How to picture the cell?

  • Thread starter Diderot
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  • #76
atyy
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I would like to make some general points.

1. "Random" is a dangerous word. It is ambiguous without careful definition. An exposition at an elementary level is given in Chapter 21, "Probability and Ambiguity" of Martin Gardner's book. Consequently, one may get into arguments about whether something is random or not, simply by having different definitions of random. Such arguments are purely semantic, and not very meaningful.

2. One of the questions of the OP is closely related to Levinthal's paradox - if a protein folds "randomly", it will take longer than the lifetime of the universe to reach the observed conformation.

The resolution is of course to ask - what is the definition of "random" consistent with the laws of physics to use in this case? One hypothesis is to use a definition of randomness that includes a "bias". Because of the randomness and the bias, protein folding can be described as random and as directed, without contradiction.

http://www.phas.ubc.ca/~steve/publication/PlotkinOnuchic_part1_QRB02.pdf
http://www.haverford.edu/biology/Courses/Bio303/rf_bio303_dill.pdf [Broken]
http://people.virginia.edu/~dta4n/biochem503/ProteinFoldingIandII.pdf
 
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  • #77
Pythagorean
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Diderot said:
Both Pythagorean and Ygggdrasil criticize my statement "Random movement of Lego parts cannot explain a complex Lego car" and both point towards the phenomenon of self-assembly. They are right if a complex Lego car is indeed the most stable structure that Lego parts can form under pressure from Brownian motion. It is not apparent however that this is the case. A ball-like structure seems more likely.

This has more to do with the inadequacies of your analogy (such basic analogies can only be carried so far). And the "most stable structure" isn't the right case for self-assembly. It's the path of least action, that doesn't always lead to the most stable structure for all time. The dynamics are important.

Lock-and-key is a simplification that helps in understanding of basic protein interaction, but it's by no means the whole story:

Choi said:
The activity of most proteins is critically dependent on attaining a unique tertiary structure that can position key amino acid residues for molecular recognition and catalysis. However, upwards of 30% of eukaryotic cellular proteins are predicted to be completely or partially intrinsically disordered (ID) (Uversky and Dunker, 2010). These intrinsically disordered proteins (IDPs) are critical for a variety of essential cellular functions like transcription, gating the nuclear pore and membrane fusion.

Despite lacking the “lock and key” interfaces of folded proteins, ID regions often contain sites of molecular recognition, even in proteins that also contain folded domains (Lee et al., 2000). Disorder has been proposed to enable two modes of ligand recognition: 1) ligand induced folding (Dyson and Wright, 2002), in which the IDP adopts a complementary interface after the initial ligand contact and 2) conformational selection (Tsai et al., 2001), in which binding occurs only if the binding site is preformed or unoccluded before ligand contact. These two binding modes depend differently on the timescale of conformational fluctuation within the IDP. Ligand induced folding necessitates fast structural transitions or ligands will diffuse away before the binding interface is formed (Zhou, 2010). To date there have been no physical measurements to support such differences in IDP conformational dynamics.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075556/
 
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This has more to do with the inadequacies of your analogy (such basic analogies can only be carried so far).
To what do you think my analogy is referring?
 
  • #79
atyy
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One could say that amidst the chaos created by diffusion the 'program of the cell' is being executed. So one could say that this program is offering 'guidance' to the parts in order to maintain the delicate balance of the cell.

Probably not... unless the program is the laws of physics itself, in which case everything runs under its guidance. We generally accept some sort of anthropic principle. That is, the components of the cell work together so nicely simply because that combination of matter happened to work out so nicely. It's not a very satisfactory explanation to the human mind, but it's basically the idea behind selection, which is "half" of evolution (the other "half" being random mutation).

What about the use of the term "program" in
http://www.ncbi.nlm.nih.gov/pubmed/9576829
http://www.ncbi.nlm.nih.gov/pubmed/9115207
http://www.ncbi.nlm.nih.gov/pubmed/19269364
http://www.ncbi.nlm.nih.gov/pubmed/20054295
http://www.ncbi.nlm.nih.gov/pubmed/18555777 ?
 
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  • #80
Pythagorean
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To what do you think my analogy is referring?

cellular processes, what else?

atyy said:
What about the use of the term "program" in

Diderot was explicitly referring to the "program of the cell". Program is somewhat acceptable for cellular processes that rely strictly on a series of genetic "instructions", but to what extent are even these subcellular processes the result of emergent physics? Only the microstructures themselves are a result of a "program" (the genes: the list of instructions). A lot of it is emergent, such as the dynamics and the macrostructures.

