Reaping the Whirlwind: protein function without stable structure


(Stephen Matheson) #242

Heh, yeah, the converse is true too; I think I mentioned elsewhere in the thread the travails of biologists making the first mouse knockouts. So many of them had no phenotype that one journal (MCB) created a section devoted to papers that reported on knockouts with no phenotype: “Mammalian Genetic Models With Minimal Or Complex Phenotypes.” The unwelcome message was that mouse genetics and physiology are so robust that you can delete an entire gene, one that had been shown unequivocally to be involved in a specific developmental process, and yield no discernible effect on the animal.


(Jay Johnson) #243

Interesting? I’ll be the judge of that! haha

I hope @Raymond_Isbell doesn’t take this as a rebuke. I credit him for at least wanting to understand. This is more of a general observation. Anyway, I’m always fascinated by the fact that people almost never take the opportunity to ask questions and learn from you guys – actual experts in the field. Instead, they’d rather argue than learn. Amazing.


(Dennis Venema) #244

It’s also often the case that an enzyme can retain its function even when significantly “trimmed” of amino acids.

Heck, there are even examples of vertebrate genes functioning in place of their invertebrate orthologs (“equivalents” for the non-biologists) despite what, a few hundred million years of divergence?


(Stephen Matheson) #245

Indeed, consider this excerpt from a paper published in 1996, about an enzyme that can still function after having its core scrambled (amino acid-wise). You might recognize this work.

The central structural feature of natural proteins is a tightly packed and highly ordered hydrophobic core. If some measure of exquisite, native-like core packing is necessary for enzymatic function, this would constitute a significant obstacle to the development of novel enzymes, either by design or by natural or experimental evolution. To test the minimum requirements for a core to provide sufficient structural integrity for enzymatic activity, we have produced mutants of the ribonuclease barnase in which 12 of the 13 core residues have together been randomly replaced by hydrophobic alternatives. Using a sensitive biological screen, we find that a strikingly high proportion of these mutants (23%) retain enzymatic activity in vivo.


(Dennis Venema) #246

Well played, sir. I did recognize it, indeed.


(Mervin Bitikofer) #247

Would you say more about this? Does it mean that the same developmental process managed to occur just fine via other pathways in the absence of the removed gene? The reason that surprises me is that (to my simple ‘understanding’ of all this) the only way we could test to see if a gene was involved in a process would be to remove it and then see if the process was affected. Hence my mental hiccup here.


(Stephen Matheson) #248

Oh, sure, sorry, yes that must seem paradoxical. The best (now classic) example is a protein called MyoD. A wealth of data from the 1980s and early 90s had established the protein as a “master regulator” of muscle development. You could put the gene into a non-muscle cell and turn it into a muscle cell. It worked on numerous cell types, and it became a classic discovery in developmental cell biology. Such “master regulators” seemed rare, and it was (and still is) remarkable to find a single protein that could exert such an effect.

Then in 1992, the shocking discovery: deleting the gene from mice caused… nothing. Muscle development was normal. There was a hint of an explanation: another gene was turned up in the mice, and we now know that MyoD and that other gene (Myf5) are redundant and work together to induce muscle. This was confirmed the next year when biologist removed both genes and saw the failure of muscle development that they predicted in the MyoD knockout.

So: MyoD was known, correctly, to be involved in muscle development, indeed to play a central role in starting the whole muscle development program. But its function is almost completely redundant with that of another gene.


(Raymond Isbell) #249

Thanks Jay for the reference. I read it and agree with it completely. Also, I see no conflict between what it says and what I say. Consequently, I find it strange that you see my paradigm as incorrect. Simply looking at the sub-systems of a larger system-of-systems does not say that a reductionist approach is invalid. In my MSEE thesis, I discovered a new approach to managing turn-off energy loss in a power switch by first reducing a class E amplifier to understand how it worked and then applying that knowledge to a different problem. It was published in the IEEE Journal of Solid State Circuits back in the 1980s. My first step in analyzing any problem is to decompose the problem into smaller and understandable parts. It works well. Sounds like you’re claiming that understanding of a complex problem can’t be helped by understanding its component parts and their integrated function.

