Genes provide only the basic blueprints for our teeth. Shapes and sizes arise from the predictable interaction of molecules that live in the jaw itself.

The pattern and regularity of mammalian teeth are not genetically inherited, per se, but reveal instead an evolutionary tool kit for their formation. Illustration by Alison Schroeer

I want you to contemplate your teeth for a moment. I’m sure they’re very familiar to you, to the point that you take them for granted (except, perhaps, on visits to the dentist), but take a moment to run your tongue over them one by one. They’re beautiful! You have, lined up in an arc in your mouth, rows of exquisite abstract sculptures, each one an enameled column, with whorls and bumps and edges in stately and regular array, all matching and meshing to chew and cut. Almost all of us have imperfections in our teeth, of course, and yet there is something exquisite in their predictable patterns and characteristic shapes.

Teeth are wonderfully diagnostic; a skilled comparative anatomist can identify your genus, tell you about your diet, and summarize your evolutionary lineage by examining the shape of a single tooth. A whole mouthful can serve as a detailed biological road map to your ancestry.

Regularity is the hallmark of the arrangement of our teeth. Humans have a standard pattern: On each side, top and bottom, we have from front to back, two incisors, a single pointed canine, two premolars, and three molars. (The third molar is the wisdom tooth, which may or may not have erupted, depending on your age, or may have been extracted.) Each of these teeth has its own characteristic size and shape and a standard pattern of cusps or bumps, a pattern that is heritable and specified to a surprising degree.

Check it out: Feel one of the molars on the left side of your mouth, then the corresponding molar on the right side, and you’ll find the same bumpy surface on both.

How does that happen? What is the nature of the set of instructions to the tooth sculptor that leads to this strongly determined morphology?

The first answer that might come to mind is that it is genetic (and it is true that the pattern is heritable), that there is some kind of template or blueprint in your genome that says, for instance, to make precisely three molars and two premolars and, further, lays out the arrangement of cusps. However, this is not the case. No such map of the jaw has been found in the genome, nor is it even clear how such a thing would be represented in an assortment of genes. Instead, the details of the architecture of the teeth are specified epigenetically. What could that possibly mean?

It means there is no simple one-to-one mapping of a gene to a phenotype—in this case the shape and size of a tooth. The genome, instead, contains instructions for interacting proteins—for instance, an activator molecule that can tell a tissue to grow a tooth or an inhibitor that can suppress a tooth—and the pattern of their activity is generated within the jaw itself, with interactions between the components leading to the emergence of specific features. You won’t find the architecture of a tooth in the genome—you have to let the tools in the genomic toolbox play out in the context of the embryonic environment to generate the pattern. Further, only a few, relatively simple genetic elements generate greater epigenetic complexity. The work of University of Helsinki biologist Kathryn Kavanagh and others on the underlying rules of tooth development is revealing that simplicity.

Tooth development begins with the formation of tiny structures called enamel knots. As the name implies, these are small dots of tissue that busily secrete enamel and build the hard matrix of the tooth, but they also have another role: They are signaling centers. While they are making a tooth, they are also sending out molecules that tell neighboring regions of the jaw whether or not to form enamel knots of their own. This function has been studied in the development of mouse molars.

Normally, mouse molars develop in a simple sequential order: The first, anterior-most molar forms, then a small bud extends back from it and expands into the second molar, and finally a third bud begins the third molar. That happens in the embryo itself, but the jaw can also be isolated and grown in a dish. Something revealing happens in culture: The first molar grows, but the second molar grows much more slowly. This suggests that something is lacking in the environment of the dish, something that promotes molar growth. In the embryo, the surrounding tissue secretes an activator molecule. By separating the molars from those tissues, the activator is diminished.

But now here’s an interesting variant on the experiment: Grow an isolated mouse jaw in a dish, but also reach in and carefully cut the tissue, separating the tiny bud of the second molar from the first molar. Now the second molar grows rapidly! What this implies is that the enamel knots of the first molar are also the source of an inhibitor, a molecule that suppresses the formation of new teeth. That makes sense—you don’t want teeth building on top of teeth. Having each tooth work to inhibit tooth formation in its neighborhood ensures that new tooth buds are reasonably spaced. Most importantly, it puts tooth morphology in the hands of a very small number of molecular controls, which can produce different arrangements of tooth sizes by changing the relative proportions of two signals.

There is an activator molecule, secreted by the surrounding tissue, that promotes growth of the enamel knots. There is also an inhibitor molecule, secreted by the enamel knots, that suppresses the formation of adjacent knots. By adjusting the relative potency of these two molecules, the organism can achieve a range of relative tooth sizes. If the activator effectiveness is increased while the inhibitor is held constant, we expect the teeth to get bigger and, in particular, the second and third molars to become relatively larger. If the activator is held constant and the inhibitor is strengthened, the first molar will stay the same size, but the second and third will become increasingly smaller in proportion. It’s like having two dials or verniers, one regulating overall tooth size and another regulating the second and third molar size relative to the first. Evolution can generate a wide range of tooth morphologies by tinkering with just two regulators.

Kavanagh and her colleagues took two further steps in explaining how teeth form. First, they quantitatively measured the effects of manipulating the interactions between the teeth and reduced the development to a simple mathematical equation, a law describing the relative proportions of molars in the embryos of laboratory mice, given the activity of two molecules, the activator and inhibitor. Then, the kicker: They applied this same equation to the distribution of tooth sizes in other mammals. With some exceptions, it still worked to accurately describe varying tooth patterns.

The idea is biological parsimony at its best. And it’s beautiful: An elaborate phenotypic architecture can be produced by the interplay of a relatively small number of components. The difficulties evolution faced in generating your teeth—those lovely permutations on a theme—are minimized by the use of subtle algorithmic variations, by rules and formulas that can only be discerned by looking beyond the genome to the epigenetic processes that shape the actual tissues.

Originally published April 29, 2008

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