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The Cell is  a Factory

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1 The Cell is  a Factory on Tue Dec 15, 2015 5:27 am

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The Cell is  a Factory

http://reasonandscience.heavenforum.org/t2245-the-cell-is-a-factory

Factories, full of machines and production lines and computers, originate from intelligent minds. No exception.
Biological cells are like a industrial park of various interconnected factories, working in conjunction.
Factory is from Latin, and means fabricare, or make. Produce, manufacture. And that's PRECISELY what cells do. They produce other cells through self-replication, through complex machine processing, computing etc. 
Therefore, they had most probably a mind as a causal agency. 
The claim is falsified and topped, once someone can demonstrate  a factory that can self-assemble, without the requirement of intelligence. 

Cells As Molecular Factories
Eukaryotic cells are molecular factories in two senses: cells produce molecules and cells are made up of molecules.
http://serendip.brynmawr.edu/exchange/bioactivities/cellmolecular

Michael Denton: Evolution: A Theory In Crisis:
The cell is a veritable micro-miniaturized factory containing thousands of exquisitely designed pieces of intricate molecular machinery, made up altogether of one hundred thousand million atoms, far more complicated than any machine built by man and absolutely without parallel in the non-living world. 

Ribosome: Lessons of a molecular factory construction
https://link.springer.com/article/10.1134/S0026893314040116

Visualization of the active expression site locus by tagging with green fluorescent protein shows that it is specifically located at this unique pol I transcriptional factory.
http://www.nature.com/nature/journal/v414/n6865/full/414759a.html

There are millions of protein factories in every cell. Surprise, they’re not all the same
http://www.sciencemag.org/news/2017/06/there-are-millions-protein-factories-every-cell-surprise-they-re-not-all-same

Rough ER is also a membrane factory for the cell; it grows in place by adding membrane proteins and phospholipids to its own membrane.
https://en.wikibooks.org/wiki/Cell_Biology/Print_version

Theoretical biologists at Los Alamos National Laboratory have used a New Mexico supercomputer to aid an international research team in untangling another mystery related to ribosomes -- those enigmatic jumbles of molecules that are the protein factories of living cells.
https://phys.org/news/2010-12-scientists-ratchet-cellular-protein-factory.html

The molecular factory that translates the information from RNA to proteins is called the "ribosome"
https://phys.org/news/2014-08-key-worker-protein-synthesis-factory.html

Quality control in the endoplasmic reticulum protein factory
The endoplasmic reticulum (ER) is a factory where secretory proteins are manufactured, and where stringent quality-control systems ensure that only correctly folded proteins are sent to their final destinations. The changing needs of the ER factory are monitored by integrated signalling pathways that constantly adjust the levels of folding assistants.
http://sci-hub.cc/10.1038/nature02262

Objection: cells are not factories, and the analogy fails.
Answer: Factory is from latin, and means fabricare, or make. Produce, manufacture. And that's PRECISELY what cells do. They produce other cells through self-replication, through complex machine processing, computing etc. They produce all organelles, proteins, membranes, parts, they make a copy of themselves. Self-replication is a marvel of engineering. the most advanced method of manufacturing. And fully automated. No external help required. If we could make factories like that, we would be able to create a society where machines do all the work for us, and we would have time only to entertain us, no work, nor money needed anymore..... And if factories could evolve to produce subsequently better, more adapted products, that would add even further complexity, and point to even more requirement of pre- programming to get the feat done.

B.Alberts, The Cell as a Collection Overview of Protein Machines: Preparing the Next Generation of Molecular Biologists
“Indeed, the entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines.”  Many of these structures are just as amazing, and more so, as the flagellum.  For a few examples, see the spliceosome, RNA polymerase, and ATP Synthase.  Another article posted yesterday on EurekAlert uses the word “machine” seven times as it discusses “an intricately complex protein machine” that adjusts the connections between neurons.
https://brucealberts.ucsf.edu/publications/BAPub157.pdf

Developing Bacillus spp. as a cell factory for production of microbial enzymes
We highlight the limitations and challenges in developing Bacillus spp. as a robust and efficient production host, and we discuss in the context of systems and synthetic biology the emerging opportunities and future research prospects in developing Bacillus spp. as a microbial cell factory.
https://www.researchgate.net/publication/237095038_Developing_Bacillus_spp_as_a_cell_factory_for_production_of_microbial_enzymes_and_industrially_important_biochemicals_in_the_context_of_systems_and_synthetic_biology

Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing
Biological cells run complicated and sophisticated production systems. The study of the cell’s production technology provides us with insights that are potentially useful in industrial manufacturing. When comparing cell metabolism with manufacturing techniques in the industry, we find some striking commonalities assures quality at the source, and uses component commonality to simplify production.  The organic production system can be viewed as a possible scenario for the future of manufacturing. 
http://pubsonline.informs.org/doi/pdf/10.1287/msom.1030.0033

Cells are very similar to factories. To stay alive and function properly, cells have a division of labor similar to that found in factories.
https://www.slcschools.org/departments/curriculum/science/Grade-7-to-8/Grade-7/documents/s3-o2-lesson-cell-as-a-factory-website-pdf.pdf

Comparing a Cell to a Factory: Answer Key
Science NetLinks is a project of the Directorate for Education and Human Resources Programs of the American Association for the Advancement of Science.
http://sciencenetlinks.com/student-teacher-sheets/comparing-cell-factory-answer-key/

The scientists from Stuttgart may have already identified the first words in the programming language for living cells. For example, in their experiments with certain tissue cells, fibroblasts, they discovered that they were, in fact, able to switch their protein-making factory between two production modes by varying the contact distance. In a 58-nanometer gold pattern, the cells produce a different kind of tissue adhesive from the extensive family of fibronectin proteins compared with what they produce when the distance between contacts is 73 nanometers.
https://www.mpg.de/794120/F003_Focus_032-037.pdf

John Kendrew uses this fitting comparison:
Any living thing can be likened to a giant factory, a factory producing chemicals, producing energy and motion, indeed reproducing itself too (which most factories cannot do!) and if one thinks of the way in which assembly lines are organized in factories one realizes immediately that all this complex of operations could not be carried out unless they were in some way organized, separated into compartments, not higgledy-piggledy.  In other words, there must be some kind of organization in the structure of an animal to enable it to carry out these processes in an orderly way. In that parallel, the DNA would be like the manuals and blueprints that prescribe in detail just how each operation is to be done, and in what order of timing. The coded information in DNA, then, would obviously be absolutely essential.  It would also be absolutely helpless unless it had the entire system of the manufacturing plant, including people or computers to read and put into action its instructions.  The DNA master copy of the production blueprints must be kept protected.  What is required first of all is a way to make working copies of just the sections needed at the moment.  These temporary copies can then be taken out into the rough-and-tumble of the production area, leaving the DNA original safely in the office.  When no longer needed, the copies are destroyed.

Cells are entire FACTORY COMPLEXES; rather just one big factory, an agglomeration of MANY factories, that together form a giant manufacturing complex. So we can distinguish the Ribosome factory, the Endoplasmic reticulum factory, the transcription factory, mitochondria as the energy production factory, etc.

  



The scientists from Stuttgart may have already identified the first words in the programming language for living cells. For example, in their experiments with certain tissue cells, fibroblasts, they discovered that they were, in fact, able to switch their protein-making factory between two production modes by varying the contact distance. In a 58-nanometer gold pattern, the cells produce a different kind of tissue adhesive from the extensive family of fibronectin proteins compared with what they produce when the distance between contacts is 73 nanometers.
https://www.mpg.de/794120/F003_Focus_032-037.pdf

Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing
http://pubsonline.informs.org/doi/pdf/10.1287/msom.1030.0033

Biological cells run complicated and sophisticated production systems. The study of the cell’s production technology provides us with insights that are potentially useful in industrial manufacturing. When comparing cell metabolism with manufacturing techniques in the industry, we find some striking commonalities assures quality at the source, and uses component commonality to simplify production.  The organic production system can be viewed as a possible scenario for the future of manufacturing. We try to do so in this paper by studying a high-performance manufacturing system - namely, the biological cell. A careful examination of the production principles used by the biological cell reveals that cells are extremely good at making products with high robustness, flexibility, and efficiency. Section 1 describes the basic metaphor of this article, the biological cell as a production system, and shows that the cell is subject to similar performance pressures. Section 4 further deepens the metaphor by pointing out the similarities between the biological cell and a modern manufacturing system. We then point to the limits of the metaphor in §5 before we identify, in §6, four important production principles that are sources of efficiency and responsiveness for the biological cell, but that we currently do not widely observe in industrial production. For example, the intestinal bacterium, Escherichia coli,  runs 1,000–1,500 biochemical reactions in parallel. Just as in manufacturing, cell metabolism can be represented by flow diagrams in which raw materials are transformed into final products in a series of operations. 

