This is not a “debate”, it’s some comments that I …

Comment on Dr. Nick Matzke Explains the Evolution of Complexity by Sean Pitman.

This is not a “debate”, it’s some comments that I randomly posted on your blog, which you have fairly weirdly strung together into a single piece and then called a “debate”. That’s all you.

Whatever you want to call it…

You still aren’t getting the difference between a “functional island” as measured by blasting a protein with multiple simultaneous mutations, and the reality, which is a web (even within a single function), the strands of which are gradually explored by a step-by-step process of various sorts of substitutions, including compensatory ones, and which would essentially never return to the starting point, or even be constrained within the region of sequences-similar-enough-to-be-identified-by-BLAST. The web covers a far, far greater area of the sequence landscape than your little island. There’s not much point in discussing more complex issues if we can’t resolve simple points like this.

I’m sorry, but I do not see how compensatory mutations 1) significantly increase the size of the islands within sequence space (as far as the absolute number of protein-based sequences in sequence space that can produce a given type of function), 2) how they create narrow paths between qualitatively different islands at higher levels of functional complexity that are significantly more likely to be traversed in a given amount of time, or 3) how they significantly narrow the non-beneficial gap distances between different islands within sequence space?

As far as I can tell, compensatory mutations are simply a way of compensating for detrimental mutations by maintaining the same basic structure and function of the system (within the overall flexibility limitations of the minimum structural threshold requirements of the system in question). I guess I just don’t see how this significantly improves the odds of finding novel islands with qualitatively novel functionality? Such has not been demonstrated anywhere in literature that I’m aware, and I personally don’t see how the odds of success could be improved by invoking compensatory mutations?

The reason for this, as far as I can tell, is that compensatory mutations are limited to producing the same basic type of structure that characterizes a particular island within sequence space. For example, “It is well known that the folding of RNA molecules into the stem-loop structure requires base pair matching in the stem part of the molecule, and mutations occurring to one segment of the stem part will disrupt the matching, and therefore, have a deleterious effect on the folding and stability of the molecule. It has been observed that mutations in the complementary segment can rescind the deleterious effect by mutating into a base pair that matches the already mutated base, thus recovering the fitness of the original molecule (Kelley et al., 2000; Wilke et al., 2003). (Link)” Of course, in this particular situation, there are very limited choices for workable compensatory mutations given the high degree of required sequence specificity of the structure.

So, as far as I can tell, this nicely illustrates my observation that compensatory mutations simply don’t produce novel structures with novel functional complexity. They simply compensate for a loss of structure/function that results from detrimental mutations by trying to get back to the original to one degree or another. This is why compensatory mutations are so constrained. Depending upon the detrimental mutation, only a limited number of compensatory mutations are possible – and most of these do not provide full functional recovery from what was lost. In other words, the original level of functionality is not entirely reproduced by most compensatory mutations. In fact, populations tend to fix compensatory mutations only when the rate of compensatory mutations exceeds the rate of reversion or back mutations by at least an order of magnitude (Levine et. al., 2000). This means, of course, that back or reversion mutations are usually the most ideal solution for resolving detrimental mutations, but are not always the first to be realized by random mutations. And, compensatory mutations are usually detrimental by themselves. That means, once a compensatory mutation occurs, it is no longer beneficial to revert the original detrimental mutation (since one would also have to revert the compensatory mutation as well). This is somewhat of a problem since since compensatory options are more common, a compensatory mutation is usually realized before a reversion mutation – up to 70% of the time (Link). However, because compensatory mutations are not generally as good as back mutations at completely restoring the original level of functionality, they are less likely to be fixed in a population – especially larger populations.

In any case, your argument that there are a number of potential compensatory mutations for most detrimental mutations (an average of 9 or so) is clearly correct. So then, doesn’t it therefore follow that these compensatory options do in fact expand the size of the island and create a net-like appearance across vast regions of sequence space? – as you originally claimed?

