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.

New limbs from old fins, part 2

Titktaalik roseae.
Image from
https://tiktaalik.uchicago.edu/index.html

The second post in my series on limb evolution is now up at the BioLogos site. This installment reviews the fossil evidence on fin-to-limb evolution, introducing the famous Tiktaalik. Next up: evidence from developmental biology.
The first post at BioLogos outlined limb structure and some historical background. The series at BioLogos was spawned by an idea here at QoD, which aimed to discuss some new findings in the fins-to-limbs story. Those new findings will be discussed in the final installment of the series at BioLogos.

*Edit July 2020: The series was consolidated into a single article on the BioLogos site. The link now goes to that single article.

New limbs from old fins, part 1

Last month, I started a series on the topic of limb evolution, here at Quintessence of Dust. That series has been transformed (through a series of intermediates) into a series of posts* at the BioLogos site. The first installment is now up, and it provides an expanded introduction to the topic and a little historical context. Subsequent posts will tackle fossils, developmental biology, genetics, the explanatory role of design, and related themes.

So go check out the introduction, and feel free to contribute comments, questions and suggestions here. And enjoy the image below, from Wellcome Images, which is featured in the post at BioLogos. Cool, huh?

*Edit July 2020: The series was consolidated into a single article on the BioLogos site. The link now goes to that single article. 

Let's see a show of autopods. Part 1.

The discovery of deep homology was a milestone in the history of evolutionary thought. Anatomical structures in distantly related organisms, structures with only the barest of functional similarities, were found to be constructed under the influence of remarkably similar genetic pathways. The original and classic example from 1989 involves genes controlling pattern in both insects and mammals – the famous Hox genes. Another great example emerged from the study of limb development and evolution in vertebrates, work beautifully described by Neil Shubin in Your Inner Fish.

The idea that the limbs of various animals are homologous – meaning that they are variations on a theme inherited from common ancestors – is certainly not new, with roots in the exploration of 'archetypes' by the great Sir Richard Owen. But deep homology goes, well, deeper, suggesting that even basic themes like 'limb' or 'eye' or even just 'thing-sticking-out-of-the-body-wall' can be identified and seen to be conserved throughout the biological world. And, importantly, deep homology points to genetic mechanisms that underlie basic themes, structural concepts so distinct that they would not be judged to be related by structural criteria alone. Consider, for example, limb development in vertebrates.

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?

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.

It's just a stage. A phylotypic stage. Part I.

Disputes and controversies in science are always a good thing. They're fun to read about (and to write about), and they're bellwethers of the health of the enterprise. Moreover, they tend to stimulate thought and experimentation. Whether scientists are bickering about evo-devo, or about stem cells in cancer, or about prebiotic chemistry, and whether or not the climate is genial or hostile, the result is valuable.

Now of course, some controversies are invented by demagogues for political purposes. The dispute in such cases is far less interesting and clearly less profitable, even if participation by scientists is necessary.

This week, two papers in Nature weighed in on a major scientific controversy that has its roots in pre-Darwin embryology, fueled by some gigantic scientific personalities and even tinged with what some would call fraud. This intense scientific dispute spawned a sort of doppelganger, a manufactured controversy that is just one more invention of anti-evolution propagandists. The Nature cover story gives us a great opportunity to look into the controversies, real and imagined, and to learn a lot about evolution and development and the things we're still trying to understand about both.

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.

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: why Notch?

The Notch signaling pathway is a golden oldie of genetics in two ways. First, it's a system that was first described at the dawn of modern genetics – named by its founder, Thomas Hunt Morgan – and used to establish some of the most basic principles of "the physical basis of heredity," as Morgan put it. (His book by that title is a founding document of modern genetics, describing in 1919 what we now call chromosomes without any knowledge of their chemical makeup.) Second, it's a system now known to be as ancient as animals themselves.

Why Notch? The name refers to the appearance of some of the first mutant fruit flies described by Morgan and his colleagues in their famous work in the early 20th century. They found flies with notched wings, and found that the trait was dominant.

Figure 1 from T.H. Morgan, "The Theory of the Gene." American Naturalist 51:513-544, 1917.

So aside from its importance in evolution and development, Notch is of historical interest to genetics. Now, Morgan was interested in Notch (the gene name is capitalized because the original trait is dominant, in case you're wondering) because of its mode of inheritance, not specifically because of its biological effects. (I mean, who cares about flies with notched wings?)

But twenty years later, things got more interesting when a different mutation in Notch was found to cause a weird (and lethal) overgrowth of the nervous system. Interesting... then, as geneticists began to probe the genetics of animal development 50 years after Morgan's initial discoveries, using the fruit fly as a model, Notch started turning up again and again. Problems in Notch signaling led to developmental problems all over the place: brain, eyes, gut, wings, bristles.

By the beginning of the 1990's, geneticists had figured out why its activity is so central to proper development: Notch controls a crucial type of cell-to-cell interaction that leads to a change in cell fate. And they had found Notch signaling in animals of every kind, including in humans, mediating the same kinds of inductive developmental interactions. It's not as complicated as it might sound – in such an interaction, two cells interact physically (they have to touch) and after the interaction one or both of the cells changes its developmental fate, choosing to become, say, a nerve cell or a skin cell. That weird brain overgrowth in the flies with no Notch activity results from a failure of cells to communicate in this way, such that all the cells on the outside of the fly's head become brain cells. (Flies, like most animals, prefer to have some skin over their brains, but in these mutants there's very little skin and lots of extra brain. Ick. See Figure 1 of this recent paper in BMC Biology for pictures; the green stain indicates nerve cells and the second animal down has the nasty trait.)

The point is that Notch signaling involves direct cell contact, and typically leads to cells making decisions about what to do when they grow up. So how does it work? Well, we know an awful lot about this particular system, and there are myriad details of mechanism and control that I'm going to skip. The very basic outline is as follows. Some cells make the Notch protein, which is a receptor. Other cells make the Delta protein, which is the signal that activates the receptor. (One useful analogy is that of locks and keys: Notch is the lock, Delta is the key.) Both proteins are displayed on the cell surface. When the two cells come into contact, the Delta protein on one cell activates the Notch protein on the other. When Notch becomes activated, it gets chopped into at least two pieces. One piece leaves the surface of the cell and travels inward to the nucleus of the cell. There, in collaboration with other proteins, it causes changes in gene expression, meaning that some genes are turned on or up and others are turned off or down.

