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Author | Topic: Towards a Hypothesis of Molecular Design | |||||||||||||||||||||||
Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
Towards a Hypothesis of Molecular Design
Though scholars in the ID movement have continually argued that Darwinian evolutionary processes are insufficient to account for the biochemical complexity that is at the heart of life, relatively little effort has been devoted to developing a testable hypothesis of intelligent design. Yet if intelligent design is to make any significant progress in academia, and if it is to lead to fruitful research, then a positive intelligent design hypothesis is sorely needed. In a previous essay, a testable hypothesis on the engineering of molecular machines was briefly described. Here, I expand on that model of biological intelligent design and discuss several predictions that necessarily follow from the hypothesis. The hypothesis will be termed molecular design. The molecular design hypothesis proposes that the components of molecular machines were engineered through the strategy of rational design, similar to the method humans use to design proteins. This, however, is only a cursory summary. More specifically, the central thesis of molecular design is that the first biological cells were contrived by engineers with intelligence analogous to our own, and that the protein machinery of these cells was designed by methods similar to our present techniques for protein design. Thus, it suggests that the method or mechanism of the intelligent design of the biochemical complexity of life was essentially rational design and directed evolution. Bear in mind that directed evolution is a very specific method of protein design, and is not synonymous with the step-by-step evolution of molecular machines.This essay will begin with an overview of rational design and directed evolution in protein design by our species. By exploring these two mechanisms of protein engineering (and more broadly, the engineering of molecular machines), predictions of the molecular design hypothesis can be more fully fleshed out. Methods in Protein Design: Rational Design and Directed EvolutionRational design involves either modifying an existing protein sequence in a determined, specified way or designing an entirely novel protein. The latter approach will be discussed later. Below is a figure (Figure 1) that depicts the general procedure behind the rational design of proteins. In rational design, knowledge of the structure and function of the protein is critical. By analyzing the structure and function of the protein, one can predict the effects of changing certain amino acids. For example, changing key amino acids might enable a receptor to bind more tightly with its ligand, increasing functionality. Figure 1. The basic process behind the rational design of proteins. Using site-directed mutagenesis, specific amino acid residues can be mutated in the desired way. The process of site-directed mutagenesis is probably familiar to all biology majors, so I am only including a figure (Figure 2) to illustrate how site-directed mutagenesis works. Figure 2. Site-directed mutagenesis. Protein sequences can also be designed de novo. That is, a novel protein can be designed from scratch instead of by modifying an existing protein. Synthetic DNA sequences are ultimately cloned and expressed, leading to the translation of the de novo protein sequence. There are numerous examples of protein sequences that have been designed de novo (see, e.g., Kuhlman et al., 2003; Fisher et al., 2011). Importantly, protein sequences designed de novo have no homologous counterparts. Under the heading of rational design comes the method of blob-level protein design (see Figure 3). As stated in the figure, the main idea behind blob-level protein design is to combine protein units of defined function (domains) to engineer a fusion protein with novel functionality. Figure 3. "Blob-level" protein design. Unlike the rational design technique, directed evolution emphasizes selection to a higher degree. Very simply, a gene sequence encoding a given protein is randomly mutated (through error-prone PCR, for example), which results in a library containing many variants of the sequence. Selection is then utilized to select the sequences which possess the desired function. Next, the selected sequences are amplified through PCR, and the process is repeated as many times as necessary.The principle methods behind protein engineering, described above, are employed for the design of single protein molecules. But what about molecular machines, which are composed of several (often dozens) of protein parts? How can such multi-component machines be engineered? Designing a protein machine would begin, of course, with planning the arrangement of protein parts (and the kinds of proteins that would be needed) such that function is produced. After this has been accomplished, the following steps would be carried out: a. The inner, core proteins of the machine would be engineered first (through rational design and directed evolution). De novo design of the first core protein would be followed by the design of a protein that could tightly bind to it. Alternatively, a protein from another machine would be borrowed so that de novo design would not be necessary. b. More and more proteins would be designed and added to the initial core proteins. c. Once the genes encoding the necessary proteins have been designed, genes regulating the assembly of the machine would be engineered. After the machine is designed, it can be modified and changed to produce a machine with a different function. These methods, then, are the major techniques behind protein engineering. Several salient points emerge that are worth mentioning:In rational design of molecular machines, protein parts are often borrowed from other systems (and modified as necessary to produce optimal functionality). This would result in statistically significant levels of sequence similarity between the components of the machine and other proteins that are not part of the machine. Proteins that are designed de novo share no statistically significant sequence similarity with other proteins (in general). When it comes to designing molecular machines, there is no step-by-step, cumulative evolution, wherein every step offers a selective advantage. Instead, the components of the machine are integrated at approximately the same time. Millions of years (and not even decades) are not needed to engineer a molecular machine with dozens of components. This is because the engineering approach has foresight. Individual parts of proteins (domains) can be swapped around to design specific functions. Tests of the Molecular Design Hypothesis What predictions naturally follow from the molecular design hypothesis? Let us suppose that we find a biological machine X, and that some of its parts are similar with a machine Y. Under current theory, this similarity is attributed to a shared ancestry. Yet it is this very similarity that can act as a springboard for testing the molecular design hypothesis. The bacterial flagellum is probably the most familiar icon of the intelligent design debate, so it will be