Aims to enumerate novel life science paradigms and theories. In the beginning of the twentieth century Lord Kelvin (may have) famously declared: 'There is nothing new to be discovered in physics now, All that remains is more and more precise measurement' That was before relativity and quantum mechanics. We thought the human genome project would unlock the workings of our bodies save a few details. Let's not make the same mistake twice. Let's explore with maniacal curiosity and critical reasoning until, truly, all that's left is refined measurement and engineering. All views presented here are completely my own and do not reflect those of anyone else. Don't take anything here too seriously yet. It's exploratory.
"Since mechanical oscillations are local, can we modulate the protein folding & its complex formation from isolated proteins using megahertz electromagnetic signals, non-locally? Here, we make a journey from atomic scale live imaging of protein complex formation to the verification of the observations made in the cell-like environment and explore the common megahertz frequency region for the tubulin protein, which is 0.8 to 8 microseconds5. It means for tubulin protein if we pump electromagnetic signal, around 2.25 MHz and 0.225 MHz, then the protein complex i.e. microtubule formation would unravel unprecedented features.
The rate of microtubule growth is surprisingly distinct across the species to regulate the vital cell processes; the regulation is disrupted, if there is a modest change in this rate6. Therefore, one can tune the delicate cellular features like the chromosomal instability7, the nuclear transport8 simply by regulating the spontaneous growth and decay of microtubule, i.e. dynamic instability. The tubulins from plant, animal and fungi retains 90–95% genetic similarity9, yet the plant-microtubules rapidly recognize to re-organize with the environmental changes, however, the animal or the fungus cannot, in contrast the animal-microtubules are extremely sensitive to regulate the growth precisely10. The universal growth-rate control mechanism cutting across the species is unresolved—several basic questions of this primary activity of the living cells have remained unanswered. For example, no in vitro synthesis could reproduce the lower (200 nm) and the upper length limits (24 μm), as observed in vivo wherein the limits follow a unique relationship with the cell-shape. How microtubule defines its limits? The unlimited growth and the random speeds of growth are always observed in vitro, even, the dynamic instability is modeled as a stochastic & a random process11. Yet, the major contemporary discoveries on dynamic instability cannot explain why in vitro growth has no limits, i.e. what that limits microtubule's growth12, 13, 14. "
Does water have a fourth phase, beyond solid, liquid and vapor?
University of Washington Bioengineering Professor Gerald Pollack answers this question, and intrigues us to consider the implications of this finding. Not all water is H2O, a radical departure from what you may have learned from textbooks.
Pollack received his PhD in biomedical engineering from the University of Pennsylvania in 1968. He then joined the University of Washington faculty and is now professor of Bioengineering. His interests have ranged broadly, from biological motion and cell biology to the interaction of biological surfaces with aqueous solutions. His 1990 book, Muscles and Molecules: Uncovering the Principles of Biological Motion, won an "Excellence Award" from the Society for Technical Communication; his more recent book, Cells, Gels and the Engines of Life, won that Society's "Distinguished Award." Pollack received an honorary doctorate in 2002 from Ural State University in Ekaterinburg, Russia, and was more recently named an Honorary Professor of the Russian Academy of Sciences. He received the Biomedical Engineering Society's Distinguished Lecturer Award in 2002. In 2008, he was the faculty member selected by the University of Washington faculty to receive their highest annual distinction: the Faculty Lecturer Award. Pollack is a Founding Fellow of the American Institute of Medical and Biological Engineering and a Fellow of both the American Heart Association and the Biomedical Engineering Society. He is also Founding Editor-in-Chief of the journal, WATER, and has recently received an NIH Transformative R01 Award. He was the 2012 recipient of the Prigogine Medal and in 2013 published his new book: The Fourth Phase of Water: Beyond Solid, Liquid, and Vapor.
Colbert Sesanker's insight:
Tensegrity, cytosociology and the gel like phase of water all contribute to the long held hypothesis that the cell is a solid state structure (see Tensegrity below).
Frohlich proposed the 'microtrabecular lattice' as the substrate of energy transfer for coherent excitations in the early 80s. The microtrabecular lattice idea WAS an artifact of early HVEM during this time. Interestingly, a solid-state cell would support coherent excitations of polar molecules (cell is saturated with these) and membranes across multiple frequency bands. Indeed, it is a new and improved revitalization of the microtrabecular concept.