Consider that the overall shape of the island remains the same – with sharp peaks and steeply sloping sides. I do not see how compensatory mutational options change this basic appearance of the island? They simply make the island 10 times larger, and much more spread out, than if there were no compensatory options (as in a case of increased specificity requirements) – which isn’t really relevant given the overall size of sequence space and the ratio of beneficial vs. non-beneficial within sequence space.

For example, say that a protein sequence experiences a point mutation that happens to be detrimental. Say there are 10 potentially compensating mutational options to “fix” this protein to some useful degree, one of which is realized. Now, let’s say that this protein experiences a second detrimental mutation in a different location. Now, there are 10 more potentially compensating mutational options, one of which is realized. What happens with each additional detrimental mutation to the sequence? Is the observation of Bloom et. al., that proteins suffer an exponential decline in functionality with each additional detrimental mutation, negated by the compensatory mutation options? Not at all. The compensatory mutations simply expand the size of the island to the extent allowed by the specificity requirements of the system, but they do not make it possible for the island stretch out indefinitely over all of sequence space. The minimum structural threshold requirements simply will not allow this. The same basic structure with the same basic function and the same minimum number of required building blocks must be maintained. And, that puts a very restrictive size limit on the overall size of the island with this type of function within sequence space (size being defined by the absolute number of protein sequences that can produce a given structure with a particular type of function). In other words, the actual maximum number of protein sequences that comprise the island is very very limited.

But, you argue, compensatory mutations may allow for narrow arms or branches to extend long distances (Hamming or Levenshtein distances) within sequence space. And, this is true. However, remember that sequence space is hyperdimensional. Changing the shape of an island comprised of a limited number of grains of sand doesn’t significantly change the odds of putting it within closer range of the next closest island within sequence space. After all, the shape of the island has a random appearance that is not biased toward other surrounding islands within sequence space. Therefore, the odds of successfully locating a different island with qualitatively novel functionality remain essentially the same as far as I can tell. There is no significant change in the minimum likely gap distances between any part of the starting island, regardless of its shape, and any other island within sequence space at higher levels of functional complexity. Other islands with other types of functions still have to be found by getting off of the original island and crossing a non-selectable gap distance – and I don’t see how compensatory mutations improve these odds?

And, that, in a nutshell, is why your proposed steppingstones in your flagellar evolution pathway simply require too many non-selectable differences to get from one to the other in a reasonable amount of time.

Re: flagellum — the word “Pallen” does not appear in your webpage, and the homology-and-unessentiality table from that paper is not discussed.

I do discuss the homologies that you proposed in your 2003 paper, “Evolution in (Brownian) space: a model for the origin of the bacterial flagellum”.

It seems to me that they key difference you see between your 2003 and your 2006 papers is the discovery of more homologies for vital structural flagellar proteins. You write:

The important overall point, as discussed in my blog post, is that of the 42 proteins in Table 1 of Pallen and Matzke, only two proteins, FliE and FlgD, are both essential and have no identified homologous proteins. This is substantially more impressive than the situation in 2003, and means that the evidence for the evolutionary origin of the flagellum by standard gene duplication and cooption processes is even stronger than in 2003. (Link)

You see, I really don’t care if every single one of the individual protein parts within the flagellum are homologous to proteins within other systems (even though a couple of them are not currently known to be homologous to anything else). This is completely irrelevant to the plausibility of the evolution of higher level systems based on pre-existing subsystems. You see, the problem is that having all the required parts to make a new type of complex system isn’t enough. Why not? Because, these parts must be modified in very specific ways before they can work together in a new specified arrangement as parts of a different type of complex system – like a flagellar motility system. And, the number of required modifications to get the parts in your proposed pathway to work together, to any selectable advantage at a higher level of functional complexity, is simply too great to be realized this side of a practical eternity of time.

How is that? After all, is it not possible for the required parts to be perfectly homologous between different systems? Well no, it’s not. If this were the case, all kinds of very different complex systems could be produced using identical subparts. The reason why this doesn’t happen is because qualitatively different complex systems require key modifications for the otherwise homologous parts to work together in different ways. And, the great number of these required non-selectable modifications to otherwise homologous parts, the exponentially greater the average random walk time. So, by the time you’re at a level when the minimum number of required non-selectable modifications is a couple dozen or so, the average time to randomly produce all of these required modifications, which cannot be guided by natural selection, is trillions upon trillions of years. And, I fail to see how compensatory mutations help to solve this problem? As far as I can tell, they do nothing to solve this problem for the ToE.