With its thousands of biochemical reactions and high number of flow connections, the complexity of the cell’s production flow matches even the most complex industrial production networks we can observe today.  The performance pressures operating on the cell’s production system also exhibit clear parallels with manufacturing. Both production systems need to be fast, efficient, and responsive to environmental changeSpeed and range of response, as well as efficiency of its production systems, are clearly critical to the biological cell. Biologists have made the argument that the evolution of the basic structure of modern cells has largely been driven by “alimentary efficiency,” or the input-output efficiency of turning available nutrients into energy and basic building blocks. In addition, it is clear that in dynamic environments, the ability of the cell to react quickly and decisively is vital to ensure survival and reproduction.  Given the “manufacturing” nature of cell biochemistry and the comparable performance pressures on it, one should not be surprised to find interesting solutions developed by the cell that are applicable in manufacturing—especially since “cell technology” is much older and more mature than any human technology. The cell never forecasts demand; it achieves responsiveness through speed, not through inventories.

The limits to responsiveness depend only on the capacity limits of the enzymes in a particular pathway. The corresponding mechanism in manufacturing is referred to as a pull system. It produces only in response to actual demand, not in anticipation of forecast demand, thus preventing overproduction. While it is difficult to make direct comparisons with manufacturing plants, some case examples illustrate that the cell operates with little waste, even in regulating its pathways. In a U.S. electric-connectors factory in the early 1990s, 28.6% of plant labor was devoted to control and materials handling, while the figure was 14.9% in a simpler and leaner Japanese plant. In a house-care products plant, a cost analysis revealed that at least 14% of production costs were incurred by production planning and quality assurance. With its 11% of regulatory genes, the cell seems to set a pretty tight benchmark for regulation efficiency. The cell also uses quality-management techniques used in manufacturing today. The cell invests in defect prevention at various stages of its replication process, using 100% inspection processes, quality assurance procedures, and foolproofing techniques. An example of the cell inspecting each and every part of a product is DNA proofreading. As the DNA gets replicated, the enzyme DNA polymerase adds new nucleotides to the growing DNA strand, limiting the number of errors by removing incorrectly incorporated nucleotides with a proofreading function. An example of quality assurance can be found in the use of helper proteins, also called “chaperones.” These make sure that newly produced proteins fold themselves correctly, which is critical to their proper functioning. Finally, as an example of foolproofing, the cell applies the key-lock principle to guarantee a proper fit between substrate and enzyme, i.e., product and machine. The substrate fits into a pocket of the enzyme like a key into a lock, ensuring that only one particular substrate can be processed.

This is comparable with poka-yoke systems in manufacturing. An everyday example of poka-yoke is the narrow opening for an unleaded gasoline tank in a car. It prevents you from inserting the larger leaded fuel nozzle. The cell’s pathways are designed in such a way that different end products often share a set of initial common steps (as is shown in Figure 2). For example, in the biosynthesis of aromatic amino acids, a number of common precursors are synthesized before the pathway splits into different final products.  A final concern is that the biological cell is the result of evolution, not design. Consider the cell’s technology, which stabilized about two billion years ago. Interestingly, the intermediates used for “products” and “machines” (enzymes) are identical. In other words, the cell can easily degrade an enzyme into its component amino acids and use these amino acids to synthesize a new enzyme (a “machine”), replenish the central metabolism, or make another molecule (a “product”), e.g., a biogenic amine. It seems an amazing achievement by the cell to build the complexity and variety of life with such a small number of components. Imagine that all industrial machines were made of only 20 different modules, corresponding to the 20 amino acids from which all proteins are made. As we further explain below, this modular approach allows the cell to be remarkably efficient and responsive at the same time.

Basically, with both products and machines being built from just a few recyclable components, the cell can efficiently produce an enormous variety of products in the appropriate quantities when they are needed.  At any moment, synthesis and breakdown for each enzyme happen in the cell. The constant renewal eliminates the need for other types of “machine maintenance.” Assembly and disassembly of the cell’s machines are so fast and frictionless that they allow a scheme of constant machine renewal.  The cell has pushed this principle even further. First, it does not even wait until the machine fails, but replaces it long before it has a chance to break down. And second, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type, but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances.

Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing
http://pubsonline.informs.org/doi/pdf/10.1287/msom.1030.0033

Biological cells run complicated and sophisticated production systems. The study of the cell’s production technology provides us with insights that are potentially useful in industrial manufacturing. When comparing cell metabolism with manufacturing techniques in industry, we find some striking commonalitiesLike today’s well-run factories, the cell operates a very lean production system, assures quality at the source, and uses component commonality to simplify production. While we can certainly learn from how the cell accomplishes these parallels, it is even more interesting to look at how the cell operates differently. In biological cells, all products and machines are built from a small set of common building blocks that circulate in local recycling loops. Production equipment is added, removed, or renewed instantly when needed. The cell’s manufacturing unit is highly autonomous and reacts quickly to a wide range of changes in the local environment. Although this “organic production system” is very different from existing manufacturing systems, some of its principles are applicable to manufacturing, and indeed, a few can even be seen emerging today. Thus, the organic production system can be viewed as a possible scenario for the future of manufacturing.

Can we say anything about possible directions that the changes in manufacturing might take? We try to do so in this paper by studying a high-performance manufacturing system that is two billion years old—namely, the biological cell. A careful examination of the production principles used by the biological cell reveals that cells are extremely good at making products with high robustness, flexibility, and efficiency. Using the biological cell as an analogy, we describe an alternative manufacturing system that we call the “organic production system,” and we argue that it holds useful ideas for possible future trends in manufacturing. Our argument is organized as follows. 

Section 2
provides a review of related literature and introduces the methodology of learning from analogies. 

Section 3
describes the basic metaphor of this article, the biological cell as a production system, and shows that the cell is subject to similar performance pressures.

Section 4
further deepens the metaphor by pointing out the similarities between the biological cell and a modern manufacturing system. We then point to the limits of the metaphor in §5 before we identify, in §6, four important production principles that are sources of efficiency and responsiveness for the biological cell, but that we currently do not widely observe in industrial production. Analogical reasoning then leads to §7, in which we formulate and illustrate the principles of an “organic production system,” based on those four distinctive principles. We also show that partial examples of its application already exist. In the final section, we discuss the relevance of this innovative production system for possible future trends in manufacturing.

First, nature manufactures its materials under life-friendly conditions (e.g., no chemical baths or high pressure or high temperature). 
Two, nature makes materials in an orderly hierarchical structure (e.g., self-similar fractals across dimensions, which arise from growing structures from the ground up). 
Three, nature relies on self-assembly—no central logic, but decentralized growth according to local rules. Four, nature customizes materials through the use of templates; the genes are templates for proteins, which become templates for material growth. The templates can be varied, so materials are made as needed and required by the environmental challenge, with little waste.

The Cell Metabolism as a Manufacturing System

The cell is quite clearly a manufacturing system. It uses a small set of inputs to “manufacture” a wide range of compounds that help it to interact appropriately with its environment, and eventually allow it to reproduce itself . The cell manages this production in a complex network of several thousands of biochemical reactions. For example, the intestinal bacterium, Escherichia coli,  runs 1,000–1,500 biochemical reactions in parallel. Just as in manufacturing, cell metabolism can be represented by flow diagrams in which raw materials are transformed into final products in a series of operations. Figure 1, for example, shows part of a biochemical pathway, which is the equivalent of a production line, in which enzymes, which are the cell’s machines, perform operations on the different types of work-in-process inventory.



As in manufacturing, each of these operations has a certain capacity, and the amount of production at each step is controlled directly by signals or indirectly by limiting the material flow. With its thousands of biochemical reactions and high number of flow connections, the complexity of the cell’s production flow matches even the most complex industrial production networks we can observe today.  The performance pressures operating on the cell’s production system also exhibit clear parallels with manufacturing. Both production systems need to be fast, efficient, and responsive to environmental change. Speed and range of response, as well as efficiency of its production systems, are clearly critical to the biological cell. Biologists have made the argument that the evolution of the basic structure of modern cells has largely been driven by “alimentary efficiency,” or the input-output efficiency of turning available nutrients into energy and basic building blocks. In addition, it is clear that in dynamic environments, the ability of the cell to react quickly and decisively is vital to ensure survival and reproduction. An important type of response, indeed, is the cell’s biosynthetic response, i.e., the response of its production systems. The cell has  competencies that allow for efficiency through energy and building block conservation, while maximizing responsiveness to environmental changes. As it is for the cell in biology, a lack of operational efficiency or responsiveness can lead to a company’s demise in industry. As has been argued by the Business Process Reengineering movement, the fate of a company may be decided by the quality of its operations rather than by its strategy. Examples abound of companies that struggled or went bankrupt because of poor operations management: Harley Davidson was on the brink of bankruptcy in 1981 because of poor product quality, high inventories, and high manufacturing costs. Boeing lost market share to Airbus in 1998 because of its inability to manufacture its backlog of ordered planes on time. Kmart filed for bankruptcy in 2000 because of poor logistics and inef- ficient supply chain management. And so on. Given the “manufacturing” nature of cell biochemistry and the comparable performance pressures on it, one should not be surprised to find interesting solutions developed by the cell that are applicable in manufacturing—especially since “cell technology” is much older and more mature than any human technology.

