Stuck on you, biological Velcro and the evolution of adaptive immunity


I’ve been back from the Australian Health and Medical Research Congress, a 6 day research fest, for a couple of weeks now. However, my brain is still full with the heady delights of the work I experienced there. My students gave reasonably well received talks, and I have a whole grab bag of experiments to do now (or get my students to do). While there were many things that were of deep societal interest at the conference, one of the things that struck me most was a throwaway line in a lecture about cell adhesion. Nectin, a “molecular Velcro” that helps cells stick together is a member if the Ig superfamily.

To explain why it set a light bulb off in my head, and how the knowledge that molecular Velcro shares a structure with immunoglobulins throws deep insight into the evolution of the adaptive immune system, I will beg you patience and do a very brief review of the immune system first.

Animals have many defences against invading microorganisms, from simple passive barriers such as skin to the immune system. When we think of the immune system, we generally think of the adaptive immune system, and more specifically, antibodies. Antibodies are proteins that bind to specific molecules (usually protein or carbohydrates) on the surface of invading microorganisms. Antibodies can be secreted, like IgG, or membrane bound as well as secreted (like IgM). The antibody protein has a constant domain and a variable domain, with the variable domain binding to the microorganism. The adaptive immune system doesn’t come with a premade set of antibodies. When an organism invades, the section of the immunoglobulin gene that makes up the variable domain get shuffled around to make variable regions that bind with exquisite sensitivity to invading micro-organisms. Of course, this is highly simplified; see here for a more detailed explanation.

Explaining how the gene shuffling mechanism came about has been one of the triumphs of molecular immunology. A series of careful investigations and elegant experiments has shown that the rearranging part of the variable domain is due to horizontal transfer and incorporation of transib transposases into the immunoglobulin gene. You can read more about it here and here.

But now you can almost hear the ID folks sneering the in background “how very fortunate that there was a proto Ig molecule for the transposases to jump into, such a molecule would be functionless and could not evolve itself”. Not only could such a molecule have a function, it is part of a widespread family of proteins whose functions lend themselves to formation of the adaptive immune system.

In establishing that the adaptive immune system evolved, we need to show that there are plausible ancestors of the proteins involved in the adaptive immune system. One of the distinguishing features of immunoglobulins is a structural feature called the Ig fold, and if you read the literature on the immune system, you will learn that the immunoglobulins are part of the Ig fold superfamily, one of the largest families in the animal kingdom. But unless you are au fait with structural molecular biology, you will not know what the commonest role for these molecules is.

Basically, they are glue. The Ig superfamily is involved in cell-to cell adhesion and cell-surface adhesion. Sticking to things, or sticking to other cells, is a fundamental biological property that is found in the deepest cell lineages. In bacteria, the Ig superfamily proteins are cell surface proteins. In sponges, the Ig surface domain is fused to a common intracellular signalling domain, tyrosine kinase. This may surprise people, as most of us thing of glue as a passive thing, but the molecular glues are also active signalling molecules. In development, they help guide cells to their destinations, in phagocytes, the cellular scavengers that, amongst other things, engulf and consume bacteria; they help direct phagocytes to sites of infection.


Proteins with an immunoglobulin structure, taken from Pancer et al., 2004. The molecular glue nectin is shown in the middle.

While immunoglobulins have an Ig fold, they also have a distinct Variable-Constant domain architecture. In the genome of the sea urchin, we see the first signs of this architecture in a number of proteins. In the sea squirt, an invertebrate chordate, the Variable –Constant architecture is clear in two classes of adhesion molecule, nectin and Junctional Adhesion Molecule (JAM). Jam is pretty interesting, as in vertebrates its relatives turn up on white blood cells involved in immunity, and play a role in phagocyte movement during inflammation. Phyolgenetically, nectin and JAM are the molecules that are closest to immunoglobulins.

Let’s take a brief recap here. Molecules which have the same overall structure as immunoglobulins are involved in cells sticking to things, especially phagocytes and other immune cells, cells which engulf bacteria. What would we expect of a proto-immunoglobulin? A protein on the white blood cell ancestors of lympocytes that sticks to things? Right now these adhesive proteins are looking good as proto-immunoglobulins. It would be better if you could demonstrate that something like nectin could bind bacteria or viruses. Well, yes, nectin and related proteins do bind viruses. The viruses actually use this adhesion to their advantage, to gain access to the cell, but adhesion molecules can bind immunologicaly important microorganisms, which is an important proof of concept.

