Protein Space and the Protein Universe: Introduction

Evolution is easier than we think, and one great way to see why is to look at what we know about protein evolution.

Proteins have been evolving on our planet for about 4 billion years. Their appearance almost certainly precedes the beginning of life itself. We still don't know how the whole thing got off the ground, but once the stage was set (in living cells), evolution began exploring Protein Space. As it did so, it slowly created the Protein Universe. Since these two concepts — Protein Space and the Protein Universe — are so central to understanding and picturing protein evolution, we should carefully define what they mean.

Does it take special genes to make a special human?

We humans think we're pretty special. Here's Hamlet, in the speech that gave this blog its name:

What a piece of work is a man! How noble in reason! how infinite in faculty! in form, in moving, how express and admirable! in action how like an angel! in apprehension how like a god! the beauty of the world! the paragon of animals!

—Hamlet, Act II, Scene II, The Oxford Shakespeare

Kemble in the role of Hamlet.
Courtesy of Wellcome Images.

It is common, at least in the West, to consider humans "the paragon of animals," typically making reference to the ancient idea of "God's image." I won't address here whether humanity is a paragon, but here's a more tractable question: what are the facets that distinguish humans from other animals? Biologically speaking, what is special about humans that sets them apart from other apes?

Anatomically, we're pretty unremarkable apes. We have enlarged gluteal muscles and other adaptations that make us good distance runners. We have fancy thumbs that make us good tool users. We have a tweaked larynx that facilitates speech. We have spineless penises that facilitate other things. And of course we have what Hamlet was talking about: big brains and associated cognitive abilities.

When a GAP is not a GAP: ARHGAP11B, the mysterious human-specific gene

A truly human-specific gene, not merely a human-specific version of an animal gene or a mammal gene or a primate gene — that is something particularly interesting. Given that the human genome is 96% identical to that of our closest relatives (chimps and bonobos), and given that so much of those genomes is composed of mobile elements that are unlikely to end up being genes at all, I and perhaps others long thought that human-specific genes would be something pretty rare.

But there they are — genes by every definition, that code for protein and are expressed in human tissues, that are unique in humans. One of the most interesting is a gene that brings together some of my personal favorite topics in biology: brain development, cellular signaling systems, and of course evolution. The gene goes by the unfortunate "name" of ARHGAP11B.

I do consider ARHGAP11B to be a unique human gene, but its name betrays its evolutionary history and its membership in a family of genes, so it's not completely unique (specifics to come). That family is the family of GAPs, a group of proteins that were the focus of my postdoctoral research years ago. GAP stands for "GTPase-activating protein," and besides being a typical morsel of biochemical jargon, the phrase is a bit of an insult to the roles played by these proteins in cellular signaling systems.

Common ancestry, bottlenecks, and human evolution

Human evolution has been in the news quite a lot recently.

• New genetic data suggest that ancient humans included both Neanderthals and Denisovans, which colonized different parts of the world but subsequently interbred with so-called modern humans and left telltale traces of this history in the genomes of living humans.
• New analysis of current genetic diversity suggests that human population size underwent interesting fluctuations throughout the history of our species, but concludes that the population never dipped below a few thousand reproducing individuals.

Unsurprisingly, these findings have been discussed in the context of Christian views of human origins. In the context of some of these discussions (among Catholics, for example), I have noticed some confusion regarding the implications of common ancestry. I will illustrate the error with a stylized example, then explain why it is an error.

Harmful genes, and sneaky, too: Genetic hitchhiking in the human genome

Genetic hitchhiking is thought to be an inevitable result of strong positive selection in a population. The basic idea is that if a particular gene is strongly selected for (as opposed to selected against), then the chunk of the genome that carries that gene will become very common in the population. The result is a local loss of genetic diversity: all (or nearly all) of the individuals in the population will have that same chunk of genetic information, whereas before the selection process acted, there might have been a lot of variation in that chunk throughout the population. And this means that areas of the human genome that are less variable between people are suspected sites of recent positive selection. Within that chunk, there are potentially many genes and genetic elements that became more common in the population by virtue of their placement near the gene that was actually selected for. Those other genes are the hitchhikers. And it's likely that some hitchhikers are bad news – they're harmful mutations that would normally become rare or extinct in the population, but instead have become common by hitchhiking.

