Reaping the Whirlwind: protein function without stable structure


(Jay Johnson) #322

Is that like a 5-star review on Amazon? I woke up this morning feeling like it was a 5 sigma significance day!

Added note: Maybe the editors of those journals weren’t as picky, er … judicious, as Stephen?


(Steve Schaffner) #323

Just like that, only a lot less frequent.


(Randy) #324

@Raymond_Isbell Mr Isbell, Thanks for your thoughts. I wonder if I’m missing the real problem–one we all struggle with. It’s whether Genesis really fits with evolution or not. I am certain I don’t know all the answers, but I have learned a lot from reading in the last 2 years. Here are some resources I have benefited from.

There are some great resources on this–1) Deb and Lauren Haarsma, “Origins,” talks about the various ways in which people believe Genesis jives with evolution (or not). they deal with concordance, strict and figurative.
2) “Evolution of Adam” and “Inspiration and Incarnation” --Pete Enns (his first is my favorite)https://peteenns.com/shop/the-evolution-of-adam/.
3) Denis Lamoureux, like Augustine, became convinced that Genesis was figurative; Augustine did it on his own in the 4th century, and Lamoureux at Regent College in Canada (I believe J I Packer was one of his teachers).Lamoureux's Evolutionary Creation
4) See Biologos, “Is Genesis Real History?” for another position. https://biologos.org/common-questions/biblical-interpretation/is-genesis-real-history
5) Four Views on the Historical Adam (see review; the Counterpoints are my favorite series) https://randalrauser.com/2014/05/an-evolving-evangelical-debate-a-review-of-four-views-on-the-historical-adam/

It’s hard to understand from our Western point of view, but Genesis wasn’t made to answer the question of “how,” but “who” and “why.” It’s just not the way things were written back then–and it’s not even the genre of later parts of the Old Testament and New Testament.

.Thank you.


(Raymond Isbell) #325

I apologize for not responding sooner, but I’m trying to read the materials recommended to make my next response current and relevant. I’m also going back and looking at the entire series and will offer some observations that will help establish a context that will aid in our discussion of the character of evidence and how we view and use it. This will take some time. I hope you all stay engaged if for no other reason it’s helping me get a better understanding of your thinking and why you believe evolution best explains the data. Also, a number of you have said some things recently that deserve a response, and I would like to do that. But for now, I’m up to my ears in reading and assessing new material. I look forward to more discussion, and I hope you do also.


(Randy) #326

Dear Mr Isbell,

Thank you for your diligence. I would not hurry; but I agree that your questions help me think, and I enjoy that. Thank you! Do you like Princess Bride quotes?

I would not expect an answer or even the first thing approaching one. Take decades, and then come back and teach me what you’ve learned! God is patient with us; He knows our hearts and is happy with our questions.

PS–sorry; I fixed the link for the Biologos “Is Genesis History”–I had copied the wrong one. I also fixed my spelling of your name in the earlier post! Sorry!


(Jay Johnson) #327

Yes, stick around. Don’t be afraid to ask questions on anything you don’t understand. Start a new thread when you come back. This one is getting unmanageable. You can link previous posts to reference them for continuity, if you want.

Here’s a howler from Sanford and Rupe, explaining away transitional forms: “The best evidence for any type of intermediate ‘ape-men’ derived from bones collected from mixed bone beds (containing bones of both apes and men), which led to the assembly of chimeric skeletons.” Those that they don’t classify as chimeras, they wave off as the result of isolated, inbred populations that underwent “genetic degradation.” In other words, everything else is just severely deformed H. sapiens. Hmmm. Evidence, please.


(Raymond Isbell) #328

Loved the movie and the quotes. Watched it with my daughters multiple times.


(Chris Falter) #330

I can’t fathom how Sanford’s assertion makes any sense. Hundreds of fossilized Homo have been found with features that are quite distinct from any extant member of the ape superfamily, including humans.


(Randy) #331

It’s so sad that some people in their 20s haven’t even heard of the movie! My wife and I say “As you wish” to say I love you sometimes-- :slight_smile:

It’s similar to Anne of Green Gables for quotes.


(Raymond Isbell) #332

While catching up my reading list, I finally got back to Stephen’s recommended paper titled “Mitotic-Exit Control as an Evolved Complex System.” (https://www.cell.com/fulltext/S0092-8674(05)00347-8) Concepts from this paper seem to capture some of the thoughts that we’ve been addressing in this discussion.

