Recorded: 03 Jun 2016
Well, uh, in baseball terms – understanding the oncogene in the bladder carcinoma is what is called an ‘earned run.’ One really works for it. But in the context of the retinoblastoma gene as I’ll tell you in the story, shortly – it was more of an unearned run – more of an accident, that I really didn’t work for.
The fact is: in 1985 I had a new post-doc – his name was Stephen Friend and he was enthusiastic to do an exciting project to clone the gene that others had implicated in the causation of a rare childhood tumor called retinoblastoma. Retinoblastoma clearly worked in a different way than the RAS oncogene that we and others had found in the context of the bladder carcinoma. The RAS oncogene was unregulated and was hyperactive. The retinoblastoma gene participated in cancer biology and cancer formation whenever the retinoblastoma gene was eliminated and therefore, one made the analogy that the RAS oncogene was like a stuck accelerator peddle on a car and the retinoblastoma gene when it was missing was like a defective brake or brake line. It deprived the cell of its ability to hault its own proliferation. That was all very speculative until the gene was actually isolated by genetic cloning and that was the goal of Stephen Friend who came to my laboratory and said he wanted to isolate the retinoblastoma gene. And being relatively open-minded I said ‘that’s all very good but you don’t know how to clone genes’ – we don’t know where the retinoblastoma gene is located exactly in the vast human genome, we don’t really have the techniques to really find it and so he being very entrepreneurial walked across the Longfellow Bridge, which connects eastern part of Cambridge to Boston, went to the Massachusetts Eye and Ear Infirmary – started a conversation and collaboration with a man there named Thaddeus Dryja who had been looking for milestones, posts, mile posts along a certain chromosome, chromosome 13, where there was significant evidence that the retinoblastoma gene was likely to be located and he worked and in a bizarre coincidence one of the milestones that Thaddeus Dryja had isolated, had chosen – lay right in the middle of the retinoblastoma gene. Well, you’ll say ‘so what!’ But, the chromosomal arm that one was being working with – the 13th Q arm – the long arm of chromosome 13 was this big and the retinoblastoma gene we realized later, was this big. What was the likelihood that one of the three or four milestones along the chromosome – one of them would lie directly in the middle of the retinoblastoma gene. But it did. And so, Stephen Friend, together with some other people in my laboratory like René Bernards who had cloning expertise, they worked with Dryja’s probe and sure enough they were able to isolate, through molecular biology techniques which were then workable, the retinoblastoma gene. I say that’s an unearned run because in fact the isolation of the gene was more of an accident. An unlikely one, which I had relatively little do with aside from the fact that I created the environment where it could happen. So I always smile when people say ‘Bob Weinberg cloned the fist tumor suppressor gene.’ One says in German [unintelligible] “far more through luck than any insight or understanding.”
The retinoblastoma gene was in part enormous luck because as I related, one of the three or four probes on the long arm of chromosome 13 – that Thaddeus Dryja had plucked out from randomly the long arm of chromosome 13 lay right in the middle of the retinoblastoma gene which itself occupied only a tiny fragment of the total length of this chromosomal arm. Of course that was one element of luck. It was also an element of luck that my postdoc Steve Friend went across the river and started talking with him at exactly at the time when he had those probes. If he had talked with him probably a year earlier it wouldn’t have worked and so there were multiple elements of luck, but just because something is lucky doesn’t mean one should turn one’s back to it.
Robert "Bob" Weinberg is Daniel K. Ludwig Professor for Cancer Research and director of the Ludwig Cancer Center at MIT, an American Cancer Society Research Professor, and is a founding member of the Whitehead Institute for Biomedical Research.
In 1982 he was one of the scientists to discover the first human oncogene, Ras, which causes normal cells to form tumors, and his lab also isolated the first known tumor suppressor gene, Rb.
He co-authored with Douglas Hanahan the landmark "Hallmarks of Cancer" paper in 2000, which laid out the six requirements for a healthy cell to become cancerous.