Details Of Nuclear Pore Complex With Spin

_{Mark

January 31, 2008

Intelligent Design}

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(Credit: Image courtesy of Rockefeller University)

From ScienceDaily (Jan. 30, 2008) A cell’s membrane-bound nucleus uses hundreds to thousands of nuclear pores as its gatekeepers, selective membrane channels that are responsible for regulating the material that goes to and from a cell’s DNA. Rockefeller scientists have nailed down the first complete molecular picture of this huge, 450-protein pore and their findings provide a glimpse into how the nucleus itself first evolved.

The group gathered and analyzed massive amounts of data to come up with a rough draft of the structure of the nuclear pore.

The scientists’ results have given them a peek into the early evolution of eukaryotic cells. Compartmentalization was made possible by membranes and coating complexes, which act “like little hands” to grab, shape and stabilize membranes.

“We think that once the cells gained this coating complex, they ran with it and started to duplicate it and specialize it,”

“Evolution is a process of duplication and divergence,” Rockefeller professor Michael Rout says. He and his colleagues saw clear evidence of this. For every protein, there was another one that looked quite similar. “These are evidence of duplication events, showing that the evolution of the complicated nuclear pore was a more straightforward affair than previously thought. It’s made of many different variations of a theme of just one unit.”

“The nuclear pore is the communication device that the nucleus uses to communicate with the rest of the cell. And if you don’t understand how that works, you don’t understand a key part of how the cell works. You have to see the cell as a machine and understand all of its parts.”

refs Nature 450(7170): 683–694 (November 29, 2007): Nature 450(7170): 695–701 (November 29, 2007) Watch the movie here.

Comments

Re-reading my last comment I realized that the last sentence came out sounding wrong. I am very interested in any prediction/hypothesis that can be developed from an ID perspective that is not already pursued by biologists. And, I am certain, so are researchers that work on the NPC. In the end, researchers are much more result-driven (rather than ideology driven). If they have a chance to figure out something important about the function of the NPC within the cell, they will jump on that opportunity, irrespective of where the idea came from (ID proponent, Engineer, Biologist, Mathematician, ...).hrun0815_{February 5, 2008
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What are the proteins and transport mechanisms related to NPC HOW do they work. What are the material and energy flows? etc. These are all generic research.
DLH, I am glad that from post to post we agree more and more. Previously, you asserted that all these approaches were specific to a design perspective or teleological approach. But it's great we now agree they are just generic research based on trying to figure out how stuff works. Great!
To test whether they have arisen via evolution vs via design: ID would predict that systems are regulated, and search for those.
So again (I'm sorry if it appears that I am repeating myself), how would ID research differ from the research currently underway. Considering that there are nearly 1 million publications in PubMed alone that contain the word 'regulation', clearly all those researchers without a 'design perspective' are aware that a) life is regulated and b) that it's an important topic to study.
I know of no basis in RM & NS to predict regulation other than assuming it exists because self reproducing life is presumed.
DLH, remember that without self reproducing life there can be no RM&NS-- So of course RM&NS presumes the presence of self reproducing life.
ID would expect selective dedicated transport mechanisms rather than diffusion as more energy and material efficient.
Well, funny thing is, the NPC actually works by diffusion. It's very clearly explained in the NPC Nature papers and in the Pemberton review. That's the interesting part-- the NPC does NOT work how humans would go about designing a transporter. But in the end, that's somewhat irrelevant.
Evolution can claim that this arises out of “natural selection”, but the probabilities of that quantitatively happening are astronomically remote beyond all credibility.[...]
So now we are reduced to discussing what evolution can and can not do. I agree those are interesting topics, but not really what I set out to argue about here. The premise of your first post was to look at the data presented in these papers from an ID perspective. So far I have not seen a single thing that would indicate that this perspective brings anything new to the table (other than the NPC could not have evolved).
More later on stoichiometric ratios of pores to DNA as an ID predictive hypothesis.
I'll be here, waiting.hrun0815_{February 4, 2008
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What are the proteins and transport mechanisms related to NPC HOW do they work. What are the material and energy flows? etc. These are all generic research. To test whether they have arisen via evolution vs via design: ID would predict that systems are regulated, and search for those. I know of no basis in RM & NS to predict regulation other than assuming it exists because self reproducing life is presumed. But I claim that begs the question. ID would expect selective dedicated transport mechanisms rather than diffusion as more energy and material efficient. Evolution can claim that this arises out of "natural selection", but the probabilities of that quantitatively happening are astronomically remote beyond all credibility. IS would posit that components are well designed and matching, and that mutations will almost always cause degradation or destruction of function. e.g. Sanford cites published estimates of 1 million to 1 for harmful vs beneficial mutations. Knock out experiments can efficiently show essentiality. The Online Mendellian Inheritance in Man documents the "experiments" and harmful consequences of mutations in peoples lives. (18,000 entries last I checked.) Evolution needs small gradual changes with positive selection for each one. The biochemical evidence of harmful impact of mutations and the cumulation of near neutral mutations flies against all evolutionary hand waving. Finding such small gradual beneficial changes if they exist would quickly consume all research budgets and computing power for even very small systems. Unless the NPC or transport structures are related to disease, I would not expect much quantitative effort in exploring large numbers of mutations. I look more for the 1000 genome project to provide quantitative results to then see what mutations have survived. More later on stoichiometric ratios of pores to DNA as an ID predictive hypothesis.DLH_{February 4, 2008
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Ah, there is the rub. BUT do they dare publish that and state that there is no Neo-Darwinian method known to achieve those, and thus ID must also be considered? Instead, we have vociferous opposition to any mention of irreducible complexity because of its implications - BUT instead we have mandated RM & NS because of its atheistic implications.