This mode of signaling is unique and extraordinary. What we have is a signaling system that takes cell-to-cell contact and converts it directly into changes in gene expression.

Now, let's think carefully about this. We have a system of receptors and activators, in the form of Notch proteins (there are at least four in humans) and Delta proteins (there are several in humans, in a few different protein families), which serve a critical and unique purpose in cell-to-cell signaling. The function is conserved in all known animals, and that's not surprising – having cells send messages to their immediate neighbors, directing them to adopt particular fates, is key to constructing tissues and organs. I hope you'll agree that we should expect to see these inductive mechanisms in the development of complex organisms. More to the point, one should expect this regardless of one's stance on questions of "intelligent design."

Here's what is surprising. The same Notch proteins are used for this purpose in every known animal. And here's why that's surprising: as far as we know, there's no reason to insist on those particular proteins playing those particular roles. It's easy to envision – and then design and create – a set of locks and keys that bear no resemblance to Notch or Delta but that can accomplish these somewhat basic purposes just as well. There's no need for such a specific solution to a basic challenge. Why does every animal use Notch? Recall the previous post in this series and how we approached this question of common design. Here, again, are our options.

1. These inductive signaling events could only be accomplished by Notch. There is a design constraint, currently unknown, which forces that choice. It may seem that the system could have been effectively constructed using a different lock-and-key combination, but in fact it could not function (or function well) any other way.
2. These inductive signaling events could be mediated in various ways, but the choice of Notch has been forced by common ancestry. The earliest animals settled on this choice, and their descendants have used it ever since.
3. These inductive signaling events could be mediated in various ways, but an intelligent designer has repeatedly chosen Notch for reasons known only to her/him/it.

Option #1 is, in my view, unreasonable. The system is not complicated in its basic design. There are no clear constraints on the choice of lock and key. A designer who is crafting an organism from the ground up need not select that particular lock/key combination, and someone who intends to argue otherwise needs to demonstrate how that particular combination is superior.

Option #3 is, I think, perfectly reasonable. The only problem is that one must know quite a lot about the designer to begin to surmise her/his/its goals and proclivities. Without that knowledge, it is no more reasonable to assume a preference than it is to assume a constraint.

The point is not that we can ever rule out preferences or other characteristics of a creator or designer. The point is that we can rarely make explanatory use of them. Consider that while we may assert that the Creator/Intelligent Designer prefers that pine trees have needles, we would not advance that as a useful explanation for why pine trees have needles. Specifically, we would never advance that as an alternative explanation in place of one that notes that today's pine trees have the same needles that last century's pine trees had, by virtue of biological ancestry.

Notch signaling represents one of the classic examples of deep homology. It seems to me that design theorists need to deal with deep homology before they can ever be taken seriously as scientific thinkers. Deep homology is crying out for explanation, and those who believe that the biosphere cries "design" are remiss in not offering a serious design-based explanation for the fact that every animal on the planet uses the same lock-and-key mechanism to achieve basic cell-to-cell inductive communication.

Next, we'll look at a recent and very interesting example of new findings that illustrate the striking conservation of Notch-mediated developmental events – an example of deep homology that could arise from the very root of animal ancestry.

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.

Deep homology and design: a new series

Recently I was reading a superb review article [doi] on the subject of a famous and important cellular signaling pathway called the Notch pathway. The author, Mark Fortini of Thomas Jefferson University, quoted James Puckle (an 18th-century English inventor and writer) on the "wonderful frame of the human body" in which "so many strings and springs" which all must "be in their right frame and order" for life and concluding that "it is next to a miracle we survived the day we were born." (If you must know, it's maxim #914 in The Club, in a section called "Death.")

This reminded me of some personal tragedy in our own family, after which Puckle's conclusion was repeated almost verbatim. It also reminded me of my need to write about the amazing homology of developmental signaling mechanisms in animals. For many months, I've listed an article on "deep homology" as the subject of my next Journal Club. But this topic won't fit into one article review, so I've decided to turn it into a little series.

Here's what Fortini writes in his introduction, after quoting Mr. Puckle:

Surprisingly, research over the past few decades has revealed that the orderly differentiation and arrangement of these many physiological ‘‘strings and springs’’ are controlled by a relatively small number of developmental signaling pathways. These pathways, including the Notch, Ras/MAPK, Hedgehog, Wnt, TGFβ, and JAK/STAT pathways, among others, are widely conserved throughout the animal kingdom and they cooperate throughout development to pattern a diverse array of tissues in different animal species.

The lingo might seem strange, but I hope the point is clear. The vast diversity of animal life, with "endless forms most beautiful," is assembled through the action of a small set of signaling systems. And, remarkably, the systems are used in the same ways in animals that couldn't be more different in behavior or structure.

This fact raises interesting questions about design and evolution. Why so few systems? Why are they used again and again, for the very same purpose? Are these choices forced by design constraints of some kind, or is there another explanation? Could it have been otherwise? Can it be otherwise? I'll tackle those questions while discussing some recent experiments in evolutionary developmental biology, or evo-devo.

And what of this phrase "deep homology"? It was coined by some of the founding minds of evo-devo – Neil Shubin, Cliff Tabin and Sean Carroll – as they considered the fact that animal limbs of every kind are "organized by a similar genetic regulatory system that may have been established in a common ancestor." And we mean limbs of every kind: whale flippers, fish fins, bat wings, human arms, and, amazingly, insect limbs. Such disparate structures may not be evolutionarily homologous (meaning that they were modified from a common ancestor) but the signaling systems that create them are homologous.

This, then, is deep homology: the sharing of signaling mechanisms that are used to create diverse (though often functionally similar) animal structures. So please join me, and maybe we'll lure interesting commenters into the discussion.

Survivor:UD -- when will they vote Matheson off?

Okay, that'll probably be the last UD moderation joke, because my irresistible charm has had its predictable (non-random) effect. I have a nice discussion going with two regulars at Uncommon Descent, StephenB and the original poster, Thomas Cudworth. I'll post my contribution below as usual, and you can read the rest of the conversation in the growing thread at Uncommon Descent.

Before you go there, have a look at this nice (older) post on randomness in the Bible, at Martin LaBar's blog, Sun and Shield. Martin is a regular commenter here, and his blog is a joy to read.

Please jump in here if you wish; I don't moderate comments and will welcome any and all.