The book, Cells, Gels and the Engines of Life builds on the central role of water for biology. It provides evidence that much of the water in the cell is very near to one or another hydrophilic surface and therefore ordered, and that cell behavior can be properly understood only if this feature is properly taken into account. It goes on to show that seemingly complex behaviors of the cell can be understood in simple terms once a proper understanding of water and surfaces is achieved.
While the book is an award-winning best seller, it has aroused controversy because it questions some long-held basic features of cell function such as membrane channels and pumps. This steps on many scientific toes. Many others have praised the insights obtained from building on a foundation of first principles (see book website above). One prominent reviewer from Harvard University opines that the book is “a 305 page preface to the future of cell biology.”
Colbert Sesanker's insight:
further details solid state cell paradigm. Reads like a childrens book in a good way (super clear and non-technical).
Cellular Tensegrity Theory. Cells and tissues are organized as discrete network structures, and they use tensegrity architecture to mechanically stabilize themselves. In the cellular tensegrity theory, complex mechanical behaviors in cells and tissues emerge through establishment of a mechanical force balance between different molecular elements in the cytoskeleton and ECM that maintains the cell in a state of isometric tension.
Solid-State Biochemistry. Many of the biochemical events that mediate cell metabolism and signal transduction proceed using solid-state biochemistry. The enzymes and substrates that mediate these biochemical reactions are physically immobilized on insoluble molecular scaffolds within the cytoskeleton, nucleus and ECM.
Integrins as Mechanotransducers. Mechanical forces impact cellular signal transduction and influence cell decision making based on their transmission across cell surface adhesion receptors, such as integrins, that mechanically couple extracellular molecular scaffolds to the internal cytoskeleton. Mechanical forces are converted into chemical and electrical signals through stress-dependent distortion of molecules that associate with load-bearing elements of the cytoskeleton.
The idea here is that an enzyme stripped of its 'cytosociology' is merely a shadow of its identity. It's naturally highly diverse environment is the key to its functioning. Offers more support for the solid state view of the cell.
Keith Porter culminated his stellar career as the founding father of biological electron microscopy by acquiring, in the late 1970s, a high-voltage electron microscope (HVEM). With this magnificent instrument he examined whole-mounts of cultured cells, and perceived within them a structured cytoplasmic matrix he named the “microtrabecular lattice”. Over the next decade Porter published a series of studies, together with a team of outstanding young colleagues, which elaborated his broader “microtrabecular concept.” This concept posited that microtrabeculae were real physical entities that represented the fundamental organization the cytoplasm, and that they were the physical basis of cytoplasmic motility and of cell-shape determination. The present review presents Porter's original images of microtrabeculae, after conversion to a more interpretable “digital-anaglyph” form, and discusses the rise and fall of the microtrabecular concept. Further, it explains how the HVEM images of microtrabeculae finally came to be considered as an artifact of the preparative methods Porter used to prepare whole cells for HVEM. Still, Keith's “microtrabecular concept” foretold of our current appreciation of the complexity and pervasiveness of the cytoskeleton, which has now been found by more modern methods of EM to actually be the fundamental organizing principle of the cytoplasmic matrix. During the impending eclipse of Porter's microtrabecular concept in the late 1980s, many of Keith's colleagues fondly described the cell as being filled, not with protoplasm, but with “Porterplasm.” Despite the fact that Keith's view was clouded by the methods of his time, it would be fitting and apt to retain this name, still today, for the ordered matrix of cytoskeletal macromolecules that exists in the living cell. In the end, the story of what happened to Porter's microtrabecular concept should be an object lesson in scientific hubris that should humble and inform all of us in cell biology, even today — particularly when we begin to think that our most recent methods and observations are achieving “the last word”.
Colbert Sesanker's insight:
frohlich proposed this lattice as the substrate of energy transfer for coherent excitations in the early 80s. Interestingly, the microtrabecular lattice idea WAS an artifact of early HVEM during this time. Originally proposed for the medium of excitations before the solid state conception solidified.