used as an example in the predictions discussed below. Prediction 1: Molecular clock analyses of protein sequences of the components of the machine should reveal a specific pattern. Under the Darwinian model, the evolution of a machine like the flagellum proceeds through the stepwise co-option of parts. For example, the flagellar ATPase would be borrowed from cellular F-ATPases and integrated with a primitive membrane pore. Next, after the evolution of gated proteins, etc., proton channels (proto-ExbB/proto-ExbD) would be co-opted to form the flagellar motor proteins MotA and MotB, respectively. A proto-MgtE copy would then associate with the flagellar motor, resulting in a FliG protein. Thus, under the Darwinian model of the origin of the flagellum, molecular clock analyses of the flagellum-specific ATPase and the F-ATPase, MotAB and ExbBD, and FliG and MgtE protein sequences should show divergence times in the following chronology: the split between the flagellum-specific ATPase and the F-ATPase --> the MotAB/ExbBD divergence --> and the FliG/MgtE split, where the arrows denote the passing of time. In contrast, the molecular design hypothesis predicts that the divergence times of the machine parts and their homologs should follow a different pattern. One might expect that the divergence times should be approximately equal, indicating that the parts of the machine originated simultaneously, but this would ignore the fact that modification of protein parts would often be necessary. As a simple example, it is clear that simply plugging the ExbB/ExbD proteins into the flagellum for motor purposes would not be optimal. ExbB and ExbD interact with a membrane protein known as TonB, so ExbB and ExbD have segments unrelated to flagellar function. If these segments were not altered in the right ways, then they could interfere with the function of the flagellum. This engineered modification of homologous components must be taken into account. As I explained earlier: this means that we cannot logically predict — from a design perspective — that molecular clocks will demonstrate that all machine components originated at about the same time. This is because if some proteins are modified more substantially than others, it would confuse the molecular clock. Protein components that have undergone more drastic modifications will have the appearance of being more ancient (using a molecular clock), while proteins that are only slightly changed will appear to have originated more recently. In particular, the design hypothesis predicts that molecular clocks will show that proteins with rapid substitution rates will have a later origin, while proteins with slow substitution rates will have an early origin. We can summarize this prediction in this manner: in general, the slower the substitution rate, the more ancient the protein will appear to be. If a protein has a slow substitution rate, then any modifications to the sequence of that protein will give the appearance of a large amount of time passing by. In contrast, even fairly extensive modifications to a protein with a rapid substitution rate will not significantly affect the molecular clock. To further refine this prediction, we can take into account the amount of modification that would be needed for a given protein. (Included here is the figure that was provided in the previous essay) Figure 4. A summary of the prediction of the molecular design hypothesis. How can we make an estimate of the amount of engineered modification needed for any given component? This can be accomplished by taking a holistic approach to the protein parts and systems in question. That is, by analyzing the functions, structures, and interactions of the proteins and systems, one can infer approximately how much modification would be needed to incorporate a borrowed part into an engineered machine. A close inspection of the flagellar rod proteins, for example (which are homologous to each other), reveals that only a minimal amount of engineering would be needed to modify one rod protein into another. Their functions and interactions are similar, as is their cellular localization. Relative to the flagellar rod proteins, a great deal of modification would be needed to turn an MgtE copy into FliG. MgtE is a magnesium transporter and is not part of a multi-component protein system, while FliG interacts with the flagellar MS-ring and motor, as well as with FliM/N. Figure 4 summarizes the prediction of the molecular design hypothesis discussed above. Prediction 2: Molecular clock analyses of synonymous sites in the proteins under consideration should demonstrate approximately equal divergence times. While engineers might find it necessary to modify a protein part borrowed from another system, this modification would take place at the amino acid level. However, molecular clock analyses are not restricted to amino acid sequences. Clock analyses can also be conducted on the synonymous sites of different two gene sequences. Since the synonymous sites would not be affected by any engineered modifications (given that the engineered changes would be done on the amino acid level), then the divergence times of machine parts as estimated from synonymous sites should be approximately equal. Furthermore, clock analyses carried out on the basis of synonymous sites should be in disagreement with clock analyses performed on non-synonymous sites. An example may be cited here. Suppose the bacterial flagellum was engineered. As such, FliG was adapted from MgtE and integrated into the flagellar system, and the flagellar ATPase was borrowed (and modified as necessary) from the F-ATPase. Through molecular clock analyses, the divergence times of FliG/MgtE and the flagellum-specific ATPase/F-ATPase could be calculated. The divergence times would be expected to match the prediction described in Prediction 1. However, keep in mind that, in reality, these parts are being engineered into the flagellum at approximately the same time. So if we could find a molecular clock method that is independent of functional requirements, it would be possible to determine if these parts truly did originate at the same time. Fortunately, a molecular clock method based on synonymous sites provides such a method. Since the synonymous sites are not modified (unless their source organisms are significantly different) by any engineering methods, clock analyses of synonymous sites should give the actual divergence times of these proteins, and those divergence times should be nearly equal. In the example above, then, all synonymous sites of the MgtE and FliG genes would be taken into consideration, and the synonymous substitution rate calculated. Next, the number of synonymous substitutions between MgtE and FliG would be determined, and thereby the divergence times of the two proteins could be established. This same procedure would be employed for the flagellar ATPase and the F-ATPase. The molecular design hypothesis predicts that the calculated divergence times of these two pairs of proteins — based on synonymous sites — should be approximately the same. Treatments of the methods and techniques behind molecular clock analyses will be found in molecular evolution and bioinformatics textbooks; these