---

I'll respond to both Thomas and StephenB here. First, to the moderator: thanks for posting my comments. The discussion has been profitable, and I take it that Thomas and StephenB would agree. Please note that I am mirroring my own contributions on my blog, Quintessence of Dust, and will continue to do that, at least so that others can participate in the conversation. (I don't moderate comments.) In answering both Thomas and StephenB, this post got pretty long, and I would understand if you asked us to move it elsewhere. Just let me know.

To Thomas @61:

I do think that your statements appear to bracket God's power, but you didn't mean to say that, and I think I see why we're struggling to understand each other here. You discuss "pure Darwinism" and "strict Darwinism" and "the naked Darwinian mechanism." Here you are referring, I gather, to random mutation and natural selection with a further stipulation: that no divine guidance of any kind is involved. (We could substitute 'design' or 'teleology' here and my point would be the same.) And you are, I think, correct in identifying that -ism with Mr. Darwin, as Prof. Hodge so ably demonstrated. Hodge was right: "Darwinism," so defined, is atheism. This may mean that I'm not a Darwinist, but a Grayist. (I would be most pleased to bear that name if I thought anyone else would get the allusion.) The point, though, is this: your criticism of Christians who embrace "Darwinism" only makes sense if those Christians embraced the Darwinism that Hodge railed against, which he correctly identified as atheism. And that means your criticism reduces to this: Christians shouldn't be atheists. I'm struggling to understand why you think so many Christians are that stupid, which we'd have to be in order to embrace the "Darwinism" that you condemn. With all due respect, you should reconsider a line of argument that can only imply abject stupidity (or perhaps evil) on the part of the Christians that you name. For my part as a Christian evolutionist, I'll gladly make the statement you call for: Darwin was indeed "partly wrong" about the "mechanism of evolution," because he insisted on ateleology, with neither scientific nor metaphysical justification. Trivial.

So, Thomas, I'm not at all sure who these Christian TEs are who embrace atheistic Darwinism. I'm pretty sure they don't exist. In any case, I'm not one of them, and my intention here at UD is to speak only for myself.

With the understanding that I do not seek to speak for others, I will say that I reject your accusation against three of the four Christian scholars you singled out. Francis Collins contradicts you on page 205 of The Language of God; Ken Miller in chapter 8 of Finding Darwin's God, and especially on pp. 238-9; Denis Lamoureux refers explicitly to evolution as a "teleological natural process ordained by God." I don't know Ayala's work on this subject well enough to know where he stands, but I very much doubt that you have gotten him right. Perhaps I have misunderstood you again, but whether you retract your accusations or not, I can't currently take them seriously.

My point about atheists was meant only to note that the viciousness of the rhetoric on UD constitutes a major deterrent to me with regard to your movement. I would not count myself among Christians who engage in such practices. But that doesn't mean I wouldn't have lunch with you. I'll even buy.

Finally, thanks for making me feel welcome as a "friendly critic." I don't buy your martyr case, and I'm mostly amused by the apocalyptic martial prose, but I also don't doubt that people have been treated unfairly. More importantly, I won't call you a bad scientist or a bad theologian for thinking about design. I may, on the other hand, point to bad science or bad theology (mostly bad science) done in the name of ID, and you and your friends are going to have to do a better job of distinguishing criticism of your ideas (some of which are spectacularly bad) from diabolical attempts to destroy you and anyone who looks like you. (Bill Dembski botched this badly in his fatwa-like rant from two weeks ago; read it carefully and see if you can understand my disgust.)

To StephenB @62:

I'm not sure what to do with most of your comments, except to thank your for taking the time to lay out your thoughts and to do it with a measure of respect. Just a few responses, then I'll answer your question at the end.

1. I do not belong to any particular school regarding God's work in the world. Kenosis is interesting -- that's all I said. Your thoughts parallel mine for the most part. I wouldn't go as far as to say that Psalm 19 and Romans 1 imply that "design in nature is detectable," but that might be because I'm suspicious of the word "design" here. I suspect that your claim regarding those scriptural passages is indicative of some very significant differences in outlook between you and I.

2. Your rebuttals of Stephen Barr are interesting and informed, but my purpose in citing his piece was to highlight Aquinas' very clear pronouncements regarding "chance" and providence. That was all.

3. You write: "God CAN use random events. The problem is, however, TEs insist that God does EVERYTHING that way." Well, StephenB, obviously I'm not a TE. I'm not sure there's any such thing as a Christian TE, by your reckoning, and I'm not sure there's anything more for us to discuss on this particular topic.

4. You asked about the various phenomena I listed as examples of scientific explanations that invoke randomness. Here's a brief overview.

a. Axonal pruning is widespread during vertebrate brain development, and is preceded by the overgrowth of axonal projections into a target field. These projections are guided by various mechanisms into that target field, but once there they find themselves in competition with an excess of other axons. These so-called exuberant axonal projections are postulated to fill the target field randomly, meaning that they display no discernible pattern. Pruning (also termed selection for obvious reasons) occurs following competition, which usually involves electrical activity of the axons. Analagous processes are involved in the elimination of excess synapses, and even excess neurons.

b. Mammalian females have 2 X chromosomes, while males have only one. Since gene dosage seems to be adjusted such that one X chromosome is enough for any given cell (which makes sense given that male cells have only one to start with), one of the two X chromosomes in every cell in a female's body is inactivated. (This occurs during early development, and results in the organism becoming a chimera of areas that express the maternal X chromosome and areas that express the paternal version.) Because the exact chromosome that will be chosen in any given cell cannot be predicted, the process is referred to as "random." Evidence in favor of this view comes from the examination of coat color in cats and mice.

c. Erosion...the Grand Canyon...think fractals. And meteorites...if I say that meteorites are falling "randomly" onto the earth's surface, would you think I was making an atheistic metaphysical claim? Or would you understand me to be saying that there seems to be no discernible pattern?

d. Random (meaning unbiased) fertilization is the basis of Mendelian genetic analysis. If I ask you about the probability of your getting cystic fibrosis based on your parents' known status as carriers, I'm assuming random fertilization. And when geneticists see non-Mendelian inheritance patterns, they don't think "design."

e. The genes that encode antibodies (in mammals, at least) are generated by a frenzy of genetic shuffling during embryonic development. The shuffling involves some non-random processes combined with an error-prone process that randomly generates vast combinations of antibody structures.

