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  • bob b
    Origami With RNA Requires Protein Chaperones 07/08/2002
    RNA, like DNA, can easily form helical structures, and can also easily collapse into a muddled knot that is hard to untangle. For it to fold into useful structures, a group of proteins called chaperones are needed. The chaperones prevent the molecules from falling into “kinetic traps” that would be hard to unfold, and make sure they fold into the “native state”, the conformation that can perform the needed function in the cell. That’s the gist of a minireview in the June 28 issue of Cell. The article discusses several new findings, “a vindication of more than two decades of work on putative RNA chaperones and will almost certainly open productive new avenues for studying the management of RNA structure formation and processing in vivo.”

    How Your Electric Motors Work 07/16/2002
    Did you know your body, and the bodies of everything from bacteria to giant Sequoia trees, run on electric motors? No kidding. We’ve reported on the amazing little protein motor ATP synthase several times before. It runs at 6000 rpm and generates ATP, which your body needs for every chemical reaction, every muscle movement, and every blink of an eye. Now, in the July issue of the journal Structure, an international team of biochemists, including one of the winners of the Nobel Prize (Dr. John E. Walker), has examined the action of this amazing molecular machine in more detail than ever before. They have analyzed just one third of the rotational cycle of the top part of the motor, called F1-ATPase. The bottom part of this two-part motor, the F0 unit, is composed of a dozen parts that turn like a merry-go-round in response to proton fuel. Attached to the center is the gamma subunit that looks like a camshaft. It has a stalk and a protruding section that rotates with the F0 ring. In contact with the cam is the non-rotating F1 machine, composed of six lobes, the alpha and beta subunits, alternately arranged like slices of an orange around the central stalk. As the cam turns, it forces changes in shape of the alpha and beta lobes, mostly the beta lobes. Arranged in pairs, the six lobes provide a three-stage manufacturing plant for ATP; while one is loading the two ingredients, another is squeezing them together, and a third is simultaneously ejecting the finished product.

    In this paper, the scientists carefully analyzed what happens to the alpha and beta subunits during one-third of the rotation. They found that the positive charges on the gamma protrusion (the cam) create an “ionic track”. Corresponding negatively-charged amino acids on the lobes, like motor brushes, respond to the ionic track by causing changes of shape in the lobes, making them move in, out, up or down appropriate to the stage of manufacture of ATP. Though the gamma shaft appears to turn smoothly, the lobes seem to snap open and shut very quickly, within nanoseconds. These “conformational changes” (i.e., moving parts) are involved in the efficient manufacture and release of ATP molecules; exactly how they do it is an area still under study. They do know, though, that the precise placement of certain electrically-charged amino acids in the various protein subunits stimulates the motions along the ionic track, so the cam involves both electrical and spatial (steric) interactions, something like a rotor in a car’s engine. The entire assembly operates at submillisecond rates, and is reversible – it can burn ATP to generate protons. The diagrams show that the motor parts look like coils, chains and complex tangles of molecules, not like the hard metal cylinders and pistons with which we are familiar, but they perform analogous functions at this submicroscopic scale. Even though the coiled amino acid chains twist and turn and stretch, the machine is stable, fast and highly efficient, The authors refer to it as a “finely tuned machine.”

    Gene Expression More Complicated Than Thought 07/22/2002
    Scientists used to think one gene produced one protein, and that a gene was an uninterrupted sequence of DNA code. No longer. Genes actually have coded regions, called exons, interspersed by non-coding regions called introns. There may be many introns per gene, and somehow the cell knows how to cut them out before making messenger RNA, which then delivers the code to the ribosome, where proteins are made. Are the introns just junk, then, destined for the cutting-room floor? Apparently not. The introns are involved in helping determine which exons get joined together, and by “alternative splicing,” the cell can get more mileage out of the gene. Some genes can code for several forms of a protein, depending on the order in which the exons are spliced together. Scientists at the University of California, Santa Cruz have developed new techniques to try to understand how cells make sense of all the pieces. Manuel Ares explains:

    “The coding sequences of our genes are all broken up and spread out, and there is a whole cellular machinery involved in patching it together so that the code makes sense. This splicing process gives the cell the ability to try new combinatorial arrangements of information. You have all this information in the genome, but then the cell can interpret it in different ways.”

    The press release says that genes are turning out to be much more complicated than originally thought. “Differences in the editing of genetic information may, in fact, be a significant source of genetic variability. Researchers ... have now taken a big step toward understanding how this editing process (known as splicing) is regulated.”

    When Your Emergency Response Team Fails, Cancer Can Result 07/26/2002
    Each cell in your body has a team of enzymes called DNA Damage Response. Like a skilled repair team, they know exactly how to fix all kinds of DNA emergencies: double-stranded breaks, broken tips, unraveled ends, and dozens of other potential problems. Many cancer cells exhibit unrepaired DNA and instability in the chromosomes. In a special section on genome stability in the July 26 issue of Science, Paula Kiberstis and Jean Marx explain that “For a cell, maintaining the integrity of its genome is of paramount importance. If it fails in this task and manages to divide anyway, both of its daughter cells may inherit an abnormal chromosome complement, with potentially dire consequences.” A current debate among biochemists revolves around whether the damage causes cancer, or the cancer causes the damage. They introduce three papers that deal with evidence that failures in DNA damage repair are implicated in many types of cancer, and conclude, “Whatever the outcome of these debates, the quest for answers has certainly produced many fascinating insights into the molecular weaponry that enables a cell to defend the integrity of its genome.”

    Protein Evolution Recipe: Add a Pinch of Mutation and Stir 07/31/2002
    In protein evolution, a lot of recombination mixed in with a little mutation provides the best results, say two scientists publishing in Proceedings of the National Academy of Sciences. Proteins, made of long chains of amino acids, have an uncanny ability to fold into just the right stable structure out of an enormous field of possible folds. How do they do it? How do proteins change through time and keep stable thermodynamically? For their mathematical model, Xia and Levitt simplified a three-dimensional problem down to two dimensions, and ignored population size and evolutionary time. They also used just short sequences – just 25 elements instead of the hundreds in most proteins. By adjusting the ratio of mutation to recombination, they were able to get sequences to converge on the “prototype sequence” (i.e., the largest set of sequences that folded into the same basic structure). This, they feel, may provide a solution to the “Levinthal Paradox” – “given the exponential size of the sequence space, how does evolution find the optimal sequence in a reasonable amount of time when the fitness landscape is flat?” They compare the ratio of recombination and mutation to temperature, and conclude: “Nature is able to adjust the ‘temperature’ of evolution by tuning the relative rates of recombination and mutation.”

    Can We Live Without SMCs? No! 08/07/2002
    That’s what Current Biology says in its Aug 6 issue in a feature entitled “Quick Guide to SMC Proteins.” OK, I give up. What are SMCs, and why do I need them?

    “What are SMCs? The Structural Maintenance of Chromosomes (SMC) proteins are a family of chromosomal ATPases highly conserved among the three phyla of life. ...”

    “What do SMCs look like? The SMC proteins are large polypeptides, each spanning 1000-1500 amino acids. They form dimers in which two anti-parallel coiled-coil arms are connected by a flexible hinge. ... The distal end of each arm constitutes an ATP-binding domain.”

    If that didn’t help, what they are saying is that this family of proteins look like tweezers that can grab DNA and keep it under control during critical processes in the cell. The article then describes how these molecular machines work and what they do. They are important in holding sister chromatids together and separating them during cell division. Some are also “implicated in DNA repair and checkpoint responses.” They are also essential for the proper separation of chromosomes during gamete formation during meiotic cell division. So how do these miniature grappling hooks do all this?

    “How do SMCs work? That is the million-dollar question in the field. Of particular interest is to understand how the two-armed structure - which is approximately 100 nm long when it’s open! - captures DNA, and how these interactions are modulated by ATP binding and hydrolysis. Condensin is able to introduce positive supercoils into DNA by using the energy of ATP hydrolysis. Further studies are required to understand the functional diversity of the SMCs.”

    “Can we live without SMCs? No! Loss of any single SMC protein in budding yeast is lethal. Given their fundamental role in maintaining genomic stability, it is of future interest to determine whether loss or mutation of SMCs is associated with tumour formation or developmental disorders in mammals.”

    The short article by Gillespie and Hirano (Cold Spring Harbor Laboratories, NY) contains a diagram of what two sample SMC proteins look like. The SMC “superfamily” work in complexes with other molecules to accomplish these vital tasks.

    The journal Science, Aug. 9 says you can’t live without ORC, either. It’s “a multi-talented, cell division protein“ complex.

    Siberian Bacteria Perform Repair in Deep-Freeze 08/20/2002
    Astrobiology Magazine claims that bacteria have been found that apparently are able to perform damage repair, even though they have been in a state of suspended animation in deep freeze for up to tens of thousands of years. Indirect methods suggest that these bacteria maintain a high ratio of left- to right-handed amino acids; if dead, the ratio would approach 50/50 over time. Cells need pure 100% left-handed amino acids to function. Because radiation even within the ice would cause damage to DNA and other essential molecules over time, Gene McDonald at JPL and colleagues feel that a certain amount of repair must be in operation, even in the deep freeze of Siberian permafrost. This gives them hope that any Martian organisms might have survived billions of years of freezing, even if changes in the environment sent them into hibernation.

    How Do Leaves Prevent Meltdown During Photosynthesis? 08/22/2002
    We all know plants harvest sunlight for energy, but what do they do when the energy is coming in too fast? Imagine coal lumps on a conveyor belt coming into a furnace. Unless there is a way to regulate the furnace, too much coal will make it overheat. Plants, it turns out, have multiple feedback loops and regulatory processes to prevent damage when the photons are coming in too fast. Scientists at Washington State studied one of these regulatory processes called nonphotochemical quenching (NPQ) and published their results in the Proceedings of the National Academy of Sciences. Although not completely understood, NPQ involves making the ATP synthase motors in the chloroplast less reactive to the flow of protons coming in. This requires high sensitivity to the acidity (pH) of the lumen, the light-harvesting portion of the chloroplast, and is regulated early in the process:

    “Furthermore, the pH of the lumen appears to be tightly regulated to a narrow range, where the stabilities of luminal components and the effective rate constants for electron transfer are near optimal. Taken together, these observations indicate that a primary regulatory step governing light energy conversion must occur at light capture, and thus likely involves NPQ, rather than at downstream electron or proton transfer reactions.”

    NPQ is also very sensitive to the amount of carbon dioxide in the atmosphere. Taken together, these regulatory controls keep the ATP synthase motors from being overloaded with protons.

    We’ve reported on ATP synthase several times, the tiny rotary motors that manufacture energy pellets (ATP) for the cell. They are powered by proton motive force generated by photosynthesis in plants and by metabolism of food in animals, ultimately from sunlight in both cases. In another paper in the current issue of Cell entitled “Photosynthesis of ATP–Electrons, Proton Pumps, Rotors, and Poise,” John F. Allen mentions these motors in a review of how electrons are cycled around during photosynthesis. In addition to praising photosynthesis as the food source for all life, he comments, “Photosynthesis is also responsible for the global redox imbalance now seen as abundant, free oxygen–our planet’s signature of life, unique in the solar system.” His illustrations of ATP synthase and the other components involved in photosynthesis, though just models, look for all the world like power plants and storage batteries connected by wiring.

    Mitochondria Challenge Evolutionary Speculations 08/26/2002
    The Scotsman reports on a paper in Nature Aug 23 (see also News and Views analysis) that challenges the long-held theory that mitochondria were captured by early eukaryotes and became symbiotic with them. Evidence of mitochondrial parts have been found in microsporidia, a primitive parasite thought to lack mitochondria. They appear to be shrunken remnants of the organelles, degenerated perhaps due to the parasite’s energy needs. Dr. John Lucocq of Dundee University where the discovery was made remarked, “This discovery changes the way we think about how cells evolved. If these parasites are a sort of living fossil, then this is a bit like a ‘missing link’ human ancestor turning out to be a present day human.”

    Another story on the mitochondria in New Scientist reports that contrary to conventional wisdom, mitochondrial DNA can be inherited from both parents. “Evolutionary biologists often date the divergence of species by the differences in genetic sequences in mitochondrial DNA. Even if paternal DNA is inherited very rarely, it could invalidate many of their findings,” says the article.