In short, homologies simply don’t cut it because it isn’t the similarities that are important, but the number of required non-selectable modifications that completely kills off evolutionary potential, in an exponential manner, beyond very low levels of functional complexity.

Sean Pitman Also Commented

Dr. Nick Matzke Explains the Evolution of Complexity
3D molecular evolution is based on the proper arrangement of characters in 2D sequences, the same as in any human language system – like English or French, etc. And, the appearance of sequence space at various levels of functional complexity is also essentially the same.

Dr. Nick Matzke Explains the Evolution of Complexity

“You mistakenly assume that human languages evolve via the same mechanism as Darwinian evolution. They do not.”

Dr. Pitman, you are the one that introduced the language metaphor to compare probabilities of genetic sequence space for new functional complexity. You are hoisting yourself on your own petard my friend!

You confuse the look of sequence space with various methods of moving about within sequence space.

All meaningful language/information systems have the same basic look of sequence spaces at various levels of functional complexity, to include an essentially uniform fairly random distribution of potentially beneficial islands within sequence space at higher levels of functional complexity. However, the mechanism by which one gets around in that space may be different. The various words that are used for similar purposes within various human languages “evolve” over time via the involvement of intelligent design (an intelligent environment if you will). The Darwinian mechanism of RM/NS does not have this option since the “environment” within which protein-based systems may evolve is not intelligent. Movement through protein-based sequence space via this method is therefore much more limited, even at the level of small individual sequences that are equivalent to most individual words in various language systems. When one starts talking about moving beyond the mere definition of small individual words, to sentences, paragraphs, and entire essays or books (i.e., higher and higher levels of functional complexity), the nature of sequence space changes exponentially with regard to the ratio of potentially beneficial vs. non-beneficial – regardless of the language/information system. With each increase in the minimum structural threshold requirement of the system (in any language/information system) the minimum likely distance between a given island and the next closest island in sequence space increases in an linear manner.

How this non-beneficial gap distance is crossed can be done with or without intelligence. It is just a matter of a significant difference in the average time required to achieve success.

If one chooses to move around in higher level sequence spaces via random mutations and function-based selection, without including intelligent manipulation of the mutations, the average random walk time required to get from one island to the next closest island within sequence space increases exponentially as the minimum gap distances increase in a linear manner. That is why the “evolution” of sentences, paragraphs, and books (and novel individual words as well) in English or Latin or Greek or Russian, etc., happens so fast – because intelligence is involved in this kind of intelligently directed “evolution”. This is not the case, however, for a mindless mechanism like RM/NS, where exponentially greater and greater amounts of time are required.

I hope this makes things a bit clearer for you…

Recent Comments by Sean Pitman

Dr. Walter Veith and the anti-vaccine arguments of Dr. Geert Vanden Bossche

Can you talk about the blood clot side affect — the rash side affect — and the other side affects listed in the VAERS document? Are these deaths and suffering are just “ho-hum” dispensable humans to the cause of good for all?

I talk about VAERS here (Link). The Herpes Zoster rash happens in a low percentage of immunocompromised people who have previously been infected with the Herpes virus (Link). While certainly uncomfortable, it’s not life-threatening and it isn’t a risk for most people. The blood clot risk is a very rare risk (about 1 in a million for young women) for the DNA vaccines, possibly related to the adenoviral vector used for the vaccines. I talk about this here (Link). There is also a very rare risk for severe immune thrombocytopenia (Link). Note that for all of these risks for the vaccines, the very same risks are much much much higher when it comes to being infected by the live COVID-19 virus. So, if you want to reduce your risk as much as possible, the best way to do that is to get vaccinated.

What is happening to cause so many side affects? How is one to know if there is a chance of dangerous side affects of the vaccine for a person?

