Peer review of my primate phylogeny manuscript

I share my email exchanges with the reviewers and editors of the Journal of Theoretical Biology, to which I have submitted my manuscript entitled "Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosemian clade containing tarsiers".  For almost one year now, these reviewers and editors have failed to find a contradiction to our story but have nonetheless yet to accept our manuscript.  For revolutionary science, peer review is the worst enemy.  But it is of course perfectly consistent with human nature that people will defend their self interest whenever there is a conflict between self interest and truth.  Just how else one could explain what have repeatedly happened in history that revolutionary ideas often take decades to become accepted.


From: Shi Huang
To: JTB (ELS)
Sent: Sunday, March 11, 2012 5:43 AM
Subject: Re: JTB-D-11-00402: Final Decision

Dear Janet,

Just checking the editor has not forgotten our manuscript. If you need more time to find a good scientific reason to either accept or reject, it is understandable.

Best,

Shi Huang

From: JTB (ELS)
To: Shi Huang
Sent: Wednesday, December 7, 2011 12:13 AM
Subject: RE: JTB-D-11-00402: Final Decision

Thank you for your message, Dr. Huang, which is being forwarded to the Editor in Chief.

Best regards,

Janet

Janet Stein Journal Manager - JTB Editorial-Production Dept. Elsevier Science 525 "B" Street, Suite 1800
San Diego, CA 92101 USA Phone: 619-699-6324 Email: jtb@elsevier.com

From: Shi Huang [mailto:shuangtheman@yahoo.com]
Sent: Tuesday, December 06, 2011 1:04 AM
To: JTB (ELS)
Subject: Re: JTB-D-11-00402: Final Decision

Dear Jenet,

I believe that there is now sufficient time for the editors to find one specific reason backed up with evidence to invalidate my manuscript. But I seriously doubt that they can find one. After all, my hypothesis includes all the proven virtues of the existing paradigm as parts of it. Thus every fact or reason that supports the existing paradigm will also support my hypothesis, and every fact that contradicts the existing paradigm will not necessarily contradict mine. In fact, I claim that that every fact that contradict the paradigm will be found to support my hypothesis. So, what could the editors do? It is simply impossible for them to find one fact that supports the paradigm while contradicts my hypothesis. The best they can do is to come up with one fact that will contradict both the paradigm and my hypothesis. This of course they will never do because it would contradict their cherished paradigm.

Therefore, it is to the best interest of science that we must find another editor to re-review the materials related to this manuscript who is not in a position of conflict of interest. I know this is hard to do and I can give you a few names to select from if you would find it helpful.

Best,

Shi

From: JTB (ELS)
To: Shi Huang
Sent: Monday, November 21, 2011 7:48 AM
Subject: RE: JTB-D-11-00402: Final Decision

Dear Shi,

I am forwarding your message to the editors.

Best regards,

Janet

Janet Stein Journal Manager - JTB Editorial-Production Dept. Elsevier Science 525 "B" Street, Suite 1800
San Diego, CA 92101 USA Phone: 619-699-6324 Email: jtb@elsevier.com

From: Shi Huang [mailto:shuangtheman@yahoo.com]
Sent: Friday, November 18, 2011 5:31 PM
To: JTB (ELS)
Subject: Re: JTB-D-11-00402: Final Decision

Dear Janet,

Thank you for your reply. Indeed, while we can always submit to another journal, it may not be fair for a journal to take 5 months to reject a paper without giving the author any specific reasons. The only reason which may seem quite sound is repeated here - "the burden of proof for revolutionary concepts/suggestions is high. Selective reading of facts do not constitute proof or evidence." But the standard should not be artificially high that no existing theory of any kind has met, which is to demand proof of the assumptions that no theory can live without. (The recent discovery of faster than light neutrinos is a challenge to Einstein's relativity theory which has the non-proven assumption of nothing has higher speed than light) I view the last sentence here as a personal attack on my integrity and competence as a professional scientist. I demand either an apology or specific details laying out which facts I have selectively ignored. I have openly made the claim that my concept/assumption has no contradictions. If the editor has evidence of my ignoring contradictions (which is what meant by selective reading of facts), please lay them out. I have repeatedly asked the editor/reviewers to give me a single contradiction, which is enough for me to withdraw the paper. But instead, they made broad statements which implied that they have found contradictions or facts that I have selectively ignored but they never said what those facts are. So, here I ask again, where is the beef?

Your journal can feel free to reject any papers but as a science journal as opposed to a religious one you must give SPECIFIC REASONS BACKED UP BY EVIDENCE. While the comments I received earlier may seem detailed and specific enough, they have been soundly dealt with in my last rebuttal. In particular, I have asked the reviewers/editors to give reasons to some of their objections that they put forward without any justification. But I have received nothing in response. I have asked them to defend the interpretation of the genetic equidistance phenomenon by their field but they did not. Selective reading of facts?

As part of the paradigm, the editor and the reviewers are in a position of self conflict and hence cannot serve as a fair referee for the present manuscript. (It is only human nature that when there is a conflict between truth and self interest - reputation, careers, grants - self interest always takes priority) Given the 5 months of time I have invested in your journal, I am reluctant to let you off the hook too easily without me gaining anything useful scientifically. So, please give me 1) a fact that I have selectively ignored, or 2) a fact that can contradict the assumptions of my hypothesis, or 3) an explanation of how the existing theory has brilliantly accounted for the genetic equidistance phenomenon, or 4) another editor who is more objective and if you need names I would be glad to give you a few. I would like to ask an independent re-review of all the materials related to this paper. To be a responsible scientist, one should care about truth. In this case, it is either black or white. Let us just settle once for all as in a boxing match, either my interpretation of the genetic equidistance phenomenon is flawed and the existing interpretation brilliant, or the opposite. For nearly 50 years, those two interpretations are the only two competing parties that are scientifically based. I look forward to hearing from you.

Best,

Shi

From: JTB (ELS)
To: Shi Huang
Sent: Friday, November 18, 2011 8:52 AM
Subject: RE: JTB-D-11-00402: Final Decision

Dear Dr. Huang,

The editor responds, “If the author is correct, no doubt we will all be rewriting molecular evolution in a couple of years. Otherwise, the original criticism stands - the burden of proof for "revolutionary" concepts/suggestions is high. Selective reading of facts do not constitute proof or evidence.”

You are welcome to submit your manuscript to a journal that may view it more favorably.

Best regards,

Janet

Janet Stein Journal Manager - JTB Editorial-Production Dept. Elsevier Science 525 "B" Street, Suite 1800
San Diego, CA 92101 USA Phone: 619-699-6324 Email: jtb@elsevier.com

From: Shi Huang [mailto:shuangtheman@yahoo.com]
Sent: Thursday, November 17, 2011 9:28 PM
To: JTB (ELS)
Subject: Re: JTB-D-11-00402: Final Decision

Hi, Janet,

It has been 5 weeks and I thought I should get some feedbacks by now. Please ask the editor if they intend to give me a full and serious response. If not, I will ask a different editor who has more objective and neutral stance to evaluate the paper, the comments, and my rebuttal. Thank you.

Sincerely,

Shi Huang

From: JTB (ELS)
To: Shi Huang
Sent: Tuesday, October 11, 2011 9:48 AM
Subject: RE: JTB-D-11-00402: Final Decision

Thank you for your message, Dr. Huang, which is being forwarded to the editor.

Best regards,

Janet Stein Journal Manager - JTB Editorial-Production Dept. Elsevier Science 525 "B" Street, Suite 1800
San Diego, CA 92101 USA Phone: 619-699-6324 Email: jtb@elsevier.com

From: Shi Huang [mailto:shuangtheman@yahoo.com]
Sent: Saturday, October 08, 2011 11:38 PM
To: JTB (ELS)
Subject: Re: JTB-D-11-00402: Final Decision

Dear Editor,

Please ignore my last email reply to your decision letter. A revised reply is now attached in this email here as well as copied below. Please forward it to the reviewers and I hope you would consider our request for a accepting a revised version.

