Basics: Sonic Hedgehog

Every time I mention this developmentally significant molecule, Sonic hedgehog, I get a volley of questions about whether it is really called that, what it does, and why it keeps cropping up in articles about everything from snake fangs to mouse penises to whale fins to worm brains. The time seems appropriate to give a brief introduction to the hedgehog family of signaling molecules.

First, a brief overview of what Sonic hedgehog, or shh, is, which will also give you an idea about why it keeps coming up in these development papers. We often compare the genome to a toolbox — a collection of tools that play various roles in the construction of an organism. If I had to say what tool Sonic hedgehog is most like (keeping in mind that metaphors should not be overstretched), it would be like a tape measure. It’s going to have multiple uses: as a straightedge, as a paperweight to hold down your blueprints, as something to fence with your coworkers on a break, and even to measure distances. It will be pulled out at multiple times during a construction job, and it’s generically useful — you don’t need one tape measure to measure windows, another to measure doors, and yet another to measure countertops. Sonic hedgehog is just like that, getting whipped out multiple times for multiple uses during development, often being used where structures need to be patterned.

Let’s dig into some of the details. I’m using the 2006 review by Ingham and Placzek for most of this summary, so if you really want to get deeper into the literature, I recommend that paper as a starting point.

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Evolving snake fangs

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Ontogenetic allometry in the fang in the front-fanged Causus rhombeatus (Viperidae) displaces the fang along the upper jaw. Scale bars, 1 mm. We note the change in relative size of the upper jaw subregions: i, anterior; ii, fang; iii, posterior. d.a.o., days after oviposition.

I keep saying this to everyone: if you want to understand the origin of novel morphological features in multicellular organisms, you have to look at their development. “Everything is the way it is because of how it got that way,” as D’Arcy Thompson said, so comprehending the ontogeny of form is absolutely critical to understanding what processes were sculpted by evolution. Now here’s a lovely piece of work that uses snake embryology to come to some interesting conclusions about how venomous fangs evolved.

Basal snakes, animals like boas, lack venom and specialized fangs altogether; they have relatively simple rows of small sharp teeth. Elapid snakes, like cobras and mambas and coral snakes, are at the other extreme, with prominent fangs at the front of their jaws that act like injection needles to deliver poisons. Then there are the Viperidae, rattlesnakes and pit vipers and copperheads, that also have front fangs, but phylogenetically belong to a distinct lineage from the elapids. And finally there are other snakes like the grass snake that have enlarged fangs at the back of their jaws. It’s a bit confusing: did all of these lineages independently evolve fangs and venom glands, or are there common underpinnings to all of these arrangements?

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Snake segmentation

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Life has two contradictory properties that any theory explaining its origin must encompass: similarities everywhere, and differences separating species. So far, the only theory that covers both beautifully and explains how one is the consequence of the other is evolution. Common descent unites all life on earth, while evolution itself is about constant change; similarities are rooted in our shared ancestry, while differences arise as lineages diverge.

Now here’s a new example of both phenomena: the development of segmentation in snakes. We humans have 33 vertebrae, zebrafish have 30-33, chickens have 55, mice have 65, and snakes have up to 300 — there’s about a ten-fold range right there. There are big obvious morphological and functional differences, too: snakes are sinuous slitherers notable for their flexibility, fish use their spines as springs for side-to-side motion, chickens fuse the skeleton into a bony box, and humans are upright bipeds with backaches. Yet underlying all that diversity is a common thread, that segmented vertebral column.

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(Click for larger image)
Vertebral formula and somitogenesis in the corn snake.
a, Alizarin staining of a corn snake showing 296 vertebrae, including 3
cervical, 219 thoracic, 4 cloacal (distinguishable by their forked
lymphapophyses) and 70 caudal. b, Time course of corn snake development
after egg laying (118-somite embryo on the far left) until the end of
somitogenesis (~315 somites).

The similarities are a result of common descent. The differences, it turns out, arise from subtle changes in developmental timing.

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Epigenetics

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Epigenetics is the study of heritable traits that are not dependent on the primary sequence of DNA. That’s a short, simple definition, and it’s also largely unsatisfactory. For one, the inclusion of the word “heritable” excludes some significant players — the differentiation of neurons requires major epigenetic shaping, but these cells have undergone a terminal division and will never divide again — but at the same time, the heritability of traits that aren’t defined by the primary sequence is probably the first thing that comes to mind in any discussion of epigenetics. Another problem is the vague, open-endedness of the definition: it basically includes everything. Gene regulation, physiological adaptation, disease responses…they all fall into the catch-all of epigenetics.