An informing quote comes from the first section titled “Top-Down Design vs Evolutionary Engineering.” It says, “Simple systems, even complicated ones, can be decomposed into modules or pieces at all scales. An automobile or modern jet aircraft, as complicated but noncomplex systems, can be understood as the sum of their subsystems: the computers, the engine, braking systems, the flight stabilizers, and other major subsystems all have a clear function in the whole. Each of these can also be broken down and understood in terms of yet smaller components, down to the most basic mechanical and electronic parts. Viewed from the design perspective, this complicated system can be put together by many engineers, each working independently on separate components according to a master, top-down design plan. Traditional engineering design depends on this top-down, modular approach and the decomposability of the system. The system must perform precisely as the sum of all the components: it is designed under this assumption.”

It then says, “Complex systems generally cannot be decomposed and built this way. Attempts to do so have met with spectacular failure.”

I completely agree, although with one exception, and that’s when Jesus Christ is the designer. Rumor is that he’s an exceptional design engineer. I would also expect that he uses a “top-down design” for the Cell since it’s not so complex that he can’t do it. I’ll even bet that he gets it right on the first pass.

The paper goes on to propose that “evolutionary engineering” can achieve what the “top-down design” approach cannot. While it’s recognized that complicated systems (the paper distinguished between a complicated and a complex system, but doesn’t identify the threshold where one ends and the other begins) can be decomposed into it’s component parts, the paper suggests/declares that complex systems exhibit function that is more than the sum of its parts, and concludes that “Complex systems generally cannot be decomposed and built this way.” The paper illustrates its point by contrasting the failed US Air Traffic Control System back in the 1990’s with the global internet of today that has incrementally grown as many different users and developers have constructively added capability over time. New capabilities that were never envisioned by the original architects are showing up daily. Thus, “evolutionary engineering” is the best approach for complex systems. (I don’t agree.)

The FAA system is supposedly an example of how a complex system employing a “top-down” design (systems engineering at its best?) has limits especially with “emergent” capabilities that are beneficial but not foreseeable. The global internet in contrast is used to illustrate “evolutionary design” that grows not by grand design, but by incremental small local improvements that improve the overall system thru natural selection. If a local improvement fails to improve a sufficiently large segment of the internet so that its cost of development and operations exceeds its value to the larger system, it will die. The reason is that it won’t generate sufficient revenue to its developers/operators to generate a profit. It will be removed by its developer(s) at the request of its investors to save money. Thus, the global internet earns its label as an “evolutionary design,” at least at a superficial level.

But let’s look a little closer. Things may not be as they appear. The contrast between a “top-down design” and “evolutionary engineering” has some hidden assumptions that may not be obvious on a first reading. In the FAA illustration, the designers are fallible human beings who don’t do well with complexity. They are easily confused, loose track of important details, lose sight of the forest for the trees, cheat, lie, and steal, and generally are inept when dealing with complex designs. Most importantly, they can’t anticipate “emergence” or “synergy” easily. Thus, if humans are the designers, it is easy to conclude that “top down” designs can’t explain complex systems, especially for the Cell.

If, however, the designer is Jesus Christ, we may need to reassess our conclusion about “top down” designs. When I get to heaven, my first request is to visit the Lord’s technical library where He keeps all His design documents. I want to see the document titled “First Eukaryotic Cell.” Then, I want to see the Change Documentation for the Fall, i.e., when Adam and Eve ate the apple, how did He change the design? I assume also that he has an amazing video library. I’ll want to watch the creation in Gen 1, the Flood, the Exodus, etc. The list of documents and videos I will want to see is endless. It may be a little weird, but that’s my idea of heaven, viz., to review engineering documentation. (Yes, I need therapy!) Can you imagine my disappointment if He says, “Sorry, no design; I just put together some solids, fluids and gases, tossed in few rules, shook it and came back in a few billion years to see if anything came out of it.” To his surprise, he finds a bunch of humans drinking beer and arguing over where they came from!

On the “evolutionary engineering” side, when we look closely, we see an implicit assumption that is questionable. The example, the global internet, may not be a good analogy for the Cell for an important reason. Natural selection for the global internet works at the level of App that can be connected to the internet easily with no potential for harmful effects. There are many changes being introduced daily in the sense that any user can develop and insert a new capability at any time without coordination with other users. The “random change” element of the “evolutionary engineering” model finds its home in a very simple and non-destructive activity, viz., develop an App, connect it to the internet, let the search engines find and expose it, and let social media praise or kill it. The “natural selection” component is provided by the market place filtering out the unfit/unprofitable. On the surface, it sounds like evolution in good form. But is it a good analogy? I say no. Let me explain.