But wait, there is more! When Behe (and most of the ID community) write on the immune system, they ignore the innate immune system. The innate immune system is very old, much older than the adaptive immune system. It is present in some form in all metazoans investigated to date. It includes amongst its repertoire secreted proteins that immobilise bacteria in a sticky mass, and a series of non-rearranging receptors for bits of bacterial cell surface. In molluscs, one of the anti-parasite molecules is FREP, which has an Ig non-rearranging V domain at the business end. In the invertebrate cephalochordate Amphioxus, there is a family of very immunoglobulin like-molecules, Variable domain Chitin Binding Proteins, which are involved in innate immunity. In lampreys and hagfish, jawless vertebrates, there are Ig fold proteins that are almost the spitting image of modern rearranging immunoglobulins that are found in the equivalent of lymphocytes and are involved in innate immunity.


Precursors of an antigen specific receptor, taken from Pancer et al., 2004

So we have evidence for a pathway from simple adhesive molecules, to signalling adhesive molecules, to signalling adhesive molecules which help defence cells, to innate immune receptors. Behe (and other ID apologists) likes to give the impression that the all elements of the adaptive immune system had to evolve simultaneously, in one burst[**]. But as we have seen, by the time the transib transposases inserted themselves into the proto-immunoglobulin gene, these molecules had hundreds of millions of years adaptation to an immune function already.

And it all started with molecular glue.

* Such as the panel on Stem Cell research, which was conducted shortly before the parliamentary vote that removed restrictions on therapeutic cloning.

** One frustrating thing is that Behe will always discuss the most complicated mammalian example, and ignore simpler systems in the same organism, or in ancestral organisms. For example, Behe presents the B-cell/T-cell interaction as if this is the only way B-cells are activated (Pgs 123-124, Darwin’s Black Box). But B-cells can be activated without T-cells, and in fish and amphibians, B-cells are also phagocytes, providing a link between the adaptive and innate immune systems. Similarly in the complement and clotting systems, Behe ignores simpler systems in simpler organisms.


  • Ono E, Tomioka Y, Watanabe Y, Amagai K, Taharaguchi S, Glenisson J, Cherel P. The first immunoglobulin-like domain of porcine nectin-1 is sufficient to confer resistance to pseudorabies virus infection in transgenic mice. Arch Virol. 2006 Sep;151(9):1827-39.
  • Kubrycht J, Sigler K, Ruzicka M, Soucek P, Borecky J, Jezek P. Ancient Phylogenetic Beginnings of Immunoglobulin Hypermutation. J Mol Evol. 2006 Oct 6; [Epub ahead of print]
  • Muller CI, Blumbach B, Krasko A, Schroder HC. Receptor protein-tyrosine phosphatases: origin of domains (catalytic domain, Ig-related domain, fibronectin type III module) based on the sequence of the sponge Geodia cydonium. Gene. 2001 Jan 10;262(1-2):221-30.
  • Du Pasquier L, Zucchetti I, De Santis R. Immunoglobulin superfamily receptors in protochordates: before RAG time. Immunol Rev. 2004 Apr;198:233-48.
  • Haruta C, Suzuki T, Kasahara M. Variable domains in hagfish: NICIR is a polymorphic multigene family expressed preferentially in leukocytes and is related to lamprey TCR-like. Immunogenetics. 2006 Apr;58(2-3):216-25. Epub 2006 Mar 16.
  • Corada M, Chimenti S, Cera MR, et al., Junctional adhesion molecule-A-deficient polymorphonuclear cells show reduced diapedesis in peritonitis and heart ischemia-reperfusion injury. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10634-9
  • Pancer Z, Mayer WE, Klein J, Cooper MD. Prototypic T cell receptor and CD4-like coreceptor are expressed by lymphocytes in the agnathan sea lamprey. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13273-8. Epub 2004 Aug 24.


Excellent, Ian, thanks!

Mere evidence is no match for the wishful thinking powers of the ID movement.


