Jessell: One type of experiment, for instance, is to take a piece of neural tissue at a time before it's been exposed to any environmental factors. You then examine the fate of those cells under that default program, so to speak. The next step is to add a potential source of an inductive signal and show that the program is changed--the cells become something else. That extrinsic signal might turn out to be, for example, hedgehog. An extrinsic signal is a protein that is excreted by one cell and which influences or changes the fate of a neighboring cell. That's a process of cell-cell communication. It changes the cell’s fate by turning one transcription factor on and turning another one off. This experimental method uses transcription factors as sort of molecular beacons to assay the existence of a diffusible or a cell-cell signal.

: The big breakthrough in your field was the discovery of the hedgehog genes in mammals. How has that work been developed?

Jessell: It turns out that there are three hedgehog genes in higher vertebrates, in mammals. Different groups cloned different hedgehogs early on. They're all interesting, but the one that is the most interesting to us is a gene that Cliff Tabin at Harvard eventually named sonic hedgehog. It turns out to be expressed in precisely those cells in the limb bud that have the limb-patterning activity. And it turns out to be expressed in just those cells under the spinal cord, in the notochord and later in the floorplate, that have the spinal-cord-patterning activity, which is what we were looking for.
   By now, many papers have established the function and the necessity of hedgehog in these signaling processes. In the context of the spinal cord, one of the surprising things to emerge is that, at least in the ventral half of the spinal cord, which generates many different cell types, hedgehog is responsible for the generation of each of those cell types. It does this by acting at different concentration thresholds to establish different cell fates.

: Different concentration thresholds?

Jessell: There is now evidence that two-fold differences in the concentration of sonic hedgehog proteins to which a cell is exposed produce very dramatic changes in the eventual fate of that cell. So we can do in vitro assays where we can essentially dial in the concentration of hedgehog and generate a predictable cell type at each concentration. There are many precedents for this, both in Drosophila and in vertebrate development. The hedgehog example, however, provides a particularly striking case, where a complex group of neurons that eventually function together--motor neurons and different types of interneurons--are all induced by the same signaling molecule, just by its acting at different concentrations. It’s a very economical way of generating cell diversity from one signaling molecule.

: How do the other two hedgehog genes fit into the developmental picture?

Jessell: Desert and indian? They're expressed in different places in the body, but to a large extent it appears that each of the proteins can substitute for one another. Basically the general property of all three proteins is the ability to be provided by one cell type and influence or change the fate of a surrounding cell type. And you use these proteins repeatedly during development to control the development of many, many different tissues. Clearly, hedgehogs are not the only proteins. And there are many other classes of inducing molecules. Hedgehogs turn out to be one of the major families, and they have unmistakably important roles in many different systems.

: The company that you helped found, Ontogeny, was started shortly after the discovery of the hedgehog genes. What was the basis for its founding?

Jessell: The true impetus was primarily Doug Melton and Andy MacMahon at Harvard. Cliff Tabin came in slightly later. We were all working on different developmental systems. Doug was working on very early stages of mesoderm formation using the frog as a system. Andy was working on the kidney and nervous system, while I was working on the nervous system. But because of all the molecular genetics that had become available, it became clear that one could think about developmental biology as a rather unified field, and that the central role of inductive factors was inescapable. And, given that there was a relatively restricted set of induction factors, it seemed that there must be some application of those factors other than just basic scientific interest.continued 

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