BioEssays

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Edited By: Andrew Moore

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Online ISSN: 1521-1878

Does constructive neutral evolution play an important role in the origin of cellular complexity?

Posted by: Editorial

Constructive neutral evolution (CNE) is a concept that aims at explaining the emergence of cellular complexity. It comprises a three step process: First, a mutation occurs which does not (or hardly) result in reduced fitness of the organism. Then further mutations lead to fixation of dependence, as reverse mutation of the single first mutation cannot restore the original viable organism. Finally, a ratchet-like increase, dependent on the fact that further similar mutations occur much more easily than they are reversed leads to ever increasing use of the activity now intensely involved in maintaining viability. In his article, Dave Speijer argues that the theory of CNE has major conceptual problems and cannot explain observed patterns of complex processes. Doolittle et al. disagree with Speijer's critique of CNE and have responded in a Commentary. They give a slightly different description of CNE and reason that CNE provides a new way to think about the evolution of complex biological processes.
We invite you to read these two articles and to contribute to the discussion.

Read the articles:

Does constructive neutral evolution play an important role in the origin of cellular complexity?
Dave Speijer
Volume 33, Issue 5, pages 344-349, May 2011

Comment on "Does constructive neutral evolution play an important role in the origin of cellular complexity?"
W. Ford Doolittle et al.
Volume 33, Issue 6, pages 427-429

Comments:

Table 1, dubious "evidence" in cols 3 to 7, by Arlins Stoltzfus
The aim of Table 1, presumably, is to reflect the status of CNE by comparing applications of CNE to alternatives in col 2. I have mentioned already that the choice of cases (col 1) is less than fair, and that the alternatives (col 2) often are not true alternatives.
Columns 3 to 7 present what is referred to as "evidence" to distinguish CNE from "selectionist models".
Note from p. 2 that Speijer himself devised the "His", "Dis" and "Exp" criteria (cols 3, 4 and 6). Previous treatments of CNE did not give criteria to distinguish between features that result mostly from CNE and those that do not, though Gray, et al. invoked the idea that some features seem extravagant or disproportionately complex-- thus the "Pro" or proportionality criterion (col 5). Likewise, adaptationists have not proposed general criteria for determining which features result from adaptive evolution. In the adaptationist research program, one merely assumes a priori that a feature is an adaptation, then looks for an explanation that fits.
Such criteria, if valid, would be useful. Speijer unveils his 3 criteria on p. 2, third column, middle paragraph. This brief paragraph does not cite any references on evolutionary theory, nor does it provide any logical justification-- perhaps because the criteria given are difficult to justify or to apply.
In regard to the His or "history" criterion (col 3), Speijer's claim is that in a CNE model, complexity will increase smoothly, whereas in a selective model, it will occur "in fits and bounds". He asserts that "rapid bursts . . . with long stable periods in between are indicative of positive selection and thus incompatible with CNE". I see no obvious reason to believe this, and Speijer provides none. Advocates of Darwinism once held the nearly opposite belief that adaptation happens smoothly and without jumps. To the extent that Darwinists have acceded to "punctuated equilibrium", they have been forced to this position by the data, not by doctrine nor by theory. Purely stochastic processes can produce complex dynamics, as one may discover by googling "sandpile effect" or "self-organized criticality".
The Dis or distribution criterion (col 4) holds that, if the nature or complexity of a trait varies in accordance with the proposed function, this is evidence for the "selectionist models" and against CNE. However, the reasoning is mistaken. Any model of evolution in some system S will produce behavior that correlates with biotic factors operating in S. In particular, due to the influence of negative selection, a neutral model can produce behavior that is non-random with respect to "functional" features, e.g., a neutral model of gene evolution can account for disparity in rates of evolution between 1st, 2nd and 3rd codon positions. Likewise, the CNE model for gene scrambling does not predict gene scrambling to evolve everywhere entirely at random, because it depends on having silent genes, such as ciliates have in their micronucleus. This would be true under any model of scrambling, neutral or adaptive. A reasonably clever biologist, given a distribution pattern X for some trait, and a set of biotic factors Y, can find ways to leverage the Y's in an ad hoc model to explain the pattern X. The CNE models have not been elaborated in this way, but there is nothing to stop a clever biologist from doing so. The fact that it hasn't been done yet is not evidence against CNE.
The Pro or proportionality criterian is reasonable, but how does one apply it objectively? Is there a metric for complexity? Is there a method for determining if a feature is inordinately complex? No. Apparently this column of "evidence" consists of opinions.

Circadian clocks, by Psi Wavefunction
Dave, Could you elaborate on the 'circadian clock' point? I've never heard any of the CNE-associated authors as much as mention circadian clocks, so I'm curious where I missed that. Thank you! Cheers, -Psi-

Table 1, col 1: inappropriate choice of cases, by Arlin Stoltzfus
This article contains countless errors of omission and commission. I'll begin with Table 1. The intention, presumbly, is to reflect the status of CNE as an evolutionary idea, by providing details about how well it applies to cases. However, the cases listed in column 1 fail to present a fair or accurate picture: 1. the table omits an entry for the CNE model for the retention of duplicate genes (Stoltzfus, 1999, Force, Lynch, et al., 1999, 2000) that has received ~2000 citations in the literature, more than any other model 2. the table omits an entry for the CNE model for gene scrambling (Stoltzfus 1999) 3. the table includes "Eukaryotic circadian clock", apparently on the sole grounds that Gray, et al. noted Sancar's description of it as a "Rube Goldberg machine". Gray, et al did not elaborate this case, other than to cite Sancar's comment. In general, only 4 cases have been worked out clearly: RNA editing in plant organelles (Covello & Gray, 1993) or kinetoplastids (Stoltzfus, 1999), spliceosome complexification (Stoltzfus, 1999), duplicate gene retention (Stoltzfus, 1999; Force, Lynch, et al., 1999, 2000), and ciliate gene-scrambling (Stoltzfus, 1999). Only 2 of these appear in Table 1. The other examples are much more casual claims that appear in Gray, et al, 2010. references: Force, A., M. Lynch, et al. (1999). "Preservation of duplicate genes by complementary, degenerative mutations." Genetics 151(4): 1531-1545. Lynch, M. and A. Force (2000). "The probability of duplicate gene preservation by subfunctionalization." Genetics 154(1): 459-473.

Reply to: Table 1, col 1: inappropriate choice of cases, by Dave Speijer
I do not know about the 'countless errors of omission and commission' of my article. However, I notice a glaring omission in this comment. From line 1 it is clear that my article is written as a reaction to the (over)extended application of CNE in (Gray, et al. 2010). Quote: '...... contains the most ambitious application of the theory of 'Constructive Neutral Evolution' (CNE) [2] to the understanding of biological complexity, yet.' The selection of cases for Table 1 (Kinetoplastid panediting, Respiratory chain complexity, Pro- and Eukaryotic ribosome complexity, Splicing/Spiceosome complexity, The eukaryotic circadian clock) is based on the ones highlighted in that publication. If Dr. Stoltzfus considers the invocation of CNE wrong, premature or even frivolous in some of these cases he has an issue with (Gray, et al. 2010). reference: Gray, et al. (2010). "Irremediable complexity?" Science 330 (6006): 920-921.