Unfortunately, I have to respectfully disagree with you here. Think about it: Do you believe that Rout et al think that the NPC is assembled from well matched components that (if reduced by mutation to the smallest functional core) would cease functioning if a further component was removed? Certainly! Indeed, many researchers are performing those very same experiments. However, Rout et al also publish a whole paper on the evolution of the NPC from coated vesicles. So, none of the facts get denied and no RM+NS is being mandated. Merely, the conclusion that IC systems are impossible to generate by evolutionary processes are denied. I'm not here to rehash that argument. Clearly that would go beyond this thread. Suffice it to say, I think this thread has clearly shown that the researchers are already studying all the possible hypothesis that you proposed from a design perspective. You claim this is due to an implicit 'design approach' by the researchers. I doubt that this is the case. But, as I said, it is impossible to disprove. We find ourselves now in a position where I claim the researchers clearly don't have a 'design perspective'. You claim that the researchers do the research because they completely internalized the 'design perspective'. In either case, it seems that we both agree that the 'design perspective' would not change the NPC research. I find that rather surprising, but I'm happy we at least can agree on that.hrun0815_{February 4, 2008
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Yes, but I expect 99.99% of them have not logically or quantitatively considered how such regulatory systems could arise from atelic presuppositions. Everyone is so used to controlled or regulated systems, that they have not grasped what it would mean to start without ANY regulation, and thus with no self reproducing cell.
You are absolutely correct. On a day-to-day basis, most biological researchers don't concern themselves much with were the first cell might have come from. I don't see what that has to do with the function and evolution of the NPC. As I said, you can study the function of the NPC independently of where it came from. And it appears that the approach (whether a designer designed the first cell or if it came about by other means) would change much one way or another.hrun0815_{February 4, 2008
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hrun0815
I can truly not believe that you are arguing that researchers who content that, for example the NPC is a product of evolution and not of a designing entity would have to study the NPC by taking ‘measurements at random times and with random parameter settings’.
I agree. I am not expecting researchers to conduct "atelic" experiments. Just to think of even how to conduct an experiment in an atelic fashion to begin to faintly grasp what "atelic" means. I would still expect researchers to do prepare professional Design Of Experiments, when testing atelic theories. See for example the quantitative measurement of the probability of single and them multiple mutations persisting and being fixed in reproducing microorganisms. You earlier said:
However, no biologist that I know of, though, disagrees that there are numerous IC structures in cells if the most basic definition of IC is used (complex functional unit consisting of multiple well matched parts, each of which is essential to the function of the whole unit).
BUT do they dare publish that and state that there is no Neo-Darwinian method known to achieve those? Ah, there is the rub. And do any dare mention that ID might also be considered? Instead, we have vociferous opposition to any mention of irreducible complexity because of its implications - BUT instead we have mandated RM & NS because of its atheistic implications. Such is the fascist control of atheistic presuppositions over majority science. Much of the discussion has been jumping into the middle of a particular example without the benefit of the larger picture and developed goals and guiding design principles. I will have to work on writing that up to show how this all fits together. Apologize that this blog has been much more stream of consciousness bits and pieces. On "well matched", See Behe's Darwin's Black Box and his explanation of the components of the mouse trap needing to be sized to each other. Many of the things that may seem obvious on the Nuclear Pore relative sizing, need to be examined and detailed when you are positing atelic vs telic design considerations. Particularly, how do those relative well fitting parts come about all together in the right time in the right order with assembly methods and structures etc.DLH_{February 4, 2008
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DLH
Do you know of any neo-Darwinian model that shows that the four laws of nature that can explain regulation?
See stochastic events based on the Strong Nuclear force, Weak nuclear force, electromagnetism and gravity. hrun0815
Biologists study regulation all the time without resorting to any mythical power that would fall outside any law of nature.
Yes, but I expect 99.99% of them have not logically or quantitatively considered how such regulatory systems could arise from atelic presuppositions. Everyone is so used to controlled or regulated systems, that they have not grasped what it would mean to start without ANY regulation, and thus with no self reproducing cell.DLH_{February 4, 2008
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My challenge on “atelic” experiments is to step back and realize how ingrained design is to try to actually envision “atelic” systems. Design of experiment (DOE) is so natural that thinking how to do an experiment without it is to help think what atelic really means. e.g. take measurements at random times and with random parameter settings. What is the probability of identifying useful results?
Ok, DLH, I think we have arrived at an impasse. I can truly not believe that you are arguing that researchers who content that, for example the NPC is a product of evolution and not of a designing entity would have to study the NPC by taking 'measurements at random times and with random parameter settings'. Are you really serious about this? Is this how intelligent design proponents define experiments from an atelic point of view? If that is the case, then you are absolutely right. All those biologists perform experiments from a 'design perspective'. After all, they are intelligent and they design experiments. Voila, Intelligent Design. But if that is the case, then ID is alive and well, performed every single day in tens of thousands of biology labs throughout the world. And, in the end, it still strengthens my point: What would be the difference between the research being done right now (e.g. on the NPC) and research from a 'design perspective'. I'd be happy (is anybody is still following this thread) for other design advocates to clarify if they share DLH's view on 'atelic' research.hrun0815_{February 4, 2008
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hrun0815 There are multiple overlapping issues. 1) ID as a theory that can detect intelligent causation. 2) ID as applied as an origins theory to detect an intelligent designer evident in biological systems and/or cosmological systems. 3) Developing ID as a descriptive theory of nature. 4) Developing ID to then have predictive power. 5) Conducting research based on ID predictions. 6) Distinguishing ID from atellic origin theories, eg acknowledging microevolution while differing non macroevolution. 7) Distinguishing research conducted to test tellic vs atellic predictions. My challenge on "atelic" experiments is to step back and realize how ingrained design is to try to actually envision "atelic" systems. Design of experiment (DOE) is so natural that thinking how to do an experiment without it is to help think what atelic really means. e.g. take measurements at random times and with random parameter settings. What is the probability of identifying useful results? In some ways Darwin was begging the question by starting with living reproducing systems and applying RM & NS, without examining if that foundation was from abiogenesis or revealed design. I hold that natural selection incorporates "cells come from cells" together with numerous regulated systems, which are evidence of design. Thus the research tasks of: R1) Search for symptoms of regulation. R2) If found then search for the components of that regulated systems are inherently from a design perspective, not an atelic perspective. Thus my exploring what parameters vary by concentration across the nucleus membrane and/or by time was searching for regulated systems. On the NPC research, distinguish between the modeling / experimental results, and then the effort to fit those results into an "evolutionary" perspective. Many of the arguments given can equally be described from an ID perspective. Examine where models were shown that would give any quantitative estimate of how that could come about, or how the nucleus could function while random mutation and supposed natural selection achieved this wondrous Nuclear Pore Complex & associated Transport structures. See Genomic Entropy and the Mystery of the Genome by John Sanford. Statistically mutations destroy far faster than possible "positive" mutations - especially if you do not have a self reproducing system to begin with.DLH_{February 4, 2008
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I submit that people are so used to recognizing and practicing design that what you say is “non-tellic” incorporates design through and through.