I could not disagree more with the quote above. Lower and higher levels of a system inform each other. Many researchers, myself included, search the literature as part of our research to see how concepts of lower level function have been integrated into successful higher-level functions to help us understand what you call “emergent properties.” It is hugely informing, and helps one see the “possibilities.” When I observe a higher-level function that I and others don’t understand, I employ a reductionist approach to examine each of the sub-functions to try and understand how they contribute. The discovery process often involves the going back and forth from the high levels to the low levels. That’s how you learn that a lower level function integrated with other lower level functions can produce something new (a researcher’s dream). Your reference called this an “emergent property.” Thus, your claim that my paradigm is incorrect suggests to me that we may not understand each other. Emergent properties in my mind do not suggest that SE is not a useful approach or may give a researcher a false view about biological systems. The James Tour paper (Open Letter to My Colleagues - https://inference-review.com/article/an-open-letter-to-my-colleagues) provided to us by Randy provides an important illustration of the “reductionist approach.” Tour’s conclusions fully illustrate and, in my mind, support my view. I think my point and argument strategy is consistent with Tours. His conclusion that life should not exist anywhere in our universe results from his assessment of the difficulties of many of the lower level chemical processes that he sees as wildly improbable when viewed from a reductionist perspective. Do you think his assessment is wrong? His (and many other very smart scientists) view of evolution is that it is a dog that won’t hunt. I’m in the same boat, but I have to admit that I haven’t looked at the evolution side carefully. That’s why I am in this forum. I want to understand your thinking. Yours, Stephen’s, Dennis’ and others’ comments sound like you’re appealing to magic instead of good science. You observe things that you don’t understand and tell me that SE is not valid because the Cell is different. Yet you’re sure that evolution is the mechanism that causes this observable that can’t be explained. Hopefully, you see my frustration. I’ve looked at all the references you’ve provided that you claim illustrate your points, but they’re problematic in that they appear to be begging the question. Lineage is an example in post #203 by Stephen. Some of the “facts” you offer as evidence are questionable. For example, the vestigial organs in whales, e.g., whale legs may have other explanations, e.g., bones to anchor muscles used for copulation. Can it be definitively argued that this latter explanation is false? If not, why then is it adduced as evidence for evolution?

A reductionist approach is the way of science. It observes, analyzes, hypothesizes, tests, and adjusts and repeats until tests confirm the hypothesis or you change the hypothesis. What we don’t do is assume your hypothesis is true and use it to argue a new hypothesis. That’s circular reasoning as you know. That’s bad science.

Rather than accuse you guys of bad science, I suspect that I just don’t understand what you’re trying to say about how we can conclude evolution is the cause. To me and my reductionist thinking, it doesn’t follow. What is it about the cell that suggests evolution is a better explanation than design. I hear lineage, RFR, language analogy, cell biology is different than human engineering, but nothing that I can verify scientifically without employing circular reasoning. I’m also seeing a lot of biological eisegesis. Would Tour agree?

A quick aside, there are a few points I need to make: 1) I use NDE because it reflects the modern view that recognizes DNA as the source of mutation. Darwin thought that acquired traits like strong backs from heavy lifting would be inherited. NDE sees mutations coming only from DNA if recall correctly. Not a big distinction, but NDE has 3 letters, and evolution has 9 so it’s easier to write. 2) Someone referred to me a Dr Isbell. I do not have a PhD in any discipline, only a MSEE though I’ve done most of the course work for the PhD. I’ve had many PhD’s work for me and most are very bright. The one drawback I’ve seen is that they tend to be narrowly focused. 3) Finally, I’m not partisan except to facts and good arguments. I have a good eye for circular reasoning that was developed in my theological training/learning. If evolution proves to be the better explanation, I’ll embrace it.


(Jay Johnson) #250

Well, everything in that post of mine was quoted from the article, so you could not disagree more with a quote from an article with which you completely agree?

We definitely don’t understand each other. I thought you might have heard of emergent properties, since it is something that engineers are aware of, such as in this article:
What are Emergent Properties and How Do They Affect the Engineering of Complex Systems?

Abstract: Emergent properties’ represent one of the most significant challenges for the engineering of complex systems. They can be thought of as unexpected behaviors that stem from interaction between the components of an application and their environment. In some contexts, emergent properties can be beneficial; users adapt products to support tasks that designers never intended. They can also be harmful if they undermine important safety requirements. There is, however, considerable disagreement about the nature of ‘emergent properties’. Some include almost any unexpected properties exhibited by a complex system. Others refer to emergent properties when an application exhibits behaviors that cannot be identified through functional decomposition. In other words, the system is more than the sum of its component parts.

