Mystery at the heart of life

_{Denyse O'Leary

December 21, 2014

Cell biology, Intelligent Design, News}

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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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Structural characterization of the substrate transfer mechanism in Hsp70/?Hsp90 folding machinery mediated by ?Hop doi:10.1038/ncomms6484 In eukarya, chaperones Hsp70 and ?Hsp90 act coordinately in the folding and maturation of a range of key proteins with the help of several co-chaperones, especially ?Hop. Although biochemical data define the ?Hop-mediated Hsp70–?Hsp90 substrate transfer mechanism, the intrinsic flexibility of these proteins and the dynamic nature of their complexes have limited the structural studies of this mechanism. http://www.nature.com/ncomms/2014/141119/ncomms6484/full/ncomms6484.htmlDionisio_{December 23, 2014
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Molecular chaperones in protein folding and proteostasis doi:10.1038/nature10317 Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance. http://www.nature.com/nature/journal/v475/n7356/full/nature10317.htmlDionisio_{December 23, 2014
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Protein Folding and the Role of Chaperone Proteins in Neurodegenerative Disease doi:10.1016/B978-008045046-9.00524-6 Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation, and intra- or extraneuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defense against misfolded, aggregation-prone proteins, and are among the most potent suppressors of neurodegeneration known for animal models of human disease. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of protection by chaperones against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation. http://www.sciencedirect.com/science/article/pii/B9780080450469005246Dionisio_{December 23, 2014
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Molecular Chaperones in Cellular Protein Folding: The Birth of a Field DOI: http://dx.doi.org/10.1016/j.cell.2014.03.029Dionisio_{December 23, 2014
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Unraveling the Mechanism of Chaperone-Mediated Protein Folding Chaperones are special proteins that aid the folding, unfolding, assembly and disassembly of other proteins. Chaperones rely on a large and diverse set of co-chaperones that regulate their specificity and function. How these co-chaperones regulate protein folding and whether they have chaperone-independent biological functions is largely unknown. http://www.rochester.edu/data-science/calendar/2014/02/unraveling-the-mechanism-of-chaperone-mediated-protein-folding.htmlDionisio_{December 23, 2014
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Polyphosphate Is a Primordial Chaperone DOI: http://dx.doi.org/10.1016/j.molcel.2014.01.012 Composed of up to 1,000 phospho-anhydride bond-linked phosphate monomers, inorganic polyphosphate (polyP) is one of the most ancient, conserved, and enigmatic molecules in biology. Here we demonstrate that polyP functions as a hitherto unrecognized chaperone. We show that polyP stabilizes proteins in vivo, diminishes the need for other chaperone systems to survive proteotoxic stress conditions, and protects a wide variety of proteins against stress-induced unfolding and aggregation. In vitro studies reveal that polyP has protein-like chaperone qualities, binds to unfolding proteins with high affinity in an ATP-independent manner, and supports their productive refolding once nonstress conditions are restored. Our results uncover a universally important function for polyP and suggest that these long chains of inorganic phosphate may have served as one of nature’s first chaperones, a role that continues to the present day. [?] http://www.cell.com/molecular-cell/abstract/S1097-2765(14)00073-2Dionisio_{December 23, 2014