Best,

Shi

Dear Editor,

Thank you for the comments. I have now read them carefully after finishing up another manuscript. It seems to me that the reviewers ignored or failed to grasp my rationale for the present work, which is that the existing paradigm of phylogenetics needs to be completely overturned because of a mistake at the beginning stage of the field. My key point is about how to interpret the genetic equidistance phenomenon. Without a valid interpretation of it, all else are meaningless. I have repeatedly stated and explained why the molecular clock and in turn the neutral theory completely failed to explain the equidistance phenomenon of macroevolution while being perfectly fine for that of microevolution. Yet, the reviewer did not in their comments raise any objections to such a most important point of mine, which could only lead me or any readers of their comments to conclude that my criticism of the clock/neutral theory and hence the entire paradigm based on it is sound and irrefutable. This of course would undercut nearly all of their comments since they are nearly all based on the existing paradigm being correct. Hence I suggest that you ask these reviewers to issue a formal opinion to explain to me as well as to the world how the clock/neutral theory has correctly/brilliantly explained the genetic equidistance phenomenon and how my MGD interpretation of it is flawed. If they cannot or refuse to do that, I would suggest that you strongly consider accepting my manuscript (of course a revised and shortened version).

Indeed, extraordinary claims require extraordinary evidence. We are now using our new hypothesis to solve major biological problems such as common diseases and our goal is to show that ours is a much more powerful theory than the existing one because it is not merely relevant to evolutionary phylogenetic problems. In this sense, this ms is presently not a high priority for us, and we have been submitting it for more than two years and we are patient. We obviously cannot put everything we have into a single manuscript. But if you keep an eye on our future papers, you will soon see how our theory will be proven and accepted in major biomedical fields not related to phylogenetics and evolution. Our model will solve major problems of everyday life for which the existing model has no clues about. The existing model will be made obsolete in the next year or two by our new model. Again, we demand as should all people a correct model to be contradiction free. If you apply that standard to our model, you will find it hard to reject and better than the existing one.

Below I have detailed response within the reviewers' comments. I look forward to hearing from you. Sincerely, Shi Huang

Reviewers' comments:

Reviewer #2: Review of the manuscript entitled "Primate phylogeny: molecular evidence for a pongid clade excluding humans and a prosimian clade containing tarsiers"

Although the title is about primate phylogeny the author writes about his new hypothesis for several pages, which suggests that all the existing methodologies are inadequate to understand evolution and phylogenetics. Hence he goes back to the simplest methods (such as counting differences between two sequences) to support his hypothesis. There are several fundamental flaws in this work and everything mentioned in the manuscript is anecdotal without any scientific validity. For instance the maximum genetic diversity (MGD) hypothesis (figure 1) suggests that a complex organism (such as human) has more constrained amino acids (in a protein) compared to that of less complex one (such as chimp). But there is no proof for this claim. To examine this, the author could have simply compared the nonsynonymous (amino acid) diversities of the orthologous genes from human and chimp. Instead he compares the amino acid identities between human, chimp and orangutan and this method does not even account simple stochastic errors (which would be very high due to the small divergence between these species). Hence it is no wonder that the author finds some genes are more similar between chimp and orangutan than between chimp and human.

The best proof for the idea of MGD is the genetic equidistance result. The reviewer simply ignored this point. The reviewer also failed to explain our observation of the dramatic difference between slow and fast evolving genes. Such difference is statistically highly significant and cannot be due to stochastic errors.

The study of molecular evolution started in the 50s by counting the number of changes or looking at the % similarities. After that we realized a number of factors such as stochastic error, multiple substitutions in the same amino acid position, difference in rate of evolution between lineages, difference in rate of evolution between amino acid positions (gamma) of a protein, base compositional difference etc. Now the author goes back to the dark ages and uses age-old methods and refutes the phylogenies inferred by a number of studies that are based on more sophisticated phylogenetic methods. Importantly the author did not even provide comparison of his methods with that of the others or showed in what way his methods are better than the other.

Our method is correct while others incorrect for the simple reason that ours is the only method that takes into account of MGD and is based on a correct interpretation of the genetic equidistance result.

The author questions about the currently accepted primate phylogenies by saying that the previous studies did not account for the higher constrained amino acid sites in complex species. However the same phylogenic relationship [eg. ((human, chimp), orangutan)] was obtained using only the non-coding neutral sequences or synonymous positions, which are free from selective constraints (see organgutan genome paper).

All the past studies used fast evolving sequences, regardless whether they are coding or non coding, synonymous or non-synonymous. These sequences have reached MGD and are noninformative to phylogenetics. It is also incorrect to consider synonymous position to be free from selective constraints. Without the concept of MGD and selective constraints, one would have no way to properly interpret the genetic equidistance result and its overlap feature as found for macroevolution. This reviewer has yet to recognize or admit how embarrassing the existing interpretation truly is (please excuse the strong words here which was only meant to wake people up since the polite words in the manuscript has yet to do so).

There are a number of problems in this study.

How did the author choose the comparisons showed in Table 1-6? What is the measure or index used to quantify the epigenetic complexity? For instance in table 1 what is the epigenetic complexity index for human, octopus and for the other mollusk? On what basis the author decided that humans are more complex than chimp? Is it based on the number of cell types in the body? If so what is that index for human and other primates? Everything should be measurable in a scientific investigation.

Obviously, the reviewer knows that it is not presently possible to give a precise count of cell types or epigenetic complexity index. But is it truly necessary for us to explain the observations in Table 1-6? No. Our explanation is the best possible and has a high chance to be true rather than false and has no known contradictions. Human is more complex than octopus and other primates is supported by numerous observations and contradicted by none. In contrast, the existing paradigm has no explanations for those observations in Table 1-6 and is in fact falsified by them. Would this reviewer prefer that no one has any explanation for the observations in Table 1-6? When all else have contradictions, should not one go for the explanation that has no contradictions? Ours may not have all the proof, but it is the only one that has no contradictions.

There is also a double standard here. The existing paradigm has ignored the issue of complexity difference among species without any proof. To me, I would not attack the paradigm by insisting on the proof issue. I would just say, fine I would grant you that assumption and see how far you can get away with it. The reality is of course that it did not go very far before it meets countless contradictions. Thus, the correct attitude towards our ideas should be the same, which is that given our assumptions of complexity difference, how far can we go with it. The fact is that we have gone very far and seen no end. No one has found a contradiction to our story. This is a scientifically accepted way of proving that one has a valid theory even if that theory has assumptions that has yet to be directly proven. We may never have the ultimate theory and we only go with the one that has the least amount of contradictions. As things stand today, the MGD hypothesis is the only one that has yet to meet a single contradiction. The scientific way to attack or refute it is not by attacking its assumptions being without proof. For example, the axioms of math or physics have no proof and yet all math or physics theories are based on them. So long the theory works and has no contradictions, it is a good working theory regardless whether its assumption has proof or not.

What is maximum number of changeable positions? How does the author measure the level of saturation in these variable regions? How does he know in "slow genes" these sites are not saturated compared to fast genes?

We have addressed these problems with more analysis. We can now show easily that slow genes have less or no saturated position, or overlap positions in our nomenclature, or coincident substitutions as used by some people. If given a chance to revise the ms, we will add those data.

Everything mentioned in the manuscript seems to be arbitrary.

I do not thing the phrase "slow evolving neutral sequences" makes any sense. Only constrained sequences evolve slower than neutral sequences. Evolution in a neutral region is simply a stochastic process there is nothing like slow (or fast) evolving neutral sequence unless the actual mutation rate itself is slow in a region of a genome, which I do not think is the case here.