Commonalities Between the Cell and Manufacturing 
Although a cell and a manufacturing plant are, of course, very different organisms , we have argued that at least some of the pressures for efficiency and responsiveness that act on the biological cell’s production systems are similar to those acting upon industrial production systems. Many solutions that these two systems have developed are similar as well. We may, therefore, expect that the biological cell holds some useful lessons for manufacturing systems, in spite of the differences. The cell has not served as a role model in the historical development of manufacturing, so we should not expect to find similarities as a result of imitation or copying. However, the cell applies many of the mechanisms that can also be observed in modern manufacturing: lean production, quality at the source, and postponement. The cell carries out a very lean operation: By using pull systems and excess capacity, the storage of intermediates is kept to a minimum within the pathways. The cell also assures quality at the source, avoiding rework loops for the repair of “broken” molecules. Finally, the cell takes advantage of modularity, component commonality and postponement in its biochemical pathways. Using Pull Systems to Avoid Overproduction In biochemical pathways, production occurs only when triggered by a downstream shortage. Or, inversely, any build-up of downstream product will immediately halt further production. As long as there is still final product available, the first enzyme or “machine” of the pathway is physically blocked by an interaction between the final product and the enzyme, a mechanism called “feedback inhibition”. When the final product of a pathway is depleted by high “demand,” the first enzyme is unblocked. As it opens up for production, it gets hold of a piece of raw material and starts processing it. The cell never forecasts demand; it achieves responsiveness through speed, not through inventories. The limits to responsiveness depend only on the capacity limits of the enzymes in a particular pathway. The corresponding mechanism in manufacturing is referred to as a pull system. It produces only in response to actual demand, not in anticipation of forecast demand, thus preventing overproduction.

Minimizing Work in Process by Using Bottlenecks to Control the Release Rate In virtually all biochemical pathways, the first enzyme is the bottleneck that limits the entry rate, as illustrated in Figure 2.



The enzymes within the pathway can process products much faster than the entry rate and, as a result, the level of intermediate products is kept to a minimum. In manufacturing, the principle of using the bottleneck to control the release of jobs into a production line is also well known. As both the pull mechanism and the upfront bottleneck are known to simplify production control in manufacturing, it is interesting to check the amount of control and regulation overhead in the two analogous systems. Escherichia coli, for instance, is known to dedicate about 11% of its genes to regulation and control. While it is difficult to make direct comparisons with manufacturing plants, some case examples illustrate that the cell operates with little waste, even in regulating its pathways. In a U.S. electric-connectors factory in the early 1990s, 28.6% of plant labor was devoted to control and materials handling, while the figure was 14.9% in a simpler and leaner Japanese plant. In a house-care products plant, a cost analysis revealed that at least 14% of production costs were incurred by production planning and quality assurance. With its 11% of regulatory genes, the cell seems to set a pretty tight benchmark for regulation efficiency.

Using Excess Capacity to Simplify Control and Lower Work in Process
It is important for the cell to keep intermediates at a low level in order to save energy and building blocks. Work in process, in the form of intermediates, is costly—first, because space comes at a premium in the cell, and second, because inventory may degrade and represents unproductive use of material. The question is whether the cell pays a price for keeping the level of intermediates at such a low level. It does have excess capacity for all but the first enzyme in its pathways, and one may wonder whether this is efficient. In manufacturing, such excess capacity may be too costly. However, if capacity becomes more flexible and more affordable, and responsiveness more important, one may see more factories in which some safety capacity, in all operations but the first, is used to lower work in process, simplify control, and increase responsiveness to sudden market changes. The clothing retailer Zara, for example, known for its quick response capabilities, is seen to use excess capacity in its distribution systems to ensure short leadtimes and to avoid costly build-up of inventories in its warehouses.

Managing Quality at the Source 
The cell also uses quality-management techniques used in manufacturing today. The cell invests in defect prevention at various stages of its replication process, using 100% inspection processes, quality assurance procedures, and foolproofing techniques. An example of the cell inspecting each and every part of a product is DNA proofreading. As the DNA gets replicated, the enzyme DNA polymerase adds new nucleotides to the growing DNA strand, limiting the number of errors by removing incorrectly incorporated nucleotides with a proofreading function.

An example of quality assurance can be found in the use of helper proteins, also called “chaperones.” These make sure that newly produced proteins fold themselves correctly, which is critical to their proper functioning. Finally, as an example of foolproofing, the cell applies the key-lock principle to guarantee a proper fit between substrate and enzyme, i.e., product and machine. The substrate fits into a pocket of the enzyme like a key into a lock, ensuring that only one particular substrate can be processed. This is comparable with poka-yoke systems in manufacturing. An everyday example of poka-yoke is the narrow opening for an unleaded gasoline tank in a car. It prevents you from inserting the larger leaded fuel nozzle.

Exploiting Postponement and Platform Strategies 
The cell’s pathways are designed in such a way that different end products often share a set of initial common steps (as is shown in Figure 2). For example, in the biosynthesis of aromatic amino acids, a number of common precursors are synthesized before the pathway splits into different final products. This commonality reduces the number of enzymes needed to synthesize amino acids, thus conserving energy and building blocks. It postpones the decision of which amino acid, and how much of it, to synthesize. Another striking example of commonality is steroids, a class of common molecules in microorganisms, plants, and animals. Steroids help in performing various biological functions, such as regulation (hormones) or solubilization of fat (bile acids). Their basic structure is a sterane skeleton, which is modified by side chains and functional groups that give the particular molecule its specific biological activity. Steroids perfectly match the industrial definition of a platform—a set of subsystems and interfaces that form a common structure from which a stream of derivative products can be efficiently developed

Limits of the Metaphor Between the Cell and Manufacturing
In the previous section, we described a set of similarities between the cell’s production principles and modern manufacturing, providing evidence of convergent evolution for both systems.

The difference is IMHO that human production lines are not resulting of evolution, but intelligent design.....

We now examine what insights and lessons we can derive from examining some of the differences between biochemical pathways and current manufacturing systems. Before turning to insight-generating differences (§6), we must first recognize the limits of the metaphor, or fundamental differences that could invalidate parts of it or prevent the transfer of the cell’s production principles to manufacturing.  First, many differences between a cell and industrial manufacturing fall outside the scope of the metaphor—many simply reflect differences in size or materials used and cannot be clearly linked with performance, or are not meaningful within the context of industrial production. For example, the enzymatic reactions in cells all exploit basic chemical equilibria and are, in principle, reversible. This is not true in manufacturing, but since the cell does not really employ this feature in a way that makes it more efficient or more responsive, we did not explore this characteristic further. For other characteristics of cell production, the difference is real and perhaps significant, but their implications would be difficult to imagine or analyze. For example, in biological cells, the basic form of energy, the ATP molecule, is so prevalent that one is tempted to attach meaning to the lack of a clear analogous element, a “currency,” in industrial production. While noteworthy, we did not include an analysis of this difference because it did not lead to clear implications. Second, the cell faces important constraints that limit the usefulness of some otherwise clear analogies. First, as mentioned in the previous section, there are physical constraints on the maximum size of the biological cell, so we have to be careful not to draw any direct conclusions about the right scale of a manufacturing unit. A second constraint faced by one-cellular organisms is that they cannot rely on contract law or memory-enabled reciprocity to establish cooperation among multiple individuals or units. Cells may, therefore, have a stronger need to be autonomous than factories or plants. We take both of these constraints into account when proposing lessons for manufacturing in §7. A final concern is that the biological cell is the result of evolution, not design.

This is evidently false since cells had to emerge fully operational prior DNA replication took place, and consequently, evolution. 

This could raise questions about the usefulness of the cell’s production principles for manufacturing. Consider the cell’s technology, which stabilized about two billion years ago. Before that time, many technologies competed for survival: for example, RNA molecules instead of DNA for the storage of genetic information, ribozymes instead of proteins for biocatalysis, and chemosynthesis as the primary mode of energy production versus photosynthesis today. However, around two billion years ago, the fundamental “cell technology,” with its production system, reached a mature design— i.e., a stable configuration of system components and their interactions. This mature design gained a dominant “market share” of biomass on the planet and has not fundamentally changed since, as it has not been outcompeted by any other technology (although countless numbers of mutations arose). This does not mean this design is perfect; on the contrary, it is known in biology that many basic elements of cells and organisms are evolutionary relics and could be improved upon, but they are stable because they are part of the system. The quirks of evolution may indeed put some limits on the applicability of the cell’s production principles. However, these limits should not be overstated. First, even if evolution comes with some constraints, it does not mean that its solutions should be disregarded. Second, human technologies also display characteristics of evolutionary systems. Take the recent evolution of software as an example. There are still some “Stone Age” routines hidden deep down in modern software (commonly referred to as legacy code) that were written 40 years ago on card punchers, were embedded in large systems, ported to new languages, cross-linked with interfaces, and made invisible to users with layers of user interfaces. These modules may no longer be optimal or efficient; system performance could be improved if they were reengineered. The reason for retention is that reengineering has been infeasible because either the improvements would have to be implemented everywhere (impossible), or the improved versions would lose compatibility and cross-sharing (debilitating). The same is true for manufacturing systems, which contain ancient relics as well (see, for example, the discussion of today’s railway-track-width standard, which may stem ultimately from the Roman warrior chariots, Fine 1998, pp. 40–41). Thus, it seems that manufacturing systems are also constrained by evolution, which should only increase the relevance of the biological cell as a useful template.