Apparently random processes are ubiquitous in biological systems, especially during development, and I'm a developmental biologist. Is it clear why I'm completely turned off by all the nonsense about random vs. God's work?

Finches, bah! What about Darwin's tomatoes?

Charles Darwin collected all sorts of cool stuff (like a vampire bat, caught while feeding on his horse) on his journey aboard the Beagle, and it has to be said that he understood little of it until after he got back. The finches that bear his name were identified as such by someone else, and his own bird collections from the Galapagos were nearly worthless due to the fact that he hadn't bothered to label specimens as to their place of origin. It was only upon their correct identification as different species of finch that Darwin realized that the birds represented what we now call an adaptive radiation.

Darwin collected a lot of plant material, too, and much of it was completely new to science. J.D. Hooker was a botanist and contemporary of Darwin, and in 1851 he wrote a little paper, "An Enumeration of the Plants of the Galapagos Archipelago; with Descriptions of those which are new" describing his studies of Darwin's collection. It was more than 100 pages long.

One unique feature of the collection was a pair of species of tomato plant. Like all other species in the archipelago, the Galapagean tomatoes resemble South American species, but are subtly different. More interestingly, the two Galapagean species are highly similar to each other (and reproductively compatible), but occupy separate habitats and exhibit some odd variations, including a striking divergence in leaf shape.

Image from Figure 1 of Kimura et al., cited below. On the left is S. cheesmaniae; on the right is S. galapagense.

How might such a variation arise in evolution? A nice study published in Current Biology two weeks ago provides the interesting answer, and addresses an important question raised by evo-devo theorists. The article is "Natural Variation in Leaf Morphology Results from Mutation of a Novel KNOX Gene," by Seisuke Kimura and colleagues at UC Davis.

Look again at the picture: the leaves pictured on the left are "normal" tomato leaves, as one might see in a Michigan garden or on the South American plants thought to be the ancestors of the Galapagean species. The leaves on the right are significantly more complex. (For lovers of botanical detail, the "normal" leaves are unipinnately compound, while the S. galapagense leaves are three- or four-pinnately compound. For the botanically challenged like me, the leaves on the right are more snowflake-like.)

This trait has long been known to be under the control of a single gene, but the nature of that gene and its effects were unknown before the experiments of Kimura et al. They did some pretty intense genetic mapping, and zeroed in on a rather small piece of the genome. Specifically, they ended up examining a region 1749 base pairs in length. Inside that region, they found exactly one change that could account for the leaf variation: a deletion of a single base pair. One DNA letter, removed from the genome, makes all that difference.

But there's more. That change isn't in the coding region of a gene, meaning that the mutation doesn't affect the structure of any protein. Like the genetic variation that Cretekos et al. studied in their analysis of bat wing development, this is an example of a change in a regulatory region of the DNA, the kind of change that evo-devo theorists have predicted to be fairly common in the evolution of new forms.

The authors showed that the teeny little one-letter change results in a huge increase in the amount of a protein called TKD1. And they did a compelling experiment similar to the one that Cretekos and colleagues did with the bat and the mouse: they took that piece of regulatory DNA (with the one-letter change) and stuck it into a tomato plant, and showed that it could induce a complex-leaf trait all by itself. No change in protein structures, just a one-letter change in a regulatory DNA region. Isn't that cool?

Kimura et al. went on to show that TKD1 reduces the formation of a complex between two other proteins, and their data suggest that the levels of TKD1 constitute a dimmer switch-like (rheostat) control on that complex, which ultimately controls the development of leaf shape.

Now, here's why this result is interesting in the context of evo-devo. A structural mutation in a protein that controls development can result in dramatic changes in form, for sure. But such a mutation will likely alter all of the processes controlled by that protein, resulting in widespread developmental reorganization. (Think "hopeful monster" here.) Evo-devo thinkers assert that regulatory changes are better suited (in general) for the induction of evolutionary changes in form, because such changes can affect isolated developmental processes without affecting the overall development of the organism. In this case, the excess TDK1 protein is able to inhibit the action of a particular complex in particular areas at particular times, without interfering in the functions of those other proteins elsewhere and at other times. Here are the concluding sentences of the paper:

Mutations affecting the expression levels of transcription factors can modify the function of a major developmental regulatory complex in some organs without interfering with its other essential roles in morphogenesis. Such dosage-sensitive interactions may be broadly responsible for evolutionary change and provide a relatively simple mechanism for the generation of natural variation.

I hope you agree that studies like this one and the bat-wing story are inherently interesting. But I hope you also see how sadly foolish it is to disparage evolutionary science as mere mythology, or to pretend to invalidate a century of evolutionary genetic analysis with a few bogus calculations. Scientists are weird enough to think tomato plant leaves on the Galapagos are worth subjecting to detailed genetic analysis, and maybe that means we're a bit on the obsessive side. But come on: we're not stupid.

Article(s) discussed in this post:

KIMURA, S., KOENIG, D., KANG, J., YOONG, F., SINHA, N. (2008). Natural Variation in Leaf Morphology Results from Mutation of a Novel KNOX Gene. Current Biology, 18(9), 672-677. DOI: 10.1016/j.cub.2008.04.008

How the bat got its wing

Nothing can be more hopeless than to attempt to explain this similarity of pattern in members of the same class, by utility or by the doctrine of final causes. The hopelessness of the attempt has been expressly admitted by Owen in his most interesting work on the 'Nature of Limbs.' On the ordinary view of the independent creation of each being, we can only say that so it is;—that it has so pleased the Creator to construct each animal and plant.

The explanation is manifest on the theory of the natural selection of successive slight modifications,—each modification being profitable in some way to the modified form, but often affecting by correlation of growth other parts of the organisation. In changes of this nature, there will be little or no tendency to modify the original pattern, or to transpose parts. The bones of a limb might be shortened and widened to any extent, and become gradually enveloped in thick membrane, so as to serve as a fin; or a webbed foot might have all its bones, or certain bones, lengthened to any extent, and the membrane connecting them increased to any extent, so as to serve as a wing: yet in all this great amount of modification there will be no tendency to alter the framework of bones or the relative connexion of the several parts.

– from On the Origin of Species, 1st Edition (1859), Charles Darwin

The wing of a bat is an amazing thing. It's not just a wing; it's clearly a modified mammalian limb. A bat looks like a lot like a rodent with really long, webbed fingers on elongated arms.