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  • bob b
    Cell’s DNA Translation Machinery Revealed in Unprecedented Detail 06/13/2002
    Japanese scientists publishing in the June 13 issue of Nature have revealed the molecular structure of the RNA polymerase holoenzyme, including its initiation factor, at 2.3 angstrom resolution (an angstrom is one ten billionth of a meter). This enzyme is one of the most important molecular machines in the cell; “The DNA-dependent RNA polymerase (RNAP) is the principal enzyme of the transcription process, and is a final target in many regulatory pathways that control gene expression in all living organisms.” It builds all the RNA molecules: messenger RNA, transfer RNA, ribosomal RNA, and others. Moreover, the machine consists of five subunits that “are evolutionarily conserved in sequence, structure and function from bacteria to humans.”

    The color models show a complex structure shaped somewhat like a lobster claw. It doesn’t work until the initiator named sigma (with four subunits itself), like a key, turns it on and attaches it to a promoter on the DNA molecule. Then it ‘melts’ the DNA at that point and unwinds the section of DNA to be transcribed, and releases the promoter. At that point, the machine undergoes a significant change in shape, and crawls along the strand, attaching RNA subunits into a chain. Apparently, two precisely-placed magnesium ions at the active site are essential for this catalytic activity. During the operation, the DNA appears to run through the cleft of the claw, the ‘active site’ somewhat like a zipper, with a series of alternating switch and trigger functions snapping together the ingredients and preparing the machine to move to the next step. To get a feel for how the machine works as it moves along, here is their description, jargon and all:

    “Taken together, these structural data allow us to propose a possible mechanism for RNAP translocation during RNA synthesis. At the step of ‘relaxation’ (after translocation, before the next reaction), the template base at position i+1 is paired with the substrate nucleoside triphosphate (NTP), the bridge helix is in an all -helical conformation, the Arg 1,096 bridges the i and i+2 DNA phosphates, and the flexible trigger loop is distal (rather than proximal) to the bridge -helix. After phosphodiester bond formation, a signal induces the movement of the trigger loop towards the bridge -helix, pushing out the ‘switch’ residues. In their flipped-out conformation, the switch residues may engage the DNA phosphate at position i+1 and bring the bridge -helix under the DNA backbone towards the i+2 nucleotide. During this step, Arg 1,096 may also switch its interacting partner from DNA phosphates to the side chain of an acidic (polar) switch residue, thus simultaneously stabilizing the flipped-out conformation of the switch residues and facilitating the translocation of the enzyme.”

    Cell Journal Marvels at Complexity, but Assumes Darwinism 06/17/2002
    Book reviews in scientific journals allow scientists to back off from the detail and jargon of a specific paper and comment on the big picture. The June 14 issue of Cell is loaded with book reviews that are a study in contrasts. Details of cellular complexity and design are juxtaposed with simplistic evolutionary explanations. Some examples :

    1. Standard Textbook: Patrick Williamson reviews the standard text Molecular Biology of the Cell (4th ed., 2002) and refers to the “dramatic complexity of the cytoplasm” that began to be revealed with electron microscopes in the 1950's. But in the end, he attributes it all “to natural selection in cobbling together solutions to pressing problems using the miscellaneous materials presented by gene duplication and mutation” ...

    “In the past, we have sometimes spoken in deprecating tones of our scientific predecessors ‘stamp-collecting’ their way through the characterization of the phylogeny and life histories of the earth’s species. Now, the genome projects have presented us with new sets of stamps to collect, characterize, describe, and explain. Like our predecessors, we can’t usually reduce our insights into a few general principles because of the way organisms have evolved, but we can always anticipate growing satisfaction with the detail and clarity of our understanding of all the many instances we find.”

    2. Mind Boggling Complexity: Max Gottesman, in a review of Genes & Signals by Ptashne and Gann (2001), slaps his head over the complexity of enzyme actions:

    “Recall the days of yesteryear when, for biologists, enzymes were enzymes and didn’t need any help in finding their substrates. Alas, those simple times are long gone. Instead we are faced with the horrible realization that proteins rarely see their ligands without being led by the nose to them. So, for example, RNA polymerase once promptly landed on a promoter and revved up to transcribe a gene. It turns out, in fact, that for most promoters, RNA polymerase requires additional proteins just to find the site. And other proteins interfere with its attachment. The number of such auxiliary factors, especially in eukaryotes, is mind boggling ... The situation is scarcely better in signal transduction. A hormone can only relay its message to the nucleus via passage through a long series of proteins, most of which have to be spatially constrained to transmit the signal. Even the simple matter of removing a piece of unwanted RNA from a transcript involves the assembly of a dozen or so proteins and RNAs, probably in a configuration that is highly specific. The reason for all this is now quite clear. Transcription cannot be ubiquitous, but is regulated by factors that respond to cellular environment, cell type, phases of the growth cycle, etc. Similarly, transduced signals are not sprayed around the cell, but are channeled toward specific effectors, as determined by the special requirements of the cell at a particular point in time.”

    3. Extreme Life: Thomas Cavalier-Smith takes a hard look at D.A. Wharton’s Life at the Limits: Organisms in Extreme Environments (2002). He likes the treatment of extremophiles and cryptobiotic organisms (those that can go into states of suspended animation), but criticizes his sparse treatment of the origin of life. He believes, contrary to the author, that eubacteria–flagella and all–are our ancestors, not archaebacteria:

    “The origin of biomolecules is much easier to understand if it occurred in a heterogeneous environment with geothermal activity to condense polymers and numerous small cool pools subject to freezing and drying to stabilize and concentrate them. The breakthrough to the first organisms in which membranes, genes, and catalysts cooperated is also much easier to understand in a cool heterogeneous environment such as polar tide pools (Cavalier-Smith, J. Mol. Evol. 53, 555-595, 2001). It seems much more likely that early proto-organisms were cryptobiotes, able to survive temporary freezing or drying, than thermophiles having to evolve the genetic code and membranes beside oceanic vents in the enormous volumes of the deep ocean, as seems currently popular in some circles.”

    4. Nuclear Pores: Amnon Harel and Douglass Forbes review Nuclear Transport (Karen Weiss, ed., 2001) and note some wonders of the nuclear pore complex:

    “During the splicing process, mature mRNA, a very large cargo, appears to form a complex with a variety of distinct non-importin beta-type proteins that together mark the mRNA for export and participate in its egress from the nucleus. ... Indeed, it has been very difficult to confirm a specific translocation mechanism for the nuclear pore, which contains multiples of 30-50 different proteins in the final 500-1000 protein nuclear pore complex.”

    5. RNA Complexity: Martha J. Fedor reviews RNA (ed. Soll, Nishimura and Moore, 2001) and notes the bewildering complexity of RNA functions in this growing “complicated field”:

    “The discovery that RNAs could catalyze biological reactions gave a clear indication that RNAs would not conform to the Central Dogma, which dictates that they exist solely to relay information between DNA genes and protein gene products. Over the ensuing decades, RNAs have turned up unexpectedly as key players in myriad cellular activities, both fundamental and exotic. ... A new class of tiny noncoding RNAs (microRNAs) recently was implicated in developmental and spatial regulation of gene expression (Ambros, Cell 107, 823-826, 2001). Really, it would be surprising if nature has stopped here in making use of this versatile macromolecule.”

    6. Molecular Machines: Ishii and Yanagida review Biology at the Single Molecule Level (ed. Leuba and Zlatanova, 2001) and show that the discovery of molecular machines is forcing a paradigm shift:

    “The history of science has shown that new concepts frequently emerge and interpretations of the data become modified as more sophisticated and accurate measuring systems are developed. New data allow us to emphasize different aspects of biological systems and to reveal aspects of those systems that had not previously been unveiled. ... As nanotechnologies have expanded, many researchers have realized that the laws that govern materials of nanometer size are very different to those applied to macroscopic machineries with which we are more familiar. Nature, however, has already developed and utilized nanotech. Life is full of nanomachines, and their functions are very different from artificial nanomachines. ... Researchers now know that protein molecules are more complex than the simple design the DNA information implies. Studying the mechanism underlying protein functions is intriguing, and prerequisite are the techniques that allow us to monitor the dynamic structure of protein molecules and directly detect the functions of proteins.”

    7. Homology and Evo-Devo Richard R. Behringer in “Hand of man, wing of bat, fin of porpoise” reviews The Evolution of Developmental Pathways by Sunderland (2002). He thinks Evo-Devo is the wave of the future:

    “Biologists have always been fascinated by the astonishing diversity of metazoan life that has evolved on Earth. It is now evident that extant species have evolved from common ancestors through genetic changes that are acted upon by natural selection. In The Origin of Species (1859), Charles Darwin discussed the “law of embryonic resemblance.” He and others before him had noted that plants and animals within the same great classes, though morphologically diverse in their adult forms, were remarkably similar in their embryonic forms. For example, the limbs of vertebrates, including “the hand of a man, wing of a bat, and fin of a porpoise,” are morphologically and functionally distinct, yet they all develop from morphologically identical limb buds in their embryos. Darwin suggested that the embryos of different species provided a glimpse of a common parent for the different classes of organisms, supporting his concept of descent with modification. Thus was born the field of evolutionary developmental biology.”

    He goes on to discuss the various controversies, questions, problems and conundrums in the field of evo-devo, but concludes it has a bright future thanks to television:

    “Finally, the current movement in the Evo/Devo field suggests a bright future. That future may be driven by those children who watched natural history programs on television and have been inspired to pursue studies and careers in biology. I predict that these young biologists will not be satisfied studying a handful of primary model organisms. I suspect that these enlightened individuals will have broader interests and will be naturally attracted to the Evo/Devo field to reveal the “hidden bond” described by Darwin that exists between common ancestors and current species.”

    8. From Cytoplasm to Cytoskeletons Don Ingber in “Putting the Cell Biology Establishment on the Stand” reviews Cells, Gels and the Engines of Life by Pollack (2001). He slays the dragon of misconceptions that the cell is simply a bag of fluid:

    “While our knowledge of the molecular widgets that comprise living cells has exploded beyond our wildest dream, our understanding of cell architecture and the relation between structure and function still remain rudimentary. For example, one mainstream cell biology textbook defines the cell as “a small membrane-bounded compartment filled with a concentrated aqueous solution of chemicals,” like a balloon filled with molasses. In fact, many biologists who work with molecules in isolation still share this view, as do virtually all lay people, including the congressmen and women who decide which science projects the government will invest in.
    Pollack views this image as a dragon that must be slain and I cannot agree more.”

    “The living cell is a chemo-mechanical machine and it uses all forces and devices at its disposal-physical as well as chemical and electrical-to carry out its miraculous tasks. The reality is that the cytoplasm is a molecular lattice, known as the cytoskeleton, that is permeated and insufflated by an aqueous solution. The different molecular filaments that comprise the cytoskeleton-microfilaments, microtubules, and intermediate filaments-position the cytoplasmic organelles. But this is not a passive support system. The same scaffolds orient many of the enzymes and substrates that mediate critical cell functions, including signal transduction, glycolysis, protein synthesis, transport, and secretion; analogous insoluble scaffolds mediate RNA processing and DNA replication within the nucleus. This use of “solid-state” biochemistry greatly increases the efficiency of chemical reactions because they are no longer diffusion limited, and it provides a means to compartmentalize different cellular activities. The cytoskeletal system also can dynamically grow and shrink within different microcompartments as a result of the action of specific molecular regulators. ... Indeed, it is through these varied functions of the cytoskeleton that living cells can exhibit behaviors that are far beyond anything observed in man-made materials. The abilities of a cell to move its entire mass upstream against the flow of blood or contract against hundred pound weights are two simple examples.”

    Tweaking the Bacterial Flagellum Motor 06/24/2002
    A team of Japanese scientists publishing in the July 7 Journal of Molecular Biology has been studying the electrical interactions of the bacterial flagellum, a molecular motor highlighted in the film Unlocking the Mystery of Life. The researchers toyed with changes at the amino acid level in some of the key proteins in the rotor and stator to see what they would do. They neutralized or reversed the charges of elements and thought they would get the motor to halt, but in some cases, it reversed direction or continued to work, but reduced the tumbling behavior and swarming of the bacteria.

