The Discovery: Evidence for a Genetic Origin of Cancer • iBiology

00:00:01;09 When I began my career in cancer research,
00:00:04;27 really nothing was known about how the disease arises.
00:00:10;15 And now we know exactly why cancer occurs.
00:00:14;19 We don't know all the causes, which is a problem.
00:00:17;17 But we do know that once those causes have done their job,
00:00:23;15 all cancer arises from the malfunction of genes.
00:00:31;07 When I arrived to take up my position
00:00:34;11 at the University of California, San Francisco,
00:00:37;10 I met Warren Levinson,
00:00:40;02 who was another newly recruited young scientist,
00:00:43;24 who had been trained to study Rous sarcoma virus.
00:00:49;22 Now, Rous sarcoma virus
00:00:53;13 was discovered by Peyton Rous at the turn of the 20th century.
00:00:57;16 And it was the first tumor virus ever described to any credible level.
00:01:04;21 It was a historic discovery.
00:01:07;13 And it was utterly neglected for over 50 years.
00:01:11;12 This was a chicken virus.
00:01:13;01 This virus was discovered in chickens originally.
00:01:15;00 And did it bother me that it was a chicken virus?
00:01:16;26 Not at all.
00:01:17;18 I was a great believer in what we call the universality of nature,
00:01:20;17 and if I could find out anything about cancer in a chicken,
00:01:24;14 I knew it would apply to humans,
00:01:26;18 and boy was I right.
00:01:30;16 The biological effects were dramatic.
00:01:32;04 You could take normal chick...
00:01:34;24 chicken fibroblasts in a petri dish,
00:01:36;22 put Rous sarcoma virus on them, on those cells,
00:01:39;20 and within 24 hours they...
00:01:43;00 their whole phenotype changed.
00:01:45;12 Their appearance changed.
00:01:46;27 Their replicative behavior changed to be more aggressive.
00:01:50;03 They started crawling over each other in a...
00:01:54;21 in a chaotic manner, like cancer cells can do.
00:01:57;24 And of course, if you put the virus into a chicken
00:01:59;26 you would also get a tumor.
00:02:02;14 That's what Rous had originally done.
00:02:04;21 That's how he discovered the virus.
00:02:08;02 He took a tumor, lysed the cells,
00:02:12;02 put it through a filter to take out any living cells,
00:02:16;05 put that lysate, or filtrate as we called it,
00:02:19;28 into... into chickens,
00:02:24;01 and they would get the same tumor.
00:02:26;01 And then he could make extracts from that tumor, filter it,
00:02:31;03 put it in another chicken, and get a tumor again.
00:02:34;07 Hence, Rous sarcoma virus.
00:02:36;10 Another very important discovery was made that
00:02:40;08 was overshadowed to an unfortunate extent
00:02:42;25 by the discovery of reverse transcriptase.
00:02:45;11 And that was a discovery made by Steven Morton,
00:02:48;15 at the University of California, Berkeley,
00:02:51;06 that Rous sarcoma virus had at least one gene
00:02:56;02 -- and it turned out to be only one gene --
00:02:58;18 that was responsible for the tumorigenic capacity
00:03:02;00 of the virus.
00:03:03;26 And that brings me to Harold Varmus,
00:03:06;06 who joined me as a colleague in 1970,
00:03:09;20 the year that reverse transcriptase was discovered,
00:03:12;15 and two years after I started my work at UCSF.
00:03:16;17 Harold joined me in an extremely informal process.
00:03:23;19 He had been a postdoctoral fellow
00:03:27;16 at National Institutes of Health,
00:03:30;28 and had taken a course in tumor viruses.
00:03:36;04 He was... he was working at the time with phage and bacteria.
00:03:39;24 And I think about five minutes into the conversation,
00:03:42;18 I decided... we gotta this guy in the lab,
00:03:45;13 because he was obviously very smart.
00:03:47;20 And we were on the same wavelength scientifically:
00:03:49;29 we wanted to do molecular biology of the virus.
00:03:52;29 And we shared other interests, cultural interests,
00:03:56;00 particularly literary interests.
00:03:59;20 We decided that we ought to look for src in normal cells.
00:04:03;27 Now, this was well before recombinant DNA.
00:04:05;29 If we'd had recombinant DNA,
00:04:07;19 we could have done the subsequent experiments in a few months.
00:04:10;17 As it was, it took four years.
00:04:13;14 And here we were helped, again, by genetics.
00:04:16;26 Peter Vogt, a long-standing collaborator of ours...
00:04:21;14 Peter Vogt was a master of the biology of these viruses
00:04:25;01 and the genetics,
00:04:27;06 and he had isolated mutants in Rous sarcoma virus
00:04:31;19 that were deletions of src.
00:04:36;02 So, we had available to us the deletion mutant,
00:04:40;01 which had no src, or a very little piece of src in it.
00:04:45;26 And of course we have the full Rous sarcoma virus genome
00:04:49;24 with src in it.
00:04:51;25 So, the idea was that we would copy...
00:04:54;19 use reverse transcriptase to copy the genome of Rous sarcoma virus
00:04:58;01 into radioactive DNA.
00:05:00;13 And then we would use the deletion mutant to fish...
00:05:03;29 to pull out, by molecular hybridization...
00:05:09;27 we would use the deletion mutant to pull out all of the nucleotide sequences
00:05:13;20 of the replicative genes
00:05:17;05 and leave the src nucleotides in the...
00:05:21;12 in the residue, if you will.