Distortions and errors in Introduction, by Arlin Stoltzfus
p. 1 states that Gray, et al. "contains the most ambitious application" of CNE. This claim is used to justify a critique of CNE based on a 2-page commentary by Gray, et al. Meanwhile, Speijer fails to address the 12-page article on CNE (Stoltzfus, 1999) that defines terms, presents 4 cases in detail, cites known biological precedents for key steps, and even presents simulation results that give the lie to Speijer's key claim-- if CNE has "conceptual problems" that make it unworkable, why do computer simulations of the gene duplication model work so well?
p. 1 states that "In [Gray, et al], the authors make a valiant effort to delineate the relative contributions of chance (in the form of CNE) and necessity (in the form of selection) to the evolution of . . ." This is one of many examples of a statement that is so far from correct, one just does not know where to start. Selection is not necessity, and CNE is not chance. CNE depends on negative selection, as Stoltzfus (1999) makes perfectly clear. Furthermore, CNE models are capable of exhibiting non-random tendencies, due both to negative selection, and to biases in the introduction of varaition.
p. 1 states that "there have always been problematic aspects regarding its application". What source does Speijer cite to show that there have "always" been problems that CNE "does not address"? Speijer cites his own letter published just last year, 11 years after Stoltzfus, 1999, and 17 years after Covello and Gray. Speijer's letter was a response to Lukes, et al, 2009, the latter being a work that had but a single paragraph about CNE. Speijer's letter did not address the more robust treatment of Stoltzfus, 1999. In short, Speijer has published 1 letter, as poorly reasoned as his present essay, and then cites this as evidence that CNE "always" has had problems that are being ignored by its proponents.
I would be happy to address Speijer's concerns if I could make any sense of them, but he assumes so much, and relies on so many mischaracterizations, that it is impossible for me to see what might be said to explain to him how CNE works, and how the thinking in CNE models can be combined usefully with positive selection (if one wishes to do so). For instance, on p. 4 he says that it is "another hidden assumption" of CNE that changes individually considered neutral can still be considered neutral when many are taken into account. It is true that a long series of neutral changes might add up to an effect that is maladaptive on an absolute scale. Lynch suggests that this might be true for the addition of introns-- each addition can occur by mutation and drift, but the net effect is a burden that slows down the cell. Because selection does not make comparisons with long-dead ancestors, this kind of downward evolution is mechanistically possible and is not a contradiction of population genetics, nor of the concept of neutral evolution. So, where is the problem? What Speijer has written simply does not reveal why he sees this as a hidden flaw in CNE.
Table 1, col 2: misleading comparisons, by Arlin Stotzfus
The intention of Table 1, presumbly, is to reflect the status of CNE by comparing it to alternative explanations listed in column 2. I have mentioned already that Speijer's choice of CNE cases in column 1 is less than fair. In addition, if one examines in detail the "selectionist models" in col 2, most of these alleged alternatives are not alternatives: * row 7, domain swapping, is not a comparable hypothesis. The CNE model in Stoltzfus (1999) addresses *spliceosome complexification* via genetic changes that split a catalytic intron (snRNAs) and that entrained various protein factors (spliceosomal proteins). By contrast, the formation of new genes by "domain swapping" or "exon shuffling" via intron-mediated events of illegitimate recombination, whether or not it is an evolutionary advantage (a dubious claim-- see Conant & Wagner), depends on an entirely different set of evolutionary chagnes: the splitting of genes into exons by addition of introns. * rows 8, 9 appear to suffer from the same flaw. Is "an extra level of regulation" or "multiple proteins encoded by one gene" an explanation for why the spliceosome is so complex? Where is the connection? * row 10, "driving force formation (Eu)karyon" reveals the degree to which this Table displays poor reasoning. Koonin & Martin argue that introns were a driving force in the evolution of eukaryotes, because they see the nucleus (the sine qua non of eukaryotes) as an adaptation in response to a plague of introns: in their scheme, the nucleus prevents translation from happening on unspliced transcripts. This is NOT an adaptive rationale for a complex spliceosome, nor even an adaptive rationale for introns and split genes-- it merely presumes them as a pre-condition for subsequent events. Proposing "driving force" for nuclear evolution as an alternative to CNE exposes how utterly this critique depends on the most naive kind of teleological thinking: Table 1 proposes that, as an alternative to a CNE model for step-by-step complexification of the spliceosome, we may simply assert that the spliceosome had to become complex so that eukaryotes later would evolve a nucleus. references: Conant, G. C. and A. Wagner (2005). "The rarity of gene shuffling in conserved genes." Genome Biol 6(6): R50.