"Few people remember Turing's work on pattern formation in biology (morphogenesis), but Turing's famous 1936 paper On Computable Numbers exerted an immense influence on the birth of molecular biology indirectly, through the work of John von Neumann on self-reproducing automata, which influenced Sydney Brenner who in turn influenced Francis Crick, the Crick of Watson and Crick, the discoverers of the molecular structure of DNA. Furthermore, von Neumann's application of Turing's ideas to biology is beautifully supported by recent work on evo-devo (evolutionary developmental biology). The crucial idea: DNA is multi-billion year old software, but we could not recognize it as such before Turing's 1936 paper, which according to von Neumann creates the idea of computer hardware and software."
Colbert Sesanker's insight:
The most interesting part is the relationship between innovation and incompleteness. There is too much deification of the static DNA sequence. Regardless, the only thing this abstraction requires is that the heritable information can be represented as a binary sequence.
"Why We Should Stop Using Brain Metaphors When We Talk About Computing.
Spectrum: It’s always been my impression that when people in computer science describe how the brain works, they are making horribly reductionist statements that you would never hear from neuroscientists. You called these “cartoon models” of the brain.
Michael Jordan: I wouldn't want to put labels on people and say that all computer scientists work one way, or all neuroscientists work another way. But it’s true that with neuroscience, it’s going to require decades or even hundreds of years to understand the deep principles. There is progress at the very lowest levels of neuroscience. But for issues of higher cognition—how we perceive, how we remember, how we act—we have no idea how neurons are storing information, how they are computing, what the rules are, what the algorithms are, what the representations are, and the like. So we are not yet in an era in which we can be using an understanding of the brain to guide us in the construction of intelligent systems."
Colbert Sesanker's insight:
finally someone calls out the lost that think the brain is one giant deep neural network or (gasp) a hierarchical hidden markov model (kurzweil in 'How to Build a Mind'). 'What is thought', by Eric Baum, is another excellent book summarizing materialistic (computational and evolutionary) views of intelligence (though I think it's optimism on the feasibility of strong AI is in error).
We develop a general formalism for representing and understanding structure in complex systems. In our view, structure is the totality of relationships among a system's components, and these relationships can be quantified using information theory. In the interest of flexibility we allow information to be quantified using any function, including Shannon entropy and Kolmogorov complexity, that satisfies certain fundamental axioms. Using these axioms, we formalize the notion of a dependency among components, and show how a system's structure is revealed in the amount of information assigned to each dependency. We explore quantitative indices that summarize system structure, providing a new formal basis for the complexity profile and introducing a new index, the "marginal utility of information". Using simple examples, we show how these indices capture intuitive ideas about structure in a quantitative way. Our formalism also sheds light on a longstanding mystery: that the mutual information of three or more variables can be negative. We discuss applications to complex networks, gene regulation, the kinetic theory of fluids and multiscale cybernetic thermodynamics.
An Information-Theoretic Formalism for Multiscale Structure in Complex Systems Benjamin Allen, Blake C. Stacey, Yaneer Bar-Yam
The Western Ghats in India rise like a wall between the Arabian Sea and the heart of the subcontinent to the east. The 1,000-mile-long chain of coastal mountains is dense with lush rainforest and grasslands, and each year, clouds bearing monsoon rains blow in from the southwest and break against the mountains’ flanks, unloading water that helps make them hospitable to numerous spectacular and endangered species. The Western Ghats are one of the most biodiverse places on the planet. They were also the first testing ground of an unusual new theory in ecology that applies insights from physics to the study of the environment.
"Konrad Zuse (1910-1995; pronounce: "Conrud Tsoosay") not only built the first programmable computers (1935-1941) and devised the first higher-level programming language (1945), but also was the first to suggest (in 1967) that the entire universe is being computed on a computer, possibly a cellular automaton (CA). He referred to this as "Rechnender Raum" or Computing Space or Computing Cosmos. Many years later similar ideas were also published / popularized / extended by Edward Fredkin (1980s), Jürgen Schmidhuber (1990s - see overview), and more recently Stephen Wolfram (2002) (see comments and Edwin Clark's review page ). Zuse's first paper on digital physics and CA-based universes was:
Zuse is careful: on page 337 he writes that at the moment we do not have full digital models of physics, but that does not prevent him from asking right there: which would be the consequences of a total discretization of all natural laws? For lack of a complete automata-theoretic description of the universe he continues by studying several simplified models. He discusses neighbouring cells that update their values based on surrounding cells, implementing the spread and creation and annihilation of elementary particles. On page 341 he writes "In all these cases we are dealing with automata types known by the name "cellular automata" in the literature" and cites von Neumann's 1966 book: Theory of self-reproducing automata. On page 342 he briefly discusses the compatibility of relativity theory and CAs."
