Primeval nanotech v. Darwinism.

Irreducible Complexity in Molecular Machine Assembly
Evolution News | @DiscoveryCSC

We know that many molecular machines are irreducibly complex (IC) in their operation. Even more IC is the process of assembling them in the cell. A good example of this is the process of building our good old standby machine, ATP synthase (review our  animation to Proceedings of the National Academy of Sciences recognize the F0 rotating part and the F1 synthesis part).

A new “tour de force” paper by He et al. in the Proceedings of the National Academy of Sciences (PNAS), co-authored by Nobel laureate John E. Walker (who at age 77 is still researching these tiny rotary engines), describes new insights into how these multi-part machines are assembled. In a companion Commentary on PNAS, three scientists (Song, Pfanner and Becker) put it bluntly: “The assembly of the mitochondrial ATP synthase is a complicated process that involves the coordinated association of mitochondrially and nuclear encoded subunits.” Here’s a taste of what they mean (don’t worry; this won’t be on the test):

Based on their findings [He et al.], they propose an elegant model of how the membrane domain of human ATP synthase is built (Fig. 1, Upper). In one branch, an F1–c-ring intermediate associates with the peripheral stalk and the supernumerary subunits e and g. In the other branch, the F1 domain first assembles with the peripheral stalk and supernumerary subunits e, g, and f. Both pathways merge in a key assembly intermediate that contains the F1 domain, the c-ring, the peripheral stalk, and the supernumerary subunits e, g, and f. In all these vestigial [i.e., incomplete] ATP synthase complexes, the inhibitory protein IF1 is enriched to prevent ATP hydrolysis by the uncoupled ATP synthase. The presence of the supernumerary subunits e, g, and f is crucial for the subsequent integration of the mitochondrially encoded subunits ATP6 and ATP8 that are stabilized by addition of 6.8PL. Thus, the proton-conducting channel between ATP6 and the c-ring is formed. At this stage, ATP synthesis is coupled to the proton-motive force and the inhibitory protein IF1 is released. Finally, DAPIT is added to the assembly line to promote dimerization and oligomerization of the ATP synthase.

Whether or not you can follow the jargon is not as important as what they witnessed:  an “elegant” process that requires precise timing and coordination. Different machine parts must arrive on schedule, and assemble into intermediate (vestigial) forms that are nonfunctional alone. An inhibitor protein makes sure the machine doesn’t switch on ahead of schedule. The proton-conducting channel has to form just right so that it doesn’t “leak” protons. Only when all the parts are ready does the machine begin to rotate, but even then, the work isn’t complete. Another player is “added to the assembly line” to position the machines on the folds of the mitochondrial membrane (called cristae) at precise angles and spacings for optimum productivity.

The parts must arrive at the construction site on time. Some of them come from the nucleus, which must seem like many miles away at the scale of the machine. Some are built locally by genes within the mitochondrial genome. Interestingly, there are differences between yeast and humans regarding which genes are encoded where, and in what order they are assembled. But the proof of the pudding is in the respiration after eating: both versions of the machine work efficiently for their respective organisms.

The intermediate structure, somewhat like a scaffold on which the machine will be built, is also irreducibly complex:

We have shown that the assembly of human ATP synthase in the inner organellar membrane involves the formation of a monomeric intermediate made from 25 nuclear-encoded proteins into which the two mitochondrially encoded subunits are inserted and then sealed by association of another nuclear-encoded protein, thereby dimerizing the complex. Association of a final nuclear protein oligomerizes the dimers back-to-face along the cristae edges.

Notice that parts from the different genomes have to work tightly together. It’s like a manufacturing plant receiving parts locally and from India that have to meet agreed-on specifications to match. There are also rules for import, just like for parts arriving from a far country. The nuclear-encoded parts have to pass through two distinct checkpoints (the inner and outer membranes of the mitochondrion), which each have their robotic security personnel to validate them and facilitate their transport to the inside.

Previous work has shown how the completed “factory” of machines is organized within the mitochondrion. A specific nuclear protein seals them in two’s (dimers) at an angle, such that the rotating F0 proton pumps can maximize the intake of proton fuel, while the F1 parts, where ATP synthesis occurs, are farther apart to not crowd the output molecules. A “final nuclear protein” joins the dimers together (oligomerizes them) along the membrane edges. The longitudinal spacing is also tightly controlled, so that they don’t crowd each other. Every point of the assembly is programmatically directed. When everything is completed, rows of ATP synthase motors are arranged like turbines in a hydroelectric plant, feeding off a flow of protons produced by upstream machines in the respiration transport chain.

