Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
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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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The molecular circadian clock orchestrates the daily cyclical expression of thousands of genes. Unraveling the molecular aspects of such interplays is likely to reveal new therapeutic strategies towards the treatment of metabolic disorders.
Chromatin Dynamics of Circadian Transcription Lorena Aguilar-Arnal and Paolo Sassone-Corsi Curr Mol Biol Rep. 1(1): 1–9. doi: 10.1007/s40610-015-0001-7

Complex complexity. :)Dionisio_{October 7, 2016
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The circadian clock has a profound effect on gene regulation, controlling rhythmic transcript accumulation for up to half of expressed genes in eukaryotes. Evidence also exists for clock control of mRNA translation, but the extent and mechanisms for this regulation are not known. [...] clock control of eEF-2 activity promotes rhythmic translation of specific mRNAs.
Circadian clock regulation of mRNA translation through eukaryotic elongation factor eEF-2. Caster SZ, Castillo K, Sachs MS, Bell-Pedersen D. Proc Natl Acad Sci U S A. 113(34):9605-10. doi: 10.1073/pnas.1525268113.

Dionisio_{October 7, 2016
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Future studies that determine targets and functions of these noncoding RNAs on a genome scale will need to be incorporated. How the constraints on the cost of gene expression constrain other biological circuits such as feedback loops, enzymatic activities, proportional regulation of promoter activities in coexpression networks, or transcriptional networks that are involved in cyclical gene expression still needs to be investigated. Future studies that empirically calculate these parameters over time can ultimately be incorporated into this model to determine total energy use and whether cycling genes contribute to an energy saving mechanism. Future experiments that empirically measure the energetic properties of all of these processes on a genome-wide basis will contribute to our overall knowledge of cycling gene energy usage.
Cycling transcriptional networks optimize energy utilization on a genome scale Guang-Zhong Wang,1 Stephanie L. Hickey,1 Lei Shi,2 Hung-Chung Huang,1,4 Prachi Nakashe,1 Nobuya Koike,1,5 Benjamin P. Tu,2 Joseph S. Takahashi,1,3,* and Genevieve Konopka Cell Rep. 2015 Dec 1; 13(9): 1868–1880. doi: 10.1016/j.celrep.2015.10.043

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Genes expressing circadian RNA rhythms are enriched for metabolic pathways, however, the adaptive significance of cyclic gene expression remains unclear. [...] rhythmic gene expression optimizes the metabolic cost of global gene expression [...] If a protein is not needed at a particular time, its production is shut down. [...] cellular processes that consume energy in the cell that may play a part in cycling gene expressions [...] [:]
[1] the transport of mRNA and protein outside of the nucleus, [2] protein folding and misfolding [...] , [3] alternative splicing [4] DNA repair
[...] this needs to be investigated further especially with regards to translational efficiency [...]
Cycling transcriptional networks optimize energy utilization on a genome scale Guang-Zhong Wang,1 Stephanie L. Hickey,1 Lei Shi,2 Hung-Chung Huang,1,4 Prachi Nakashe,1 Nobuya Koike,1,5 Benjamin P. Tu,2 Joseph S. Takahashi,1,3,* and Genevieve Konopka Cell Rep. 2015 Dec 1; 13(9): 1868–1880. doi: 10.1016/j.celrep.2015.10.043

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The spindle assembly checkpoint (SAC) is a key mechanism to regulate the timing of mitosis and ensure that chromosomes are correctly segregated to daughter cells. The recruitment of the Mad1 and Mad2 proteins to the kinetochore is normally necessary for SAC activation. This recruitment is coordinated by the SAC kinase Mps1, which phosphorylates residues at the kinetochore to facilitate binding of Bub1, Bub3,
Synthetic Physical Interactions Map Kinetochore-Checkpoint Activation Regions Guðjón Ólafsson and Peter H. Thorpe G3 (Bethesda). 6(8): 2531–2542. doi: 10.1534/g3.116.031930