Your observation is valid over a much broader range. It applies perfectly to all kinds of woo. Parapsychology, alternate medicine, faeries, the works.

One frustrating thing is that Behe will always discuss the most complicated mammalian example, and ignore simpler systems in the same organism, or in ancestral organisms.

This is the biggest frustration that laypeople and undergrad students have with ID arguments. We don’t have the background to bring up the crucial pieces of evidence which they - persumably on purpose! - omit. That is why the general info on talkorigins and new posts like this one are so valuable to us (besides being fascinating and educational!).

This is the biggest frustration that laypeople and undergrad students have with ID arguments. We don’t have the background to bring up the crucial pieces of evidence which they - persumably on purpose! - omit.

The evidence isn’t crucial, when the ID arguments are so fallacious (aka IDiotic).

Dear Ian,

In the mouse eye, JAM-A appears to regulate cell shape and is expressed in the blood vessels of the tunica vasculosa and later in the cornea and lens. More interestingly, JAM-2 & -3 associate with the cell polarity protein PAR-3 at tight junctions and may play a role in endothelial cell polarity.

Cell polarity is crucial to animal architecture. Is it possible that the players in adaptive immunity or even innate immunity had their dies cast when animals started making epithelial sheets?


Just back from Christmas holidays, far from internet access.

In comment 151921

In the mouse eye, JAM-A appears to regulate cell shape and is expressed in the blood vessels of the tunica vasculosa and later in the cornea and lens. More interestingly, JAM-2 & -3 associate with the cell polarity protein PAR-3 at tight junctions and may play a role in endothelial cell polarity.

Cell polarity is crucial to animal architecture. Is it possible that the players in adaptive immunity or even innate immunity had their dies cast when animals started making epithelial sheets?

It is entirely possible. It certainly seems as if adaptive immunity and embryology are linked. Phagocytes, the cells that swallow bacteria and such, are probably the most primitive cellular component of the adaptive immune response, and they have important roles in remodelling tissues in embryogenesis. As I said, finding and sticking to things is an ancient and key adaptation of cells, required for cells to find their way around during embryogenesis and wound repair, two things that phagocytes do, as well as finding and sticking to bacteria. It is likely these functions were linked from the first, when metazoans arose.

Belay that, they were probably linked beforehand. Just found this reference showing amoeba have an integrin-like protein (containing an Ig superfold) that is important for phagocytosis, cell adhesion and spreading (but not cell-cell interactions). EMBO Rep. 2006 Jun;7(6):617-21. So cell adhesion and defence are very, very old, predating metazoans. By the time agnathans appear on the scene, over 300 million years of evolution have resulted in phagocytic protolympocytes armed with non-rearranging Ig molecules, a valuable part of the innate immune system, ideally poised to take advantage of a fortuitous insertion of the transposon RAG elements resulting in adaptive immunity. Even today, some mammalian lymphocyte populations bear non-rearranging Ig molecules which are used in innate immunity

Wow, looks like gurglemask found one of those gobbledygook text generators, though not a very good one. No one could confuse that nonsense as being written by a person.

Are we to take it to mean he finds the preceeding scientific discourse to be equally impenetrable? I suppose to the unintelligent, most of the world appears as gobbledygook.