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DnaK Functions as a Central Hub in the E. coli Chaperone Network DOI: http://dx.doi.org/10.1016/j.celrep.2011.12.007 Cellular chaperone networks prevent potentially toxic protein aggregation and ensure proteome integrity. Here, we used Escherichia coli as a model to understand the organization of these networks, focusing on the cooperation of the DnaK system with the upstream chaperone Trigger factor (TF) and the downstream GroEL. Quantitative proteomics revealed that DnaK interacts with at least ?700 mostly cytosolic proteins, including ?180 relatively aggregation-prone proteins that utilize DnaK extensively during and after initial folding. Upon deletion of TF, DnaK interacts increasingly with ribosomal and other small, basic proteins, while its association with large multidomain proteins is reduced. DnaK also functions prominently in stabilizing proteins for subsequent folding by GroEL. These proteins accumulate on DnaK upon GroEL depletion and are then degraded, thus defining DnaK as a central organizer of the chaperone network. Combined loss of DnaK and TF causes proteostasis collapse with disruption of GroEL function, defective ribosomal biogenesis, and extensive aggregation of large proteins. http://www.cell.com/cell-reports/abstract/S2211-1247(11)00017-9?_returnURL=http%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124711000179%3Fshowall%3DtrueDionisio_{December 23, 2014
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#12 PeterJ Interesting. Thanks. Didn't know weed smoking was legal in K-tan :)Dionisio_{December 23, 2014
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Has anyone checked this out yet? http://www.newscientist.com/article/mg22430000.900-is-the-answer-to-life-the-universe-and-everything-37.htmlPeterJ_{December 22, 2014
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Networking galore: intermediate filaments and cell migration. doi: 10.1016/j.ceb.2013.06.008. Intermediate filaments (IFs) are assembled from a diverse group of evolutionarily conserved proteins and are specified in a tissue-dependent, cell type-dependent, and context-dependent fashion in the body. IFs are involved in multiple cellular processes that are crucial for the maintenance of cell and tissue integrity and the response and adaptation to various stresses, as conveyed by the broad array of crippling clinical disorders caused by inherited mutations in IF coding sequences. Accordingly, the expression, assembly, and organization of IFs are tightly regulated. Migration is a fitting example of a cell-based phenomenon in which IFs participate as both effectors and regulators. With a particular focus on vimentin and keratin, we here review how the contributions of IFs to the cell's mechanical properties, to cytoarchitecture and adhesion, and to regulatory pathways collectively exert a significant impact on cell migration. http://www.ncbi.nlm.nih.gov/pubmed/23886476Dionisio_{December 22, 2014
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The biological functions of miRNAs DOI: http://dx.doi.org/10.1016/j.tcb.2014.11.004 Despite their clear importance as a class of regulatory molecules, pinpointing the relevance of individual miRNAs has been challenging. Studies querying miRNA functions by overexpressing or silencing specific miRNAs have yielded data that are often at odds with those collected from loss-of-functions models. In addition, knockout studies suggest that many conserved miRNAs are dispensable for animal development or viability. In this review, we discuss these observations in the context of our current knowledge of miRNA biology and review the evidence implicating miRNA-mediated gene regulation in the mechanisms that ensure biological robustness. http://www.cell.com/trends/cell-biology/abstract/S0962-8924(14)00197-4Dionisio_{December 22, 2014
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Close Encounter of the Third Kind: The ER Meets Endosomes at Fission Suites DOI: http://dx.doi.org/10.1016/j.devcel.2014.12.008 The endoplasmic reticulum (ER) forms functional contacts with several cellular organelles and regulates processes such as mitochondrial fission. In a recent issue of Cell, Rowland et al. (2014) extend these findings to endosomes, showing that the ER contacts endosomes at sites containing the WASH subunit FAM21, where it forecasts fission events. http://www.cell.com/developmental-cell/abstract/S1534-5807(14)00805-3?elsca1=etoc&elsca2=email&elsca3=1534-5807_20141222_31_6_&elsca4=Cell%20PressDionisio_{December 22, 2014
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#6 Mauna Yes, and sometimes even using the same chaperones! Now, where is the instructions manual for those procedures? Let's ask gpuccio! :)Dionisio_{December 22, 2014
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#3 Seversky
No argument, there are still mysteries at the heart of the cell but we still aren’t any closer to deciding if there was some intelligence involved.
