Oncogenes: A Genetic Paradigm for Cancer
Transcript of Part 1: Forging a Genetic Paradigm for Cancer
00:00:03.10 Hello. I am Mike Bishop from the University of California, San Francisco, and I am going to talk with you about cancer, 00:00:10.05 what we presently know about the disease and how we are trying to apply that knowledge. 00:00:14.18 Cancer is the most fearsome of human adversaries. 00:00:19.20 In the United States as many as one in three individuals will develop the disease and one in four will die of it. 00:00:26.05 It is soon to become the leading cause of death in this country and worldwide, more than 8 million individuals die of cancer every year. 00:00:34.29 We have not been doing well in our struggle against cancer until recently. 00:00:40.26 Consider this comparison. Between 1975 and 2005 mortality from cardiovascular disease decreased by 70%, 00:00:51.00 whereas that of cancer decreased by only 7.5%. 00:00:54.25 Numbers of this sort have inspired disappointment and even skepticism amongst the public and the press. 00:01:00.15 Witness this lead article in Newsweek in 2008. 00:01:03.09 Now we can rationalize our difficulties with cancer. Consider this comparison again. 00:01:10.02 Cardiovascular disease is essentially a single disease of a single organ system with a single cause. 00:01:16.21 Whereas cancer has multiple causes, numerous causes, and every organ system has its own forms of cancer. 00:01:25.07 There are at least a hundred discrete forms of human cancer. 00:01:30.04 But we have been able to cut through this complexity with a unifying simplification that we call the genetic paradigm of cancer. 00:01:37.15 And that is that all cancer arises through the malfunction of genes. 00:01:42.13 I am going to tell the story in three chapters. 00:01:48.05 In the first chapter, I will review the history of how we came to this insight. 00:01:53.09 In the second chapter I will talk about the challenges that it represents and the promise. 00:02:00.09 And in the third chapter I will delve more deeply into one application of this insight in therapeutics for cancer. 00:02:08.11 Five paths of investigation converged to give us the genetic paradigm for cancer. 00:02:17.15 The first of these paths was the most elemental. 00:02:21.06 And that is the fact that cancer is a heritable cellular phenotype. 00:02:25.18 Cancer cells breed true. One of the first persons to recognize this was a man named Rudolf Virchow, a German pathologist, 00:02:34.10 who in 1858 pointed out that the metastases of cancer resembled the primary tumors, 00:02:40.23 as if the metastases and the primary tumors might have a common origin. 00:02:48.11 It had previously been believed that what we call a metastases might be tumors of independent origin. 00:02:54.17 This insight also inspired Virchow to coin a well-known aphorism that "All cells come from cells" 00:03:05.11 to advertise the newly emerging theory of the cell. 00:03:09.27 Virchow would not have been in position to know how close he was to the truth. 00:03:20.07 We now know that most if not all cancers have their origin in a single cell. 00:03:26.16 All of the cells in a cancer have a lineage that can be traced back to one cell that went awry sometime in the past. 00:03:35.25 Now there are subtleties to this that we will explore a little later, but fundamentally, this is another testimony 00:03:42.18 to the extraordinary durability of the malignant phenotype once it has been established. 00:03:48.05 Let me dramatize that durability with a story that has been widely appreciated because of a best-selling book. 00:03:57.29 And that is the story of Henrietta Lacks. In 1951, Mrs. Lacks died of cervical cancer at Johns Hopkins University. 00:04:08.16 Cells from her cancer were put into test tubes and Petri dishes and have been propagated ever since. 00:04:16.06 It is estimated that they have been propagated to a quantity of at least 20 tons. 00:04:23.22 Or others put it this way, more HeLa cells, as they are called, now exist than all of the visible stars in the universe. 00:04:34.08 This of course is a stunning testimony to the stability of the malignant phenotype. 00:04:39.21 In conclusion, the durability of the malignant phenotype clearly suggests a genetic underpinning. 00:04:47.23 The second of our paths to the genetic paradigm of cancer involved the recognition that there are external causes of cancer, 00:04:57.06 and that many of these causes act by damaging DNA by causing mutations in our genes. 00:05:03.19 As long ago as 1761 Dr. John Hill, a physician in London, noticed an association between the use of snuff 00:05:11.27 and the occurrence of cancer of the tongue, jaw, throat. 