"To me, the universe is simply a great machine which never came into being and never will end. The human being is no exception to the natural order. Man, like the universe, is a machine. Nothing enters our minds or determines our actions which is not directly or indirectly a response to stimuli beating upon our sense organs from without."
Studies in germ-free (GF) mice demonstrate that the gut microbiota (GM) is a regulator of bone mass.The GM affects bone mass via effects on the immune status, which in turn regulates osteoclastogenesis.Probiotic and prebiotic treatments may impact GM composition and affect bone metabolism.The GM may be a novel therapeutic target for osteoporosis.
The gut microbiota (GM), the commensal bacteria living in our intestine, performs numerous useful functions, including modulating host metabolism and immune status. Recent studies demonstrate that the GM is also a regulator of bone mass and it is proposed that the effect of the GM on bone mass is mediated via effects on the immune system, which in turn regulates osteoclastogenesis. Under normal conditions, the skeleton is constantly remodeled by bone-forming osteoblasts (OBs) and bone-resorbing osteoclasts (OCLs), and imbalances in this process may lead to osteoporosis. Here we review current knowledge on the possible role for the GM in the regulation of bone metabolism and propose that the GM might be a novel therapeutic target for osteoporosis and fracture prevention.
Donald E. Ingber is the Founding Director of the Wyss Institute for Biologically Inspired Engineering at Harvard University, the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children's Hospital, and Professor of Bioengineering at the Harvard School of Engineering and Applied Sciences. He received his B.A., M.A., M.Phil., M.D. and Ph.D. from Yale University. Dr. Ingber is a founder of the emerging field of biologically inspired engineering, and at the Wyss Institute, he oversees a multifaceted effort to identify the mechanisms that living organisms use to self-assemble from molecules and cells, and to apply these design principles to develop advanced materials and devices for healthcare and to improve sustainability. He also leads the Biomimetic Microsystems platform in which microfabrication techniques from the computer industry are used to build functional circuits with living cells as components. His most recent innovation is a technology for building tiny, complex, three-dimensional models of living human organs, or "Organs on Chips", that mimic complicated human functions as a way to replace traditional animal-based methods for testing of drugs and establishment of human disease models. In addition, Dr. Ingber has made major contributions to mechanobiology, tissue engineering, tumor angiogenesis, systems biology, and nanobiotechnology. He was the first to recognize that tensegrity architecture is a fundamental principle that governs how living cells are structured to respond biochemically to mechanical forces, and to demonstrate that integrin receptors mediate cellular mechanotransduction. Dr. Ingber has authored more than 375 publications and 85 patents, and has received numerous honors including the Holst Medal, Pritzker Award from the Biomedical Engineering Society, Rous-Whipple Award from the American Society for Investigative Pathology, Lifetime Achievement Award from the Society of In Vitro Biology, and the Department of Defense Breast Cancer Innovator Award. He also serves on the Board of Directors of the National Space Biomedical Research Institute, and is a member of both the American Institute for Medical and Biological Engineering, and the Institute of Medicine of the National Academies.
Colbert Sesanker's insight:
The Ingber lab of Harvard university is leading a * revival * (note this is not new) of the solid-state and tensegrity paradigms of the cell. See below for details of these paradigms. These two paradigms are intimately related to:
1. Models of Coherent Excitations (e.g., Frohlich's rate equation)
2. Cytoskeletal structures and the Molecules scaffolded to them. (e.g., Microtubule Network)
3. Fourth Gel phase of water discovered by Pollock. (as applied to solid-state paradigm)
"Water has three phases – gas, liquid, and solid; but recent findings from our laboratory imply the presence of a surprisingly extensive fourth phase that occurs at interfaces. This finding may have unexpectedly profound implication for chemistry, physics and biology."