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Altenberg 2008 is over

Massimo Pigliucci has posted the notes, parts 1, 2, and 3, from the Altenberg meeting that was unfortunately over-hyped by the creationist crowd (no blame for that attaches to the organizers of this meeting). It sounds like it was a phenomenally interesting meeting that was full of interesting ideas, but from these notes, it was also clearly a rather speculative meeting — not one that was trying to consolidate a body of solid observations into a coherent explanation, but one that was instead trying to define promising directions for an expansion of evolutionary theory. That’s also the message of the concluding statement of the meeting.

A group of 16 evolutionary biologists and philosophers of science convened at the Konrad Lorenz Institute for Evolution and Cognition Research in Altenberg (Austria) on July 11-13 to discuss the current status of evolutionary theory, and in particular a series of exciting empirical and conceptual advances that have marked the field in recent times.

The new information includes findings from the continuing molecular biology revolution, as well as a large body of empirical knowledge on genetic variation in natural populations, phenotypic plasticity, phylogenetics, species-level stasis and punctuational evolution, and developmental biology, among others.

The new concepts include (but are not limited to): evolvability, developmental plasticity, phenotypic and genetic accommodation, punctuated evolution, phenotypic innovation, facilitated variation, epigenetic inheritance, and multi-level selection.

By incorporating these new results and insights into our understanding of evolution, we believe that the explanatory power of evolutionary theory is greatly expanded within biology and beyond. As is the nature of science, some of the new ideas will stand the test of time, while others will be significantly modified. Nonetheless, there is much justified excitement in evolutionary biology these days. This is a propitious time to engage the scientific community in a vast interdisciplinary effort to further our understanding of how life evolves.

That’s a little soft — there are no grand reformulations of the neo-Darwinian synthesis in there, nor is anyone proposing to overturn our understanding of evolution — but that’s what I expected. It’s saying that there are a lot of exciting ideas and new observations that increase our understanding of the power of evolution, and promise to lead research in interesting new directions.

Unfortunately, one reporter has produced an abominably muddled, utterly worthless and uninformed account of the Altenberg meeting that has been picked up by many crackpots to suggest that evolution is in trouble. This not only ignores a fundamental property of science — that it is always pushing off in new directions — but embarrassingly overinflates the importance of this one meeting. This was a gathering of established scientists with some new proposals. It was not a meeting of the central directorate of the Darwinist cabal to formulate new dogma.

Where one ignorant kook dares to assert her inanity, you know the Discovery Institute will stampede after her. Both Paul Nelson and now Casey Luskin have cited her lunatic distortions favorably. Luskin’s account is egregiously incompetent, as we’ve come to expect — he even thinks Stuart Pivar was an attendee. Pivar is an eccentric New York art collector, heir to a septic tank fortune, who has no training in science and whose “theory” is a nonsensical bit of guesswork that is contradicted by observations anyone can make in a basic developmental biology lab. He was not at the meeting. No one in their right mind would even consider inviting him to such a serious event. Maybe if it was a birthday party and they needed someone to make balloon animals, he’d be a good man to have on hand.

Now we can move beyond the garbled hype of the creationists. Pigliucci lists several concepts up there that have promise for further research, and that may help us understand evolution better. That’s the productive result of the meeting, and the only part that counts. Those concepts are also going to be discussed by many other scientists at many other meetings — even I talked about some of them recently — but don’t let the liars on the creationist side confuse you into thinking that the fact that scientists are talking about new ideas is a sign that evolution is in crisis. Talking about new ideas is normal science.

Pathological cephalopod

Teratology is so interesting — it gives us hints about the mechanisms driving developmental processes. In some cases, when you just have a few isolated instances, it can be frustrating, because there isn’t enough information to go much beyond speculation. Here’s one of those tantalizing cases: an octopus with branching tentacles.

