Stepwise evolutionary pathways to highly specific protein binding partners. That seems imposs--

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The context here is a protein-evolution scenario that seems to be near a frontier of accessibility via standard Darwinian mechanisms. They’re called orthogonal binders defined this way in the abstract of a new paper in Cell Systems: “Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs.”

This seems a candy store for (say) a scientifically-trained person engaged in (and paid for) motivated reasoning and safely insulated from the scientific literature. After all, it is (IMO) hard to imagine–at first blush–how two proteins could evolve, together, to bind each other with such high specificity that their close relatives are excluded from the conversation. It gets comically worse when/if we trot out a scenario in which the partners would need nearly 20 mutations to get to their happy place, and we can make the whole thing seem literally impossible by stipulating that every step in the trajectory has to result in a fitness increase. Yo, evolution, let’s see you do that!

Evolution: :man_shrugging: Okay!

Abstract:

Some protein-binding pairs exhibit extreme specificities that functionally insulate them from homologs. Such pairs evolve mostly by accumulating single-point mutations, and mutants are selected if they exhibit sufficient affinity. Until now, finding a fully functional single-mutation path connecting orthogonal pairs could only be achieved by full enumeration of intermediates and was restricted to pairs that were mutationally close. We present a computational framework for discovering single-mutation paths with low molecular strain and apply it to two orthogonal bacterial endonuclease-immunity pairs separated by 17 interfacial mutations. By including mutations that bridge identities that could not be exchanged by single-nucleotide mutations, we discovered a strain-free 19-mutation path that was fully functional in vivo. The change in binding preference occurred remarkably abruptly, resulting from only one radical mutation in each partner. Furthermore, each of the specificity-switch mutations increased fitness, demonstrating that functional divergence could be driven by positive Darwinian selection.

Here’s a great paragraph from their Discussion (the paragraph before it is also excellent and clear):

A key question in the evolution of orthogonal binding pairs is how ultrahigh specificity evolves by a single-mutation trajectory without crossing a fitness valley. Our results provide a case-study in which each of the specificity-switching mutations are not only tolerated but may endow their host with a selective advantage relative to the parental population due to functional asymmetry in the interacting pair, as in a toxin-antitoxin system. This polarizes the function-altering evolutionary process, increasing the likelihood of selecting a long series of mutations, whereas the reverse mutations are counter selected. In other words, the functional asymmetry in the toxin-antitoxin system suggests preferred directions for the evolutionary process depending on specific environmental conditions.

They make the main caveat clear:

An important question that is left unanswered by our study is how general the observations we made here are to the emergence of novel protein-protein interactions. Only very few previous studies reconstructed mutational trajectories at the single-mutation level, and unlike our results, they demonstrated multiple paths that go through generalist or promiscuous intermediates that bind both extant partners. The abruptness of the functional transition that we observe may be due to the properties of colicin endonuclease/Im pairs, including high specificity barriers, high affinity, and functional asymmetry. Although these properties are extreme in colicins, we hypothesize that they are not unique to them or even to toxin/antitoxin systems and that they are likely to be typical of high-affinity and -specificity receptor/ligand systems where functional insulation is essential.

Evolution is easy, my friends.

Paper is open access, even in Seattle:
https://www.cell.com/cell-systems/fulltext/S2405-4712(25)00095-X

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Evolution says, “Hold my beer!” :clinking_beer_mugs:

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Michael Behe: [nervously sweating and silently grumbling]

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Wishful thinking!

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This is not what the story of HCQ resistance in Malaria nor Lenski’s LTEE experiments are telling us, not at all.

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Are you accusing these scientists of lying about what they observed in their lab?

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No single example or experiment really tells us broadly about evolution. That’s as much of a problem for both creationists or evolutionists aiming to extrapolate from such individual cases to broad patterns of evolution.

