However, when new blood vessels grew into the small tumors from the adjacent vascularized tissues of the eye, for example, retina or iris, the tumors grew quickly and overtook the eye. Because the new vessels were elicited at a distance, Folkman hypothesized that the tumors secreted a diffusible, angiogenic growth factor. He termed the soluble hypothetical substance “tumor angiogenesis factor (TAF).” Using the eye as a model and observing the angiogenic response of the vascularized ocular tissues, Folkman further speculated that TAF was also operative in ocular neovascularization. If TAF could be blocked with an antibody, he reasoned, a new way of treating cancer and neovascular eye disease would emerge.

For more than a decade, Folkman had difficulty obtaining grant support. The reasons varied—the lack of direct proof for TAF, his competing surgical and administrative responsibilities, and his lack of a PhD. In later years, he often joked about this difficult period, and frequently quoted one particularly stinging NIH study section review. It concluded with the following sentence, “If TAF exists, it is solely in the mind of the applicant.”

Folkman knew that if he were to silence his critics, he would have to provide direct proof for the existence of TAF. Before the search for TAF could begin though, Folkman had to develop the tools to discover it. Thus, his laboratory established the first capillary endothelial cell cultures; the first endothelial DNA synthesis assay; and proliferation, migration, and tube formation assays. These quantitative methods replicated the key steps in angiogenesis in vitro. His laboratory also developed the first in vivo angiogenesis models—the chicken choroiallantoic membrane and the corneal angiogenesis assays.

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