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Now that is fascinating. Look at limb formation as an abstract developmental problem in which you first have to initiate a protrusion from a specific place on the body wall; the protrusion has to elongate to a specific length; and it has to be patterned along its length. Cephalopod limb patterning doesn’t involve any branching elements, unlike vertebrate limbs which show a limited radiation of bony elements as you go distally. Vertebrates can exhibit phenomena like polydactyly which are basically counting errors or expansions of a field; the mechanisms for that don’t seem likely to be the case in cephalopods. What I’d guess is that this is an example of errors in initiation. Whatever the signal is that triggers limb extension from the body was triggered again and again as the arm grew, creating sub-arms and sub-sub-arms. This could be a consequence of a mutation that lifted normal constraints that pattern limb initiation (this animal lived for some time, and produced offspring with normal limbs, all of which died shortly after hatching, unfortunately, a result that is ambiguous in determining whether the problem is genetic), or it could be an environmental signal that mimics the normal developmental signal. You can’t tell from one dead octopus!

It’s still cool, though, and says we need more research on cephalopod development.

Atlanta GECCO 2008

I’m on my way home, and am actually using a fast internet connection at the airport — I’d forgotten what it was like! I quickly uploaded a few essential files, and my mail software is downloading my email. Unfortunately, I’d need a really fast connection to handle all that — the number of messages pouring in might actually hit 5 digits. If you’re hoping for a reply to anything, you might well be out of luck here.

Atlanta has been very pleasant, with friendly people and good company. I’ll have to come back sometime. The meeting itself was challenging for a mere biologist, but I might have absorbed a few glimmerings. At least it’ll help me dig into the literature a little more.

As for my talk, and since I haven’t had time to put much science here lately, I’m making my GECCO 2008 talk available as a pdf. These presentations are always a little cryptic when handed out without my explanatory overview, but at least in this one I’ve included my presenter notes, which might help a little bit. The first half is an overview of some concepts in evo devo, which includes those little reminders of what I was supposed to say; the last half is a description of two experiments, and I’m afraid my notes are a little thin there — the data in the research always seems self-explanatory to me. Sorry about that, you should have registered for the conference!

Email download complete: it didn’t quite hit 5 digits, only 9865 messages in the last few days. Maybe if I included the spam that gmail filters out for me…

Ack! I couldn’t add this note from the airport because “Your computer was automatically blacklisted (blocked) by the network due to an abnormal amount of activity originating from your connection.” Curse you, Boingo! What good are you if I can’t even download email without you suspecting I’m up to no good?

Altenberg meeting next week: expect evolution to simply evolve slightly

Remember Suzan Mazur, the credulous reporter hyping a revolution in evolution? She’s at it again, publishing an e-book chapter by chapter on the “Altenberg 16”, this meeting that she thinks is all about radically revising evolutionary biology.

I can tell that Massimo Pigliucci — one of the 16 — is feeling a little exasperation at this nonsense, especially since some of the IDists have seized on it as vindication of their delusions about the “weakness” of evolutionary theory. He’s got an excellent post summarizing some of the motivation behind this meeting, which is actually part of a fairly routine process of occasional get-togethers by scientists with similar ideas to hash out the concepts. Here’s the actual subject of discussion at the Altenberg meeting.

The basic idea is that there have been some interesting empirical discoveries, as well as the articulation of some new concepts, subsequently to the Modern Synthesis, that one needs to explicitly integrate with the standard ideas about natural selection, common descent, population genetics and statistical genetics (nowadays known as evolutionary quantitative genetics). Some of these empirical discoveries include (but are not limited to) the existence of molecular buffering systems (like the so-called “heat shock response”) that may act as “capacitors” (i.e., facilitators) of bursts of phenotypic evolution, and the increasing evidence of the role of epigenetic (i.e., non-genetic) inheritance systems (this has nothing to do with Lamarckism, by the way). Some of the new concepts that have arisen since the MS include (but again are not limited to) the idea of “evolvability” (that different lineages have different propensities to evolve novel structures or functions), complexity theory (which opens the possibility of natural sources of organic complexity other than natural selection), and “accommodation” (a developmental process that may facilitate the coordinated appearance of complex traits in short evolutionary periods).

Now, did you see anything in the above that suggests that evolution is “a theory in crisis”? Did I say anything about intelligent designers, or the rejection of Darwinism, or any of the other nonsense that has filled the various uninformed and sometimes downright ridiculous commentaries that have appeared on the web about the Altenberg meeting? Didn’t think so. If next week’s workshop succeeds, what we will achieve is taking one more step in an ongoing discussion among scientists about how our theories account for biological phenomena, and how the discovery of new phenomena is to be matched by the elaboration of new theoretical constructs. This is how science works, folks, not a sign of “crisis.”