So IF this is indeed true and if, as we found in this thread, the researchers are already performing all the research that would be indicated from a teleological perspective, then the scientific research at our Universities should be in pretty good shape, right? Now, if we found a good hypothesis from a design perspective on the NPC that is not actively being pursued (or has already been performed), then things would be quite different. However, I still am quite perplexed that you commend these researchers multiple times on this brilliant research project, yet still consider them sufficiently 'confused' that they can publish a) a paper that deals exclusively with the evolution of the NPC from a more primitive structure and b) perform all their research from a design perspective. PS, I just saw this part of your post:
DLH: consider “atelic” experiments that are not allowed to use any “Design of experiment”, since that by definition includes design in the experiment.
Are you suggesting that the design of an experiment by a researcher is already a case of using a design perspective or a teleological approach? I must be misunderstanding this.hrun0815_{February 4, 2008
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I challenge you to examine whether research allegedly planned from an “atelic” perspective - without purpose or design - is actually without design.
So you are no back to asserting that these smart folks are in a way unknowingly performing their research from a design perspective? See comment #23, #24 and #25. I can't argue against this in any way. All I have to say is this: the 'atelic' perspective does not deny functionality. All the predictions from a design perspective you have made in this thread follow equally from an atelic point of view. As I said, nobody denies that the NPC has a function and performs it well. Whether some being created the NPC to perform this function is immaterial to studying said function. And I think that becomes abundantly clear when we compare your suggestions to what is actually done.
Do you know of any neo-Darwinian model that shows that the four laws of nature that can explain regulation?
What do you mean? Biologists study regulation all the time without resorting to any mythical power that would fall outside any law of nature. (Regulation gets nearly 1 million hits on PubMed.)hrun0815_{February 4, 2008
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hrun0815 I challenge you to examine whether research allegedly planned from an "atelic" perspective - without purpose or design - is actually without design. I submit that people are so used to recognizing and practicing design that what you say is "non-tellic" incorporates design through and through. e.g., consider "atelic" experiments that are not allowed to use any "Design of experiment", since that by definition includes design in the experiment. On Life is Regulated Do you know of any neo-Darwinian model that shows that the four laws of nature that can explain regulation? - Especially regulation in the first cell? Yet regulation is inherent in most electrical and mechanical engineering designs. Thus, regulation appears to be a natural result of intelligent causes.DLH_{February 4, 2008
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On your previous question of consequences of IC, I would put error proofing and deleting as one of the symptoms of being designed.
Why would error proofing follow from IC? Are there no IC structures that come without error proofing?
Restating ‘Well matched”: Design parameters have critical tolerances. The concept Irreducibly Complex overlaps the design summary: Life is Regulated
I am surprised at the broad generality of these statements. I certainly agree with both of them. Design parameters do have critical tolerances and life is regulated. But who would disagree? ALL components of a functional unit have critical tolerances. For that to be true they don't have to be designed. For example, I bet that for every component of anything failure will occur if the temperature is increased sufficiently. Thus, there is a critical tolerance. What does that specifically tell us about studying the NPC from a teleological point of view? In the end, I guess, it comes back to what I said in my previous post: Does it come as a surprise to you that the teleological ID approach (to study e.g. the NPC) is apparently no different from the non-teleological biological approach?hrun0815_{February 4, 2008
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1) There will be a normal allowable size range for mediated transport. 2) There are tolerances for docking requirements of macromolecules onto the transport molecules. I.e., transport plus load must fit within the Nuclear Pore Complex. 3) Larger molecules must be expressed inside the nucleus, or transported through the wall in components and assembled inside. E.g., compare the international space station compared with the size limitation in the rocket payloads.
DLH, locking at the Pemberton and Paschal review, do you think any of these three hypothesis differ in any way from what non-teleological researchers might hypothesize about NPC function (or in fact have already extensively studied in the past 20 odd years)? Frankly, so far I have seen only three types of 'teleological predictions/hypothesis' about the NPC in this thread: 1) predictions that are already invalidated by observed facts (e.g. RanGTP gradient important for scaling) 2) predictions that have already been made and confirmed by non-teleological researchers (e.g. redundancy of NPC, cargo size limitations, ...) 3) predictions that are currently under investigation by non-teleological researchers Does it come as a surprise to you that the teleological ID approach is apparently no different from the non-teleological biological approach?
Modeling the flexibility of the mediated transport of macromolecules compared to the nuclear pore complex will be a key challenge.
I don't understand this sentence. Could you clarify?
As from Roman chariot to space shuttle booster, the mediated transport through the Nuclear Pore Complex has consequential design implications of maximum size for all related macromolecules that need to be transported through the cell nucleus wall.