should be consulted if the reader is interested in a further understanding of the subject. I will now describe two predictions of the molecular design hypothesis that arise from special cases. Prediction 3: Fusion proteins. Fusion proteins are proteins that are composed of two or more fused proteins — proteins that originally functioned independently. Recombinant technology is widely used to create fusion proteins, and fusion proteins can also arise through random mutations. If a fusion protein is a component in a biological machine, this provides an opportunity to test the molecular design hypothesis. In Figure 5, protein C is a protein component in a molecular machine hypothesized to have been engineered. Protein C is a fusion protein: the red portion is similar to protein A, and the green portion is similar to protein B. To engineer protein C, these two proteins (A and B) must be fused together. But this is not always the whole picture. For the fusion protein C to function in the context of the engineered machine, modification to proteins A and B would be done. In other words, the protein sequence of protein A would have to be tweaked in just the right way so that it fits nicely with the rest of the machine, and the same applies to protein B. There is one more element to this, however. It is not likely that both proteins A and B would have to be tweaked to the same degree, since these are, after all, proteins with different functions. So the sequence of protein A, for example, is modified more substantially than protein B. The two proteins are then fused using recombinant DNA technology, and the resulting protein is integrated into the engineered machine. The molecular clock starts ticking for each of the two domains in the fusion protein (the red and green portions). This is where the prediction stems from. Based on the molecular design hypothesis, I would predict that molecular clock analyses of the different parts of the fusion protein (that is, molecular clock analyses of each domain in the fusion protein with its homologous counterpart) should yield different divergence times. The logic of this prediction is simple: (a) the parts A and B were modified to different degrees, skewing the molecular clock, and making one appear more ancient, (b) the molecular clock then starts ticking (once they have been fused and the machine has been deployed in the wild), with the fusion protein accumulating substitutions. Since the original modification to the proteins A and B skewed the molecular clock, the molecular design hypothesis predicts that in general, molecular clock analyses of the parts of a fusion protein should show one of the parts to be more ancient than the other. Figure 5. A fusion protein engineered from two different proteins. The asterisks represent the amount of modification that has been done to each protein part, as well as the subsequent accumulation of substitutions. Here it should be emphasized that the Darwinian theory of the origin of molecular machines leads to a different prediction. Within the evolutionary framework, proteins A and B simply fuse, and at that moment the molecular clock starts ticking for the novel fusion protein. The prediction would be that the different parts of the fusion protein diverged at the same time from their respective homologs. Prediction 4: Protein domains. This prediction concerns duplicate protein domains that carry out the same function in the same protein. Suppose we have a protein component, A, which consists of the domains B, B, and C. The two B domains serve the same function in protein A, and are homologous to a domain in another protein (this ancestral domain will be termed B1). Since the two B domains function in the same way, an equal amount of modification would be done to them (if any at all). From an engineering perspective, the two domains would be placed in protein A at the same time. They would subsequently diverge. When compared to B1, then, they should be genetically equidistant. Therefore, molecular design predicts that domains with the same function in a protein should be equidistant from their ancestral domain. Again, this is not predicted if a molecular machine is the product of evolutionary processes. Duplicate domains need not arise simultaneously. Instead, a domain can be incorporated in a protein, and only later a second domain of the same type might be integrated with the protein. It is true, of course, that duplicate domains can evolve at the same time. But this is not a prediction of current theory. Current theory would be able to explain the above observation, but it would not predict it. Conclusion I have endeavored to describe the molecular design hypothesis in greater depth than in the previous essay. Several predictions of the hypothesis were delineated; there are undoubtedly more that were not discussed here. The next step from here is to actually test the hypothesis. This can be accomplished using standard bioinformatics techniques. By experimentally determining if these predictions are met it will be possible to detect artificiality — or the lack thereof — in molecular machines. Having said this, I wish to strongly encourage intelligent design proponents to do more than simply critiquing the current view on biological origins. A mechanistic model of intelligent design is what is needed, and this is what I have attempted to outline. Thoughts? References Kuhlman, B., Dantas, G., Ireton, G.C., Varani, G., Stoddard, B.L., Baker, D., 2003. Design of a novel globular protein fold with atomic-level accuracy. Science 302(5649), 1364-8. Fisher, M.A., McKinley, K.L., Bradley, L.H., Viola, S.R., Hecht, M.H., 2011. De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth. PLoS One 6(1), e15364. doi: 10.1371/journal.pone.0015364. Edited by Genomicus, : No reason given.
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Admin Director Posts: 13103 From: EvC Forum Joined: |
Thread copied here from the Towards a Hypothesis of Molecular Design thread in the Proposed New Topics forum.
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Percy Member Posts: 22887 From: New Hampshire Joined: Member Rating: 6.9 |
Hi Genonicus,
Your post assumes but does not describe your view of how the intelligent designer operates, so tell me if these steps are roughly correct:
Even if intelligent design engineers are responsible for only 1% of all genetic changes, given the number of species on Earth and the time periods involved this is a massive task requiring the coordinated activity of at least millions of individuals full time. We shouldn't have to be looking into our microscopes for evidence of their presence. Their garbage dumps alone should be everywhere. And why are they doing this? How did they get here? Where are they hiding? And more importantly, how did the intelligent designer evolve? Sorry to have ignored the specifics in your post, but it seems to me that you've skipped over a lot of obvious issues to jump way down into a fantasy of detail. --Percy
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Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
Hi Percy,
You raise good points. Unfortunately, I did not clarify some important issues that relate to the model described in the OP.