00:05:16.28 We now call snuff by the disarming term "smokeless tobacco," but its consequences can be just as onerous as illustrated by this figure. 00:05:26.15 Soon thereafter, Percival Pott made a landmark observation. 00:05:32.10 He recognized that scrotal cancer was very common in chimney sweeps in London. 00:05:38.27 And he made a leap, an induction, and attributed this incidence of cancer to the soot 00:05:46.21 that was accumulating on the skin of the chimney sweeps. 00:05:50.29 With the emergence of the industrial revolution more and more external causes of cancer became apparent. 00:05:58.26 Mainly from large industrial exposures, or in the case of X-rays, 00:06:05.16 in the case of experimentalists who were working with X-rays in the early days after their discovery. 00:06:13.25 To give you a sense of the power of these observations, consider the chemical 2-naphthylamine, 00:06:21.17 which we now know can cause bladder cancer. 00:06:24.23 Individuals who work with this chemical and have exposure for at least five years are almost guaranteed of having bladder cancer. 00:06:38.00 Here is a list of some of the other examples, and the point of this list is to dramatize the great variety of cancers 00:06:49.02 that can emerge from external causes, from exposure to industrial chemicals and physical agents. 00:06:56.28 But could this be replicated in experiment? 00:07:02.23 Could it be proven that these external agents were causing the cancer? 00:07:07.27 In 1915, Katsusaburo Yamagiwa reported that he could induce skin cancer in rabbit ears by the repeated application of coal tar. 00:07:20.00 This was a riveting discovery. It was the first direct demonstration that a chemical could elicit cancer. 00:07:29.08 Yamagiwa was ecstatic over his discovery, so much so that he wrote a commemorative haiku in his own beautiful calligraphy. 00:07:40.01 Roughly translated the haiku reads, "Cancer was produced. Proudly I walk a few steps." 00:07:47.21 By 1938 a great variety of external agents, mainly from industrial sources had been identified as causes of cancer. 00:07:58.06 and the thought that there are external causes of cancer was well established. 00:08:04.04 Now how do these agents work? Well, the first clue came from the work of one of America's great scientists, H. J. Muller, 00:08:14.09 who working with fruit flies discovered that X-rays caused mutations in the genes of the fruit fly. 00:08:20.15 Some years later, American scientist Bruce Ames discovered using a very clever bacterial test that many carcinogens are mutagenic. 00:08:34.06 Not all, but many. 00:08:38.03 The third of our convergent paths to the genetic paradigm of cancer involved the study of abnormal chromosomes in cancer cells. 00:08:47.26 In 1903, Walter Sutton was a PhD student working at Columbia University. Sutton was working with grasshoppers. 00:09:00.06 And from his studies he was the first to reach the solid conclusion that chromosomes are carriers of heredity. 00:09:09.10 He published that work, but never published another paper. Instead he became a surgeon and died prematurely at the age of 39. 00:09:18.22 In 1914, the German biologist Theodor Boveri while studying worms and sea urchins had a vision. 00:09:31.02 And in a famous monograph published an argument that the abnormalities of chromosomes might account for cancer. 00:09:40.04 He anticipated the current form of the genetic paradigm with a remarkable prescience, but there was no evidence for his vision until 1959 00:09:53.03 when two scientists in Philadelphia, Peter Nowell and David Hungerford, the latter of whom was still a graduate student, 00:10:00.19 discovered a miniature chromosome, an abnormal chromosome that was unique to the cells of chronic myeloid leukemia. 00:10:08.20 The chromosome was dubbed the Philadelphia chromosome in honor of the city where it was discovered. 00:10:15.06 Now the nature of this chromosome was not known until 1972 when Janet Rowley, working at the University of Chicago, 00:10:22.25 demonstrated that the Philadelphia chromosome results from a reciprocal translocation between two chromosomes, chromosomes 9 and 22. 00:10:33.06 Here is an image of what Janet Rowley had discovered. 00:10:39.09 The two chromosomes essentially swapped pieces. 00:10:42.03 In the end a piece of chromosome 22 is now on chromosome 9, and a piece of chromosome 9 is now on chromosome 22. 00:10:53.18 That is the Philadelphia chromosome. 00:10:56.23 We now know that abnormalities of chromosomes are common in human cancer, 00:11:03.24 and sometimes there is sheer chaos among the chromosomes. 00:11:08.05 Consider this example of colon cancer. 00:11:11.14 Here are the normal human chromosomes arrayed and colored so you can distinguish one from another. 00:11:17.15 And here are the chromosomes from the colon cancer. 