Ribosome Assembly

Viewers of cellular animations like those in Unlocking the Mystery of Life could never forget the assembly-line process inside the ribosome, where precisely-sequenced messenger RNAs are matched with transfer RNAs carrying amino acids to form proteins. The entrance tunnels for the ingredients and the exit tunnels for the polypeptides, and everything in between, must be positioned exactly for correct operation. The ribosome is certainly one of the most stunning examples of information translation in all of nature. But how is the ribosome itself built?

Nature  has provided an early version of an unedited manuscript by Sanghai et al. about ribosome assembly. Although it has been accepted for publication, it will be subject to editorial revisions. The subject matter, though, appears to show another stunning case of irreducible complexity in the construction of this important molecular machine. Here’s the Abstract:

Early co-transcriptional events of eukaryotic ribosome assembly result in the formation of precursors of the small (40S) and large (60S) ribosomal subunits. A multitude of transient assembly factors regulate and chaperone the systematic folding of pre-ribosomal RNA subdomains. However, due to limited structural information, the role of these factors during early nucleolar 60S assembly is not fully understood. Here we have determined cryo-EM reconstructions of the nucleolar pre-60S ribosomal subunit in different conformational states at resolutions up to 3.4 Å. These reconstructions reveal how steric hindrance and molecular mimicry are used to prevent both premature folding states and binding of later factors. This is accomplished by the concerted activity of 21 ribosome assembly factors that stabilize and remodel pre-ribosomal RNA and ribosomal proteins. Among these factors, three Brix-domain proteins and their binding partners form a ring-like structure at rRNA domain boundaries to support the architecture of the maturing particle. Mutually exclusive conformations of these pre-60S particles suggest that the formation of the polypeptide exit tunnel is achieved through different folding pathways during subsequent stages of ribosome assembly. These structures rationalize previous genetic and biochemical data and highlight the mechanisms driving eukaryotic ribosome assembly in a unidirectional manner.

The requirements of IC are met in this description: “a multitude of transient assembly factors” regulate and systematically fold the proteins that will be used to construct the machine. The authors mention “21 ribosome assembly factors that stabilize and remodel” the RNA and proteins before the machine is even operational. Inside the growing ribosome, a scaffold holds factors for the exit tunnel in place. Everything is choreographed in time and space with “mechanisms driving… assembly in a unidirectional manner.”

Here we see numerous parts working together on a timeline. The parts alone do not work individually. You can have all the proteins delivered to the construction site, and nothing will happen without the programmed mechanisms to put them together in order. Some parts hold others in place, others guide the folding of protein parts, and some even prevent premature assembly. All the pathways for assembly of the subdomains are regulated by a master program, so that each group of steps follows a “unidirectional” plan toward the finished product. It’s a marvelous IC assembly process that produces an IC machine. If five parts of a mousetrap are sufficient to indicate IC, how about dozens of parts, all following a programmatic sequence of assembly?

In Unlocking, concerning the assembly of the bacterial flagellum, Paul Nelson described how the hierarchical IC of machine assembly in the cell challenges Darwinian theory. “In order to construct that flagellar mechanism, or tens of thousands of other such mechanisms in the cell, you require other machines to regulate the assembly of these structures. And those machines themselves require other machines for their assembly.” Jonathan Wells nailed the point by saying, “If even one of these pieces is missing, or put in the wrong place, your motor isn’t going to work. So this apparatus to assemble the flagellar motor is itself irreducibly complex. In fact, what we have here is irreducible complexity all the way down.”

Ancient whale returns for second helping of Darwinists' homework.

Of Whales and Timescales
Andrew Jones

Joshua Swamidass, assistant professor in the Department of Pathology and Immunology at Washington University, has responded to an Evolution News article about whale evolution. The original article concluded:

We don’t find the “pattern” that evolution predicts “should be found in the fossil record at certain times.” Rather, we find that truly aquatic whales appear abruptly. And even if we accept some of the fossils as “intermediates” between whale and land mammals, there is not enough time for the complex adaptations needed for whales’ fully aquatic lifestyle to evolve. Whatever the correct explanation is for the origin of whales, unguided evolutionary mechanisms are not the answer.

