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  • bob b
    Muscles Use Gears, Automatic Transmission 01/28/2007
    Analogies may not be perfect representations of reality, but it must pique the interest of all of us the way Elisabeth Pennisi in Science1 compared muscle to cars and bicycles:

    “One look at a ballerina as she pirouettes and poses drives home the remarkable ability of our muscles to adapt to diverse biomechanical demands. Manny Azizi and Thomas Roberts, biomechanists at Brown University, have now found that as certain muscles contract, they vary their shape to balance the need for speed and force. It’s as if these muscles have a builtin automatic transmission, says Azizi....
    [Azizi’s] simulations showed that certain muscle shapes caused contracting pinnate fibers to shift to a less steep angle. When that happens, the muscle’s overall height decreases more than it would have had the fibers maintained their angle. In other words, the virtual muscle shifted into the equivalent of a high gear ratio, increasing the speed of contraction.... Azizi then looked at whether real muscles acted this way. He had expected that each pinnate muscle would have just one gear ratio, that is, undergo a characteristic shape change, and therefore be strong or contract fast but not have both features.... [they found] the muscle operated at a lower gear and took full advantage of the dense packing of pinnate fibers....
    Just as one changes gears on a bicycle to crawl up an ever-steeper hill, “the direction of change in the muscle gears matches the mechanical demands of contraction,” Azizi said. Moreover, the muscle’s shifting of gears required no nervous system input, occurring automatically depending on the load applied.”

    Imagine--your muscles are like a bicycle with automatic transmission. The gearbox of muscle surprised the researchers. “A single muscle undergoes not one shape change but a range of different shape changes under different circumstances,” Azizi found. While pinnate muscles can rotate under light loads, they are prevented from rotation under heavy loads by the pull on the fibers. “Thus, although pinnate muscles are supposedly specialized for force, under light demand, they can also work fast,” Pennisi explained. A colleague admired this study “assessing muscle architecture with relation to function.”
    1Elisabeth Pennisi, “News Focus: SOCIETY FOR INTEGRATIVE AND COMPARATIVE BIOLOGY MEETING: Muscle Fibers Shift Into High Gear,” Science, 26 January 2007: Vol. 315. no. 5811, p. 456, DOI: 10.1126/science.315.5811.456b.

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  • bob b
    Cell Membrane Has Ticket-Operated Turnstiles 01/27/2007
    Cells are like castles surrounded by walls. A wall without gates, however, would prevent commerce and trap the inhabitants inside. The cell has ingenious gates that control the flow of goods and services through its outer membrane under tight surveillance and quality control. This controlled flow, as opposed to passive diffusion or osmosis, is termed active transport. Depending on the type of import or export required, the cell uses a variety of mechanisms. It might wrap the cargo in clathrin proteins and send it through in a self-mending breach of the walls (endocytosis; 05/15/2005, 11/04/2005, bullet 7). It might use one of the specialized authenticating channels through the membrane (e.g., aquaporins 04/18/2002 and ion channels, 05/29/2002). It might export genetic material or proteins through one of the pumps, or secretion systems (10/11/2005, 11/10/2004). Or, it might check cargo through one of the varieties of self-operating ticketed turnstiles.
    A description of one of these gates excited awe in a commentary in PNAS.1 Robert M. Stroud summarized decades of work on a kind of lactose turnstile. Key researcheers published their latest results in the current issue of the journal. They believe they have finally figured out how this molecule-sized machine works. It is a protein, 417 amino acids long, folded into a kind of rocking turnstile in the membrane. For a lactose passenger to get through the membrane using this transporter, it has to pay the fare. A proton must first be inserted into the active site. Then, the lactose molecule gets in and fastens its seat belt, so to speak. The nanomachine then undergoes a conformational change that seals off the outside and opens the door to the inside, where the passengers undock. Then, the gate automatically repositions itself for the next load. Called LacY, or lactose permease, this molecular machine operates with practically 100% efficiency: each proton ticket grants admittance to one and only one lactose passenger.
    LacY is one of a whole family of gates called the “Major Facilitator Superfamily” (MFS).2 “The mechanism most probably pertains to the many other transporters of the MFS that are found throughout all domains of life,” Stroud says. Another member of this family, for instance, is called the GlpT. This machine works with a reverse-ticketing process; a phosphate outside the cell is exchanged for a glycerol phosphate inside.
    Stroud was palpably delighted with the elucidation of the mechanism of these intriguing machines after so much research for many years. Here’s what he said about the LacY device:

    “The MFS of transporters can be run in reverse, such that outward movement of lactose, driven by reverse concentration gradient, can generate an H+ gradient across the membrane; LacY can work in either direction toward a coupled equilibrium. It is a beautiful example of energy transduction at the level of the membrane and is a near-perfect machine in the sense that the stoichiometry3 is always 1:1 without any leakage.”