    Different species of bacteria have different types of flagellar motors. Some run off protons (H+), and some run of sodium ions (Na+). The sodium motors spin up to five times faster than their proton counterparts. Earlier work had shown that mutations to a certain protein MotA in the proton motors could cause failure. These researchers mutated the homologous protein PomA in the sodium motor and still got it to work, so apparently there are other unknown factors involved in torque generation in these varieties.

    How Does the Cell Route Messages? Through Its Switchboard 06/26/2002
    Another “level of complexity” has been found in the cell, according to story in SciNews. Researchers at Johns Hopkins School of Medicine have found that signal transduction, the way that cells transmit signals from the external environment to the nucleus, is not just an automatic cascade of chemical reactions, but is regulated by a “switchboard” so that the nucleus is not swamped: “It’s a wonder cells make it through the day with the barrage of cues and messages they receive and transmit to direct the most basic and necessary functions of life.” The switching system involves first detecting messages coming through channels in the cell membrane onto receptors, then tagging them with one of two delivery signals, calcium or cyclic adenosine monophosphate (cAMP). A whole class of proteins called PDZ proteins are now seen to be involved just in deciding which signalling molecule will be used. The delivery tag determines how the nucleus will respond to the message. The study by Donowitz et al. into the tagging of messages for delivery into the nucleus was published in the June 20 issue of Nature. A related story about how the nucleus signals which genes to express is found on UniSci.

    The New Science of Protein Sociology 06/27/2002
    A news feature in Nature June 27 explores the new science of protein complexes:

    “ ...the classic view of many cellular processes involves proteins interacting with one another in linear pathways, coming together as they shift around in the cell's cytoplasm. In recent years, however, biologists have realized that many important cellular functions are actually carried out by protein complexes that act as molecular ‘machines’”

    The article explains that some complexes, like the ribosome, stay together for long periods, whereas others join loose fellowships for temporary tasks. Some proteins are versatile and belong to several clubs. In some cases, it is the complexes that are conserved between very different animals, but the individual proteins differ. New techniques of electron microscopy are allowing scientists to visualize these protein complexes in this cutting-edge field of structural biology.
    Last edited by bob b; October 16, 2006, 03:32 PM.

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  • bob b
    Cell Assembly Line Workers Tethered Together 04/04/2002
    A paper by two Harvard biochemists in the April 4 Nature explores new findings that the molecular machines that perform gene expression are all tied together (coupled) in assembly-line fashion, so that one process hands off to the next instead of waiting for the next machine to show up by chance:

    “Recent studies lead to the view that, in contrast to a simple linear assembly line, a complex and extensively coupled network has evolved to coordinate the activities of the gene expression machines. The extensive coupling is consistent with a model in which the machines are tethered to each other to form “gene expression factories” that maximize the efficiency and specificity of each step in gene expression.”

    In describing the elaborate processes that read and translate DNA, the paper uses the words machine or machinery 53 times, and factory or factories 10 times. And there’s more: “Superimposed on this pathway is an RNA surveillance system that eliminates aberrantly processed or mutant pre-mRNAs and mRNAs” – i.e., a quality control subsystem.

    Why Cancer Is Rare 04/04/2002
    Anyone who has been diagnosed with cancer, or had a loved one with it, knows what a frightening and unwelcome surprise it is. But according to Robert Weinberg, cancer researcher at the Whitehead Institute for Biomedical Research, the surprise is that our bodies are usually so successful in preventing it: “There are so many things that need to go wrong, so it is not surprising that, in a lifetime, cancer is actually rare.” Most cancers are caused by mutations, and very few cancers are caused by a single mutation. Mutations tend to accumulate as the cancer progresses; that is why early treatment is usually successful. Weinberg’s comment appears in a status report on cancer research by Alison Abbott in the April 4 Nature.

    Two Unlike Proteins Do the Same Job 04/06/2002
    Two unlike organisms, yeast and a protozoan, have proteins that bind to telomeres; these proteins are required for chromosome end protection and telomere replication. They look alike and do the same job, but are very different in amino acid sequence, reports a paper in the April 5 Science. The authors believe this “indicates that mechanisms of telomeric end protection are widely conserved throughout evolution.”

    In another paper in the same issue, British biochemists have found a chromatin protein that is conserved in archaea, bacteria, and eukaryotes (including people). The protein Sir2, in combination with Alba, is important for repressing expression of genes not needed at the time. They conclude that “this partnership may have been highly conserved throughout evolution.”

    Bacteria Are Champion Proofreaders 04/10/2002
    A team of Australian biochemists has examined the structure of just one of the “proofreading enzymes” in E. coli bacteria in unprecedented detail, and formulated a hypothesis for how it works. That it does work, and works extremely well, is described in the introduction to their paper published in the April issue of Structure:

    “Fidelity of DNA replication is determined by three processes: base selection by a DNA polymerase, editing of polymerase errors by an associated 3'-5' exonuclease, and postreplicative mismatch repair. In Escherichia coli, these processes contribute to duplication of the genome by the replicative DNA polymerase III (Pol III) holoenzyme with error frequency ~10-10 per base pair replicated.”

    In other words, with its proofreading machinery, the bacterium makes a error once in 10 billion DNA letters.

    First Cell Not Salt-Tolerant 04/15/2002
    Charles Apel of UC Santa Cruz has found that the first cell could not have formed in salt water, so it must have formed in fresh, reports Academic Press and the NASA Astrobiology Institute.

    “This is a wake-up call,” says mineralogist Robert Hazen of the Carnegie Institution of Washington in Washington, D.C. “We’ve assumed that life formed in the ocean, but encapsulation in freshwater bodies on land appears more likely.” Geologist L. Paul Knauth of Arizona State University in Tempe adds that Earth’s early oceans were up to twice as salty as they are today–making it even more difficult for viable cells to arise.

    Astrobiologists had assumed lipid molecules would self-organize into vesicles, but apparently salt makes them fall apart. Apel’s findings were delivered at last week’s Astrobiology Conference, and will be reported in an upcoming issue of Astrobiology Journal.

    Cell Water Channels Continue to Amaze 04/18/2002
    If you enjoyed our December 20 story about aquaporins, the water gates of the cell, you’ll want to read this update posted by the University of Illinois with a cool animation of how the complex channel (made up of more than 100,000 atoms) allows a water molecule through in a billionth of a second, but keeps smaller protons out. Summarizing their paper in the April 19 Science, they explain:

    “Aquaporins, a class of proteins, form transmembrane channels found in cell walls. Plants have 35 different proteins of this type. Mammals, including humans, have 10, with many of them in the kidney, brain and lens of the eye.”

    When working correctly, said Klaus Schulten, the Swanlund Professor of Physics at the UI, the transport of water between plant cells lets flowers bloom and leaves stand sturdily, for example. In mammals, the machinery processes water efficiently to help maintain optimum health.

    They go on to describe the problems that broken channels can cause: diabetes, cataracts, and breakdown of other organs…. A single aquaporin can process a billion water molecules per second without letting a single interloper through.

    Evolution of an Enzyme Explained by Lateral Gene Transfer 04/29/2002
    In the April 30 issue of Current Biology, a team of Canadian scientists claims to have found a relationship in an enzyme (ATP Sulfurylase) between archaea, bacteria and eukaryotes. They propose that lateral gene transfer (LGT) is the mechanism that spread this capability from one group to the other, and may be more important than mutation during redundancy (MDR) as a mechanism of evolution. If so, this puts a new twist on protein evolution: “As with the MDR model, it will be important to determine how functionally identical duplicates can escape from frequent silencing mutations until one of the duplicates acquires rare advantageous mutations. In any case ... the prevalence of LGT among prokaryotes and the ‘quantum’ leaps over sequence space it permits (in contrast to point mutation) suggests it could play a more important role in the evolution of gene function than previously recognized.”

    Another DNA-Mending Protein Discovered 05/14/2002
    Scientific American reports on a research paper that identified a protein named ATR as able to mend DNA damaged by ultraviolet light. The researchers explain, “ATR appears to act as a switch that starts the repair process and also stops cells from proliferating while they are being repaired.”

    DNA Has Its Own Immune System: RNA 05/17/2002
    The May 17 issue of Science has a special Viewpoint feature about the RNA library, or RNome (the RNA counterpart of the genome). We all know about DNA and proteins; RNA was long thought to be just the messenger/translator between the two. Scientists have increasingly found RNA molecules, however, to perform many crucial functions including signalling and expressing genes.

    • Gary Riddihough introduces the new concept of the RNome and its multi-faceted role in many vital functions, such as protecting DNA from invasion.

    • Gisela Storz describes an “expanding universe” of non-coding RNAs, including micro-RNAs (sequences of 20-22 bases), with a multitude of functions that we are just beginning to understand.

    • Ronald Plasterk describes RNA as the genome’s immune system, protecting DNA from viral attack and damage.

    • Phillip Zamore says that RNA “reflect an elaborate cellular apparatus that eliminates abundant but defective messenger RNAs and defends against molecular parasites such as transposons and viruses.”

    • Paul Ahlquist discusses how RNA can silence genes, which makes it a central player in gene expression.

    • A team of scientists at Rockefeller University has elucidated the core structure of RNA polymerase at high resolution. RNA polymerase is a chief molecular machine involved in transcription of DNA. It makes a copy of a gene from a DNA molecule that can be ferried by messenger RNA to a ribosome, where transfer RNA assembles the amino acids based on the coded sequence into a protein machine. The researchers show RNA polymerase to be a complex system with multiple roles and moving parts, assisted by a suite of other protein machines. They say it is “conserved in structure and function among all cellular organisms,” from bacteria to man.

    Proteins Climb Mountains 05/20/2002
    Scientists at Caltech have found that proteins climb an energy mountain to get home. Nature Science Update describes how a protein chain begins as a string of amino acids, but must go through a complicated folding process that it calls “one of biology’s fundamental mysteries.” The scientists measured the “energy landscape” in the folding process. To get to its “native fold,” in which it is properly folded and functional, it must climb an energy mountain and settle in just the right valley on the other side. On the way, there are several pitfalls that the protein must avoid or else it becomes a useless tangle. Their research is published in the Journal of the American Chemical Society.

    Membrane Channels Are Doorways to Health – or Death 05/29/2002
    The latest issue of Neuron, May 30 has an essay about membrane channels and their importance. The authors of “Channels Gone Bad” begin:

    “Channels regulate ion flow across membranes and are an essential component of cell function. Indeed, nearly all cell membranes contain ion channels, proteins with diverse roles, and sometimes highly complex behaviors. Channels are activated and inactivated by many signals and their function regulated by countless processes. Yet, beware of the aberrant channel. Channels that open when they shouldn’t, channels that do not open very well or at all, channels that stay open too long, misplaced channels, lack of channels, too many channels; all these scenarios can have disastrous consequences.”

    They describe some of the horrible consequences of mistakes in the genes that code for these complex proteins: cancer, numerous types of disease, and death.

    Published the same day, the May 30 Nature has a report on how ion channels open and close their gates, and features two more papers on this subject by the pioneer in this field, Roderick MacKinnon of the Howard Hughes Medical Institute: the crystal structure and gating mechanisms and conformational changes of potassium ion channels. The papers contain detailed pictorial models of how the channels and their selectivity filters attract and transmit the correct molecules rapidly and accurately, but repel interlopers.

    DNA Translation Machinery Is the Major Cell Building Project 05/31/2002
    “The ribosomal RNA [rRNA] genes encode the enzymatic scaffold of the ribosome and thereby perform perhaps the most basic of all housekeeping functions. However, recent data suggests that they might also control important aspects of cell behavior.” Thus begins a minireview in the May 31 issue of Cell, which says that one of the biggest, if not the ultimate, cellular subsystem is preparing and controlling the machinery to translate DNA into proteins:

    “An actively cycling eukaryotic cell expends between 35% and 60% of its total nuclear transcription effort in making the 18S, 5.8S, and 28S ribosomal RNAs (rRNA) (Paule, 1998 , and references therein). The 5S rRNA and the small nucleolar RNAs required for ribosome biogenesis, account for another 10% to 20%. Thus, the assembly of the translational machinery occupies around 80% of nuclear transcription in yeast, while in the proliferating mammalian cell as much as 50% is dedicated to this goal. Even relatively small changes in this commitment are likely to have extensive repercussions on the cell’s economy, limiting proliferation rates and perhaps even cell fate. ... Though little is known of the changes that occur in vivo, one would suspect that, given the longevity of ribosomes and the highly variable proliferation rates of different somatic cell types, rRNA transcription rates must be regulated over a wide range if neither a ribosome deficit nor an overproduction is to occur.”