You cannot imagine how pleased I was to see this — not because I was at all concerned about this meeting, but because I’ve been scribbling down notes for the last few weeks on the subjects I want to discuss in my keynote at GECCO 2008, and that’s practically an outline of my plans. I was going to go over some of these concepts and define them and give examples; I didn’t have molecular buffers on my list (maybe I’ll have to add it), and I was going to say a bit about conservation/canalization vs. plasticity, but at least I’m reassured that I’m on the right track.

Amphioxus and the evolution of the chordate genome

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This is an amphioxus, a cephalochordate or lancelet. It’s been stained to increase contrast; in life, they are pale, almost transparent.

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It looks rather fish-like, or rather, much like a larval fish, with it’s repeated blocks of muscle arranged along a stream-lined form, and a notochord, or elastic rod that forms a central axis for efficient lateral motion of the tail…and it has a true tail that extends beyond the anus. Look closely at the front end, though: this is no vertebrate.

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It’s not much of a head. The notochord extends all the way to the front of the animal (in us vertebrates, it only reaches up as far as the base of the hindbrain); there’s no obvious brain, only the continuation of the spinal cord; there isn’t even a face, just an open hole fringed with tentacles. This animal collects small microorganisms in coastal waters, gulping them down and passing them back to the gill slits, which aren’t actually part of gills, but are components of a branchial net that allows water to filter through while trapping food particles. It’s a good living — they lounge about in large numbers on tropical beaches, sucking down liquids and any passing food, much like American tourists.

These animals have fascinated biologists for well over a century. They seem so primitive, with a mixture of features that are clearly similar to those of modern vertebrates, yet at the same time lacking significant elements. Could they be relics of the ancestral chordate condition? A new paper is out that discusses in detail the structure of the amphioxus genome, which reveals unifying elements that tell us much about the last common ancestor of all chordates.

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IEDG2008: Model systems are dead, long live model systems

I’ve discovered a couple of important things at this meeting.

One, late night sessions at west coast meetings are deadly for any of us coming from more eastern time zones. At least the morning sessions are low stress.

Two, I haven’t heard one Drosophila talk yet, and the message is clear: we’re now in the stage of evo-devo in which everyone is diversifying and chasing down a wide array of species. There was a bit of model-system bashing, but at the same time, everyone is acknowledging the crucial role of those traditional, but weird and derived, lab critters in providing a point of comparison and being the source of many of the tools being used to explore phylogeny now. I thought, though, that the smartest comment of the evening was that now everything is a model system.

I’ve got some dense piles of notes on the evening session, but I’m going to give you the short version of everything, with an emphasis on the novel twists.

Michael Akam talked about segmentation genes, which every developmental zoologist now knows inside and out — trust me, this is a familiar topic with over 25 years of detailed research … in Drosophila. Akam made the point that now it’s looking clear that three of the major segmented phyla, the arthropods, annelids, and chordates, may be using related genes to accomplish segmentation, but they seem to be using different mechanisms — so he considers the question of whether segmentation in these three is homologous is still an open question. He also discussed recent work on the centipede Strigamia (definitely not a lab animal: they can’t breed them in the lab yet, so all the work is done by collecting embryos in the field, in Scotland). They have a dynamic pattern of segment addition that is very different from what you find in flies, and more similar in some ways to chodate segmentation.

Chelsea Specht talked about floral evolution in the Zingiberales. I’m an animal guy, so even the most basic stuff in this talk was entirely new to me. I know the general rules of the spatial development of in the fruit fly of the plant world, Arabidopsis, and she gave us a bit of context there, reminding us of the concentric development of sepals, petals, stamens, and carpels. The Zingiberales are a large and diverse group of plants that includes bananas and ginger, and one characteristic is an extravagant modification of the canonical pattern, with extra stamens, a loss of select stamens, and a fusion of stamens to form a novel structure, the labellum, which in these plants functionally replaces the petals. So of course they’re looking into the genes involved in the patterns, which turn out to be the familiar Arabidopsis genes redeployed in new patterns.

Paul Sereno had a talk that took a very different tack, and was unfortunately giving it at the equivalent of 11:00pm Minnesota time, so I’m sorry to say I didn’t follow it carefully. He was discussing the analysis of morphology, and was advocating the development of tools and techniques to compare data sets in addition to the usual output, phylogenetic trees. He was making the case that a lot of morphological studies are actually very poor (a creationist in the audience would have loved it, largely because he wouldn’t have understood the context) because the input data sets of different studies are not comparable.

And now I have to get back to work and listen to the next set of talks.