Swamidass writes:

Looking at this progression [of skulls] we uncover an amazing fact. Surprisingly, whales have the same body plan as a terrestrial mammal! It’s the same body plan, with several intermediate forms. Looking at several features (e.g. ears, bone density, teach), we can see this transition beautifully. Look how we can see the nostrils slowly move back to the top of the head…

Yes, it is beautiful. One adapted for land, another for water, and one is intermediate. But take care; nothing is actually moving in those pictures. Any transition is in the interpretive imagination of the beholder.

Getting back to the claim that millions of years is “not enough time.” There is no genetic or mathematical analysis to back up this conjecture. What types of genetic changes are required for whale evolution? How unlikely or likely are they?

Consider a paper published in PLOS Computational Biology,  “The Time Scale of Evolutionary Innovation.” The authors explore how long it should take for evolution to make a complex coordinated change to a sequence. They find that mutation alone would be little different from creating a completely fresh sequence each time using random letters, but that if natural selection is acting to “regenerate” the original sequence, and if the original sequence happens to be near the target, then evolution is much more likely to make the transition. This should be common sense, I think. Note the core result: a sequence of length L requiring only k specific coordinated changes will require Lk+1 trials. They describe this as “polynomial” because it is polynomial in L but it is exponential in k.

What this means is, if it takes 100 generations for a specific mutation to occur, it will take (at least) 10 thousand generations for a specific set of 2 mutations to occur, and 100 million generations for a specific set of 4 mutations to occur. At human generation lengths that would be 2 billion years. Two billion years, for a 4-letter “innovation.” That puts a hard limit on what kind of magic we can expect from evolution. This basic problem is then greatly exacerbated by population genetic effects; each mutation must not only occur, it must become fixed or at least well established in the population, and there is no selection to help until you get the last mutation in the set.

Now consider the mutations that actually have occurred in humans in recent human history. Some have been interesting, including significant tweaks to melanism, and milk digestion, but none of them are spectacular (no X-Men) and certainly none have constructed new biochemical systems or new healthy morphology. The waiting times problem informs us that all the mutations in the history of the human species must have been similarly banal. Think about that for a moment. Are you surprised? You should be if you believe we evolved from something like an ape. Evolution has to work one step at a time. It cannot do the kind of complex coordinated magic that a human designer or engineer can. If you believe humans evolved, you have to believe it can happen without any complex coordinated changes at all (in this context complex means just 4 or more specific letters at the same time — not 4 new proteins). In fact, the exponential character of the waiting times problem tells us that all of evolution must have been similarly limited, right back to the Cambrian explosion. In turn, that raises the question of how the radical innovations of the Cambrian explosion could have occurred

From a Batmobile to a Yellow Submarine

The Evolution News article argued that for a land mammal to become a whale, or a Batmobile to become a Yellow Submarine, it would require multiple coordinated changes. To many people this would be a trivial and common sense assumption, even without the detail given in the article. However, citing another paper, “Molecular evolution tracks macroevolutionary transitions in Cetacea,” Swamidass pushes back:

It is remarkable how many of the changes required for whale evolution are caused by loss of function mutations (which end causing “pseudogenes”), or small tweaks to proteins. This is one of the big surprises of mammalian evolution. Large changes can take place with tweaks to the genetic code. Eyes adapt to underwater vision by losing a rhodopsin gene. Hind Limbs are lost with the loss of a homeobox gene. Taste buds are lost when two genes are lost. Smell receptors are almost entirely lost in most species too. In all these cases, we see remnants of the broken genes, and in many cases the details of how these losses increase function are well understood.

This is all true. It is true that overall efficiency can be increased by losing unused functional components. On a design view, it makes sense to deactivate things that are not being used. Often this needs no more than a flip of a switch, and this no great challenge for evolution either. On the other hand, why would the random loss of information make a functional body plan? Researchers have created legless mice by knocking out a Hox gene, in an effort to understand snakes, but the resulting mice were simply paralyzed and could not mate. Also, note that at some point evolution has to explain the origin of all the proteins, Hox genes, as well as the rhodopsins and receptors that have been lost, and that is rather more difficult. An evolutionary process that creates nothing new is soon going to run out of other organisms’ proteins to borrow.

Remarkably, it does not appear any new enzymes or de novo genes are required in whale evolution. It appears that small tweaks to existing proteins, or loss or alteration of the function of existing genes, account for the changes we see at this point.

