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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.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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