The reality is that different genes evolve at different rates. And yet the neutral theory explains all these genes using the same idea. According to this theory, the slow evolving genes also have neutral sequences but they somehow evolve slower than those in the fast genes. Being located in a region of a genome that has slow mutation rate could be a good reason. The reviewer may not have any proof for thinking that such is not the case. But worth than that, his thinking does not help us understand puzzles, such as how to explain the genetic equidistance result.

The way orthologous sequences of primates were identified is not correct. I am sure the data contains a lot of paralogous genes. Since the complete genomes of many primates are available a reciprocal BLAST hit is necessary at the genome level (comparing all genes) to identify orthologs. Furthermore there are several repositories (like ENSEMBL) where orthologs are readily available.

This can be improved indeed but I doubt it will affect the conclusion in any way.

I can list a number of more errors, inconsistencies and flaws in this manuscript. And the manuscript is poorly written and extremely lengthy. I do not think this work meets the standards of JTB.

Reviewer #3: The current paper elaborates on a previously published hypothesis that states that sequence divergence between any two species is affected by the 'complexity' of the species in question. Based on the assumption that 'slow evolving genes' are inherently more accurate for phylogenetic reconstruction better suited for phylogenetic reconstruction, the author attempts to provide evidence for the grouping of a pongid clade (chimpanzee, orangutan and gorilla) sister to humans. The currently accepted phylogenetic relationships instead indicate that chimpanzees are closer to humans than they are to the other apes.

The idea that that 'slow evolving genes' are inherently more accurate for phylogenetic reconstruction better suited for phylogenetic reconstruction is not an assumption, it is a self evident concept supported by numerous facts, the best of which is the genetic equidistance result. If one accept the notion of MGD, then the use of slow genes necessarily follows. But can one refute the reality of MGD? One could only if one could offer an alternative interpretation of the genetic equidistance result. But for the past 50 years, there is only the molecular clock and in turn the neutral theory interpretation and our MGD interpretation. The clock/neutral theory is valid for microevolution over short time scales and explains the small amount of overlap positions or saturated positions. But precisely because it works for microevolution, it cannot also explain macroevolution over long time scales where there are a large amount of overlap positions. It is where the MGD works. Two opposite phenomena require two different ideas.

I would first like to mention that I like the author's approach of thinking 'out of the box', instead of accepting current practices in phylogenetics. I agree there are several shortcomings with current phylogenetic methodology, and there is a need to develop better methods. The author also provides a good review about evidence supporting the human-pongid split.

This reviewer's position is more objective. I would just like to point out that any methodology with several shortcomings should not be taken seriously. No single contradiction or shortcomings should be the golden standard for a valid theory or methodology. I hold the MGD hypothesis and the methods associated with it to that standard. I welcome all attempts to invalidate it by way of contradicting it with either logic or facts. Unfortunately, I do not see a single contradiction offered by these comments here.

I do have some major concerns about the manuscript as it stands now. It is clear to me that the paper cannot be accepted for publication in its current state. Given how long the paper is, I am unable to give detailed comments. But I highlight some of my major concerns below, and have some suggestions that I think will improve the quality of the manuscript.

Firstly, the manuscript is an extremely lengthy essay, and I really think the message can be conveyed in a paper less than half the current length (it is currently 83 pages and ca 25000 words long).

We can shorten it in a revised ms. Most people would write books on a novel theory. Ours is not a typical filling in detail kinds of papers and an exception to the length rule may not be asking for too much.

The term 'epigenetic complexity' is vague, and something the reader will find hard to grasp. You state 'Epigenetic complexity is defined by the total number of cell types and epigenetic molecules, which is largely consistent with our naïve notion of organismal complexity and an independent calculation of organismal complexity based on information theory'. What are 'epigenetic molecules'? Do you mean that epigenetic complexity is proportional to the number of cell types? If so, why? You need to define the term in a more understandable way, especially since it used very often and is a central theme in the whole paper.

I have explained the concept in more detail in my first published paper on the MGD idea and I am sure the reviewer would find it worth reading. Again, as I explained above, in the worst case scenario, the epigenetic complexity as I defined now could be just an assumption. But whether it is a proven concept is not important as long as it explains nature without contradictions. The axioms of math or physics have no proof but that have not prevented us from using Newton or Einstein's theory to explain nature.

The concept of 'complexity' is again quite obscure. You state 'Complexity is inferred from greater number of cell types as indicated by, e.g., advanced nervous system and hence more variety of neuron types, and time of appearance in the fossil record (complex organisms generally appeared later) (Huang, 2008b; Huang, 2009a)'. All extant organisms have had exactly the same time since the origin of life to evolve. By 'time of appearance in fossil record', you mean the time since the origin of the particular species. Lets consider a bacterium that speciated in the last 10 000 years ago, for instance. Would you consider this more complex than humans? If yes, why? If not, why? Take any extant species. If this species speciates into two new species, does it mean that the two new ones are more complex compared to the ancestor? My point here is that the age of a species is entirely unrelated to its phenotypic complexity as perceived by us humans.

Here we have used species to mean different things. You are talking about subspeciation within a kind whereas I am talking about speciation of different kinds. The bacteria kind or the fish kind evolved earlier than the primate kind. I would of course need to make my point more explicit.

I refer to two examples where you define a species to be more complex in relation to an another one. i) 'The octopuses have complex nervous systems and are considered among the most intelligent invertebrates' ii) 'Snakes maybe simple reptiles without limbs whereas birds have complex flying capacities'. Your analyses about sequence divergence in these taxa are heavily redundant on your perception of how complex they are. Why is being considered intelligent by humans 'complex' in terms of genetic interactions? Why is having wings as opposed to having evolved limbless locomotion more complex? The point I am trying to make is that it does always make sense at the level of genes to talk about perceived complexity of species. True, the number of cell types varies between taxa (for instance unicellular organisms have fewer cell types than humans). However, genes in unicellular organisms can have highly complex epigenetic interactions with other genes. On the other end of the spectrum, a gene in humans may encode a single protein in all cells it is expressed in. Hence, I am not convinced by the argument that 'complexity' of a species is an important determinant of how

sequences evolve in that particular species.

Again, the point here is that you may disagree with my assumption about which is more complex, but you cannot refute the fact that my assumption works in what counts, which is to explain sequence alignment observations without a single contradiction. You may try your favorite assumptions, such as being intelligent is the least complex, and see where and how far that would take you. I can tell you right away that you cannot go very far with any other assumptions other than mine. Just try explain the genetic equidistance result and explain to me how the MGD interpretation is not the best possible explanation. Finally, it is human that cares about a theory to explain nature. That theory must at a minimum makes sense to humans. Making sense is the only way human can judge a theory. If a theory requires humans to be less complex than bacteria, it may be a valid theory to bacteria from another planet but would be senseless to humans. If humans then cannot make sense of that theory, then what practical use does it serve for humans to understand nature and how is human supposed to judge it correct? At this point, to consider intelligent as complex or wings more complex than limbless makes sense to we humans, and that is all that we can ask for in a theory that would only answer to we humans. If there are more objective truth that will make no sense to we humans, we humans would just say, sorry we could care less as it is irrelevant to our brain and our brain has no way of making sense of it and hence judging its validity.

'It is common sense that genetic diversity cannot increase indefinitely with time and has a maximum limit being restricted by function or epigenetic complexity'. This is definitely not 'common sense'!

