Discovering Programmed Cell Death

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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.

This Talk

Speaker: H. Robert Horvitz

Audience:

General Public
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Student
Educators of Adv. Undergrad / Grad
Researcher
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Recorded: March 2011

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Talk Overview

Horvitz recalls the “aha!” moment when he realized that his lab’s work on programmed cell death, or apoptosis, in C. elegans was relevant to cancer in humans. This finding solidified his belief that the fundamental principles of biology are likely conserved across most species.

Speaker Bio

H. Robert Horvitz

Robert Horvitz is a Professor in the Biology Department, the McGovern Institute for Brain Research, and the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, as well as a Howard Hughes Medical Institute Investigator. Horvitz studies the development and behavior of C. elegans. His pioneering studies led to the identification of… Continue Reading