Chance and regularity in the development of the fly eye

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What has always attracted me to developmental biology is the ability to see the unfolding of pattern—simplicity becomes complexity in a process made up of small steps, comprehensible physical and chemical interactions that build a series of states leading to a mostly robust conclusion. It’s a bit like Conway’s Game of Life in reverse, where we see the patterns and can manipulate them to some degree, but we don’t know the underlying rules, and that’s our job—to puzzle out how it all works.

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Another fascinating aspect of development is that all the intricate, precise steps are carried out without agency: everything is explained and explainable in terms of local, autonomous interactions. Genes are switched on in response to activation by proteins not conscious action, domains of expression are refined without an interfering hand nudging them along towards a defined goal. It’s teleonomy, not teleology. We see gorgeously regular structures like the insect compound eye to the right arise out of a smear of cells, and there is no magic involved—it’s wonderfully empowering. We don’t throw up our hands and declare a miracle, but instead science gives us the tools to look deeper and work out (with much effort, admittedly) how seeming miracles occur.

One more compelling aspect of development: it’s reliable, but not rigid. Rather than being simply deterministic, development is built up on stochastic processes—ultimately, it’s all chemistry, and cells changing their states are simply ping-ponging through a field of potential interactions to arrive at an equilibrium state probabilistically. When I’d peel open a grasshopper embryo and look at its ganglia, I’d have an excellent idea of what cells I’d find there, and what they’d be doing…but the fine details would vary every time. I can watch a string of neural crest cells in a zebrafish crawl out of the dorsal midline and stream over generally predictable paths to their destinations, but the actions of an individual melanocyte, for instance, are variable and beautiful to see. We developmental biologists get the best of all situations, a generally predictable pattern coupled to and generated by diversity and variation.

One of the best known examples of chance and regularity in development is the compound eye of insects, shown above, which is as lovely and crystalline as a snowflake, yet is visibly assembled from an apparently homogenous field of cells in the embryo. And looking closer, we discover a combination of very tight precision sprinkled with random variation.

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PZ Myers’ Own Original, Cosmic, and Eccentric Analogy for How the Genome Works -OR- High Geekology

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I’m teaching my developmental biology course this afternoon, and I have a slightly peculiar approach to the teaching the subject. One of the difficulties with introducing undergraduates to an immense and complicated topic like development is that there is a continual war between making sure they’re introduced to the all-important details, and stepping back and giving them the big picture of the process. I do this explicitly by dividing my week; Mondays are lecture days where I stand up and talk about Molecule X interacting with Molecule Y in Tissue Z, and we go over textbook stuff. I’m probably going too fast, but I want students to come out of the class having at least heard of Sonic Hedgehog and β-catenin and fasciclins and induction and cis regulatory elements and so forth.

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Lamprey skeletons

Bone is a sophisticated substance, much more than just a rock-like mineral in an interesting shape. It’s a living tissue, invested with cells dedicated to continually remodeling the mineral matrix. That matrix is also an intricate material, threaded with fibers of a protein, type II collagen, that give it a much greater toughness—it’s like fiberglass, a relatively brittle substance given resilience and strength with tough threads woven within it. Bone is also significantly linked to cartilage, both in development and evolution, with earlier forms having a cartilaginous skeleton that is replaced by bone. In us vertebrates, cartilage also contains threads of collagen running through it.

These three elements—collagen, cartilage, and bone—present an interesting evolutionary puzzle. Collagen is common to the matrices of both vertebrate cartilage and bone, yet the most primitive fishes, the jawless lampreys and hagfish, have been reported to lack that particular form of collagen, suggesting that the collagen fibers are a derived innovation in chordate history. New work, though, has shown that there’s a mistaken assumption in there: lampreys do have type II collagen! This discovery clarifies our understanding of the evolution of the chordate skeleton.

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Chicken, archosaur…same difference

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My daughter is learning about evolution in high school right now, and the problem isn’t with the instructor, who is fine, but her peers, who complain that they don’t see the connections. She mentioned specifically yesterday that the teacher had shown a cladogram of the relationships between crocodilians, birds, and mammals, and that a number of students insisted that there was no similarity between a bird and an alligator.