What’s the difference between the FAA systems and the global internet that should make us take a step back and reflect a bit? The component parts of the FAA system follows the description of a complex system identified by INCOSE , viz., “systems with rich interdependence among diverse components, non-linearity, open systems boundaries, networks of causality and influence (vice linear causal chains), emergence, varied and changing system goals, self-organization, and multi-level adaptation.” I need to emphasize in particular the attribute of “rich interdependence.” Does this apply to the global internet? For the internet developers of new Apps can develop independently, publish a link so that others can find it, and sit back and watch market forces go to work. But what if there’s extensive interdependence between every new App and many of the internal functions of the internet? If that were so, then every App developer would have to coordinate with the global internet staff of function managers to determine if their App will indeed connect without being destructive. This, of course, is the bane of “top down designs.” We wouldn’t have the internet today if that were the case.

Now we need to ask the question: “Which is the better model for the Cell?” Can we say that every new protein or group of proteins coming from a random gene/allele mutation is like adding an App to the internet? If so, we’d have to admit that the cell is virtually insensitive to the new resulting proteins coming from those mutations. Can we say that? If not, then the global internet analogy as a complex system exhibiting “evolutionary engineering” is not a good one.

This takes us back to the question of the which applies best to the Cell, does it reflect a “top down design” or “evolutionary engineering?” The answer seems to hinge on the sensitivity of all the Cell’s proteins to a new one coming from a mutation. So far you guys claim that the Cell is more like the internet analogy where changes to a protein are not destructive. That, of course, implies that you don’t see “rich interdependence” between the Cell’s proteins. Of course, you claim that RFR overcomes the potential destructive effects of mutated proteins. If that’s the case you have good evidence to support it, right? How many proteins in the Cell have been observed, measured, and published to demonstrate this insensitivity (by RFR). If only a few, is it fair to claim its universal in the Cell? If that were the case, I wonder why Doug Axe’s paper (JMB-2004-341, 1295-1315) shows the Cell to be very sensitive? If I recall correctly, as he mutated a specific protein, it became non-functional very quickly. From that he inferred an estimate of the prevalence of functional protein sequences at the level of one in 10^77.

Maybe I’m over simplifying, but your apparent assumption that the Cell’s proteins are insensitive to changes in other proteins resulting from mutations of nucleotide bases in the genes/alleles is not a good one. If indeed it is a bad assumption and the Cell exhibits the kind of complexity described by INCOSE (rich interdependence among diverse components), then “evolutionary engineering” cannot happen.

Hopefully, we’re not back where we started. I saw the internet analogy as a really bad one, so I decided to try and say why and see what you think. I’m sure you’ll push back and claim that protein interdependence is there, but because of RFR the destructive effects are eliminated. Thus, the “evolutionary engineering” and its internet analogy are legitimate. Perhaps, but if the interdependence came first before RFR, how did the mutations not destroy the Cell long before RFR appear? Mutations work against RFR ever coming to the rescue. Of course, if you reject interdependence of the proteins, then the internet analogy works. But then you wouldn’t need RFR, and it would never evolve.

What say you?


#333

@Raymond_Isbell Way back at post 26 Stephen posted a couple of links on protein diversity that showed this was in fact already known to be a good assumption. In the torrent of reading material suggested perhaps you missed it.


(Stephen Matheson) #334

Hundreds, perhaps thousands across the tree of life.

No one ever claimed that, and we’ve been over this before.

His paper doesn’t show that, and isn’t about that. In another paper, he showed that one enzyme could absorb wholesale mutation and amino acid replacement with frequent sparing of activity.

You’re not just oversimplifying. We don’t need to make assumptions about robustness, and no one ever claimed that all proteins are insensitive to changes. This is maybe the fourth time this has been told to you.

Might there be a problem with how you are approaching the topic? Are you reading to understand? It looks to me like you aren’t trying to understand at all.