Final post, by Dave Speijer
'countless errors of omission and commission', ' displays poor reasoning', 'I would be happy to address Speijer's concerns if I could make any sense of them, but he assumes so much, and relies on so many mischaracterizations, that it is impossible....', 'exposes how utterly this critique depends on the most naive kind of teleological thinking', 'one of many examples of a statement that is so far from correct, one just does not know where to start.' Etcetera.... This is just a random sampling from Dr. Stolzfus posts over the last few days, which I quote in case some readers might consider me too harsh in some of the following paragraphs. Even if Dr. Stolzfus were correct in all his assertions, I find his bullying style totally misplaced. On top of that, he really is quite consistently wrong. I have always been amazed by how preconceptions may trigger people to come up with the weirdest interpretations of texts. Dr. Stolzfus' posts go beyond this, however. Apparently, he has not been able to read the paper objectively. Dr. S. can not make sense of my article because he throws it into the procrustean bed of his certainties (of which he has an amazing supply) where it ends up beyond recognition. Where to begin? I'll start with the most obvious points:
1. Overstating my criticism of CNE. The fact that I mention conceptual problems regarding CNE's assumptions does NOT mean that I think these have to be deadly flaws. Dr. S. states that I have implied that these conceptual problems 'make it unworkable' (his direct quote, so one can see again how he keeps reacting to his own interpretations, not to what I wrote). Even from the title of my article it is clear that I do consider CNE a consistent approach. It is the overreaching and the occasional closed-mindedness in its application that I objected to (also something consistently misrepresented by Dr. S.). Again, the selection of examples was made by Gray et al in the Science perspective I reacted to. If Dr. S. thinks the 'Eukaryotic circadian clock' should not have been associated with CNE, does that mean he now agrees that Gray et al overreached in mentioning it in their discussion?? (this also answers the post of Psi Wavefunction).
2. Forgetting interspecies competition. I quote from the third post of Dr. S.: 'For instance, on p. 4 he says that it is "another hidden assumption" of CNE that changes individually considered neutral can still be considered neutral when many are taken into account. It is true that a long series of neutral changes might add up to an effect that is maladaptive on an absolute scale. Lynch suggests that this might be true for the addition of introns-- each addition can occur by mutation and drift, but the net effect is a burden that slows down the cell. Because selection does not make comparisons with long-dead ancestors, this kind of downward evolution is mechanistically possible and is not a contradiction of population genetics, nor of the concept of neutral evolution. So, where is the problem? What Speijer has written simply does not reveal why he sees this as a hidden flaw in CNE.' I can almost imagine this complete quote surfacing during lectures 'Very basic introduction to evolutionary theory' followed by the question: 'Now what is the flaw here?' The world of Dr. S. is the world of population genetics only. He totally omits interspecies competition. The 'downward evolved' descendant could possibly be competed to extinction under conditions where the long-dead ancestors might have had a much better chance (evolution has no foresight, remember?). Dr. S.' quote is really breathtaking (and not in a positive way). If I practised Dr. S.'s quite cumbersome style I would now come up with at least 7 references (each having 'thousands of citations'), but instead I'll just allow him to Google it and take it from there.
3. Going for the 'worst' interpretation. I could illustrate how Dr. S. has the strange masochistic tendency to always go for the interpretation he can get most worked-up about, but I'll leave it to the interested reader to ferret them out. Meanwhile, in the 'Early view' section of BioEssays, a critical comment regarding my article by Ford Doolittle et al. has appeared, showing that one can engage my arguments in a normal non-dogmatic fashion. Not surprisingly, I disagree with some of their assertions (to paraphrase them) and will try to respond to them later on.
4. Closed-mindedness. One of the main reasons to write my critique was the fact that I noticed a lack of open mindedness regarding alternatives for CNE, or regarding interpretations in which it was coupled to evolvability (the 'overreaching' I mentioned). I think the reactions of Dr. S. have only strengthened my belief that it was high time.
5. Incorrectly invoking teleology. Dr. S. characterizes my mentioning Koonin & Martin's interesting model regarding the origin of the nucleus (the defining characteristic of eukaryotes) as an adaptation in response to a 'plague of introns' (the nucleus preventing translation of unspliced transcripts) in the context of explaining why we find introns, exons and highly complex spliceosomes as 'the most naive kind of teleological thinking'. Let's make this as simple as possible: if we start out with 2 identical archaea populations, one with a (pre)endosymbiont having split genes and one without, the first population would favor those (chance) mutations that separate translation from splicing, the second one would not. This could then open up pathways to higher levels of organization ('evolvability' arguments), and descendants of the first population would outcompete descendants of the second. This means positive selection would be part of the explanation for the fact that nowadays all eukaryotes etc etc etc...... According to Dr. S this means that I say that splicing and spliceosomes came about in order for nuclei to evolve. Mindboggling. Evolvability arguments are NOT teleological. Whereas this could be an honest mistake, it more likely demonstrates blind dogmatism. From my article: 'Another source of confusion comes from the fact that selectionist models are still couched in a sort of teleological shorthand (....). Of course such descriptions are shorthand for Darwinian evolution, starting with chance (mutations). This means that both CNE and selectionist models can not 'explain' the first chance occurrences. To quote Stoltzfus......' Still Dr. S. twists my arguments in a teleological mould. When talking about 'teleology' there is of course an 'elephant in the room': theology. My stating that frequent recurring population 'take over' by certain specific types of mutations by chance alone is highly unlikely gives a quote that can be misused by the religiously inclined (see reactions in Laurence A. Moran's Sandwalk; http://sandwalk.blogspot.com/2011/02/dawkins-darwin-drift-and-neutral-theory.html). Taken out of context (it is abundantly clear I hold SELECTION responsible), it is quoted to imply there is a third source of complexity which presumably works by design: Another demonstration of 'reading what one wants to read' but now from a different perspective. Let me state for the record that I have no secret religiously based inclinations towards teleological explanations: I am, and always have been, an atheist.
6. Bullying with citation record. I now have to deal with the fact that Dr. S. likes to bring up points that have nothing to do with the discussion as such, but should silence opposition anyway. Science is 'open', meaning that ideas should be evaluated based on their merits. Dr. S., however, uses the 'upstart' defence: citing my 'feeble' citation record in these matters (comparing them to his own 'thousands of citations' record). I do not consider this a 'minor' point: in conjuction with his style of debating this would really suppress an unrestrained discussion of ideas. I indeed come from the field of biochemistry and worked on RNA editing for about 8 years (meanwhile obtaining my PhD). Everyone working on kinetoplastid RNA editing is puzzled by this weird process and after I started working on different projects I published a new model for its spread in populations that at least convinced the referees of being interesting enough to publish and which was highly recommended by the faculty of 1000. This in turn lead to an invitation to write a review chapter on 'The evolutionary aspects of RNA editing' in the NAMB series of Springer Verlag (volume 20: RNA editing; edited by Uli Goeringer). The letter to PNAS was indeed my first published 'contact' with CNE. Now all of this is not to blow my own trumpet (a really tiny trumpet at that) because I think my model must be true, but to explain my temerity in discussing CNE in BioEssays. My model is totally untested (as I make clear in the BioEssays article) and I would jump at the possibility of a real test (e. g. comparing two kinetoplastid species with very limited editing, one evolving under a constant regime necessitating full mitochondrial involvement, the second under a regime alternating between full and limited involvement: extensive spread should then only be observed in the second batch; however, organellar transformation is not at a level allowing this yet). Why do I mention this? I think my model elegant and it can explain differences in editing levels (which CNE can not do so easily) because it correlates them with the complexity of kinetoplastid species lifecycles. It actually makes experimental (not only modelling) predictions (see below: 8. Difficulty of finding criteria for distinguishing between CNE an 'adaptionist' models). If this gave negative results I would also consider CNE as a viable explanation for the spread of kinetoplastid panediting (see point 1).
7. Gene duplications. Dr. S. is upset that I have not mentioned CNE's contribution to the field of gene duplications. Most biologists already agree that having chance 'gene duplications' will allow diversification so the connection with evolvability is clear from the start (probably Gray et al. do not stress it precisely for this reason). CNE comes in because without duplicate gene preservation by subfunctionalization it is claimed the extra copies would dissappear before diversification could ever occur. This case seems very convincing, although it brings another conceptual problem. If one copy is without function it is much easier to evolve a new function than when selection still restricts this by necessitating both copies to work (OK, I am really being a bit mischievous now).
8. Difficulty of finding criteria for distinguishing between CNE and 'adaptionist' models. In his last post (so far, pfffff) Dr. S. gives me a lot of flack regarding the criteria I came up with distinguishing between CNE and 'adaptionist' models. First of all, there were no criteria proposed yet (which is surprising in itself). Upon proposing some criteria I am scolded for the fact that I propose new criteria. Secondly, he states that the proportionality criterion can not be applied objectively. I mention myself that 'Judging 'proportionality' is somewhat arbitrary...' and there clearly is indeed no metric for complexity. However, that does not mean a sensible discussion is impossible. He then has to admit the proportionality criterion is not unreasonable, the distribution criterion might even be used to elaborate CNE and not surprisingly he does not discuss the experimental criterion. His reaction to the history criterion, however, is the most telling (I quote in full): 'In regard to the His or "history" criterion (col 3), Speijer's claim is that in a CNE model, complexity will increase smoothly, whereas in a selective model, it will occur "in fits and bounds". He asserts that "rapid bursts . . . with long stable periods in between are indicative of positive selection and thus incompatible with CNE". I see no obvious reason to believe this, and Speijer provides none. Advocates of Darwinism once held the nearly opposite belief that adaptation happens smoothly and without jumps. To the extent that Darwinists have acceded to "punctuated equilibrium", they have been forced to this position by the data, not by doctrine nor by theory.' So these stupid Darwinists had to be convinced by data, but if I now base the history criterion on these data he sees no obvious reason to believe this. This takes special pleading also to a whole new level .
I am sorry to have taken up so much of the readers' time and for not listing any references (because they can be found so easily and Dr. S. has taken up enough of MY time already). Against my better judgement I started replying to earlier posts, though I know these kind of Internet exchanges tend to be about clashing ideologies, scoring, reverting to questions that were already dealt with previously, bullying, swamping with posts, and less about fair exchanges to gain more insight. I'll neither read nor respond to further posts. Dr. Stoltzfus, in more ways than one, you have lost me.
Dave Speijer

