Article up in the Guardian

My first column is up on the Guardian web site: it’s a brief introduction to asymmetries in snails, an abbreviated version of the post that I fleshed out with a little more detail.

I have to complain a little, though: the title says the observation of shared molecules between molluscs and humans “proves” we’re related. I really don’t like the use of the word “proof”, because it doesn’t — it is compatible with the hypothesis, or it supports the idea, but biologists don’t dabble in proofs.

There’s also an error on my part: I somehow transposed the stomach and liver. I know where these organs are, seriously — I teach part of an A&P course — so I blame my too-fast typing. Now no one is ever going to let me take a scalpel to their abdomen, ever.

Basics: Imprinting

I’ve been busy — I’m teaching genetics this term, and usually the first two thirds of the course is trivial to prepare for — we’re covering Mendelian genetics, and the early stuff is material the students have seen before and are at least generally familiar with the concepts, and all I have to do is cover them a little deeper and with a stronger quantitative component. That’s relatively easy.

The last part of the course, though, is where we start moving into uncharted waters for them, and every year I have to rethink how I’m going to cover the non-Mendelian concepts, and sometimes my ideas work well, and sometimes they don’t. If I teach it for another 20 years, I’ll eventually reach the point where every lecture has been honed into a comprehensible ideal. At least that’s my dream.

Anyway, one of the subjects we’re covering in the next lecture or two is imprinting, and I know from past experience that this can cause mental meltdowns in my students. This makes no sense if you’re used to thinking in Punnett squares! So I’ve been reworking this little corner of the class, and as long as I’m putting together a ground-up tutorial on the subject, I thought I might as well put it on the web. So here you are, a basic introduction to imprinting.

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Snails have nodal!

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My first column in the Guardian science blog will be coming out soon, and it’s about a recent discovery that I found very exciting…but that some people may find strange and uninteresting. It’s all about the identification of nodal in snails.

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Why should we care? Well, nodal is a rather important — it’s a gene involved in the specification of left/right asymmetry in us chordates. You’re internally asymmetric in some important ways, with, for instance, a heart that is larger on the left than on the right. This is essential for robust physiological function — you’d be dead if you were internally symmetrical. It’s also consistent, with a few rare exceptions, that everyone has a stronger left ventricle than right. The way this is set up is by the activation of the cell signaling gene nodal on one side, the left. Nodal then activates other genes (like Pitx2) farther downstream, that leads to a bias in how development proceeds on the left vs. the right.

In us mammals, the way this asymmetry in gene expression seems to hinge on the way cilia rotate to set up a net leftward flow of extraembryonic fluids. This flow activates sensors on the left rather than the right, that upregulate nodal expression. So nodal is central to differential gene expression on left vs. right sides.

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What about snails? Snails are cool because their asymmetries are just hanging out there visibly, easy to see without taking a scalpel to their torsos (there are also internal asymmetries that we’d need to do a dissection to see, but the external markers are easier). The assymetries also appear very early in the embryo, in a process called spiral cleavage, and in the adult, they are obvious in the handedness of shell coiling. We can see shells with either a left-handed or right-handed spiral.

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Chirality in snails. a, Species with different chirality: sinistral
Busycon pulleyi (left) and dextral Fusinus salisbury (right). b, Sinistral (left)
and dextral (right) shells of Amphidromus perversus, a species with chiral
dimorphism. c, Early cleavage in dextral and sinistral species (based on ref.
27). In sinistral species, the third cleavage is in a counterclockwise direction,
but is clockwise in dextral species. In the next divisions the four quadrants
(A, B, C and D) are oriented as indicated. Cells coloured in yellow have an
endodermal fate and those in red have an endomesodermal fate in P. vulgata
(dextral)15 and B. glabrata (sinistral)28. L and R indicate left and right sides,
respectively. d, B. glabrata possesses a sinistral shell and sinistral cleavage
and internal organ organization. e, L. gigantea displays a dextral cleavage
pattern and internal organ organization, and a relatively flat shell
characteristic of limpets. Scale bars: a, 2.0 cm; b, 1.0 cm; d, 0.5 cm; e, 1.0 cm.