    The minireview by Tom Moss and Victor Stefanovsky, “At the Center of Eukaryotic Life,” goes on to describe many functions of ribosomal RNA, including regulatory functions previously unknown. rRNA molecules appear to silence some genes, a mystery that may be explained by having backup copies available in case damage occurs to the highly active rRNA genes. They conclude, “Recent work argues that the rRNA genes are not simply bystanders in the decisions on cell fate. Understanding the regulatory network surrounding the rRNA genes is then an essential part of understanding cell growth regulation. It may even turn out that the housekeeper is in fact keeping the house.”

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  • bob b
    Batteries, Chaperones, Translators: Wonders of the Cell Continue to Dazzle 03/08/2002
    Recent techniques have allowed scientists to peer into the cell at 1.6-nanometer resolution. What has appeared in sharp detail is a veritable factory of living machines that can manufacture things, charge batteries, edit code and much more. The March 8 issue of Science has several papers that explore more the complex goings-on inside our cells, and even the cells of the lowly bacterium E. coli:

    • Battery Rechargers: Three biochemists have described how some anaerobic bacteria recharge their batteries. To get work done, all organisms have to use electricity. They do this by pushing charges the way they don’t want to go (against the energy gradient), creating an electromotive force (in this case, PMF or proton motive force). The authors examined the proton pump in the membrane of E. coli, and found that it is a complex of very complicated protein molecules shaped somewhat like a mushroom. It effectively passes proteins down a 90-angstrom channel somewhat like an electric wire, using a series of chemical reactions called a redox loop.

    • Assembly Plant: The cell is a crowded place. Newly manufactured proteins, if not protected before folded into their proper shape, can turn into harmful gunk. Not to worry; a family of chaperone proteins is at their service to whisk the proteins to safe barrel-shaped havens where they can fold in peace. Two German biochemists have examined the process from newly-synthesized chain to folded protein:

    “To become functionally active, newly synthesized protein chains must fold to unique three-dimensional structures. How this is accomplished remains a fundamental problem in biology. Although it is firmly established from refolding experiments in vitro that the native fold of a protein is encoded in its amino acid sequence, protein folding inside cells is not generally a spontaneous process. Evidence accumulated over the last decade indicates that many newly synthesized proteins require a complex cellular machinery of molecular chaperones and the input of metabolic energy to reach their native states efficiently.”

    They describe some of the bad things that can happen: aggregation or clumping, which might be implicated in Alzheimer’s disease and Huntington’s disease, among many other problems. The paper describes a staggering array of complex chaperone molecules and procedures that work together to prevent trouble under a wide variety of conditions.

    • Editing Room: Two Greek biochemists from Crete peer into the process of transcribing a gene of DNA into messenger RNA, which then travels to the ribosome to build a protein. It’s not a simple job. The DNA is bundled tightly into balls of chromatin and nucleosomes, preventing the editing apparatus from getting to it. Again, not to worry: there is a squad of chromatin-unscramblers to unlock the precious code and let the translator, RNA-polymerase II, scan the code and build the messenger RNA. Think of scrolls locked in a library of ancient manuscripts that need to be translated into English. These scrolls contain the instructions for building machines. You need someone with a key to let you in, then you need a way to safely unroll the scroll to the right spot. These steps must precede the translation and manufacturing processes. In this paper, the scientists found that two squads are needed. A pre-initiation complex (PIC) gets the unrolling machinery ready before the door is unlocked. A chromatin-remodeling squad unlocks the door. The unlocking is actually more like unscrambling tightly-wound strands so that the PIC can get to it, before the translator can do its work.

    Scientists Coax Molecules to Self-Assemble 03/12/2002
    Nanotechnology, the use of molecules to build machines, is a hot topic these days. Makers of these invisibly-small robots are imitating nature, taking their cues from living systems. In the March 12 preprints of the Proceedings of the National Academy of Sciences, there are two papers describing how scientists have gotten molecules to self-assemble into structures. One team got star-shaped building blocks to assemble into tubes: “Entropically driven self-assembly of multichannel rosette nanotubes.”. In the same issue of PNAS, another team describes how molecular-size machines and motors might be built from various molecules in “Controlled disassembling of self-assembling systems: Toward artificial molecular-level devices and machines”.

    Gates of the Cell Open to Awe-Struck Eyes 03/12/2002
    The cover story of the March 9 Science News Vol 161:10, pp 152-154 is about ion channels, the complex gates that attract and channel electrically-charged atoms into the cell (see our Jan 17 and Mar 7 headlines on this topic). The article has color diagrams of the complex proteins that make up the channels and describes how they function: the KcsA potassium channel, for instance, “can shuttle up to 100 million potassium ions across a cell membrane in a single second while keeping out similarly charged sodium ions, whose smaller size would seem to make the passage easier.” (Sidelight: Nature Science Update reports that scientists have engineered a synthetic chloride channel, imitating nature.) The importance of ion channels is emphasized:

    “Literally every single thought or action involves these channels. After all, among their duties is regulation of the electrical excitability that nerve cells use to communicate and that muscles exploit to contract.”

    Roderick MacKinnon and other researchers who first revealed their intricate structure were surprised that lowly bacteria had fully-formed ion channels:

    “There was something even more surprising. No one had previously reported voltage-gated ion channels in a microbe. Jellyfish were the simplest creatures known to possess such channels. It was generally thought that microbes, which lack muscles and nervous systems, don’t need the high-speed reactions that voltage-gated ion channels permit.”

    “This changes the whole evolutionary picture of [ion] channels,” says Clapham. “It means that bacteria, the most primitive life forms, have what was thought to be a very specialized channel.”

    The descriptions of these channels and their fast-acting voltage-regulated gates borders on awe at times. MacKinnon, though pleased at the possibility of medical advancements now that ion channels are becoming better understood, “admits that he’s motivated more by the thrill of understanding these remarkable proteins. ‘I just wonder how nature does things,’ he says. ‘How did nature make an electrical signal go from my brain to my toes so fast? The more you learn about what the ion channels have to do to make that signal, the more incredible it seems.’”

    DNA Computer Demonstrated 03/14/2002
    Meet the DNA computer: humans using biological molecules to perform non-biological calculations. Dr. Leonard Adelman of USC got DNA to work a difficult combinatorial problem, says a news release at Jet Propulsion Laboratory which partly funded the research. The advantage of DNA molecules is that they can operate in a massively-parallel fashion, unlike serial processing done by our familiar electronic computers. They are also very energy efficient and capable of storing vast quantities of information. Adelman exults:

    “We’ve shown by these computations that biological molecules can be used for distinctly non-biological purposes. They are miraculous little machines. They store energy and information, they cut, paste and copy. They were built by 3 billion years of evolution, and we’re just beginning to tap their potential to serve non-biological purposes. Nature has given us an incredible toolbox, and we’re starting to explore what we might build.”

    Adelman’s report is published in the March 15 Science.

    Did Proteins Self-Organize? 03/19/2002
    The Proceedings of the National Academy of Sciences for March 19 published a supplement on “Self-organized complexity in the physical, biological, and social sciences.” In the only paper of the colloquium that might bear on evolution, Hans Frauenfelder of Los Alamos labs considers Proteins: Paradigms of Complexity. He describes complexity: “A system can be called complex if it can assume a large number of states or conformations and if it can carry information.” Proteins and DNA, he explains, can assume so many possible combinations that they make astronomical numbers seem small by comparison: yet proteins and DNA carry information, “Hence proteins, and in general biological systems, are complex.” He describes the complex conformations of amino acid chains, the energy landscape of protein interactions, and the many functions they perform. Then he concludes with this enigmatic statement :

    “This brief sketch should make it clear that proteins are truly complex systems and that the complexity can be described through the energy landscape. The complexity has arisen through evolution. The structure and function of proteins are coded in the DNA. Within the living system, proteins are part of a complex proteins network, and the complex interactions in the network may control the actual function. Can this be called self-organized?”

    Biologists Drowning in Complexity 03/21/2002
    So admits an opinion page, “Pursuing Arrogant Simplicities,” in the March 21 Nature, stating :

    “Generating vast sets of data from stressed cells in order to determine patterns of gene expression is an immense step forward. But beware the false impression that we are close to understanding how networks of genes regulate one another’s expression, and generate phenotypes such as cellular development and behaviour. Even the true scale of most genetic networks is unknown. And biologists know that genes are just one aspect of control: protein switches and molecular signalling networks are still a largely uncatalogued universe. ...
    .... Even after one absorbs a thousand or more pages of text, one would still be unlikely to have a feel for the variability and complexity of even the simplest microbe.”

    The comments were made in regard to universities that are building multi-disciplinary centers to model biology, warning them not to take life too simplistically. While the editors encourage a search for simple, breakthrough hypotheses to model such things as genetic networks, the editors ask, “But what if, as some biologists suggest, there may be no possible model simpler than life itself?”

    Factory Recall: How the Cell Deals with Assembly Errors 03/22/2002
    From DNA to protein – the process of transcription and translation, in which a messenger RNA (mRNA) reads the DNA template and ferries the information to a ribosome, where transfer RNAs (tRNA) assemble amino acids into protein chains, is an elaborate process coordinated with dozens of enzymes, signals and molecular machines. The mRNA is supposed to come with a “termination codon” a specific series of nucleotides that tells the ribosome the chain is complete. But what is the ribosome to do when the mRNA is missing the termination codon, or has it in the wrong place? If it releases a misfit protein, the results could be disastrous. Not to worry: the cell has control procedures to recognize the error and dismantle the misfit protein before it gets into circulation. Two papers in the March 22 issue of Science explain new findings about the factory recall system, termed nonsense-mediated messenger RNA decay and nonstop messenger RNA decay. Several mechanisms are involved. Though complicated, they resemble human assembly lines with inspectors that stamp bad parts defective, so that downstream workers know to send them to the recycle bin (an exosome or proteasome) instead of the shipping room. Other mechanisms resemble instructions from a high-tech spy novel: something like “if the messenger arrives more than 22 minutes late or is lacking his security clearance emblem, activate his self-destruct mechanism.” In her perspective summary, Lynne E. Maquat begins, “Prokaryotic and eukaryotic cells have evolved remarkable quality assurance mechanisms at virtually every step of gene expression.” Maquat also has a summary of the processes in the March 19 issue of Current Biology.

    Cell’s Motors– Are Really Motors 03/26/2002
    James Marden and Lee Allen from Penn State, writing in the March 26 PNAS, “Molecules, muscles, and machines: Universal performance characteristics of motors” have graphed the net force vs mass of motors from molecular size to rocket engines. They found essentially no difference between biological motors like ATP synthase, the bacterial flagellum, dynein and other nano-scale molecular machines and man-made motors:

    “Animal- and human-made motors vary widely in size and shape, are constructed of vastly different materials, use different mechanisms, and produce an enormous range of mass-specific power. Despite these differences, there is remarkable consistency in the maximum net force produced by broad classes of animal- and human-made motors.”

    In addition, they compared “flying birds, bats, and insects, swimming fish, various taxa of running animals, piston engines, electric motors, and all types of jets” and found them to all fall on the same line of force per mass, except in a few cases where viscosity of the medium was a factor. “Remarkably,” they state, “this finding indicates that most of the motors used by humans and animals for transportation have a common upper limit of mass-specific net force output that is independent of materials and mechanisms.” They are not sure if living things have achieved a theoretical upper limit of performance per unit mass, but conclude: “In the meantime, we perhaps can only marvel that millions of years of natural selection on animals and a few centuries of experimentation with machines have resulted in an empirical and evolutionary solution to the problem; ...”

    As is typical each week in the Proceedings of the National Academy of Sciences, the same issue has a plethora of additional research papers about wonders of living cells: for example,

    • How cells protect against UV damage
    • How water pores help secretory vesicles swell up like water balloons
    • How taste buds detect sweetness
    • How cells protect their proteins from oxidative damage
    • How the cell maintains the integrity of its mitochondrial DNA
    • Another essential protein that regulates cell division

    Another Protein Chaperone Found 03/28/2002
    German scientists writing in the March 28 Nature have described another “protease-chaperone machine” in cells that is widely conserved in living things. Named DegP, this molecular machine has two functions: if it cannot refold a badly-folded protein, it dismantles it. Its functions appear to be heat sensitive. The six-sided cluster of protein chains forms a barrel-shaped cavity, with “a construction reminiscent of a compactor.” Customers are guided by tentacle-like “gatekeepers” into the machine, and the door is closed. If the customer just needs cleaning to refold, the lint is scraped off and the molecule is ejected to refold; otherwise, it is compacted and destroyed. The machine is apparently versatile enough to handle many different kinds of proteins.