In the last few years, large amounts of genetic information have become available that have enabled biologists to look for evidence of such phenomena in the human genome. Specifically, two major projects have collected genetic data for the purpose of analyzing genetic variation among humans. One project, the International HapMap Project, mapped and quantified sites in the human genome that are known to vary among humans by a single genetic letter. These sites are called single nucleotide polymorphisms, or SNPs (pronounced "snips"). The project has mapped millions of these sites in a group of 270 humans representing various lineages. Another project that has made the news recently is the 1000 Genomes Project, which also seeks to provide a picture of human genetic variation using more people (more than 1000 at present) and slightly different technology. Efforts like these have taken analysis of the human genome to a new level. No longer do we merely wonder what "the" human genome is like – we can begin to learn about how genetic differences give rise to biological differences such as susceptibility to particular diseases.

Genetic hitchhiking in English

The next post will discuss recent evidence for genetic hitchhiking in humans. So, what do we mean when we say that genes can hitchhike? To make sense of this phenomenon, we first need to review chromosomes and sexual reproduction.

Most people know that sexual reproduction creates offspring that are genetically distinct from both of the their parents. That's true, but the genetic scrambling that occurs is more significant than is sometimes reported. Let's start by looking at chromosomes.

Like every other animal (or plant or pretty much any other organism), your genetic endowment is carried in chunks of DNA called chromosomes. You have 23 of these chunks, which are rather like volumes in a set of encyclopedias. More completely, you have 23 pairs of these volumes; one set was contributed by your mother and the other by your father. Each of your parents had a complete set, also consisting of a set from Mom and a set from Dad. When your mother made the egg that became the zygote that became you, she provided you with one copy of each volume in the set, and she chose those copies randomly. For example, she may have chosen her dad's copy of chromosome 1, but her mom's copy of chromosome 2. Just by virtue of this random picking process, she made an egg with a shuffled version of her own genetic cards. Dad did the same when he made his sperm, and so your genetic complement is an amalgamation of your parents' genomes which were amalgamations of your grandparents' genomes, and so on.

"The stamp of one defect": an endless series on harmful mutations

Not surprisingly, Hamlet weighed in on the nature vs. nurture question, at least once.

So, oft it chances in particular men,
That for some vicious mole of nature in them,
As, in their birth,―wherein they are not guilty,
Since nature cannot choose his origin,―
By the o’ergrowth of some complexion,
Oft breaking down the pales and forts of reason,
Or by some habit that too much o’er-leavens
The form of plausive manners; that these men,
Carrying, I say, the stamp of one defect,
Being nature’s livery, or fortune’s star,
Their virtues else, be they as pure as grace,
As infinite as man may undergo,
Shall in the general censure take corruption
From that particular fault: the dram of eale
Doth all the noble substance of a doubt,
To his own scandal.

– Hamlet, Act I, Scene IV, The Oxford Shakespeare

It is certainly true that "the stamp of one defect" can wreak havoc on the scale that Hamlet describes, and whether the result is a debilitating physical limitation or damage to "the pales and forts of reason," the outcome is tragic by any measure.

Reflecting on the reality of inherited dysfunction, we might be tempted to assume that a "vicious mole of nature" is something seen only "in particular men," and that those who are not so characterized (let's call them "normal people") have been dealt a genetic hand that lacks such devilish cards. Normal people don't have bad genes.

Okay, so in the real world I suspect that most people are not so naïve; if you're reading this blog, then you probably know that bad genes can be carried by normal, healthy people. Nevertheless, when we think about bad genes – or more technically, deleterious mutations – we are likely to think that they are not very common.