And of course, the programs anyway, are a result of physics of long temporal scales. We isolate a particular set of molecules and the way they interact and call it a program, but it's a goal-oriented program like a software engineer would write.
 
  • #81
atyy
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Diderot was explicitly referring to the "program of the cell". Program is somewhat acceptable for cellular processes that rely strictly on a series of genetic "instructions", but to what extent are even these subcellular processes the result of emergent physics? Only the microstructures themselves are a result of a "program" (the genes: the list of instructions). A lot of it is emergent, such as the dynamics and the macrostructures.

Somewhat acceptable? I can find many more references. Those I gave you include "Cell" and "Nature". Not that the results have to be correct, but I would imagine they indicate very acceptable usage. Here are more examples, where it is used in "homeostatic program".

http://www.ncbi.nlm.nih.gov/pubmed/17113390
http://www.ncbi.nlm.nih.gov/pubmed/22053049
http://www.ncbi.nlm.nih.gov/pubmed/19594634

Edit: Here's another example "Checkpoints are comparable to the program in a washing machine that checks if one step has been properly completed before the next can start. Checkpoint defects are considered to be one of the reasons behind the transformation of normal cells into cancer cells." http://www.nobelprize.org/nobel_prizes/medicine/laureates/2001/presentation-speech.html
 
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  • #82
Pythagorean
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Regardless, there's no "program of the cell".
 
  • #83
Ygggdrasil
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- About diffusion as a transport mechanism -
Earlier I wrote: “So the different bits must all be highly specified and have just one possibility to fall into place”. This is in line with the ‘lock and key theory’; mentioned by Darwin123. However in case of multiple identical locks and keys, there are also multiple places (locks) for the individual keys and vice versa.

The lock and key theory is not applicable to the phenomenon of 'self-assembly' of identical parts into ordered structures, because all the particles are identical. The emergence of these ordered structures must be explained by the tendency of parts to form the most stable structure when under pressure from Brownian motion (or when being shaken as in the movie).

Both Pythagorean and Ygggdrasil criticize my statement "Random movement of Lego parts cannot explain a complex Lego car" and both point towards the phenomenon of self-assembly. They are right if a complex Lego car is indeed the most stable structure that Lego parts can form under pressure from Brownian motion. It is not apparent however that this is the case. A ball-like structure seems more likely.

Yes, you are essentially correct. Self-assembly will not work unless it is driven by the conversion of chemical potential energy into heat. That said, protein-protein interactions are driven by these forces, which explains how exothermic binding reactions can drive the transport of molecules to specific compartments of the cell through Brownian motion alone.

Also, self-assembly processes can produce structures that are non-spherical. Just look up DNA nanotechnology, which can create nearly any arbitrary 2D or 3D shape.
 
  • #84
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This has more to do with the inadequacies of your analogy (such basic analogies can only be carried so far).
To what do you think my analogy is referring?
cellular processes, what else?
The Lego analogy was referring to imaginary cell parts without difference in shape and way too many possibilities to connect. The analogy is part of step by step reasoning towards the necessity of highly specified parts (very much unlike Lego parts).
If the different bits have the possibility to form all sorts of chemical bonds the only result can be chaos.
Random movement of Lego parts cannot explain a complex Lego car.
So the different bits must all be highly specified and have just one possibility to fall into place.
There is no point in telling me that the analogy is inadequate in regard to real cellular processes, because that is exactly what I’m trying to point out.
 
  • #85
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The motion of the molecules is not directed by any intelligence, so far as we can tell. So far, the molecules seem to be governed by the same rules of physics as is the case in nonliving organisms.
ScienceDaily (Sep. 16, 2012) — Johns Hopkins scientists report what is believed to be the first evidence that complex, reversible behavioral patterns in bees -- and presumably other animals -- are linked to reversible chemical tags on genes. http://www.sciencedaily.com/releases/2012/09/120916160845.htm
> The question is: 'who is controlling the epigenetic switchboard’? <
 
  • #86
atyy
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The motion of the molecules is not directed by any intelligence, so far as we can tell. So far, the molecules seem to be governed by the same rules of physics as is the case in nonliving organisms.