Image from Animal Diversity Web at the University of Michigan.

Recent genetic analyses have yielded a fairly solid outline of the evolutionary history of bats, which have left a somewhat poor fossil record in which the earliest fossil bats look pretty much like modern bats. It seems that bats arose relatively quickly during evolution, acquiring their distinctive feature – powered flight – in a few million years. No transitional forms have yet been found, which is a shame, because this particular evolutionary transition is the kind that is otherwise reasonably approachable for the detailed study of how changes in form come about.

The fossils can't yet show us how paws gave rise to wings, but that doesn't mean we can't test specific hypotheses regarding the paths that evolution could have taken. In fact, developmental biologists have enormous resources that can be brought to bear on the question, by virtue of decades of research on the development and genetics of the wingless terrestrial bat better known as the mouse. A few months ago, an interesting new report described one kind of genetic change that can lead to bat-like bodies, and the findings put some new wind in the sails of evo-devo.

Two of the more remarkable aspects of bat wing structure are the forelimbs and the forelimb digits, what humans would call the arms and the fingers. Both are dramatically elongated in the adult animal, despite getting off to a very typical start during early development. Check it out: in the picture below, bat and mouse limbs are compared with the image scaled so that body lengths are comparable.

Image from Figure 1 of Cretekos et al., cited below.

Developmental biologists have some pretty good ideas about how this might arise physiologically: certain growth factors (called bone morphogenetic proteins, or BMPs) are known to control limb growth, and some BMPs seem to be turned up in developing bat fingers. But the genetic mechanisms underlying these processes are unknown.

Enter Chris Cretekos and colleagues, then working in a group in Houston headed by Richard Behringer. They set out to examine the genetic underpinnings of the elongation of the forelimbs (arms) of bats, using the formidable tools of mouse developmental genetics. And, clearly, they also sought to directly test one of the central hypotheses of evo-devo: that changes in regulatory DNA sequences (as opposed to changes within the genes themselves) are a potent source of variation in evolution. Consider the beginning of their abstract:

Natural selection acts on variation within populations, resulting in modified organ morphology, physiology, and ultimately the formation of new species. Although variation in orthologous proteins can contribute to these modifications, differences in DNA sequences regulating gene expression may be a primary source of variation.

– From C.J. Cretekos et al., "Regulatory divergence modifies limb length between mammals, Genes & Development 22:141-151, 15 Jan. 2008

Besides their expertise in mouse genetics, the authors brought two major assets to their study: 1) they had already carefully mapped the development of the short-tailed fruit bat (Carollia perspicillata, "our model Chiropteran"); and 2) they knew a lot about the genetic control of limb length in other mammals. In particular, they knew that the protein Prx1 is known to influence limb elongation, by controlling the expression of other genes. So they hypothesized that changes in the activity or level of Prx1 might underlie the difference in limb length between bats and mice, and they were well-equipped to do the experiments.

First, the authors examined the Prx1 gene in the two species, and found that the overall structure of the gene is very similar in both mice and bats, and that the actual coding sequences of the two genes are almost completely identical. (Aligning the coding sequences showed that more than 99% of the amino acids are the same in both species.) In other words, the part of the Prx1 gene that codes for protein is almost certainly not a source of variation between mice and bats. This could mean that Prx1 doesn't have anything to do with the difference between forelimb length in these two species, or it could mean the the difference is generated, at least in part, by variation in the regulation of the gene. Cretekos et al. postulated that altered Prx1 regulation might be involved, and designed a cool experiment to address this possibility.

They already knew that the Prx1 gene in mice contains known regulatory elements in particular locations within the gene. (Such elements are often located in the DNA sequences that precede the coding region.) When they looked at the bat gene, they found similar elements in the same location, but these elements showed some intriguing variation: when the two regions were aligned, they shared only 67% identity, meaning that a third of the DNA bases were different in mouse and bat. They did some nifty cell biology to show that this region did function as a regulator of the expression of Prx1, then did something that biologists could only dream about before the genomic era: they altered the mouse genome by replacing the mouse regulatory region with the corresponding region from the bat genome. In other words, they gave a mouse a piece of a bat's genome, without actually changing the coding sequence of any gene.

The result was dramatic, although it won't sound that way at first. The mice with the bat DNA displayed forelimbs that were 6% longer than normal. Why is this a dramatic result? Well, first of all, think about a 6% change in a major structural attribute. If adult males in a certain country average 5'10" in height, a 6% increase would mean an increase of more than 4 inches. But more importantly, the Prx1 gene is known to account for about 12% of forelimb length – mice that lack the gene altogether show a 12% reduction in forelimb length. That 6% change reflects a huge change in Prx1 activity, a change that was completely due to alterations in regulatory DNA sequences without any change in coding sequence.

If that's not impressive enough, the authors went on to examine the importance of this regulatory region in mice, by deleting it altogether. The result was very surprising, but very interesting: limb length in mice was completely unaffected by the loss of this chunk of regulatory DNA. (The region we're discussing is 1000 bases in length.) This means that the Prx1 gene of both bats and mice contains a regulatory region that is completely dispensable for normal development but that can be altered to generate significant changes in limb length, which points to significant evolutionary potential in genetic regions that seem unimportant. Here's how the authors say it:

Maintenance of redundant enhancers for essential developmental control genes would allow changes in expression pattern to arise from mutations that alter regulatory activity while preserving the required gene function.

So, why is this significant? Here are two aspects of the story that are worth highlighting.

1. The results provide strong (and rare) experimental support for the ideas of the evo-devo school. The currently-heated debate over the merits of evo-devo is focused on the central evo-devo claim that morphological evolution (i.e., evolutionary changes in form) is driven to a large extent by changes in the regulation of gene expression, and less so by changes in the structures of the proteins that are encoded. To simplify, evo-devo postulates that significant evolutionary change – like that discussed here – is more likely a result of the varied use of a protein toolkit than a result of modification of the toolkit itself. Cretekos et al. have presented a case in point, and one that is considered outstanding in that it documents a morphological gain; many previous examples showed only losses.

2. The results provide a sharp picture of what Darwin's vision of "successive slight modifications" means in terms of developmental biology. In this case, the modifications (of a redundant regulatory region) can yield significant anatomical remodeling without altering protein structure at all.