I may have to send this news article to school with her: investigators have found that a mutation in chickens causes them to develop teeth—and the teeth resemble those of the common ancestor of alligators and chickens, an archosaur.

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Tentacle sex, part deux

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When male squid get together with their female friends, they have a couple of nuptial options: they can go ahead and use their charm to court the female, or they can just start poking her with tentacles full of sperm in mating frenzy. Now some of you guys might be thinking the latter option sounds good (what’s the point of living the life of a squid if you can’t be selfish and uninhibited, right?), while the ladies and gentlemen here might think the former is better. A study of the mating behavior of squid close-up and in the lab suggests that it’s true: taking one’s time and mating cooperatively is much more likely to get the sperm in the right place and improve the likelihood of reproductive success. And as a bonus it’s got some lovely photos of squid caught in flagrante.

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Tentacle Sex

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Doesn’t everyone just love cephalopods? I find them to be a fascinating example of a body plan radically different from our own, the closest thing to a truly alien large metazoan on our planet. I try to keep my eyes open for new papers on cephalopod development, but unfortunately, they are rather difficult to study and data is sadly thin and tantalizing.

I just ran across a pair of papers by Jantzen and Havenhand (2003a, b) on squid mating. That’s close enough to development for me!

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It’s not just the genes, it’s the links between them

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Once upon a time, I was one of those nerds who hung around Radio Shack and played about with LEDs and resistors and capacitors; I know how to solder and I took my first old 8-bit computer apart and put it back together again with “improvements.” In grad school I was in a neuroscience department, so I know about electrodes and ground wires and FETs and amplifiers and stimulators. Here’s something else I know: those generic components in this picture don’t do much on their own. You can work out the electrical properties of each piece, but a radio or computer or stereo is much, much more than a catalog of components or a parts list.

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Electronics geeks know the really fun stuff starts to happen when you assemble those components into circuits. That’s where the significant work lies and where the actual function of the device is generated—take apart your computer, your PDA, your cell phone, your digital camera and you’ll see similar elements everywhere, and the same familiar components you can find in your Mouser catalog. As miniaturization progresses, of course, more and more of that functionality is hidden away in tiny integrated circuits…but peel away the black plastic of those chips, and you again find resistors and transistors and capacitors all strung together in specific arrangements to generate specific functions.

We’re discovering the same thing about genomes.

The various genome projects have basically produced for us a complete parts list—a catalog of bits in our toolbox. That list is incredibly useful, of course, and represents an essential starting point, but how a genome produces an organism is actually a product of the interactions between genes and gene products and the cytoplasm and environment, and what we need next is an understanding of the circuitry: how Gene X expression is connected to Gene Y expression and what the two together do to Gene Z. Some scientists are suggesting that an understanding of the circuitry of the genome is going to explain some significant evolutionary phenomena, such as the Cambrian explosion and the conservation of core genetic processes.

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Evolution of a polyphenism

Here’s some very cool news: scientists have directly observed the evolution of a complex, polygenic, polyphenic trait by genetic assimilation and accommodation in the laboratory. This is important, because it is simultaneously yet another demonstration of the fact of evolution, and an exploration of mechanisms of evolution—showing that evolution is more sophisticated than changes in the coding sequences of individual genes spreading through a population, but is also a consequence of the accumulation of masked variation, synergistic interactions between different alleles and the environment, and perhaps most importantly, changes in gene regulation.

Unfortunately, it’s also an example of some extremely rarefied terminology that is very precisely used in genetic and developmental labs everywhere, but probably makes most people’s eyes glaze over and wonder what the fuss is all about. I’ll try to give a simple introduction to those peculiar words, and explain why the evolution of a polyphenic pigment pattern in a caterpillar is a fascinating and significant result.