"Water and Cell Biology: Contemporary views of cell biology consider water merely as a background carrier of the more important molecules of life. However, water may be a central player in life processes."
Colbert Sesanker's insight:
Pollack describes how the highly structured 4th phase of water present in the cell can lower the viscous damping of vibrating molecules (e.g., proteins)
"Importantly, working with collaborators, such as Drs. Ning Wang (Dept. of Respiratory Biology, Harvard School of Public Health) and Dimitrije Stamenovic (Dept. of Biomedical Engineering, Boston U.), we have been able to demonstrate that living mammalian cells behave mechanically like tensegrity structures. Moreover, we have developed a theoretical formulation of the tensegrity model starting from first mechanical principles that has yielded accurate qualitative and quantitative predictions of many static and dynamic cell mechanical behaviors. We are currently trying to extend and strengthen this computational approach to explain systems-wide mechanical properties in mammalian cells, and to explore their hierarchical basis
The cellular tensegrity model proposes that the whole cell is a prestressed tensegrity structure, although geodesic structures are also found in the cell at smaller size scales (e.g. clathrin-coated vesicles, viral capsids). In the model, tensional forces are borne by cytoskeletal microfilaments and intermediate filaments, and these forces are balanced by interconnected structural elements that resist compression, most notably internal microtubule struts and ECM adhesions. However, individual filaments can have dual functions and hence bear either tension or compression in different structural contexts or at different size scales (e.g. contractile microfilaments generate tension, whereas actin microfilament bundles that are rigidified by cross-links bear compression in filopodia). The tensional prestress that stabilizes the whole cell is generated actively by the contractile actomyosin apparatus. Additional passive contributions to this prestress come from cell distension through adhesions to the ECM and other cells, osmotic forces acting on the cell membrane, and forces exerted by filament polymerization. Intermediate filaments that interconnect at many points along microtubules, microfilaments and the nuclear surface provide mechanical stiffness to the cell based on their material properties and on their ability to act as suspensory cables that interconnect and tensionally stiffen the entire cytoskeleton and nuclear lattice."
Colbert Sesanker's insight:
The solid state view of the cell where enzymes and substrates that mediate biochemical reactions are physically immobilized and secured on cytoskeletal scaffolds, the ECM and organelles would supply a suitable medium for coherent excitations.
"Due to his work, the cytoskeleton is now widely believed to be a tensegrity structure, and tensegrity mechanics at the cellular level is now close to replacing all previous mechanical models of the cell."
"Increasing evidence indicates that the post-translationally modified histones serve as extremely selective binding platforms for specific regulatory proteins that drive distinct nuclear processes.
It has been known for over 45 years now that histones can be post-translationally modified by specific enzymes that ‘write?a histone code by adding or removing a number of different chemical modifications, including acetyl, phosphoryl and methyl groups (Figure 2). Since these modifications occur only on specific amino acid residues on specific histones in various eukaryotic organisms, these observations strongly linked the modifications?involvement in nuclear processes. For example, the acetylation of key lysine residues of histone H3 and H4 by enzymes known as histone acetyltransferases (HATs) was known to play a pivotal role in transcriptional activation."
"Fertile queens and sterile workers are alternative forms of the adult female honeybee that develop from genetically identical larvae following differential feeding with royal jelly. We show that silencing the expression of DNA methyltransferase Dnmt3, a key driver of epigenetic global reprogramming, in newly hatched larvae led to a royal jelly–like effect on the larval developmental trajectory; the majority of Dnmt3 small interfering RNA–treated individuals emerged as queens with fully developed ovaries. Our results suggest that DNA methylation in Apis is used for storing epigenetic information, that the use of that information can be differentially altered by nutritional input, and that the flexibility of epigenetic modifications underpins, profound shifts in developmental fates, with massive implications for reproductive and behavioral status."
Colbert Sesanker's insight:
The bee colony is genetically identical, but Queens are made when workers feed larva 'Royal Jelly' for an extended period of time. Queens exhibit vastly different gene expression patterns from workers. This is caused by epigenetic modifications.
The queen differentiation program was replicated by blocking (using small siRNA to silence methyltransferase Dnmt3) CpG methylation in larva.