ScienceDaily (Sep. 16, 2012) — Johns Hopkins scientists report what is believed to be the first evidence that complex, reversible behavioral patterns in bees -- and presumably other animals -- are linked to reversible chemical tags on genes. http://www.sciencedaily.com/releases/2012/09/120916160845.htm
> The question is: 'who is controlling the epigenetic switchboard’? <

Intelligence, to the extent that it is a useful concept(s) in science, never means that the laws of physics are violated. As an example, this link from the evolution faq uses the term "intelligence" in a way consistent with the underlying laws of "physics" (in that artificial world). http://boxcar2d.com/index.html

I don't know about the specific case in the Feinberg paper, but there is a notion of "swarm intelligence" applicable in some circumstances to bees. http://www.scholarpedia.org/article/Swarm_intelligence

Here is a free article that discusses some molecular details that may be relevant.
http://www.ncbi.nlm.nih.gov/pubmed/15572455
"Here, we report on the identification of a substance produced by adult forager honey bees, ethyl oleate, that acts as a chemical inhibitory factor to delay age at onset of foraging. Ethyl oleate is synthesized de novo and is present in highest concentrations in the bee's crop. These results suggest that worker behavioral maturation is modulated via trophallaxis, a form of food exchange that also serves as a prominent communication channel in insect societies. Our findings provide critical validation for a model of self-organization explaining how bees are able to respond to fragmentary information with actions that are appropriate to the state of the whole colony."
 
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  • #87
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The Lego analogy was referring to imaginary cell parts without difference in shape and way too many possibilities to connect. The analogy is part of step by step reasoning towards the necessity of highly specified parts (very much unlike Lego parts).

There is no point in telling me that the analogy is inadequate in regard to real cellular processes, because that is exactly what I’m trying to point out.
And he is pointing out that it is your analogy, having nothing to do with any response others have made to your OP.
Leggo blocks are interesting in that they have been designed to have multiple connection points so that there is no one stable configuration to them. Oddly, this is the opposite of what you are saying. The shapes were carefully designed so that one can make more than one shape. In this case, the corporate chaos in their configuration is the result of design. Leggo's were designed to be random.
Not much different from the computer simulations that impressed you as being random. You did not see pictures of actual molecules forming structures with random motions. These were make believe molecules that were following random paths. The thing is that there could not be any mystical purpose to their motion because these cartoon molecules were programmed not to have any order in their motion.
You initially said that there had to be some order in the motion of the molecules that was the result of some programming or purpose. However, the motion that you saw had actually been programmed not to show any order. Random number generators were used, but the final results are independent of the random number generator chosen. There was no specific random number generator necessary to make the order emerge.
The order that you saw emerge from the cartoon molecules was not due to any organized motion. It came from their initial shapes. I conjecture that you are now going to claim that the shapes had to be programmed according to a certain order. However, that is an issue separate from the initial one of this thread. However, I did try to address that second issue already by referring to a study by Lenski and Blount.
The specific shapes are also due to another type of random variation in the heredity of the organism. Physically, the variation in heredity is random. Scientists have studied the physical processes of inherited variations such as mutation. Again, the direction of inherited variation is for the most part random. They arise through the random motion of molecules, that were already discussed. There is no programming in mutation. So how come the results of many accumulated variations show order? For instance, why do the molecules and processes show shapes far more specific than any Leggo block?
The shapes are determined by a highly unrandom process called natural selection. It is natural selection that makes a generalized shape into a very specific one.
I posted a link about an article by Lenski and Blount. This article showed how random mutations accumulated into very specific chains of chemical reactions. The shapes of some of the molecules changed to make certain chemical reactions more probable and other chemical reactions less probable.
The experiment was very tightly controlled so that each mutation could be tracked back to the original ancestor to whom that mutation occurred. For instance, the bacteria in their experiment were castrated! The cells were mutilated so that they couldn't perform any process similar to sexual reproduction. All these bacteria could do is split. They had to reproduce asexually.
Note that this would have seriously restricted the amount of variation that was possible. Castration should have prevented the bacteria from reaching their full evolutionary potential. The changes observed in this experiment were less than what would have been seen in "wild type" bacteria.
What were seen were huge changes in the chemistry of this bacteria. The castrated bacteria, among other things, evolved to consume citrate in an oxygen atmosphere.
There would probably have been even more amazing changes for a viral bacteria. More sex, more recombination, more inherited variation, and more evolution. So why were the bacteria castrated? To prove something that you are trying hard not to believe.
By tracking each mutation back to the source, Lenski and Blount proved that the mutations were random. No mutation occurred that was so complex it required a programmer to design. These were all "small" mutations. No miracle occurred in any one generation. They could prove it because they could track the changes.
So here is an example where natural selection, acting on "random mutations", resulted in an "improbable" change. The individual changes were random. However, the accumulated change was not random.
One other thing that may help you understand is the "organized" shape of a snowflake.
Usually we see snowflakes that are clumped together. So few people, at least the urban ones, have seen snowflakes just after they were formed before collision. However, I have been in the country in areas where the snowflakes fall without interference. They are intricate six-fold shapes with amazing order to them.
A few snowflakes are identical. Maybe as many as two snowflakes in a thousand are identical. However, this is a small fraction. The vast majority of snowflakes are not alike. They have amazing variety, yet each type of snowflake shows unmistakable order. Here is something you should consider.
The shape of a snowflake has nothing to do with programming either. A snowflake forms by diffusion. The water molecules in vapor are moving randomly. The water molecules, although simple, have specific shapes. However, each water molecule has a trajectory and an orientation that is random.
The order comes from another type of natural selection. The sticking probability of a snowflake is biased by heat exchange with the atmosphere. The water molecules tend to stick at points on the flake, not flat areas. So a region with lots of points gets more water vapor to make even more points. In other words, the points reproduce with survival of the fittest.
The variation in snowflakes is caused by random variation modulated by a selection process. It isn't selection in the sense of an organism. The selection does not have purpose as animals understand it. However, it is selection. The selection shapes the random process into an order pattern.
Diffusion does result in order. Small variations can accumulate with selection into an ordered pattern. That is self assembly.
 