True, that is not where the challenge to whale evolution lies. But why is it remarkable to see no new genes? It turns out that a large number of genes are taxonomically restricted or ORFan genes. That means they seem to appear without evolutionary history in the twigs and leaves of the tree of life. Moreover, some even  turn out to be essential, which would be very odd if they have been added last by evolution. The existence of these genes is a common problem elsewhere in the evolutionary story, even though it appears not to be relevant to whales. Protein coding genes are hard to explain when they appear de novo — see  Doug Axe’s work as well as this recent EN article .

Also, there does not appear to be any reason that a large number of these changes must happen at the same time. They appear gradually in the tree, and it’s not clear at all why they would need to be “coordinated”. They do not appear to need to occur at the same place and time to be useful. So this does not make these transitions unlikely.

This is where we have to disagree. Some of the changes listed might be independent, small, and easy, but there are also some pretty massive, complex ones that would seem to need coordination. For one example, losing tooth enamel does not make baleen plates. For another, whale testes are inside the body. In itself this appears to be a trivial change, and it makes good design sense in terms of streamlining. That is, until you try to implement it, and find that mammalian testes become infertile if kept too warm, so now you need a cooling system, or else a redesign of the reproductive system. It is not so trivial any more. And the changes do need to be coordinated. What selective advantage is there in a cooling system? None unless you have testes there. What selective advantage is there in internal testes? None, unless a cooling system is there. It turns out that dolphins and whales have mysteriously acquired an elaborate counter-current cooling system that keeps the testes the same cool temperature as its fins! That system is not trivial, and it is not going to evolve with just one or two mutations.

A Design Perspective

Considering this from a design perspective, and speaking as one experienced in doing design, it’s going to be tough to convince me that one could “evolve” a program with a series of single-letter changes, deletions, and random copy-pasting, all while it continues to compile and function. The notion is in conflict with our experience of how complex functional systems actually work.

We have also argued that homoplasies constitute evidence of common design. Swamidass argues these can be explained by convergent evolution

Also, we also see convergent mutations between whales, bats (echolocation), and beavers (diving adaptations to blood). These “homoplasies” are the rare exceptions to the nested clade pattern of common descent, and are exactly what we expect in evolutionary process, just like we see recurrent mutations in cancer, and convergent evolution in human HLA variation. Everyone agrees that human variation arises by natural processes, and that cancer arises by natural processes, yet we see homeoplasies here too; this is what we expect from common descent.

But another way of looking at it is that evolutionists have adapted their expectations in response to the evidence that homoplasies exist. They have long known about character traits that don’t fit the canonical Darwinian explanation of a branching tree, and convergent evolution has long been proposed as an explanation, but the truth is the authors of the original paper on bats and whales found this particular result “surprising” and “remarkable.”  From my own experience, I remember trying to persuade an evolution-evangelist that molecular homoplasies exist between extremely distant species, and he wouldn’t believe me! I will try to explain why.

Now, convergent evolution can happen, but it really depends on the particular circumstances. Convergence in cancer and HLA are different from convergence between bats and dolphins because they both involve very high mutation rates, coupled with strong selection effects acting on very small changes. In HLA the changes are concentrated in a tiny region of the genome. In cancer, strong positive selection acts on mutations that each help the cancer, but destroy some normal function.

It is one thing to find weak points where cars tend to break independently in the same place, or even how one breakage leads to another (e.g., brakes first then everything else as it careens of the road). It would be quite strange if cars independently acquired sonar capabilities, and even more so if the software upgrades were identical.

Imagine you assign a coding exercise to computer-science students. It is quite possible that two students would come to roughly the same solution, since there are likely only a few good solutions. That is how convergent evolution is supposed to work. However, what if they had not only the same general solution, but identical code too? Or imagine two history students write an essay about the causes of World War I. It is possible they come to the same conclusion. But if you see identical prose, you have to suspect plagiarism: it strongly suggests that the text or code was designed once and then used multiple times.

And that is why my friend did not believe me; because he did not believe the coding sequences would converge. It is easy to imagine, if evolution could find complex solutions at all, that it could find something similar again, but it is much harder to imagine that evolution would converge on the same code, since the mutations that write it are supposed to be random, especially if the code has been diverging for some time. However, now that we have found that there are molecular homoplasies at great taxonomic distance, the committed evolution-believers are surprisingly unfazed: all it means, they argue, is that there must be only one solution that works and natural selection finds it every time (while listening to Wagner). That’s an interesting theory, but can you prove it? If the evolution of complex traits is so predictable and reliable, it seems we should be able to set it up and see it happening.