If I understand you right, this is not so much a prediction about the NPC as it is a prediction about structures assembled from components that passed through the NPC. Again, do you really think that a teleological approach is required to hypothesize that the size of the NPC limits the size of components that can be utilized in the cell (if these components are required to be transported through the NPC)? Why would this very general statement be obviously true if the NPC was designed but NOT obviously true if the NPC was NOT designed? If the statement is obviously true IRRESPECTIVE of the origin of the NPC, then the non-teleological approach is (at least in this case) no detriment to this research, right. This is what is really puzzling me, the fact that whether or not the NPC is designed apparently does not have any bearing on the research on the structure and function of the NPC and on the consequences for the cell due to the structure and function of the NPC.hrun0815_{February 4, 2008
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hrun0815 One design principle is to Preserve the design Thus I expect the use of detailed error proofing and correction. This will become more important and the system becomes more complex. I just realized that: Tight physical tolerances in the nuclear pore complex & related transport mechanisms act as an effective proofing and error deleting mechanism. i.e., by eliminating components with mutations causing physical changes outside the design boundaries. e.g., too big to fit, or where the docking station changes to no longer match the transporter's docking station. I expect this principle will apply elsewhere where materials must be transported through pores. On your previous question of consequences of IC, I would put error proofing and deleting as one of the symptoms of being designed. Restating 'Well matched": Design parameters have critical tolerances. The concept Irreducibly Complex overlaps the design summary: Life is RegulatedDLH_{February 4, 2008
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hrun0815 Thanks for the clues on dimensions. I found the following on regulation of ATP transport: ATP Transport Through a Single Mitochondrial Channel, VDAC, Studied by Current Fluctuation Analysis, Tatiana K. Rostovtseva* and Sergey M. Bezrukov, Biophys J, May 1998, p. 2365-2373, Vol. 74, No. 5
A working model of the VDAC pore (Colombini et al., 1987; Mannella et al., 1989) envisages a barrel with a diameter of 2.4-3.0 nm composed from a tilted alpha -helix and a beta -sheet.
Following is another report exploring the large macromolecule mediated transport vs small molecule transport. A Pathway Separate from the Central Channel through the Nuclear Pore Complex for Inorganic Ions and Small Macromolecules. JBC Papers in Press, August 28, 2007, DOI 10.1074/jbc.M703720200, Armin Kramer1, Yvonne Ludwig, Victor Shahin, and Hans Oberleithner
The proposed alternative “peripheral” route for ions and small solutes is therefore presumably hydrophilic in nature. Some further support is provided by the observation that the diameter of the peripheral channels, 10 nm (4), matches the molecule size exclusion limit of 9 nm for passive diffusion (6).
DLH_{February 3, 2008
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hr0815 Thanks for the feedback. Yes, I would like to explore the implications of “Irreducible Complexity”. Here are some preliminary thoughts. (PS I am trying to get the links working) You cited the definition of Irreducible Complexity:
a complex functional unit consisting of multiple well matched parts, each of which is essential to the function of the whole unit.
We had noted system failure on lack of an irreducible component. Lets now explore “multiple well matched parts”. Consider: In what way is spacecraft design based on horses? See: What Is the Link Between a Horse's Arse and Space Shuttles? - The oldest and the newest means of transportation, Lucian Dorneanu, Science Editor Softpedia In summary, the shuttle booster rockets had to go through a tunnel on a 4' 8.5" standard gauge rail train, based on Liverpool and Manchester Railway, based on tramways, based on collier carts, based on wagon wheel ruts in Imperial Roman strata (“streets”) which were based on standardized Roman war chariots, which in turn were based on the width of the back end of the Roman war horse. A key design principle is to use standardized parts with robust design tolerances. Thus rockets sized for safe tolerances in the tunnels based on standardized roman war chariots. In biochemistry, a corresponding example is the size of capillaries to fit Red Blood Cells (RBC) to transport oxygen via hemoglobin. E.g., The squeezing of red blood cells through capillaries with near-minimal diameters D. Halpern a1 and T. W. Secomb Journal of Fluid Mechanics Digital Archive (1989), 203: 381-400 Axisymmetric motion of a file of red blood cells through capillaries, C. Pozrikidis, Phys. Fluids 17, 031503 (2005); Modeling the flow of dense suspensions of deformable particles in three dimensions, Michael M. Dupin, Phys. Rev. E 75, 066707 (2007) (17 pages) These proportionalities appear to scale with Red Blood Cell/Capillary size. E.g., see: Red blood cells: Centerpiece in the evolution of the vertebrate circulatory system Snyder, Gregory K, Sheafor, Brandon A, American Zoologist, Apr 1999 Mutations resulting in deformation of red blood cells can result in capillary blockage. E.g., in sickle cell disease. Following are some examples of detailed modeling: Mathematical and mechanical modeling of vaso-occlusion in sickle cell disease Higgins, John M., MSc. Thesis, Harvard University--MIT Division of Health Sciences and Technology. This is one example of what happens when there is a change from the “well matched parts” of irreducible complex systems due to mutations. Now apply this principle to Nuclear Pore Complexes and related transport mechanisms. As with Red Blood Cells in capillaries, I expect there will be similar design criteria and consequent impacts of going outside such robust design boundaries in the transport mechanisms relative to the Nuclear Pore Complex sizes. 1) There will be a normal allowable size range for mediated transport. 2) There are tolerances for docking requirements of macromolecules onto the transport molecules. I.e., transport plus load must fit within the Nuclear Pore Complex. 3) Larger molecules must be expressed inside the nucleus, or transported through the wall in components and assembled inside. E.g., compare the international space station compared with the size limitation in the rocket payloads. As we noted above, very few viable mutations suggests very tight tolerances on the dimensions involved in the transport mechanisms & nuclear pore complex. For the loads, see: Naim et al.
Small molecules, . . . can pass unassisted by diffusion which becomes increasingly restricted as the particle approaches a size limit of ~ 10 nm in diameter.”

“. . .facilitated translocation . . .can accommodate objects with a diameter of up to ~ 40 nm.”
“Passive and Facilitated Transport in Nuclear Pore Complexes is Largely Uncoupled.” J. Biological Chemistry Vol 282, No. 6, pp 3881-3888. Modeling the flexibility of the mediated transport of macromolecules compared to the nuclear pore complex will be a key challenge. As from Roman chariot to space shuttle booster, the mediated transport through the Nuclear Pore Complex has consequential design implications of maximum size for all related macromolecules that need to be transported through the cell nucleus wall.DLH_{February 3, 2008
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Consider what would the impact be of reducing the gradient by 95%?