Well, there are some folks out there who have decided for everybody else to tell our kids in public school textbooks that it's a known fact that it all happened by the power of the magic formula RV+NS+T=E! As you well said, there are still mysteries at the heart of the biological systems.Dionisio_{December 22, 2014
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The thing about folding proteins is that 2 cells consistently fold them the SAME way. That is, it can't be computationally hard to randomly fold a protein at Point A into Position B. The fact that this random fold is NOT useful requires that there be "assembly instructions". You can start with a bag containing all of the pieces of a tent, but if you do NOT: 1) assemble them is something real close to the right order, and 2) emplace the pieces in SPECIFIC places, what you get is NOT a "tent". Especially if you throw the fabric on the ground and pound the stakes through the middle of it. The fact that 2 isolated cells (isolated in time is probably more instructive than isolated in space) perform the assembly EXACTLY the same way argues strongly against any random process.mahuna_{December 21, 2014
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1. Marks, R. J. II et al. 2013. Biological Information: New Perspectives. Hackensack, NJ: World Scientific Publishing Co. Pte. Ltd. - Book available in sections at http://www.worldscientific.com/worldscibooks/10.1142/8818#t=toc 2. Kapranov P., et al. 2005. Examples of complex architecture of the human transcriptome revealed by RACE and high density tiling arrays. Genome Res 15:987–997. Available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1172043/ 3. Birney E., et al. (Encode Project Consortium) 2007. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816. Available at http://www.nature.com/nature/journal/v447/n7146/full/nature05874.html 4. Itzkovitz S., Hodis E., Sega E. 2010. Overlapping codes within protein-coding sequences. Genome Res. 20:1582–1589. Available at http://www.ncbi.nlm.nih.gov/pubmed/20841429 5. He H., et al. 2007. Mapping the C. elegant noncoding transcriptome with a whole genome tiling microarray. Genome Res 17:1471-1477. Available at http://www.ncbi.nlm.nih.gov/pubmed/17785534 6. http://www.mcld.co.uk/hiv/?q=HIV%20genome 7. http://nsmn1.uh.edu/dgraur/niv/sabath_phd_thesis.pdfbornagain77_{December 21, 2014
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as to: "but we still aren’t any closer to deciding if there was some intelligence involved." But WE are very decided that unguided processes were not involved! :) Multiple Overlapping Genetic Codes Profoundly Reduce the Probability of Beneficial Mutation George Montañez 1, Robert J. Marks II 2, Jorge Fernandez 3 and John C. Sanford 4 - published online May 2013 Excerpt: In the last decade, we have discovered still another aspect of the multi- dimensional genome. We now know that DNA sequences are typically “ poly-functional” [38]. Trifanov previously had described at least 12 genetic codes that any given nucleotide can contribute to [39,40], and showed that a given base-pair can contribute to multiple overlapping codes simultaneously. The first evidence of overlapping protein-coding sequences in viruses caused quite a stir, but since then it has become recognized as typical. According to Kapronov et al., “it is not unusual that a single base-pair can be part of an intricate network of multiple isoforms of overlapping sense and antisense transcripts, the majority of which are unannotated” [41]. The ENCODE project [42] has confirmed that this phenomenon is ubiquitous in higher genomes, wherein a given DNA sequence routinely encodes multiple overlapping messages, meaning that a single nucleotide can contribute to two or more genetic codes. Most recently, Itzkovitz et al. analyzed protein coding regions of 700 species, and showed that virtually all forms of life have extensive overlapping information in their genomes [43]. 38. Sanford J (2008) Genetic Entropy and the Mystery of the Genome. FMS Publications, NY. Pages 131–142. 39. Trifonov EN (1989) Multiple codes of nucleotide sequences. Bull of Mathematical Biology 51:417–432. 40. Trifanov EN (1997) Genetic sequences as products of compression by inclusive superposition of many codes. Mol Biol 31:647–654. 41. Kapranov P, et al (2005) Examples of complex architecture of the human transcriptome revealed by RACE and high density tiling arrays. Genome Res 15:987–997. 42. Birney E, et al (2007) Encode Project Consortium: Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799–816. 