Complex complexity.Dionisio_{October 6, 2016
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@2077 error correction: professor L.M. of the U of T in Canada did not write (explicitly) that he knew exactly how morphogen gradients form, as it was incorrectly stated @2077. professor L.M. of the U of T in Canada just answered a simple 'yes/no' question affirmatively. A copy of that brief exchange of comments with professor L.M. of the U of T in Canada is available upon request. At some point professor L.M. of the U of T in Canada stated that he won't discuss with me because I don't ask honest questions, whatever that means. I was looking forward to a serious discussion where I could benefit from the professor's knowledge of biology, but he decided to quit. Let's hope that professor L.M. of the U of T in Canada will reconsider his decision and will come back to continue our serious polite discussion on the most interesting biology related issues.Dionisio_{October 6, 2016
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[...] the microtubule-binding properties of the Ska complex may primarily aid in coordinating PP1 recruitment to, or activity at, kinetochores. [...] recruitment is a critical function of the Ska complex for opposing mitotic kinases that destabilize kinetochore-microtubule attachment and that signal the spindle checkpoint. [...] the Ska complex may integrate chromosome alignment at metaphase with full recruitment of PP1, thus opposing spindle checkpoint kinases signaling and promoting the metaphase-anaphase transition.
The human SKA complex drives the metaphase-anaphase cell cycle transition by recruiting protein phosphatase 1 to kinetochores Sushama Sivakumar,1,2,3 Pawe? ? Janczyk,4 Qianhui Qu,2,3 Chad A Brautigam,5 P Todd Stukenberg,4,* Hongtao Yu,2,3,* and Gary J Gorbsky eLife. 5: e12902. doi: 10.7554/eLife.12902

Complex complexity. :)Dionisio_{October 6, 2016
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The next few years of research will impart various degrees of nuances and answers to these and many other intriguing yet unresolved questions and promise to be an exciting time for mitosis investigators.
How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

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[...] there exist important yet unanswered questions that remain tantalizing areas for further research in attachment responsive SAC activity. Some of these questions include: ( a ) what is the precise molecular link between the Ndc80 complex, the key kMT attachment pivot and SAC activity? ( b ) what is the direct or indirect role of the KMN network in SAC silencing in the absence of dynein/dynactin motor machinery? ( c ) does the “Constitutive centromere-associated network” (CCAN) have any role in distinguishing attached vs unattached kinetochores and regulating the SAC?
How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

Dionisio_{October 6, 2016
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Precise knowledge of how kMT attachments trigger the removal of SAC components from kinetochores or how the checkpoint proteins feedback in to the attachment machinery remains elusive. Our understanding of the integration and coordination between kMT attachment and SAC signaling is still very primitive, and definitely warrants extensive deliberation. [...] the exact nature of SAC signaling is poorly understood [...] How such a mechanical sensory signal is transduced into a biochemical signaling cascade remains enigmatic [...]
How the SAC gets the axe: Integrating kinetochore microtubule attachments with spindle assembly checkpoint signaling Shivangi Agarwal and Dileep Varma Bioarchitecture. 5(1-2): 1–12. doi: 10.1080/19490992.2015.1090669

Dionisio_{October 6, 2016
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[...] it is tempting to speculate that there are classes of MAPs that use defined sets of binding motifs and therefore compete with each other for MT real estate (40). This will be an important area for future cryo-EM–based structural studies.
Near-atomic cryo-EM structure of PRC1 bound to the microtubule Elizabeth H. Kellogg,a,b,1 Stuart Howes,c,1,2 Shih-Chieh Ti,d Erney Ramírez-Aportela,e Tarun M. Kapoor,d Pablo Chacón,e and Eva Nogales Proc Natl Acad Sci U S A. 113(34): 9430–9439. doi: 10.1073/pnas.1609903113 PMCID: PMC5003279 Inaugural Article Biophysics and Computational Biology

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Protein folding has been described as both exceedingly complex and remarkably simple We anticipate that this work will open up new avenues for addressing poorly understood aspects of protein-folding kinetics, including the molecular mechanisms of cotranslational and chaperone-assisted folding.
Structure-Based Prediction of Protein-Folding Transition Paths William M. Jacobs, Eugene I. Shakhnovich DOI: http://dx.doi.org/10.1016/j.bpj.2016.06.031 Biophysical Journal Volume 111, Issue Pages 925–936