Until now, the only organisms thought to use nodal in setting up left/right asymmetries were us deuterostomes — chordates and echinoderms. In the other big (all right, bigger) branch of the animals, the protostomes, nodal seemed to be lacking. Little jellies, the cnidaria, didn’t have it, and one could argue that with radial symmetry it isn’t useful. The ecdysozoans, animals like insects and crustaceans and nematodes, which do show asymmetries, don’t use nodal for that function. This suggests that maybe nodal was a deuterostome innovation, something that was not used in setting up left and right in the last common ancestor of us animals.

That’s why this is interesting news. If a major protostome group, the lophotrochozoa (which includes the snails) use nodal to set up left and right, that implies that the ecdysozoans are the odd group — they secondarily lost nodal function. That would suggest then that our last common ancestor, a distant pre-Cambrian worm, used this molecule in the same way.

Look in the very early mollusc embryo, and there’s nodal (in red, below) switched on in one or a few cells on one side of the embryo, the right. It’s asymmetrical gene expression!

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Early expression of nodal and Pitx in snails. a, 32-cell stage L.
gigantea expressing nodal in a single cell. b, Group of cells expressing Pitx in
L. gigantea. c, Onset of nodal expression in B. glabrata. d, A group of cells
expressing Pitx in B. glabrata. e, 32-cell L. gigantea expressing nodal (red) in
a single cell (2c) and brachyury (black) in two cells (3D and 3c).
f-h, brachyury (black) is expressed in a symmetrical manner in progeny of 3c
and 3d blastomeres (blue triangles in g), thus marking the bilateral axis, and
nodal (red) is expressed on the right side of L. gigantea in the progeny of 2c
and 1c blastomeres, as seen from the lateral (f) and posterior (g, h) views of
the same embryo. i, A group of cells expressing nodal (red) in the C quadrant
and Pitx (black) in the D quadrant of the 120-cell-stage embryo of L.
gigantea. j, nodal (red) and Pitx (black) expression in adjacent areas of the
right lateral ectoderm in L. gigantea. L and R indicate the left and right sides
of the embryo, respectively. The black triangle in b and i, the green, yellow
and pink arrows in f and i, and the black and pink arrows in f and h point to
the equivalent cells. Scale bars: 50µm.

Seeing it expressed is tantalizing, but the next question is whether it actually does anything in these embryos. The test is to interfere with the nodal-Pitx2 pathway and see if the asymmetry goes away…and it does, in a dramatic way. There is a chemical inhibitor called SB-431542 that disrupts this pathway, and exposing embryos to it does interesting things to the formation of the shell. In the photos below, the animal on the left is a control, and what you’re seeing is a coiled shell (opening to the right). The other two views are of an animal treated with SB-431542…and look! Its shell doesn’t have either a left- or right-handed twist, and instead extends as a straight tube.

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Wild-type coiled and drug-treated non-coiled shells of B.
glabrata. Control animals
(e) display the normal sinistral shell morphology. Drug-treated animals
(f, g, exposed to SB-431542 from the 2-cell stage onwards) have straight
shells. f and g show an
individual, ethanol-fixed, and shown from the side (f) and slightly rotated
(g).

What this all means is that we’ve got a slightly better picture of what genes were present in the ancestral bilaterian animal. It probably had both nodal and Pitx2, and used them to build up handedness specializations. Grande and Patel spell this out:

Although Pitx orthologues have also been identified in non-deuterostomes such as Drosophila melanogaster and
Caenorhabditis elegans, in these species Pitx has not been reported in
asymmetrical expression patterns. Our results suggest that asymmetrical expression of Pitx might be an ancestral feature of the bilaterians.
Furthermore, our data suggest that nodal was present in the common
ancestor of all bilaterians and that it too may have been expressed
asymmetrically. Various lines of evidence indicate that the last common ancestor of all snails had a dextral body. If this is true, then our
data would suggest that this animal expressed both nodal and Pitx on
the right side. Combined with the fact that nodal and Pitx are also
expressed on the right side in sea urchins, this raises the possibility
that the bilaterian ancestor had left-right asymmetry controlled by
nodal and Pitx expressed on the right side of the body. Although
independent co-option is always a possibility, the hypotheses we present can be tested by examining nodal and Pitx expression and function in a variety of additional invertebrates.

It’s also, of course, more evidence for the unity of life. We are related to molluscs, and share key genes between us.