(Raymond Isbell) #335

Actually I did read as much as I could. Some of the references required fees that I’m not ready to invest in at this point. The Abstracts, however, were interesting, and are part of what has prompted me to keep pushing back. The papers recognize the sensitivity problem, and even recognize the potential conflict with evolvability. The paper from Science - 21Feb2014: Vol 343, Issue 6173, pp. 875-77 not only recognizes the problem, but admits to gaps in their understanding, viz., “The variation in genetic sequences determining the binding of transcription factors is believed to be an important facet of evolution. However, the degree to which a genome is robust, that is, able to withstand changes and how robustness affects evolution is unclear

What this is telling me is that robustness is an adjective employed to describe an end effect (cell resists self-destruction when a mutation occurs) while at the same time it is not well understood. The conclusion of the paper was that transcription factor binding seems to have a beneficial effect so that cell sensitivity to mutation was reduced. This and other evidence seem to confirm to you and others in this group that evolution is more akin to the global internet analogy than the “top down design.” In my mind, it says the opposite and suggests that design is a better explanation for the simple reason that the apparent Fault Tolerance built into the cell via transcription factor binding and likely other mechanisms are hard problems. In my world hard problems are rarely solved by random actions. Hopefully, you can see the challenge this narrative poses.

I also noted in my previous post that robustness no doubt evolves in per your narrative, which means that without the robustness there in the first place, the cell will be much more sensitive to mutations that in turn will resist its evolution to the more robust state where mutation could gain the insensitivity it requires to become insensitive. The problem seem doubly hard under the evolution scenario.

As I said before the ID likelihood estimate of getting a single functional protein out of a sequence space of 150 amino acids which is currently (their model) 1 in 10^154 is grossly underestimated. When you start to consider all the addition proteins that must be in place and working in coordination with perhaps as many as 1000 other proteins along with even more proteins with Fault Tolerance function (proteins that give it RFR), it seems so unlikely that it’s hard to imagine how anyone can believe something like that. How can you can believe something like this can occur by chance? What am I not seeing?


(Raymond Isbell) #336

Has a full map been developed to show the genes links to their proteins and array of functions including those that provide the Fault Tolerance (RFR) needed? If not, then how can you be confident evolution is the best explanation. How do you rule out design?

I’m reading them, and in some cases, several times. Instead of explaining or justifying your conclusions, they seem to be making the case for design even stronger. See my last post. I’m clearly missing something that you’re seeing and I’m not. The concepts in the papers seem straight forward enough, but something is missing. I’m not willing to give up yet.


(Stephen Matheson) #337

Because evolution as an explanation does not depend on knowing everything about “RFR” for every protein. This is now the fifth repetition of that.

I think it’s more likely that you approach the topic freighted with huge assumptions and preferences that don’t fit (or are outright wrong), so you can’t understand even the broad themes much less the specific facts and knowledge that matters. For example, you seem completely committed to “design” as being completely the opposite of evolution. You are committed to a specific, narrow, and flawed view of how “design” applies to cells. And while you pound on those square pegs in hopes that they’ll fit into round holes, you neglect the work it will take to understand very basic concepts in biology (what proteins are, and what mutations are, and the meaning of variation, and the meaning of robustness as it is being used by all of the biologists in this conversation). I can’t tell whether you intend to ever do the work. I don’t see the point of continuing to revisit your misconceptions, especially when they have come back 3,4,5 times.


(Stephen Matheson) #338

That quote is from the general summary of the paper, and the authors are using it to point to the knowledge gap that they are about to fill. I think your citation of it here is potentially misleading. Thought you’d want to know.

Oh dear. That’s really far off. “Resisting self-destruction” isn’t a topic at all in that paper. Do you think that’s what we mean by “robustness?” Because it’s not.

What the paper shows is that large gene expression networks are more robust to small changes, and then shows that the nature of these networks (in mammals and yeast) are such that both evolvability and robustness can coexist.

Look, that paper is pretty technical, and I think it would be unreasonable to expect you to understand it. I know that you are lacking a lot of basic biological fluency, which merely reflects your finitude (who has the time to read everything?) and your background, which seems to involve almost no biological problem-solving or analysis. I think some of the review articles that I pointed you to might be better places to start. But there is no way forward for you that doesn’t involve learning the basics of biology.

Robustness to mutational change is a fact of biology. We know a lot about how it works (the HSP90 subfield is absolutely remarkable), and yet there is much we don’t know. If you find yourself doubting robustness to change in cells, then you should take that as an indication that you still have a lot of basic stuff to learn.


(Raymond Isbell) #339

I keep asking because I don’t get a coherent answer. Instead I get a lot circular reasoning. RFR is present to protect the cell from destructive mutations so that evolution can happen. Where does RFR come from? Evolution! You’ve completed the circle.


(Randy) #340

I think you have to look at other evidence for evolution to put it all together.


(Raymond Isbell) #341

Time will tell. Thanks for the encouraging tone.


(Randy) #342


Another favorite quote–