Your post assumes but does not describe your view of how the intelligent designer operates, so tell me if these steps are roughly correct... As a whole, those steps do not represent my views on how the intelligent designers operated. Instead, I would suggest the following steps: 1. A gram-positive cell structure is designed (a feasible technological achievement: see, e.g., Rasmussen et al., 2003; Budin and Devaraj, 2012). The DNA --> RNA --> proteins system is engineered as well. 2. The core molecular machinery -- such as ATP synthases, transcription-related machinery, metabolic enyzmes, etc. -- of this cell is designed by synthetic DNA engineering. De novo design of protein structures occurs at this point. 3. Next, the unnecessary (but nonetheless very useful) protein machines are engineered. This involves a combination of both de novo protein design and the borrowing of parts and subsystems from other machines, as described in this essay. At the DNA level, this would involve changing a variety of nucleic acid positions, so probably several steps would be needed to check and re-check to ensure that the desired function is being produced. The genes for front-loading would also be introduced. 4. The organism (or cluster of organisms) then reproduces, transmitting the changes to their descendants. 5. The gram-negative and Archaea cell structures are then engineered from the gram-positive cells. The molecular machinery and functions specific to these prokaryotic groups are constructed. 6. The gram-positive, gram-negative, and Archaea cells are allowed to reproduce, producing a sizable population of organisms. 7. These organisms are then seeded onto Earth (either directly or as a consequence of the dispersal of these organisms throughout the cosmos). 8. These organisms evolve over time, giving rise to the eukaryotic complexity that we see today. This answers the objection that (a) a huge number of resources would be needed, since only the most basic cells are designed, and (b) that evidence of this intelligent design should be present beyond the cell. While such an engineering achievement would be impressive, it's not at all a monumental task. With regards to the next questions you ask, I can only offer speculation. The questions, while interesting, aren't completely relevant to the specific hypothesis that certain molecular machines were engineered.
And why are they doing this? How did they get here? Where are they hiding? And more importantly, how did the intelligent designer evolve? I don't know, but I don't think that's a problem for the hypothesis. References Budin, I., Devaraj, N., 2012. Membrane Assembly Driven by a Biomimetic Coupling Reaction. Journal of the American Chemical Society 134 (2), 751 DOI: 10.1021/ja2076873. Rasmussen, S., Chen, L., Nilsson, M., Abe, S., 2003. Bridging nonliving and living matter. Artif Life. 9(3), 269-316. Edited by Genomicus, : No reason given. Edited by Genomicus, : No reason given.
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Percy Member Posts: 22887 From: New Hampshire Joined: Member Rating: 6.9 |
Hi Genomicus,
The steps I described assumed your hypothesis was that significant evolutionary steps are carried out by designing the necessary DNA and then inserting it into the reproductive cells of existing lifeforms on Earth. This would, of course, be a labor intensive effort requiring continuous activity (including up through the present) that would leave behind a great deal of evidence. The steps you described seem more consistent with a hypothesis that the first life was designed, manufactured and seeded on to Earth, and that evolution took over after that. The possibility that life was seeded here from somewhere else is already an accepted hypothesis, but your hypothesis introduces the additional idea that it was designed and manufactured rather than natural. This raises the obvious conundrum that if the origin of life on Earth required a designer, then the origin of life on the designer's home planet also required a designer, and the origin of life on the designer's designer's home planet also required a designer, and so forth ad infinitum. To break the conundrum one must accept that although Earth lacks the necessary qualities for abiogenesis, there must have been at least one planet where life arose naturally, and that life on one of these planets must be the ultimate origin of life here. But why do you believe life couldn't have arisen naturally here on Earth, but could have arisen naturally elsewhere? There must be a compelling reason to believe this (and interstellar travel, too) in order to justify the amount of intellectual effort it would take to understand the details of your proposal. It just seems to me that before discussing how many fairies can dance on the head of a pin, one must have a compelling reason for believing fairies exist. --Percy
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bluegenes Member (Idle past 2698 days) Posts: 3119 From: U.K. Joined: |
Genomicus writes: Prediction 1: Molecular clock analyses of protein sequences of the components of the machine should reveal a specific pattern. Under the Darwinian model, the evolution of a machine like the flagellum proceeds through the stepwise co-option of parts. Correct. But there are problems with your molecular clock predictions. Firstly, we could put forward an evolutionary hypothesis that the core parts of the ancestral flagellum (an "Ur-flagellum that is ancestor to all the modern variables - there could be millions of these) evolved over less than 1 million years more than 1 billion years ago. Then, all things being equal, it would be impossible to distinguish the relative ages of the diverging proteins by molecular clocks because the actual ages would be 99.9% the same. In addition, the enormous number of generations in an old system like this would mean problems with saturation and parallel mutations on the diverging genes, as well as with changes in the mutation rate of different copies. The evolution of the core flagellum in less than 1 million years (~2 billion generations of a group of organisms with a very large effective population size) is perfectly plausible. You get from a fish to an elephant in far fewer generations than that!
Geno writes: this means that we cannot logically predict — from a design perspective — that molecular clocks will demonstrate that all machine components originated at about the same time. This is because if some proteins are modified more substantially than others, it would confuse the molecular clock. Protein components that have undergone more drastic modifications will have the appearance of being more ancient (using a molecular clock), while proteins that are only slightly changed will appear to have originated more recently. This would also apply with natural selection. Some of the duplicated genes will have had more beneficial mutations that have gone to fixation via positive selection than others after duplication.
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bluegenes Member (Idle past 2698 days) Posts: 3119 From: U.K. Joined: |
To explain further.