Though they started at opposite ends of the socioeconomic spectrum, McCulloch and Pitts were destined to live, work, and die together. Along the way, they would create the first mechanistic theory of the mind, the first computational approach to neuroscience, the logical design of modern computers, and the pillars of artificial intelligence. But this is more than a story about a fruitful research collaboration. It is also about the bonds of friendship, the fragility of the mind, and the limits of logic’s ability to redeem a messy and imperfect world.
Nice story. On the other hand, it exemplifies the magic of finding what you're looking for:
"Which got McCulloch thinking about neurons. He knew that each of the brain’s nerve cells only fires after a minimum threshold has been reached: Enough of its neighboring nerve cells must send signals across the neuron’s synapses before it will fire off its own electrical spike. It occurred to McCulloch that this set-up was binary—either the neuron fires or it doesn’t. A neuron’s signal, he realized, is a proposition, and neurons seemed to work like logic gates, taking in multiple inputs and producing a single output. By varying a neuron’s firing threshold, it could be made to perform “and,” “or,” and “not” functions."
Oh yes. After days of mulling over binary operations one begins to see strange things. Hallucinations, flashes of bits saturating everything. All of a sudden, one no longer inhabits a world of things, but a world of bits. The bits, deeply burned into the cornea like a cataract, never seem to get out the way. Is that a brain, or is it bit soup? Ahh, I never thought about it that way. What a *nice* way to think about it.
"There was a catch, though: This symbolic abstraction made the world transparent but the brain opaque. Once everything had been reduced to information governed by logic, the actual mechanics ceased to matter—the tradeoff for universal computation was ontology. Von Neumann was the first to see the problem. He expressed his concern to Wiener in a letter that anticipated the coming split between artificial intelligence on one side and neuroscience on the other. “After the great positive contribution of Turing-cum-Pitts-and-McCulloch is assimilated,” he wrote, “the situation is rather worse than better than before. Indeed these authors have demonstrated in absolute and hopeless generality that anything and everything … can be done by an appropriate mechanism, and specifically by a neural mechanism—and that even one, definite mechanism can be ‘universal.’ Inverting the argument: Nothing that we may know or learn about the functioning of the organism can give, without ‘microscopic,’ cytological work any clues regarding the further details of the neural mechanism."
The idea here is that the map from behavior to neural mechanism is one to many. They are many turing complete circuit topologies, so the idea of finding THE circuit for behavior or action X breaks down.
"My research focuses on applying information theory and complexity science to genomics, synthetic and network biology. With backgrounds in math, computer science and philosophy, I think of myself as a kind ofexperimental philosopher or a computational natural scientist. (Greg Chaitin once referred to me as a "new kind of practical theoretician")."
Colbert Sesanker's insight:
Contributions to the aesthetically justified dream of unlocking the binary code of nature
"Experiments with selection pressures to maximize network perfor- mance and minimize connection costs yield networks that are significantly more modular and more evolvable than con- trol experiments that only select for performance."
Colbert Sesanker's insight:
This paper demonstrates the emergence of modularity in networks artificially evolved to maximize performance and minimize connection cost. Compare with previous attempts that argue modularity is under selective pressure to convey evolvability.
"Scientists were shocked to learn that about 90 percent of the fibers in the primary visceral nerve, the vagus, carry information from the gut to the brain and not the other way around."
"The enteric nervous system uses more than 30 neurotransmitters, just like the brain, and in fact 95 percent of the body's serotonin is found in the bowels."
Colbert Sesanker's insight:
Was there any reason to assume no link?
"The second brain doesn't help with the great thought processes…religion, philosophy and poetry is left to the brain in the head," says Michael Gershon, chairman of the Department of Anatomy and Cell Biology at New York–Presbyterian Hospital/Columbia University Medical Center, an expert in the nascent field of neurogastroenterology and author of the 1998 book The Second Brain"
Somehow he 'knows' the gut 'doesn't help' with higher order cognitive reasoning. Even if the gut served as a switch to initiate different cognitive programs, that would certainly constitute 'help' and seems plausible. Indeed, if there is feedback between the gut and higher order cognition, one would have to accept the gut is part of the system mediating the higher order cognition.
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