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gpuccio @2076: Yes, agree it's a very interesting paper, which proves the amazing power of the magic combination of RM+HGT+NS+T+... that has produced such an astonishing complex complexity! :)Dionisio_{October 5, 2016
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There must be something we do not know. Something has been missed or overlooked [...] [...] nothing we put together approaches the complexity that exists in the live cell. [...] even our best simulations and cartoons have an incomplete picture of the environment [...] [...] we do not even know what is in the cell. [...] the strong interactions we thought we understood are not correct [...]
The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

There yet? :) The author of this paper should have asked professor L.M. of the U of T in Canada, who wrote in this very blog that he knew exactly how morphogen gradients form! :)Dionisio_{October 5, 2016
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Dionisio: "The Dark Matter of Biology" Great paper! Here is some special treasure from it:
Cells are like tiny computers. They receive inputs, they perform calculations, and they respond. The calculations they perform are done within signaling networks written in the language of PTMs of proteins. These proteins have already been translated and folded (to the extent that they are folded) using a more basic genetic code written in the DNA of the organism. Using the computer analogy, the genetic code, written in DNA, acts like the operating system of the cell. The operating system is important for directing the underlying activities for creation of hardware (proteins), but it does not inform us about how the proteins talk to each other and interact. The signaling code, written in PTMs, is like a software program, also called applications, or ‘‘apps’’ for short. Previous reviews have used the description of a code to envision the posttranslational states of tubulin’s carboxy-terminal tail (54–56). However, the code for the apps is probably not a simple one-to-one cipher. Rather, the PTM code is likely combinatorial, statistical, and complex in nature. Further, different codes can be written, erased, and rewritten on the same proteins repeatedly, adding complexity over time and space.
gpuccio_{October 5, 2016
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The dark matter of biology is likely to have multiple, vital roles to regulate signaling, rates of reactions, water structure and viscosity, crowding, and other cellular activities. We need to create new tools to image, detect, and understand these dark-matter species if we are to truly understand fundamental physical principles of biology.
The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

Complex complexity. :)Dionisio_{October 5, 2016
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The inside of the cell is full of important, yet invisible species of molecules and proteins that interact weakly but couple together to have huge and important effects in many biological processes. Such “dark matter” inside cells remains mostly hidden, because our tools were developed to investigate strongly interacting species and folded proteins.
The Dark Matter of Biology Jennifer L. Ross Biophysical Journal Volume 111, Issue 5, Pages 909–916 Biophysical Perspective http://dx.doi.org/10.1016/j.bpj.2016.07.037

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[...] little is known about the molecular mechanisms that distinguish diapause from non-diapause in this important mosquito species. [...] we know little about how mosquitoes are able translate complex environmental signals into the developmental switch that evokes the complex hormonal and physiological traits that comprise the diapause syndrome. It is our hope that a more comprehensive investigation of the functional roles of the genes described in this study, along with an expansion to additional time points, will result in a clearer understanding of the intriguing diapause phenotype.
Comparative Transcriptomics Reveals Key Gene Expression Differences between Diapausing and Non-Diapausing Adults of Culex pipiens David S. Kang,1 Michael A. Cotten,1 David L. Denlinger,2 and Cheolho Sim PLoS One. 2016; 11(4): e0154892. doi: 10.1371/journal.pone.0154892

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Maternal factors play essential roles in coordinating embryonic cell fates in time and space. More studies are needed in future to unravel the function of the multifaceted cell fate regulator Ascl1. Further study is needed to better understand how the pre-neurula expression of Ascl1 functions as a transactivator and promotes neurogenesis. It remains unclear whether or how much Ascl1 protein is maternally stored.
A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT Li Gao,1,* Xuechen Zhu,1,* Geng Chen,1 Xin Ma,2 Yan Zhang,1 Aftab A. Khand,1 Huijuan Shi,1 Fei Gu,1 Hao Lin,1 Yuemeng Chen,3 Haiyan Zhang,1 Lei He,1 and Qinghua Tao Development. 143(3): 492–503. doi: 10.1242/dev.126292