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  • bob b
    Cellular Motor Vehicles Souped Up for Speed 12/06/2001
    The awe is palpable in Susan Gilbert’s News and Views entry in the Dec. 6 issue of Nature, “Cell biology: High-performance fungal motors.” Reviewing recent findings, she introduces the subject matter:

    “Motor proteins are tiny vehicles that move molecular cargoes around inside cells. These minute cellular machines come in three broad families, the kinesins, the myosins and the dyneins. There are over 250 kinesin-like proteins, and they are involved in processes as diverse as the movement of chromosomes and the dynamics of cell membranes. They all have a similar catalytic portion, known as the motor domain, but beyond this they are astonishingly varied - in their location within cells, their structural organization, and the movement they generate.”

    She spends time especially on the “Ferrari” of these motor vehicles, a kinesin from the fungus Neurospora crassa, that can move along its microtubule tracks at 2.5 microns per second, five times faster than other similar kinesins (if this molecule were the size of a car, it would top 1200 mph). Describing three possible means of achieving such speeds, she suggests ways microbiologists might learn more about “these splendid molecular machines.”

    Two other papers (1), (2) in the same issue discuss ATPase or ATP synthase, the molecular motor of exquisite precision and function discussed earlier in Creation-Evolution Headlines. The second describes how it is involved in helping stomata (openings) in a plant leaf open and close to exchange gases. Apparently ATPase creates an electrical potential that works with other proteins that are responsive to blue light.

    These motor vehicles (80 times smaller than a wavelength of light) and the microtubule tracks they run on have been likened to a nanotrain or intracellular railroad system in the cell.

    Mature Muscle Stem Cells Can Make Blood 12/11/2001
    Nature Science Update is reporting that mature muscle cells in mice have stem cells that can migrate to form blood cells, then come back and make more muscle, an “amazing thing,” according to the University of Pittsburgh researchers who reported to the American Society for Cell Biology. They weren’t even looking for stem cells in the muscle tissue. Helen Blau at Stanford says, “It shows that cells can go in many different directions given the right environment.” She believes the traditional view that stem cells permanently lose their ability to produce other cell types is changing. Others argue that research on embryonic stem cells should continue.

    Cells Squeeze Out Their Dead 12/13/2001
    Cells die, and if left in place in tissues, they would shrivel, rot and leave a hole. Something must be done, and the cellular machinery is built to handle every contingency. At the American Society for Cell Biology meeting this week, the process was described by London biologists, reports Science Now. Early in its death throes, the dying cell sends out a warning to neighboring cells, who produce extra motor proteins actin and myosin. These go into action retracting the healthy cells around it into a contractile ring, as if saying Heave ho on cue, squeezing the dead cell out like toothpaste, then reforming the intact tissue. The scientists switched the proteins on and off in skin epithelial tissue to test their hypothesis.

    Wonders of the Water Gate 12/20/2001
    The Dec. 20 issue of Nature has a detailed description, with diagrams, of one of the water gates inside you (and all living things): AQP1, one of the aquaporins, the superfamily of complex proteins in cell membranes that transport water into the cell interior. There are ten families of these water channels. In this paper, Berkeley scientists achieve the highest yet resolution (2.2 Angstroms) of the structure of AQP1, and show it to be a highly-organized, specifically shaped and sized pore with inner and outer vestibules, between which is a constriction region with a “selectivity filter” that lets water in but not anything else.

    DNA Damage Response Team to the Rescue 01/04/2002
    Americans proudly hail the firefighters and cops that go to work when terror strikes, but did you know your body has an even more heroic team that flies into action when DNA gets damaged? It’s called the DDR - DNA Damage Response team. The hearty band of specialized enzymes can handle any contingency: broken strands, loose ends, typos, kinks, twists and numerous other emergencies. During complex operations like duplication and translation, the DDR team has its P&P (policies and procedures) down pat, including checkpoints and feedback mechanisms to ensure repairs are made quickly, or that irreparable damage triggers the appropriate salvage and disposal operations.

    Writing in the Jan 4 issue of Science, a team of seven geneticists, biochemists and biologists have determined that no less than 23 separate genes code for the DDR (and there are probably more). In addition, they noted an “extraordinary level of conservation of molecular mechanisms in DDR pathways” in all living things, from the worms they studied to man. Many kinds of cancer can be traced to defects or mutations in these genes, that leave the cell like a city without a fire department.

    Ancient Cells Proofread Better 01/08/2002
    Four biochemists from Stratagene in California, writing in the Proceedings of the National Academy of Sciences, have identified a complex “proofreading” enzyme that improves DNA copying accuracy up to 100-fold. The enzyme is composed of multiple protein chains and can survive high temperatures (around 200oF). Although with this proofreading enzyme copying is slowed down (550 nucleotides per minute instead of 2,800 without the proofreading), the fidelity is greatly increased. It apparently works by breaking down a product called dUTP produced by other construction pathways. dUTP can poison a replicating DNA chain by substituting uracil. All living things contain a suite of proofreading enzymes, including members of this family of enzymes (dUTPases) that “read ahead” and find dUTP to cut it out of the growing DNA strand. But this one is not only highly effective, it works at high temperatures. The surprise is that this bulky, complex enzyme was found in a single-celled organism of the kingdom Archaea (“ancient ones”) which includes bacteria that thrive in hot springs.

    Note: Several other papers on DNA proofreading can be found in the January 8 preprints of PNAS, each equally interesting and amazing, such as this paper by biochemists at the University of Washington on nucleotide excision repair (NER), the ability of enzymes to repair breaks in DNA caused by ultraviolet light damage. (They studied this in yeast)

    How Life Defends Against Harmful Mutations 01/31/2002
    Different populations have different ways of defending themselves against the destructive effects of harmful mutations, say David C. Krakauer of the Sante Fe Institute and Joshua B. Plotkin of Princeton, in a paper “Redundancy, antiredundancy, and the robustness of genomes” in the Jan 29 Proceedings of the National Academy of Sciences. Although presuming genetic mutations are a source of evolutionary novelty, they explain that damage must be guarded against.

    The authors propose that small populations of large organisms (like mammals) use redundancy to maintain fitness: i.e., copies of genes and backup systems. But large populations of small organisms, like bacteria, appear to employ antiredundancy strategies: i.e., they are hypersensitive to mutation, but employ methods of removing harmful mutants:

    “Assuming a cost of redundancy, we find that large populations will evolve antiredundant mechanisms for removing mutants and thereby bolster the robustness of wild-type genomes; whereas small populations will evolve redundancy to ensure that all individuals have a high chance of survival. We propose that antiredundancy is as important for developmental robustness as redundancy, and is an essential mechanism for ensuring tissue-level stability in complex multicellular organisms. We suggest that antiredundancy deserves greater attention in relation to cancer, mitochondrial disease, and virus infection.”

    The authors propose a mathematical model for explaining the dynamics of redundancy and antiredundancy in differing populations. Populations exhibiting redundancy have hilly fitness landscapes with steep, narrow peaks. Antiredundant populations have a flat fitness landscape with small peaks, forming a “quasispecies” of mutants with similar fitness.

    Rotating Gate in the Cell Membrane a “Beautiful Design” 02/12/2002
    Another gateway into the cell has been explored, and it’s a beauty, say the three biochemists who describe it in the Proceedings of the National Academy of Sciences Feb 12 online preprint. This one is called KcsA, a potassium ion channel that is critically important for nerve impulses in humans, but also is used by bacteria. KcsA is one of many membrane proteins that are subjects of intense scrutiny by biochemists. It is so effective, it can let in 10,000 potassium (K+) ions for every unwanted sodium ion (Na+), even though sodium ions are smaller but have same charge.
    How the KcsA channel does this was a surprise. Apparently, four helical rod-shaped parts rotate clockwise in such a way as to keep parts of the gate rigid while allowing other parts to flex. To picture this in a simplified way, visualize four chopsticks hanging vertically, forming a square looking from the top down. Each stick has a pivot point about 1/3 of the way down, allowing it to rock. The bottom ends of the sticks are bundled together in the shape of an inverted teepee, in such a way that as each stick pivots, the bottoms trace out a circle. Moving in concert, they cause a rotary motion that allows the potassium ions funnelling into the stiff upper part, the “selectivity filter” wide berth as they exit into the interior of the cell. The selectivity filter, like a one-way ID-checking turnstile, attracts positive potassium ions but keeps unwanted molecules out.
    The authors explain how only a clockwise rotation allows the gate to work. They did not state the rotation rate of the gate, but it must be phenomenal; the throughput of KcsA is an astonishing 100 million ions per second, very near the diffusion limit. The authors apparently could not help expressing a little awe in their otherwise straightforward scientific paper; they used the word “design” twice: “The interplay of the two pivot points is a beautiful design by nature for solving the gating problem of KcsA,” and “The swinging rotational motion of TM2 helices with two pivot regions is an exquisite design by nature to ensure an effective gating of KcsA without having to loosen up the structural integrity near the intracellular side of channel in the open state.”

    Presto! Prestin Wins the Gold in Molecular Motor Race 02/21/2002
    A “new type of molecular motor, which is likely to be of great interest to molecular cell biologists” has been discovered. Named prestin, this protein motor, made up of 744 amino acid units, is a speed demon, ferrying negative ions across cell membranes in millionths of a second. It appears to function as part of the mechanical amplifier in the cochlea, helping the ear to achieve its “remarkable sensitivity and frequency selectivity.” Nature Molecular Biology Reviews describes the unique features of this biological machine:

    "Prestin is a new type of biological motor. It is entirely different from the well-known and much-studied classical cellular motors in that its function is not based on enzymatic processes, but on direct voltage-to-displacement conversion. The action of prestin is also orders of magnitude faster than that of any other cellular motor protein, as it functions at microsecond rates."

    Prestin has an external voltage sensor that causes it to respond. Its action apparently mediates changes in length of the outer hair cells of the cochlea, greatly amplifying the responsiveness of vibrations reaching the inner ear. The illustration in the article shows how the cochlear amplifier works to provide variable, automatic, amplitude-dependent response. The “gain” on low-level signals can be 1000-fold, but intense signals are not amplified. This allows the brain to hear very faint signals but not get saturated by loud ones.

    Update 02/26/2002: A paper in the Proceedings of the National Academy of Sciences describes prestin further and finds that it is dependent on regulation by thyroid hormone.

    Sound begins as miniscule pressure waves in the air. These are first channeled by the outer ear into a tunnel, where they set up vibrations in the eardrum, then are transmitted mechanically through three lever-action bones to the inner ear, then are amplified by hair cells in the cochlea (each responding to its own characteristic frequency), which open and close ion channels that send electrical pulses down the auditory nerves. The brain, then, sorts out all this information to determine frequency, amplitude, direction, and meaning.

    Delays in hearing could be dangerous. The rapid response of prestin and all the other components of our amazing sound system helps us to hear in real time. Scientists are just now beginning to understand the details of operation of the long-mysterious cochlea, with its keyboard-like rows of inner hair cells and outer hair cells that expand and contract in perpendicular directions.

    Bewildering Complexity – RNA Editing 02/21/2002
    The Feb 22 issue of Cell contains a paper by Alabama biochemist Stephen J. Hajduk entitled “Editing Machines: The Complexities of Trypanosome RNA Editing.” RNA editing is critical to the accurate building of molecular machines like ATP synthase vital to cells. The author asks, “How many proteins does it take to edit an RNA?”

    "Recent studies, using conventional protein purification, homology modeling, and mass spectrometric analysis, have focused on identifying the components of editing complexes. This is an important yet somewhat bewildering exercise since at least a dozen proteins have been identified that putatively contribute to RNA editing in trypanosomes."

    He describes how these proteins form editing complexes, and how RNA strands pass through several iterations of editors on their way to the protein assembly plant. In the last section, “Increasing complexities and unresolved issues,“ Hajduk states: “As we begin to understand the composition of the editing machinery, new complexities emerge.”

