A simple story gets complicated

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People, scientists included, are always looking for simple, comprehensible explanations for complex phenomena. It’s so satisfying to be able to easily explain something in a sound bite, and sound bites are so much more easily accepted by an audience than some elaborate, difficult collection of details. For example, we often hear homosexual behavior reduced to being a “choice,” the product of a “gay gene,” a “sin,” or something similarly absolute and irreducible…suggesting that it is part of a diverse spectrum of sexual behaviors with multiple causes and that different individuals are different in their behaviors is almost certainly the more accurate description, but that doesn’t satisfy our need for straight, simple, linear causal mechanisms. This is true of most animal behavior, I think—you just can’t crunch it down to one single agent that drives much of anything.

I thought there was one excellent counter-example, though, one that suggested at least some complex behaviors might be reducible to a discrete source: the mating behavior of Microtus voles. It was such a simple, clean story; new results suggest that it was too clean, and that there’s much more to the behavior than was thought.

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Coming to Life

Books from Nobel laureates in molecular biology have a tradition of being surprising. James Watson(amzn/b&n/abe/pwll) was catty, gossipy, and amusingly egotistical; Francis Crick(amzn/b&n/abe/pwll) went haring off in all kinds of interesting directions, like a true polymath; and Kary Mullis(amzn/b&n/abe/pwll) was just plain nuts. When I heard that Christiane Nüsslein-Volhard was coming out with a book, my interest and curiousity were definitely piqued. The work by Nüsslein-Volhard and Wieschaus has shaped my entire discipline, so I was eagerly anticipating what her new book, Coming to Life: How Genes Drive Development(amzn/b&n/abe/pwll) would have to say.

It wasn’t what I expected at all, but I think readers here will be appreciative: it’s a primer in developmental biology, written for the layperson! Especially given a few of the responses to my last article, where the jargon seems to have lost some people, this is going to be an invaluable resource.

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Generic bumps and recycled genetic cascades

How do you make a limb? Vertebrate limbs are classic models in organogenesis, and we know a fair bit about the molecular events involved. Limbs are induced at particular boundaries of axial Hox gene expression, and the first recognizable sign of their formation is the appearance of a thickened epithelial bump, the apical ectodermal ridge (AER). The AER is a signaling center that produces, in particular, a set of growth factors such as Fgf4 and Fgf8 that trigger the growth of the underlying tissue, causing the growing limb to protrude. In addition, there’s another signaling center that forms on the posterior side of the growing limb, and which secretes Sonic Hedgehog and defines the polarity of the limb—this center is called the Zone of Polarizing Activity, or ZPA. The activity of these two centers together define two axes of the limb, the proximo-distal and the anterior-posterior. There are other genes involved, of course—this is no simple process—but that’s a very short overview of what’s involved in the early stages of making arms and legs.

Now, gentlemen, examine your torso below the neck. You can probably count five protuberances emerging from it; my description above accounts for four of them. What about that fifth one? (Not to leave the ladies out, of course—you’ve also got the same fifth bump, it’s just not quite as obvious, and it’s usually much more tidily tucked away.)

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Diploblasts and triploblasts

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Carl Zimmer wrote on evolution in jellyfish, with the fascinating conclusion that they bear greater molecular complexity than was previously thought. He cited a recent challenging review by Seipel and Schmid that discusses the evolution of triploblasty in the metazoa—it made me rethink some of my assumptions about germ layer phylogeny, anyway, so I thought I’d try to summarize it here. The story is clear, but I realized as I started to put it together that jeez, but we developmental biologists use a lot of jargon. If this is going to make any sense to anyone else, I’m going to have to step way back and explain a collection of concepts that we’ve been using since Lankester in the 19th century.

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The evolution of deuterostome gastrulation

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Do vertebrate embryos exhibit significant variation in their early development? Yes, they do—in particular, the earliest stages show distinct differences that mainly reflect differences in maternal investment and that cause significant distortions of early morphology during gastrulation. However, these earliest patterns represent workarounds, strategies to accommodate one variable (the amount of yolk in the egg), and the animals subsequently reorganize to put tissues into a canonical arrangement. Observations of gene expression during gastrulation are revealing deeper similarities that are common in all deuterostomes—not just vertebrates, but also the invertebrate chordates (tunicates and cephalochordates) and echinoderms.