It is definitely the case that some things are more difficult to evolve than others, and that the environment and selective schemes, and the genetic background of the organisms, all matter with respect to how easily any particular thing evolves.
Just to pick an example the Cit+ phenotype evolved more easily in Scott Minnich’s experiment because they employed a different selection scheme that much more strongly rewarded intermediate mutations. Weirdly creationists have been trying to spin that result as incomprehensibly being a problem for evolution. Which literally doesn’t make logical sense.

Another interesting example experiment that seems to defy a lot of recent creationist rhetoric about “reductive evolution”, is from the Ratcliff lab where they’re working on experimentally evolving multicellularity. They have found the curious result that selecting for increased organismal size has favored and stabilized whole genome duplication in all replicate cell lines in the experiment:

Abstract

Whole-genome duplication (WGD) is widespread across eukaryotes and can promote adaptive evolution1,2,3,4. However, given the instability of newly formed polyploid genomes5,6,7, understanding how WGDs arise in a population, persist, and underpin adaptations remains a challenge. Here, using our ongoing Multicellularity Long Term Evolution Experiment (MuLTEE)8, we show that diploid snowflake yeast (Saccharomyces cerevisiae) under selection for larger multicellular size rapidly evolve to be tetraploid. From their origin within the first 50 days of the experiment, tetraploids persisted for the next 950 days (nearly 5,000 generations, the current leading edge of our experiment) in 10 replicate populations, despite being genomically unstable. Using synthetic reconstruction, biophysical modelling and counter-selection, we found that tetraploidy evolved because it confers immediate fitness benefits under this selection, by producing larger, longer cells that yield larger clusters. The same selective benefit also maintained tetraploidy over long evolutionary timescales, inhibiting the reversion to diploidy that is typically seen in laboratory evolution experiments. Once established, tetraploidy facilitated novel genetic routes for adaptation, having a key role in the evolution of macroscopic multicellular size via the origin of evolutionarily conserved aneuploidy. These results provide unique empirical insights into the evolutionary dynamics and impacts of WGD, showing how it can initially arise due to its immediate adaptive benefits, be maintained by selection and fuel long-term innovations by creating additional dimensions of heritable genetic variation.

The cells now have double the genome size than when the experiment began. Population genetics implies that this expanded genome must be under more relaxed selection, possibly facilitating more constructive neutral evolution going forward. It will be very interesting seeing what comes of this experiment in the future.

Other curious products of this experiment already, is that the multicellular colonies have evolved massively increased toughness:

We are currently running a Lenski-inspired Multicellularity Long Term Evolution Experiment (MuLTEE), which we hope will continue for at least the next 25 years. So far, we have currently put snowflake yeast through >1,000 rounds (~5000 generations) of selection for larger group size, evolving multicellular yeast that are ~20,000 times larger than their ancestor. These individual snowflake yeast remain clonal and are visible to the naked eye (larger than fruit flies). They have accomplished this feat through sustained biophysical adaptation, evolving far more elongated cells that ‘entangle’, increasing their mechanical toughness by over 10,000-fold. Individual snowflake yeast evolve from being weaker than gelatin, to as strong and tough as wood. You can read more about this work here. In this system, we are investigating the genomic causes and consequences of multicellular evolution, the origin of multicellular development, emergent fluid flows, and are examining how multicellularity becomes entrenched, preventing reversion (see current projects).

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No, not at all. I was replying to @Nesslig20 post at 3.

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Oh, OK. I think you are probably right. Behe has nothing to worry about, since his fans and followers are completely incapable of understanding scientific evidence. For example, when a paper was published on the evolution of choloroquine resistance in malaria that completely refuted his claims in The Edge of Evolution, Behe brazenly lied about this and said it was actually a vindication for him! And, even more incredibly, most of his followers simply believed him.

A Key Inference of The Edge of Evolution Has Now Been Experimentally Confirmed | Evolution News and Science Today

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You’re not familiar with either story. If you were accurate, you would have stated, >‘This is not what Mike Behe [who has zero experience in either field] tells credulous laypeople like me, who are unwilling to go beyond hearsay to evidence.’

Try engaging with the evidence YOURSELF, Gilbert. It tells a very different story.

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I can’t get the full article. What magnitudes of affinities are they studying?