Molecular evolution: improve a protein by weakening it

In the cartoon version of evolution that is often employed by critics of the theory, a new protein (B) can arise from an ancestral version (A) by stepwise evolution only if each of the intermediates between A and B are functional in some way (or at least not harmful). This sounds reasonable enough, and it's a good starting point for basic evolutionary reasoning.

But that simple version can lead one to believe that only those mutations that help a protein, or leave it mostly the same, can be proposed as intermediates in some postulated evolutionary trajectory. There are several reasons why that is a misleading simplification – there are in fact many ways in which a mutant gene or protein that seems to be partially disabled might nevertheless persist in a population or lineage. Here are two possibilities:

1. The partially disabled protein might be beneficial precisely because it's partially disabled. In other words, sometimes it can be valuable to turn down a protein's function.

2. The effects of the disabling mutations might be masked, partially or completely, by other mutations in the protein or its functional partners. In other words, some mutations can be crippling in one setting but not in another.

In work just published by Joe Thornton's lab at the University of Oregon*, reconstruction of the likely evolutionary trajectory of a protein family (i.e., the steps that were probably followed during an evolutionary change) points to both of those explanations, and illustrates the increasing power of experimental analyses in molecular evolution.

What a selfish little piece of...

"The Selfish Gene." "Selfish DNA." Oh, how such phrases can get people bent out of shape.  Stephen Jay Gould hated such talk (see a little book called The Panda's Thumb), and Richard Dawkins devoted more time to answering critics of his use of the term 'selfish' than should have been necessary. Dawkins' thesis was pretty straightforward, and he provided real examples of "selfish" behavior of genes in both The Selfish Gene and its superior sequel, The Extended Phenotype. But there have always been critics who can't abide the notion of a gene behaving badly.

Leaving aside silly bickering about the attribution of selfishness or moral competence to little pieces of DNA, let's consider what we might mean if we tried to imagine a really selfish piece of DNA. I mean a completely self-centered, utterly narcissistic little piece of DNA, one that not only seeks its own interest but does so with rampant disregard for other pieces of DNA and even for the organism in which it travels. Can we imagine, for example, a piece of DNA that deliberately harms its host in order to propagate itself?

Sure, we might picture genes acting in naked self-interest, perhaps colluding to create an organism that can fly and mate but can't eat. We can picture genes driving organisms to take outrageous risks in order to reproduce. And we can picture millions and millions of "jumping genes" that don't seem to care at all about the host's welfare while they hop about in bloated mammalian genomes. (If you are one who prefers to think of these transposable elements as beautifully-designed marvels of information transfer and storage, you can have a pass on that last one for now, because you won't like where we're going with this.) But can we picture a gene that actively harms its host in order to get ahead?

Genetics, evolution, and sexual orientation: the gay extinction hypothesis

Three weeks ago, I went to the Cornerstone Music Festival with my two oldest kids. For the second year, I was an invited speaker in the festival's excellent seminar program. This year, my two series were entitled "Alien Worlds" and "Zombies on Jeopardy" – exploring extreme biology and human nature, respectively. It was fun, if a little too hot for a day or so.

At one point, I was discussing human intelligence and its genetic underpinnings. And I got a loaded question, paraphrased thus: "What happens when you substitute 'sexual orientation' for intelligence? Is homosexuality 'genetic' and if so, what does that mean for Christian views of sexuality?" (The Cornerstone Festival is a Christian music festival, known for embracing music at the 'fringes' while remaining consistent with most mainstream evangelical sensibilities, including a typically evangelical view of homosexuality.) I answered that sexual orientation also has a fairly significant heritable component, meaning that some of the variation in sexual orientation is accounted for by genetics. Then I got a followup question/comment, delivered with intriguing smugness, and paraphrased as follows: "Homosexuality can't be genetic, because homosexuals don't have kids and so the trait will be eliminated from the population." Without going into the complexity of sexual orientation as a biological phenomenon, I will critique this person's claim, since I hear it from Christians with disheartening frequency.