I didn’t say SE wasn’t a useful approach. I was simply trying to get across the notion that even if you fully understood every subsystem and routine in the cell, you still would have an incomplete model, because the sum really is more than its parts in biology.

Yes, Tour’s assessment is wrong. He has a very specific objection to Origin of Life (OOL) studies based on his expertise in organic chemistry, and many people, including me, share his skepticism that science ever will solve the puzzle of life from non-life. However, he goes too far when he says that it is impossible for life to have arisen anywhere else in the universe. That might be true, but proving that negative is equally impossible. (We haven’t even finished looking in this solar system!) I respect Tour, but he steps outside his expertise, which he readily admits, when he talks about his issues with common descent and evolution. Tour is undoubtedly a smart guy, but as for the “many other” smart scientists like him, where are they? The landscape isn’t exactly crawling with James Tours, now, is it? Certainly, intelligent people can disagree, but when I see 98% of the intelligent saying “yea,” and only 2% of the intelligent saying “nay,” I’m pretty sure where my money is going. (Plus, I’ve read the arguments on both sides, and it wasn’t hard to make up my mind to join the 98%.)

This is a really good example of the trap that you’re falling into. The problem is that the “facts” keep piling up, and the “what-ifs” and “maybes” to explain them away keep piling up, as well. It’s taking the apologist’s approach to everything in a never-ending search for loopholes in the evolution story. It’s like Jesus saying, “Love your neighbor as yourself,” and the lawyer immediately asking, “And who is my neighbor?”

If you really want to try to learn about evolution, try reading it with an attitude of “Maybe this is correct,” rather than “This must be wrong.” I realize that it’s hard to suspend our own biases, but give it a try. Just a suggestion.

NDE is actually an outdated view, not the modern view. Trust me. Just say “evolution.”


(Raymond Isbell) #251

Wow! At first I thought you had me by the short hairs. Ouch. But after reading it again I see the answer. I thought those were your words (they weren’t in quotes) and that you were referring to my attempts at using SE, not the paper’s antecedent concept of emergent properties where the sum may be greater than what would be predicted from its parts or an outright new function emerges. Having read it again I agree with it especially in its context (not yours) with one exception which is why I recoiled when I read your text. It’s a simple change. Where it says, “…which prevents use of a reductionist approach.” I would change “prevents” to “limits.” I suspect the author would too if it were brought to his attention.

This is interesting. It appears you’ve never build anything where large sums of money or human lives depend on your being successful. If you had, you would know “what ifs” and “maybes” if left unaddressed cost lives, wreck careers, and destroy programs. One of the strongest attributes I consider when hiring a scientist is their awareness and approach to organizing and managing what they don’t know. Do they understand risk management? As I learn more about evolution, I’m really taken aback at how easily evolutionists accept an argument that favors their view, and how quick they push back on any argument that challenges that view. I watched Dennis Venema’s YouTube video today titled “Why I Accept Evolution (And Why You Probably Should As Well).” In it he outlined the argument for evolution, and illustrated it with the Whale narrative. One phrase that struck me as odd is what he termed “testable hypotheses.” One hypothesis was that modern cetaceans are descended from ancestral terrestrial organisms through a series of transitional forms. (The quality of “transitional forms” found so far is leaves room for doubt.) He makes a prediction that modern cetaceans “might” display vestigial structures during embryonic development. The test proposed is to compare cetacean and mammalian embryos. He offers only one interpretation of rear limb buds, and it’s not the bone anchor option. In my view if a test is considered to be a valid test, it must identify other potential outcomes, identify criteria by which outcomes would be assessed, and argue convincingly why non-selected outcomes are rejected, e.g, why would the bone anchor be ruled out. Instead, I heard an eisegetical narrative that shows favoritism toward evolution. I’m also a little puzzled at why you would call my approach to be careful, critical and complete as “falling into a trap.” Looks like you’re going to favor evolution whether it’s true or not.