Okay, I like your upfront approach. Let us see if the opposite of my position is common sense or even reasonable. So without a limit, two cytochrome c gene A and B could one day share no sequence similarity and yet still have similar cytochrome c function. Then, gene A could go on to give rise to C and B could lead to D, and so on it goes. We could therefore one day have countless different genes for cytochrome c. All these infinite number of genes share no sequence similarity with each other and yet all have the same cytochromce c function. Is that a picture you can entertain as common sense or reasonable? To me as well as to all sane people you care to raise the issue, it is completely senseless and against all known laws of science, which is one way of proving that its opposite must be common sense. It is common sense to say that certain constructs/buildings/functions can only be built by a limited number of choice of materials. You cannot build a bridge with water. The opposite of this common sense is that a function can be constructed by an unlimited number of choice of materials. Now, I have justified my position and I would like to hear your reason for justifying that my position is not common sense. I insist on hearing your reasons because I have seen other reviewers to just say no to my position without a reason. It was more like an emotional response, to argue for the sake of argument.

Use of 'sister species' - The term 'sister species' looses its meaning as used in this manuscript. By definition sister/sibling species are closest relatives of each other. However, you have used the term to refer to a pair of ingroup taxa compared to an out group.

I do not follow this comment. Sister species is a relative term, always relative to a third group. If the third group is an outgroup, then of course the two in group species would be closer to each other than either is to the outgroup, and thus meets the definition of sister groups. Relative to monkey, Africans and orangutan are sisters. Relative to mouse, Africans and monkey are sisters. Relative to great apes, Africans and Europeans are sisters.

You attempt to define slow evolving genes in your own way 'Slow evolving genes that contain slow evolving neutral sequences are defined as genes that show high identity between the simpler taxon C and a more complex taxon that is most similar to C in phenotypes'. Similarity in phenotype is extremely subjective. I would say a chimpanzee is more similar to a human compared to an orangutan based on hair colour and/or other characters. Would you agree? The point here is that if you want to provide a definition, it has to be an objective definition. Moreover the term slow evolving gene is self-descriptive, and you cant attempt to change its meaning. I suggest you use some other term to avoid confusion.

In some sense it is subjective but that is only because for some small number of closely related species we have yet to know how to classify phenotype similarities. But in most cases we do know how, like vertebrates versus invertebrates. Thus my definition works in most cases and is therefore a workable one in most cases. A few cases of exceptions due simply to our limited knowledge should not be reason to invalidate a workable definition that is inherently sound and logical. Being subjective is not inherently bad so long it can offer a coherent scientific view. all scientific laws of math and physics are subjective as they are based on axioms that are sensible to humans for which humans have no way of knowing if also sensible to other brains. The danger of being subjective is that one can too easily change views to accommodate objective facts. But such kind of subjective views can be easily exposed as non factual and nonscientific by factual contradictions or by its failure to give a coherent account of nature. This is the reason I place high premium on the notion of no single contradiction to a theory that necessarily will have unproven assumptions and subjective notions. The scientific way of judging a theory is not by demanding all its assumptions and subjective notions are proven, which has never been done to any theory known so far, but is by demanding no single contradiction in its story of nature. The existing paradigm has numerous assumptions and subjective notions such as universal constant substitution rate, the neutrality of most mutations, and no complexity difference among species. I do not buy this paradigm not because of these assumptions but because these assumptions do not lead one to a coherent story of nature that has no contradictions. It has not even explained to me the genetic equidistance result of macroevo while it did for that of microevo.

In your analyses where you attempt to show that humans are sister to a clade consisting of chimpanzees, orangutans and gorillas, you have used only slowly evolving genes as defined by you.  Your classificaiton into slow and fast evolving genes is arbitrary (98% similarity between 'simple' species, 85% similarity), etc. Why is this? Why don't you use a standard 80% or 50%?

The fact that I can show a group of genes being different from the rest such as those above 98% identity from those below is a major contradiction to the existing paradigm. There is nothing unreasonable in my definition. Percent identity is just one of the factor to consider in this definition. Another is that the slow and fast group as defined by a seemingly arbitrary number such as 80% should show clear difference in a equidistance testing analysis. If they dont show a difference, we would know that we have not defined the cutoff number correctly and we will just seek a new number to test until we found one that meets our criterion. We have now another way to distinguish fast and slow genes. Fast genes should show a high number of overlap positions or saturated mutation sites whereas slow ones should not. This can be easily counted.

You choose genes that are more similar among 'simpler' species compared to humans. For instance, in the human-orangutan-chimpanzee comparison, you choose the genes that are 98% or more similar between orangutan and a 'similarly complex' species (chimpanzee), and designate these as 'slow evolving genes'. Based on similarity between such genes, you come to the conclusion that orangutans and chimpanzee are more closely related to each other than either of them is to humans This is circular reasoning. You first choose genes on the criterion that they are very similar between two taxa, and eventually conclude that the two taxa are similar to each other based on similarity. That said, I am not trying to assert that humans are chimpanzees are more closely related. Your hypothesis may well be true, but you need proper evidence to support it. Your current reasoning is not tenable.

My way to chose such genes is logically sound as explained in the ms. This way may have potential pitfalls as you have correctly noticed. But such pitfall is not real problem for the soundness of the method because we do have negative controls. One control is that fast evolving genes selected by the same notion of similarity between orangutan and gorilla do not show orang and gorilla to be closer to each other than orang and human. If your circular argument is truely the reason for our observation on the slow genes, you would have a hard time to explain the opposite observation with the fast evolving genes. A second control is that the slow genes selected based on orang and gorilla similarity shows gorilla and chimpanzee to be equidistant to orangutan, which is not expected if your circular argument is true (you would expect to see gorilla closer to orang). Third, the same method did not fail to correctly identify other well supported clades such as monkey ape clade to the exclusion of prosimeans. Thus, there is a point to be learned here for evolutionary biologists in general. One should always keep an eye on the coherence of the whole picture. This means no contradictions. This also means when all other negative controls work as expected, then we should accept the positive result regardless whether we like it or not or whether it fits with our old notions. Because if we dont, we allow ourselves contradictions. When all other patterns follow our method, why should human and chimpanzee be an exception to that pattern? If you can easily accept that exception without a reason, you grant to much incoherency into nature, which has of course become a habit given the existing paradigm is alive only because people has a habit of overlooking contradictions. It is a well known motto among evolutionary biologists that all rules/patterns/laws in biology have exceptions. I dont buy that and I challenge every one to contradict the MGD. A law with contradictions simply means you have not found the complete law. Why is such plain truth which deems us stupid being overlooked while the self-deceiving and self-promoting notion of all rules have exceptions being favored among us? Of course, no one should be surprised given that evolutionary biologists are only human.

Ignoring the circularity, the 'phylogenetic analysis' of primates presented here is not a true phylogenetic reconstruction, but based on distance data i.e. a phenetic method.

As explained just above, there is no circularity here, not if one looked all of the results presented. Whether a distance method is phenetic or whatwever is irrelevant to a truthful construction of phylogeny. The inherent soundness of the logic and reason behind the method should be the deciding factor. It is non sensible to use genetic distance or similarity that is really a reflection of MGD to infer phylogeny, which is what is being done by all existing methods. It is non-sensible to even attempt to construct phylogeny when one has no real understanding of the reason for the genetic equidistance phenomenon.

'Although proteins have more sequences under natural selection than non-coding DNA, they stillhave neutral sequences so long they show difference between species and the method here only makes use of the neutral sequences' The relationship between showing difference between species and having neutral sequences is not clear. If two species are similar in sequences at a particular chromosomal, does it mean that selection acts on this region? On the other side of the coin, why can't differential selection in species lead to changes in non-neutral regions of the chromosome?