Products and Machines Are Built from a Small Set of Common Building Blocks
The cell uses a small set of basic materials to produce an extremely wide variety of tools and products. As production technologies become more advanced, manufacturing may see a similar convergence around a common set of versatile materials. Four nucleotides, twenty amino acids, some saccharides, and fatty acids are the basic building blocks that are used for the synthesis of major cell molecules: DNA, proteins, polysaccharides, and lipids, respectively. These ingredients of life are so universal that nucleotides, amino acids, saccharides, and fatty acids can easily be exchanged across species, usually when they devour one another. A second, lower level of commonality is found in the central metabolism. Here, a limited number of about 30 intermediates can be identified, which serve as precursors for the abovementioned nucleotides, amino acids, saccharides, fatty acids, and many other biomolecules. Interestingly, the intermediates used for “products” and “machines” (enzymes) are identical. In other words, the cell can easily degrade an enzyme into its component amino acids and use these amino acids to synthesize a new enzyme (a “machine”), replenish the central metabolism, or make another molecule (a “product”), e.g., a biogenic amine. It seems an amazing achievement by the cell to build the complexity and variety of life with such a small number of components. Imagine that all industrial machines were made of only 20 different modules, corresponding to the 20 amino acids from which all proteins are made. As we further explain below, this modular approach allows the cell to be remarkably efficient and responsive at the same time. Basically, with both products and machines being built from just a few recyclable components, the cell can efficiently produce an enormous variety of products in the appropriate quantities when they are needed. In industry, parts commonality and material versatility are on the rise, but at a very rudimentary level. For example, supply chains are designed with common processes upfront and the differentiating operations at the end . The Franco-German company, SEW, produces small and medium-size electric motors for a wide range of industrial applications. For a certain line of motors, there are 50 million customer-specific variants, but by clever localization of the customized parts in a few modules of the motor, fewer than a thousand different parts suffice to yield this amount of variety.


Production Equipment Is Added, Removed, or Renewed Instantly
The capacity of the cell’s pathways can be adjusted almost immediately if the demand for its products changes. If the current capacity of a pathway is insufficient to meet demand, additional enzymes are “expressed” to generate more capacity within a certain range. Once the demand goes down, these enzymes are broken down again into their basic amino acids. This avoids waste as the released amino acids are then used for the synthesis of new proteins. At any moment, synthesis and breakdown for each enzyme happen in the cell. The constant renewal eliminates the need for other types of “machine maintenance.” Assembly and disassembly of the cell’s machines are so fast and frictionless that they allow a scheme of constant machine renewal. In some industrial manufacturing settings, we are also witnessing signs of the emergence of flexible capacity. Some of these companies do not repair their manufacturing equipment, but have it replaced. Take, for example, a contract manufacturer in Singapore that provides semiconductor assembly and test services for INTEL, AMD, and others. Its manufacturing equipment includes die bonders, wire bonders, and encapsulation and test equipment, all organized in pools. As soon as one machine goes down, the managers work with the equipment supplier to make a one-to-one replacement. All this goes very rapidly indeed. This policy makes sense because the low cost of a machine compared to the cost of downtime makes it economically feasible to have a couple of machines idle in the somewhat longer repair cycle. One can imagine this practice spreading as manufacturing equipment becomes more standardized and less expensive, and as the cost of a capacity shortage increases. In this scenario, machines are still repaired, although at the supplier site rather than on the manufacturing floor. The cell has pushed this principle even further. First, it does not even wait until the machine fails, but replaces it long before it has a chance to break down. And second, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type, but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances.


Job in the FactoryCell OrganelleFunction of the organelle
Shipping/Receiving DepartmentPlasma membraneRegulates what enters and leaves the cell; where cell makes contact with the external environment
Chief Executive Officer (CEO)NucleusControls all cell activity; determines what proteins will be made
Factory floorCytoplasmContains the organelles; site of most cell activity
Assembly line (where workers do their work)Endoplasmic Reticulum (ER)Where ribosomes do their work
Workers in the assembly lineRibosomesBuild the proteins
Finishing/packaging departmentGolgi apparatusPrepares proteins for use or export
Maintenance crewLysosomesResponsible for breaking down and absorbing materials taken in by the cell
Support beams (walls, ceilings, floors)CytoskeletonMaintains cell shape
Power plantMitochondria/chloroplastsTransforms one form of energy into another


A factory is a facility where goods are manufactured for export.  A factory consumes raw materials and energy in an effort to sustain its workers and provide resources to others.  This is analogous to the functioning of a cell

Cell Factories
The primary objective of research on Cell Factories is to reach a better understanding of how living cells manage to be productive, and how the industry can use these cellular processes to further design and operate safe, efficient, reproducible and sustainable bioprocesses. 14  Information is transferred from stable stored information (DNA) converted to an intermediate (mRNA, rRNA, tRNA) of variable stability, exported from the nucleus to the cytoplasm where mRNA is then translated into Protein. This is gene expression, the products of this process are used either within the cell, exported (exocytosis) or used to replace worn out components. 15

The cell is a factory, that has various computer like hierarchically organized systems of  hardware and software, various language based  informational systems, a translation system, huge amounts of precise instructional/specified, complex information stored and extract systems to make all parts needed to produce the factory and replicate itself, the scaffold structure, that permits the build of the indispensable protection wall, form and size of its building, walls with  gates that permits  cargo in and out, recognition mechanisms that let only the right cargo in, has specific sites and production lines, "employees", busy and instructed to produce all kind of necessary products, parts and subparts  with the right form and size through the right materials, others which mount the parts together in the right order, on the right place, in the right sequence, at the right time,   which has sophisticated check and error detection mechanisms all along the production process, the ability to compare correctly produced parts to faulty ones and discard the faulty ones, and repeat the process to make the correct ones;

highways and cargo carriers that have tags which recognize where to drop the cargo where it's needed,  cleans up waste and has waste bins and sophisticated recycle mechanisms, storage departments, produces its energy and shuttles it to where it's needed, and last not least, does reproduce itself. The salient thing is that the individual parts and compartments have no function by their own. They had to emerge ALL AT ONCE, No stepwise manner is possible, all systems are INTERDEPENDENT and IRREDUCIBLE. And it could not be through evolution, since evolution depends on fully working self-replicating cells, in order to function.  How can someone rationally argue that the origin of the most sophisticated factory in the universe would be probable to be based on natural occurrence, without involving any guiding intelligence?  To go from a bacterium to people is less of a step than to go from a mixture of amino acids to a bacterium. — Lynn Margulis

Molecular machines in biology
http://reasonandscience.heavenforum.org/t1289-molecular-machines-in-biology

It is now clear that most functions in the cell are not carried out by single protein enzymes, colliding randomly within the cellular jungle, but by macromolecular complexes containing multiple subunits with specific functions (Alberts 1998). Many of these complexes are described as “molecular machines.” Indeed, this designation captures many of the aspects characterizing these biological complexes: modularity, complexity, cyclic function, and, in most cases, the consumption of energy. Examples of such molecular machines are the replisome, the transcriptional machinery, the spliceosome, and the ribosome.

Quantum biology 6
One of the simplest and most well-studied examples is the light-harvesting apparatus of green-sulphur bacteria (Fig. 1)


The Cell is a factory.
the Nucleus is the control office.  The cell membrane the security guard and wall. The cytoskeleton is like the support structures.The Cytoplasm is like the Air and the Factory FloorThe endoplasmic reticulum is like the Assembly Line. Ribosomes are information translation devices.  The Golgi Apparatus is like the Alpha and Beta Testers. Lysosomes are like the Janitors. Vacuoles are the Storage Units. The Mitochondria is the Powerplant. Chloroplasts are like the Solar Panels.

Proteins are true nanomachines in charge of most biological roles in living cells, a feat they accomplish by self-assembling into sophisticated 3D structures that exploit thermal, and on occasion chemical, energy to change shape in response to stimuli. 13

The Nucleus is like the control office.
Stores the information for our body/ the factory
controls the cell/factory
most important part of the cell/company

The cell membrane is like the security guard
only lets certain things enter and leave the cell/factory
makes sure the things the cell/factory needs comes in.
makes sure the things that would be bad for the cell/factory can't come in

The cytoskeleton/ the cell wall is like the support structures
Gives support to the building
Gives the building a shape

The Cytoplasm is like the Air and the Factory Floor
Takes up most of the cell's volume
Covers almost all of where the work is being done

The endoplasmic reticulum is like the Assembly Line
The E.R. serves as the site of production for proteins
The assembly line is where all of the products are made

Ribosomes are like the Employees on the Floor
Ribosomes make the proteins, so they are the employees of the cell
The Employees on the floor are the people who make all of the products that are shipped out

The Golgi Apparatus is like the Alpha and Beta Testers
The Golgi Apparatus makes sure the Products put out by the E.R. will work
The alpha and Beta testers are there to make sure the Factory's products come out the way they should

Lysosomes are like the Janitors
The Lysosomes contain digestive enzymes to clean up the cell and get rid of waste
The Janitors always make sure the factory is clean

Vacuoles are like the Storage Units
The vacuole is there for storage
The storage units in a factory store the thing that will be needed for future use

The Mitochondria are like the Powerplant
The Mitochondria break down food molecules to create energy for the cell
The Powerplant of the factory creates energy for the Factory

The Chloroplasts are like the Solar Panels
The chloroplasts are only in some cells (plant cells) and they create energy from sunlight
Not everyone has Solar Panels, and they soak up the energy made by the sun

https://docs.google.com/presentation/d/1wKdTv5AeYQuVF4AcK6jhIhnSUYWEut_8m2dGQrjDXOo/edit#slide=id.g3217d827_0_49