What, by Arlin Stoltzfus
After publishing a commentary attributing multiple "conceptual problems" to CNE, and depicting those who have described or invoked it as "proponents" who "easily dismiss" alternatives and whose work "stifles thought", Speijer seems to be shocked to find that his work should be criticized in strong terms. He considers it "bullying".
I am sorry to have hurt Speijer's feelings. Nevertheless, his opening statement demonstrates precisely why Speijer's approach must be criticized in the harshest terms. Of about 1800 words and about 85 statements I posted here, the 5 statements quoted as a "random sampling" by Speijer seem to be the 5 most provocative. I looked back over what I wrote, and only found 1 other phrase that might have been included in this set of 5. [Aside from describing his errors and distortions as "countless"-- when, in fact, I merely stopped counting after a few dozen--, I stand by what I wrote, including the bits that sound harsh out of context.]
For comparison, some actual random samples (drawn using random numbers) from my text are given at the bottom of this message. As the reader will see, these give quite a different impression.
The term "random sample" is sacrosanct to scientists who care about rigor. Speijer's use of this term to refer to a highly biased, cherry-picked sample is the kind of distortion that runs throughout his arguments-- like saying that there have "always been" "conceptual problems" with CNE that its proponents don't address (citing his own incomprehensible letter published just last year), or justifying his choice of circadian clocks in Table 1 by saying that it was "highlighted" by Gray, et al. (who mention "circadian clock" precisely zero times: they merely cite a commentary by Sancar, who refers to it as a "Rube Goldberg" machine).
Random samples of text from my previous posts here. Sample 1 is a random choice of 5 sentences; sample 2 is the same, but weighted by words (more words, more chance the sentence will be picked); and sample 3 is the same, weighted by characters. A spreadsheet to generate such samples is available.
sample 1
* Table 1, col 2: misleading comparisons [section heading]
* The Dis or distribution criterion (col 4) holds that...
* Mistakes, p. 1 [section heading]
* p. 1 [quoting Speijer] "In [Gray, et al], the authors make a valiant effort to delineate ..."
* What source does Speijer cite to show that there have "always" been problems that CNE "does not address"?
sample 2
*The intention of Table 1, presumbly, is to reflect the status of CNE...
* He asserts that "rapid bursts ... with long stable periods in between are indicative of positive selection and thus incompatible with CNE".
* The CNE models have not been elaborated in this way, but there is nothing to stop a clever biologist from doing so.
* Speijer fails to address the 12-page article by Stoltzfus, 1999, which...
* I would be happy to address Speijer's concerns if I could make any sense of them...
sample 3
* RNA editing in plant organelles (Covello & Gray, 1993) or kinetoplastids (Stoltzfus, 1999)...
* row 10, "driving force formation (Eu)karyon" reveals the degree to which this Table displays poor reasoning...
* This brief paragraph does not cite any references on evolutionary theory...
* Likewise, the CNE model for gene scrambling does not predict gene scrambling to evolve everywhere...
* Speijer fails to address the 12-page article by Stoltzfus, 1999, which...

Complexity space and other issues, by Pavel Flegontov
Although Dr Speijer promised not to read further posts, I feel like writing some comments on his treatment of CNE. Most misconceptions in Speijer's paper were explained in the commentary by Doolittle and others, however I would like to stress one point. Dr Speijer does not mention complexity space at all, while this is a very important concept. Hence Speijer's discussion of 'forward' and reverse mutations is vague and misleading: "CNE categorically states that reversal of the changes must be much less likely than their occurrence. In most examples this is just assumed to be true, as complexity is seen to increase." (Does constructive neutral evolution play an important role in the origin of cellular complexity?, page 347) "...a ratchet-like increase, dependent on the fact that further similar mutations occur much more easily than they are reversed leads to ever increasing use of the activity now intensely involved in maintaining viability." (page 344) The author does not state clearly the reason why, according to the CNE model, mutations leading to complexity are more probable. Instead he writes that this is just assumed. Low effective population size/genetic drift are essential initial conditions, and exploration of the almost infinite space of complex structures is an outcome. Complex states are far more numerous than simple ones, hence neutral mutations (in the CNE model), or slightly deleterious mutations (see Fernandez A, Lynch M, 2011. Non-adaptive origins of interactome complexity. Nature doi:10.1038/nature09992) promote a random walk through complexity space. The walk can continue indefinitely, likely exploring more and more complex states. As long as the complexity burden is not too high... But, luckily, the evolvability argument, so dear to Dr Speijer, comes into play: many 'strange' complex features, although limiting multiplication rates, appear to be useful for something else, including rapid speciation and adaptation. Of course, Dr Speijer is far from teleological arguments. But he does not believe in the power of genetic drift: "Neutral changes are proposed to take over the complete population by chance (genetic drift). Though not very likely, this can happen, especially with small populations or population bottlenecks: Giving rise to isolated idiosyncrasies, such as described above [14]. They are, however, unlikely to do this over and over again by chance alone." (pages 346-347) That is why, as Doolittle and others pointed out (page 1), Speijer conflates micro- and macroevolution, and fails to recognize that evolvability etc. help some lineages with 'complexity burden' already established to spread, that CNE and evolvability act at different levels. CNE deals with this very deep and neglected undercurrent of evolutionary processes, a random walk through complexity space. And some other points in response to the last post by Speijer: 2. "Forgetting interspecies competition. ... I can almost imagine this complete quote surfacing during lectures 'Very basic introduction to evolutionary theory' followed by the question: 'Now what is the flaw here?' The world of Dr. S. [Stoltzfus] is the world of population genetics only. He totally omits interspecies competition. The 'downward evolved' descendant could possibly be competed to extinction under conditions where the long-dead ancestors might have had a much better chance (evolution has no foresight, remember?)." I dare say eukaryotes have accumulated huge complexity burden, they multiply too slowly, are often not metabolically versatile, and generally 'downward evolved' in Speijer's terms. Why aren't they outcompeted by prokaryotes with their streamlined, 'carefully selected' cells and extreme propagation rates? Another 'very basic introduction to evolutionary theory' question. Because eukaryotes have a number of complex features (most probably acquired initially through neutral mechanisms) that allow them to populate other ecological niches, etc, and escape most direct competition. Two levels of evolution again. 6. "Everyone working on kinetoplastid RNA editing is puzzled by this weird process and after I started working on different projects I published a new model for its spread in populations that at least convinced the referees of being interesting enough to publish and which was highly recommended by the faculty of 1000. This in turn lead to an invitation to write a review chapter on 'The evolutionary aspects of RNA editing' in the NAMB series of Springer Verlag (volume 20: RNA editing; edited by Uli Goeringer)."Concerning Speijer's model of evolution of RNA editing in Kinetoplastida I can quote our recent CNE-based paper (Flegontov P, Gray MW, Burger G, Lukes J, 2011. Gene fragmentation: a key to mitochondrial genome evolution in Euglenozoa? Curr Genet doi:10.1007/s00294-011-0340-8): "Trypanosoma species have the most complex life cycles among trypanosomatids, and the correlation between life cycle complexity and the extent of RNA editing has received considerable attention in the form of sophisticated hypotheses (Speijer 2006, 2007, 2010, 2011). This latter author doubts that a neutral ratchet would be able to generate the extensive editing observed in kinetoplastids, and argues that although the initial occurrence of limited editing might follow the model of Covello and Gray (1993), rampant spread of editing, probably early in the kinetoplastid lineage, required some selective advantage (Speijer 2007). Speijer suggests that the most plausible advantage is a scrambled genome itself, because universally essential gRNA genes scattered in the genome prevent accumulation of large-scale deletions and chromosome losses at life cycle stages (or in certain environments) when most of the mitochondrial genes are dispensable. In this scenario, rampant accumulation of gRNA genes was selected for in lineages that evolved such metabolic versatility, the dixenous trypanosomes in particular. However, there may be a rather simple explanation: complex life cycles in parasites imply severe population bottlenecks, leading to genetic drift and further spread of editing, which were counteracted by reverse transcription and substitution in species with simpler life cycles. ... Moreover, segregation of most gRNAs on separate genomic molecules (minicircles) can render the genome even more vulnerable to degradation at certain life cycle stages (Savill and Higgs 1999), especially because of the sheer bulk of DNA and selective disadvantage probably associated with it: partial or complete minicircle losses are extensively documented in T. brucei (Lai et al. 2008; Schnaufer et al. 2002, 2005) and Leishmania tarentolae (Gao et al. 2001; Thiemann et al. 1994). Thus, in our view, gRNA genes do not prevent this bulk of DNA from being lost, but it is selection at the species level that prevents petite (=dyskinetoplastic) strains, constantly generated de novo, from spreading, since they usually lack ef?cient transmission mechanisms (Lun et al. 2010; Schnaufer 2010)."
Pavel Flegontov, Laboratory of Molecular Biology of Protists, Institute of Parasitology, Ceske Budejovice, Czech Republic