    Introns Found in Primitive Eukaryote 02/26/2002
    Science Now reports that introns have been found in Giardia, a primitive eukaryotic single-celled organism. Sometimes considered “junk DNA,” introns are pieces of genetic code that do not code for proteins, that have to be cut out of the strand by genetic scissors called spliceosomes before transcription can begin. Introns were thought to have evolved later in the eukaryotic line, but here they were, scissors and all, in an early “primitive” eukaryote. The original paper is in the Feb 19 Proceedings of the National Academy of Sciences.

    Protein Folding an Olympic Event 02/27/2002
    A news release from the University of Pennsylvania puts biological molecules into the Winter Olympics:

    "It’s a long-simmering debate in the world of physical chemistry: Does the folding of proteins into biologically active shapes better resemble a luge run - fast, linear and predictable - or the more freeform trajectories of a ski slope? New research from the University of Pennsylvania offers the strongest evidence yet that proteins shimmy into their characteristic shapes not via a single, unyielding route but by paths as individualistic as those followed by skiers coursing from a mountain summit down to the base lodge."

    The researchers, who published in this week’s Proceedings of the National Academy of Sciences, found a great deal of variety in the paths and rates of folding. Only when a protein is folded correctly can it perform its function. Misfolded proteins are the cause of many serious diseases. The team explains that there are chaperones on hand to fix errors:

    In the skiing analogy, chaperones could be thought of as rescue helicopters that return wayward skiers to the summit so they can try to make their way down the mountain again,” said [Feng] Gai, an assistant professor of chemistry at Penn.

    Protein folding is fiendishly intricate, yet crucial to the chemistry of life - so much so that a small army of biologists and chemists has devoted itself to better understanding the process.

    Another article in another source describes just how fiendishly intricate the process is. The March 12 issue of PC Magazine has a feature section on Technology in America. Alan Cohen describes how supercomputers, after showing their skill in deciphering the human genome, are trying to tackle the puzzle of protein folding:

    "Problems like protein folding, where the number of possible shapes for the average-size protein is greater than the number of atoms in the universe, are far more complex. Thus, such problems require “a tighter, faster, parallel machine, where the processors of each work in conjunction with the others,” says Professor [David A.] Bader [director of the High Performance Computer Lab at the University of New Mexico]."

    "... Advances like these require intense computation, and as impressive as the clusters that sequenced the genome are, they’re not enough for this new phase.

    IBM’s Blue Gene project, which will be able to perform 1 quadrillion operations per second, sets out to tackle protein folding. IBM scientists estimate that calculating the folding process of even a very small protein on today’s most powerful computer would take 300 years. Even Blue Gene, once completed in 2005, will take a year to crunch the numbers."
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    Duke Biologists Deny Validity of Molecular Classification 07/02/2001
    Scientists at Duke University claim to have debunked the method of classifying mammals and other organisms based on mitochondrial DNA sequences. The molecular method claims the platypus is related to the kangaroo, for instance, and that widely disparate animals like hippos and whales had a common ancestor. The Duke scientists analyzed nuclear genes with computer software that supported the older common-sense classification used by paleontologists that groups animals based on morphology (outward structure and anatomical similarities). The article starts by saying, “Classifying kangaroos and platypuses together on the evolutionary family tree is as absurd as adding your neighbors to your own family ancestral line simply because they share your love of the opera, according to scientists at Duke University.”

    Clones Express Genes Differently 07/06/2001
    Why do so many cloned embryos die before birth? Why do the ones that survive have abnormalities? According to scientists at MIT reported by Scientific American News, it’s because clones express genes differently than the donor; i.e., even though the donor and the clone have identical DNA, they do not activate the same genes in the same way. Apparently there are “epigenetic” factors at work, influences other than the coded language of life. These include enzyme tags on genes that affect their expression. Embryonic stem cells with nuclei from donors can have different tags that cause them to develop in wildly different ways, producing chimeras (monsters), abnormally large offspring, or survivors that while appearing outwardly normal have hidden abnormalities that can lead to problems later.

    Human Genome 07/10/2001: The BBC reports that some scientists dispute earlier estimates that the human genome only has 30,000 genes. Using different statistical techniques, they claim it has over twice as many: 70,000 or more.

    Update 08/24/2001: A report in Nature puts the number at 42,000 but admits it could go higher than 50,000. One of the difficulties is the algorithms used to estimate the number of genes, and the lack of knowledge of function of various sequences.

    Update 11/28/2001: According to EurekAlert, scientists at Cold Spring Harbor laboratories, Long Island NY, now have a computer program able to spot gene "on" switches and promoters. They think the number of human genes is now between 50,000 and 60,000.

    See also the report in the Feb 22, 2002 issue of Science about discussion among members of the AAAS.

    Plants Talk to Themselves in Email 07/13/2001
    How does one part of a plant know that another part is under attack, or how do the roots know the weather is changing and affecting the leaves? According to Nature, plants have a busy system of email messages spreading the news. Scientists have discovered messenger RNA (mRNA) molecules travelling from cell to cell and onto their own little Internet (the phloem), that apparently let one part of the plant know what’s going on in another part.

    25 Years of Study on DNA Copy and Repair Mechanisms Summarized 07/18/2001
    The July 17 issue of the Proceedings of the National Academy of Sciences contains a long paper by two MIT biochemists on what we have learned so far in 25 years of study of enzymes that help copy and repair DNA: the DNA polymerases. Apparently these wonder molecules not only synthesize DNA but repair a number of different kinds of errors. The coordination of which polymerase is activated and tosses the baton to another is still poorly understood. Most of the work has been done on E. coli, a prokaryote (simpler one-celled organisms lacking a nucleus), but the situation is even more complex in the eukaryotes (all higher organisms), “where both the number of DNA polymerases and the level of complexity of the events are far greater.”

    The authors seem truly amazed at the performance of these submicroscopic molecules. Some sample sentences:
    • A common, defining feature of these DNA polymerases is a remarkable ability to replicate imperfect DNA templates . . .
    • The recent discovery of additional eukaryotic DNA polymerases...further complicates the already daunting issue of understanding the control systems that govern which DNA polymerase gains access . . . .
    • A growing body of evidence suggests that an important additional level of control results from DNA polymerases being "coached" as to their correct biological role through interactions with other proteins associated with the particular DNA substrate . . . .
    • In addition to their roles in chromosomal DNA replication, DNA polymerases participate in numerous DNA repair pathways, including double-strand break repair, mismatch repair, base excision repair and nucleotide excision repair . . . .
    • Elaborate regulatory controls and a sophisticated system of protein-protein contacts ensure that the...gene products carry out their appropriate biological roles. However, as is so often the case in science, the discoveries of today are posing even more challenging questions for tomorrow.

    Frankenstein Bacteria Jumpstart Evolution With Lightning 08/01/2001
    According to Nature Science Update, researchers in France simulated lightning in soil with spark discharges and observed bacteria incorporating plasmids (DNA rings) into their genomes. They conjecture that this method of horizontal gene transfer might be instrumental in evolution.

    Quotable Quote 08/02/01: “The simplest living cell is so complex that supercomputer models may never simulate its behavior perfectly. But even imperfect models could shake the foundations of biology.” – W. Wayt Gibbs, “Cybernetic Cells,” Scientific American (August 2001), p. 53.

    Master On-Off Switch for Genes Found: A Second Genetic Code? 08/10/2001
    Researchers at the University of Virginia have been studying a type of protein structure called chromatin that surrounds DNA, and believe it acts as a switch to turn genes off or on. If so, this is another source of information, like a second genome, that helps regulate DNA genes. Dr. C. David Allis, a biochemist, states: “We believe that what is telling the cell to make those choices is an overall code that may significantly extend the information potential of the genetic DNA code. For some time, we have known that there is more to our genetic blueprint than DNA itself. We are excited that we are beginning to decipher a new code, what is referred to as an epigenetic code.” The story was reported by SciNews.

    Motor and Clutch Proteins Identified for Cellular Highways 08/17/2001
    Did you know that cells have their own interstate highway system, with actin filaments serving as streets and microtubules serving as freeways? That motors send their cargo zipping down the lanes? EurekAlert reports that biologists at the University of Illinois, publishing in Science, believe they have identified the clutch that puts the motor in neutral or clicks it into gear. While studying pigment organelle movement in animals that can change color, like chameleons, they think they have uncovered a universal system for moving parts around the cell. The clutch is a complex molecule named calcium/calmodulin-dependent protein kinase II (CaMKII); it works to engage or disengage a motor protein they had earlier identified as myosin-V.

    Electricity Propels Cell Cargo 08/21/2001
    Cells need to move stuff around through microtubules, little subway tunnels, and build proteins on assembly lines called ribosomes. How do they attract the trucks to the cargo bay and move them along the track? One factor appears to be static electricity. Scientists found ways to calculate the electrostatic potential of microtubules and ribosomes, and found that they have complex quilted patterns of positive and negative charges, with a net negative charge that helps attract the ingredients and propel them along, according to a paper published online in the Proceedings of the National Academy of Sciences.

    The paper is technical, but has some nice illustrations of microtubules in cross section. It shows how the little tunnels are not simple structures like hoses, but elaborate, precise arrangements of molecules as intricately crocheted as a quilt. The main ribosome components have 88,000 to 95,000 atoms apiece, arranged to create the proper electrostatic potential.

    Of Centromeres and Telomeres 10/05/2001
    Two cell biology reports are revealing that “mere” parts of DNA are vital. A news release in Nature announced that a university team in Cleveland, Ohio has sequenced the centromere of the human genome. These are the junction points that join the two strands of chromosomes. They consist of long repetitive sequences of genetic letters. Though no one understands how they work at this point, they parcel out equal shares of chromosomes during cell division. Flaws in the centromeres are implicated in many cancers.

    In a second news item, a paper in the journal Cell discusses the role of telomeres in cell death and cancer. Telomeres are the “end caps” on DNA strands that prevent them from unraveling; at each cell division, the length of the telomere is reduced by one unit. Researchers found that the shortest telomere determines when the cell signals itself to die, not the average telomere length. Scientific American comments that cells with short telomeres act as if the DNA strand has broken, and receive a signal to “arrest or die as a protection against chromosome rearrangement and cancer.” When the telomere-repair tool, telomerase, is present, it lengthens the telomere just enough to function. Runaway telomere lengthening appears to be a characteristic of some cancers. A related paper published online in the Proceedings of the National Academy of Sciences demonstrates that “telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors.”

    Virus Motor Packs DNA Under High Pressure 10/18/2001
    University of California at Berkeley scientists have measured the force with which viruses stuff their DNA into protein bottles called capsids. A little molecular motor at the lid of the bottle is able to pack the coiled DNA with 60 piconewtons of pressure. On a human scale, that is ten times the pressure in a champagne bottle. The team is now studying whether the pressure is used to inject the DNA into the host bacterial cell, and whether the packing motor rotates as do some other molecular motors studied, such as the bacterial flagellum.

    Thermodynamics of Cellular “Steam Engines” Described 10/22/2001
    Three Japanese scientists have analyzed the thermodynamics of molecular motors in living cells in a new paper in the Biological Proceedings of the Royal Society. They compare the thermodynamic properties of macroscopic steam engines vs. the microscopic motors like dynein and myosin-V involved in cellular transport and cell division. They describe how these “remarkable microscopic engines” are able to perform a biased random walk (like a ratchet), even though buffeted by Brownian (thermal) motion, and perform useful work. The same equations shown here for linear molecular motors should be applicable to rotary motors like ATP synthase.

    Tiny RNAs: A Whole New World of Regulators Discovered 10/26/2001
    Cell biologists have uncovered a whole new class of regulators that control development and gene expression: micro-RNAs, or miRNAs. These short sequences of genetic material (usually around 10-30 nucleotides, much smaller than genes) that had “almost escaped detection until now,” may number in the hundreds or thousands in the cells of all living things. They work not by coding for proteins, but by latching onto messenger RNAs, that are en route to the protein assembly plants, and inhibiting them until the right time, thus acting as switches or timing controls. But the range of possible functions is just now beginning to be explored. One geneticist comments, “Each miRNA is probably matched to one or more other genes whose expression it controls. Their potential importance to control development or physiology is really enormous. If there are hundreds of these in humans and each has two or three targets that it regulates, then there could be many hundreds of genes whose activity is being regulated this way.” Three reports on miRNAs are in the Oct 26 issue of Science. See also this summary in SciNews.