Meanwhile, can you hear the students accused of plagiarism? But sir, it’s the only solution! And we are both geniuses! Hmm. If you are both geniuses, I look forward to your next assignment.

There is a much more parsimonious solution: common design.

Either way, the larger problem is that the changes involved in adapting a generic mammalian template into a whale are certainly not all simple, independent, single-letter changes. It seems obvious that multiple coordinated changes would be needed, and it turns out that would require a lot longer than mere millions of years.

Internet porn and diminishing returns.

After human exceptionalism:Ascent of the law of the jungle?

Now It's "Posthumanist Ethical Pluralism"
Wesley J. Smith 

The New York Times continually publishes  opinion pieces and news articles aimed at undermining human exceptionalism and the understanding that we have the highest moral value.

This is exceedingly dangerous. If human life doesn't have the highest ultimate objective value simply and merely because it is human -- an equal value to be distinguished from all other life forms on the planet -- there is no way to philosophically defend universal human rights.

Moreover, if we can't distinguish between our inherent value and that of animals, we will not elevate their status to our level but diminish our own to theirs.

Now, the Times has an extended interview with anti-humanist scholar Cary Wolfe, conducted by Natasha Lennard. Wolfe, who directs Rice University's Center for Critical and Cultural Theory, advocates a "posthumanist ethical pluralism" among us and with the rest of life on the planet.

Of course, Wolfe makes the usual claim among such believers that what is done to an animal or other life form should be judged as morally equivalent to the same thing being done to a human. From the interview:

N.L.: How might a posthumanist approach to undoing interspecies hierarchies intervene with structures of violence among humans themselves? Trump's election reflects and emboldens white supremacy and misogyny to a frightening degree. Could a posthumanist intervention risk moving focus away from a direct and much needed struggle against these things, or could it help?

What a moronic question. Can we all roll our eyes and hoot in unison?

And catch the big-brained vapid answer:

C.W. Oh, I think it can help enormously, by drawing out more clearly the broader base that these struggles share in what I've called a posthumanist ethical pluralism. My position has always been that all of these racist and sexist hierarchies have always been tacitly grounded in the deepest -- and often most invisible -- hierarchy of all: the ontological divide between human and animal life, which in turn grounds a pernicious ethical hierarchy. As long as you take it for granted that it's O.K. to commit violence against animals simply because of their biological designation, then that same logic will be available to you to commit violence against any other being, of whatever species, human or not, that you can characterize as a "lower" or more "primitive" form of life. This is obvious in the history of slavery, imperialism and violence against indigenous peoples. And that's exactly what racism and misogyny do: use a racial or sexual taxonomy to countenance a violence that doesn't count as violence because it's practiced on people who are assumed to be lower or lesser, and who in that sense somehow "deserve it."

But we don't believe any of that. Indeed, we have instituted increasingly stringent animal welfare laws precisely because we understand that as humans we have duties of humane care toward animals.

Moreover, raising chickens for eggs and inseminating cows does not lead to "rape culture."

What the hell would instituting a society based on "posthuman ethical pluralism" mean in actual practice? Unsurprisingly such practical questions are left unanswered in the interview:

C.W. The first imperative of posthumanism is to insist that when we are talking about who can and can't be treated in a particular way, the first thing we have to do is throw out the distinction between "human" and "animal" -- and indeed throw out the desire to think that we can index our treatment of various beings, human or not, to some biological, taxonomic designation. Does this mean that all forms of life are somehow "the same"? No, it means exactly the opposite: that the question of "human" versus "animal" is a woefully inadequate philosophical tool to make sense of the amazing diversity of different forms of life on the planet, how they experience the world, and how they should be treated.

If we reject the moral hierarchy of life with us at the apex, does it mean we can't eat meat? Does it mean we must fundamentally harm ourselves by ceasing animal experimentation?

In the real world -- yes, I know that is not where professors tend to live -- all of this is simply unworkable. And the potential adverse impact of trying to impose policies based on such thinking would do unquantifiable harm to human thriving.

But do note that the entire discussion rests on the extent and depth of human moral duties that we assign to ourselves. And indeed, the entire question proves the moral hierarchy that Wolfe is at such pains to deny. No other species in the known universe could even engage the question, much less decide that altruism requires elevating morally lesser life forms into equal -- or higher -- consideration with our own.