I am only applying the neutral theory here since this theory treats most of such differences as neutral. More correctly, many such differences are due to natural selection. But even if due to natural selection, the accumulation of such differences may still follow a clock like pattern, as is demonstrated by a recent Richard Lenski Nature paper on bacteria evolution in the lab. One sound way to make sense of the similar behavior for neutral and non neutral mutations is to notice that they share the common property of random fixation. Natural selection is in contrast to artificial selection, one is random and the other intentional and non random. Selection the process per se is not random but the outcome is random because the environmental change is random for natural selection. The outcome of artificial selection is non random because the environmental change is non random. Thus fixation of mutations by artificial selection is not random and should not follow a clock like pattern, but fixation of mutations by natural selection is random, in the same sense as random drift, and thus should follow the behavior of neutral mutations.

'A molecular clock calibrated from one fossil split time should produce divergence times consistent with other fossil records and other independently calibrated molecular clocks.' This is not entirely true. Fossils only provide minimum estimates of times of divergence, they can never provide absolute times. You also need to take this into account in your discussion about divergence times within the hominoid clade.

In an ideal situation, this should be true. Granted that some fossil record may not be complete, but here we are talking about those well established beyond any reasonable doubt. The mammal radiation or the Cambrian explosion are such records.

Overall, I don't think the author provides convincing evidence or reasoning to support his/her argument that 'complexity of species' (however defined) affects the rate of evolution of sequences. The 'phylogenetic analysis of primates has several problems, some of which I have discussed in this review.

In the final analysis, I suggest that you all pay attention to the genetic equidistance result. Once you fully understood it, you may see where I am coming from. I can see clearly that you have yet to understand how destructing it truly is to the existing paradigm and that you have not paid attention to what I wrote about it, since you are still thinking as if the interpretation of this result by the existing paradigm is sound rather than completely embarrassing. Thank you all again and I would greatly appreciate your feedbacks. I am not biased in any way and much more objective than most scientists. You dont have to do much talking to convince me your position or theory, just give me a few sentences on how your position or theory could easily take care of the genetic equidistance result of both microevol and macroevo. To help you out, I grant you that your theory is perfect for the equidistance phenomenon of microevo. I just have trouble seeing how it could also explain that of macroevo, where there are a large amount of overlap positions or saturated positions. I look forward to hearing your reply.

Kurt Godel: 'I don't believe in empirical science. I only believe in a priori truth'

The great logician Kurt Godel is absolutely brilliant in saying: 'I don't believe in empirical science.  I only believe in a priori truth'. 

As both a bench scientist in an empirical field of science and a theoriest, I would only rephrase that I only believe in emprical science that is consistent with a priori truth or intuition.  Much of biological knowledge today is not based on intuition and the chief theory in biology today, ie the modern evolution theory, is largely based on a negation of intuition.  No wonder you never see truly brilliant minds like a Godel or Einstein to have any admiration for the Darwinian theory of evolution.    

Random enrichment of minor alleles of common SNPs affects complex traits and diseases

We have recently submitted a manuscript for publication as well as an abstract to a human genome variation meeting.  The work represents an application of the MGD hypothesis in solving major real world biomedical problems.  The results confirm the MGD hypothesis and invalidate the neutral theory that has prevailed for nearly half of a century.  The flawed neutral theory has no real world relevance to major biomed problems and no neutral theory experts are known to have contributed anything to research of major biomedical importance (not Kimura, not Ayala, not Nei, not Blair, not Avise, not Felsenstein).  In contrast, the MGD hypothesis can and will survive even without relying on its value to evolution research.  Much of our ongoing research have nothing to do with evolution.  Stay tuned for more of our results on the genetic basis of complex traits and complex diseases about which the neutral paradigm has absolutely no clues. 

Random enrichment of minor alleles of common SNPs affects complex traits and diseases. 

Dejian Yuan^1#, and Zuobin Zhu^1#, Xiaohua Tan¹, Jie Liang¹, Ceng Zeng¹, Jiegen Zhang², Jun Chen², Long Ma¹, Ayca Dogan³, Gudrun Brockmann³, Oliver Goldmann⁴, Eva Medina⁴, Xian Man¹, Ke Yi¹, Yanke Li¹, Qing Lu¹, Yimin Huang¹, Dapeng Wang⁵, Jun Yu⁵, Hui Guo¹, Kun Xia¹, and Shi Huang^1*

¹State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China; ²High Performance Computing Center, Modern Educational Technology Center, New Campus, Central South University, Changsha, Hunan 410083, China. ³Department of Crop and Animal Sciences, Faculty of Agriculture and Horticulture, Humboldt-Universität zu Berlin, Invalidenstraße 42, 10115 Berlin, Germany;  ⁴Infection Immunology Group, HZI – Helmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany;  ⁵CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100029, PR China; Graduate University of Chinese Academy of Sciences, Beijing 100049, PR China. 

*Correspondence to:  Shi Huang, huangshi@sklmg.edu.cn  

#These authors contributed equally to this work.

The prevailing null hypothesis in population genetics and molecular evolution posits that most common SNPs are neutral but this has yet to be formally tested by experimental science.  We employed two strategies to determine whether the minor alleles (MAs) of common SNPs are minor because of natural selection.  First, we analyzed multiple panels of genetic reference populations or recombinant inbred lines (RILs) in model organisms (yeast, worm, fly, mouse, and rat), and identified the MAs of common SNPs in each panel and the fraction of MAs that each strain carries.  We measured the brood size of 104 C. elegans RILs and did genotype-phenotype correlation analysis for the brood trait as well as for ~4700 published and unpublished traits for various RIL panels archived at GeneNetwork.  Although beneficial to immunity as is expected, more MAs correlated significantly with poor measurements in many adaptive traits, including reproductive fitness, life span, tumor susceptibility, anxiety, depression, startle response, and learning and memory.   In addition, more MAs were significantly linked with sensitivity to alcohol, methamphetamine, cocaine, pain, and antipsychotic drugs, and levels in glucose, resistin, insulin, IL-17, iron, and dopamine.  Random enrichment of MAs of common SNPs accounted for as much as 49% of total trait variation in some phenotypes in RILs such as transferrin saturation and food intake.  The majority of the ~4700 traits examined did not significantly correlate with MAs, including blood pressure and morphine response.  Different MA-linked traits may or may not share the same set of MAs with related traits sharing more MAs than non-related traits.  Second, we analyzed 21 published GWAS datasets of common diseases and identified the MAs of common SNPs in each control population and the fraction of MAs each control or case carries.  In Europeans or European Americans, more MAs were significantly and repeatedly linked with type 2 diabetes, Parkinson’s disease, psychiatric disorders, autoimmune diseases, alcohol and cocaine addictions, lung cancer, less life span, and lower education level achieved, but not hypertension and opiate and marijuana addictions.  Thus, the effects of excess MAs in humans are remarkably similar to those in model organisms, suggesting that the link between excess MAs and diseases/traits in humans is causal since it can be replicated in model organisms.  These data indicate that most SNPs in any species are functional or under Darwinian natural selection and open a new avenue of inquiry into the genetic basis of complex traits/diseases.  They confirm a self-evident intuition in construction that any system of great order can allow some random errors/noises in building blocks but only to a limit. 

Why naming an axiom may seem pompous but is not

My friend Joe, a biology professor at a US public university, gave me some great feedbacks after I emailed him my essay “The second axiom of construction and the second axiom of biology” as posted here on July 9, 2011. Below, I post his email feedbacks and my responses, which deal with axioms and the random nature of natural selection.

My essay: “The Second Axiom of Construction and the Second Axiom of Biology posit that any system can allow a certain degree of random noises or errors in its building blocks, and such limited degree of random errors may confer zero, negative, or positive values to the functioning/survival of the system under certain random environmental circumstances.

This axiom underlies the whole of the modern evolution theory composed of Neo-Darwinism and Kimura’s Neutral theory and is the foundation for microevolution and population genetics where there is no change in system complexity over time. (In contrast, the First Axiom of Biology is the foundation for macroevolution where there is change in system complexity over time.)”