1) https://en.wikipedia.org/wiki/Molecular_machine
2) https://docs.google.com/presentation/d/1wKdTv5AeYQuVF4AcK6jhIhnSUYWEut_8m2dGQrjDXOo/edit#slide=id.g3217d827_0_49
3) http://www.nature.com/scitable/topic/cell-communication-14122659
4) http://reasonandscience.heavenforum.org/t2229-development-of-multicellular-organisms?highlight=multicellular
5) https://en.wikipedia.org/wiki/Cellular_differentiation
6) http://www.nature.com/ncomms/2015/150908/ncomms9224/abs/ncomms9224.html
7) Genetics, Analysis and Principles, 4th edition, page 690
8  Molecular biology of the cell, B.Alberts, 6th ed. page 141
9) https://www.mpg.de/9271053/annual-report-2014-sourjik.pdf
10) http://www.biomedcentral.com/1752-0509/4/82
11) Molecular biology of the cell, B.Alberts, 6th ed. page 737
12) http://reasonandscience.heavenforum.org/t2193-apoptosis-cell-s-essential-mechanism-of-programmed-suicide-points-to-design?highlight=apoptosis[/size]
13) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003694/
14) https://cordis.europa.eu/biotech/src/ab-1.htm
15) https://cellbiology.med.unsw.edu.au/cellbiology/index.php/Cell_Export_-_Exocytosis[/b]



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2 Re: The Cell is  a Factory on Tue Dec 15, 2015 10:08 am

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Information Management for Factory Planning and Design 

Manufacturing   and Factory  location:
In a human factory:
The term manufacturing location represents the external perspective. Within the scope of developing business sectors, market offers, and necessary processes, a suitable manufacturing location has to be selected from a global perspective. Sometimes a web of different manufacturing companies produces subparts at different locations and countries, each factory at a different place producing different parts, which then are sent to a central assembly factory. The whole process must be coordinated and managed. The factories communicate with each other to coordinate the whole manufacturing process. In order to quickly seize opportunities for a complex product or system, a number of factories
can temporarily join together for a project and bundle their processes and resources.
In the cell:
In a developing animal embryo, the four fundamental processes are happening in a kaleidoscopic variety of ways, as they give rise to different parts of the organism. 4 Like the members of an orchestra, the cells in the embryo have to play their individual parts in a highly coordinated manner. In the embryo, however, there is no conductor—no central authority—to direct the performance. Instead, development is a self-assembly process in which the cells, as they grow and proliferate, organize themselves into increasingly complex structures. Each of the millions of cells has to choose for itself how to behave, selectively utilizing the genetic instructions in its chromosomes. The mechanism that sets up the basic body plan of the developing fly is surprisingly precise. ( that is, that coordinates where the individual cells have to be )  Question : had these instructions not have to be pre-programmed through a intelligent  mind?


Morphology of Factory Types
In a human factory:
Various types of factories can be made, depending on the requirement of production. The choosing and decision making of which factory type is required is a mental process.

In the cell:
In developmental biology, cellular differentiation is the process of a cell changing from one cell type to another. Most commonly this is a less specialized type becoming a more specialized type, such as during cell growth. Differentiation occurs numerous times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. 5
The Development of Multicellular Organisms Requires the OrchestratedDifferentiation of Cells 6
Each multicellular organism begins as a single cell. For this cell to develop into a complex organism, the embryonic cells must follow an intricate program of regulated gene expression, cell division, and cell movement. Programming is throughout a mental process.  The developmental program relies substantially on the responses of cells to the environment created by neighboring cells. Cells in specific positions within the developing embryo divide to form particular tissues, such as muscle.

Factory planning:
Factory planning covers all activities in the fold-out, except the installation parts, when developing a (new) factory. It extends from investigating the feasibility of the factory.

Factory design:  
The main result from the factory design is the factory layout.

Information management within factory planning and design:
This part focuses on the information that needs to be managed within factory planning and has a deeper focus on factory design. Information management in this research is not about PLM (Product Lifecycle Management) as many people will relate to. Information management in this research means how all the information within a domain can/should be organized, structured, represented and presented for the best use and reuse, both for humans and applications. This is also the foundation for a good realization of PLM or rather MLM (Manufacturing lifecycle management) in this case.

Factory layout planning:
it is also about the information needed to develop a factory layout. Factory layout can be manufacturing system layout, building layout, or safety layout. flow simulation, scheduling and optimization for fine tuning of the layout.

Equipment supply:  
management of equipment and raw material supply

Process planning:
The focus of process planning is how a part or product should be manufactured in a machine or a manufacturing system. The planning handles the selection of the right type of process, sequence planning, measurement planning, appropriate fixture design etc.

Production Planning and Control



In a human factory:
The control loop, as depicted above, is well suited as a model for planning the production.  Based on these a production planning and control system (PPC) uses various
methods to generate a production plan that is then further broken down into in-house production plans, procurement plans, and supply plans. The key tasks of production planning and control include planning the production program, planning the production requirements, and planning and control of external procurements and in-house manufactured items. Production program planning determines which products should be produced in which quantities during the next planning periods.
In the cell: 
This separation of the DNA from the protein synthesis machinery provides eukaryotic cells with more intricate regulatory control over the production of proteins and their RNA intermediates.

Communication:
In a human factory:
Communication networks must be established and kept during factory operation as well. Material and communication flows, need to be re-integrated constantly. Communication has become a decisive production factor. Whereas mistakes in the physical material flow become evident sooner or later, those in the mental communication flow usually remain hidden.
In the cell:
the relevance of cell communication is quite vast, but major areas of fundamental research are often divided between the study of signals at the cell membrane and the study of signals within and between intracellular compartments.Cell signaling (cell signalling in British English) is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue homeostasis. Errors in cellular information processing are responsible for diseases such as cancerautoimmunity, and diabetes.

Quantity and Variant Flexibility
In a human factory:
one of the predominant characteristics of production in a turbulent market is strong demand fluctuations and a simultaneous increase in the number of variants and their components. Whereas up until now it was possible to at least partially counter the variant problem with a skillful modular construction, the increasing quantity fluctuations pose a dilemma for enterprises. 
There are two basic production concepts :
A rigid production concept, characterized by extensively automated individual processes, linked workstations, long setup times and a small workforce usually operated in 2 or 3 shifts is defined by two limits in the output quantity
The aim of a flexible volume production concept is to cover the volume fluctuations in the market as well as possible by first extending the economic upper and lower limits 



By doing so, an economic production is even then possible when the sales volume is small—most likely due to an adjustable degree of automation. Moreover, it aims to quickly
adjust the technical upper limit, e.g., through modular workstations.

The planning of either a rigid or flexible volume concept is a mental process. 
In the cell:
The environments in which cells grow often change rapidly.6 For example, cells may consume all of a particular food source and must utilize others. To survive in a changing world, cells evolved have designed mechanisms for adjusting their biochemistry in response to signals indicating the environmental change. The adjustments can take many forms, including changes in the activities of preexisting enzyme molecules, changes in the rates of synthesis of new enzyme molecules, and changes in membrane transport processes.Filamentous Structures and Molecular Motors Enable Intracellular and Cellular Movement The development of the ability to move was another important stage in the evolution of cells  design invention  capable of adapting to a changing environment. Without this ability, nonphotosynthetic cells might have starved after consuming the nutrients available in their immediate vicinity.

Networking and Cooperation
External physical network and cooperation:
Of a human factory:
A clear ability to network externally with respect to logistics, organizational aspects, and communications technology has to be ensured in order to effectively co-operate with suppliers, development partners, and customers. Cooperations include development partners (for sub-systems), production partners (for part and component families) as well as logistic partners (for supplying parts, distributing goods and interim storage).
Of the cell:
Signals are transduced within cells or in between cells and thus form complex signaling networks. For instance, in the MAPK/ERK pathway is transduced from the cell surface to the cell nucleus by a series of protein-protein interactions, phosphorylation reactions, and other events. Signaling networks typically integrate protein-protein interaction networksgene regulatory networks, and metabolic networks.
Internal networking and cooperation:
In a human factory:
The functional factory is organized into areas using the same technology through which a number of different products are routed e.g., mechanical processing, electronic manufacturing, and assembly.
In the cell:
Enzymes work in teams, with the product of one enzyme becoming the substrate for the next. The result is an elaborate network of metabolic pathways that provides the cell with energy and generates the many large and small molecules that the cell needs  8
The metabolic balance of a cell is amazingly stable. Whenever the balance is perturbed, the cell reacts so as to restore the initial state. The cell can adapt and continue to function during starvation or disease. Mutations of many kinds can damage or even eliminate particular reaction pathways, and yet—provided that certain minimum requirements are met—the cell survives. It does so because
an elaborate network of control mechanisms regulates and coordinates the rates of all of its reactions. These controls rest, ultimately, on the remarkable abilities of proteins to change their shape and their chemistry in response to changes in their immediate environment.
Proteins in the cell never act alone. Even the simplest cellular functions, such as transport of a molecule across the cellular membrane or defining the site of future cell division, are normally executed by groups of interacting proteins. These groups are best represented as protein networks, where nodes correspond to individual proteins and edges represent their interactions. The more complex the task, the larger and more complex is the underlying network, and ultimately all functional networks can be connected into a cell-wide network. 9
The structure of composite functional modules containing co-transcriptional regulation interaction and protein-protein interaction reflected the cooperation of transcriptional regulation and protein function implementation and was indicative of their important roles in essential cell functions. In addition, their structural and functional characteristics were closely related and suggesting the complexity of the cell regulatory system. 10





Modular organization
Of a human factory:
Starting with adapting the resources primarily in view of reducing overhead costs, business processes were radically reorganized along the value adding chain. Largely autonomous mini-factories were created within the factory from a number of product/ market combinations. Consequently, products and processes were also frequently redesigned to be more modular.

