03 July 2009

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.

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