00:11:20.21 In some instances there are three instead of two. In some instances there you see what Rowley had found before. 00:11:30.07 Chromosomes have swapped pieces. 00:11:31.18 Here is a piece of a red chromosome on a blue gray chromosome. 00:11:35.21 This kind of chaos suggests that havoc has been wreaked with the genes in the cancer cell. 00:11:43.25 Now what might be the genetic consequences of both mutagenesis by external agents 00:11:51.25 and the chromosomal mayhem that we find in cancer cells? 00:11:56.02 The answer to this question came from the discovery that certain cancer genes carried in viruses 00:12:02.27 are actually derived from normal cells, from cellular genes that we call proto-oncogenes. 00:12:08.28 This story began in 1909 when Peyton Rous at the Rockefeller Institute discovered a virus 00:12:16.05 that causes sarcomas in chickens, Rous Sarcoma Virus. 00:12:20.02 It was a complete mystery as to how this virus caused cancer until 1970 when Steven Martin at the University of California, Berkeley, 00:12:32.04 isolated a mutant of Rous Sarcoma Virus that demonstrated temperature sensitive transformation. 00:12:41.11 In other words the virus could create a cancer cell at one temperature, but not at another. 00:12:47.07 Here is an illustration of what Steven Martin had discovered. 00:12:51.22 These are normal chicken fibroblasts growing in culture, and here's what those fibroblasts look like near 24 hours 00:13:01.00 after having been infected with Rous Sarcoma Virus. 00:13:04.16 What Martin discovered was that if he infected the cells at 35 degrees with this mutant, 00:13:13.02 the cells transformed, but as soon as the cells were shifted to a higher temperature, 00:13:18.10 they reverted to the normal state. 00:13:22.02 You could cycle the cells back and forth between the transformed and the normal state just by shifting the temperature. 00:13:28.08 To geneticists, this meant that there was at least one gene that was clearly responsible for eliciting the neoplastic transformation. 00:13:36.24 We came to call these genes oncogenes and the gene in Rous Sarcoma Virus was dubbed src because it elicits sarcomas. 00:13:46.09 In due course we learned that Rous Sarcoma Virus has four genes, only four genes, arrayed along its RNA genome as illustrated here. 00:13:57.02 Three of these genes are responsible for viral reproduction. 00:14:01.23 The fourth, the src gene, is responsible for cancer but only the induction of cancer. 00:14:09.22 It is not required for replication of the virus. 00:14:11.26 The seeming irrelevance of src to the welfare of the Rous Sarcoma Virus inspired our research group in San Francisco 00:14:21.14 to ask whether this gene might actually be acquired from a normal cell. 00:14:26.19 That it is an accident of nature. That proved to be the case. At some time in the past during the course of replication, 00:14:36.14 the virus that became Rous Sarcoma Virus acquired a cellular gene and inserted it into its own genome creating the viral oncogene src. 00:14:49.09 At first it seemed that Src might be a mere curiosity. 00:14:55.25 But many other retroviral oncogenes were identified, and in almost every instance these too were found to be acquired from the normal cell. 00:15:04.28 The cellular genes that gave rise to the viral oncogenes became known as proto-oncogenes. 00:15:12.08 This led to a larger hypothesis. If a change in a proto-oncogene can create a viral oncogene, 00:15:23.20 why could not the same sort of thing occur within the cell without the intervention of the virus? 00:15:29.20 Why couldn't proto-oncogenes become the progenitors of cellular oncogenes? 00:15:39.29 That thought was made a reality by the discovery that proto-oncogenes are affected by genetic abnormalities in human cancer. 00:15:50.22 Three forms of abnormalities were involved in this discovery. The first was something known as gene amplification. 00:15:58.11 A focus on a chromosome, the DNA at that locus, 00:16:04.02 replicates many times over, sometimes giving rise to little chromosomes that are thrown off and called double minute chromosomes, 00:16:17.12 which then can re-insert into a chromosome and create what is called a homogeneously staining region. 00:16:22.17 This was first observed with a proto-oncogene known as MYC in human cancer cells. 00:16:28.22 The consequence is gross overproduction of the gene product. 00:16:33.15 The second abnormality involved translocation of the sort first described for the Philadelphia chromosome. 00:16:40.15 Translocations of the MYC gene were the first to be seen, and these translocations alter the control of the expression of MYC 00:16:52.04 and again create a gross overproduction of the gene product. 