The process once again utilizes the bipartite character of genes already discussed, namely that "genes are composed of two domains: one for gene regulatory information and one for protein coding information." Hanahan first prepares his manufactured gene, known as a hybrid. The gene regulatory domain he designs as it would occur in a normal mouse, but the protein coding domain he takes from an oncogene, so-called because it is known to induce cancer. Next, he removes fertilized eggs from a normal mouse, introduces his hybrid gene with a very fine capillary pipette, and then reimplants this injected embryo back into a foster mother that goes on to give birth to what is defined as a transgenic mouse, that is, one that is carrying an artificially created gene. When the transgenic mouse mates with a normal mouse, about half of the second-generation mice inherit a set of DNA that now includes this new gene, still recognized by its regulatory information as a normal gene but whose protein instructions code for cancer growth. As Hanahan put it, "Half of the progeny of this mating carry the hybrid oncogene. Every one of those dies of tumors. Their normal brothers and sisters live normal lives."

Beyond proving that oncogenes are heritable, and that only the protein coding portion is necessary to cause cancer in the offspring, Hanahan found some other suggestive patterns. First, although an affected mouse has this deadly oncogene throughout its DNA and thus in every cell of its body, only some of the cells develop tumors. Second, the tumors that do develop arise at unpredictable times during the course of the mouse's life. "From this we infer that there are other, rate-limiting events in tumors," and that simply possessing the gene does not predict whether and especially when a cell will develop into a tumor, Hanahan emphasized. All of the cells must be classified as abnormal, but they seem to undergo what he referred to as a sort of dynamic evolution as the organism ages. He has seen this phenomenon in several different environments. For example, even if all 10 mammary glands of a transgenic mouse express an oncogene, the offspring mice inevitably, and reproducibly, develop only one tumor, on average.

With an insulin gene promoter, he has observed the "cancer gene" expressed in all of the insulin-producing cells of the islets of the pancreas at 3 weeks, but only half of these islets begin abnormal proliferation 4 weeks later. At 9 weeks, another phenomenon is seen that Hanahan believes may be more than coincidental, that is, an enhanced ability to induce the growth of new blood vessels, called angiogenesis. Of the 400 islands of cells expressing the oncogene, one-half show abnormal cell proliferation, yet the percentage of full-blown tumors is only about 2 percent. Prior to solid tumor forma-



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