Joe’s comments: “This is true, but I fail to see why you are trying to put a name to it. This is a given, known to everyone. The concept that any system has a certain amount of tolerance for noise is an accepted concept for any endeavor or study. The only thing people would argue about with this is how much tolerance any particular system has under what conditions. Calling it the “Second Axiom of Construction” is just going to make you sound pompous and aggrandizing unless you are just using them to basically abbreviate a later discussion by listing a few basic concepts accepted by everyone and showing how they apply to the main point. Besides, I expect engineers have already put a name to this concept long ago.”

My response: Your reaction is absolutely natural. My wife, a PhD biologist, strongly urged me not to use the word axiom in my university websites and grant applications. She thinks that people will not take it well, if only for psychological reasons. I fully recognize this type of concerns. I wish there is a way out of it. The reason I put a name like axiom to it is pretty sound. First, it is a given, known to everyone, as you correctly said. But that is precisely what an axiom is, a self-evident truth that everyone can see. There is always a straight line connecting two dots, which is Euclid's first axiom. Second, just because every one can see it does not mean it is unnecessary to formally make it a law or axiom. It is only when a self evident idea is being actually utilized to describe nature in a scientific way, it is formally recognized as a law or axiom. So, putting a name to such an idea marks the beginning of a branch of science. There are many other self-evident ideas yet to be incorporated into science and hence yet to be called an axiom. An axiom may be obvious to everyone but its specific connection to a branch of science is not obvious before it is made (even though it is always obvious in hindsight). Thus, the inventor of an axiom always deserves credit for making such a connection, which may seem trivial but is really not and takes a rare kind of creativity. Third, I expect as you did that people in the past should have already put a name to both the first and second axiom of construction as in my nomenclature. But as far as I know no one did in the past 5000 years of human history. This is not unexpected however because the scientific value of such axioms is not evident until one has an appreciation for DNA as the building blocks of life, which of course only becomes possible in the last 60 years.

So here is something I would like to hear your suggestions. How to avoid being perceived as pompous and aggrandizing when it is really a purely scientific practice to call some self evident idea an axiom, which is merely meant to be an abbreviation for a concept, or as you correctly pointed out: I am “just using them to basically abbreviate a later discussion by listing a few basic concepts accepted by everyone and showing how they apply to the main point.” One may try to use intuition in place of axiom. But while that may avoid being viewed as pompous, it is against the standard practice in science since the time of Euclid all the way to Newton and to today. Even some philosophers like Spinoza used the word axioms to label their ideas in order to make them more law like or science like. In the last analysis, truth/history and I could care less if I appear grandiose or over confident so long I am right. To some people, one will always be perceived as grandiose the moment he is suggesting that he has better ideas than someone like Darwin. Being mis-perceived by some in the beginning is always a part of the package of striving to be a revolutionary.

My essay: “For the neutral errors that confer zero values to the functioning/survival of the system under a certain random environmental circumstance, the accumulation of such errors is determined by random drift and linearly related to time, as described by Kimura’s neutral theory. For the non-neutral errors that confer either negative or positive survival values, the survival values are dependent on the environmental circumstances, which are and can only be random in nature. Thus, the accumulation of non-neutral errors is determined by random natural selection by random environmental circumstances. Since natural selection is overall a completely random process (see my post on April 9, 2009 and other posts on the random nature of natural selection), the fixation of non-neutral mutations by natural selection is effectively no different from that of neutral mutations and is therefore also linearly related to time given long enough time that allows for multiple rounds of selection and de-selection.”

Joe’s comments: “As long as you are saying that you are discussing long term responses and can’t predict a priori how the environment may change and drive specific natural selections, you may be able to get away with saying natural selection is random, but once the parameters are set, natural selection is the antithesis of random. It is very much a directed responses and not a random process from that point. Probabilistic yes, but not random. The two are very different. You need to make sure you are clarifying your proper frame of reference for this assertion.”

My response: You are right to say natural selection the process is not random. You are also right to say that if one cannot predict the environment, then natural selection is random. I have written several entries in my blog to argue why one should call natural selection random. The key point here is that a non-random process does not guarantee a non-random outcome. In evolution, what really matters is the cause and the effect. If the cause is random, then the effect is random, regardless whether the process from cause to effect is random or not. For example, a mutation event in a gene at the level of DNA is random. However, the biochemical process from this mutation to the manifestation/expression of mutant protein/phenotype is not random. And yet, we always call the mutant phenotype (the final outcome following the random mutation in the beginning) randomly caused. In the same way, the outcome of natural selection is always random because the environmental change in nature is always random. It is helpful to contrast natural selection (NS) with artificial selection (AS). The environmental change in artificial selection is not random, and hence the outcome of it is not random. If you call NS non-random, then what are you going to call AS? NS and AS are complete opposites. To say natural selection the process is not random is not wrong but is a trivial and irrelevant truth to say because the end result is what we care. To say NS is non-random must exclude the environmental change in the concept of NS, but then NS is no different from AS. But everyone understands that NS is different from AS, and that difference lies strictly in whether the environmental change is random or intentional. So calling NS non-random is flawed even from a purely logical or linguistic point of view and is guilty of sophism or disguised displacement of concept.

In fact, the random drift process per se, which led to the fixation of neutral variations, is in fact not random in the same way that NS the process is not random. Imagine a fraction of population randomly drifted into a new geographic location and then an earthquake killed all of the individuals in the old location. The genotypes that survived in this case would be a result of random drift rather than natural selection. However, the dying process per se of the individuals located in the earthquake zone, from earthquake to the death of individuals, which may involve bleeding to death, crushing to death, etc, is anything but random or fully predictable. So, this example illustrates that even random drift of neutral variations may involve a non-random process. Thus, calling natural selection non-random because natural selection the process is not random should equally justify calling random drift non-random. The bottom line is that both the results of natural selection and random drift are random because the environmental changes are always random.

Joe’s comments: “I disagree anyway. If this was true, that there is no difference between neutral and selected mutations, the neutral theory would work just fine. Positive mutations have a chance of increasing, but negative mutations will by necessity be eliminated over time unless they are in some way tied to a positive mutation that has a contribution that outweighs the negative. Thus, negative mutations will decrease over time while positive ones will increase on average. Because they have different vectors, they can’t be random even if they are not determinant, but probabilistic. Moreover there is plenty of evidence that mutation rates are neither random nor clocklike. Several other studies have found mutation rates in E. coli increasing in response to high selective pressure, and if I am not mistaken, even the locations of such mutations are not necessarily random. Now over the long haul, what may be a positive trait now may be a negative trait later as the environment changes, but it is unlikely that this can be an across the board assumption. Some traits are going to be positive in almost every situation, while some negative traits will be negative no matter where you put them.”

My response: It is true that mutation rates may vary depending on environmental selections. But the positive and negative selections cancel each other out so that the average mutation rate would be similar to the mutation rate under neutral selections. I agree with you that "Now over the long haul, what may be a positive trait now may be a negative trait later as the environment changes, but it is unlikely that this can be an across the board assumption. Some traits are going to be positive in almost every situation, while some negative traits will be negative no matter where you put them." However, I think that such traits that are positive in almost every situation is extremely rare. They would have little impact on the clock like divergence which is contributed or determined by the average mutations that are more abundant and can be either positive or negative depending on environments. In fact I can’t think of any traits that are always positive. The Chinese yin-yang philosophy, which I believe is fundamentally correct, says that every fundamental trait has opposites yin and yang which are never absolute and neither can exist without the other. Too much of goodness is bad and too much badness is good. Is being rich always good? Absolutely not. Is being top of the class in school always good? Absolutely not. Is being at the top of the food chain always good? No. Is being at the bottom always bad? No.