In the cell:
Many proteins, particularly those found in eukaryotic species, have a modular structure composed of two or more domains with different functions. For example, certain transcription factors have discrete domains involved with hormone binding, dimerization, and DNA binding. 7


Size and internal factory space organization, compartmentalization and layout 
In a human factory:
The compartmentalization of production functions and requirements into operational units that can be manipulated between alternate production schemes to achieve the optimal arrangement to fit a given set of needs. In a reconfigurable manufacturing system, many components are typically modular (e.g., machines, axes of motion, controls, and tooling – see example in the Figure below). When necessary, the modular components can be replaced or upgraded to better suit new applications. 


In the cell:




Compartmentalization increases the efficiency of many subcellular processes by concentrating the required components to a confined space within the cell. Where a specific condition is required to facilitate a given subcellular process, this may be locally contained so as not to disrupt the function of other subcellular compartments. For example, lysosomes require a lower pH in order to facilitate degradation of internalized material. Membrane bound proton pumps present on the lysosome maintain this condition.

Recycling Economy
In a human factory:
The products themselves should also be designed so that they consume as few as possible resources that are detrimental to the environment during their use. Moreover, the components and materials contained in them should be reused as much as possible or recycled.
In the cell:
Recycling Endosomes Regulate Plasma Membrane Composition 
most receptors are recycled and returned to the same plasma membrane domain from which they came; some proceed to a different domain of the plasma membrane, thereby mediating transcytosis; and some progress to lysosomes, where they are degraded. Cells can regulate the release of membrane proteins from recycling endosomes, thus adjusting the flux of proteins through the transcytotic pathway according to need. This regulation, the mechanism of which is uncertain, allows recycling endosomes to play an important part in adjusting the concentration of specific plasma membrane proteins.

Waste bin:
In a human factory:
Attention should be paid to manufacturing waste, e.g., metal chips as well as the ancillary and operating materials related to them such as emulsions, lubricants, grease, acids, alkaline solutions, etc.
In the cell:

Improperly processed mRNAs and other RNA debris (excised intron sequences, for example) are retained in the nucleus, where they are eventually degraded by the nuclear exosome, a large protein complex whose interior is rich in 3ʹ-to-5ʹ RNA exonucleases

Controlled factory implosion
Of a human factory:
Sometimes, factories are imploded to provide space for new buildings and new developments. 
In the cell:
apoptosis, programmed cell death
Like engineers carefully blowing up a bridge, cells have intricate, programmed suicide mechanisms. The signal is sent and an apparatus of destruction is activated. But suicide hardly fits the evolutionary narrative. Wasn’t this all about survival, reproductive advantages and leaving more offspring? Why would a cell evolve intricate and complex suicide machinery? 12

The make of machines and factories, and what it tells us in regard of molecular machines in the cell

The most complex molecular machines are proteins found within cells. 1 These include motor proteins, such as myosin, which is responsible for muscle contraction, kinesin, which moves cargo inside cells away from the nucleus along microtubules, and dynein, which produces the axonemal beating of motile cilia and flagella. These proteins and their nanoscale dynamics are far more complex than any molecular machines that have yet been artificially constructed.

Probably the most significant biological machine known is the ribosome. Other important examples include ciliary mobility. A high-level abstraction summary is that, "[i]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Flexible linker domains allow the connecting protein domains to recruit their binding partners and induce long-range allostery via protein domain dynamics. 


Engineering design process

All text in red requires INTELLIGENCE.  

Research
A significant amount of time is spent on locating information and researchConsideration should be given to the existing applicable literature, problems and successes associated with existing solutions, costs, and marketplace needs.

The source of information should be relevant, including existing solutions. Reverse engineering can be an effective technique if other solutions are available on the market. Other sources of information include the Internet, local libraries, available government documents, personal organizations, trade journals, vendor catalogs and individual experts available.

Feasibility

At first, a feasibility study is carried out after which schedules, resource plans and, estimates for the next phase are developed. The feasibility study is an evaluation and analysis of the potential of a proposed project to support the process of decision making. It outlines and analyses alternatives or methods of achieving the desired outcome. The feasibility study helps to narrow the scope of the project to identify the best scenario. A feasibility report is generated following which Post Feasibility Review is performed.
The purpose of a feasibility assessment is to determine whether the engineer's project can proceed into the design phase. This is based on two criteria: the project needs to be based on an achievable idea, and it needs to be within cost constraints. It is important to have engineers with experience and good judgment to be involved in this portion of the feasibility study.

Conceptualization

Following Feasibility, a concept study (conceptualizationconceptual engineering) is performed. A concept study is the phase of project planning that includes producing ideas and taking into account the pros and cons of implementing those ideas. This stage of a project is done to minimize the likelihood of error, manage costs, assess risks, and evaluate the potential success of the intended project.
Once an engineering issue is defined, solutions must be identified. These solutions can be found by using ideation, the mental process by which ideas are generated. The following are the most widely used techniques:
trigger word - a word or phrase associated with the issue at hand is stated, and subsequent words and phrases are evoked.

morphological chart - independent design characteristics are listed in a chart, and different engineering solutions are proposed for each solution. Normally, a preliminary sketch and short report accompany the morphological chart.

synectics - the engineer imagines him or herself as the item and asks, "What would I do if I were the system?" This unconventional method of thinking may find a solution to the problem at hand. The vital aspects of the conceptualization step is synthesis. Synthesis is the process of taking the element of the concept and arranging them in the proper way. Synthesis creative process is present in every design.

brainstorming - this popular method involves thinking of different ideas, typically as part of a small group, and adopting these ideas in some form as a solution to the problem

Design requirements
Establishing design requirements is one of the most important elements in the design process, and this task is normally performed at the same time as the feasibility analysis. The design requirements control the design of the project throughout the engineering design process. Some design requirements include hardware and software parameters, maintainability, availability, and testability

Preliminary design
The preliminary design, or high-level design (also called FEED), bridges the gap between the design concept and the detailed design phase. In this task, the overall system configuration is defined, and schematics, diagrams and layouts of the project will provide early project configuration. During detailed design and optimization, the parameters of the part being created will change, but the preliminary design focuses on creating the general framework to build the project on.


Detailed design

Following FEED is the Detailed Design (Detailed Engineering) phase which may consist of procurement as well. This phase builds on the already developed FEED, aiming to further elaborate each aspect of the project by complete description through solid modeling,drawings as well as specifications.

Some of the said specifications include:
Operating parameters
Operating and nonoperating environmental stimuli
Test requirements
External dimensions
Maintenance and testability provisions
Materials requirements
Reliability requirements
External surface treatment
Design life
Packaging requirements
External marking

Computer-aided design (CAD) programs have made the detailed design phase more efficient. This is because a CAD program can provide optimization, where it can reduce volume without hindering the part's quality. It can also calculate stress and displacementusing the finite element method to determine stresses throughout the part. It is the engineer's responsibility to determine whether these stresses and displacements are allowable, so the part is safe.

Production planning and tool design
The production planning and tool design consist in planning how to mass-produce the project and which tools should be used in the manufacturing of the part. Tasks to complete in this step include selecting the material, selection of the production processes, determination of the sequence of operations, and selection of tools, such as jigs, fixtures, metal cutting and metal forming tools. This task also involves testing a working prototype to ensure the created part meets qualification standards.

Production
With the completion of 
qualification testing and prototype testing, the engineering design process is finalized. The part must now be manufactured, and the machines must be inspected regularly to make sure that they do not break down and slow production.



Factory and machine planning and design, and what it tells us about cell factories and molecular machines

http://reasonandscience.heavenforum.org/t2245-factory-and-machine-planning-and-design-and-what-it-tells-us-about-cell-factories-and-molecular-machines

Some steps to consider in regard of factory planning, design and operation

All text in red requires INTELLIGENCE :

Choosing Manufacturing   and Factory location
Selecting Morphology of Factory Types
Factory planning
Factory design
Information management within factory planning and design
Factory layout planning
Equipment supply
Process planning
Production Planning and Control
establishing various internal and external  Communication networks 
Establishing Quantity and Variant Flexibility
The planning of either a rigid or flexible volume concept depending of what is required
Establishing Networking and Cooperation
Establishing Modular organization
Size and internal factory space organization, compartmentalization and layout 
Planning of recycling Economy
Waste management
Controlled factory implosion programming

All these procedures and operational steps are required and implemented in human factories, and so in biological cells which operate like factories. It takes a lot of faith to believe, human factories require intelligence, but cells, far more complex and elaborated, do not require intelligence to make them, and intelligent programming to work in a self sustaining and self replicating manner, and to self disctruct, when required.  