Grande C, Patel NH (2009) Nodal signalling is involved in left-right asymmetry in snails. Nature 457(7232):1007-11.

Cephalopod venoms

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The history of venoms is a wonderful example of an evolutionary process. We’re all familiar with the idea of venomous snakes, but the cool thing is that when we examine exactly what it is they’re injecting into their prey, it’s a collection of proteins that show a nested hierarchy of descent. Ancient reptiles had a small and nasty set of poisons they would use, and to improve their efficacy, more and more have been added to the cocktail; so some lizards produce venomous proteins, while the really dangerous members of the Serpentes produce those same proteins, plus a large array of others.

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So something like CRISP (Cystein RIch Secretory Protein) is common to all, but only the most refined predators add PLA2 (Phosopholipase A2) to the mix.

Now lethally poisonous snakes are nice and cute and all, but we all know where the interesting action really is: cephalopods. Let’s leave the vertebrates altogether and look at a venomous protostome clade to see what they do.

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Relative glandular arrangements of a cuttlefish and b octopus. Posterior gland is shown in green; anterior, in blue. Orange structure is the beak.

Brian Fry, who did all that excellent work characterizing and cataloging the
pharmacy of venoms secreted by poisonous snakes, has also turned his hand to the cephalopods. He examined the products of the venom glands of octopus, squid, and cuttlefish, and found a range of proteins, some unique, and others familiar: CAP (a CRISP protein), chitinase, peptidase S1, PLA2 and others. There are a couple of interesting lessons in that list.

First, evolution doesn’t just invent something brand new on the spot to fill a function — what we find instead is that existing proteins are repurposed to do a job. This is how evolution generally operates, taking what already exists and tinkering and reshaping it to better fulfill a useful function. Phospholipase A2, for instance, is a perfectly harmless and extremely useful non-venomous protein in many organisms — we non-toxic humans also make it. We use it as a regulatory signal to control the inflammation response to infection and injury — in moderation, it’s a good thing. What venomous animals can do, though, is inject us with an overdose of this regulator to send our local repair and recovery systems berserk, producing swelling that can incapacitate a tissue. Similarly, a peptidase is a useful enzyme for breaking down proteins in the digestive system…but a poisonous snake or cephalopod biting your hand can squirt it into the tissues, and now it’s being used to digest your muscles and connective tissue. Some effective venoms are simply common proteins used inappropriately (from the perspective of the target).

Another interesting observation is that cephalopods and vertebrates have independently converged in using some of the same venoms. In part, this is a consequence of historical availability — all animals have phospholipases,, since they are important general signalling molecules, so it’s part of the collection of widgets in the metazoan toolbox from which evolution can draw. It’s also part of an inflammation pathway that can be exploited by predators, in the same way that we have shared proteins used in the operation of the nervous system that can be targeted by neurotoxins. So there is independent convergence on a specific use of these proteins as toxins, but one of the things that facilitates the convergence is a shared ancestry.

In fact, some very diverse groups seem to consistently settle on the same likely suspects in their venoms.

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But finally, there must also be physical and chemical proteins of these particular proteins that must also predispose them to use as toxins. After all, animals aren’t coopting just any protein for venoms — they aren’t injecting large quantities of tubulin or heat shock proteins into their prey. There must be something about each of the standard suspects in venoms that make them particularly dangerous. What the comparative evolutionary approach allows us to do is identify the common molecular properties that make for a good venom. As Fry explains it,

Typically the proteins chosen are from
widely dispersed multigene secretory protein families with
extensive cysteine cross-linking. These proteins are collectively much more numerous than globular enzymes,
transmembrane proteins, or intracellular protein. Although
the relative abundance of these protein types in animal
venoms may reflect stochastic recruitment processes, there
has not been a single reported case of a signal peptide
added onto a transmembrane or intracellular protein or a
hybrid protein expressed in a venom gland. A strong bias is
also evident for all of the protein-scaffold types, whether
from peptides or enzymes. Although the protein scaffolds
present in venoms represent functionally and structurally
versatile kinds, they share an underlying biochemistry that
would produce toxic effects when delivered as an “overdose”. Toxic effects include taking
advantage of a universally present substrate to cause
physical damage or causing changes in physiological
chemistry though agonistic or antagonistic targeting. This allows the new venom gland protein to have an
immediate effect based on overexpression of the original
bioactivity. Furthermore, the features of widely dispersed
body proteins, particularly the presence of a molecular
scaffold amenable to functional diversification, are features
that make a protein suitable for accelerated gene duplication and diversification in the venom gland.