The article was a notable advance for evo-devo and for evolutionary science, but soon there will surely be many others like it. Desperate or ignorant creationists will always find a way to avoid facing the explanatory power of common descent, but scientists are just plugging away, and for every blog post by a creationist ignoramus, there are 30 unheralded publications in the biological literature that advance our understanding of common descent and the mechanisms that generate biological novelty. And they're fun to read.

Article(s) discussed in this post: Cretekos, C.J. et al. (2008) Regulatory divergence modifies limb length between mammals. Genes & Development 22:141-151.

This is your fetal brain on drugs.

We interrupt this series on "junk DNA" and rampant folk science to bring you a months-overdue Journal Club.

I wonder how many of my readers remember this little tidbit of American genius:



I remember some very funny spoofs, mostly on T-shirts. (Back then, I think the Internet was still a toy for geeks at the NCSA.) "This is your brain. This is your brain on drugs. This is your brain on drugs with a side of bacon. Any questions?"

Marijuana, as I recall, was typically included as one of the frying pans that could turn your central nervous system into a not-very-heart-healthy staple at Denny's. It was – and probably still is – easy to get the impression that smoking pot would hollow out your skull and make you into the inspiration for a character played by Keanu Reeves.

But that's baloney. Long-term marijuana use is certainly not without effects on the brain (duh), but its most abundantly-documented pathological outcome is, well, stupidity. (Mild stupidity. How such an effect is detected in an American population is not so clear to me.) And gosh, if we intend to stamp out stupidity-enhancing behavior through legal action, we'd better send the Marines to Hollywood right now. Seriously, there are few well-established long-term negative effects of using cannabis, and most of those are associated with smoking marijuana and not with the neurological impact of cannabis itself. (Full disclosure: I have never had a joint to my lips, and the closest I've come to inhaling is second-hand at the occasional concert. It would seem that my stupidity has a different cause.)

The rules are different, though, when developing brains are the subject, and it doesn't matter whether the neuroactive substance is legal or not. Maybe pot doesn't mess up a young adult's brain, but that doesn't mean it won't affect a fetal brain. And in fact, some recent studies indicate that we should pay close attention to the possibility that fetal brain development is affected by cannabis. One of those studies, "Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity" by Paul Berghuis and colleagues, published in Science last May, suggests that mammalian prenatal brain development is likely to be significantly impacted by cannabis. It's an interesting paper for that reason, and because it deals with two of the subjects of my own research: neuronal growth cones and Rho GTPase signaling. I'll briefly explain those terms later.

The active ingredient in pot is a chemical called Delta(9)-tetrahydrocannabinol, or THC. THC affects the brain by activating receptors on particular types of neurons in the brain, causing these neurons to release less of their neurotransmitters (the normal chemical signals used for communication among neurons). While a serious intelligent design proponent might need to claim that the "purpose" of these receptors is to help people respond to pot (to suppress nausea while on chemotherapy, for example), scientists instead sought and found the chemicals within the brain that normally act on these receptors. These chemicals are called endocannabinoids, signifying that they are cannabis-like but originate from within. (After biologists discovered the endocannabinoids, they subsequently discovered the receptors, but that's not an issue here.)

This means that a first step toward discovering the potential roles of endocannabinoids in brain development is the identification of the parts of the developing brain that display the receptors. If you know where the receptors are, then you know where the chemicals are likely to act. And those are the areas that are likely to be affected by cannabinoids like THC, that come from outside.

Neurons are the brain cells that send and receive electrical signals. A typical neuron has many (perhaps thousands) of dendrites, which receive signals from other neurons, and one axon, which transmits signals to other cells, often a great distance away.
	A typical neuron. Image credit: NIH, NIDA

During brain development, neurons have to develop their magnificent and specific architectures. Beginning as a boring little round ball, a neuron has to sprout and extend dendrites and (typically) a single axon. The axon must somehow migrate to its final position, which may be in a completely different part of the body or right next door.

When Berghuis et al. looked for endocannabinoid receptors in the developing brain, they found them in the cerebral cortex, and specifically they found them in the growing axons of the cerebral cortex. In case you haven't been introduced to the cerebral cortex, it is thought to be responsible for "all forms of conscious experience."

Layers of the developing cerebral cortex of a mouse. The red streaks are developing axons that are displaying endocannabinoid receptors. From Berghuis et al., Figure 1D.

They found the receptors in other developing brain regions, too, and they showed that the endocannabinoids are likely to be produced in those regions at those times. The somewhat surprising result raises the possibility that cannabinoids affect how the brain develops, by affecting how the axons develop.

What might these effects be? The authors found that the receptors were clustered right at the growing tips of these developing axons. This region is called the growth cone, and it's one focus of my own research, because it's obviously the place where the axon is continuously elongating, and it's a place where the skeleton of the cell must be always remodeling.

The growth cone of a mouse neuron. The red indicates structural elements of the growth cone; the green blobs are endocannabinoid receptors, and the yellow smudges indicate where the red and green overlap. From Berghuis et al., Figure 2C.

If endocannabinoid receptors are located right on the growth cone, then they are positioned to influence speed and direction of axon outgrowth. Yikes!

Okay, so endocannabinoids (and, of course, THC from pot smoke) are uniquely positioned to affect growing axons in the brain. But what's the effect? The authors show that one effect is the inhibition of steering mechanisms in the growth cone. In my favorite experiment, they put neurons into an electric field, where the growth cones tend to steer toward the negative pole. When the neurons were treated with an endocannabinoid, they failed to show this preference.

Axon growth in an electric field. Each black tracing represents the behavior of one axon. On the left, notice that untreated axons tend to grow toward the negative pole (left side), and many of those that are growing toward the positive pole are turning away from it. On the far right, notice that axons treated with the endocannabinoid grow in every direction and don't care about the electric field; the center shows how they grow when there's no electric field at all. From Berghuis et al., Figure 3D .

The authors went on to show that this effect seems to result from the activation of a well-known signaling system inside cells, mediated by a protein called RhoA. RhoA is a Rho GTPase, and I'll spare you the details since you've probably read all my papers already. :-) What matters is this: Rho signaling is known to be involved in axon growth, and is generally a negative influence on axon growth. In fact, some attempts to stimulate axon growth in the spinal cord after injury (and paralysis) are focused on the inactivation of RhoA and its partners. So this connection between endocannabinoids and Rho GTPases is further evidence of a specific – and likely negative – influence of cannabinoids on axon outgrowth in the developing brain.