    Leakage would allow contraband through. Experimental inventory shows all goods accounted for, before and after. The protein undergoes “large global conformational changes to transport the cargo” that are reversible, providing “oscillation between structural states that become accessible alternately to one side or the other, which can therefore be coupled to other sources of energy.”
    Understanding how these machines work could lead to treatments for diseases caused by their malfunctions, such as cystic fibrosis and lactose malabsorption, as well as to new methods for administering antibiotics and chemotherapeutic drugs.
    1Robert M. Stroud, “Transmembrane transporters: An open and closed case,” Proceedings of the National Academy of Sciences USA, 10.1073/pnas.0610349104, published online before print January 24, 2007.
    2Another superfamily of transporters, the ATP Binding Cassette (ABC) family, is driven by ATP hydrolysis inside the cell.
    2Stoichiometry refers to the ratios of combining elements in a chemical reaction, from the Greek stoichea, “basic principles,” as used in Colossians 2:8.

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  • bob b
    Cells Use Zip Codes to Determine Their Body Location 01/13/2007
    Scientists reported in an article in PLOS1 that cells have the equivalent of a Zip-code built in to their DNA that codes their location in the body. Skin cell DNA from 47 locations on a subjects were compared. Three locations on the DNA were found to correspond to the location of the cell in the body, specifying whether it came from the upper or lower torso, near to or far from to the center of the body, and near to or far from the surface of the body. How cells know where they are in the body has always been a puzzle, and now it turns out the cell address is coded into the DNA:

    "A major question in developmental biology is, How do cells know where they are in the body? For example, skin cells on the scalp know to produce hair, and the skin cells on the palms of the hand know not to make hair. Overall, there are thousands of different cell types and each has a unique job that is important to overall organ function. It is critical that, as we grow and develop, each of these different cells passes on the proper function from generation to generation to maintain organ function. In this study, the authors present a model that explains how cells know where they are in the body. By comparing cells from 43 unique positions that finely map the entire human body, the authors discovered that cells utilize a ZIP-code system to identify the cell?s position in the human body. The ZIP code for Stanford is 94305, and each digit hones in on the location of a place in the United States; similarly, cells know their location by using a code of genes. For example, a cell on the hand expresses a set of genes that locate the cell on the top half of the body (anterior) and another set of genes that locates the cell as being far away from the body or distal and a third set of genes that identifies the cell on the outside of the body (not internal). Thus, each set of genes narrows in on the cell?s location, just like a ZIP code. These findings have important implications for the etiology of many diseases, wound healing, and tissue engineering."

    1 Rinn JL, Bondre C, Gladstone HB, Brown PO, Chang HY (2006) Anatomic Demarcation by Positional Variation in Fibroblast Gene Expression Programs. PLoS Genet 2(7): e119 DOI: 10.1371/journal.pgen.0020119