The thing about risk is that it is impossible to know, ahead of time, exactly how a particular person will react. That’s just the nature of the concept of “risk”…

Are vaccinated women who get the vaccine during pregnancy, or get pregnant and give birth having any side affects among their babies?

No. I talk about this rumor here (Link).

Also, have your children been vaccinated? What is your opinion of elementary or high schools requiring the vaccine for school children? Which childhood conditions need to be studied before administering the vaccine to children with these conditions?

The mRNA vaccines are not approved for children under the age of 16. They are currently in the trial phase of testing for younger children. My own boys are 9 and 11 years of age, so no, they haven’t been vaccinated yet. However, once approved, I would be getting them vaccinated since even children are at risk for long-term injury and sickness from COVID-19 (30% of children get Long-Hauler’s following even asymptomatic infections with COVID-19). As far as childhood “conditions”, I know of no common childhood conditions which would preclude vaccination…

What “empirical evidence” is there that mRNA vaccines do not cause any side affects “a year or two or three down the line”? Is there a study I can read – link?

As I’ve already mentioned, the evidence for this is the very long history that we’ve had with vaccines and understanding how they work with the human immune system. When complications arise, they do so within the first few months for large populations (Link). It is extremely unlikely that something brand new and unexpected will come to light years down the line (Link). Also, by that time, millions will have been killed and permanently injured by the very real and very well-known risks of the COVID-19 virus itself.

Yes, your glowing recommendation is convincing with several issues not addressed in the glow.

I have addressed most of your questions already in other posts on this topic…

Do you recommend a yearly booster vaccine like now is being developed? I think big Pharma announced a flu/covid combo vaccine coming out for next fall. What is your opinion please?

For now, it seems likely to me that the mRNA vaccines will produce immunity lasting more than a year, likely several years. However, as with most viruses, the COVID-19 virus mutates. If a new mutant strain comes along that “breaks through” the immunity provided by the original vaccine(s), then yes, a booster would be necessary. However, if enough people would get vaccinated quickly, it would make the odds of such breakthrough mutations less likely.

Thanks for your help in understanding the full spectrum of topics about these mRNA vaccines.

Thank you for your thoughtful questions.

Dr. Walter Veith and the anti-vaccine arguments of Dr. Geert Vanden Bossche
It’s certainly highly advisable to look at both sides of the issue. However, many, including Dr. Veith, just aren’t doing this in an evenhanded manner where the overall weight of evidence is carefully considered and laid out for evaluation. Your own claims, in particular, aren’t exactly balanced and unbiased either…

First off, the mRNA vaccines are not just “experimental”. They have been extensively studied now for over 30 years. Scientists are very well aware of how they work. There is no significant mystery here. Also, they were subjected to very large clinical trials in both humans and animals that were double-blinded and placebo-controlled. These trials included 70,000 human participants (combined between the Pfizer and Moderna trials), who have been carefully observed now for over six months. The Pfizer mRNA vaccine is now eligible for full FDA approval. Past experience with vaccines tells us that the vast majority of adverse outcomes, if they happen, happen within the first few months. The argument that something serious will turn up a year or two or three down the line simply isn’t based on empirical evidence. And, simply sitting back to “see this pandemic play out” is a recipe for continued disaster – costing millions of lives worldwide.

The weight of scientific evidence that is currently in hand very strongly supports the very high efficacy as well as the safety of the mRNA vaccines as compared to the risks of getting infected by the live COVID-19 virus – to include up to 1/3 of people of all ages ending up with long-term sicknesses and injuries from originally mild and even asymptomatic cases of COVID-19 (Link). This isn’t something to play around with. The mRNA vaccines are truly a miraculous gift to humanity. Take advantage of it…

The Arguments of Adventists Opposed to Vaccines
Here’s a pre-print of a paper demonstrating that the antibodies produced in response to the mRNA vaccines are actually more effective, and probably last long-term, as compared to a natural infection (Link). This is yet additional information in favor of the idea of going ahead and getting vaccinated against COVID-19 even if one has already been previously infected.