I will listen to more of the pro-evolution videos and read the materials such as the Berkeley evolution series to ensure I’m being complete. As the horses are making the first turn the ID horse holds a slight lead. But the evolution horse is right behind it and making a lot of noise. I’m not sure who’s going to win yet, but there’s still lots of track left to cover.


(Randy) #252

Mr Isbell, my sincere thanks for watching the video that I suggested. There is no hurry from my perspective in bringing conclusions. Most of us on this forum were probably YEC to start with (I was) and I can tell you it took me about 10 years to come to a change in position; and at 47, I am still learning a lot more, especially over the last 3 years.

I think that the video probably seemed a bit under-evidenced in that area because of the need to keep things short. You might enjoy his book, “Adam and the Genome,” but also Lamoureux’ online videos, website and books (Evolutionary Creation; “I Love Jesus and I Accept Evolution;” or, “Evolution: Scripture and Nature Say Yes”; though the latter is perhaps more geared to those who are just starting, and less nuanced). Lamoureux’s Evolutionary Creation

I hope you don’t mind an introduction, but I Googled your name and found this nice website. https://www.returntotheword.com/Raymond-Isbell Congratulations on your lifelong dedication to the Bible and to learning.

I’m a family physician in Michigan. I grew up as a missionary kid in a wonderful, mostly Muslim (95%) country. I still have friends among those who live there and others who came to the US. I don’t consider myself a biologist or scientist, but have enjoyed my interaction with those here. I attend a wonderful, YEC Baptist church who accept me despite my views on evolutionary creation (though I don’t broadcast them so as to avoid causing stress). http://fbcfremont.com/. I regard many YEC Christians as having a deep knowledge of God from the Bible and living for Him, and while we disagree in some things, they frequently have a maturity that can teach me life lessons. Many of my family also are YEC.

Thanks.


(Jay Johnson) #253

I knew exactly what had happened as soon as I saw it, but the fact remains that you took great issue with it when you thought the words were mine, and no problem with it when the words were someone else’s. Them hairs are pretty short, however you want to slice em.

You presume more than you should. There’s a healthy skepticism, and there’s an unhealthy skepticism. I didn’t mention your “apologetic bias” by accident, and I’m not really trying to win a debate with you. I’m actually trying to help you out, for many have already walked the path you’re just now setting out upon.

As Pascal said, we must know when to doubt, when to submit, and when to judge.

How easily evolutionists accept an argument that favors their view? Really? You should take a look at @Joel_Duff’s blog, https://thenaturalhistorian.com/. I’ll let his work speak for itself regarding which group is more gullible.

Other than that, your dialogue with me is another example of what I mentioned previously, which is a missed opportunity. Why are you debating with me? I don’t even have a bachelor’s degree in biology. Meanwhile, you take issue with @DennisVenema’s video, when he has been interacting with you right here. Good goshamighty Joe Friday! Why don’t you take the opportunity to ask him directly?

Hey, Dennis, has anyone considered the “bone-anchor option” to explain whale rear limb buds?

See how easy that was?


(Stephen Matheson) #254

Disclaimer: I haven’t watched Dennis’ video. But I know him well, and I know what his purpose in discussing testable hypotheses, and so I know that the preceding is a mischaracterization of Dennis’ discussion. It’s so bad that it’s making me (and, I suspect, most others here) wonder about your intentions.

The point of a “testable hypothesis” is to advance a prediction (a hypothesis) that arises from the proposal that whales have ancestors with legs. The prediction is that the whales will show evidence of leg development, that is somehow suppressed during embryonic development. That prediction has nothing to do with whether vestigial legs do this or that, especially since the whales in question do not normally have legs. Even if the limb buds had a developmental “function,” the test would be a good one, since it is simply a prediction made based on the proposed shared developmental program. All of that other stuff that you claim makes a “good test” is spurious.

You missed the point of Dennis’ argument. Then, worse, you lapsed into your tired, disrespectful dismissal of the people on the forum. It’s tiresome and it’s not constructive and it’s a shame that you can’t figure out how to discuss ideas while listening to the people you are conversing with.


(Chris Falter) #255

This is a very interesting suspicion to voice, brother Raymond. I would like to ask some questions to help you reflect on the argument you made. I am not trying to cross-examine you; I just want to help you think through the reasoning process. Consider these questions a form of “stress test,” perhaps.