Alu need to know about parasitic DNA: Alu elements and blindness

Age-related macular degeneration (AMD) is a leading cause of blindness in humans, and the leading cause of visual impairment during advanced age. The condition comes in two basic forms, the most severe of which is untreatable. Called geographic atrophy (GA), this condition involves the steady destruction of the retinal pigment epithelium, a layer of tissue in the eye that is essential for the health and maintenance of the photoreceptors in the retina. Loss of the pigment epithelium means certain death for the photoreceptors, and that means visual impairment and then blindness for the affected person.

A major publication in Nature last month (Kaneko et al., "DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration," Nature 17 March 2011) now points to one likely cause of AMD, and in the process provides a chilling example of what can happen when the parasitic Alu elements in our genomes (see the previous post for an introduction) are left unrestrained.

Alu need to know about parasitic DNA: Introduction to Alu elements

Defenders of intelligent design theory often dwell on the topic of "junk DNA," which has been molded into a masterpiece of folk science. The ID approach to "junk DNA" involves a fictional story about "Darwinism" discouraging its study, and a contorted and simplistic picture of a "debate" about whether "junk DNA" has "function." The fictional story is ubiquitous despite being repeatedly debunked. But the picture of an ongoing "debate" about "function" is harder to sort out. Like most propaganda, that picture contains enough truth to sound plausible. (Browse my "Junk DNA" posts, and work by Ryan Gregory and Larry Moran, for more information on errors and folk science associated with these topics.)

There is, in fact, some scientific disagreement about functions of various elements in genomes, but it's not the crude standoff that ID apologists depict, and it has very little to do with "Darwinism." The debate, if we must call it that, is about at least two matters: 1) the extent to which certain genomic elements contribute to normal function or development of organisms; and 2) the means by which we might determine this. The debate is not about whether non-coding DNA can have function, or even about whether some segments of non-coding DNA do have function. That debate was invented by anti-evolution propagandists.

It's just a stage. A phylotypic stage. Part III: Fish and more

Given that disputes over the existence and meaning of the phylotypic stage and the hourglass model have simmered in various forms for a century and a half, the remarkable correspondence between the hourglass model and gene expression divergence discovered by Kalinka and Varga and colleagues would be big news all by itself. But amazingly, that issue of Nature included two distinct reports on the underpinnings of the phylotypic stage. The other article involved work in another venerable model system in genetics, the zebrafish.

The report is titled "A phylogenetically based transcriptome age index mirrors ontogenetic divergence patterns" and is co-authored by Tomislav Domazet-Loso and Diethard Tautz. To understand how their work has shed light on the phylotypic stage and the evolution of development, we'll need to look first at an approach to the analysis of evolutionary genetics that these two scientists pioneered: phylostratigraphy.

It's just a stage. A phylotypic stage. Part II: The flies

The controversy about the existence of the phylotypic stage is more than some bickering about whether one blobby, slimy fish-thing looks more like a Roswell alien than another one does. It's about whether the phylotypic stage means something, whether it tells us something important about development and how developmental changes contribute to evolution. To answer such a question, we need more than another set of comparisons of the shape and movements of embryos and their parts. We need a completely different way of looking at the phylotypic stage, to see if something notable is going on under the hood. So vertebrates all look the same at the tailbud stage. What does that mean?

Embryos look the way they do because of the positions and behaviors of the cells that make them up. The cells in an embryo all have the same DNA, and the link between that DNA and those specific cell behaviors is the basic process of gene expression. (This is a fundamental principle of developmental biology.) And by gene expression, we usually mean the synthesis of messenger RNA under the direction of genes in the DNA. Different cell types express different sets of genes, and the orchestration of the expression of particular genes at particular times is a big part of what makes development happen. When considering the phylotypic stage, then, developmental biologists wondered: is the apparent similarity of embryos at that stage reflected by similarities in gene expression. Or, more specifically, does the hourglass model hold up when we look at gene expression? This was the focus of the two articles in last Friday's Nature that inspired the cool cover.