H. Hubert, you are right. No one would confuse that nonsense as being written by a person. A lot of the preceding scientific discourse does look like gobbledygook to me. That’s not why I posted this baloney though. (I didn’t even think of that, actually). So you may say: well, does this individual even know WHY they did post here? The answer to that is that this cut-up is partially composed of a text I found on this web site, from 2004, maybe one written by another fool, in your book, but one that stirred up some thought in me. It railed on and on about ‘the nihilism of science’ and ‘the nihilism of reality’. I processed a tiny bit of it into some other pernicious baloney, nonsense that makes more sense than comment #154472. I’m not sure that I’m actually unintelligent. If I was a scientist, I would probably have ignored comment #154472 altogether, if I thought ‘gurglemask’ was nothing but an a malicious clown, a troll. I think the world can seem like gobbledygook to intelligent people too. I went to this party where people were playing this game, I think they called it monster cards. They had had sessions where they drew up these cards - each of them were different - each had a name - like Scar-Face, Random-Face, some were creatures, some were events, some were abstract feelings, all different kinds of stuff. Then they would play them against each other, - the simplest game was just X vs Y. Medusa vs. Rogue Scientist. Sea-Anemone vs. Thunder Perfect Mind. etc. Some times the kinds wouldn’t seem to match. But the player had to convince each other, and everyone actually, that some kind of domination had transpired. They played more complex games too - poker, gin rummmy, etc. Each person would have to make up their own criteria for categories …Mer-man, Sea-an-enemy, Pufferfish and Jaws, OK- 4 of a kind, sea creatures.(Later we also used them for divination.) The thing is, everyone playing had to ‘buy it’. Alchohol greased the wheels on that score. Since then I have OFTEN thought that life is very much like this game. You have to make up your own cards, or use cards others have made, play them convincingly. Now I can speculate that, as a scientist,maybe these ideas don’t interest you very much. Your field of activity is somewhat well delineated, you’re not dealing as much with subjective phantasms and suggestions. I’m not a scientist, and these ideas do interest me - the relations between reason and irrationality…HOW is life different from gobbledygook? For many people it isn’t - not because they’re stupid, or, not only because they’re stupid, but because they want to interpret things ‘for themselves’…in the absence of faith in any absolute authority. There is faith in science, there is the pseudo-scientific religion of the masses, the popular interpretations of science’s findings to date. I’m very interested in the science of philosophy - that’s what led me to this web site - nothing has convinced me that there is AN authoritative interpretation of the various findings of the multitudinous branches of scientific research.( Sure, there is a high degree of order, when you are looking at things under the microscope, but then there’s everything else too - Nature, people, information, art.) I have no reason to believe you have such a faith either. I’m enjoying responding to your response, that’s the heart of the matter. I do question the dogmatism implied in that response - it’s as though you know just what intelligence is, and that you’re sure things aren’t gobbledygook. Anyway, these motifs - the philosophy of science, and science’s relation with other fields of human thought, were being treated in this forum at the time I first encountered it, so when I got this text from the gobbledygook generator, and I was excited to share it with someone, I came here. Allright, I gotta go home, catch a bus thank you

(here’s the slightly moresensical text)

All cement has wrapped its face around the spoken word AMEN cut in two by a window gathers talkative dust to the phonemes fear and light: possible permutations of polar extremes showing the identity of contradictions and the contradictoriness of identities. As soon as the question of memory is pursued,my mind is no longer a battlefield beneath the gaze of the hashish smoker I’ll entwine my spittle a liberated music does not really live in narcotics the reader, the thinking person, the person waiting, are just as much types of Illuminati as the hashish smoker, and they are profaner. Nevertheless, hashish, opium, and whatever else could well provide the introductory course for profane illumination (this is especially true of the graphic work, the stickmen or greymen of George Grosz) when the swords of gravel, in violation of their early commitment to demystification, enter the grey doorhandle icicle a social system of delicate venom free of domination the unconscious does not come to light as many paintings as would seduce it into believing my smileyface spider on the Kraftwerk bleachfork ensemble (delicately entwining its villainesses, its fingers of poor mental armies) they are repelled by muchmore necklaces the radical isolation caused by Nietzsche’s experimental efforts to realize the slime and mire of Nature’s corruption in the Kabbalist tradition, philosophy was a “third thing,” an ungovernable mouth entering the artwork placed on the vassals’ hands comparable to “riddle-solving” or “deciphering” fear and light the sweating cremation a liberated music a grasshopper of smooth stone dust dust of more stones no philosophy can paste into the text more earth swords of many paintings the silver screen’s unhallowed tears they are our selves: exiles, crooks, whores, gamblers (hodge-podge-interpreted to exist at all) they will identify with other rebels hoodlum grasshoppers (space Aliens) headstones, ice-forks, nemeses of ice-forks emptied of much more blue orchids the other poems to emerge from this late cluster, perfect though chilling showing how their adequacy demonstrates the inadequacy of reality its unrelenting negativity - in fact, a utopian emblem, a secret affirmation “regrouping the dream elements” without liquidating them


“When man has achieved the goal he has set himself - to enslave Creation - then he will be completely empty: god and ghost.” E.M. Cioran

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This page contains a single entry by Ian Musgrave published on December 20, 2006 2:36 PM.

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