Speijer's essays is not about CNE, by Arlin Stoltzfus
Ultimately, Speijer's essay is not really about CNE. The reader of his essay will not learn the components of the CNE schema (neutral fixations, bias in the introduction of variation, excess capacities, negative selection), because Speijer does not identify them clearly or apply them correctly. He repeatedly mischaracterizes CNE as "chance", when in fact CNE has components that create non-random behavior (e.g., on p. 3-4 he charges CNE with a "conceptual problem" for relying on "chance" to explain multiple neutral changes of the same type, while in the actual CNE schema, such repetitions reflect a bias).
Furthermore, the reader will not come away with a clear sense of what CNE represents as a scientific idea. CNE is an abstract schema, not a "theory" that makes a substantive claim about the actual world. The definitive treatment of CNE (Stoltzfus, 1999) presents it literally as a "scheme" for generating models. It is what software developers would call a "design pattern". What makes it a pattern is that it can be applied to multiple cases.
Going further, there is a sense in which CNE is a model, not just a scheme, because in one case (gene duplication), the application of the CNE scheme is accompanied by simulation & mathematical results. For scientists who value rigor, this kind of formalization is vital. Hand-waving explanations are a dime a dozen. A clever biologist can wave his hands and assert that X accounts for Y. Proving that a hypothetical process X can generate an expected result Y is what separates speculation from modeling (of course, showing that, in theory, X can account for Y is only one step toward determining whether, in reality, X' does account for Y'). Speijer's hand-waving complaints of "conceptual problems" with CNE would seem laughable when set side-by-side with a simulation model that works, but the reader won't know this, because Speijer does not mention this important point.
Thirdly, the reader will not come away with a clear sense of how the CNE schema has been applied, because Speijer cherry-picks his cases, ignoring the crucial gene-duplication model, and aiming at various soft targets from Gray, et al. There are 6 (arguably 7) cases in which CNE has been applied to a case (nearly all in Stoltzfus, 1999), to the extent of identifying which aspects of a system represent excess capacities, what biases are at work, etc., half of which Speijer fails to mention at all (gene duplication, scrambling, the cyt18/tyrRS example, and codon capture). It is a distortion to suggest or imply that there is a CNE model for the evolution of circadian clocks, or of respiratory complexes. One might describe these features more accurately as candidates or "suspects" that might benefit from a yet-to-be-developed CNE explanation. Gray, et al. list a handful of such candidates in parentheses, but focus on cyt18/tyrRS.
Fourth, the reader of Speijer's essay will not come away with a sensible approach to evaluate and apply CNE. As mentioned above, CNE is not a theory, but a schema. While one CNE case has been formalized, the others are at the stage of hand-waving explanations, like the hand-waving explanations that Speijer curiously refers to as "selectionist models" in Table 1. Attempting to evaluate a hand-waving explanation, or to compare 2 hand-waving explanations, is largely a fool's errand-- an elaborate exercise of stating opinions and presenting them as scientific conclusions.
Attempting to pass judgment on CNE, when so little real work has been done on it, is premature. Speijer gives the impression that CNE "proponents" are running amok, when in fact-- to my disappointment-- little has happened with the idea since it was introduced, which is presumably why Gray, et al. tried to revive interest. Except for the case of gene duplication, invocations of CNE, as well as adaptive alternatives for the same features, remain hand-waving explanations. While it is a useful scientific endeavor to explore ideas verbally, trying to use hand-waving arguments to pass judgment on hand-waving explanations is a waste of time. The next task for anyone interested in origins of complex features is to take half-formed ideas (adaptive or otherwise) and turn them into rigorous testable models.
Unfortunately, by failing to describe CNE accurately, Speijer's essay leaves the reader ill-equipped to contribute to this more rigorous approach to science.



Life and death with arsenic

Posted by: Editorial

Is it possible that arsenate could replace phosphate in some of the chemicals that are required for life?

Abstract:
Arsenic and phosphorus are group 15 elements with similar chemical properties. Is it possible that arsenate could replace phosphate in some of the chemicals that are required for life? Phosphate esters are ubiquitous in biomolecules and are essential for life, from the sugar phosphates of intermediary metabolism to ATP to phospholipids to the phosphate backbone of DNA and RNA. Some enzymes that form phosphate esters catalyze the formation of arsenate esters. Arsenate esters hydrolyze very rapidly in aqueous solution, which makes it improbable that phosphorous could be completely replaced with arsenic to support life. Studies of bacterial growth at high arsenic:phosphorus ratios demonstrate that relatively high arsenic concentrations can be tolerated, and that arsenic can become involved in vital functions in the cell, though likely much less efficiently than phosphorus. Recently Wolfe-Simon et al. [1] reported the isolation of a microorganism that they maintain uses arsenic in place of phosphorus for growth. Here, we examine and evaluate their data and conclusions.

Read the article:
Life and death with arsenic
Barry P. Rosen, A. Abdul Ajees and Timothy R. McDermott
Volume 33, Issue 5, May 2011, pages 350-357

Comments:

Post-publication peer review, by Rosie Refield
The authors should not have dismissed the extensive and well-supported online evaluation of the Wolfe-Simon paper with the single sentence "This paper has generated significant commentary, often as anonymous electronic communications." Many of the points that Rosen et al. present without attribution were first raised by other researchers in online articles, in authoritative blogs and in signed comments. The subtitle "Arsenic life" is even taken from the discussion's Twitter hashtag "#arseniclife".

Critiques, anonymity and expertise, by Athena Andreadis
I concur with Dr. Redfield. The vast majority of those who critiqued the Wolfe-Simon results did not do so anonymously. They published the critiques using their real names and many, like her and me, are practicing research biologists. The Agency That Cried "Awesome!" The Agency That Cried "Awesome!" http://www.starshipreckless.com/blog/?p=3668

Response to Dr. Redfield, by Timothy McDermott
Our submission to BioEssay was in direct response to an editorial invitation to present our views of the Wolfe-Simon et al. paper (1). We accepted the invitation with the overarching goals being to provide an objective assessment of the general concept of arsenic replacing phosphorus in cellular activities and to provide a general evaluation of the Wolfe-Simon et al. paper. TRM and BPR do not monitor electronic contributions that are not subject to some level of editorial screening (i.e. that are not part of the peer-reviewed literature), and so we were unaware of these commentaries until notified by colleagues, some of which we did read prior to submitting our manuscript. Because of the nature of the topic, one or both of the principle authors were well aware of the general information mentioned. Fundamentally, the Internet discussions we encountered contained comments that did not require citation for at least two reasons: i) they reflected general knowledge that in our opinion was not necessary to cite, not even as a personal communication because they were not specifically directed to any of the authors via telephone, email or in person; and more importantly ii) at present, Internet communications/contributions of the sort being discussed here are not components of the peer-reviewed literature and thus are not placed on record as part of the official scientific discourse. When (or if) such commentary were to be officially recognized as part of the official and recordable scientific exchange, then we (and others) will endeavor to thoroughly and appropriately cite all relevant references within the format of the journal (i.e. article length, word number, number of citations, etc). Our use of "Arsenic life" derived from the fictional book Brain Plague authored by Joan Slonczewski (cited in our paper), with whom BPR collaborated while on sabbatical at Yale University (1979 - 1980), when Professor Slonczewski was a doctoral student under the late Dr. Robert Macnab in the Department of Molecular Biophysics and Biochemistry (BPR's expertise in the arsenic field was specifically acknowledged by Slonczewski in Brain Plague). We are not sure what a "Twitter hashtag" actually is, but since they presumably are not actual references, we will continue to ignore this type of commentary for purposes of formal citations until it becomes clear that the scientific journals and community have adopted new criteria, standards, and procedures. For example, BioEssays currently does not allow authors formally to cite Internet commentary of the sort referred to by Dr. Redfield. As part of our response to Dr. Redfield, we also take this opportunity to offer a general comment on the use of the Internet to "review" the technical literature. To be perfectly clear, to the extent that we are familiar with those who offered signed comments regarding the particular case of the Wolfe-Simon et al. paper, we do not in any way question their scientific expertise. Signed comments should be applauded and indeed offer a measure of authenticity, but nevertheless these "chat room" environments are not constrained or screened and at times become ad hominem attacks, which have no place in the scientific literature. And, further, such communications do not, themselves, offer specific citations to support their position. If they are to be viewed as authoritative and do not simply reflect general knowledge, then they too should at least refer to important, foundational papers that support their view. In general and not in reference to the case of the Wolfe-Simon et al. paper, until there is a process in place to screen and edit such commentary (such as here for our current scientific exchange with Dr. Redfield), there remains a credibility issue. We are all aware of the massive misinformation that pervades the Internet and that is why so many simply choose to ignore it rather than track it as part of their efforts to stay informed of the scientific literature pertinent to their research. Because of such accuracy issues, at present and in its current structure, organization and process, the term "authoritative blogs" far too often represents an oxymoron. 1) Wolfe-Simon F, Blum JS, Kulp TR, Gordon GW, Hoeft SE, Pett-Ridge J, Stolz JF, Webb SM, Weber PK, Davies PC, Anbar AD, & Oremland RS (2010). A bacterium that can grow by using arsenic instead of phosphorus. Science, Published online 2 December 2010 [DOI:10.1126/science.1197258]