DLH, very likely the directionality of transport would be impaired. I predict this because we know how the gradient affects transport and because we know the outcome of experiments where the gradient has actually been inversed. Interestingly, I again don't see a difference in what you would hypothesize from design principles and what biologists hypothesize and test from their non-teleological point of view. Also the non-teleological researchers know that for processes to run you require energy. That is completely independent whether a designer created the NPC or whether the NPC evolved.
I was thinking of comparing process rates in the eukaryotic nucleus, eukaryotic cytoplasm, and in prokaryotic cells. The difference may relate to size and design methods to accommodate scaling factors. e.g., if eukaryotic cells are 1000 times larger than prokaryotic cells. Can this high RanGTP gradient be needed to scale up in size?
DLH, RanGTP is not a major factor in the overall energy flow and maintenance within a cell. And remember, we are talking here about a gradient of RanGTP, not GTP itself. As you are surely aware of, GTP is substantially smaller than the diffusion limit of the NPC, so it will be fairly evenly distributed across the nucleus and the cytoplasm. Thus, I find it highly unlikely that this gradient 'may relate to accomodate scaling factors'. Especially if we take into account that both prokaryotic and eukaryotic cells show quite the range in size. The smallest eukaryotic cells are less than a micrometer in diameter while the largest ones are over 100 micrometer in diameter (1 million fold difference). Interestingly, the largest bacteria have a diameter of 750 micrometer and are thus nearly 1 billion times larger than the smallest eukaryotic cell. Yet, still the small eukaryotic cell likely has the same RanGTP gradient for transport and spindle assembly, while the largest prokaryote does not. I have quite direct question about this: How did you come up with this hypothesis? And upon further thought, do you think it is one that a group of researchers should seriously pursue? Do you think it would maybe be more fruitful for researchers to simply look which proteins for example interact with RanGTP, which processes get messed up when you interfere with the gradient, what proteins and processes are required to maintain the gradient, ... With this approach researchers indeed found how the gradient drives selective transport and in addition how this gradient impacts the assembly of the mitotic spindle. And currently numerous times are delving further into the details at how exactly RanGTP impacts these processes and if there are others it impacts. As an aside, unfortunately, you have not found the time to answer my question about what we could predict if we indeed confirmed that the NPC is IC. All I can say is that I am still very interested in discussing this topic. Maybe you could just let me know whether or not you agree that this is worth discussing.hrun0815_{February 3, 2008
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hrun0815 I am brainstorming/ exploring ways to apply design principles. Apologize for being a novice at the biochemistry. I have read Pemberton and Paschal's review. Now to study/digest it. Consider what would the impact be of reducing the gradient by 95%?: E.g., possible design principles: 1) Energy is need for processes. 2) A given process rate requires a corresponding energy supply rate (power). 3) Energy supply rates below that will slow that process. 4) A given high energy supply rate is required to maintain a high process rate. By
‘not having that without a nucleus wall’
I was thinking of comparing process rates in the eukaryotic nucleus, eukaryotic cytoplasm, and in prokaryotic cells. The difference may relate to size and design methods to accommodate scaling factors. e.g., if eukaryotic cells are 1000 times larger than prokaryotic cells. Can this high RanGTP gradient be needed to scale up in size?DLH_{February 3, 2008
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This large RanGTP concentration gradient is worth exploring as to its ramifications.
Yes. It is worth studying. In fact, it is and has been studied extensively. It is crucial for selective and efficient transport. It is also know how the RanGTP gradient is being maintained. In fact, the paper that you mention (by Pemberton and Paschal) gives quite an extensive view on a number of the implications of the gradient. Did you study the review? It actually gives so much detailed information on the 'ramifications' on the gradient: how RanGTP is maintained at high concentrations in the nucleus, how the enzymes that regulate the conversion of RanGTP/RanGDP are sequestered in the nucleus and the cytoplasm respectively, how the affinity of the different karypherin/cargo complexes to RanGTP/RanGDP regulates directional transport into and out of the nucleus, and how the RanGTP gradient is not only important for nucleo-cytoplasmic transport but also for formation of the spindle. Did you have any other specific 'ramifications' in mind that ought to be explored but are not already?
(And the implications of not having that without a nucleus wall.) What do you see as the implications of that gradient vs not having it?
I don't have to look at implications of having or not having the gradient. It certainly has been experimentally tested. For example, it has been shown that by reversing the gradient transport can be reversed in its direction. Thus, biologists concluded that it is important for the directionality of transport. Numerous other experiments have been done and many of them are summarized and referenced in the Pemberton review. I don't see what you mean by 'not having that without a nucleus wall' though, so I can't really reply to that.
That supports the hypothesis of irreducible complexity.
It is known (and somewhat unsurprising) that a number of components of the transport machinery are essential for eukaryotic cells. I thought, though, there were much more specific requirement before something can be called irreducibly complex. It can be a little confusing, since there are apparently multiple definitions of IC. However, no biologist that I know of, though, disagrees that there are numerous IC structures in cells if the most basic definition of IC is used (complex functional unit consisting of multiple well matched parts, each of which is essential to the function of the whole unit). That's why I said the following:
Let’s assume for a second that we actually confirmed that the NPC is irreducibly complex. With that information in hand, what predictions can we make? And how do these differ from the predictions and hypothesis that the ‘non-teleological’ researchers of this study (or other researchers) made?
I'd still be interested in discussing this, since you point out in a number of posts that you hypothesize the NPC to be IC.hrun0815_{February 2, 2008
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hrun0815 Encourage you to look at: Shape and Structure, From Engineering to Nature, Adrian Bejan, Cambridge, 2000. Many of the principles he gives can be applied to NPCs in cells. (Bejan attributes some things to evolution, but without any basis for that. The principles naturally fit design.) Pemberton & Paschal 2005 cite Kalab et al Science 2002 that:
"a RanGTP concentration difference of more that 100-fold between the nucleus and the cytoplasm
This large RanGTP concentration gradient is worth exploring as to its ramifications. (And the implications of not having that without a nucleus wall.) What do you see as the implications of that gradient vs not having it? Pemberton & Paschal 2005 comment that:
"To date, however, there are no known disease-causing mutation in the soluble components of the nuclear transport machinery, which includes karyopherins, Ran and its regulators. The absence of mutations and chromosomal translocations underscores the essential nature of soluble transport components even at the single cell level.