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  • bob b
    This Bacterium Moves Like a Tank 01/03/2007
    Mark McBride (U of Wisconsin) has been trying for a decade to figure out how a gliding bacterium glides. His conclusion: the microbe has tire treads like a conveyor belt that make it roll over a variety of surfaces, like an all-terrain vehicle.
    According to a U of Wisconsin press release, the Department of Energy (DOE) is interested in this bacterium, Cytophaga hutchinsonii, because it can digest paper and other forest by-products. This is the first step in converting biomaterial into ethanol, to use as fuel.
    Of the cell’s “parts list,” McBride identified 24 genes involved in its gliding motility. He attached tiny latex spheres to the cell surface and then watched them move in all directions. “The cell wall appears to have a series of moving conveyer belts,” he said. He described these nearly invisible filaments as like tire treads, “designed to help the organism move over a variety of surfaces, like an all-terrain vehicle.” He believes these structures also convey cellulose into the interior of the cell, toward specialized organelles that digest it.
    Figuring out how this cell digests cellulose is still a work in progress. Unlike other bacteria that know the trick, this one “may use either a novel strategy or novel enzymes.” The Department of Energy is interested in this research. It may help our energy-hungry civilization “find other renewable materials that will be cost-effective alternatives, such as paper pulp, sawdust, straw and grain hulls.”
    What really intrigues McBride about his research on C. hutchinsonii, though, is what makes it go. He and his students have been comparing it with another gliding bug, Flavobacterium johnsoniae, that although “not closely related,” may “use the same basic machinery to move.” How different are these two? McBride claimed, “You are more closely related to a fruit fly than these two organisms are to each other.”

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  • bob b
    Cell Zippers, Linemen and Editors Put on a Show 12/28/2006
    The golden age of cell biology continues. Scientists keep unlocking the secrets of cellular machinery with newer and better techniques. With the curtain rising on a show we could not previously imagine, played out on a stage so small it took centuries of scientific work to even see it, biochemists are discovering amazing tricks that the little autonomous actors have been performing all along, right inside of us.

    Zip me up, road crew: A press release on EurekAlert pointed to a new paper in Cell1 where researchers found a kind of monorail zipper. The original paper by Kikkawa and Metlagel actually calls it a “molecular ‘zipper’ for microtubules.” The EurekAlert article discusses “Roadworks on the motorways of the cell.” Cellular highways are 3-D monorails that run in all directions and are constantly being formed and recycled. Composed of protein units of tubulin, they first form into sheets that fold into a tube shape. That’s where Mal3p comes in. This little protein zips up the edges of the tube, forming a stable structure that would otherwise unravel easily. The zipper even forms an alternate trackway for the molecular “trucks” that use the microtubules to deliver goods all over the cell (12/04/2003, 02/25/2003, 07/12/2004).

    Mr. Goodwrench, the inchworm: DNA is tightly compacted in the cell, but needs to be unwound frequently for translation and duplication. A family of machines called helicases unwind the double helix as part of the process. Scientists wondered how the machine travels up and down the helix, and have now found that one particular helicase named UvrD both twists and jumps in a two-part power-stroke. The authors of another paper in Cell2 describe this as a “wrench-and-inchworm” mechanism. Each step, which traverses one DNA base at a time, requires two ATP fuel pellets. See also 06/19/2003, 01/05/2006, bullet 9, and 10/27/2005, bullet 3; see 01/19/2005 about an RNA helicase.

    Not many typos get past this editor: Life depends on 20 specialized translators that connect the DNA code to the protein code (see 09/16/2004 for historical background, and 06/09/2003 and its embedded links for conceptual background). The awkwardly-named “aminoacyl-tRNA synthetases” (AARS for short) are highly specialized to connect the two codes correctly and edit out mistakes before they cause serious trouble. A paper in PNAS3 discussed one of the ways the AARS for the amino acid phenylalanine works. For jargon lovers, the model is: “the role of the editing site is to discriminate and properly position noncognate substrate for nucleophilic attack by water.” To test the model, they tinkered with some of the pieces of the protein machine and watched the editing precision drop dramatically. The precision of the active site is part of the “translational quality control,” they said (see 12/20/2003, 09/09/2002).

    Oxygen can be bad for your health: We like to breathe in that oxygen, but in the wrong places it can be a poison. Authors of another paper in PNAS4 found that “oxidized messenger RNA induces translation errors.” They put the gene for the light-glowing protein luciferin into rabbits (imagine a glowing Bugs Bunny) in both oxidized and non-oxidized forms. Although the oxidized translation machine stayed intact, the “translation fidelity was significantly reduced.”

    How could such precision translation machinery evolve? A paper in Structure,5 another Cell Press journal, bravely investigated the evolution of the genetic code (see 11/01/2002 for a previous attempt). They understood the requirement for high fidelity:

    “This specificity is critical for the accuracy of the genetic code, which has to be maintained to the highest degree to prevent mistranslation, that is, incorporation of the wrong amino acids at specific codons.”