Dr. Walter Veith and the anti-vaccine arguments of Dr. Geert Vanden Bossche
What a deal for us, you mean. Without this deal, the mass production and distribution of life-saving vaccines and other medications wouldn’t be possible.

Dr. Walter Veith and the anti-vaccine arguments of Dr. Geert Vanden Bossche
The FDA initially granted Emergency Use Authorization (EUA) in December of 2020. The FDA usually requires at least six months of data for the clinical trial participants before full FDA approval is granted. Pfizer, in particular, has previously said that it planned to apply for full FDA approval this month (April 2021). With full FDA approval, Pfizer would be allowed to sell its vaccine directly to hospitals and other health care providers. (Link)

The process required to get the initial EUA from the FDA is fairly extensive and detailed upfront. The mRNA vaccines (put out by Pfizer and Moderna) underwent double-blinded placebo-controlled trials in 70,000 humans, along with double-blinded placebo-controlled trials with animals as well – at the same time. These Phase III trials continued for 10 weeks and showed >95% efficacy against COVID-19 infections – far better than expected. Perhaps even more impressively, none of those vaccinated had severe COVID-19 symptoms, required hospitalization, or died – while more than two dozen such cases were noted in the placebo arms (along with 6 deaths). This data, together with other data dealing with vaccine production protocols and other such safety data, was taken into account as the basis for the FDA’s EUA.

Of course, since the general rollout of the mRNA vaccines worldwide, the data has only gotten better. Take the results of the rollout in Israel for example (since Israel is far ahead of the rest of the world in the percentage of its population that it has been able to vaccinate). So far, the mRNA vaccines in Israel have shown a 98.9% efficacy rate in “preventing hospitalizations” from COVID-19 (Link). That’s amazing! The data in the US is similar with less than 1 in 1 million deaths for those vaccinated so far (Link). Now, let’s say that the overall death rate for COVID-19 is 1% (or 1 in 100 people on average, but exponentially higher with age beyond the age of 50). The mRNA vaccines would be able to reduce that death rate to between 1 in 100,000 and 1 in a million! That’s miraculous! It truly is!

“The 2 mRNA vaccines have similar efficacy of approximately 95% for the prevention of symptomatic COVID-19 and nearly 100% efficacy in preventing death from COVID-19 after 2 doses.” (Rio and Malani, JAMA, March 4, 2021)

If that’s not enough, around 1/3 of people who come down with a COVID-19 infection who don’t die, will end up with some long-term illness or injury (Link). Commonly, these long-term injuries involve the lungs, heart, and brain – and affect even 1/3 of those who had no symptoms or just mild symptoms during their initial infection. The mRNA vaccines can dramatically lessen “Long-Hauler’s Syndrome” as well… and are even showing some benefit for those who already have long-term illnesses as many seem to recover once they get vaccinated.

Given that the technology for the mRNA vaccines isn’t new either (mRNA vaccines have been studied for over 30 years now), it isn’t like scientists don’t have a very good understanding as to how they work and what to look out for already. Known potential risks have been solved, such as ADE. Also, the mRNA vaccines require no adjuvants, like mercury or aluminum. They are the cleanest vaccines ever produced since they also require no culture on any kind of cellular tissue or organic medium.

In short, the mRNA vaccines will have full FDA approval very soon, and for very good reason. They have been studied and tested far more than most vaccines or other drugs or medications have been tested before receiving full FDA approval. They have demonstrated amazing efficacy, far far better than expected, and are far far safer than getting sick with the live SARS-CoV-2 virus. I don’t know about you, but I’ve lost more than a dozen family friends to this pandemic so far. So, not only have I been vaccinated with the Pfizer vaccine, but my wife as been vaccinated (Moderna), both of my parents have been vaccinated (Moderna), both of my wife’s parents have been vaccinated (Pfizer), my brother and his wife have been vaccinated (Moderna), all three of my wife’s siblings and their spouses have been vaccinated (Pfizer and Moderna)… and many more. I highly recommend that you do the same as soon as the vaccine becomes available to you!

For more information, you might find some benefit from a short talk I just gave on this topic: Link