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Nutrition and lifestyle, known to modulate aging process and age-related diseases, might also affect telomerase activity. [...] what we eat, how we eat and how much we eat, together with lifestyle significantly, can affect our telomerase/telomere system with a great impact on healthspan. “Similes cum similibus curantur” and in nature is still hidden the secret of healthy and long life whereas telomerase could represent the distinctive target. Many mechanisms and pathways underlie nutrition, lifestyle and longevity including telomere length modulation.
Nutrition and lifestyle in healthy aging: the telomerase challenge Virginia Boccardi,1 Giuseppe Paolisso,2 and Patrizia Mecocci1 Aging (Albany NY). ; 8(1): 12–15. doi: 10.18632/aging.100886

Dionisio_{October 4, 2016
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Further studies will probably reveal other wound?induced factors required to decide whether the regeneration initiation program should continue, and if so which tissues should be replaced. Non?genetic cues, such as reactive oxygen species and calcium, are generically released upon injury in a number of organisms [...] whether and how they may contribute to regeneration initiation through interactions with positional cues remains an open question. Planarians can regenerate after virtually all amputation scenarios. This requires a robust system that instructs stem cells to correctly replace missing tissues.
Go ahead, grow a head! A planarian's guide to anterior regeneration. Owlarn S, Bartscherer K. Regeneration (Oxf). ;3(3):139-55. doi: 10.1002/reg2.56. eCollection 2016.

Complex complexity. :)Dionisio_{October 4, 2016
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The planarian regeneration field is at an extremely exciting place, poised to contribute to our understanding of physiological networks in pattern formation [...] Much more work is needed to unify bioelectric and biochemical signaling. In particular, bi?directional regulatory loops between specific chemical pathways, chromatin state, and spatial voltage distributions need to be characterized. Physiological networks also need to start being incorporated into the advanced modeling platforms, which heretofore largely focus on gene regulatory networks and biochemical gradients [...] [...] it is unclear currently which of the many phenotypes exhibited in the literature are in fact permanent, or what mechanisms mediate the permanence. In planaria, ventral nerve cord integrity synergizes with GJC to determine whether a head forms at a wound (Oviedo et al. 2010); this interaction is currently not understood but is probably a gateway to understanding the relationship between neural and non?neural bioelectric signaling in pattern control. One of the major areas for future development, in addition to specific techniques and datasets, is advances in conceptual integration of molecular data and algorithmic understanding of the regenerating body as a computational distributed system [...]
Physiological controls of large-scale patterning in planarian regeneration: a molecular and computational perspective on growth and form. Durant F, Lobo D, Hammelman J, Levin M Regeneration (Oxf). 3(2):78-102. doi: 10.1002/reg2.54.

Dionisio_{October 3, 2016
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Top-down models may facilitate altering encoded goal states (e.g., target morphologies), bypassing the complexity explosion currently facing regenerative medicine’s attempts to control complex shape by tweaking molecules. [...] a better understanding of the bioelectric code may allow optogenetic or similar methods to rewrite the target morphology in vivo, inducing cells to build desired patterns as a kind of universal constructor. Interestingly, this effort may also pay off in the reverse direction, shedding light on the semantics of bioelectric states in the brain. However, cybernetic strategies are applicable to top-down regulation via any mechanism, not only bioelectricity, and can readily be explored in the context of biomechanical forces, gene regulatory networks, etc. For example, an area to be investigated is the application of active inference models to gene-regulatory networks and protein interaction networks, attempting to analyze their dynamics as an information-processing structure. Computer engineering and neuroscience serve as proofs-of-principle that efficient control of complex systems can be pursued with top-down models of goal-directed activity. Concepts such as feedback control and goal-seeking algorithms must also be included in training courses that nowadays focus principally on differential equations for gradients and network analysis, omitting complementary perspectives from computer science and engineering despite the ubiquitous calls for a deeper integration across disciplines.
Re-Membering the Body: applications of computational neuroscience to the top-down control of regeneration of limbs and other complex organs G. Pezzuloa and M. Levin Integr Biol (Camb). 7(12): 1487–1517. doi: 10.1039/c5ib00221d