Citation of web pages in BioEssays articles, by Andrew Moore
As the editor of BioEssays, I would like to clarify the matter of the citability of web-based information sources in BioEssays: BioEssays allows websites /web pages (including blog posts) to be specifically quoted, and the URL given, in the body text, information boxes, tables or figure captions of articles - i.e. "informally" cited - anywhere but in the reference list of a scientific article (e.g. articles in rubrics "Hypotheses", "Think again", "Recently in press", "Review essays", "Problems & Paradigms"). There are some rubrics where we also allow web page citations to be included in the bibliography (reference list) of the article as a "formal" citation, e.g. in the rubrics "Ex laboratorio" and "Commentary".
Examples of articles from 2011 containing web page citations (informally and formally cited) are:
Review-style articles:
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000036/full
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000077/full
Commentaries:
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000111/full
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000068/full
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000112/full
Ex laboratorio:
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000142/full
http://onlinelibrary.wiley.com/doi/10.1002/bies.201000139/full
Andrew Moore
Editor-in-Chief
BioEssays
Disclaimer: The opinions expressed in this post are my own, and do not necessarily represent those of my employer. This account is not sponsored or endorsed by my employer.



The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan

Posted by: Editorial

Protect yourself against oxidative damage and live longer?

Abstract:
Recent work on a small European cave salamander (Proteus anguinus) has revealed that it has exceptional longevity, yet it appears to have unexceptional defences against oxidative damage. This paper comes at the end of a string of other studies that are calling into question the free-radical damage theory of ageing. This theory rose to prominence in the 1990s as the dominant theory for why we age and die. Despite substantial correlative evidence to support it, studies in the last five years have raised doubts over its importance. In particular, these include studies of mice with the major antioxidant genes knocked out (both singly and in combination), which show the expected elevation in oxidative damage but no impact on lifespan. Combined, these findings raise fundamental questions over whether the free-radical damage theory remains useful for understanding the ageing process, and variation in lifespan and life histories.

Read the article:
The free-radical damage theory: Accumulating evidence against a simple link of oxidative stress to ageing and lifespan
John R. Speakman and Colin Selman
Volume 33, Issue 4, pages 255-259, April 2011



The proportional lack of archaeal pathogens: Do viruses/phages hold the key?

Posted by: Editorial

Abstract:
Although Archaea inhabit the human body and possess some characteristics of pathogens, there is a notable lack of pathogenic archaeal species identified to date. We hypothesize that the scarcity of disease-causing Archaea is due, in part, to mutually-exclusive phage and virus populations infecting Bacteria and Archaea, coupled with an association of bacterial virulence factors with phages or mobile elements. The ability of bacterial phages to infect Bacteria and then use them as a vehicle to infect eukaryotes may be difficult for archaeal viruses to evolve independently. Differences in extracellular structures between Bacteria and Archaea would make adsorption of bacterial phage particles onto Archaea (i.e. horizontal transfer of virulence) exceedingly hard. If phage and virus populations are indeed exclusive to their respective host Domains, this has important implications for both the evolution of pathogens and approaches to infectious disease control.

Read the article:
The proportional lack of archaeal pathogens: Do viruses/phages hold the key?
Erin E. Gill and Fiona S.L. Brinkman
Volume 33, Issue 4, pages 248-254, April 2011



A battle over brains: What determines brain size?

Posted by: Editorial

Is brain size positively correlated mainly with basal metabolic rate, instead of depending on maternal input during gestation or suckling of young?

Suddenly a particularly cold and long winter strikes, going on into what was normally Spring. Food for small, furry "warm-blooded" mammals is scarce. Switching off the heating to save energy is certain death, but what about the brain? After all, that does consume an enormous amount of energy. Well, no, that simply can't be powered down either - not even a little bit. So, it looks like the end of the road for everyone. Surely evolution wouldn't have allowed that to happen, and this is essentially the extreme case of a theory proposed in BioEssays by Karin Isler, based on identifying a link between basal metabolic rate (BMR) and brain size: a necessary energetic flexibility to cope with extreme environmental variations, it is claimed, sets an upper limit on brain size, the "Grey Ceiling", brain size in general being positively correlated with BMR. But important parts of that paper disagree - for example in the case of marsupial brains - with a recently proposed theory explaining brain size on the basis of constraints on maternal input, the so-called "Neonatal Maturity Hypothesis" (NMH), published in PNAS last year by Vera Weisbecker and Anjali Goswami. Weisbecker and Goswami also develop their ideas based on the NMH in a paper in BioEssays.
Read the papers, and see what you think ...
Andrew Moore

Neonatal maturity as the key to understanding brain size evolution in homeothermic vertebrates
Vera Weisbecker and Anjali Goswami
Volume 33, Issue 3, pages 155-158, March 2011

Energetic trade-offs between brain size and offspring production: Marsupials confirm a general mammalian pattern
Karin Isler
Volume 33, Issue 3, pages 173-179, March 2011

Marsupials indeed confirm an ancestral mammalian pattern: A reply to Isler
Vera Weisbecker and Anjali Goswami
Volume 33, Issue 5, pages 358-361, May 2011



Ion flux and the function of endosomes and lysosomes: pH is just the start

Posted by: Editorial

The flux of ions across endosomal membranes influences endosome function not only through regulation of the luminal pH

Abstract:
The ionic nature of endosomes varies considerably in character along the endocytic pathway. Counter-ion flux across the limiting membrane of endosomes has long been considered essential for full acidification and normal endosome/lysosomal function. The proximal functions of luminal ions, however, have been difficult to assess. The recent development of transgenic mice carrying mutations in the intracellular chloride channels (ClCs) has provided a tool to uncouple ClS influx from endosomal acidification. Intriguingly, many of the defects of the endo-lysomal system attributed to aberrant pH persist in the ClS-deficient mice implying a direct regulatory role for ClS influx in endosome function. These observations may begin to explain the abundance of endosomal ion transporters, including ClCs, sodium-proton exchangers, two-pore channels and mucolipins, that have been localized to endo-lysosomes, and the extensive changes in luminal ion composition therein. In this review, we summarize what is known regarding the mediators of endosomal ion flux, and discuss the implications of changing ionic content on endo-lysosomal function.