I.D. hypothesis (A): Intelligent designers design and construct the core flagellum all at the same time more than 1 billion years ago. I.D. hypothesis (B): Intelligent designers design and construct the core flagellum in a number of stages involving a number of visits to the planet over a very long period of time, with long time gaps between visits. Evolutionary hypothesis (C): The core flagellum evolves in stages during less than 1 million years more than 1 billion years ago. Evolutionary hypothesis (D): The core flagellum evolves in stages over a very long period of time, with long time gaps between stages. With regards to molecular clock related predictions, A and C make the same ones, as do B and D. Research could support one pair of hypotheses over the other, but couldn't distinguish within the pairs AC and BD.
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Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
Hi Percy,
The steps I described assumed your hypothesis was that significant evolutionary steps are carried out by designing the necessary DNA and then inserting it into the reproductive cells of existing lifeforms on Earth. This would, of course, be a labor intensive effort requiring continuous activity (including up through the present) that would leave behind a great deal of evidence. The steps you described seem more consistent with a hypothesis that the first life was designed, manufactured and seeded on to Earth, and that evolution took over after that. The possibility that life was seeded here from somewhere else is already an accepted hypothesis, but your hypothesis introduces the additional idea that it was designed and manufactured rather than natural. That is correct.
This raises the obvious conundrum that if the origin of life on Earth required a designer, then the origin of life on the designer's home planet also required a designer, and the origin of life on the designer's designer's home planet also required a designer, and so forth ad infinitum. The thesis that biological, terrestrial cells can only plausibly arise through the actions of engineering in no way implies that all possible life forms require intelligent intervention in order to arise. It is undoubtedly possible that other life forms exist, based on alternative biochemistries or materials, and that these life forms could plausibly evolve through unplanned chemical interactions. Indeed, it is quite obvious that alternative life forms do exist: humans have designed such life forms (see, e.g., Virgo et al., 2012, wherein a self-replicating machine was manufactured from small pieces of plastic that contained magnets). Thus, it is perfectly possible for life forms to exist that are not based on our biochemistry. The next question, then, is whether these life forms could evolve without the input of intelligent agents. I would contend that a number of scenarios could be postulated whereby a self-replicating system could arise in the absence of intelligence and then evolve into a variety of taxa. Self-replicating systems, after all, are not unique phenomena in nature (consider, for example, crystal growth and replication). While the origin of biological life on Earth might pose a problem to evolutionary models, it is plausible for other forms of life to evolve, and then proceed to engineer the biological cells that are on earth. Just saying.
To break the conundrum one must accept that although Earth lacks the necessary qualities for abiogenesis, there must have been at least one planet where life arose naturally, and that life on one of these planets must be the ultimate origin of life here. But why do you believe life couldn't have arisen naturally here on Earth, but could have arisen naturally elsewhere? There are several reasons why it would be more plausible for a life form to evolve on a planet other than Earth. In the first place, in contrast to other planets, life on Earth would not have very much time to evolve. The Earth is estimated to be roughly 4.5 billion years old, with life arising relatively shortly after the origin of our planet. This gives only a small amount of time for life to evolve on Earth (on a cosmic scale). The notion that life arose on another planet is attractive because it provides more time for life’s origin. Secondly, some other planet might possess an environment more favorable to the origin of some self-replicating system (as a simple example, it might be saturated with an abundance of amino acids, making the formation of functional amino acid strings more probable).
There must be a compelling reason to believe this (and interstellar travel, too) in order to justify the amount of intellectual effort it would take to understand the details of your proposal. The reason I’m proposing this hypothesis is pretty simple. At present, there are no mechanistically plausible models for the origin of cellular life on Earth. An engineering approach would provide an alternative hypothesis to current proposals for the origin of life; furthermore, since there are some clues of design within the cell, it makes sense to follow-up these clues with a hypothesis of design. References Virgo, N., Fernando, C., Bigge, B., Husbands, P., 2012. Evolvable physical self-replicators. Artif Life. 18(2), 129-42.
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Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
Hi bluegenes, and thanks for your critique.
Prediction 1: Molecular clock analyses of protein sequences of the components of the machine should reveal a specific pattern. Under the Darwinian model, the evolution of a machine like the flagellum proceeds through the stepwise co-option of parts.
Correct. But there are problems with your molecular clock predictions. Firstly, we could put forward an evolutionary hypothesis that the core parts of the ancestral flagellum (an "Ur-flagellum that is ancestor to all the modern variables - there could be millions of these) evolved over less than 1 million years more than 1 billion years ago. Then, all things being equal, it would be impossible to distinguish the relative ages of the diverging proteins by molecular clocks because the actual ages would be 99.9% the same. Right, but that scenario would still lead to a different set of predictions. The evolutionary scenario you outlined would result in the prediction that the core flagellar proteins all diverged from their non-flagellar homologs at approximately the same time. This is not what the molecular design model I described predicts. Instead, the molecular design model predicts different divergence times for different proteins, depending on two factors: their substitution rates and the amount of modification that would be required to change a non-flagellar component into a flagellar component.