Mapping fitness: bacteria, mutations, and Seattle

Thinking about fitness landscapes can stimulate detailed discussion and consideration of the meanings and limitations of such metaphors, and my introductory comments at The Panda's Thumb did just that. Most notably, Joe Felsenstein pointed us to the various ways these depictions can be employed, and urged everyone to use caution in interpreting them. All too true, but the goal here is modest: I want to discuss the interesting questions that arise when considering the relationship between genotypes and phenotypes, i.e., how a particular genetic makeup influences fitness, whether the genetic makeup in question is simple or complex, and however fitness is conceived. These questions can take further discussion in all sorts of directions, but there are two that I have in mind in this series. First, I want to point to increasing capacity of scientists in their ability to examine these relationships experimentally. Second, I want to highlight the failure of design creationists to address or even to understand such matters.

Mapping fitness: landscapes, topographic maps, and Seattle

The concept of a "fitness landscape" is a fundamental idea in evolutionary biology, first introduced and established during the so-called "evolutionary synthesis" in the early 20^th century. It was the great Sewall Wright who pictured adaptation as a "walk" through a landscape (pictured below), where the walking is done by variants (of an organism or a molecule) and the landscape is a theoretical representation of the relative fitness of the variants. (J.B.S. Haldane did similar work around the same time, but Wright's paper is much better known perhaps because it's more accessible to non-experts. See Carneiro and Hartl in PNAS earlier this year for more.)

It's a simple concept, and a helpful one, though sometimes subject to over-interpretation. And it helps to frame some of the big questions in evolutionary genetics. One of those big questions is this one, stated somewhat simplistically: how do the variants navigate to fitness peaks, if there are fitness valleys that separate the peaks? (The ideas is that fitness is higher on the peaks, and so a population would be unlikely to descend from a local peak into a valley.) In other words, given a particular fitness landscape, what are the evolutionary trajectories by which variation can explore that landscape?

How bad genes can escape the Grim Reaper (and why this is good)

Last month, PZ Myers wrote an interesting piece at the Panda's Thumb in which he discussed some problems with very simple models of evolutionary genetics. One of his main themes was the idea that many genetic changes are neutral with regard to fitness; instead of immediately triggering selection (positive or negative), they're just "tossed into the stewpot." I recently joined the crew at PT, so for my first post I picked up on PZ's point and discussed a very recent article that describes one way in which organisms can carry seemingly deleterious genes around with them.

The concept of interest is called "developmental buffering," and it's just another fascinating biological phenomenon that creationists and ID propagandists are wise to ignore.

Read the article at the Panda's Thumb.

Behe and probability: one more try

Almost two years ago, I reviewed Michael Behe's latest book, The Edge of Evolution, here on the blog. I was unimpressed, to say the least, and remain of the opinion that Behe should not be considered a serious scientific thinker given his failure in that ludicrous book.

Since then, my posts have been referenced occasionally in the blogosphere, typically by people trying to explain Behe's surprisingly crude mishandling of probability in the context of genetics. One particular point has been singled out as a mistake on my part, and some ID defenders want that mistake to rescue Behe's argument. Let me describe the so-called mistake, then explain why I'm right.

Carnival of Evolution 14

Welcome to Quintessence of Dust and to the 14th Edition of the monthly Carnival of Evolution. Thanks for stopping by, and for supporting scientific carnivalia, members of a taxon that seems to be flirting with extinction.

One good reason to visit a carnival: brain stimulation. Brain Stimulant offers some thoughts and speculations on Free Will and the Brain, touching briefly on themes of selection and adaptation, and he doesn't charge as much as the clinic would.