    How Plants Stand Up 10/26/2001
    Plants are able to stand erect because of their rigid cell walls. Scientists have known that cell walls contained a complex carbohydrate called RG-II, but didn’t know its function. Now, scientists at the University of Georgia have figured out that RG-II forms a fishnet-like arrangement held together by boron atoms that, along with cellulose, gives the cell wall rigidity something like reinforced concrete. This carbohydrate, one of the most complex in nature and used by all plants, requires a host of enzymes to manufacture:

    “RG-II has been known as an obscure, structurally weird polysaccharide that plants make,” said Malcolm O’Neill, senior research associate at UGA’s CCRC. “But we had no idea why plants went to all the effort to make it. There are 50 to 60 enzymes involved, 12 different sugars and 22 different linkages. There’s even one sugar that’s actually not been found anywhere else.”

    They observed that mutants lacking a crucial side chain on the carbohydrate, or lacking boron, end up as dwarfs. The plants returned to normal by the addition of the missing ingredients.

    Cell’s Golgi Body Recycles Itself Continuously 11/12/2001
    The Golgi apparatus, a maze of channels near the nucleus of a cell whose function was mysterious a few decades ago, is gradually revealing its secrets. Scientists at Virginia Tech and Heidelberg have found that the proteins making up the apparatus are constantly being renewed, according to EurekAlert. One of the scientists describes what the Golgi body does:

    "The Golgi apparatus is a complex organelle. It is involved in the processing of proteins destined for either secretion or for the outer surface of the cell. Traditionally, scientists have looked on the Golgi apparatus as a fixed structure that processed proteins in an assembly-line fashion.

    The organelle is a cup-shaped arrangement of layers of flattened sac-like membranes that’s located in a characteristic place near the cell’s nucleus. Proteins are processed through the layers of the Golgi apparatus, with enzymes in each layer causing modifications as the proteins proceed through the layers, finally to be shuttled into vesicles that take them to the cell’s surface.

    Vesicles are bubble-like containers that bud from the Golgi apparatus and transport proteins to the cell's surface membrane. The vesicles themselves are made of proteins, which are absorbed by the surface membrane when they have completed their mission. Proteins are delivered to the Golgi apparatus for processing in vesicles that bud from the endoplasmic reticulum. Therefore . . . “there is a constant flow of materials from the endoplasmic reticulum through the Golgi and to the cell’s outer surface."

    The new “central finding” about the Golgi body is that it is “not a fixed structure, but that every component of it is recycled through the endoplasmic reticulum. This recycling allows the replacement of frayed proteins, acting as a kind of quality control to ensure the structure can perform its function.”

    Update 01/11/2001: More on the Golgi apparatus in Science, “the central protein sorting station of the cell,” especially how it creates protein vesicles for transport: a very complicated series of steps involving enzymes and lipids working together.

    How Did Cell Nucleus Evolve? Nobody Knows 11/19/2001
    In a new Explore feature, Scientific American investigates current thinking about how eukaryotic cells evolved a nucleus, and concludes that no theory currently explains all the facts. Some think that early cells developed a symbiotic relationship with bacteria or archaea, but the nucleus has unique features that are not present in either assumed progenitor. Every theory has serious objections. One biochemist admits, “We really probably don’t have any idea what happened. It does seem like, whatever happened, it was probably very complicated and not very sensible.”

    How the Ameba Crawls 11/22/2001
    Yale scientists have gained new insight into how cells move, reports EurekAlert. They’ve revealed the 3-D structure of seven proteins called the Arp2/3 complex that assembles actin proteins into filaments, which push the front of the cell forward. A similar process (actin polymerization) is involved in white blood cells moving to the site of an infection, and in neurons branching out into the million miles (more or less) of axons and dendrites in the human brain. Thomas Pollard of Yale, co-author of the paper in Science, explains how it works. Chemicals in the environment send messages to the Arp2/3 complex, which in turn cause it to orient the cell and move in a particular direction. He says, “Actin and Arp2/3 complex work like a peculiar motor in a car to make the cell move forward. Rather than turning wheels, the filaments grow like branches of a bush to push the cell forward. Arp2/3 complex is very ancient, having evolved in primitive cells well over one billion years ago.”

    Your Non-Essential Genes Protect You 11/23/2001
    Scientists at the National Institutes of Health have been scanning through 3,760 non-essential genes in yeast and finding them not so useless after all. So far, they have found 107 that apparently protect from radiation and toxins in the environment. Non-essential genes are ones the organism can live without – grow and develop into maturity without apparent harm. When danger lurks, however, these genes are switched on and provide protection. Since these genes in yeast and mammals are similar, they expect similar protection is afforded humans by these “non-essential” genes. (Source: EurekAlert.)

    Sunburn Repair Protein Found 11/26/2001
    A protein named interleukin-12, a type of cytokine, has been found to be effective in reversing damage caused by the sun’s ultraviolet light. According to Nature Science Update, it appears to work by activating the DNA to edit out mistakes: “The protein appears to stimulate a cellular editing system that snips damaged pieces of DNA out of the sequence,” the report states. Cells with interleukin-12 were actually able to reverse sunburn damage. If IL-12 is this effective, other cytokines may also be involved in DNA repair. “This is probably the tip of the iceberg,” says Kenneth Kraemer of the National Institutes of Health, commenting on the paper in Nature Cell Biology.
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    Protein Sequencing Makes Winning Lottery Look Easy 04/04/2001
    In the world of protein molecules, it is possible for two totally different proteins to perform the same function, much like you can open a jar with your hand or with a wrench. But while discussing this fact, Nature Science Update today makes some surprising admissions about the improbability of getting a usable protein by chance. In an article about bioengineering, author John Whitfield states: “If you wanted to make a working protein, but didn’t know where to start, how many rolls of the biochemical dice would it take to get lucky? One hundred billion, say Anthony Keefe and Jack Szostak, of the Massachusetts General Hospital in Boston, who’ve tried it to hunt out proteins to do a predetermined job from a vast number of random genes.
    “These sort of odds make buying a lottery ticket seem like a sound investment. They suggest, says Ronald Breaker, a molecular biologist at Yale University, New Haven, Connecticut, that you’d have to strain a sizeable quantity of primordial soup before you found something that evolution could get its teeth into.”

    Common Ancestor of Plant Carbon-Fixing Found? 04/16/2001
    A report published in the Proceedings of the National Academy of Sciences claims that a protein similar to the one that fixes carbon from CO2 has been found in green sulfur bacteria. The protein appears to perform some other functions in the bacterium as well.

    Biological Motor Caught on Film 04/18/2001
    The Japanese have succeeded in capturing images of ATP Synthase, the world’s tiniest motor, according to Nature Science Update. This incredibly small proton motor rotates at thousands of RPM and cranks out ATP molecules, the energy currency for all living things. Your body has uncounted trillions of these motors spinning right now, providing the energy for every heartbeat, muscle contraction and chemical process. The Japanese images of the motors show unprecedented detail and, for the first time, actually show the little motor turning. “We couldn’t ever build a motor that small - but nature has,” remarks one scientist. On April 24, Science reported on this story with a picture of how they photographed one of nature’s most “splendid machines.”

    Eye Neurons See Their Way to the Brain 04/20/2001
    Through a series of clever experiments on frogs and fruit flies, researchers at the University of Utah have identified some of the genes responsible for the development of eyes and their nerve connections to the brain. Without the genes, the neurons seem to get lost and go in circles, but with the gene, the neurons “see” their way to the proper connection point in the brain.

    Article 04/17/2001: Tom Bethell, writing for the American Spectator an article entitled “The Road to Nowhere” (reproduced on the Discovery Institute website, claims “The genome isn’t a code, and we can”t read it.” He reports how the human genome is far more complex than earlier claimed, because the old one-gene one-protein hypothesis appears to be incorrect; a gene can code for several tens of proteins. The article contains statements by Dr. David Baltimore, James Watson and other prominent DNA scientists to the effect that it may be many decades before we understand how the human genome works and what it says; predictions that our computers could crack the code appear overly optimistic.

    Cell News 04/16/2001: Two articles from the Journal of Cell Biology on wonders in the cell, summarized in EurekAlert: (1) A story about control mechanisms involved in cell division, and (2) A story about how yeast cells are able to keep their nuclei in the center. There is also a story summarized in Science Now describing how plants can sense the cold and adjust their processes to keep from freezing. And on April 18, (4) EurekAlert published a summary of a study that explores how white blood cells are able to find their way to infected areas.

    Our Humanness: Gene Sequence, Gene Activity, or Something More? 04/24/2001
    Both Nature and Scientific American summarized today the flavor of discussions from the Human Genome Meeting that just concluded in Edinburgh; apparently, it is not the sequence of our genes, but the amount of activity in the way they are expressed, that makes us human. Gene sequences between humans and chimpanzees differ by as little as 1.3%. Something else is clearly involved in making us what we are. A German scientist found that although the sequences of genes in apes and people are similar, their expression in the brain is poles apart. The genomes of all mammals are so similar that “it’s hard to understand how they can produce such different animals, says Sue Povey, who works on human gene mapping at University College London in England. What drives similar genes to have such divergent degrees of expression, if it is not DNA? No one knows. On April 27, ABC News posted a story about the relation of the genome to the “proteome,” the protein library, with some illustrations of how proteins work.

    Did Crystal Power Make Proteins Southpaws? 05/01/2001
    NASA astrobiologists have published a paper in the Proceedings of the National Academy of Sciences on experimental evidence that calcite crystals and other minerals might selectively concentrate left- and right-handed amino acids (click here for summaries in Scientific American or Nature. NASA’s Astrobiology Site also has a lay-audience version of the story.) All living organisms incorporate only left-handed amino acids into their protein chains; the choice of left or right appears to be arbitrary, but life depends on 100% of one hand or the other. In these experiments, the team achieved yields of just under 10% preference for one hand. This is significant for origin of life scenarios, the paper concludes, because minerals could have not only concentrated one hand over the other but also arranged them into chains.

    Proteins Are Vastly More Complicated than Previously Realized 05/03/2001
    That’s the title of a report today on SciNews. Biochemists are realizing that proteins are not just static 3-D shapes; they are subject to dynamic forces of stretching, pushing and pulling that affect their function. Protein folding has been likened to a kind of delicate origami, but researchers at the University of Washington take the analogy further: “Imagine trying to fold a delicate origami crane from silk paper - while you’re in a wind tunnel. In fact, imagine trying to fold the origami in a wind tunnel while countless other hands are also pulling at the paper. And yet, that’s comparable in complexity to what the hundreds of thousands of cells and proteins are doing in your body right now.” Dr. Viola Vogel is in the forefront of this new field that studies how protein functions change under dynamic stresses. “We are very excited about this because we believe a new field is being born: non-equilibrium protein structure-function analysis. It’s very exciting to think about how nature regulates and controls function. We went from viewing the cell as a bag full of proteins a decade ago to a view of the cell as a dynamic place where proteins assemble and change under mechanical forces,” she says. An update summary 05/29/2001 in Scientific American claims that proteins are moving all the time, very fast, and that these motions affect their functions.

    Astrobiologists Give Up on Primordial Soup, Look to Comets 05/21/2001
    A feature story in Science News May 19, 2001 (pp. 317-319) deals with origin of life woes. In “Cosmic Chemistry Gets Creative,” Jessica Gorman rounds up the usual suspects (McKay, Chyba, Bada, et al) to put a positive spin on a desperate situation: the old Miller primordial soup theory appears dead, so they are looking to seeding earth with prebiotic chemicals via comets. Scientists are blasting material together to try to form building blocks of life in hypothetical comets, and see if they could survive the fiery plunge to earth.

    Distributed Shipping Design Found in Nerve Cells 05/25/2001
    Researchers at the Howard Hughes Medical Institute have found that dendrites, the long stems on neurons, have the ability to manufacture their own proteins. Erin M. Schuman, Institute investigator from CalTech, remarked on the economy and efficiency of this design: “It’s like the difference between centralized and distributed freight shipping,” she said. “With central shipping, you need a huge number of trucks that drive all over town, moving freight from a central factory. But with distributed shipping, you have multiple distribution centers that serve local populations, with far less transport involved.”