To simplify, killing something with a secreted poison typically involves reusing an extant protein, but not just any protein — only a subset of the proteins in an animal’s proteome has just the right properties to make for a good venom. Therefore, we see the same small set of proteins get independently coopted into the venom glands of various creatures.

Fry BG, Roelants K, Norman JA (2009) Tentacles of venom: toxic protein convergence in the Kingdom Animalia. J Mol Evol Mar 18. [Epub ahead of print].

Guiyu oneiros

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A fish is a fish, right? They’re just a blur of aquatic beasties that most people distinguish by flavor, rather than morphology or descent. But fish are incredibly diverse, far more diverse than terrestrial vertebrates, and there are significant divisions within the group. Most people know of one big distinction, between the Chondrichthyes (fish with cartilaginous skeletons, like sharks and rays) and the Osteichthyes (fish with bony skeletons), but there’s another particularly interesting split within the Osteichthyes: the distinction between Sarcopterygians (the word means “fleshy fins”, and we call them lobe-finned fishes colloquially) and the Actinopterygians, the ray-finned fishes. The lobe-finned fishes most distinctive feature is the muscular and bony central core of their fins — extant forms are the coelacanth and lungfish. It is this lineage that led to us terrestrial tetrapods, but other than that successful invasion of the land, the sarcops were something of an aquatic failure, with only a few genera surviving. The ray-finned fishes, on the other hand, are a major success story, with more than 28,000 species today. To put that in context, there are only about 5,500 species of mammals.

The Sarcopterygii and the Actinopterygii must have begun diverging a long time ago, and a couple of questions of interest are a) when did the last common ancestor of both groups live, and b) what did it look like? We don’t have a good and specific answer yet, because Osteichthyes origins are lost far, far back in time, over 400 million years ago, but every new discovery edges us a little closer. What we now have is a well-preserved fossil of a fish that has been determined to be an early sarcopterygian, and it tells us that a) the last common ancestor had to have lived over 419 million years ago, the age of this fossil, and the divergence probably occurred deep in the Silurian, and b) this animal has a mosaic of primitive Osteichthyan features, which tells us that that last common ancestor may well have shared some of these elements. It is another transitional fossil that reveals much about the gradual separation of two great vertebrate groups.

And here it is:

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(Click for larger image)
a, b, A near-complete fish in part and counterpart. c, Close-up view of the anterior portion of the trunk shield in dorsal view, showing MD1 and MD2 flanked by rhomboid scales. d, Close-up view of the dorsal fin spine. MD1, first median dorsal plate; MD2, second median dorsal plate. Scale bar, 1 cm.

That may be a bit disappointing at first — it looks like Silurian road-kill — but really, that’s a remarkable good and useful specimen. The animal was covered with thick bony scales, and the skull was built of thick bony plates, and so while it was squashed flat by pitiless geology, the pieces are all there, and it can be reassembled into a much more fishy state. This drawing may be more satisfying:

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a, Restoration of the entire fish in lateral view. b, Interpretive drawing of the holotype V15541. Areas shaded in grey are unknown, and are reconstructed from other early osteichthyans. ano, anterior nostril; br, branchiostegal ray; cla, clavicle; cle, cleithrum; drs, dorsal ridge scale; dsp, dorsal fin spine; et, extratemporal; eta, accessory extratemporal; f.add, adductor fossa; f.gl, glenoid fossa; gu, gular; ju, jugal; l.ext, lateral extrascapular; lj, lower jaw; m.ext, median extrascapular; mx, maxillary; n.sp., spiracular notch; op, opercular; pa, parietal shield; pcl, postcleithrum; pop, preopercular; ppa, postparietal shield; psc, presupracleithrum; pt, post-temporal; scl, supracleithrum; sop, subopercular; sp., pectoral spine; tr, lepidotrichia; vrs, ventral ridge scale.

