Discovering Programmed Cell Death
Transcript of Part 1: Discovering Programmed Cell Death
00:00:16.03 In 2002, I had the great honor of sharing the Nobel prize in physiology or medicine 00:00:25.21 with Sydney Brenner and John Sulston. 00:00:29.02 This prize was awarded in honor of our studies of the nematode Caenorhabditis Elegans. 00:00:37.07 And, for me, the major recognition was for studies that my laboratory had done 00:00:45.10 concerning the phenomenon of programmed cell death 00:00:50.17 also known as apoptosis. 00:00:54.02 In short, we were studying the basic developmental biology of this nematode, 00:01:00.16 this roundworm, C. elegans. 00:01:02.25 And, by doing so, we found mechanisms for programmed cell death, for apoptosis 00:01:11.24 that proved to be conserved amongst animals, including human beings, 00:01:18.07 and elucidated mechanisms that are now being used 00:01:24.10 for targets in pursuits of treatments for human diseases 00:01:31.27 as diverse as neurodegenerative diseases, autoimmune disorders, and cancer. 00:01:39.15 Now, I'm sometimes asked when I knew that our studies of this worm would prove relevant 00:01:48.22 to human biology and human disease. 00:01:52.25 And, in a sense, I think that from the beginning, I thought this would probably be the case, 00:01:58.28 despite the fact--and I should say this emphatically-- 00:02:04.22 despite the fact that some peers and also some NIH study sections 00:02:09.27 don't think much about studies of any organisms that are not mammals. 00:02:16.01 My bias and the culture in which I had grown up was that an understanding of basic biology 00:02:25.28 in any organism was likely to reveal features that would prove to be widespread 00:02:33.28 maybe even universal, 00:02:37.09 and that the biological principles that emerged would be informative in a very, very broad way. 00:02:44.18 And the reason I believe that really goes back to my own training. 00:02:49.08 I did my PhD studies on the bacteriophage, T4. 00:02:56.15 Now going back some years before that, in the early days of phage studies, 00:03:01.29 there were individuals like Luria and Delbrook who were interested in studying the genetics of phage, 00:03:10.09 and they were criticized. Some people said, "Phage, they're not even going to have genes." 00:03:17.24 And those who accepted the fact that they might have genes said, 00:03:22.07 "Well, even if they have genes, those genes are not going to be relevant. 00:03:27.00 "They're going to have nothing whatsoever to do with the genes we care about--genes in human beings." 00:03:35.07 Now, of course, everybody in biology today knows (or perhaps I should say should know) 00:03:41.23 that the history proved these critics wrong. 00:03:44.07 It was studies of bacterial viruses that led to the elucidation of the basic mechanisms of heredity, 00:03:55.01 that led to the definition and understanding of the genetic code, 00:04:02.23 and led to the revolution in genetic engineering that so characterizes 00:04:08.06 both biological research and the pharmaceutical industry's efforts today. 00:04:14.22 So, I had the sense, from this phage background, that our studies of C. elegans would prove to be general, 00:04:23.29 but I couldn't know that. 00:04:25.27 So the question then is when did I know? 00:04:30.27 When did I have the Aha! moment that said, "Okay, what we're doing is going to be relevant?" 00:04:41.05 And the answer to that is easy. 00:04:43.12 The answer is February 12, 1992. 00:04:48.27 This was the day that I got a fax from a graduate student in my lab, Michael Hengartner. 00:04:56.21 I was at a scientific conference, and Michael had been studying one of the genes 00:05:02.12 that we had characterized in our analyses of C. elegans programmed cell death, 00:05:06.16 a gene called ced-9. Ced for cell death abnormal, gene number 9. 00:05:13.20 And ced-9 was a key gene in the regulation of programmed cell death in C. elegans. 00:05:22.11 And what Michael was trying to do was to characterize this gene, 00:05:26.29 not just through formal genetic analysis, but also through molecular analysis. 00:05:34.06 And the first step in this process was to identify a molecular clone of ced-9 00:05:39.29 and look and see that it reminded us of any other gene that was known. 00:05:45.13 What Michael's fax told me was that when he had searched the literature, 00:05:52.12 and this was very early days of gene sequencing of this sort... 00:05:56.10 When he has searched the database and looked to see if there were any similar genes out there, 00:06:05.13 one emerged at the top of the list, far above anything else. 00:06:11.04 And this match was a human gene. 00:06:15.06 It was a human cancer gene--a proto-oncogene known as Bcl2. 00:06:22.02 Now, ced-9 had been shown to protect cells in C. elegans from programmed cell death--our studies. 00:06:31.10 Bcl2, from work of cancer biologists, had been shown to protect cells against programmed cell death, 00:06:42.16 and to cause cancer because it was protecting cells from dying that normally should die. 00:06:53.02 So, cells that should die instead lived. That led to their survival, 00:06:58.26 and consequently led to cancerous growth. 00:07:04.18 So, this finding that a worm gene that protects against programmed cell death during C. elegans development 00:07:12.08 and a human gene that protects against programmed cell death, and when misexpressed 00:07:19.04 basically would protect cells that should die from doing so, thereby leading to cancer. 00:07:25.18 This finding said that these two genes that function similarly look similar in their sequence. 00:07:36.20 And, this was the finding that said to me that if these two genes are so similar in both function and structure, 00:07:46.00 there must be a pathway of genes that is similar between organisms as diverse as this microscopic groundworm and us. 00:08:00.12 This was a moment of excitement. 00:08:04.07 I was absolutely thrilled because what it said was that the studies we had been doing in terms of analysis of C. elegans 00:08:17.02 were going to be relevant to an understanding of human biology and human disease. 00:08:24.10 I should add that it was this finding that made the biomedical community pay attention. 00:08:31.24 Prior to this, I was basically doing abstract genetic studies of an organism most people were paying no attention to 00:08:41.07 involving a phenomenon that most people were paying no attention to. 00:08:46.20 Suddenly, we were working on a gene and a pathway that was key in human disease. 00:08:55.19 Our work was no longer abstractions from genetics, 00:09:00.17 but suddenly had a strong foothold in the future of human biology. 00:09:09.24 And I would say the rest is history. 00:09:14.10 At least, for me. Thank you.