In addition, the enormous number of generations in an old system like this would mean problems with saturation and parallel mutations on the diverging genes, as well as with changes in the mutation rate of different copies. These are technical issues related to the methods used in molecular clock analyses. Molecular clock analyses, however, are no longer simply a matter of calculating the number of substitutions per site between two sequences and dividing that by 2r (the substitution rate doubled), as was done in the 70s. While the problems you detail are worthy of consideration, they are not insurmountable. Models of sequence evolution can be employed to ameliorate the effects of saturation (plain ole’ molecular phylogenies are affected by saturation, too, so sophisticated models of sequence evolution have been developed to partially resolve this problem). Furthermore, some flagellar proteins share a good deal of sequence similarity with their homologous counterparts (e.g., the flagellar rod proteins share unambiguous sequence similarity, as do several of the ATPase components), implying that the sequence divergence of these proteins are constrained, and this, in turn, means a relatively minimal amount of saturation and homoplasy. As for changes in the mutation rates in different lineages, this is not a problem that has been ignored by the molecular evolution specialists. Relaxed molecular clocks are often utilized instead of strict molecular clocks to account for rate variation; in particular, uncorrelated relaxed clock methods are very useful for estimating divergence times despite rate variation among lineages. Drummond et al. (2006) have described some of the techniques used for relaxed molecular clocks.
this means that we cannot logically predict — from a design perspective — that molecular clocks will demonstrate that all machine components originated at about the same time. This is because if some proteins are modified more substantially than others, it would confuse the molecular clock. Protein components that have undergone more drastic modifications will have the appearance of being more ancient (using a molecular clock), while proteins that are only slightly changed will appear to have originated more recently.
This would also apply with natural selection. Some of the duplicated genes will have had more beneficial mutations that have gone to fixation via positive selection than others after duplication. Possibly, but that would violate the molecular clock. This is, of course, possible, but there are models out there that can take rate variation into consideration (as stated above). Moreover, statistical approaches (e.g., based on a Bayesian framework) may be used to determine if a strict molecular clock model (that is, a constant molecular clock) or a non-clock model is a better explanation for the dataset. Programs like MrBayes are able to accomplish these analyses. As an example, when I used MrBayes 3.2 to test the strict clock model against the non-clock model for ExbB/MotA and ExbD/MotB, the strict clock model was found to be superior to the non-clock model. Also, while the scenario you postulate is possible under a Darwinian framework, it is not predicted by it. This is a crucial point. While Darwinian evolution might be able to explain any observations that match the predictions of the molecular design hypothesis, it does not predict it. You state that this would also apply with natural selection, implying that it is predicted under an evolutionary model. In other words, it seems (to me, at least) that you contend that an evolutionary model predicts that different protein components will show different divergence times with their homologs, and in a pattern that coincides with what molecular design predicts. But earlier you postulated a scenario wherein all the proteins originated in a time-span of 1 million years or so, with the result that the divergence times from their homologs would be approximately equal. So which is it? Does an evolutionary model for the origin of the ur-flagellum predict that all the proteins diverged from their homologous counterparts at about the same time or that their divergence times are significantly different, depending on the amount of modification that would be needed to incorporate them into the flagellum? In my humble opinion, the answer to this question is obvious: there is no prediction here from an evolutionary perspective. The evolutionary model could only explain these observations, but it does not predict them. On the other hand, the molecular design hypothesis logically leads to the specific predictions described in the OP.
To explain further. I.D. hypothesis (A): Intelligent designers design and construct the core flagellum all at the same time more than 1 billion years ago. This would not lead to the prediction that the divergence times of flagellar proteins from their homologs would be equal because some modification would be required to incorporate the homologs into a flagellar system. This is in contrast to the Darwinian model explained here:
Evolutionary hypothesis (C): The core flagellum evolves in stages during less than 1 million years more than 1 billion years ago. In summary, the molecular design hypothesis outlined in the OP makes specific predictions concerning molecular clock analyses, while the scenario that certain biological machines evolved does not make these predictions. To add a bit to this discussion, I would also be interested in looking at molecular clock analyses of two different molecular machines (and their homologous counterparts): a bacterial molecular machine that was present in the LUCA, and a eukaryotic molecular machine. If one envisions a scenario wherein gram-negative and gram-positive prokaryotes were designed (along with their core molecular machinery), we would predict that the bacterial molecular machine would match the predictions of the molecular design hypothesis, whereas the eukaryotic molecular machine should be consistent with an evolutionary explanation. For example, if we look at the spliceosome, will molecular clock analyses show a pattern of co-option that is consistent with a pathway of selectable steps? Would this pattern result for the bacterial flagellum as well? I suspect that that pattern would hold for the spliceosome, but not for the bacterial flagellum. Only time will tell, but this would be another way to test the molecular design hypothesis. References Drummond AJ, Ho SYW, Phillips MJ, Rambaut A (2006) Relaxed Phylogenetics and Dating with Confidence. PLoS Biol 4(5): e88. doi:10.1371/journal.pbio.0040088. Edited by Genomicus, : No reason given.
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bluegenes Member (Idle past 2698 days) Posts: 3119 From: U.K. Joined: |
Genomicus writes: Right, but that scenario would still lead to a different set of predictions. The evolutionary scenario you outlined would result in the prediction that the core flagellar proteins all diverged from their non-flagellar homologs at approximately the same time. This is not what the molecular design model I described predicts. Yes, it does. It predicts the same actual time, but not the same "molecular clock" time because, as you say here:
Genomicus writes: Instead, the molecular design model predicts different divergence times for different proteins, depending on two factors: their substitution rates and the amount of modification that would be required to change a non-flagellar component into a flagellar component. And these variants also apply to my specific evolutionary hypothesis. The amount of modification would vary whether achieved by mutation and selection or by design, and substitution rates would vary. The two hypotheses make the same predictions, and I agree that it's possible that they could be falsified by the application of relaxed molecular clocks if the core flagellum did actually develop over long periods of time with significant gaps in the times of divergence.