    They tried to envision the transition from a hypothetical “RNA world” (07/11/2002) of miscellaneous floating ribozymes to the DNA-mRNA-tRNA-protein system now universally employed in all living things. That’s no small order. It requires a good imagination, as their introduction makes clear:

    “Since the discovery of ribozymes and the development of the idea of life first emerging from an RNA world (Gilbert, 1986), biologists have struggled to imagine the logical progression of events that led to proteins. At the same time, regardless of what the imagination can conjure, a connection to reality has to be made. That, in turn, requires experiments to test specific hypotheses or to provide an opportunity for serendipitous findings.
    To go from RNA to proteins requires the genetic code—triplets of nucleotides representing single amino acids. The modern code is an algorithm determined by aminoacylation reactions, whereby each of 20 amino acids is linked to its cognate tRNA that bears the anticodon triplet of the code. The 20 aminoacyl tRNA synthetases (one for each amino acid) that catalyze these reactions are ancient proteins that were present in the last common ancestor of the tree of life (Carter, 1993 and Cusack, 1997). As the eons passed, the tree split into the three great kingdoms—archaea, bacteria, and eukarya, which encompass all life forms. Yet, the genetic code remained fixed, with the same 20 aminoacyl tRNA synthetases making the same connections between anticodon triplets and amino acids. Thus, clues to the history of the transition from the RNA world to proteins might be imbedded in the tRNA synthetases themselves.”

    The best they could do was to suggest that a few of the aminoacyl-tRNA-synthetases hold hints of a prior RNA-ribozyme ancestry. Three of them, for instance, perform the editing while gripped to the transfer RNA (tRNA), resembling a “ribonucleprotein” that might have been the successor to the initial ribozymes in the RNA soup. The words might, may and perhaps were evident in their article, however. These speculative words looked pretty stark next to the clear evidence of precision in the translating machinery. The AARS for glutamine, for instance, is able to distinguish between four very similar-looking molecules and pick the right one. A conformational change in the binding pocket kicks out the interlopers and makes sure the correct amino acid gets attached to the tRNA. Their conclusion, therefore, seemed to make a giant leap of faith:

    “Thus, what is reported in this most recent work on GluRS—that a synthetase can use tRNA to direct a conformational change that perfects amino acid specificity, using in part a contact with the tRNA itself—may provide a general mechanism of tRNA-dependent amino acid specificity. The much bigger implication is that perhaps this functional interaction is a picture or a “holdover” from an earlier era in the evolution of the genetic code.”

    1Kikkawa and Metlagel, “A molecular ‘zipper’ for microtubules,” Cell, Volume 127, Issue 7, 29 December 2006, Pages 1302-1304.
    2Lee and Yang, “UvrD Helicase Unwinds DNA One Base Pair at a Time by a Two-Part Power Stroke,” Cell, Volume 127, Issue 7, 29 December 2006, Pages 1349-1360.
    3Ling, Roy and Ibba, “Mechanism of tRNA-dependent editing in translational quality control,” Proceedings of the National Academy of Sciences USA, published online before print December 21, 2006, 10.1073/pnas.0606272104.
    4Tanaka, Chock and Stadtman, “Oxidized messenger RNA induces translation errors,” Proceedings of the National Academy of Sciences USA, published online before print December 26, 2006, 10.1073/pnas.0609737104.
    5Schimmel and Yang, “Perfecting the Genetic Code with an RNP Complex,” Structure, Volume 14, Issue 12, December 2006, Pages 17291730.

    Hope you enjoyed this another peek into cellular wonders. We had to throw in an evolutionary tale just for the sheer contrast of seeing actual scientific investigation into observable machinery operating with high fidelity and quality control juxtaposed against the speculations of certain humans forced by their worldview to imagine that it just happened by chance. You can see what they’re up against.