00:05:24;08 It worked like a charm.
00:05:26;23 It was hard work.
00:05:29;04 The first hints that it would work came from
00:05:33;14 a postdoctoral fellow named Ramareddy Guntaka,
00:05:36;18 but he had a full-blown project well underway.
00:05:39;09 And once he had shown that we could probably make a probe this way,
00:05:43;00 we recruited another postdoctoral fellow, Dominique Stehelin,
00:05:47;00 to run with it.
00:05:49;18 And he did, in spades.
00:05:52;07 We began to make this src-specific probe.
00:05:55;21 We were... we were able to demonstrate its specificity
00:05:58;26 in a variety of ways.
00:06:00;27 He was able to make this probe consistently,
00:06:05;05 and to use it,
00:06:08;19 and soon found that the probe
00:06:13;02 would react with normal chicken DNA.
00:06:14;26 If you want to use the probe to
00:06:19;17 assess the presence of the sequences in the probe in DNA,
00:06:24;10 you first have to take the DNA apart,
00:06:26;22 denature it as they say.
00:06:29;08 The strands separate.
00:06:30;26 And then you put the radioactive probe in there,
00:06:33;15 and you allow the seq...
00:06:36;02 the strands to reassociate.
00:06:38;14 And the radioactive probe gets taken up in the mix.
00:06:42;02 And so, although the bulk of the DNA
00:06:45;04 will reassociate with its unlabeled original complement,
00:06:50;07 some of it will reanneal with the radioactive probe.
00:06:53;15 There was something in the DNA of normal avian cells
00:06:57;04 that was homologous to the oncogene,
00:07:00;03 the cancer gene,
00:07:01;29 of Rous sarcoma virus.
00:07:03;14 And we called it "cell src",
00:07:05;02 for the sake of the argument.
00:07:06;21 If you fiddled with the reaction conditions,
00:07:08;20 the probe would react with DNA from any avian species we tested,
00:07:11;17 including the most primitive species,
00:07:14;12 such as ostrich or the ratite...
00:07:17;02 the so-called ratites: the ostrich, the emu, the rhea.
00:07:20;26 Incidentally, it was not easy to come by the DNA for these creatures,
00:07:24;05 but we managed one way or another.
00:07:27;14 I vividly remember the morning that Dominique
00:07:31;17 brought us the first positive results.
00:07:34;10 They'd come in late Saturday evening,
00:07:38;14 when Harold and I,
00:07:40;21 who were in a partnership at the time,
00:07:43;02 that lasted for 15 years,
00:07:45;13 first saw the data.
00:07:48;13 I... I was dumbfounded.
00:07:53;22 I recognized that this was a heretical discovery,
00:07:58;25 and that we were gonna have to...
00:08:00;27 we were gonna have to construct an airtight argument.
00:08:04;07 So, I think I was a little less enthusiastic
00:08:07;08 than Dominique would have liked,
00:08:08;26 because he was beside himself with excitement.
00:08:12;08 But Harold and I both understood from the get-go
00:08:15;29 that if this was real we were looking...
00:08:21;02 we were looking at a possible entree
00:08:25;03 to the very fundamental underpinning of cancer.
00:08:34;17 By the time I gave my Nobel lecture,
00:08:39;01 I had a slide with something like 30 retroviral oncogenes,
00:08:44;14 each of which had a demonstrable proto-oncogene progenitor,
00:08:50;07 if you will, in normal cells.
00:08:52;27 And as they... as the number mounted,
00:08:54;24 it became clear that here was...
00:08:57;10 here was the makings of a fun...
00:09:00;23 of a... a unifying theory of cancer.
00:09:06;01 And we were cautious about how we stated that publicly, at first.
00:09:12;22 But by the early '80s,
00:09:15;10 I was using that term,
00:09:17;14 a unifying theory of how all cancers come about.
00:09:22;01 It was a gradually building thrill
00:09:26;12 to realize that we had the cancer cell by the neck,
00:09:30;15 in terms of understanding it.
00:09:32;13 Not in terms of throttling it,
00:09:35;05 but in terms of understanding it.

This Talk

Speaker: J. Michael Bishop

Audience:

Educators of H. School / Intro Undergrad
Student
Educators of Adv. Undergrad / Grad
Researcher
Educators

Recorded: August 2018

Talk Overview

Dr. J. Michael Bishop tells us the story of his Nobel Prize-winning discovery of cellular proto-oncogenes. Bishop was studying how the Rous Sarcoma Virus (RSV) causes cancer in chickens by expressing the viral protein called Src. Together with Dr. Harold Varmus, Bishop discovered that the chicken genome normally expresses a homolog of the viral Src protein that they called cellular-Src (c-Src). This finding led them to the remarkable conclusion that RSV had incorporated a mutated oncogene version of the normal chicken c-Src protein, and, provided the first evidence that mutations in our own genes can be linked to cancer development.

Learn more about this and other discoveries at The Explorer’s Guide to Biology (XBio).

Speaker Bio

J. Michael Bishop

J Michael Bishop

Dr. Bishop received his undergraduate degree from Gettysburg College and his M.D. from Harvard Medical School. Harvard provided Bishop with his first research experience and introduced him to the study of animal viruses. Bishop completed his clinical training at Massachusetts General Hospital and pursued a research fellowship at the National Institutes of Health. In 1968,… Continue Reading