Genomicus writes: Also, while the scenario you postulate is possible under a Darwinian framework, it is not predicted by it. This is a crucial point. While Darwinian evolution might be able to explain any observations that match the predictions of the molecular design hypothesis, it does not predict it. Neither general evolutionary theory nor a general intelligent design hypothesis make the predictions that your specific I.D. hypothesis and my specific evolutionary hypothesis make. I gave an example of an I.D. hypothesis that would match the slow, long term evolution of the flagellum (the designers revisiting the planet many times and making adjustments). Another would be more down your street. That is, the front loading of non-flagellar bacteria with functional proteins that could later evolve by duplication and mutation into flagellar proteins. This is where I think you're going wrong. Every time you make a specific I.D. hypothesis, I can match it with a specific non-telic evolutionary hypothesis. It's no good pointing out that the general theory of evolution does not make the predictions of your specific hypothesis, because neither does the general proposition that life was designed. But you can make specific I.D. hypotheses that are incompatible with all evolutionary hypotheses. The standard young earth creationist model is an example of this. We cannot make evolutionary hypotheses to fit the prediction that all life should appear suddenly ~6,500 years ago. So, as you seem to understand that the general proposition of I.D. doesn't make predictions (no biosphere would be incompatible with it), can you "old earth common descent" I.D. advocates make specific I.D. hypotheses that make predictions that cannot also be the predictions of specific evolutionary hypotheses, as the "young earthers" do?
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Taq Member Posts: 10271 Joined: Member Rating: 7.4 |
Does an evolutionary model for the origin of the ur-flagellum predict that all the proteins diverged from their homologous counterparts at about the same time or that their divergence times are significantly different, depending on the amount of modification that would be needed to incorporate them into the flagellum? In my humble opinion, the answer to this question is obvious: there is no prediction here from an evolutionary perspective. The evolutionary model could only explain these observations, but it does not predict them. On the other hand, the molecular design hypothesis logically leads to the specific predictions described in the OP. As you note, the theory of evolution only describes the mechanisms involved in the process of evolution. The theory can not take a genome and predict its evolutionary future. However, I don't see how design makes the predictions you claim. An advanced race that stops by every million years and makes tweaks would produce the opposite pattern from the one hypothesized.
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Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
Hi bluegenes,
Genomicus writes:
Yes, it does. It predicts the same actual time, but not the same "molecular clock" time because, as you say here:Right, but that scenario would still lead to a different set of predictions. The evolutionary scenario you outlined would result in the prediction that the core flagellar proteins all diverged from their non-flagellar homologs at approximately the same time. This is not what the molecular design model I described predicts. Instead, the molecular design model predicts different divergence times for different proteins, depending on two factors: their substitution rates and the amount of modification that would be required to change a non-flagellar component into a flagellar component. bluegenes: And these variants also apply to my specific evolutionary hypothesis. The amount of modification would vary whether achieved by mutation and selection or by design, and substitution rates would vary. Yes, but it must be emphasized that if the ur-flagellar proteins originated in a 1 million year timespan, then a constant molecular clock would date their origin to be at about the same time. Your specific evolutionary theory therefore would postulate a non-constant molecular clock/rate variation as you suggest above. But a constant molecular (or nearly constant) is also perfectly possible under the evolutionary model (though not included in the specific hypothesis you outline). This will become an important point in a below argument.
Neither general evolutionary theory nor a general intelligent design hypothesis make the predictions that your specific I.D. hypothesis and my specific evolutionary hypothesis make. I gave an example of an I.D. hypothesis that would match the slow, long term evolution of the flagellum (the designers revisiting the planet many times and making adjustments). Another would be more down your street. That is, the front loading of non-flagellar bacteria with functional proteins that could later evolve by duplication and mutation into flagellar proteins. This is where I think you're going wrong. Every time you make a specific I.D. hypothesis, I can match it with a specific non-telic evolutionary hypothesis. It's no good pointing out that the general theory of evolution does not make the predictions of your specific hypothesis, because neither does the general proposition that life was designed. I proposed a specific, non-ad hoc model for the engineering of certain biological molecular machines. The logical consequences that result from that model were then explored, and several predictions were delineated. On the other hand, IMHO your specific hypothesis is not biologically realistic and would require the insertion of ad hoc explanations. Let me elaborate on this. Suppose we find a certain biological machine X in various prokaryotic taxa. Based on the molecular design model, specific predictions could be made concerning the pattern of divergence times among the components. It is a logical consequence of the hypothesis. Now then, you suggest that the ancestral parts of the machine X arose in a span of, for example, 1 million years. When each component originated, the molecular clock was violated because of an accelerated rate of mutation to get just the right amount of modification (even though this result is also possible under a nearly-constant molecular clock model). The results are the same in both instances, or so it would seem. However, for your hypothesis to work, you would have to explain why every single component of the system fits with your scenario. For example, if machine X has 24 core components (like the bacterial flagellum does), your hypothesis needs to explain why every single one of them (specifically, the ones that have homologous counterparts, or are fusion proteins) underwent the same pattern of violating the molecular clock in the precise way of undergoing a rapid substitution rate so that they would fit nicely with the rest of the machine parts. Your model needs to explain this, preferably in a non-ad hoc fashion, since we know that protein sequences are perfectly capable of fitting a nearly-constant molecular clock (I don’t think I need to bring up the many examples of protein sequences that conform to a nearly-constant molecular clock). In other words, your hypothesis will be hard-pressed to explain why none of the protein components evolved at a nearly-constant molecular clock, when this is not only biologically possible but also seen in a variety of protein sequences. And if some protein parts did evolve and originate at a nearly-constant molecular clock, then this would result in a prediction different from the molecular design hypothesis. We would expect the divergence times of some of the proteins (the ones that originated at a nearly-constant clock) to cluster closely together, and not necessarily in the pattern expected from molecular design. More specifically, if we find a fusion protein wherein both domains demonstrate approximately the same divergence times, this would represent the actual age of the system. Thus, it would be predicted that the divergence time of any protein component that originated in a manner consistent with a constant clock would match with the divergence time of the fusion protein domains (approximately). So, we should expect, from an evolutionary perspective, that some divergence times should cluster closely together (and not in a pattern expected from molecular design), and if there is a fusion protein whose domains have equal divergence times, then the clustering should occur around this fusion protein. In summary, then, your hypothesis doesn’t seem to be able to explain why all components of a system should violate the molecular clock while they descend from their ancestral sequences. The problem gets worse the more systems we consider. Your hypothesis might be able to wave-away this problem when we only consider a few biological systems, but if we find that many biological systems (particularly prokaryotic machines and systems) fit the prediction of molecular design, IMHO your hypothesis will start looking awfully ad hoc.