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  • bob b
    Animal Plan IT 12/15/2006
    Imitating animal technology is one of the hottest areas in science. The engineering and information technology (IT) observable in living things continues to astonish scientists and makes engineers want to imitate nature’s designs. Biomimetics is leading to productive, useful discoveries helping solve human problems and leading to a better life for all. Here are some recent examples of how scientists are working to reverse-engineer technical feats on the Animal Plan Net:

    Underwater jet propulsion lab: Squid know how to maneuver in ways that are the envy of submarine operators. That’s why researchers at U of Colorado are trying to imitate the “vortex ring” method of propulsion, according to Live Science. “Vortex rings are formed when a burst of fluid shoots out of an opening, moving in one direction and spreading out as it curls back.” If mastered, this technology might not only help underwater exploration subs, but permit the designing of microscopic craft that “guide tiny capsules with jet thrusters through the human digestive tract, enabling [doctors] to diagnose disease and dispense medications, the researchers said.”

    Skin so shiny: The octopus and its relatives, cuttlefish and squid, have an unusual skin that is perfect for camouflage, reports News@Nature. A group at Woods Hole, Massachusetts found a protein with “remarkable properties” that is responsible: it reflects light almost perfectly. Roger Hanlon found that the bottom layer of octopus skin is made up of cells called leucophores “composed of a translucent, colourless, reflecting protein” that has such perfect broadband reflection, “they reflect all wavelengths of light that hit at any angle.”
    Cuttlefish have an additional trick. Their leucophores are covered by flat platelets called iridophores that enhance “the brightness of the whiteness,” Hanlon said, adding, “These are very complex 3-D cells.” The protein involved is appropriately named reflectin.
    Reporter Katherine Sanderson explained how this knowledge can help humans. “The molecules that make octopus skin so successful as a dynamic camouflage could provide materials scientists with a new way to make super-reflective materials.” Such knowledge would be of interest to law enforcement and the military. Not only would this protect those working at night; some day, a Halloween costume made of cuttlefish skin could look pretty scary.

    Too cool watercraft Jet skis are going to seem like kid stuff when “Dolphin watercraft” become popular. Look at the picture on CNet News. The high-performance, submersible Dolphin can leap above the waves and do barrel rolls, just like a dolphin. Are these for real? Believe it or not; Innespace Productions has a website and picture gallery.
    The boats really do look like dolphins and come in one-person and two-person versions. Designers Dan Innes and Rob Piazza explain the principle: “These positively buoyant vessels use their forward momentum and the downward lift of their wings to literally fly below the water’s surface. This radical departure from the typical method of sinking below the surface allows the Dolphins to achieve an unparalleled level of freestyle performance.”
    As a result of their mimicry wizardry, their “fully functional show ready watercraft” is able to “perform sustained dives, huge jumps, barrel rolls, and many other amazing acrobatic tricks.” After their upcoming 2007 Dolphin demonstration tour, everybody will want one. Will this be the next competitive sport? Maybe someday Sea World will have live dolphins and their trainers in Dolphin watercraft competing side by side for audience applause. (If the inventors can get theirs to eat fish and reproduce, then they’ll really be onto something.)

    [b]Bug in a fix: Microbes may not be animals per se, but they also have technical secrets to teach us big animals. A deep-sea microbe at a scorching hot vent figured out how to fix nitrogen at a record temperature, 92°C, reported Science Daily and News@Nature. Though both articles speculated on how this new form of nitrogen fixation might have evolved, the feat has chemists interested in learning “to better mimic the process for industrial use.” Current artificial methods of fixing nitrogen to produce fertilizer are costly and inefficient compared to the way microbes do it. News@Nature quoted a French scientist saying, “Given the importance of nitrogen fixation in global agriculture and the creative exploitation of novel organisms by the biotechnology industry, a heat-stable nitrogenase is likely to find a useful industrial application.”

    Robo-flagellum: Live Science reported that somebody is already trying to mimic the bacterial flagellum. An Australian inventor has achieved higher rpm with less twisting force by imitating the way bacteria swim. Some day, his tiny inventions may be able to swim through your blood vessels, hopefully for beneficial ends: “Ultimately, tiny microrobots would give surgeons the ability to avoid traumatic and risky procedures in some cases,” Bill Christensen reported. “A remotely-controlled microrobot would extend a physician’s ability to diagnose and treat patients in a minimally invasive way.” Imagine surgery without scalpels and anesthesia. Could we see a day where you get surgery at an outpatient clinic, and watch a microbot in real time on a monitor screen as it swims on command inside you to the problem area with a load of medicine? It tickles just thinking about it.