But is there any evidence of a specific effect on brain development, in an animal? The final experiment presented in the paper is a genetic experiment, in which the authors examined the brains of mice in which the endocannabinoid receptor (one in particular) was genetically deleted in certain parts of the brain. And they found that certain neurons in the cerebral cortex of these mutant mice had lost almost half of their inputs, presumably due to the inability of the incoming axons to find their way to the recipient neurons. In other words, when the receptors were deleted from a subpopulation of neurons, those neurons evidently had trouble making their normal connections.

What this means is that to whatever extent the human brain resembles the mouse brain with regard to expression of cannabinoid receptors and their function in growth cones, the developing human brain is potentially vulnerable to damage, or at least alteration, by exposure to THC. And as the authors note, this may partly explain recent findings (in rats) that point to permanent alterations in brain function in pot users – alterations that may predispose these people to much more serious addictions.

I've long been inclined to skepticism regarding anti-pot hysteria, and I strongly support efforts to legalize and legitimize medical use of cannabis. But these data should make us look hard at the potential implications of cannabis exposure during human development.

Article(s) discussed in this post: Berghuis, P., et al. (2007) Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity. Science 316:1212-1216.

They selected teosinte...and got corn. Excellent!

Evolutionary science is so much bigger, so much deeper, so much more interesting than its opponents (understandably) will admit. It's more complicated than Michael Behe or Bill Dembski let on, and yet it's not that hard to follow, for those who are willing to try. The best papers by evolutionary biologists are endlessly fascinating and scientifically superb, and reading them is stimulating and fun.

Yet, as an experimental developmental biologist reading work in evolutionary biology, I often find myself yearning for what we call "the definitive experiment." Molecular biology, for example, can point to a few definitive experiments -- elegant and often simple -- that provided answers to big questions. Sometimes, while examining an excellent evolutionary explanation, I think, "Wouldn't it be great if they could do the experiment?"

Now of course, plenty of evolutionary biology is experimental, and I've reviewed some very good examples of experimental evolutionary science on this blog. But when it comes to selection and the evolution of new structures and functions, the analysis often seems to beg for an experiment, one that is simple to conceive but, typically, impossible to actually pull off -- there's not enough time. The previous Journal Club looked at one way around this limitation: bring the past back to life. Even better, though, would be to find an example of evolutionary change in which the new and old forms are still living, so that one could do the before-and-after comparison. It would look something like this: take a species, subject it to evolutionary influences of some kind until the descendants look significantly different from the ancestors, then compare the genomes (or developmental processes) of the descendant and the ancestor, in hopes of discovering the types of changes at the genetic or developmental level that gave rise to the differences in appearance or function of the organisms. That would be a cool experiment.

In fact, that kind of experiment has been done, more than once. The best example, in my opinion, involves an organism far less sexy than a dinosaur or a finch or a whale: Zea mays, better known as corn (or maize).

Corn is a grass, but a grass that's been so extensively modified genetically that it's barely recognizable (to non-specialists like me) as a member of that family. Wait...genetically modified? Yes, and I'm not talking about the really modern tricks that gave us Bt corn or Roundup Ready corn. In fact, the wonderful stuff they grow in Iowa is quite different from the plants that humans first started to harvest and domesticate in Central America a few millenia ago. Corn as we know it is the result of a major evolutionary transformation, driven by selection at the hands of humans. (I don't find the natural/artificial selection distinction at all useful, since there's no explanatory difference, but you can refer to the selection under consideration here as 'artificial' if it makes you feel better.) The story has been a major topic in evolutionary genetics for decades, but it's largely absent from popular discussions, probably because the Discovery Institute has wisely avoided it. I hope it will soon be clear why you won't find the word 'teosinte' anywhere at discovery.org.

For many years, the origin of corn was a mystery. Like most known crops, it was domesticated 6000-10,000 years ago. But unlike other crops, its wild ancestor was unknown until relatively recently. Why this odd gap in our knowledge? Well, it turns out that corn is shockingly different -- in form, or morphology -- from its closest wild relative, which is a grass called teosinte, still native to southwestern Mexico. In fact, corn and teosinte are so different in appearance that biologists initially considered teosinte to be more closely related to rice than to corn, and even when evidence began to suggest a genetic and evolutionary relationship, the idea was hard to accept. As John Doebley, University of Wisconsin geneticist and expert on corn genetics and evolution, puts it: "The stunning morphological differences between the ears of maize and teosinte seemed to exclude the possibility that teosinte could be the progenitor of maize." (From 2004 Annual Review article, available on the lab website and cited below.)

But it is now clear that teosinte (Balsas teosinte, to be specific) is the direct ancestor of corn. In addition to archaeological evidence, consider:

• The chromosomes of corn and teosinte are nearly indistinguishable at very fine levels of structural detail.
• Analysis using microsatellite DNA (repetitive DNA elements found in most genomes) identified teosinte as the immediate ancestor of corn, and indicated that the divergence occurred 9000 years ago, in agreement with archaeological findings.
• Most importantly, a cross between corn and teosinte yields healthy, fertile offspring. So, amazingly, despite being so different in appearance that biologists initially considered them unrelated, corn and teosinte are clearly members of the same species.

The basic idea, then, is that corn is a domesticated form of teosinte, exhibiting a strikingly distinct form as a result of selection by human farmers. And that means that we have a perfect opportunity to examine the genetic and developmental changes that underlie these "stunning morphological differences." We can do the experiment.

First, have a look at an example of one of the evolutionary changes in teosinte under human selection.

The small ear of corn on the left is a "primitive" ear; the brown thing on the right is an ear from pure teosinte. (Both are about 5 cm long.) The "primitive" ear is similar to archaeological specimens representing the earliest known corn. Image from John Doebley, "The genetics of maize evolution," Annual Review of Genetics 38:37-59, 2004. Article downloaded from Doebley lab website.

The thing on the far left is a teosinte "ear," the far right is our friend corn, and the middle is what you get in a hybrid between the two. Photo by John Doebley; image from Doebley lab website.

The pattern of branching of the overall plant is also strikingly different between corn and teosinte, and you can read much more on the Doebley lab website and in their publications.

When I first heard about this work at the 2006 Annual Meeting of the Society for Developmental Biology, I was astonished at the amount of basic evolutionary biology that was exposed to experimental analysis in this great ongoing experiment. Here are two key examples of the insights and discoveries generated in recent studies of corn evolution.