Another good reason: you can bump into real scientists, the kind who actually work on evolution. Ryan Gregory has a day job as an expert on genome evolution, but somehow finds the time to blog at Genomicron. Recent entries there include fascinating pictures of ongoing field work. For this month's carnival, be sure to read two reviews of the ideas of Stephen Jay Gould, focusing on controversial papers by Gould published in 1980 and 1982. You may find that you have been misinformed about Gould's positions, and you'll surely learn more about evolution.

Michael White at Adaptive Complexity is another blogging scientist, and he writes very clearly about parasitic DNA in Selfish Gene Confusion.

David Basanta is a biologist who runs a cool blog called Cancerevo: Evolution and cancer, which is subtitled "Studying cancer as an evolutionary disease." Check it out, and don't miss his recent piece on Stem cells and ecosystems.

Zen Faulkes is a biologist who blogs at Neurodojo. That's cool enough, but the subtitle of that blog is "Train your brain." Hey, this could be a theme for the whole carnival! He recently wrote about a walking bat in New Zealand. Bat evolution...we can't get enough of that. I've written about it myself.

Brains and their origins come up in an extensive discussion of early animal evolution at AK's Rambling Thoughts. The post is The Earliest Eumetazoan Progression.

At The Loom, the peerless Carl Zimmer discusses AIDS in chimps and the relevance of the story to conceptions of scientific progress. AIDS and The Virtues of Slow-Cooked Science is engrossing and important. And John Wilkins discusses some new fossil apes in an excellent recent post at Evolving Thoughts.

John Lynch reviews a new book on Alfred Russell Wallace. Caveat lector. Brian at Laelaps takes us on a historical tour of the work of Florentino Ameghino. Are those elephants or not? Brian's discussion is typically excellent.

At The Spittoon, AnneH discusses new findings concerning both the past and the future of the mammalian Y chromosome.

Hoxful Monsters is a future host of this carnival; Nagraj recently reviewed some recent work on pattern formation in the development of spiders. Wonderful evo-devo stuff.

Someone at Wired wrote some swill about the "10 Worst Evolutionary Designs" which annoyed a few smart bloggers. At Deep-Sea News, Dr. M sets the record straight. The title is self-explanatory: Worst Evolutionary Designs? No! Brilliant Solutions to the Complexity of Nature and Constraints.

Larry Moran at Sandwalk is attending a conference entitled Perspectives on the Tree of Life. He's posted reviews of days one and two so far.

And that's our carnival. Thanks for reading, and on the way out I hope you'll look at my nearly-complete series on Notch and deep homology.

Next month's edition will appear at Southern Fried Science. To submit posts, use the submission form found at the Carnival of Evolution site. And if you like the carnival, help us promote it with a link, and/or consider hosting. More info at the carnival site.

Deep homology and design: common design and its implications

Consider these not-so-random samples from the animal world: a cockroach, a zebrafish, a mouse. What do these creatures have in common?

Left to right: American cockroach (Periplaneta americana), zebrafish (Danio rerio), house mouse (Mus musculus). Cockroach image from Wikimedia Commons, zebrafish and mouse from Wellcome Images.

Well, they're all animals and that means they're all eukaryotes, for example. They all have DNA-based genomes. They all like water to some extent. They all have muscles that cause them to move. And so on.

But let's think of them in a different way. Let's think of them as things that exhibit design. (Not Design. Just design.) We see similarities like the ones we just listed, and we see some dramatic differences. Insect, exoskeleton, open circulatory system. Fish, gills, egg-laying. Mammal, milk, hair, live birth, temperature control. We can see elements of common design (limbs and joints, eyes, nerves) and elements of specialized design (lungs, fins, antennae).

Now let's forget everything we know about common descent and adopt an Intelligent Design perspective. This isn't hard to do: just think of each animal as a machine that was designed to be the way it is. The machines have some common design elements and some specialized design elements. Now this is important: let's assume that each machine was designed separately, such that design decisions were made on a case-by-case basis (for each type of machine, not for each individual machine). In other words, let's think of the cockroach as designed from the ground up to be a cockroach, and the fish and the mouse likewise. Simple, right? I think so.