    Question: would a lab technician be able to tell which entity running under flagellum power in a human bloodstream was intelligently designed, and which one evolved by chance over millions of years?

    If so, fire him for incompetence. Even a real dolphin could tell that a high-performance watercraft had to be intelligently designed. Don’t even ask the inventors unless you want to get slugged. The Dolphin boat didn’t just “emerge” by chance in their machine shop. They made it on porpoise.

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  • bob b
    Mutations Accelerate Each Other’s Damage 12/14/2006
    As reported in our 10/14/2004 entry, mutations do not work in isolation; even the good kind usually conspire against the host. This fact has been largely ignored by neo-Darwinists. Some researchers at the Weizmann Institute in Rehovot, Israel, writing in Nature,1 tested the interaction of mutations (epistasis) on proteins. They found, in short, that harmful mutations usually accelerate the loss of fitness above what would occur in isolation. Some organisms exhibit robustness against mutations, though, as in well-known cases of antibiotic resistance. The team tested the robustness of E. coli while mutating a gene for a lactamase (TEM-1) that confers some resistance to ampicillin. They found that, at best, the organisms could hold out at a threshold level of fitness only temporarily. Beyond the threshold, death was speedy and inevitable. This was even after they removed the bad mutations:

    “Subjecting TEM-1 to random mutational drift and purifying selection (to purge deleterious mutations) produced changes in its fitness landscape indicative of negative epistasis; that is, the combined deleterious effects of mutations were, on average, larger than expected from the multiplication of their individual effects. As observed in computational systems, negative epistasis was tightly associated with higher tolerance to mutations (robustness). Thus, under a low selection pressure, a large fraction of mutations was initially tolerated (high robustness), but as mutations accumulated, their fitness toll increased, resulting in the observed negative epistasis. These findings, supported by FoldX stability computations of the mutational effects, prompt a new model in which the mutational robustness (or neutrality) observed in proteins, and other biological systems, is due primarily to a stability margin, or threshold, that buffers the deleterious physico-chemical effects of mutations on fitness. Threshold robustness is inherently epistatic—once the stability threshold is exhausted, the deleterious effects of mutations become fully pronounced, thereby making proteins far less robust than generally assumed.”

    Their study also casts doubt on the ultimate survivability of so-called “neutral” mutations. These initially have no obvious effect on the fitness of the organism. This may be due to backup copies of a gene, suppressors of the mutated gene, and other mechanisms the cell uses to mask the damage. Eventually, however, the threshold is exceeded and the system collapses just as rapidly as a cell toppled by interacting harmful mutations.
    The authors of this study gave no indication that beneficial mutations can add up and help an organism. In fact, they failed to say anything about evolution that would provide hope for progress. By contrast, they offered a “new model” that sounds distinctly anti-evolutionary: cells are programmed to hold off the damage of mutations as long as they can, but will ultimately collapse under a mutational load. They concluded that “proteins may not be as robust as is generally assumed.” Their real-world experiment on bacteria showed robustness to mutations only to a certain point, then everything raced downhill:

    “Thus, theory and simulations have predicted a tight correlation between robustness and epistasis. Our work provides an experimental verification of this correlation and proposes a mechanism that accounts for it. Our model implies that any biological system that exhibits threshold robustness, or redundancy robustness, is inevitably epistatic. In such systems, mechanisms that purge potentially deleterious mutations, such as recombination (through sexual reproduction and other mechanisms) are of crucial importance, as they help to maintain this threshold. In this way, recombination, threshold robustness and negative epistasis may be interlinked—each being an inevitable by-product of the other.”

    They seem to be saying not only that mutations are not sources of positive fitness gains, but other proposed mechanisms like recombination are only stopgap measures to protect against the death spiral that would result when “randomly drifting proteins” gang up (negative epistasis) to cause a terror attack in the organism.
    1Bershtein et al, “Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein,” Nature 444, 929-932 (14 December 2006) | doi:10.1038/nature05385.

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  • bob b
    The Nature of Cellular Tech 11/30/2006
    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 easier. Perhaps 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.

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  • bob b
    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).

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  • bob b
    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.

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  • bob b
    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.

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  • bob b
    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.

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  • bob b
    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.”

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  • bob b
    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.

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  • bob b
    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.

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