00:16:56.28 Third, single point mutations were discovered in another proto-oncogene known as RAS in human tumor cells. 00:17:07.27 This point mutation converted the protein from a controlled state to an uncontrolled state. 00:17:17.03 The protein activity could now run rampant. 00:17:20.24 We now know of several hundred proto-oncogenes that have been implicated in human cancer. 00:17:27.23 Several hundred genes of the normal cell that if altered in one way or another can contribute to the genesis of cancer. 00:17:37.17 Now, the malady here is exaggerated activity, which we can equate to a jammed accelerator. 00:17:47.22 Formally speaking, it is a gain of function, and it is genetically dominant. 00:17:53.21 You need have this happen to only one of the two copies in the cell for the difficulty to arise. 00:18:01.19 Our fifth path to the genetic paradigm of cancer involved the study of congenital cancer 00:18:10.20 and incidentally uncovered an entirely new form of cancer gene. 00:18:16.13 This work departs from the fact that about 5% of human cancer is strongly hereditary. 00:18:22.23 And it began with a study of a childhood tumor known as retinoblastoma, and here is an example. 00:18:32.26 In some instances, retinoblastoma is inherited in a very strong manner, 00:18:38.02 as illustrated in this family tree, where every red box or circle indicates a case of childhood retinoblastoma. 00:18:46.01 The first hint to what was going on here was the discovery of a defective chromosome 00:18:52.24 in familial retinoblastoma, inherited retinoblastoma. 00:18:56.18 It involved chromosome 13, and it was discovered that in some cases of retinoblastoma, there was a focal deletion. 00:19:08.00 A piece of this chromosome was missing. This band here had disappeared in the chromosome of the family. 00:19:18.26 It was immediately apparent that this deletion segregated with the disease in families. 00:19:22.29 And in due course through the use of molecular biology, a single gene was identified as the culprit. 00:19:31.08 A gene that was known as the retinoblastoma gene, or RB1. 00:19:35.20 And it was the loss of this gene that was causing the trouble. 00:19:39.24 Here is how we understand the inheritance of retinoblastoma. 00:19:45.12 One of the two chromosomes in the family is carrying this deficiency. 00:19:54.10 And some time during the early life of the child, the corresponding normal copy in the other chromosome 00:20:01.20 is also damaged for one reason or another. Now the cell is totally deficient in this gene, and that gives rise to the cancer. 00:20:11.28 A retinoblastoma also occurs as a spontaneous tumor. 00:20:16.04 And in that instance, there is no inherited abnormality. 00:20:21.04 Both copies of the gene are damaged during early life, giving rise to the cancer. 00:20:33.28 And both of these are rare events, so as a consequence, for two of them to occur in the same lineage of cells, 00:20:40.18 it makes this a very rare tumor and one in perhaps 30,000 people. 00:20:46.23 So this is a new form of cancer gene, a genetic deficiency that we now know is present in both congenital and sporadic cancer. 00:20:59.15 And the affected genes are known as tumor suppressors because in their absence cancer is favored. 00:21:06.17 Typically both copies of the genes are defective in a tumor, and that is how we usually spot them. 00:21:13.08 And the deficiency is genetically recessive because both copies must be affected. 00:21:20.19 Here are a few prominent examples. These examples were... almost all of them were discovered first by the study of inherited cancer. 00:21:33.09 But with the latter day techniques of genomics, we can now identify tumor suppressor genes 00:21:40.04 without any assistance from congenital cancer or heritable cancer. 00:21:45.26 Now the malady here is loss of a gene or its activity, 00:21:50.22 which we could equate to a faulty brake as opposed to the jammed accelerator of proto-oncogenes. 00:21:57.11 So the geneticist calls this a loss of function, and it is genetically recessive. 00:22:03.25 So we have identified two major culprits in cancer cells, proto-oncogenes, which suffer gain of function in tumor cells, 00:22:16.24 and tumor suppressor genes which suffer loss of function in cancer cells. 00:22:22.25 And these two collaborate in ways that we don't fully understand just yet to produce the final malignant state. 