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Genomicus Member (Idle past 2163 days) Posts: 852 Joined: |
As you note, the theory of evolution only describes the mechanisms involved in the process of evolution. The theory can not take a genome and predict its evolutionary future. However, I don't see how design makes the predictions you claim. An advanced race that stops by every million years and makes tweaks would produce the opposite pattern from the one hypothesized. That is correct. The broad thesis that life was somehow designed doesn't predict the specific cases described in the OP. However, the molecular design hypothesis does make those predictions, and while you can formulate an evolutionary model that makes those same predictions, that evolutionary model runs into difficulties, as detailed in my response to bluegenes (message 12). Edited by Genomicus, : No reason given.
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Taq Member Posts: 10271 Joined: Member Rating: 7.4 |
That is correct. The broad thesis that life was somehow designed doesn't predict the specific cases described in the OP. However, the molecular design hypothesis does make those predictions, and while you can formulate an evolutionary model that makes those same predictions, that evolutionary model runs into difficulties, as detailed in my response to bluegenes (message 12). Your design hypothesis is entirely arbitrary. There is no reason to expect one outcome over another. That is the problem.
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bluegenes Member (Idle past 2698 days) Posts: 3119 From: U.K. Joined: |
Genomicus writes: However, for your hypothesis to work, you would have to explain why every single component of the system fits with your scenario. For example, if machine X has 24 core components (like the bacterial flagellum does), your hypothesis needs to explain why every single one of them (specifically, the ones that have homologous counterparts, or are fusion proteins) underwent the same pattern of violating the molecular clock in the precise way of undergoing a rapid substitution rate so that they would fit nicely with the rest of the machine parts. Your model needs to explain this, preferably in a non-ad hoc fashion, since we know that protein sequences are perfectly capable of fitting a nearly-constant molecular clock (I don’t think I need to bring up the many examples of protein sequences that conform to a nearly-constant molecular clock). These proteins have been co-opted into new functions. So, positive selection would explain an initial rapid substitution rate after duplication or fusion. The hypothesis you're referring to was that the machine parts are 99.9% the same age. That means that we will not be able to tell their order of arrival by molecular clocks, because molecular clocks are not 99.9% accurate. It means that any molecular clock related predictions would be the same as those for an instantly designed "machine", so far as synonymous mutations are concerned. In your O.P., you point out that the amount of modification required can distort molecular clocks. This applies whether the modification is done by mutation and selection or by engineering.
Geno in the O.P. writes: this means that we cannot logically predict — from a design perspective — that molecular clocks will demonstrate that all machine components originated at about the same time. This is because if some proteins are modified more substantially than others, it would confuse the molecular clock.Protein components that have undergone more drastic modifications will have the appearance of being more ancient (using a molecular clock), while proteins that are only slightly changed will appear to have originated more recently. In particular, the design hypothesis predicts that molecular clocks will show that proteins with rapid substitution rates will have a later origin, while proteins with slow substitution rates will have an early origin. We can summarize this prediction in this manner: in general, the slower the substitution rate, the more ancient the protein will appear to be. If a protein has a slow substitution rate, then any modifications to the sequence of that protein will give the appearance of a large amount of time passing by. In contrast, even fairly extensive modifications to a protein with a rapid substitution rate will not significantly affect the molecular clock. To further refine this prediction, we can take into account the amount of modification that would be needed for a given protein. Indeed, a high neutral substitution rate on both diverging proteins would diminish the effects of adaptation to a new function on one of them. What you're really describing are effects that could easily arise from established evolutionary processes, and would apply under my hypothesis that the core flagellum evolved relatively rapidly. I say "relatively", because one million years does equal 2 billion generations, and I see no reason why it would take anywhere near that many to evolve a flagellum under selection pressure for motility. Still, you're making by far the best effort to make I.D. hypotheses that make predictions that I've seen on this site, so keep it up. But I think what you may be doing, perhaps unconsciously, is using your knowledge of evolution to identify quite likely evolutionary scenarios, and then deciding that your designers have designed in a way that would fit them. Once again, why didn't the designers front load the proteins for the core flagellum? Wouldn't it be technically much easier to do this than to front load with metazoa in mind?
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