That supports the hypothesis of irreducible complexity.DLH_{February 2, 2008
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On irreducible complexity, one example is regulatory systems. See Behe on blood clotting etc. We predict that biochemical systems exhibit regulation, irreducibility, and energy flows.
Well, I hope you can see why I was puzzled by your comment about IC and redundancy not being exclusive. It appears that Behe specifically defines IC to be mutually exclusive from rendundancy (a system that contains redundancy can, by definition, be further reduced without losing its function).
So when looking at a new system, systematically search for those factors. Failure of any of those will result in disorder, disease or death. vs RM & NS requiring mutation for creating function.
Is this in response to teleological vs. non-teleological approaches. I am certain you are aware that biologists study failure in factors that lead to disorder, disease or death all the time. Just like in the teleological approach, biologists assume that a structure has a function and try to figure out what it is.
PS Study other designed transportation systems to see what methods are used that may be found in NPC. e.g. FedEx, UPS etc. Recycling containers, barcode labels, energy flows, etc.
Interesting. It might not surprise you that the Nobelprize winner in medicine Gunther Blobel (1999) who studied cellular transport of proteins extensively found (what he termed) the ZIP code for proteins. Again, it is striking that your suggestion overlaps directly with what non-teleological researchers have studied already. However, it might interest you (once you start reading about the function of the NPC), how very different the NPC actually is from how humans would design a selective transporter. Earlier models of NPC function were closely aligned with how humans might design such a structure. Yet, the newer finding spearheaded by Rout et al (but also by a number of other groups) showed that the biological reality is quite different.hrun0815_{February 2, 2008
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hrun0815 My apologies for loose terminology. I need to be more precise in distinguishing the different families of proteins, vs cytoplasmic filaments etc. I was envisioning deleting an increasing portion of the cytoplasmic filaments. On the other nucleoporins (nups), I anticipate that there will be further functions discovered that will be progressively reduced or destroyed as some of those nucleoporins are deleted. "A little knowledge is a dangerous thing." I will read up more on NPC and sleep on it for a month or two before commenting further on NPC. On irreducible complexity, one example is regulatory systems. See Behe on blood clotting etc. We predict that biochemical systems exhibit regulation, irreducibility, and energy flows. So when looking at a new system, systematically search for those factors. Failure of any of those will result in disorder, disease or death. vs RM & NS requiring mutation for creating function. See John Sanford, Genomic Entropy and the Mystery of the Genome. Summarizing, the mutational load in the biochemical system will accumulate, resulting in increasing degradation of function. PS Study other designed transportation systems to see what methods are used that may be found in NPC. e.g. FedEx, UPS etc. Recycling containers, barcode labels, energy flows, etc.DLH_{February 2, 2008
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You just made my point. The full functionality must also be considered when addressing irreducible complexity and robustness.
DLH, I honestly do not understand how I made your point. You proposed to remove THE COMPLETE NPC and then test if ALL functionality of the NPC is still retained. If that is your measure then everything that has a function is irreducibly complex. If you remove it, it's function is lost.
This is an ad hominem attack. Please desist. I would not be linking to and citing contents of papers without having read some, though obviously not as thoroughly as you have.
DLH, I just couldn't understand how you can propose and experiment to remove the complete NPC and then test if the function of the NPC is retained in its entirety. Likewise, the properties of the NPC (redundancy of many of the components, permeability to ions and small proteins, ...) are laid out in every basic introduction to a paper dealing with the NPC. That's why it was surprising to me that you would have read a completely paper on the NPC without being aware of these very basic facts about the structure. I hope you can understand WHY I came to that conclusion. I do apologize that you felt insulted. In no way do I want to invalidate any of your factual arguments by appealing to a negative character trait in you. I only wish to engage in your arguments themselves.
Robustness indicates multiples of the one component or multiple parallel systems.
I am well aware of what robustness indicates. It is, for example, well studied at the example of the NPC in multiple papers. The point that I was making was that on the one hand you propose that the finding of deleting a single component causing loss of function would indicate design. Only to post in the next post the the finding of deleting a single component NOT causing loss of function would also indicate design. That's very difficult to argue with.
DLH: Robustness and irreducible complexity are separate but not exclusive properties.
AND
Behe: “Irreducible Complexity is a characteristic of systems “wherein the removal of any one of the parts causes the system to effectively cease functioning.”
It appears that Behe thinks that indeed IC and redundancy are mutually exclusive. If a system has built in redundancy, then removal of any of the parts will NOT cause the system to cease functioning.
A major design principle is: Energy is required for function.
It is again surprising how the 'teleological perspective' overlaps with the non-teleological approach. The energy requirement for transport (as for many other functions) has been and is being studied extensively. In fact, studying energy flow was critical to understanding how selective transport through the NPC occurs. The diffusion-exclusion model, for example came about directly from the fact that the energy trail was followed. I suggest the 2000 JCB paper by Rout. Leaving all this aside, I was wondering if we could still get back to the following:
hrun0815: Let’s assume for a second that we actually confirmed that the NPC is irreducibly complex. With that information in hand, what predictions can we make? And how do these differ from the predictions and hypothesis that the ‘non-teleological’ researchers of this study (or other researchers) made?
hrun0815_{February 2, 2008
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hrun0815
If you delete ALL Nups then there will be no NPC, thus there will be no function.