    Cell Nucleus Surface More Complicated than Expected 06/14/2001
    Researchers at North Carolina State University made an unexpected discovery: cell nuclear membranes are groovy. The surfaces of some plant cells were found to contain tunnels and grooves with complex channels used by RNA, enzymes and organelles to enter and exit the cell’s master control center. They found that parts of the endoplasmic reticulum (a system of folded channels) passes right into the center of the nucleus, and watched organelles moving along actin filaments in the grooves. Dr. Nina Allen, botanist at the university, said, “The implication of this discovery is that we need to look more closely at communications between the nucleus and the cytoplasm, and we need to understand why these grooves and tunnels are there.”

    What they witnessed was a highly complex transportation system at work. Imagine a city with overlapping monorails shuttling cargo loads in all directions, with loading docks, signalling systems and security checks: this is what goes on in miniature inside the cell. The picture of the cell that is being slowly revealed to our instruments is one of bewildering complexity.

    PNAS Explores How Cells Transport Freight 06/19/2001
    The June 19 Proceedings of the National Academy of Sciences has a colloquium section devoted to molecular kinesis, a fancy term for the study of how cells ship their freight around, such as from nucleus to cytoplasm and back. Some common themes in the colloquium are: (1) Cells are much more complex than we previously thought; (2) There is still much we don’t know; (3) Any slip-ups in the machinery mean disease or death.

    Bacteria Genes Evolved, Not Hopped, into Human Genome 06/25/2001
    Evolutionists have come up with an explanation for 113 genes that were earlier reported to be candidates for horizontal gene transfer from bacteria to humans. They say that the genes have a common ancestor, but that some lines lost the gene. The explanation is published in Nature Science Update, which claims that “the gold standard for establishing whether horizontal gene transfer has occurred is drawing up evolutionary trees to trace a candidate gene’s inheritance.”

    Cells Use Triple Fail-Safe Systems During Division 06/28/2001
    During cell division, when millions of DNA base pairs are duplicating, a lot could go wrong and lead to runaway duplication – e.g., cancer. Now, scientists have found at least three mechanisms that drastically reduce the chance of failure. According to Scientific American. Joachim Li at the University of California, San Francisco, said, “We eventually demonstrated that not one or two but at least three distinct controls have to be turned off simultaneously for cells to start replicating again. This is unlikely to happen by accident, so this multilayered protection is virtually fail-safe. That’s what you want when there is no room for error.”
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    started a topic Archive: Cell Trends Too

    Archive: Cell Trends Too


    This thread presents evidence to back up my opinion that the apparent complexity and sophistication of cellular mechanisms is growing with time and additional research.
    My source is

    New Role for Ubiquitous ATP Molecule: Pain Trigger 10/26/2000
    Nature’s Feature of the Week reports on a new role for the amazing ATP molecule. “ATP – adenosine triphosphate – is to the body what oil is to the industrialized world. Produced in virtually every cell of every living thing, it is the primary power source for reactions as diverse as muscle contraction, protein synthesis and heat generation. Now new research confirms a very different role for ATP – as a trigger for pain receptors.”

    Multiple functions for parts is an example of design efficiency and elegance. The 1997 Nobel prize winners in chemistry found that ATP in living things from single-celled organisms to man is generated by a complex three-phase proton motor. One biologist was heard to say that if these mechanisms stopped working, you would be dead before you hit the ground.

    Cells Do Their Own Triage 01/30/2001
    According to an article in this week's Science News (Vol 159 p. 54, 01/27/01), specialized proteins perform emergency first aid and morgue duty. Proteins dubbed "chaperones" are able to recognize badly-folded proteins and fix them. Another protein acts as a coroner and breaks apart proteins that are beyond repair.

    Proteins cannot perform their duties if they are not folded properly. The folding gives the protein chain (a string of amino acids) its three-dimensional structure, which is essential to its function. This kind of intricate molecular origami is accomplished partly by the affinities of parts of the molecule for each other due to the specific order of amino acids (that is why the sequence of amino acids cannot tolerate much error), and partly with the assistance of helper enzymes. But mistakes happen. How does the cell recognize an error?

    Gentlemen, Start Your Engines 01/23/2001
    The Proceedings of the National Academy of Sciences describe more findings about our amazing molecular motor, ATP Synthase (a complex enzyme that won its elucidators the 1997 Nobel Prize). Your body has trillions of these tiny motors in the mitochondria of cells. Each motor is 200,000 times smaller than a pinhead, and rotates at 6000 RPM, generating three ATP molecules per revolution (if these motors stopped, you would be dead before you hit the floor). The motor is reversible and can be used as a proton pump. ATP is the energy currency of every living thing. An active person can generate his/her body weight in ATP in a day’s time. Today’s report describes more details of the rotor and stator, and contains color diagrams of these amazing molecular machines on which all life, even bacteria, depends.

    “Dead” Plant Cells Regulate Their Water Intake 01/26/2001
    Xylem isn’t just deadwood, according to a new study in the journal Science. The woody cells respond to changes in salinity and mineral content, and can regulate the speed at which water rises in the stem. How a tree can pump water up hundreds of feet is still a feat not thoroughly understood, and now this study casts new light on a function of cells thought to be inert. Reported in ScienceNOW 29 December 2000: 2

    New Function Discovered for Human Brain Glia Cells 01/29/2001
    Glia cells, which make up 90% of the human brain, are not as functionless as earlier believed, according to a story in the journal ScienceNOW 26 January 2001: 1 .They play an important role in determining how many connections the neurons can make with each other.

    Satoshi P. Tsunoda, Robert Aggeler, Masasuke Yoshida, and Roderick A. Capaldi
    Rotation of the c subunit oligomer in fully functional F1Fo ATP synthase
    PNAS published January 23, 2001, 10.1073/pnas.031564198

    Newly-Published Human Genome Reveals Mysteries 02/12/2001
    The Los Angeles Times has two stories about surprising discoveries being made now that the fully-mapped human genome is being published (on Charles Darwin’s birthday, by the way). The first is that differences between humans are small. The other is that our functional genome is only about twice that of a fly or roundworm and only a hundred more genes than a mouse. Apparently the rest of our genome contains a great deal of transposed material from other species, which may explain much of so-called “junk DNA.” Nature is providing a new online news and information service on the human genome, the Genome Gateway, and also has several gene-related stories on its daily Nature Science Update page. Not to be outdone, Science has a special issue devoted to the human genome, free to all users.

    Protein Folding Regulated by Quality Control 02/20/2001
    The upcoming Feb. 29 issue of the Philosophical Transactions of the Royal Society is devoted to protein folding and disease. As we reported earlier, it has been discovered that cells have chaperones that supervise and proofread the folding of amino acid chains of which proteins are composed. In the preface to this edition of the Transactions, the editors speak of the quality control processes of the cell, stating that “Failure to satisfy the quality control process, particularly by proteins resulting from genetic mutations, is associated with a wide range of diseases including cystic fibrosis and diabetes.” (Normally, misfolded proteins are “rigorously excluded” from the cell.) “And because it is so strongly linked to fundamental cellular activities, any aberrations in the folding process will lead to malfunctioning of the organism involved, and hence to disease.”

    Cells are much, much more than building blocks or aggregates of organic molecules: they have central storage of information and detailed processes for carrying out instructions and correcting mistakes. Without these, life could not exist. Considering how precise the quality controls must still be maintained in this cursed, mutating world, Dr. Joseph Henson used to say, “The surprising thing is not that we get sick, but that we are ever well.”

    Biological Motor Has Tight Specifications 02/21/2001
    Scientific American has an article about dynein, a protein essential to cell division, which the article describes as a protein motor composed of 12 parts. Researchers have found that “in order to function properly, dynein’s components must have a certain form and must fit together in a particular way. Problems with even a single component, it turns out, can have disastrous effects.” This line of research may help lead to anticancer treatments by disarming dynein in cancer cells. Click here for the Ohio University press release with further details.

    Genetic Potential Increases 02/22/2001
    New findings provide further evidence that the old “one gene – one enzyme” paradigm is incorrect. Researchers at Johns Hopkins have found that two genes in combination can make multiple proteins through a process called trans-splicing. Apparently messenger RNA can simultaneously read both halves of a DNA molecule in opposite directions and splice them together. This increases the protein-generating potential of the human genome, which was announced earlier this week to have fewer genes (around 30,000) than expected.
    This means the DNA stores vastly more information than could be stored on one strand, the other being just a template. It is just one of many marvels sure to come out of our ongoing investigation of the genetic code. The whole story of transcription by messenger RNA to transfer RNA to protein, accompanied by a host of specialized enzymes, is dazzlingly complex and exquisite in its precision and speed.

    Life From Nonlife Made Simple 03/05/2001
    “Missing Links Made Simple” is the voilà! title from an article in today’s Nature, summarizing an experiment announced in the Proceedings of the National Academy of Sciences. The vexing problem of the origin of proteins, specifically how to get amino acids to link up with peptide bonds, has evaded naturalistic solution for decades. But researchers from Scripps Institute have found that short segments of Transfer RNA (tRNA) assisted by puromycin molecules carrying amino acids can form peptide bonds without the assistance of ribosomes, provided some imidazole is around to help. They claim that this process also encodes some information into the chain: the tRNA bound to the puromycin better when their sequences matched. “The evolution of this control over protein manufacture holds the key to the emergence of the living from the non-living worlds.”

    If-Then Algorithm Found in Brain Wiring 03/08/2001
    Scientists at UC San Francisco have found a wiring algorithm for nerve cells in developing embryos. Nerve cells, or axons, use neurotransmitters to guide their growing ends toward their proper connection sites: attractants call out “this way” and repellants say “keep out.” But what if both an attractant and a repellant appear at the same time? They found that the repellant wins the draw, and the repellant receptor then physically binds to the attractant receptor to deactivate it.

    Update 03/12/2001: Scientific American summarizes a report in the journal Science about how growing tips of nerve cells send signals. Scientists found that they use short bursts of calcium, lasting only 300 milliseconds, to scout out their surroundings as they grow toward their destinations.

    Biochemist Claims Ancestor to ATP Enzymes Found 03/09/2001
    A Purdue biology professor claims that acetate kinase resembles the structure and function of other metabolizing enzymes in bacteria and archaea, and may be the common ancestor of these enzymes that utilize ATP for energy.… Notice that even though the these enzymes have an outward resemblance (a similar fold), they have entirely different amino acid sequences.

    How Do Cilia Move in Concert? 03/12/2001
    Cilia, the microscopic hair-like projections on some single-celled organisms such as Paramecium and in the human body such as the lining of the esophagus and digestive tract, have long puzzled biologists with their ability to beat in synchronized wave patterns. In the March 22 issue of the Biological Proceedings of the Royal Society, two Israeli scientists use 3D modelling to simulate how this motion is achieved and find that the viscosity of the surrounding medium influences the motion.

    Update 03/14/2001: Nature has just published a paper … on the bacterial flagellum. The flagellum is now seen as a reversible helical propeller that allows the bacterium to switch between running and tumbling modes.

    Natural Amplifier Found in Inner Ear 03/27/2001
    A paper in the Proceedings of the National Academy of Sciences, summarized here in Scientific American, describes new findings about how ears work. A newly discovered “motor protein” named prestin acts as an amplifier. Found on the tips of the microscopic outer hair cells in the cochlea, it takes the electrical energy converted by the inner hair cells and converts it back into mechanical energy, thus amplifying the sound.

    The pressure waves in the air that make up sound can be as low as 2 x 10-5 N/m2, yet the sensitivity of the eardrum, the ossicles, and the cochlea to these whispers of sound is astounding – the ear can handle intensities of a million million to one. The eardrum’s microscopic vibrations are amplified by the bones of the middle ear twentyfold as they transmit from air to fluid in the inner ear, where further amplification takes place. This article provides just one more detail on the process. Like all other proteins, prestin is made up of hundreds of amino acids, all left-handed, that are arranged in a precise sequence to allow it to perform its job as an amplifier

    Eye Does Image Processing 03/28/2001
    A scientist at U C Berkeley claims that stacks of cells in the retina process the image received by the photoreceptors, then sends 12 parallel data sets to the brain that contain only the bare essentials of the image. “What the eye sends to the brain are mere outlines of the visual world, sketchy impressions that make our vivid visual experience all the more amazing,” the report claims.
    Last edited by bob b; October 15, 2006, 10:25 AM.