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You’re completely right. Behe will probably not even bother and just ignore all of this like usual.

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Can you specify why you think the paper you are referring to on the evolution of chloroquine resistance refutes Behe’s claims in the EoE?
I’ve read the piece at EN you’ve pointed to but could not find anything in it supporting your claims.

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Of course you couldn’t. That was Behe’s intention: To confuse and mislead people who lack understanding of evolutionary biology and who share Behe’s ideological bias towards a worldview in which God directly and observably intervenes in the physical world. Let no one deny that Behe is an excellent propagandist.

Here is good summary of why that paper was very bad news for Behe:

Sandwalk: Understanding Michael Behe

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Oh shoot, sorry to everyone about that. The paper was OA when I read and posted, but it isn’t now (it was probably a “Featured Article” that is free for a time.) Now I can’t get the full text either, and I didn’t save the PDF when I had the chance. If anyone has access and can send me a copy, I’d be grateful, otherwise I have a library trip planned for the weekend. Again, sorry about that. My habit is to write about OA papers or, when they are paywalled, to offer to provide a PDF to my PS friends.

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This is a great point, completely true and clearly stated.

Let me assure my fan base that my book and ongoing work on Evolution Is Easy will endeavor to make it clear that I’m not advancing some silly shallow “law” of evolution or anything else, and I hope (perhaps with your help) to avoid giving anyone the impression that evolution is a singular thing that can be labeled “hard” or “easy” or whatever comes between those descriptors. What I do want to write about is this: many (or perhaps all) of us are prone to thinking (feeling, more accurately) that evolution is hard, when in fact we can see through examples (like the one in this post) and through reflection that it is far easier than we think.

But still: thanks to @Rumraket for that calibration. He gets a free copy before the 2035 release date. :sweat_smile:

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Coincidentally, for me as someone completely outside of these fields, I recently began wondering about discussions I recall from the 1970’s (the last time I did much study of biology) on the relatively difficult-to-evolve (?!!) ability of some organisms to degrade and utilize lignin. So yesterday I did my version of a “deep dive” to update my knowledge and see what had been learned in the past half century. I was blown away as I came upon these concepts:

(1) Lignin’s amorphous and branching structure makes it physically difficult for most enzymes to cleave and process.

(2) The LMEs (lignin modifying enzymes) found in white-rot fungi was a major evolutionary leap.

(3) Their use of free radicals, such as those involving manganese, suggest very complex and long evolutionary pathways.

(4) Some suggest that there was a “lignin gap” in the Carboniferous Period when many plants developed high lignin content for support but there weren’t yet a lot of organisms around which were capable of decomposing those lignins. And this likely helped form coal deposits relatively quickly, as compared to later times when white-rot fungi came along and reduced coal formation.

(5) There was a resulting “arms race” between lignin-producing plants and the microbes which were evolving better pathways to break down the lignin.

Now, as an untrained layperson I hope I managed to get most of that right. In any case, I came away with a new appreciation of just how powerful evolutionary processes can be. I will confess that that even this recent study makes me very prone to thinking in terms of “easy” versus “hard” evolutionary steps—so I’m very interested in what you are saying. (And I certainly believe you!) So your book title Evolution is Easy intrigues me.

As a layperson, I will never write a book on these topics. But if I did the title would probably simply be Evolution is Cool! I just think evolutionary processes, however easy or hard they may be, are most definitely amazing.

Of course, I also can’t help but reflect on how little “creation science” helps explain any of this. I’m not just taking a cheap jab. I’m reflecting on many years dealing with the Young Earth Creationist community.

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It was great, and super interesting. Lignin is one of the case studies in Andreas Wagner’s most recent book Sleeping Beauties (which is worryingly close to “evolution is easy” but what can ya do). You might enjoy a piece he wrote at the Guardian on those topics.