Complex complexity.Dionisio_{October 3, 2016
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Directed cell migration is a complex process that involves front-rear polarization, characterized by cell adhesion and cytoskeleton-based protrusion, retraction, and contraction of either a single cell or a cell collective. Single cell polarization depends on a variety of mechanochemical signals including external adhesive cues, substrate stiffness, and confinement. In cell ensembles, coordinated polarization of migrating tissues results not only from the application of traction forces on the extracellular matrix but also from the transmission of mechanical stress through intercellular junctions.
Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues. Ladoux B1, Mège RM2, Trepat X3. Trends Cell Biol. 26(6):420-33. doi: 10.1016/j.tcb.2016.02.002

Complex complexity. :)Dionisio_{October 2, 2016
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Further understanding will require a more profound insight into active and passive properties of actomyosin as well as intermediate and MT networks at various time and length scales. It will also require a more precise determination of force transmission at cell–cell contacts and its regulation by ECM mechanical properties and cell matrix adhesion. There is also an urgent need to progress in the molecular understanding of cellular and subcellular methanol sensing at cell-cell and cell-matrix contacts and on instructive biochemical cues mobilized at the various scales. Clearly, we are at early ages of the understanding of this multistate polarization by mechanical cues. This is, however, a crucial bottleneck in understanding cell and tissue polarization in 2D layers and 3D matrices in reconstituted tissues as well as in understanding the general principles underlying morphogenetic movements.
Front-Rear Polarization by Mechanical Cues: From Single Cells to Tissues. Ladoux B1, Mège RM2, Trepat X3. Trends Cell Biol. 26(6):420-33. doi: 10.1016/j.tcb.2016.02.002

Work in progress... stay tuned. :)Dionisio_{October 2, 2016
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[...] it is not clear why, in a given cell population, cells can exhibit different migration behaviors despite using the same machinery and being subjected to the same pro-migration cues. What we do know about the mechanisms that govern cell migration only serves to underscore the complexity of the system, particularly in cases where there is more than one input signal.
Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues Francois Bordeleau1 and Cynthia A. Reinhart-Kinga Version 1. F1000Res 5: F1000 Faculty Rev-1819. doi: 10.12688/f1000research.7884.1

Complex complexity. Emphasis mine.Dionisio_{October 2, 2016
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There has been immense progress in our understanding of the factors driving cell migration in both two-dimensional and three-dimensional microenvironments over the years. However, it is becoming increasingly evident that even though most cells share many of the same signaling molecules, they rarely respond in the same way to migration cues. To add to the complexity, cells are generally exposed to multiple cues simultaneously, in the form of growth factors and/or physical cues from the matrix. Understanding the mechanisms that modulate the intracellular signals triggered by multiple cues remains a challenge.
Tuning cell migration: contractility as an integrator of intracellular signals from multiple cues Francois Bordeleau1 and Cynthia A. Reinhart-Kinga Version 1. F1000Res 5: F1000 Faculty Rev-1819. doi: 10.12688/f1000research.7884.1

Complex complexity. Emphasis mine.Dionisio_{October 2, 2016
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Further experiments are also needed to answer a number of other questions. [...] we cannot help but wonder how many similar structures have been missed in the cells of other organisms and therefore are still waiting to be discovered.
Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

Dionisio_{October 1, 2016
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[...] the direction in which the invagination forms is under the control of the same signaling pathway that controls planar cell polarity. Confirming that the invagination does indeed anchor the centrosome will require further study, in particular to identify the molecular components that govern how the invagination forms.
Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

Dionisio_{October 1, 2016
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Cells in textbooks tend to have simple shapes, with surfaces that merely separate the contents of the cell from the outside world. However, this is far from the truth.
Cellular fingers take hold Yukiko M Yamashita eLife. 2016; 5: e19405. doi: 10.7554/eLife.19405

this is far from the truth? Does that mean that biology textbooks are not telling the truth?Dionisio_{October 1, 2016
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