00:22:28.26 A variety of events can create the genetic malfunctions in cancer, and these all can affect either a proto-oncogene or tumor suppressor gene. 00:22:38.06 They include: gain or loss of entire chromosome; 00:22:41.27 focal amplification or deletion within a chromosome, as I illustrated for you with the retinoblastoma gene; 00:22:47.14 chromosomal translocations, as I illustrated for you with both the Philadelphia chromosome and the case of the proto-oncogene MYC; 00:22:56.18 a direct mutation in the gene product, which activates the gene product in the case of a proto-oncogene, 00:23:02.04 but inactivates it in the case of a tumor suppressor gene; or defective control of expression, either up or down. 00:23:09.06 Up for a proto-oncogene, down for a tumor suppressor gene. 00:23:13.15 And all of these have been observed in human cancer. 00:23:17.27 Now how can we authenticate the powerful circumstantial evidence that these genes are involved in cancer? 00:23:26.20 And there are four general approaches. First, what I call guilt by association. 00:23:31.28 If you find the Philadelphia chromosome in every case of chronic myeloid leukemia, 00:23:37.08 which is essentially the case, surely it has something to do with the disease. 00:23:41.02 We can also install replicas of the damaged proto-oncogene or tumor suppressor gene in mice, 00:23:50.18 and this often leads to the production of tumors, and it often leads to production 00:23:58.15 of the same kind of tumor in which the lesion was originally identified in human cancers. 00:24:05.12 And finally, in very recent years, it has been possible to demonstrate that targeting 00:24:11.16 at least a few of these abnormalities with therapeutics gives rise to a therapeutic response. 00:24:17.09 Something I will talk about in greater detail in my second and third chapters. 00:24:24.00 Now how many of these adverse events are required to produce a malignant cell? 00:24:28.18 Epidemiologists were among the first to approach this problem. 00:24:32.00 And by simply charting the incidence of a particular tumor against age, 00:24:38.18 they reached the conclusion that multiple events were required, and by mathematical analysis of the data, 00:24:45.25 they could assign a rough approximation of the number of events required to give rise to certain cancers. 00:24:52.15 For example, childhood leukemia, only a few events were required which was probably the reason that these diseases occur in children. 00:25:00.15 Lung cancer, 6 or more, and prostate, which we commonly associate 00:25:05.02 with the late middle age and elderly, may involve 20 or more discrete events. 00:25:11.19 If we look at this in a biological sense, we see evolution in miniature. 00:25:23.29 An initial event occurs in a single cell, causing that cell to replicate. 00:25:31.04 And then an event occurs in one member of that population, which changes the cell yet again. 00:25:38.29 This happens multiple times, giving rise finally, to a tumorigenic clone. 00:25:46.18 We call this tumor progression, and at the genetic level, the molecular level, we believe, and in fact we have been able to show 00:25:58.29 that what is happening over the course of time is the accrual of independent genetic events. 00:26:04.29 So that by the end there is a combination of these events that give rise to the malignant cell. 00:26:12.17 Recently it has become apparent that sometimes a cataclysmic event can occur that shatters an entire chromosome, 00:26:23.23 and the pieces are then stitched back together in a random order. 00:26:31.06 This is a... and this single event can create more than one cancer gene along the array of the chromosome. 00:26:38.03 We do not know how often this occurs but it obviously would be an accelerating event in tumor progression. 00:26:45.03 So we have reached our genetic paradigm for cancer, and it has these components. 00:26:54.06 There are many causes of cancer, but they all work by damaging genes or otherwise disturbing the function of the genes. 00:27:04.08 Both gain and loss of gene function are involved, cooperate in some way in the production of the tumor. 00:27:11.23 Multiple genes are involved, from as few as one or two to as many as twenty or more depending on the cancer and the age that it arises. 00:27:20.26 There is a stepwise evolution of malignancy, 00:27:24.09 probably resolving from the selection of favorable properties of the evolving malignant cell. 00:27:31.04 And there is this cooperation among gain and loss of function. 00:27:36.14 In 1978, Susan Sontag published a book entitled "Illness as Metaphor." 00:27:45.05 In that book she described cancer as "overlaid with mystification", "a triumphant mutation", an "inescapable fatality". 00:27:54.12 The emergence of the genetic paradigm for cancer has got the mystification in retreat, 00:28:01.09 exposed the triumphant mutation, and rendered that inescapable fatality vulnerable. 00:28:08.18 This is a triumph of modern science that offers great hope for the future management of cancer, 00:28:16.26 and it is that hope that I will turn to in the second chapter of my story. 00:28:22.17 Thank you for listening.