Jessell: At that time most biotechnology research had really used molecular cloning as a major impetus to the generation of biopharmaceuticals. Genentech with t-PA, and Amgen with erythropoietin (EPO), are good examples. Those are not so dissimilar. t-PA is tissue plasminogen activator. It is a very successful Genentech product for immediate treatment of heart attacks. EPO is used in a variety of different conditions. Those companies essentially took a factor that was suspected of being involved in a disease, and cloned it. I think what we wanted to do is stay more closely wedded to the developmental process and understand an entire program of differentiation, rather than supplying one factor that ameliorates a particular condition.

: Can you give us an example of how understanding the developmental process might lead to a therapy?

Jessell: Probably the best example, and one that has a high probability of coming to practical fruition in the context of Ontogeny, is in the case of pancreatic differentiation and its applicability to diabetes. Diabetes clearly depends on the production of a single protein insulin from pancreatic BETA cells. Despite the availability of insulin by injection, it turns out that the long-term prognosis for diabetics is not so great because it is very difficult to stabilize the concentration of insulin through injection. If one could understand developmentally the mechanisms that control the generation of BETA cells, in the same way that one now understands, for example, the mechanisms that control motor neuron differentiation, then one might in principle be able to take a progenitor cell which exists even in the adult animal, expose it to the right combination of factors in the right regimen, and get that cell to turn into a BETA cell.
   And so one can then think in a not-too-distant future about taking a BETA-cell progenitor cell, amplifying that cell so that you get a large stock of progenitor cells, and then exposing them to an appropriate differentiation signal that will turn them into BETA cells. The next step would be to use cell implantation methods to provide those cells as an endogenous source of insulin and thereby achieve a more stable glucose-insulin relationship.

: Doesn't this require that you have the necessary progenitor cells as well as the inducing molecules to differentiate them?

Jessell: There are two problems here, and this is an important distinction. There is no point in being able to take three adult progenitor cells and add a factor to get them to turn into BETA cells if the end result will be something like three BETA cells--such a small quantity is not going to be enough to do anything for anybody. So there are two steps to the process: one is to find a cell that has proliferative division capacity and then expand that cell, using the one cell to generate a hundred million cells, each of which retains the ability to respond to the inducing signal to turn into BETA cells. The second step is to make those cells do what you want them to do.
   And so the stem-cell companies are now focusing on how to make a lot of these cells in the hope that once they’ve made them, something is going to come along and get the cells to differentiate. Whereas at Ontogeny, at least initially, we’re working to understand the process of getting a stem cell to do what we want.