hundreds of cells resemble the purported gastrulae of demosponges, before the development of parenchymella larvae, although at this stage demosponges exhibit evidence of gastrulation, with a differentiated superficial layer of micromeres surrounding a core of macromeres.”

    If juvenile and adult forms of these organisms appeared in the strata, would they resemble the Cambrian animals? Or do these embryos represent experiments in cell division that would later explode into the diversity of Cambrian forms? Take your pick: the Indiana U press release says, “Either these embryos are primitive and don’t have a clear blastocoel, or a blastocoel existed but didn’t survive the preservation process.” See also a story posted on the UK Telegraph.
    --------------------------------------------------------------------------------
    1Hagadorn et al, “Cellular and Subcellular Structure of Neoproterozoic Animal Embryos,” Science, 13 October 2006: Vol. 314. no. 5797, pp. 291-294, DOI: 10.1126/science.1133129.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

  14. #44
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    A Cell Technology Show 11/17/2006
    The basic units of life continue to astound scientists with their tricks. Here are a few recent samples:

    1. Valuable junk: The complementary or “antisense” strands of certain RNAs that latch onto messenger RNAs are not just junk anymore. Science Daily reported that these genetic oddities, “previously thought to have no function, may in fact protect sex cells from self-destructing.” Nobody would want that to happen. Up till now these strands of genetic material were thought to have no meaning at all. Now, “considering how widespread these antisense transcripts are, I wouldn’t be surprised if these findings eventually lead us to discover an entirely new level of gene regulation.” Another said, “This points to an entirely new process of gene regulation that we’ve never seen before in eukaryotic cells.”
    2. Fishers of molecules: How do DNA transcribers move? Do they crawl like an inchworm down the strand? No; the answer is even more surprising. Researchers at UCLA found that “transcription proceeds initially through a ‘scrunching’ mechanism in which, much like a fisherman reeling in a catch, RNAP [RNA Polymerase] remains in a fixed position while it pulls the flexible DNA strand of the gene within itself and past the enzyme’s reactive center to form the RNA product.” See EurekAlert for the details. The original papers in Science actually use the abstruse technical term “scrunching.” Another press release on EurekAlert has a picture of the “scrunching machine.”
    3. Diamonds from the rough: EurekAlert reported that another molecular machine is involved in gene expression. Another RNA polymerase builds micro-RNAs formerly thought to be junk, but now seen to be important in regulating the expression of genes. Scientists seem to be excited these days about treasure-hunting in the genetic junkyard. This discovery “broadens understanding of a rapidly developing area of biology known as functional genomics and sheds more light on the mysterious, so-called ‘junk DNA’ that makes up the majority of the human genome.”
    4. Of all the nerve dancers: Neurons cover themselves in myelin sheaths that are critical to their function. A press release from Vanderbilt U compared this to the insulation on electrical wiring in your house. “The formation of myelin sheaths during development requires a complex choreography generally considered to be one of nature’s most spectacular examples of the interactions between different kinds of cells,” reporter David Salisbury wrote. A group at Vanderbilt succeeded at filming part of the dance. “We discovered that this process is far more dynamic than anyone had dreamed,” commented one team member. It’s a good thing the dancers usually get their act together. Failure can result in “blindness, muscle weakness and paralysis, loss of coordination, stuttering, pain and burning sensations, impotence, memory loss, depression and dementia.” Ouch. Read the details and look at frames from the movies they made.
    5. At your service: Science Daily also had a story about the DNA Repair Team in the cell. Its motto, announces the title, is “to protect and to serve.” The article, based on Salk Institute research, began, “When you dial 911 you expect rescuers to pull up at your front door, unload and get busy--not park the truck down the street and eat donuts.” Same for the cell, it continues: “just before it divides, it recruits protein complexes that repair breakage that may have occurred along the linear DNA chains making up your 46 chromosomes.” There’s even a protein complex scientists have named 9-1-1. At the ends of chromosomes, the versatile repair crew knows how to call in additional support to tuck in the ends of the strands and form a protective cap. “Be thankful your cells are so clever,” the article states: “Erroneous fusion of chromosome ends would be disastrous, leading to cell death or worse.” No donut breaks for these skilled technicians; they are on the job 24 x 7.
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

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    Outsource Our Energy Woes to the Microbes 11/18/2006
    Do we need to dig for oil forever? Do we need to fret and fume over energy policy as more consumers compete for decreasing resources? What if there were a virtually inexhaustible supply right under our noses? That’s what the American Society for Microbiology asked in a press release reproduced by EurekAlert. “The answer to one of the world’s largest problems – the need for clean, renewable sources of energy – might just come from some of the world’s smallest inhabitants – bacteria,” it teased. Why reinvent the wheel, when microbes already know how to get fuel from the sun and other readily-available resources? Some day, the article continues, you may be shopping for some really cool gadgets for the home:

    “Imagine the future of energy. The future might look like a new power plant on the edge of town – an inconspicuous bioreactor that takes in yard waste and locally-grown crops like corn and woodchips, and churns out electricity to area homes and businesses,” says Judy Wall of the University of Missouri - Columbia, one of the authors of the report.
    Or the future may take the form of a stylish-looking car that refills its tank at hydrogen stations. “Maybe the future of energy looks like a device on the roof of your home – a small appliance, connected to the household electric system, that uses sunlight and water to produce the electricity that warms your home, cooks your food, powers your television and washes your clothes. All these futuristic energy technologies may become reality some day, thanks to the work of the smallest living creatures on earth: microorganisms,” Wall says.
    The study of microbial fuels is in its infancy, and current products are not yet cost-effective. But the potential is enormous. Microbes already know how to make “numerous fuels including ethanol, hydrogen, methane and butanol.” They can also convert food sources directly into electricity.
    Farmers and gardeners can look forward to a bright future, too, once scientists learn the secrets of low-energy nitrogen fixation mastered by bacteria. EurekAlert reported that scientists are making progress understanding how the amazing machines called nitrogenases work. Dinitrogen molecules are the toughest nuts to crack because of their triple bonds. Man’s method (the Haber process), used to make ammonia fertilizer, is costly and energy-intensive. Somehow, nitrogenase splits these tightly-bound atoms apart with ease at room temperature. If we can figure out how bacteria achieve this feat, and replicate it, the economic boom that might result – with benefits for solving world hunger – can only be imagined.
    By the way, when planning your future biotechnology home, with its termite air conditioning system (09/21/2004), don’t forget the worms (09/14/2004) for clean and efficient garbage disposal. No worries; it will be a cinch to order whatever you need from your spinach cell phone (09/21/2004).
    Random changes are destructive to any carefully crafted piece of work, such as a computer program, a novel or the genome of a lifeform.
    Matt 23:24Ye blind guides, which strain at a gnat, and swallow a camel.

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