So, in sum, if we correctly view natural selection as random, then most fixed mutations that contribute to genetic distance are randomly fixed, regardless whether the process is by random drift or natural selection (both of which may involve a non-random process). Thus they in turn should behave like a clock, which is what we actually observe. We can test this by performing two divergence experiments, one by artificial selection and one by natural selection. The prediction would be that within a fixed time, AS should produce a large genetic distance while NS would not.

Making the existing model obsolete

Numerous scientists in the past 150 years have repeatedly challenged the Darwinian macroevolution theory (few has problems with the microevo part though for which Darwin and 4 others deserve our great respect). And many in the future will continue to challenge it until it falls, with ever more devastating facts and reasons. Actually, if one wants to be really honest about it as future history book would tell it, the Darwinian speculation on macroevolution has already been knocked down cold nearly 50 years ago by the first observation in molecular evolution, the genetic equidistance result. That is the reason for the invention of the ad hoc epicycyle known as the molecular clock, which must negate natural selection at the level of molecules and hence made Darwinism irrelevant/false for molecular evolution. How can one then hold on to Darwinism if it is false for molecular evolution? Well, by disconnecting molecules from phenotypes as has been done by the ad hoc Neutral theory of macroevo (again the Neutral theory of microevo is fine) for the past 50 years. But that is truly an absurd ad hoc notion since all other areas of modern biology support a tight unity as the rule rather than the sideshow. Just imagine whether any Neutralist would happily expose himself to low dose radiation. Indeed, the molecular clock hypothesis and the Neutral theory have now been proven false for macroevolution (my paper is the latest for doing just that). As a result, the existing model is largely irrelevant/false for molecular macroevolution. It is the reason for numerous false conclusions on molecular phylogeny, which we are now trying to correct.

Therefore, it is already a forgone conclusion that there is zero chance that Darwin’s macroevo theory will ever be accepted as a law of nature the way Newton’s laws are. Furthermore, because of its counter-intuitive nature, there is no chance that it will ever be accepted by the majority of the lay public no matter what the majority of scientists may say about it. However, it would not go away simply because some scientists have openly attacked it with irrefutable reasons or how absurd it truly is at its core. It must be pushed away or replaced by a better theory. And that is the only possible way. As Buckminster Fuller famously put it: “You never change things by fighting the existing reality. To change something, build a new model that makes the existing model obsolete.” The Darwinian theory however must be the hardest to replace because no other theory in the past could match it in its immense non-scientific ramifications. Even though it is a doomed sitting duck, it would remain alive and well as long as it remains the best we have got and as long as the best we can do to it is to pick on its obvious problems.

So, is there a theory on the horizon that stands a realistic chance of making the Darwinian model obsolete? Numerous scientists as well as lay people have put forward many new evolution theories that purport to be better than the Darwinian orthodoxy. (One of the latest most outspoken critics who also happens to have published his own theory is the biology professor John A. Davison, who unfortunately is more focused on fighting rather than using his theory to solve real puzzles, which may not be by choice however since his theory really has little relevance to most details of evolution.) But none has so far gained any traction. The key reason as I see it is that these theories, regardless whether their main themes are right or wrong, all fail to make themselves relevant to the detailed facts of evolution that professionals are concerned with daily in their research. None of them is relevant to molecular evolution, the most active field of evolutionary research in the past 50 years and will continue to be so for any foreseeable future in light of the genome sequencing revolution that is going on at the momment. (From my perspective, this is to be expected since I am not aware of anyone who has properly understood molecular evolution.) They cannot offer alternative interpretations to most facts that are at least equally legitimate as the existing model. This weakness is rarely realized by others especially the theorists themselves but is obvious to me for the simple reason that my own theory is like no other theory in this regard. It explains more detailed facts and does so more coherently (with the least amount of ad hoc ‘epicycles’) than the existing model. Better still, it is relevant not only to historical problems but also to major problems of today, such as common diseases (manuscript in preparation). It is more than just about evolution. In comparison, the best Darwin’s theory has done to contemporary non-evolutionary problems is really trivial, such as bacteria drug resistance. The late NAS member professor Phil Skell is famous for his position that Darwinism does not serve as the cornerstone of biological thought that many claim it does.

To solve major new problems, in addition to old ones such as the genetic equidistance result, for which the existing model has no clues about or has provided incorrect solutions, should be the most effective way of replacing the existing model. That is the way we have taken and should be the way for any challenger to take. We are unique or the first in this regard in the past 150 years since the “Origin”. It should be fun for me as well as those who have understood the new MGD hypothesis to watch in the coming years how the existing model will be made obsolete by our new one. It is only a matter of how and when rather than if, at least to me when not in my modest mood. It would be expectedly a long and hard struggle but nonetheless interesting to watch. It has been almost 4 years now and so far so good. We are still at the first stage of three stages that a new idea would typically go through on its way to accepted truth. This is the stage of being ignored. It is extremely positive at this stage however that we have not seen a knock out punch from any of the critics who are reviewers of our papers, friends, colleagues, and Internet forum commentators. Also positive is the fact that we are having easier and easier time getting published in mainstream journals and we have met a few good reviewers who have understood and liked our ideas. We are presently submitting manuscripts that would hopefully mark the end of the first stage. We are using our ideas to solve real world problems of everyday life, which would make it hard for people to ignore. We will force our ideas on to the working benches of medical genetists who could care less about evolution theories.

I view scientific discovery at the highest level, i.e., the level of laws, as creations, in the same sense as a great piece of art. I had an ambition and serious training to be an artist in my youth even though I also enjoyed mathematics. I speak in part from personal experience that science at this level is revolutionary art/artist in every important aspect, including aesthetics, simpliticity, seemingly impossible unity of polar opposites, fine tuned perfection, destruction, joy to the creator, solitude, struggle, and bipolar temparament. To anyone with an ambition of doing science at this level, the following words should be inspirational.

Every act of creation begins with an act of destruction.

Pablo Picasso

A successful work of art is not one which resolves contradictions in a spurious harmony, but one which expresses the idea of harmony negatively by embodying the contradictions, pure and uncompromised, in its innermost structure.

Theodore Adorno

(Yes, the MGD hypothesis coherently unites micro- and macro-evolution not by ignoring their differences/contradictions like the existing model does but by highlighting it and making a point of their opposite natures.)

The man with a new idea is a crank - until the idea succeeds.

Mark Twain

We think in generalities, but we live in detail.

Alfred Whitehead

(The MGD hypothesis has universal intutions and takes care of a vast number of details. The Darwinian model of macroevolution or any other evo theory in the past fails on both accounts: it has no presentable or sensible generalities and cannot account for key details such as the genetic equidistance result.)

A creation of importance can only be produced when its author isolates himself, it is a child of solitude.

Johann Wolfgang von Goethe

The reasonable man adapts himself to the world; the unreasonable one persists in trying to adapt the world to himself. Therefore all progress depends on the unreasonable man.

George Bernard Shaw

The mere formulation of a problem is far more often essential than its solution, which may be merely a matter of mathematical or experimental skill. To raise new questions, new possibilities, to regard old problems from a new angle requires creative imagination and marks real advances in science.

Albert Einstein

(The solution to the nearly half a century old puzzle of genetic equidistance and the realization of a new feature of it--the overlap feature—as we have achieved in recent papers should be a watershed event in the history of evolutionary science. I have come to realize that doing science at the highest level means asking new questions in places of detail where few thought there is a problem. The most important problems are not those grand ones out in the open, which are either logical next step questions or un-solvable ones with today’s knowledge. No science can be greater than revolutionary science. Revolution necessarily means to see unsolved problems in little details that the existing model does not see or has fooled everybody to think solved. More difficult for revolutionary science today, as compared to Copernicus’s days, is to not merely deem the existing model wrong but must also make its proven virtues shine even brighter as a part of the new model. This is difficult in practise because it means that you must know enough about the existing model but in doing so you risk being fooled by it or becoming an insider. And few revolutions were started by insiders. One way to get around this is to have your revolutionary idea first and then get yourself acquainted with the existing model. If the idea is of the axiom kind, one could in principle come up with it without any expertise in any particular branch of science. There is no reason that the First Axiom of Construction that I proposed should be beyond the capabilities of ancient people 5000 years ago.)