43. Itzkovitz S, Hodis E, Sega E (2010) Overlapping codes within protein-coding sequences. Genome Res. 20:1582–1589. http://www.worldscientific.com/doi/pdf/10.1142/9789814508728_0006 Multiple Overlapping Genetic Codes Profoundly Reduce the Probability of Beneficial Mutation George Montañez 1, Robert J. Marks II 2, Jorge Fernandez 3 and John C. Sanford 4 - May 2013 Conclusions: Our analysis confirms mathematically what would seem intuitively obvious - multiple overlapping codes within the genome must radically change our expectations regarding the rate of beneficial mutations. As the number of overlapping codes increases, the rate of potential beneficial mutation decreases exponentially, quickly approaching zero. Therefore the new evidence for ubiquitous overlapping codes in higher genomes strongly indicates that beneficial mutations should be extremely rare. This evidence combined with increasing evidence that biological systems are highly optimized, and evidence that only relatively high-impact beneficial mutations can be effectively amplified by natural selection, lead us to conclude that mutations which are both selectable and unambiguously beneficial must be vanishingly rare. This conclusion raises serious questions. How might such vanishingly rare beneficial mutations ever be sufficient for genome building? How might genetic degeneration ever be averted, given the continuous accumulation of low impact deleterious mutations? http://www.worldscientific.com/doi/pdf/10.1142/9789814508728_0006 Biological Information - Overlapping Codes 10-25-2014 by Paul Giem - video https://www.youtube.com/watch?v=OytcYD5791k&index=4&list=PLHDSWJBW3DNUUhiC9VwPnhl-ymuObyTWJ Overlapping Genetic Codes 12-6-2014 by Paul Giem - video https://www.youtube.com/watch?v=3WZy0n60_ZUbornagain77_{December 21, 2014
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Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.
Yes, you can say they are like a city or like a factory or whatever the current analogy is but it's still an analogy. They are also very different from human cities and factories in so many ways. Do the similarities outweigh the differences or vice versa and by what measure? This is still the "I can't believe it's not butter" style of argument, it's so complex I can't believe it wasn't designed. But our instinctive reaction to perceived complexity proves nothing, one way or the other. No argument, there are still mysteries at the heart of the cell but we still aren't any closer to deciding if there was some intelligence involved.Seversky_{December 21, 2014
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' The cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture.' Sounds like my Catholic Church, though Francis seems to have some work on his hands making it 'fantastically' efficient. At least, as regards the Curia and the Vatican bank.Axel_{December 21, 2014
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The unfathomed complexity inherent in a 'simple' cell cannot be overstated. The folding of a single protein, out of the billion proteins present in a cell*, clearly gets this point across. It is known that proteins do not find their final folded form by random processes:
The Humpty-Dumpty Effect: A Revolutionary Paper with Far-Reaching Implications - Paul Nelson - October 23, 2012 Excerpt: Anyone who has studied the protein folding problem will have met the famous Levinthal paradox, formulated in 1969 by the molecular biologist Cyrus Levinthal. Put simply, the Levinthal paradox states that when one calculates the number of possible topological (rotational) configurations for the amino acids in even a small (say, 100 residue) unfolded protein, random search could never find the final folded conformation of that same protein during the lifetime of the physical universe. Therefore, concluded Levinthal, given that proteins obviously do fold, they are doing so, not by random search, but by following favored pathways. The challenge of the protein folding problem is to learn what those pathways are. http://www.evolutionnews.org/2012/10/a_revolutionary065521.html Confronting Science’s Logical Limits – John L. Casti – 1996 Excerpt: It has been estimated that a supercomputer applying plausible rules for protein folding would need 10^127 years to find the final folded form for even a very short sequence consisting of just 100 amino acids. (The universe is 13.7 x 10^9 years old). In fact, in 1993 Aviezri S. Fraenkel of the University of Pennsylvania showed that the mathematical formulation of the protein-folding problem is computationally “hard” in the same way that the traveling-salesman problem is hard. http://www.cs.virginia.edu/~robins/Confronting_Sciences_Logical_Limits.pdf
That no one really has a firm clue how proteins are finding their final folded form is made clear by the immense time (a few weeks) it takes for a few hundred thousand computers, which are linked together, to find the final folded form of a single protein:
A Few Hundred Thousand Computers vs. (The Folding Of) A Single Protein Molecule – video https://www.youtube.com/watch?v=lHqi3ih0GrI
The reason why finding the final form of a folded protein is so hard for super-computers is that it is like the 'traveling salesman' puzzle, which are 'Just about the meanest problems you can set a computer (on) '.