Read the article:
Ion flux and the function of endosomes and lysosomes: pH is just the start
Cameron C. Scott and Jean Gruenberg
Volume 33, Issue 2, pages 103-110, February 2011



Oxygen radicals shaping evolution: Why fatty acid catabolism leads to peroxisomes while neurons do without it

Posted by: Editorial

FADH2/NADH flux ratios determining mitochondrial radical formation were crucial for the eukaryotic invention of peroxisomes and catabolic tissue differentiation

Abstract:
Oxygen radical formation in mitochondria is a highly important, but incompletely understood, attribute of eukaryotic cells. I propose a kinetic model in which the ratio between electrons entering the respiratory chain via FADH2 or NADH is a major determinant in radical formation. During the breakdown of glucose, this ratio is low; during fatty acid breakdown, this ratio is much higher. The longer the fatty acid, the higher the ratio and the higher the level of radical formation. This means that very long chain fatty acids should be broken down without generation of FADH2 for mitochondria. This is accomplished in peroxisomes, thus explaining their role and evolution. The model explains many recent observations regarding radical formation by the respiratory chain. It also sheds light on the reasons for the lack of neuronal fatty acid (beta-) oxidation and for beneficial aspects of unsaturated fatty acids. Last but not least, it has very important implications for all models describing eukaryotic origins.

Read the article:
Oxygen radicals shaping evolution: Why fatty acid catabolism leads to peroxisomes while neurons do without it
Dave Speijer
Volume 33, Issue 2, pages 88-94, February 2011



Dynamin self-assembly and the vesicle scission mechanism

Posted by: Editorial

Abstract:
Recently, Gao et al. and Chappie et al. elucidated the crystal structures of the polytetrameric stalk domain of the dynamin-like virus resistance protein, MxA, and of the G-domain dimer of the large, membrane-deforming GTPase, dynamin, respectively. Combined, they provide a hypothetical oligomeric structure for the complete dynamin protein. Here, it is discussed how the oligomers are expected to form and how they participate in dynamin mediated vesicle fission during the process of endocytosis. The proposed oligomeric structure is compared with the novel mechanochemical model of dynamin function recently proposed by Bashkirov et al. and Pucadyil and Schmid. In conclusion, the new model of the dynamin oligomer has the potential to explain how short self-limiting fissogenic dynamin assemblies are formed and how concerted GTP hydrolysis is achieved. The oligomerisation of two other dynamin superfamily proteins, the guanylate binding proteins (GBPs) and the immunity-related GTPases (IRGs), is addressed briefly.

Read the article:
Dynamin self-assembly and the vesicle scission mechanism
Nikoloaus Pawlowski
Volume 32, Issue 12, pages 1033-101039, December 2010



Beautiful is not (necessarily) right: Overcoming the Phryne's trial syndrome

Posted by: Editorial

Today, attractive coloured images are a must in any respectable journal. Some journals even instruct contributors to produce a graphical abstract to summarise the contents of the paper in a pictorial form. But does all this increasingly picture-book science really do particular service to knowledge?

Read the article:
Beautiful is not (necessarily) right: Overcoming the Phryne's trial syndrome
Victor de Lorenzo
Volume 32, issue 12, page 1011, December 2010



Replication stress, a source of epigenetic aberrations in cancer?

Posted by: Editorial

Abstract
Cancer cells accumulate widespread local and global chromatin changes and the source of this instability remains a key question. Here we hypothesize that chromatin alterations including unscheduled silencing can arise as a consequence of perturbed histone dynamics in response to replication stress. Chromatin organization is transiently disrupted during DNA replication and maintenance of epigenetic information thus relies on faithful restoration of chromatin on the new daughter strands. Acute replication stress challenges proper chromatin restoration by deregulating histone H3 lysine 9 mono-methylation on new histones and impairing parental histone recycling. This could facilitate stochastic epigenetic silencing by laying down repressive histone marks at sites of fork stalling. Deregulation of replication in response to oncogenes and other tumor-promoting insults is recognized as a significant source of genome instability in cancer. We propose that replication stress not only presents a threat to genome stability, but also jeopardizes chromatin integrity and increases epigenetic plasticity during tumorigenesis.

Read the article:
Replication stress, a source of epigenetic aberrations in cancer?
Zuzana Jasencakova and Anja Groth
Volume 32, Issue 10, pages 847-855, October 2010



RNA world good bye?

Posted by: Editorial

Modern cells feature proteins that might have supported a prebiotic polypeptide world but nothing indicates that RNA world ever was

Abstract

Modern cells present no signs of a putative prebiotic RNA world. However, RNA coding is not a sine qua non for the accumulation of catalytic polypeptides. Thus, cellular proteins spontaneously fold into active structures that are resistant to proteolysis. The law of mass action suggests that binding domains are stabilized by specific interactions with their substrates. Random polypeptide synthesis in a prebiotic world has the potential to initially produce only a very small fraction of polypeptides that can fold spontaneously into catalytic domains. However, that fraction can be enriched by proteolytic activities that destroy the unfolded polypeptides and regenerate amino acids that can be recycled into polypeptides. In this open system scenario the stable domains that accumulate and the chemical environment in which they are accumulated are linked through self coding of polypeptide structure. Such open polypeptide systems may have been the precursors to the cellular ribonucleoprotein (RNP) world that evolved subsequently.

Read the article:
The RNA dreamtime
Charles G. Kurland
Volume 32, Issue 10, pages 866-871, October 2010

Comments:

The Peptideosome, by William Martin
Kurland has taken a rather extreme stance here with the view that the ancestral ribosome had no RNA components, being composed only of protein, with RNA making its way into the act of translation comparatively late in evolution. That will seem rather upside down to many. But that is not the only extreme stance taken in his paper, because he also states "...the eukaryotes are the ancestral lineage from which the divergence of archaea and bacteria are thought to have been driven by reductive pressure..." as a premise. So in the author's dreamtime essay, i) the ribosome is derived from an ancestral peptideosome lacking RNA components and ii) prokaryotes are derived from eukaryotes. The former proposal is irreconcilable with any literature on the evolution of the genetic code. The latter proposal is irreconcilable with the circumstance that all bioenergetic membranes in eukaryotes (the membranes that provide energy to run all else) are found within endosymbiotic organelles of prokaryotic origin (chloroplasts and mitochondria). Is the horse to be derived from the cart that stands before it? And where the energy comes from to run that peptideosome is another issue. It presently appears unlikely that Kurland's paper will become as prominent as Gilbert's "The RNA World", which stands for the concept at the focus of his attack.



Can we do better than existing author citation metrics?

Posted by: Editorial

Throughout the world, research bodies have begun to quantify research quality through citation analysis. Both Britain and Australia now incorporate a bibliometric element when assessing institutional research output. The Institute for Research Information and Quality Assurance was recently established with the core goal of evaluating research performance funded by the German Research Foundation. In China, authors have been asked to publish only in journals indexed in the Institute for Scientific Information (ISI) Science Citation Index and which therefore receive an Impact Factor. Some individual institutions have even more specific requirements. With so many researchers and specialised disciplines, it is tempting for funding agencies and governments to reduce an author's publication career to a single metric. It is also spectacularly difficult.

Read the article:
Can we do better than existing author citation metrics?
Adam Finch
BioEssays, Volume 32, Issue 9, pages 744-747, September 2010

Comments:

Appointments vs. careers, by Victor de Lorenzo
Publishing in a high-impact journal guarantees (in most cases) that the paper in question is high quality, because the reviewing process is supposed to be tougher. However, being high-quality does not mean that one particular article will have a high impact. If the issue is prestige or selection of candidates for a position, I understand that institutions employ IF of journals for their internal policies, appointments etc. If the issue is real impact, other criteria such as the H factor might be more useful to assess the value of individual careers. What is a must, however, is that the articles are referenced in PubMed -if not they become altogether invisible. I am afraid that in my own field (Microbial Biotech), excellent journals such as Microbial Biotechnology and BioEngineered Bugs are not listed in PubMed (no idea why), whereas others, somewhat dying old-fashion journals happily show up. I have the impression that -given enough time- actual impact/citations of specific articles will be more important than the IF of the host journals.