Why would you assume that the author of the statement, Ingrid Lobo, Ph.D. is so imprecise in her use of language that she really intended to say something quite different than what she actually said?

Do you think that successful scientists are very poor communicators who often say things in writing that they really do not mean? Is that your experience?

Curious, too, that the thing Lobo did not actually say but allegedly meant to say is, coincidentally, precisely your opinion of the matter. Is it possible that psychological bias may be at work in your assertion about that the author’s intention?

Yours,
Chris

P.S. Consider your assumption that the article’s author was male. Do you see how easy it is to read in assumptions that are inaccurate?


(Jay Johnson) #256

Sort of a digression, but sort of not … The discussion is starting to remind me of a couple of passages from Wittgenstein in On Certainty:

In certain circumstances we consider a calculation to be sufficiently checked. What gives us a right to do so? Experience? May that not have deceived us? Somewhere we must finish with justification, and then there remains the proposition that we calculate like this. (212)
If someone supposed that all our calculations were uncertain and that we could rely on none of them (justifying himself by saying that mistakes are always possible), perhaps we would say he was crazy. But can we say he is in error? Does he not just react differently? We rely on calculations; he doesn’t; we are sure; he isn’t. (217)

Basically, we accept the fact that checking must come to an end. Eventually, we must act on it.


(Raymond Isbell) #257

I was just answering your most recent challenge, and I also just saw the video. They’re related so I commented. This is an open forum so I feel it’s Ok to address the group, and that was my intention. I figured Dennis would see just as easily if I addressed it to him. I plan to look at more of his work and get his book, and compare it to those on the other side. By the way, if you (or anyone else) want to read a good book that’s objective, carefully reasoned and documented, I recommend the 2017 book “Contested Bones,” by Rupe and Sanford. I mentioned it once in this forum. Reading it will demonstrate you have an open mind as I do. My first loyalty is to the truth. The other sides are a distant second. I feel like a kid in a candy store being retired and able to look deeply into this stuff. I’m not taking any of this personally so the barbs do not hurt.


(Raymond Isbell) #258

The only clue is coherence and consistency with her larger message. Read it carefully, and you’ll see how “limits” is a better fit than “prevents.” I learned that from Bible study, i.e., to look for coherence and consistency. Helps me to identify “proof texting” and other deceptive hermeneutical practices.


#259

@Raymond_Isbell

Have you seen the YouTube video series which reviews this book?

When the first quote in the book has been taken out of context that is a red flag for me.


(Raymond Isbell) #260

You really need to chill. You’re misreading most of what I say, and you clearly have a “defensive” edge. Your characterization of my attitude toward folks in this forum is not true. This kind of debate like theology and politics is a full contact sport. Everybody gets knocked around and even bloodied every now and then. You need to watch the video. I thought it was a good representation of his position, but it seemed to be a youthful audience (not seasoned evolutionists). However, I saw weakness in his not mentioning other possible ways to interpret the embryonic evidence. Also, if the evidence is not conclusive which I think is the case for this video, be up front about it. Instead, he states that his and many other similar type evidences build a strong case for evolution. I disagree.

Finally, I really do believe that you guys do not understand systems engineering. You reject the fact that a complex integrated system-of-systems is sensitive to both the effects of individual sub-system changes and the effects of integrated performance changes based on a single mutation. There clearly is some Fault Tolerance build in (designed or evolved), but that has limits. Too much of it will have bad effects on system performance. One other quick thought. In the James Tour Open Letter to His Colleagues, he mentioned the role of saccharides as information-rich molecules. He says “Saccharides are information-rich molecules. Glycosyl transferases encode information into glycans and saccharide binding proteins decode the information stored in the glycan structures. This process is repeated according to polysaccharide branching and coupling patterns.11 Saccharides encode and transfer information long after their initial enzymatic construction.12 Polysaccharides carry more potential information than any other macro-molecule, including DNA and RNA. For this reason, lipid-associated polysaccharides are proving enigmatic”

This is where the C4 functionality (that SE demands) is found.

If I were doing biological research, this where I would focus. That’s where the secret sauce is hiding. SE tells me that! SE is yelling at biologists, but they are not listening.


(Raymond Isbell) #261

I haven’t but I intend to listen to it. Thanks. I like counter-views. It invites critical thinking. Thanks.