Molecular machines: 

The most complex molecular machines are proteins found within cells. 1 These include motor proteins, such as myosin, which is responsible for muscle contraction, kinesin, which moves cargo inside cells away from the nucleus along microtubules, and dynein, which produces the axonemal beating of motile cilia and flagella. These proteins and their nanoscale dynamics are far more complex than any molecular machines that have yet been artificially constructed.

Probably the most significant biological machine known is the ribosome. Other important examples include ciliary mobility. A high-level-abstraction summary is that, "[i]n effect, the [motile cilium] is a nanomachine composed of perhaps over 600 proteins in molecular complexes, many of which also function independently as nanomachines." Flexible linker domains allow the connecting protein domains to recruit their binding partners and induce long-range allostery via protein domain dynamics. 

Engineering design process

The engineering design process is a methodical series of steps that engineers use in creating functional products and processes. 2

All text in red requires INTELLIGENCE  

locating information and research
feasibility study 
evaluation and analysis of the potential of a proposed project 
process of decision making. Outlines and analyses alternatives or methods of achieving the desired outcome
feasibility report is generated 
determine whether the engineer's project can proceed into the design phase
the project needs to be based on an achievable idea
concept study (conceptualization, conceptual engineering
project planning 
solutions must be identified
ideation, the mental process by which ideas are generated
morphological chart - independent design characteristics are listed in a chart, and different engineering solutions are proposed for each solution. Normally, a preliminary sketch and short report accompany the morphological chart.
the engineer imagines him or herself as the item and asks, "What would I do if I were the system?" 
Synthesis is the process of taking the element of the concept and arranging them in the proper way. 
Synthesis creative process is present in every design.
thinking of different ideas, typically as part of a small group, and adopting these ideas in some form as a solution to the problem
Establishing design requirements is one of the most important elements in the design process
feasibility analysis
Some design requirements include hardware and software parameters, maintainability, availability, and testability
the overall system configuration is defined, and schematics, diagrams, and layouts of the project will provide early project configuration. 
detailed design and optimization
the preliminary design focuses on creating the general framework to build the project on.
further elaborate each aspect of the project by complete description through solid modeling,drawings as well as specifications.
Some of the said specifications include:
Operating parameters
Operating and nonoperating environmental stimuli
Test requirements
External dimensions
Maintenance and testability provisions
Materials requirements
Reliability requirements
External surface treatment
Design life
considering packaging requirements and implant them
External marking

production planning and tool design


planning how to mass-produce the project and which tools should be used in the manufacturing of the part. 
selecting the material, selection of the production processes, determination of the sequence of operations, and selection of tools, such as jigs, fixtures, metal cutting and metal forming tools. 
start of manufactoring

the machines must be inspected regularly to make sure that they do not break down and slow production



Someone can object and say, that human invented machines do nor replicate, and therefor the comparison is invalid. Fact is however, that replication adds further complexity , since humans have not been able to construct self replicating machines in large scale. This is imho what every living cell is able and programmed to do. In order to so so, extremely complex celluar mechanisms are required, like DNA replication. 

1) https://en.wikipedia.org/wiki/Molecular_machine
2) https://en.wikipedia.org/wiki/Engineering_design_process



Last edited by Admin on Wed Jul 19, 2017 10:36 pm; edited 3 times in total

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3 Re: The Cell is  a Factory on Mon May 01, 2017 6:46 am

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Imagine you would be the most genius inventor of all time, more intelligent than the ten most brilliant and intelligent men of all time, Faraday, Spinoza, DaVinci, Descartes, Galilei, Leibnitz, Newton, Einstein, Goethe, and Terence Tao ( i.Q 230 ) and responsible for the creation  of:

-The Sunway TaihuLight - the most powerful and fastest supercomputer on Earth, installed in China, with 125 petaflops, 10,649,600 cores, and 1.31 petabytes of primary memory, using 10.6 million cores, and five times faster than the fastest supercomputer in u.s.a.
-the world's smallest hard disk' with 500x more storage space than best hard drive,  manipulating chlorine atoms in order to store a kilobyte of data on a microscopic storage drive
-some of the most advanced computer programming languages, like Rust, which runs incredibly fast, SQL, JAVA, Python, C++, and a few more.
-the most Technologically Advanced, extreme Power Plant in the world, a hydropower plant like no other, able to generate as much electricity as a nuclear power plant and, at the flip of a switch, act as a giant battery.
-inventor of the World's largest concentrated solar plant, the Noor complex in Morocco
-the inventor and builder  of the most advanced manufacturing facility in der world, today Tesla's  NUMMI Plant in Fremont, California, accommodating 14000 workers, which on top would have the ability to self-replicate ( which adds a huge quantity of more complex processes ) with fully automated recognition mechanisms and gates that permit  only the right cargo in and out, which has sophisticated check and error detection mechanisms all along the production process,  the ability to compare correctly produced parts to faulty ones and discard the faulty ones, and repeat the process to make the correct ones ( no recall is ever required ) and all this process fully automated and pre-programmed,
- the Most Complicated Watch Ever Made, the Vacheron Constantin Reference 57260 pocket watch with 57 distinct complications, sold for a record of us$ 11 million

now imagine this creator would give you all his inventions as a free gift. And you would not only not recognize him for what he is, did, and gave you for free,  but deny and ignore him completely, as if he would not exist.
Furthermore, you would DESTRUCT his free gift, and blame him for a unperfect job.  

How do you think would he feel with your behavior?

God is that inventor. He made your body and each single cell with:

- a gene regulatory and expression network and a transcription factor code, a  specific and pre-programmed code of gene expression which knows when, where and how to turn a gene on or off to be expressed, transcribed, and translated to produce specific cell products required in the cell for various tasks
- a nucleus, which stores DNA,  the smallest storage device possible and known, a trillion times denser than a CD, and far denser than the world's smallest hard disk,
- the genetic code, equivalent to a computer language, but 1 million times more robust than any comparable code, and less prone to errors
- encoding, transmission, and decoding of the information stored in DNA through a ultracomplex molecular machinery, like RNA polymerase, the Ribosome, chaperones etc.
- mitochondria, the power plant in the cell, which provides energy to your cells, with its amazing, almost 100% efficient ATP synthase machines,  far surpassing even the most advanced human technology
- photosynthesis, about 95% efficient when it comes to the first step of capturing light’s energy, far ahead of any human invented  solar photovoltaic system
- the cell, the most advanced factory,  the most detailed and concentrated organizational structure known to humanity
- circadian clocks, or circadian oscillators, are a biochemical oscillator that oscillates with a stable phase relationship to solar time

his inventive and creative power exceeds anything we could ever imagine or fathom. But we misuse our body, many destroy it with drugs, alcohol, various kinds of addictions, and forget completely about our creator and forget, that our body is not ours, but we are only administrators of it, besides our time, and all goods we receive. We are accountable for all we do.

Its not for nothing, that the apostle Paul writes in 1.Corinthians 3:
16 Do you not know that you are the temple of God and that the Spirit of God dwells in you? 17 If anyone defiles the temple of God, God will destroy him. For the temple of God is holy, which temple you are.

But God in his foreknowledge knew we would decide against him, and provided a solution for all destruction he knew we would provoke.  The bible says that this universe one day will be destructed in flames, and he will create a new place, that is eternal.  And he invites you to become a resident there in the future. All depends on you if you want to go there, or not.

All Things Made New
Apocalypse 21 Now I saw a new heaven and a new earth, for the first heaven and the first earth had passed away. Also, there was no more sea. 2 Then I, John,[a] saw the holy city, New Jerusalem, coming down out of heaven from God, prepared as a bride adorned for her husband. 3 And I heard a loud voice from heaven saying, “Behold, the tabernacle of God is with men, and He will dwell with them, and they shall be His people. God Himself will be with them and be their God. 4 And God will wipe away every tear from their eyes; there shall be no more death, nor sorrow, nor crying. There shall be no more pain, for the former things have passed away.” 5 Then He who sat on the throne said, “Behold, I make all things new.” And He said to me,[b] “Write, for these words are true and faithful.” 6 And He said to me, “It is done![c] I am the Alpha and the Omega, the Beginning and the End. I will give of the fountain of the water of life freely to him who thirsts. 7

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4 Re: The Cell is  a Factory on Tue Jun 20, 2017 8:31 pm

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Biological cells and their extraordinary manufacturing capabilities

It surprises me that the following paper has not been discovered by the ID community yet. A proponent of ID could not have made a better case for ID, than authors of following mainstream science paper did, comparing humanly-made factories and production lines to  Biological cells, which are examples of ID par excellence. The advanced production solutions implemented in cells excel human-made factories, machines, and production lines by far and so point to an intelligent designer/creator. For that reason, I don't think cells are LIKE factories, but they ARE in a literal sense the most advanced factories known in many ways, which following paper outlines extraordinary well. A must read for any advocate and proponent   of ID: following is a resume, the whole paper can be read at the link below at the end:

Organic Production Systems: What the Biological Cell Can Teach Us About Manufacturing
http://pubsonline.informs.org/doi/pdf/10.1287/msom.1030.0033

Biological cells run complicated and sophisticated production systems. The study of the cell’s production technology provides us with insights that are potentially useful in industrial manufacturing. When comparing cell metabolism with manufacturing techniques in the industry, we find some striking commonalities assures quality at the source, and uses component commonality to simplify production.  The organic production system can be viewed as a possible scenario for the future of manufacturing. We try to do so in this paper by studying a high-performance manufacturing system - namely, the biological cell. A careful examination of the production principles used by the biological cell reveals that cells are extremely good at making products with high robustness, flexibility, and efficiency. Section 1 describes the basic metaphor of this article, the biological cell as a production system, and shows that the cell is subject to similar performance pressures. Section 4 further deepens the metaphor by pointing out the similarities between the biological cell and a modern manufacturing system. We then point to the limits of the metaphor in §5 before we identify, in §6, four important production principles that are sources of efficiency and responsiveness for the biological cell, but that we currently do not widely observe in industrial production. For example, the intestinal bacterium, Escherichia coli,  runs 1,000–1,500 biochemical reactions in parallel. Just as in manufacturing, cell metabolism can be represented by flow diagrams in which raw materials are transformed into final products in a series of operations.