Much Madness is divinest Sense —

To a discerning Eye —

Much Sense — the starkest Madness —

’Tis the Majority

In this, as All, prevail —

Assent — and you are sane —

Demur — you’re straightway dangerous —

And handled with a Chain —

Emily Dickinson

Making the simple complicated is commonplace; making the complicated simple, awesomely simple, that's creativity.

Charles Mingus

(To connect a simple intuition/axiom with a vast number of details of science is not obvious before it is done. It is no different and could be as hard as to go from axioms to a proof of a hard mathematical hypothesis. Biologists face the task of distilling the common pattern/axiom by observing a vast number of natural and seemingly isolated facts. The more facts and hence more complexity one needs to account for the harder it is to find the common simple pattern/axiom. Hence creativity at this level is hard and the outcome is the most beautiful. The ultimate beauty is the unity of the ultimate complexity with the ultimate simplicity. Professor Stephen Wolfram expressed similar views in his “New Kind of Science” that simple rules/patterns underlie the unfolding of complexity in nature.)

When I am working on a problem I never think about beauty. I only think about how to solve the problem. But when I have finished, if the solution is not beautiful, I know it is wrong.

Buckminster Fuller

Below is short piece inspired by the above quotations, titled “Science at its best is art”

In science, no ad hoc epicycles is a sure sign of simplicity and hence beauty. No ad hoc epicycles of course means no contradictions. To be a great scientist, it helps if not necessary to have training in classical art and to develop a good taste in aesthetics.

First, good taste concerns motivation and choice of fields. It would lead one to be bored with mere filling details kind of routine science. Nonetheless, science needs both kinds of scientists, the majority happy with routines while an extreme minority unhappy with it. Finding/creating laws of great importance is so much more aesthetically appealing than mere fact/stamp collection. Of course it is practically much harder to achieve success and carries a high risk of failure, but an appreciation for aesthetics is usually tied to idealism rather pragmatism. People whose first priority is to feed oneself and one’s family are less likely to be concerned with aesthetics or even truth. Not every one can afford to be idealistic and those few who can should consider themselves lucky. One thing positive out of China’s Cultural Revolution under Chairman Mao’s leadership is the upbringing of a generation of young idealistic dreamers who did not waste their youth devoted to passing exams and therefore were fortunate to have had a more complete development of all human faculties. If I would turn out to be successful, the Darwinists should in part blame it on a member of their own cohort, Mao.

Second, art training concerns standard of beauty and ability to spot ugliness. It would lead one to have a keen eye/sense for imperfections and imbalances, and to pay attention to the whole or the unity of details within the whole. The little imperfections/imbalances that most see as trivial would appear glaringly disturbing to the aesthetically gifted/trained. While doing painting in my youth, I learned to routinely look at my work from a distance in order to keep balance of the whole. "Go some distance away because the work appears smaller and more of it can be taken in at a glance, and a lack of harmony of proportion is rapidly seen." -- Leonardo da Vinci. So, training in art would almost surely lead one to become obsessed with harmony, an essential quality of a great scientist.

Good taste in aesthetics prevents the publication/release of premature productions. I am constantly amazed by the fine tuned perfection of a great piece of music or painting. Any little twist would make it worse and every little detail is a logical necessity. A great art is always born (meaning published or released to the public) perfect, with the creator alone deserving the sole credit for it. There are no peer reviewers or high impact journals necessary to make great art happen. The artist has a universal standard for perfection that he can apply to his work himself, which is beauty and harmony, which makes peer review unnecessary. The great scientist has that standard too and would not publish a work that lacks beauty. Beauty and a creater of good taste serve as the best safeguard against faulty productions. Beauty alone in his work is sufficient for a lone creator to challenge the world, not to mention betting his life on it.

Third, art trains the intuitive sense, essential for creativity in science as in anything else.

Finally, art trains the mind to be able to better spot the main features/patterns among noises. The trained or gifted in art can paint a portrait of a live person that looks like the real person but the others cannot. Learning to paint nature the way it is may help the mind to more easily grasp nature for what it is in scientific terms. Both the artistic and scientific renditions of nature require a common faculty of the mind, a keen sense for the major features of nature. A common error for most evolutionary biologists is to mistake the noise and trivial as the main feature. Their portraits of nature are like the paintings of the untrained.

Second Axiom of Construction and Second Axiom of Biology

The Second Axiom of Construction and the Second Axiom of Biology posit that any system can allow a certain degree of random noises or errors in its building blocks, and such limited degree of random errors may confer zero, negative, or positive values to the functioning/survival of the system under certain random environmental circumstances.

This axiom underlies the whole of the modern evolution theory composed of Neo-Darwinism and Kimura’s Neutral theory and is the foundation for microevolution and population genetics where there is no change in system complexity over time. (In contrast, the First Axiom of Biology is the foundation for macroevolution where there is change in system complexity over time.)

For the neutral errors that confer zero values to the functioning/survival of the system under a certain random environmental circumstance, the accumulation of such errors is determined by random drift and linearly related to time, as described by Kimura’s neutral theory. For the non-neutral errors that confer either negative or positive survival values, the survival values are dependent on the environmental circumstances, which are and can only be random in nature. Thus, the accumulation of non-neutral errors is determined by random natural selection by random environmental circumstances. Since natural selection is overall a completely random process (see my post on April 9, 2009 and other posts on the random nature of natural selection), the fixation of non-neutral mutations by natural selection is effectively no different from that of neutral mutations and is therefore also linearly related to time given long enough time that allows for multiple rounds of selection and de-selection. Thus, the genetic distance between any two species is linearly related to time like a clock, regardless whether the errors that contribute to such distance are fixed due to random drift or random natural selection. Evidence for beneficial mutations to behave in a clock like manner has been shown recently (Barrick et al., 2009). Our recent molecular dating study has also shown a remarkable concordance between molecular dating and fossil dating. Thus empirical evidence supports the notion that there is a strong linear correlation between genetic distance and time of divergence even if such distance is largely contributed by non-neutral mutations. In theory, as long as we correctly view natural selection to be what it really is (it really is random), we can easily make sense of the clock like behavior of the non-neutral mutations within the neutral theory framework. The fixation of the non-neutral mutations has one fundamental property in common with that of the neutral mutations. They are both random. Over long periods of time and numerous random environmental changes, the number of positive selections will roughly equal the number of negative selections. Thus, the canceling out of each other the positive and negative selections makes non-neutral mutations to effectively behave as no different from neutral mutations.

So, the modern evolution theory (Neo-Darwinism plus the Neutral theory) is not completely counter-intuitive or non-sensible. As a theory of microevolution and population genetics, it is completely sensible or intuitive and flows readily from the self-evident Second Axiom of Biology. But as a macroevolution theory, it is completely non-sensible or counter-intuitive as it must negate the First Axiom of Biology. The more complete MGD hypothesis takes into account both of the Axioms of Biology and fully grants the modern evolution theory to be what it really is or has been proven to be (a theory of population genetics and microevolution or the microevolutionary phase of macroevolution).

I may formally introduce The Second Axiom of Construction and Second Axiom of Biology in a future paper.

Barrick, J.E., Yu, D.S., Yoon, S.H., Jeong, H., Oh, T.K., Schneider, D., Lenski, R.E., and Kim, J.F. (2009). Genome evolution and adaptation in a long-term experiment with Escherichia coli. Nature 7268, 1243-1247.