Now it looks like a kind of armored, spiky salmon with a thick muscular body (and yes, I too wonder about flavor, and would like to taste a slab of that). It’s definitely not a salmon, though — the bony structure is a curious set of compromises where some features are distinctly sarcopterygian, some look like they belong on a primitive actinopterygian, and others are unique or show affinities to characters of ancient extinct fishes, like rhipidistians. This is very cool. What we see here are relics of an ancient common osteichthyan ancestor, which are being honed into the specific characteristics of the Sarcopterygii. The analysis of the totality of the animal’s features, though, place it more in the lobe-finned than the ray-finned clade. That places it on a branch of the line leading to us…a very, very old branch, making this your many-times-great grand uncle, or cousin only a few million times removed. Now my curiosity about a taste-test is making me feel mildly cannibalistic.

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The topology is the most parsimonious tree arising from a matrix of 23 taxa coded for 153 morphological characters (tree length = 292, consistency index = 0.572, retention index = 0.737, rescaled consistency index = 0.421). The numbers at nodes indicate bootstrap support (where the value is greater than 50%) and Bremer decay index (bottom and top numbers, respectively). Eif., Eifelian; Ems., Emsian; Fam., Famennian; Fras., Frasnian; Giv., Givetian; Gor., Gorstian; Loch., Lochkovian; Lud., Ludfordian; Prag., Pragian.

When you look at that diagram, what should jump out at you is all the diversity in the Devonian, the so-called Age of Fishes, and the paucity of representative fossils from the Silurian…which is exactly where all the interesting branch points in the fish family tree are located. Once again, paleontology is a predictive science, and this tells us where to look for the next batch of exciting and informative fossils.

Zhu M, Zhao W, Jia L, Lu J, Qiao T, Qu Q (2009) The oldest articulated osteichthyan reveals mosaic gnathostome characters. Nature 458:469-474.

Octopods from the Cretaceous!

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Several new and spectacular cephalopod fossils from 95 million years ago have been found in Lebanon. “Spectacular” is not hyperbole — these specimens have wonderfully well-preserved soft parts, mineralized in fine-grained calcium phosphate, and you can see…well, take a look.

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Keuppia levante sp. nov. from the Upper Cenomanian (Metoicoceras geslinianum Zone) of Hâdjoula (Lebanon). A,
holotype, MSNM i26320a. B, sketch of the holotype.

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A major change in stem cell policy

Today, President Obama signed a bill lifting the Bush restrictions on stem cell research. You really must go listen to his speech on the occasion — he seems to get what scientific research is all about. Man, it’s been a long eight years, and oh is it wonderfully good to hear an eloquent defense of scientific research from our president, for a change.

The ugly little goblins of the Bush years still plague us, though; compare the uplifting message of knowledge from Obama with this fundamentally fallacious opinion piece from the carnie barker of junk science, Steven Milloy. And by “fundamentally fallacious”, I mean that it’s problems are far deeper than his usual slithery tweaking of the facts to misrepresent the evidence and the science — I mean that right at the core of Milloy is an absolute lack of comprehension of the very nature of science, and it’s right there, exposed and naked and hideous.

His problem? He thinks his ignorance of the field is an accurate picture, and he thinks science ought to be more like a vending machine: put in your nickel, and the bubble gum you wanted pops out.

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Elephantine errors from Ray Comfort

So Ray Comfort is now complaining on the revered pages of the respected publication, World Net Daily about me. The article is full of dishonest misquotes, but let’s zip right to Ray’s scientific misunderstandings. They are deep and painful. He has this bizarre idée fixe that the necessity of every species having males and females somehow greatly reduces the probability that new species could arise. It’s total nonsense, and I dismissed it briefly when I commented on it before.

“I know Ray is rather stupid, but who knew he could be that stupid. This has been explained to him multiple times: evolution does explain this stuff trivially. Populations evolve, not individuals, and male and female elephants evolved from populations of pre-elephants that contained males and females. Species do not arise from single new mutant males that then have to find a corresponding mutant female – they arise by the diffusion of variation through a whole population, male and female.”

Ray has read that, and failed to grasp the central concept. Take a look at the workings of Ray Comfort’s mind as he attempts to wrestle with a simple idea: the hamster wheel is wobbling, but the poor beast lies dead with legs up in its cage, and nothing is turning over.

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