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On July 10, 2016, Alfred G. Knudson, Jr.,  MD , PhD, a leader in cancer research, died at the age of 93 years. We deeply mourn his loss. Knudson's two‐hit hypothesis, published in 1971, has been fundamental for understanding tumor suppressor genes and familial tumor‐predisposing syndromes. To understand the molecular mechanism of two‐hit‐initiated tumorigenesis, Knudson used an animal model of a dominantly inherited tumor, the Eker rat. From the molecular identification of  Tsc2  germline mutations, the Eker rat became a model for tuberous sclerosis complex ( TSC ), a familial tumor‐predisposing syndrome. Animal models, including the fly, have greatly contributed to  TSC  research. Because the product of the   TSC 2 / Tsc2  gene (tuberin) together with hamartin, the product of another  TSC  gene (  TSC 1 / Tsc1 ), suppresses mammalian/mechanistic target of rapamycin complex 1 ( mTORC 1), rapalogs have been used as therapeutic drugs for  TSC . Although significant activity of these drugs has been reported, there are still problems such as recurrence of residual tumors and adverse effects. Recent studies indicate that there are  mTORC 1‐independent signaling pathways downstream of hamartin/tuberin, which may represent new therapeutic targets. The establishment of cellular models, such as pluripotent stem cells with   TSC 2 / Tsc2  gene mutations, will facilitate the understanding of new aspects of  TSC  pathogenesis and the development of novel treatment options. In this review, we look back at the history of Knudson and animal models of  TSC  and introduce recent progress in  TSC  research.

Mourning Dr. Alfred G. Knudson: the two‐hit hypothesis, tumor suppressor genes, and the tuberous sclerosis complex