What does all that mean? If you think of development as a formal dance, the earliest stages are like the prelude; everyone is getting out of their chairs around the ballroom, looking for partners and working their way towards the floor. The dispositions of the dancers are variable and somewhat chaotic, and vary from dance to dance. Once they get to their positions, however, we’re finding that not only is there a general similarity in their arrangements, but they’re all dancing to the very same tune. In this case, one of the repeated motifs in that tune is a gene, Nodal, which is active in gastrulation and shows a similar pattern in animal after animal.

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Development, medicine, and evolution of the neck and shoulder

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Neck anatomy has long terrified me. Way back when I was a grad student, my lab studied the organization and development of the hindbrain, which was relatively tidy and segmental; my research was studying the organization and development of the spinal cord, which was also tidy and segmental. The cervical region, though, was complicated territory. It’s a kind of transitional zone between two simple patterns, and all kinds of elaborate nuclei and new cell types and structural organizations flowered there. I drew a line at the fifth spinal segment and said I’m not even going to look further anteriorly…good thing, too, or I’d probably still be trying to finish my degree.

Fortunately, Matsuoka et al. were braver than I was and they have applied some new molecular techniques to sort out some of the details of how the neck and shoulder are assembled. This is a developmental study of how the muscles and bones of the shoulder girdle and neck are derived, and what they’ve identified is 1) a fairly simple rule for part of the organization, 2) an explanation for some human pathologies, and 3) some interesting observations about evolution. It is very cool to find a paper that ties together molecular genetics, development, paleontology, and medicine together so inseparably.

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Bicoid evolution

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I’ve written about this fascinating Drosophila gene, bicoid, several times before. It’s a maternal effect gene, a gene that is produced by the mother and packaged into her eggs to drive important early events in development, in this case, establishing polarity, or which end of the egg is anterior (bicoid specifies which end of the egg will form the fly’s head). Bicoid is also a transcription factor, or gene that regulates the activity of other genes. We also see evidence that it is a relatively new gene, one that is taking over a morphogenetic function that may have been carried out by several other more primitive genes in the ancestral insect.

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Bicoid, nanos, and bricolage

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Intelligent Design creationists are extremely fond of diagrams like those on the left. Textbook illustrators like them because they simplify and make the general organization of the components clear—reducing proteins to smooth ovoids removes distractions from the main points—but creationists like them for the wrong reasons. “Look at that—it’s engineered! It’s as if God uses a CAD program to design complex biological systems!” They like the implication that everything is done with laser-guided precision, and most importantly, that every piece was designed with intent, to fill a specific role in an apparatus that looks like it came out of a high-tech machine shop at a Boeing aerospace lab.

This is, of course, misleading. Real organelles in biology don’t look glossy and slick and mechanical; they look, well, organic, with fuzziness and variability and, most importantly, mistakes and slop. What these biological machines look like is not the precisely engineered output of a modern machine shop, but like bricolage. Bricolage is a term François Jacob used to contrast real biology with the false impression of nature as an engineer. It’s an art term, referring to constructions made with whatever is at hand, a pastiche of whatever is just good enough or close enough to the desired result to make do. It covers everything from the sculptures of Alexander Calder to those ticky-tacky souvenirs made from odd bits of driftwood and shells glued together that you can find at seashore gift shops.

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Zygotic genes

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Last week, I wrote a bit about maternal genes, specifically bicoid, and described how this gene was expressed in a gradient in the egg. Bicoid is both a transcription factor and a morphogen. The gene product regulates the activity of other genes, controlling their pattern of expression in the embryo. Today I thought I’d get more specific about the downstream targets of bicoid, the gap genes.

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Transcription factors and morphogens

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In my previous comments about maternal effect genes, I was talking specifically about one Drosophila gene, bicoid, which we happen to understand fairly well. We know its sequence, we know how it is controlled, and we know what it does; we know where it falls in the upstream and downstream flow of developmental information in the cell. So today I’m going to babble a bit more about what bicoid is and does, and how it works.

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