With its thousands of biochemical reactions and high number of flow connections, the complexity of the cell’s production flow matches even the most complex industrial production networks we can observe today.  The performance pressures operating on the cell’s production system also exhibit clear parallels with manufacturing. Both production systems need to be fast, efficient, and responsive to environmental change. Speed and range of response, as well as efficiency of its production systems, are clearly critical to the biological cell. Biologists have made the argument that the evolution of the basic structure of modern cells has largely been driven by “alimentary efficiency,” or the input-output efficiency of turning available nutrients into energy and basic building blocks. In addition, it is clear that in dynamic environments, the ability of the cell to react quickly and decisively is vital to ensure survival and reproduction.  Given the “manufacturing” nature of cell biochemistry and the comparable performance pressures on it, one should not be surprised to find interesting solutions developed by the cell that are applicable in manufacturing—especially since “cell technology” is much older and more mature than any human technology. The cell never forecasts demand; it achieves responsiveness through speed, not through inventories.

The limits to responsiveness depend only on the capacity limits of the enzymes in a particular pathway. The corresponding mechanism in manufacturing is referred to as a pull system. It produces only in response to actual demand, not in anticipation of forecast demand, thus preventing overproduction. While it is difficult to make direct comparisons with manufacturing plants, some case examples illustrate that the cell operates with little waste, even in regulating its pathways. In a U.S. electric-connectors factory in the early 1990s, 28.6% of plant labor was devoted to control and materials handling, while the figure was 14.9% in a simpler and leaner Japanese plant. In a house-care products plant, a cost analysis revealed that at least 14% of production costs were incurred by production planning and quality assurance. With its 11% of regulatory genes, the cell seems to set a pretty tight benchmark for regulation efficiency. The cell also uses quality-management techniques used in manufacturing today. The cell invests in defect prevention at various stages of its replication process, using 100% inspection processes, quality assurance procedures, and foolproofing techniques. An example of the cell inspecting each and every part of a product is DNA proofreading. As the DNA gets replicated, the enzyme DNA polymerase adds new nucleotides to the growing DNA strand, limiting the number of errors by removing incorrectly incorporated nucleotides with a proofreading function. An example of quality assurance can be found in the use of helper proteins, also called “chaperones.” These make sure that newly produced proteins fold themselves correctly, which is critical to their proper functioning. Finally, as an example of foolproofing, the cell applies the key-lock principle to guarantee a proper fit between substrate and enzyme, i.e., product and machine. The substrate fits into a pocket of the enzyme like a key into a lock, ensuring that only one particular substrate can be processed.

This is comparable with poka-yoke systems in manufacturing. An everyday example of poka-yoke is the narrow opening for an unleaded gasoline tank in a car. It prevents you from inserting the larger leaded fuel nozzle. The cell’s pathways are designed in such a way that different end products often share a set of initial common steps. For example, in the biosynthesis of aromatic amino acids, a number of common precursors are synthesized before the pathway splits into different final products.  A final concern is that the biological cell is the result of evolution, not design. Consider the cell’s technology, which stabilized about two billion years ago. Interestingly, the intermediates used for “products” and “machines” (enzymes) are identical. In other words, the cell can easily degrade an enzyme into its component amino acids and use these amino acids to synthesize a new enzyme (a “machine”), replenish the central metabolism, or make another molecule (a “product”), e.g., a biogenic amine. It seems an amazing achievement by the cell to build the complexity and variety of life with such a small number of components. Imagine that all industrial machines were made of only 20 different modules, corresponding to the 20 amino acids from which all proteins are made. As we further explain below, this modular approach allows the cell to be remarkably efficient and responsive at the same time.

Basically, with both products and machines being built from just a few recyclable components, the cell can efficiently produce an enormous variety of products in the appropriate quantities when they are needed.  At any moment, synthesis and breakdown for each enzyme happen in the cell. The constant renewal eliminates the need for other types of “machine maintenance.” Assembly and disassembly of the cell’s machines are so fast and frictionless that they allow a scheme of constant machine renewal.  The cell has pushed this principle even further. First, it does not even wait until the machine fails, but replaces it long before it has a chance to break down. And second, it completely recycles the machine that is taken out of production. The components derived from this recycling process can be used not only to create other machines of the same type, but also to create different machines if that is what is needed in the “plant.” This way of handling its machines has some clear advantages for the cell. New capacity can be installed quickly to meet current demand. At the same time, there are never idle machines around taking up space or hogging important building blocks. Maintenance is a positive “side effect” of the continuous machine renewal process, thereby guaranteeing the quality of output. Finally, the ability to quickly build new production lines from scratch has allowed the cell to take advantage of a big library of contingency plans in its DNA that allow it to quickly react to a wide range of circumstances.

Factory and machine planning and design, and what it tells us about cell factories and molecular machines
The Cell is  a Factory
http://reasonandscience.heavenforum.org/t2245-factory-and-machine-planning-and-design-and-what-it-tells-us-about-cell-factories-and-molecular-machines

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5 Re: The Cell is  a Factory on Sat Aug 12, 2017 12:48 pm

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How to recognize high-tech intelligent design in biology, if no he is a construction analogous to the products of human technology?
Such molecular machines, such as engine or bacterial and ATP synthase is almost analogy engines manufactured by man. In other words, they have all the characteristics of advanced technical devices intelligently designed.
Some molecular machines have all the characteristics of high-tech projects, but do not have counterparts in human technology. For example, polymerase, helicase, vesicular transport or the most complex biological machine ribosome.
Do these machines have counterparts in human technology. Do they have all the characteristics of intelligent design? :
http://haha.nu/…/simple-animation-to-explain-complex-princ…/
http://commons.wikimedia.org/…/Category:Animations_of_engin…
http://twistedsifter.com/…/animated-gifs-that-explain-how-…/
https://www.lhup.edu/~dsimanek/museum/machines/machines.htm
http://explain3d.com/
BIOLOGICAL MACHINE. Some of them have analogous counterparts in human and advanced technology others do not. However, they all have the characteristics of high-tech devices and intelligently designed. There are many criteria that allow the recognition of intelligent design in nature.
Helicase:
http://www.youtube.com/watch?v=h9OZL0jOmTU
http://bioslawek.files.wordpress.com/…/helikazxa-z-mareckim…
http://www.youtube.com/watch?v=bePPQpoVUpM
http://www.youtube.com/watch?v=pgLEnjkNNlA
DNA replication:
http://www.youtube.com/watch?v=4jtmOZaIvS0
http://www.youtube.com/watch?v=OnuspQG0Jd0
http://www.youtube.com/watch?v=27TxKoFU2Nw
Sytnhase ATP:
http://www.youtube.com/watch?v=9kP79bTd5aA
http://www.youtube.com/watch?v=PjdPTY1wHdQ
http://bioslawek.files.wordpress.com/…/silnik-desygnat-pomp…
http://bioslawek.files.wordpress.com/…/mc582yn-wodny-dyskus…
Flagellum:
http://www.youtube.com/watch?v=Ey7Emmddf7Y
Spliceosome:
http://www.youtube.com/watch?v=FVuAwBGw_pQ
Bacteriophage:
http://www.youtube.com/watch?v=Dfl4F1R0Hv0
http://www.youtube.com/watch?v=qyaM577oaG4
http://www.youtube.com/watch?v=4PnPNkkfCt4
Vesicular transport:
http://www.youtube.com/watch…
http://www.youtube.com/watch?v=eRslV6lrVxY
http://www.youtube.com/watch?v=q-Er5sEaj2U
http://www.youtube.com/watch?v=u2lieHDDYPY
Kinesin-'molecular truck':
http://www.youtube.com/watch?v=y-uuk4Pr2i8
http://bioslawek.files.wordpress.com/2014/02/t1.jpg…
Mechanical stress activated channels (mechanoreceptors) in the auditory cells (the hairy cells):
http://www.youtube.com/watch?v=1VmwHiRTdVc
http://www.cochlea.eu/…/ouverture-des-canaux-de-transductio…
http://bioslawek.files.wordpress.com/…/cellule-ciliee-d-une…
Ribosomes:
http://www.youtube.com/watch?v=Jml8CFBWcDs
http://www.youtube.com/watch?v=q_n0Ij3K_Ho
http://www.youtube.com/watch?v=ID7tDAr39Ow
http://www.youtube.com/watch?v=D5vH4Q_tAkY

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