You just made my point. The full functionality must also be considered when addressing irreducible complexity and robustness.
loss of function after deletion of any component
Robustness indicates multiples of the one component or multiple parallel systems. Robustness and irreducible complexity are separate but not exclusive properties. If there is NO robustness in a critical component, then deletion of that component will cause the system to fail. E.g., the I35W bridge in Minneapolis. When a component is robust, then a at least certain portion of those components must fail before the systems fails. e.g. you probably have dual brake systems in your car. Lose either one and you probably can still stop (if given enough distance) - but not as well as with both.) However, delete both and your toast - Brakes are an irreducibly complex function of a vehicle as is the engine for the design of safe travel. Which is why they are mandated. A component can still be critical and have robustness with multiple components. When all those fail, then the system fails.
I can only assume that you STILL have not read a single paper in the NPC.
This is an ad hominem attack. Please desist. I would not be linking to and citing contents of papers without having read some, though obviously not as thoroughly as you have. A major design principle is: Energy is required for function. i.e., follow the energy trail. If energy flow is hindered or stops. function will slow or stop. e.g., when you turn off your light, motor, computer. It seems obvious when stated, but i often see "evolution" described with no acknowledgment of the critical importance of energy flows. Besides, we have just begun to explore some of the data and possible functions and from those infer higher design principles. Eventually there is a top level goal, then objectives and design principles, etc. that give explanatory and predictive capability. I have just sketched out a little of the process. Before proceeding any further, please read about: Robust Design e.g., Robust Design / Taguchi Quality Methods Robust Design through Design of Experiments" Robust design optimization and robust optimal control Please read: Genetic Redundancy: The Ultimate Evidence of the Design of Life, by Peter Borger, ISCID Brainstorms 19. September 2006 16:23. Please also read the following on Irreducible Complexity (Links from ResearchID.org) --------------------- "Irreducible Complexity is a characteristic of systems "wherein the removal of any one of the parts causes the system to effectively cease functioning."Behe MJ (1996) ''Darwin's Black Box''. ISBN 0684834936, p.39. According to William Dembski in his ''No Free Lunch'', Irreducible Complexity is explained as: :"A system performing a given basic function is irreducibly complex if it includes a set of well-matched, mutually interacting, non-arbitrarily individuated parts such that each part in the set is indispensable to maintaining the system's basic, and therefore original, function. The set of these indispensable parts is known as the irreducible core of the system."Dembski, WA (2001) ''No Free Lunch'', ISBN 0742512975, p. 285. Michael Behe has also proposed a definition applicable to evolutionary pathways: :"An irreducibly complex evolutionary pathway is one that contains one or more unselected steps (that is, one or more necessary-but-unselected mutations). The degree of irreducible complexity is the number of unselected steps in the pathway."Behe, MJ (2002) "A Response to Critics of Darwin’s Black Box." PCID, Vol. 1.1, January-March, 2002; http://www.iscid.org. What does this loss of function mean for biological adaptation? Certain biological structures in nature exhibit a specific type of interdependence between parts which could elude current evolutionary explanation. Understanding Irreducible Complexity could bring clarity to the nature of these structures. -------------- * Irreducible Complexity -- ISCID "Encyclopedia of Science and Philosophy" article * Irreducible Complexity Revisited -- Document on DesignInference.com * Molecular Machines -- Michael Behe at ARN.org * Irreducible Complexity Revisited -- Mike Gene at IDthink.net * Irreducible Complexity: What it is and Popular Misconceptions: "crevo" * The Miracle of Co-option -- Critical thinking on co-option by GilDodgen at UncommonDescent.com ---------------- Maybe then we can proceed productively.DLH_{February 2, 2008
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Retaining function after deleting a large portion of Nups shows high robustness - an important design function.
So retaining function after deleting a large portion would be an important design function and loss of function after deletion of any component would also be an important 'design function' (indicating irreducible complexity).
One way to test this is what happens when ALL of the Nups are deleted? Is ALL functionality still present? e.g. is selective transport still supported? This may be an essential feature but one which does not require ALL of the Nups. See Fig 6 where a single potential is similar to a multi-potential.
Again, DLH, I can only assume that you STILL have not read a single paper in the NPC. If you delete ALL Nups then there will be no NPC, thus there will be no function. What does that show?
I am not denying credit. On the contrary, Rout et al. have done excellent work in deducing and quantifying a very complex structure. They may fully believe neo-darwinian evolution can fully explain the origin of it.
But you asserted in the previous post that they were doing the research (unknowingly) from a teleological point of view. DLH: "That appears to be working from an implicit teological view even though it is frequently stated as an evolutionary point of view."
Personally, the more I see of its complexity and function, the more skeptical I am that such essential components could originate by blind chance. How can you have reproduction and thus selection without these components first being in place in eukaryotic cells?
Sure, that I understood. But looking back at the discussion, I can only assume that you reached this conclusion simply by looking at the complexity of the NPC and reading the ScienceDaily blurb. Even now, so many posts into this discussion you suggest to delete ALL Nups and ask if ALL functionality is retained. It's certain that you have not even read the PLoS paper that actually discusses in depth the evolutionary findings on the study of the NPC (i.e. the connection between coated vesicles and the NPC). I wonder if we could get back to a prior question that fell a little bit along the wayside: What predictions/hypothesis does the teleological point of view make that the non-teleological point of view does not make (or which has not already been answered by non-teleological research). So far you suggested: - Checking if functionality is retained upon deletion or mutation of the NPC. -- Done and answered. - Checking if deletion of the whole NPC (all Nups) abolishes all function. -- Done and answered. Are there other teleological predictions that I might have missed?hrun0815_{February 2, 2008
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hrun0815 Note that I stated 3) on irreducibly complex as a hypothesis - not an assertion. i.e., to be tested against further facts etc. Thanks for the observation:
"You can, in fact, remove a surprisingly large chunk of Nups or even some Nups in combination without a loss of function of the NPC."
I assume you are referring to articles like: Efficiency, selectivity and robustness of the nuclear pore complex transport, A. Zilman, S. DiTalia, B. T. Chait, M. P Rout, M. O. Magnasco (Submitted on 26 Sep 2006)
We also show that transport is relatively insensitive to changes in the number and distribution of FG-nups in the NPC, due mainly to their flexibility; this accounts for recent experiments where up to half of the total mass of the NPC has been deleted, without abolishing the transport.