Among the many sources of inspiration (for me) are:

  1. The discovery in the mid-20th century of unexpected and vast diversity/variation in proteins. This scientific and historical fact remapped my thinking about proteins and genes, from fixed points in conceptual space to clouds. That in turn remapped my vision of evolutionary exploration from “point-to-point” to “cloud-to-cloud.” For me, that was a big change.
  2. This review article on protein evolution (by Joe Thornton and others) dismantles, step by glorious step, the belief that protein evolution is nearly impossible.

The wild truth is that a person who believes the earth to be spectacularly young is a person who must embrace evolution that is spectacularly fast. And if you need evolution to run at blinding speed, you need either supernatural help or… you need it to be easy.

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Wow. That makes so much sense. What a great “remapping.” For me it immediately brought to mind the spectacular time-lapsed agar petri dish video where bacteria are dealing with increasing antibiotic concentrations. Just in case we have a visitor on PS who has never seen it:

That Sleeping Beauties article is spectacular. Growing up farming–which included baling hay and managing grazing cattle and sheep–I was particularly struck by this:

Why did grasses have to wait 40m years for their proverbial spot in the sun? This mystery deepens once you know that, early on, evolution endowed grasses with multiple survival-enhancing innovations. Among them are chemical defences like lignin and silicon dioxide that grind down the teeth of grazing animals. These features also protect grasses against drought, as do sophisticated metabolic innovations that help them conserve water.

I was well aware of the lignin and sand content of hay—we tended to speak of sand rather than silicon dioxide or the old-timers would have thought us odd—but I had never stopped to consider that both are evolved defenses against grazing animals. (I should have figured that out.)

A quick Gemini search explained to me:

Grasses (and many other plants, but especially grasses) are known as silica accumulators . They have evolved specialized transport mechanisms in their roots to absorb dissolved silicic acid (H4SiO4) from the soil water. * * Once inside the plant cells, the silicic acid polymerizes and deposits as solid, amorphous silica bodies called phytoliths (from Greek, “plant stones”).

  • These phytoliths form in various shapes and sizes within the cell walls, epidermal cells, and other tissues. They are literally microscopic, rigid, and abrasive particles within the plant’s structure.
  • Evolved Defense Mechanism:
  • These internally produced phytoliths serve as a powerful physical defense mechanism against herbivores:
    • Abrasiveness: When a grazing animal (like a cow, horse, or even an insect) chews on grass containing phytoliths, these silica bodies act like tiny shards of glass or sandpaper. They abrade and wear down the teeth of grazers, especially the enamel.
    • Reduced Digestibility: The presence of silica can also make the plant tougher and less digestible, reducing the nutritional value the herbivore can extract from a given amount of forage.
    • Discomfort/Damage to Mouthparts: The abrasive action can cause discomfort or even damage to the animal’s mouthparts and digestive tract, discouraging excessive grazing.
  • This is an evolutionary arms race: As grazers evolved stronger teeth to handle tough grasses, grasses evolved to incorporate more silica to make themselves less palatable and more damaging to the grazers’ teeth.

On the farm we considered the sand primarily a mechanical contaminant. But we were also aware that there was silica somehow incorporated into the hay (but didn’t know much more than that.) I recall very tedious/laborious sharpening of the blades on the saw-tooth long-blades (perhaps five feet long) of our old 1950’s hay mower. Mowing hay—in our case a mixture of bluegrass, brome, clover, and timothy grass—was sometimes likened by the Purdue University agriculture professors as “cutting a field of tiny glass shards.” And that is certainly a well-evolved defense against anything chomping/cutting into a field of grasses.

Thanks for giving me a dose of education today.

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One aspect of that study that is not often mentioned: There were bacteria that evolved even stronger resistance to the antibiotic, but these strains simply died out without spreading in the population. The reason: They had arisen in the middle the section, rather than at the border where they would have encountered a higher concentration of antibiotic. Therefore, their resistance did not provide a selective advantage.

At a single stroke, this refutes two canards often raised by anti-evolutionists: That adaptations are exceedingly difficult to evolve, and that they arise thru teleologically driven “intelligent genetic engineering.”

Spatiotemporal microbial evolution on antibiotic landscapes - PMC

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