  • #88
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ScienceDaily (Sep. 16, 2012) — Johns Hopkins scientists report what is believed to be the first evidence that complex, reversible behavioral patterns in bees -- and presumably other animals -- are linked to reversible chemical tags on genes. http://www.sciencedaily.com/releases/2012/09/120916160845.htm
> The question is: 'who is controlling the epigenetic switchboard’? <
I can do one better. I saw a demonstration just yesterday of plastic pieces, not directly controlled by anything, self assemble into a sphere. Here are links to similar demonstrations. You can watch the video and tell us who is controlling the switchboard of these plastic pieces.
The links have a video showing the self assembly of a model of the polio virus. Olson used a computer to carve models of pieces of the polio virus capsid. Magnets were placed at the edges of the pieces. The pieces fit together to form a spherical shaped body, which is a model of the entire polio virus.
I just attended a seminar by Olson where he demonstrated this “self assembly” among other things. After I the seminar, he let me shake the container myself. The sphere rearranged several times when it was “softly” shaken. Note that one can see many failed “attempts” by the pieces to rearrange themselves. However, these intermediate forms fall apart. The final result is one of two stable forms for the polio capsid.
Olson places the sphere in a sealed container. When he shakes vigorously, the sphere breaks up into separate pieces. When he shakes gently, the pieces assemble into the sphere.
One caveat. Without a core, there are two stable forms of the capsid. One stable form has a trapped piece inside the nearly assembled capsid. There is a hole in the capsid. Olson assured me that could be prevented by placing a model of the RNA core in the container. That is closer to the situation in a real cell, where the stable form with the hole doesn’t occur. However, he didn’t include the core in the container that I shook. the version of the simulation that I took part in had two outcomes. A capsid with a hole in it occurred about half the trials.
The motion is not “programmed”, beyond the amplitude of the shaking. The vigor of the shaking is analogous to temperature. However, the motion of the pieces is random. This is how the OP originally framed her question. The statement is there had to be some will governing the motion of the pieces. This clearly is not true.
If there is programming involved, then it is in the shapes of the separate pieces. There is no purpose and no will to the individual motions.
He also described experiment where he mixed two types of pieces of opposite chirality. When shaken, the mixture formed two polio virus models of opposite chirality. So the fact there is more than one “stable structure” is irrelevant. The random motion ends up separating the assembled pieces. I didn’t see that demonstration, but I have no difficulty believing it.
He also claims to have done the experiment with an automatic shaker. The pieces still assembled. There was no programming in the shaker. When the shaking was restricted to a range of vigor, the sphere self assembles.

Short link showing just the self assembly of the polio virus model.
”Arthur Olson (www.mgl.scripps.edu [Broken]) gives a very engaging demonstration of how molecular recognition and self-assembly can be explored using an innovative, hybrid user interface that combines 3D solid printing…”

Longer video with a more complete lecture. Basically, he is talking about a new type of computer interface which he used in making these pieces of polio virus. However, this discussion may give you a better idea of how biochemists see the universe.
http://vimeo.com/26198903
“Arthur Olson (mgl.scripps.edu) gives a very engaging demonstration of how molecular recognition and self-assembly can be explored using an innovative, hybrid user interface that combines 3D solid printing and his own augmented reality environment. He argues that a synthesis of both abstract & 3D visualization is needed to understand biological processes. He then presents impressive, cutting-edge methods for fast, integrated, and large-scale macromolecular visualization. This talk was presented at VIZBI 2011, an international conference series on visualizing biological data (vizbi.org) funded by NIH & EMBO. This video was filmed and distributed with permission under a creative common license.”
 
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