1. Does the evolution of new features require new, rare, mutations in major genes?

Perhaps this seems like a stupid question to you. Anti-evolution propagandists are eager to create the impression that evolutionary change only occurs when small numbers of wildly improbable mutations somehow manage to help and not hurt a species. And in fact, experimental biology has produced good examples of just such phenomena. But there is at least one other genetic model that has been put forth to explain the evolution of new forms. This view postulates that many major features exhibited by organisms are "threshold" traits, meaning that they are determined by many converging influences which add together and -- once the level of influence exceeds a threshold -- generate the trait. The model predicts that certain invariant (i.e., never-changing) traits would nevertheless exhibit significant genetic variation, since evolutionary selection is acting on the overall trait and not on the individual genetic influences that are added together. Hence the implication that...

...populations contain substantial cryptic genetic variation, which, if reconfigured, could produce a discrete shift in morphology and thereby a novel phenotype. Thus, evolution would not be dependent on rare mutations, but on standing, albeit cryptic, genetic variation.

--from Nick Lauter and John Doebley, "Genetic Variation for Phenotypically Invariant Traits Detected in Teosinte: Implications for the Evolution of Novel Forms," Genetics 160:333-342, 2002.

In that paper, the authors show that several invariant traits (e.g., number of branches at the flower) in teosinte display significant genetic variation. In other words, the traits are the same in every plant, but the genes that generate the traits vary. The variation is 'cryptic' because it's not apparent in basic genetic crosses. But it's there. The authors ask: "How can cryptic genetic variation such as we have detected in teosinte contribute to the evolution of discrete traits?" Two ways: 1) the variation is available to modify or stabilize the effects of large-effect mutations; and 2) variation in multiple genes can be reconfigured such that it adds up to a new threshold effect. Note that the first scenario is clearly applicable to the kind of evolutionary trajectory outlined by Joe Thornton's group and discussed in a previous post. The second scenario is particularly interesting, however, since it addresses an important question about the role of selection. Consider the authors' discussion of this issue:

At first glance, cryptic variation would seem inaccessible to the force of selection since it has no effect on the phenotype. However, if discrete traits are threshold traits, then one can imagine ... that variation ... could be reconfigured such that an individual or population would rise above the threshold and thereby switch the trajectory of development so that a discrete adult phenotype is produced. We find this an attractive model since evolution would not be constrained to “wait” for new major mutations to arise in populations. (Italics are mine; ellipses denote deletion of technical jargon, with apologies to the authors.)

In fact, in a 2004 review article, Doebley is bluntly critical of the assumption that new mutations were required during the evolution of corn, and seems to suggest that this view led researchers significantly astray:

There is an underlying assumption in much of the literature on maize evolution that new mutations were central to the morphological evolution of maize. The word "mutation" is used repeatedly to describe the gene changes involved, and Beadle led an expedition ("mutation hunt") to find these rare alleles. The opposing view, that naturally occurring standing variation in teosinte populations could provide sufficient raw material for maize evolution, was stated clearly for the first time by Iltis in 1983. Although new mutation is likely to have made a contribution, anyone who has worked with teosinte would agree that teosinte populations possess abundant genetic variation. [...] Allowing for cryptic variants and novel phenotypes from new epistatic combinations to arise during domestication, it is easy to imagine that maize was domesticated from teosinte.

--John Doebley, "The genetics of maize evolution." Annual Review of Genetics 38:37-59, 2004.

Compare that discussion, and others like it in the paper I'm quoting, with the yapping about mutations that passes for anti-evolution criticism of evolutionary genetics. I can find no evidence that Michael Behe or any other ID theorist has even attempted to seriously address the importance of genetic variation in populations. I haven't read The Edge of Evolution yet, but I have it right here, and the index suggests that Behe hasn't tried to engage genetics beyond the high school level. There's a good reason why Behe is an object of scorn in evolutionary biology. He wants you to think it's because his critics are mean. No; it's much worse than that.

2. Does evolutionary change ever result from a "gain of information," or does Darwinian evolution merely prune things out?

It would be easy to get the impression from various creationists and ID proponents that mutation and selection can only remove things from a genome. Young-earth creationist commentary on "microevolution" (a yucky term for the now-undeniable fact of genetic change over time) always adds that this kind of change involves NO NEW INFORMATION. (The caps are important, apparently, since caps and/or italics are de rigueur in creationist denialism on this topic.)

Similarly, Michael Behe wants you to think that beneficial (or adaptive) mutations are some kind of near impossibility, and that when they do happen it's almost always because something's been deleted or damaged, with a beneficial outcome.

Studies of evolution in corn and teosinte (and other domesticated plants), not to mention findings like the HIV story on Abbie Smith's now-famous blog, tell a different -- and, of course, more wonderfully interesting -- story. In a minireview on the genetics of crop plant evolution in Science last June, John Doebley notes that most of the mutations that led to major evolutionary innovations occurred in transcription factors, which are proteins that turn other genes on and off. Then this:

Another remarkable feature of this list is that the domesticated alleles of all six genes are functional. If domestication involved the crippling of precisely tuned wild species, one might have expected domestication genes to have null or loss-of-function alleles. Rather, domestication has involved a mix of changes in protein function and gene expression.

In other words, the new genes are not dead or damaged; they're genes that are making proteins with new functions. ('Allele' is just the term for a particular version of a particular gene, and 'null', as you might have guessed, is a version that is utterly functionless, as though the gene were deleted entirely.) Now, if you've even flipped through The Origin of Species, you might not be surprised by Doebley's conclusion:

Given that the cultivated allele of not one of these six domestication genes is a null, a more appropriate model than "crippling" seems to be adaptation to a novel ecological niche -- the cultivated field. Tinkering and not disassembling is the order of the day in domestication as in natural evolution, and Darwin's use of domestication as a proxy for evolution under natural selection was, not surprisingly, right on the mark.

The change from teosinte to corn happened in about a thousand years. That's fast evolution. Apply selection to a varying population, and you get new functions, new proteins, new genes, completely new organisms. Fast.

So in summary, we can do the experiment. And we've done the experiment. ('We' being John Doebley and his many able colleagues.) And we've learned a lot about evolution and development. Now if we can just get people to read it. Then they'll know more about evolution, and about God's world, and about the trustworthiness of the anti-evolution propaganda machines that are exploiting the credulity of evangelical Christians.