Retaining function after deleting a large portion of Nups shows high robustness - an important design function. Robustness does not in itself negate irreducible complexity. A system can be both robust and irreducibly complex in various combinations. One way to test this is what happens when ALL of the Nups are deleted? Is ALL functionality still present? e.g. is selective transport still supported? This may be an essential feature but one which does not require ALL of the Nups. See Fig 6 where a single potential is similar to a multi-potential. I am not denying credit. On the contrary, Rout et al. have done excellent work in deducing and quantifying a very complex structure. They may fully believe neo-darwinian evolution can fully explain the origin of it. Personally, the more I see of its complexity and function, the more skeptical I am that such essential components could originate by blind chance. How can you have reproduction and selection without these components first being in place in eukaryotic cells? Abiogenesis is the critical foundation that Neo-Darwinian evolution assumes but for which it has no detailed explanation or mechanism. Scientists have just begun to plumb the depths of the complexity and interrelated functions. For example I look forward to learning more of the transport energy requirements:
TIAR nuclear import but not export is a Ran-GTP-dependent mechanism The signal-mediated accumulation of import cargo in the nucleus or export cargo in the cytoplasm requires energy, most frequently linked to the small GTPase Ran. . . . We also showed that TIAR/TIA-1 nuclear import depends on the Ran-GTPase energy system. . . . Moreover, in contrast to nuclear import, TIAR and TIA-1 nuclear export is not dependent on Ran-GTP as it is maintained upon depletion of the Ran-GTP pool. . . . we verified that ATP depletion inhibited the Ran-GTPdependent nuclear import of the shuttling hnRNP A1 (Siomi et al., 1997).
Identification of the sequence determinants mediating the nucleo-cytoplasmic shuttling of TIAR and TIA-1 RNA-binding proteins Tong Zhang, Nathalie Delestienne, Georges Huez, Véronique Kruys and Cyril Gueydan, Journal of Cell Science 118, 5453-5463 PS Pemberton & Paschal state that the following Karyopherin-beta family genes are essential in yeast: Kap95, Kap121, Crml, and Cse1. This suggests that some combination of nuclear pore complex and related karyopherin-beta transport mechanisms are irreducibly complex.DLH_{February 2, 2008
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If NPC is irreducibly complex, then removal of any gene/protein causes failure, and mutations probably cause reduced function or loss of function. Conversely, searching for causes of disorder or disease point to searching for mutations in related irreducibly complex functions.
DLH, again, it's rather surprising that you make the assertion/hypothesis that the NPC is irreducibly complex without really looking into any of this. You can, in fact, remove a surprisingly large chunk of Nups or even some Nups in combination without a loss of function of the NPC. I suggest to at least read one of the reviews on the NPC. So, not only did your hypothesis lead you wrong, but in addition, the non-teleological researchers already did the experiments a long time ago. So it seems that maybe in this case, the teleological view does not bring anything new to the table.
My understanding of Random Mutation and Natural Selection (RM & NS) is that it has no goal or purpose. It is only evaluated based on effective reproductive capability.
Exactly. And that's why researchers continually study the function of complex structures within cells to see how they impact efficient growth, survival and reproduction.
That appears to be working from an implicit teological view even though it is frequently stated as an evolutionary point of view.
How do you figure? So the non-teleological asserts that there are numerous complex structures within cells that serve no function towards survival and reproduction? You just previously stated the opposite, namely that everything in evolution is selected for efficient reproduction. And really, you are asserting that all these biologists actually study biology (unknowingly) with a teleological view? It's surprising that you are not willing to give the researchers who performed this incredibly complex study more credit. They are smart enough to figure out the composition, structure and function of the NPC, but are unaware that they have been performing the study from a teleological point of view?hrun0815_{February 2, 2008
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hrun0815 Thanks especially for that last link to Rout's publications. Excellent source. See: Reverse Engineering for some description. Thanks for the note on ion concentrations. I was thinking of the sodium/potassium pump and rapidly blogging without carefully checking that out or thinking it through. ( I have read some - obviously I need to read and digest more.) As you pointed out, I now need to correct to: 5) Form a cell wall to maintain the ion gradients. 6) Provide sodium/potassium pumps in the cell wall (plasma membrane)capable of regulating the Na, K and Ca ions. So that takes us back to what is regulated by the nuclear pore complex and why. My understanding of Random Mutation and Natural Selection (RM & NS) is that it has no goal or purpose. It is only evaluated based on effective reproductive capability.
from a biological point of view people wonder why pores and membranes are used. People try to figure out functions of the nuclear pore, try to discover the way transport is regulated and what bearing that has on cellular functions.
That appears to be working from an implicit teological view even though it is frequently stated as an evolutionary point of view.
What you are identifying here don’t sound like design principles to me, but mere like potential functions of a membrane in an organisms.
Step by step. Identify the data, then function, then back out to the design principles. I have quickly sketching some of the issues involved.
3)? Let’s assume for a second that we actually confirmed that the NPC is irreducibly complex. With that information in hand, what predictions can we make
If NPC is irreducibly complex, then removal of any gene/protein causes failure, and mutations probably cause reduced function or loss of function. Conversely, searching for causes of disorder or disease point to searching for mutations in related irreducibly complex functions. I understood the Online Mendelian Inheritance in Man to be a repository for such and that it almost exclusively documented genetically inherited harmful mutations (out of the current 18,000 entries.) So back to more carefully thought through productive writing.DLH_{February 2, 2008
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DLH, sometimes it has been argued (not by you, but by others for example on ARN's discussion board) that scientists like to hide their own research and only make it accessible to other researchers. Apparently, Dr. Rout paid a substantial fee for every single one of his publications to make the downloads freely available to everyone. The Nature papers and numerous other papers on the NPC can be freely downloaded on his lab webpage: http://www.rockefeller.edu/labheads/rout/publications.phphrun0815_{February 2, 2008
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