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Vertebral variation, Hox genes, development, and cancer

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First, a tiny bit of quantitative morphological data you can find in just about any comparative anatomy text:

mammal number of vertebrae
cervical thoracic lumbar sacral caudal
horse 7 18 6 5 15-21
cow 7 13 6 5 18-20
sheep 7 13 6-7 4 16-18
pig 7 14-15 6-7 4 20-23
dog 7 13 7 3 20-23
human 7 12 5 5 3-4

The number of thoracic vertebrae varies quite a bit, from 9 in a species
of whale to 25 in sloths. The numbers of lumbar, sacral, and more caudal vertebrae also show considerable variation. At the same time, there is a surprising amount of invariance in the number of cervical vertebrae in mammals — as every schoolkid knows, even giraffes have exactly the same number of vertebrae in their necks as we do. What makes this particularly striking is that other vertebrates have much more freedom in their number of cervical vertebrae; swans can have 22-25. I was idly wondering why mammals were so limited, and stumbled onto a couple of papers that addressed exactly that question (Galis & Metz, 2003; Galis, 1999). Galis’s explanation is that it is a developmental constraint that may have something to do with the incidence of cancer.

Development is an intricately choreographed process that treads a dangerous line. On one side is stability; but development is in many ways a destabilizing process, in which cells have to change their path and form new tissues, and stability is not compatible with it. On the other side is chaos, unregulated proliferation — cancer. During development, the organism has to foster proliferation and change to a greater degree than it can tolerate later, and that loosening of constraints represents a danger. Galis suggests that one reason we mammals may always have 7 cervical vertebrae is that the regulatory genes that specify the number of vertebrae are coupled to processes that otherwise regulate cell fates, and that modifications to those genes that would cause variation in vertebra number would also lead to unacceptable increases in the frequency of embryonal cancers.

This isn’t at all an improbable idea. Genes exhibit bewilderingly complex patterns of expression, and pleiotropy (the regulation of multiple phenotypic characters by a single gene) is the rule, not the exception. The Hox genes, the particular genes that control the identity of regions along the length of the animal, are known to switch on and off in proliferating mammalian cell lines in culture. Perhaps the Hox genes involved in defining cervical vertebrae are somehow also involved in controlling cell proliferation, making them dangerous targets for evolution to tinker with?

Galis provides several lines of evidence that this is the case. To see whether variation in cervical vertebra number leads to increased incidence of cancer, we need to look for instances of variation in mammalian vertebrae.

There isn’t much variation in cervical vertebra number, though. There is an exception: sometimes, the 7th cervical vertebra is found to undergo a partial homeotic transformation and forms a pair of ribs, which are normally found only on thoracic vertebrae. Humans develop cervical ribs with a frequency of about 0.2%; do they also develop cancers? The answer is yes, with a frequency 125 times greater than the general population.

Another place to look would be in phylogenetic variation — between groups rather than within a population. It turns out that there are two groups of mammals that do have a non-canonical number of cervical vertebrae: one manatee genus and two genera of sloths. No data is available on frequencies of embryonal cancers in either, and Galis reports that manatees at least seem to have a low incidence of cancer. One explanation is that both sloths and manatees have exceptionally slow metabolic rates, which in itself will reduce the frequency of cancer, since it will reduce the rate of oxidation damage; the idea is that this low cancer rate may have made these organisms more tolerant of variation in these genes.

An open question is how birds can have greater variability in the number of cervical vertebrae — they certainly don’t have low metabolic rates. One suggestion is that the coupling between these particular Hox genes and a predilection for cancer is unique to mammals. Another possibility is that birds possess other, unidentified mechanisms that reduce free radical production, reduces oxidative damage, and makes them relatively cancer-free. Galis cites several studies that show that birds do seem to be less severely afflicted with cancers than us mammals.

It’s an interesting idea, but the evidence so far is a collection of correlations. I’d be interested in seeing some direct analyses of the role of patterning genes on carcinogenesis. Still, it’s the first answer I’ve seen to explain why such a peculiar restriction in morphology should be nearly universal within a whole class of animals, when other classes allow so much more diversity.

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Galis, F and JAJ Metz (2003) Anti-cancer selection as a source of developmental and evolutionary constraints. BioEssays 25:1035-1039.

Galis, F (1999) Why do almost all mammals have seven cervical vertebrae? Developmental constraints, Hox genes, and cancer. J Exp Zool (Mol Dev Evol) 285:19-26.

A rising starlet in evo-devo

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Nematostella, the starlet anemone, is a nifty new model system for evo-devo work that I’ve mentioned a few times before—in articles on “Bilateral symmetry in a sea anemone” and “A complex regulatory network in a diploblast”—and now I see that there is a website dedicated to the starlet anemone and a genomics database, StellaBase. It’s taking off!