DNA computer helps traveling salesman - Philip Ball - 2000 Excerpt: Just about the meanest problems you can set a computer (on) belong to the class called 'NP-complete'. The number of possible answers to these conundrums, and so the time required to find the correct solution, increases exponentially as the problem is scaled up in size. A famous example is the 'traveling salesman' puzzle, which involves finding the shortest route connecting all of a certain number of cities.,,, Solving the travelling-salesman problem is a little like finding the most stable folded shape of a protein's chain-like molecular structure -- in which the number of 'cities' can run to hundreds or even thousands. http://www.nature.com/news/2000/000113/full/news000113-10.html
of note: protein folding is found to be 'NP-complete'
Combinatorial Algorithms for Protein Folding in Lattice Models: A Survey of Mathematical Results – 2009 Excerpt: Protein Folding: Computational Complexity 4.1 NP-completeness: from 10^300 to 2 Amino Acid Types 4.2 NP-completeness: Protein Folding in Ad-Hoc Models 4.3 NP-completeness: Protein Folding in the HP-Model http://www.cs.brown.edu/~sorin/pdfs/pfoldingsurvey.pdf
Yet it is exactly this type of ‘traveling salesman problem’ that quantum computers excel at:
Speed Test of Quantum Versus Conventional Computing: Quantum Computer Wins - May 8, 2013 Excerpt: quantum computing is, "in some cases, really, really fast." McGeoch says the calculations the D-Wave excels at involve a specific combinatorial optimization problem, comparable in difficulty to the more famous "travelling salesperson" problem that's been a foundation of theoretical computing for decades.,,, "This type of computer is not intended for surfing the internet, but it does solve this narrow but important type of problem really, really fast," McGeoch says. "There are degrees of what it can do. If you want it to solve the exact problem it's built to solve, at the problem sizes I tested, it's thousands of times faster than anything I'm aware of. If you want it to solve more general problems of that size, I would say it competes -- it does as well as some of the best things I've looked at. At this point it's merely above average but shows a promising scaling trajectory." http://www.sciencedaily.com/releases/2013/05/130508122828.htm
Thus we have evidence that proteins are very likely finding their final folded form by some method of quantum computation. ,,,, If so, this far exceeds anything man has yet accomplished in regards to quantum computation although billions have been spent trying! Here is the paper that proved that protein folding belongs to the physics of the quantum world and that protein folding does not belong to the physics of the classical world:
Physicists Discover Quantum Law of Protein Folding – February 22, 2011 Quantum mechanics finally explains why protein folding depends on temperature in such a strange way. Excerpt: Their astonishing result is that this quantum transition model fits the folding curves of 15 different proteins and even explains the difference in folding and unfolding rates of the same proteins. That's a significant breakthrough. Luo and Lo's equations amount to the first universal laws of protein folding. That’s the equivalent in biology to something like the thermodynamic laws in physics. http://www.technologyreview.com/view/423087/physicists-discover-quantum-law-of-protein/
And here is a paper outlining that quantum computation is indeed possible in proteins:
Quantum states in proteins and protein assemblies: The essence of life? – STUART HAMEROFF, JACK TUSZYNSKI Excerpt: It is, in fact, the hydrophobic effect and attractions among non-polar hydrophobic groups by van der Waals forces which drive protein folding. Although the confluence of hydrophobic side groups are small, roughly 1/30 to 1/250 of protein volumes, they exert enormous influence in the regulation of protein dynamics and function. Several hydrophobic pockets may work cooperatively in a single protein (Figure 2, Left). Hydrophobic pockets may be considered the “brain” or nervous system of each protein.,,, Proteins, lipids and nucleic acids are composed of constituent molecules which have both non-polar and polar regions on opposite ends. In an aqueous medium the non-polar regions of any of these components will join together to form hydrophobic regions where quantum forces reign. http://www.tony5m17h.net/SHJTQprotein.pdf
* A given cell may make more than 10,000 different proteins, and typically contains more than a billion protein molecules at any one time. http://www.netfuture.org/2012/May1012_184.html#2bornagain77_{December 21, 2014
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