Preventing a self-fulfilling prophecy, by Sui Huang
One central, rarely articulated consequence of citation metrics, notably the impact factor (IF), is that they promote the "rich get richer" phenomenon, a.k.a. self-fulfilling prophecy. Papers in journals with high IF are more cited because these journal are more widely read, which in turn increases the IF of these journals. Thus, a paper gets attention in great part not because of WHAT it says but WHERE it is published... The positive feedback loop leads to a skewed distribution of IFs among the journals (possible a power-law distribution) with just a handful of extremely influential journals. This in turn means that there is an oligarchy of editors in the publication business which is not healthy for diversity of viewpoints. Indeed, who will disagree that editors of Nature, Science and Cell all think very much alike and actually steer the global longer term course of scientific research - How can we diminish their power? I suggest one simple way to disrupt this positive feedback loop which will re-establish diversity: When reporting the number of times a paper is cited (=C) as a measure for importance of a paper, one should normalize it by the IF of the journal where it is published that is: use C/IF. This will diminish, albeit crudely, the effect of the IF of the journal on the probability that a paper is cited. In other words: given two equally cited papers, the one that was published in a small, low IF journal is probably more remarkable.



How did vertebrate teeth evolve?

Posted by: Editorial

Questions: How did vertebrate teeth evolve? Outside>in, inside>out, or a mixture?

Abstract
Essentially we show recent data to shed new light on the thorny controversy of how teeth arose in evolution. Essentially we show (a) how teeth can form equally from any epithelium, be it endoderm, ectoderm or a combination of the two and (b) that the gene expression programs of oral versus pharyngeal teeth are remarkably similar. Classic theories suggest that (i) skin denticles evolved first and odontode-inductive surface ectoderm merged inside the oral cavity to form teeth (the 'outside-in' hypothesis) or that (ii) patterned odontodes evolved first from endoderm deep inside the pharyngeal cavity (the 'inside-out' hypothesis). We propose a new perspective that views odontodes as structures sharing a deep molecular homology, united by sets of co-expressed genes defining a competent thickened epithelium and a collaborative neural crest-derived ectomesenchyme. Simply put, odontodes develop 'inside and out', wherever and whenever these co-expressed gene sets signal to one another. Our perspective complements the classic theories and highlights an agenda for specific experimental manipulations in model and non-model organisms.

Read the article:
The odontode explosion: The origin of tooth-like structures in vertebrates
Gareth J. Fraser, Robert Cerny, Vladimir Soukup, Marianne Bronner-Fraser, J. Todd Streelman
Volume 32, Issue 9, pages 808-817, September 2010



Between genes and phenotype: How do the new insights of systems biology affect the theory of Darwinian evolution?

Posted by: Sui Huang

According to Neo-Darwinian theory of evolution, natural selection acts on a phenotype and ultimately selects for a genotype that encodes the former. While the sheer complexity of the machinery that processes DNA sequence information to produce a selectable phenotype is acknowledged, modern evolution biology still operates in a climate of thinking in which it is tacitly assumed that a genotype maps more or less in a linear and deterministic fashion into a phenotype. This core assumption underlies almost all evolutionary concepts. However, insights from the new domains of systems biology of gene networks and from physical theories of complexity now expose the limitation of the implicit notion of genotype-phenotype mapping.

Departure from the concept of a direct genotype-to-phenotype mapping includes the following phenomena that are at the center of investigation in systems biology and biocomplexity:
 

  • Gene expression noise generates a wide range of random variation of phenotype that can last and be transmitted over several cell generations and thus could serve as substrate for selection (temporarily)
  • Multistability due to non-linearity in biochemical networks allow the very same genome to produce a number of discretely distinct, enduring phenotypes (encoded by "network attractors") - as most prosaically manifest in the variety of cell types in metazoan. Conversely, many pathways can lead to the very same phenotype.
  • Covalent chromatin modification and DNA methylation - confusingly labelled "epigenetic modification" - provide a non-genetic mode of modifying information transmitted by genomic DNA without mutations,
     

These and other related phenomena have in common that they afford a channel for non-genetic inheritance. This essentially decouples selection from genetic mutation, thus questioning a core tenet of Neo-darwinism. How do the new insights of systems biology affect the theory of Darwinian evolution? Do existing concepts of evolution need to be revisited? Could phenomena, such as bursts in fossil record, genetic assimilation, Baldwin effect, apparent Lamarckism, etc that have challenged Darwinian orthodoxy be explained if evolution biology embraces systems biology and incorporate the above features of complex system? .
 

REFERENCES:

  1. Bard, J. A systems biology view of evolutionary genetics: network-driven processes incorporate much more variation than evolutionary genetics can handle. This variation is hard to formalise but allows fast change. Bioessays 32, 559-63 (2010).
  2. Brock, A., Chang, H. & Huang, S. Non-genetic heterogeneity--a mutation-independent driving force for the somatic evolution of tumours. Nat Rev Genet 10, 336-42 (2009).
  3. Huang, S. Back to the biology in systems biology: what can we learn from biomolecular networks. Brief. Funct. Genomics Proteomics 2, 279-297 (2004).
     

Sui Huang (Editorial Board)
University of Calgary
Canada

Comments:

Natural selection on cellular stated: even more controversial, posted by Mark Isalan
Evidence is growing for natural selection working in real time (on very short timescales) on the very "network attractors" mentioned above. In particular, the work of the Yomo group (e.g. Kashiwagi A, Urabe I, Kaneko K, Yomo T. Adaptive response of a gene network to environmental changes by fitness-induced attractor selection. PLoS One. 2006 Dec 20;1:e49.) suggests that cells can use attractor states as a substrate for a kind of natural selection. A selection pressure for fitness could in principle select the most optimal metabolic state without any genetic change. The source of 'heredity' can be the stability of the attractor state(s). The source of 'variation' can be the stochastic flipping between states. The cells which are in the fittest state at any given time have a fitness advantage and multiply (e.g they switch on a metabolic gene for a nutrient source that has become available; various scenarios are possible). We are not used to thinking about 'evolution' working on such short timescales, and being reversible, but it is apparent that this could be a form of natural selection. The end result is that cells could adapt and optimise themselves to changing conditions merely by using natural selection, without the need for signalling machinery or complicated gene networks. We are finding that this kind of way of thinking about gene networks is very useful in trying to dissect out what happens when you 'rewire' a cell and create lots of new connections in a large network (e.g. Isalan M, Lemerle C, Michalodimitrakis K, Horn C, Beltrao P, Raineri E, Garriga-Canut M, Serrano L. Evolvability and hierarchy in rewired bacterial gene networks. Nature 452: 840-5, 2008). Looking for attractor states - which the bacteria select according to the prevalent fitness pressure - could be a way to make understanding these complicated systems more tractable.

Multi-scale complexity, posted by Victor de Lorenzo
This is indeed a tricky issue. That KO-ing a given gene results in a recognizable phenotype does not imply a direct causality, because the primary effect of the mutation has most often to go through a multi-scale complexity itinerary in which many other factors participate. For instance, the microbial pathogenesis literature is packed with examples in which one mutant in one gene makes bacteria attenuated in their virulence phenotype. The problem is that the same gene might be controlling many other functions entirely unrelated to pathogenesis, not only the one that we look at. Perhaps one could consider two (or more) levels of functionality for the products of genes. A primary function related to their intrinsinsic biochemical or structural properties (an enzyme, a DNA-bending protein etc) and then an emergent, context-dependent (secondary?) function that relies on the connectivity of such properties with other molecular partners in a network. Under this notion, selective pressure would operate at all levels of the complexity pyramid, not only from the final-phenotypic end straight into the gene...

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