Now, let's look under the hood of each machine and ask detailed questions about how it's built, again with the assumption that it was designed. Not just its overall structure, but also the procedures used for its assembly. Let's look, in other words, at its molecular machinery – machinery for signaling between cells and tissues, machinery for signaling within individual cells, machinery for directing gene function during development and normal function. And let's focus specifically on the signaling systems in these creatures and in their developmental stages. What would we expect to see? Well, let's consider some basic scenarios.

1. Maybe the signaling systems will be roughly the same – or even largely the same – in all three animals. This would imply that such systems are hard to assemble and perhaps even harder to tune and maintain, and therefore we would conclude that there are very few ways to make a working system. The only other explanation would refer to preferences on the part of the designer, who was unconstrained by design limitations but nevertheless insisted on doing things a certain way.

2. Maybe the signaling systems will differ between the three animals, to such an extent that it is clear that the choice of a system is somewhat arbitrary, arbitrary in the sense that the choice of a particular system is largely independent of the context or the function that is specified. The implication is that there are plenty of ways in which cells and molecules can communicate, and no strong constraints on the designer's choices.

Now of course we may find examples of both scenarios in our analysis. Perhaps some signaling systems will appear to be highly constrained while others will be largely different among the three species. The point, though, is this: when examining machines that were separately designed, common design implies either design constraint or designer preference. Divergent design implies a lack of design constraint. There are no further options: either the designer was constrained, or she wasn't; if unconstrained, she could nevertheless choose a favorite scheme and leave the impression that she was somehow constrained.

Designer constraint could arise in various ways. It could be that a particular signaling system is uniquely suited to a particular purpose. It could be that a particular signaling system is highly robust to damage or other challenges. It could be that there are only a handful of different possibilities due to limitations in the raw materials. One variation of that last possibility would look a lot like how evolution is known to work: the designer tweaks the system a little at a time, working with the materials supplied by each generation and therefore constrained by common descent.

Design proponents can be stunningly cavalier about all this. "Common elements in animal biology? Well of course! Common design!" But wait: common design implies either design constraint (that was the best way to do it – or the only way to do it) or designer preference (she just happens to like it that way), and those are dramatically different from an explanatory standpoint.

It turns out that signaling systems in animal development are so universally conserved that they require an extraordinary explanation. The commonality of the elements is so striking that it took most biologists by surprise when it first became evident, and remains one of the most remarkable facts of developmental biology today. We'll look at some recent advances in this area of evo-devo in posts to come.

But one last thing: I'd like to try a thought experiment to illustrate how we might approach questions of signaling in animal cells and embryos. Consider a group of 50 people who have agreed to help with your experiment. You divide them into pairs and tell each pair to send one person out of the room. Then you tell the remaining people to greet their partners upon their return, using a single word of their choosing that is certain to convey the greeting. You observe that all of the people employ either "hello" or "hi" for this purpose.

Question: would you conclude that "hello" and "hi" are uniquely suited for the task, and that no other word could possibly have worked? I hope you would seek another explanation and perhaps consider trying the experiment in, say, Shanghai or Guadalajara. You would conclude, I wager, that the word itself is of little explanatory value. In other words, the choice of a word was constrained, but not by anything specific to the word itself. In Shanghai, it's "ni hao." Maybe somewhere it's "duuuuuuude." And in a matter of minutes, you could change it to "ahoy" or "blorp" or anything you want.

And if you really wanted to probe the notion of constraint in human conversation, you would ask your 25 pairs of subjects to come up with an identifying word or phrase that they could call out to find each other in the dark. You would find, of course, that the choice of that word or phrase would be almost completely unconstrained.

What does all this have to do with signaling systems and design? That's for next time. Till then, blorp.