HomeArticlesJ. Michael Bishop (UCSF) Part 1: Forging a genetic paradigm for cancer
J. Michael Bishop (UCSF) Part 1: Forging a genetic paradigm for cancer
September 8, 2019
Hello. I am Mike Bishop from the University of California, San Francisco, and I am going to talk with you about cancer, what we presently know about the disease and how we are trying to apply that knowledge. Cancer is the most fearsome of human adversaries. In the United States as many as one in three individuals will develop the disease and one in four will die of it. 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. We have not been doing well in our struggle against cancer until recently. Consider this comparison. Between 1975 and 2005 mortality from cardiovascular disease decreased by 70%, whereas that of cancer decreased by only 7.5%. Numbers of this sort have inspired disappointment and even skepticism amongst the public and the press. Witness this lead article in Newsweek in 2008. Now we can rationalize our difficulties with cancer. Consider this comparison again. Cardiovascular disease is essentially a single disease of a single organ system with a single cause. Whereas cancer has multiple causes, numerous causes, and every organ system has its own forms of cancer. There are at least a hundred discrete forms of human cancer. But we have been able to cut through this complexity with a unifying simplification that we call the genetic paradigm of cancer. And that is that all cancer arises through the malfunction of genes. I am going to tell the story in three chapters. In the first chapter, I will review the history of how we came to this insight. In the second chapter I will talk about the challenges that it represents and the promise. And in the third chapter I will delve more deeply into one application of this insight in therapeutics for cancer. Five paths of investigation converged to give us the genetic paradigm for cancer. The first of these paths was the most elemental. And that is the fact that cancer is a heritable cellular phenotype. Cancer cells breed true. One of the first persons to recognize this was a man named Rudolf Virchow, a German pathologist, who in 1858 pointed out that the metastases of cancer resembled the primary tumors, as if the metastases and the primary tumors might have a common origin. It had previously been believed that what we call a metastases might be tumors of independent origin. This insight also inspired Virchow to coin a well-known aphorism that “All cells come from cells” to advertise the newly emerging theory of the cell. Virchow would not have been in position to know how close he was to the truth. We now know that most if not all cancers have their origin in a single cell. 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. Now there are subtleties to this that we will explore a little later, but fundamentally, this is another testimony to the extraordinary durability of the malignant phenotype once it has been established. Let me dramatize that durability with a story that has been widely appreciated because of a best-selling book. And that is the story of Henrietta Lacks. In 1951, Mrs. Lacks died of cervical cancer at Johns Hopkins University. Cells from her cancer were put into test tubes and Petri dishes and have been propagated ever since. It is estimated that they have been propagated to a quantity of at least 20 tons. Or others put it this way, more HeLa cells, as they are called, now exist than all of the visible stars in the universe. This of course is a stunning testimony to the stability of the malignant phenotype. In conclusion, the durability of the malignant phenotype clearly suggests a genetic underpinning. The second of our paths to the genetic paradigm of cancer involved the recognition that there are external causes of cancer, and that many of these causes act by damaging DNA by causing mutations in our genes. As long ago as 1761 Dr. John Hill, a physician in London, noticed an association between the use of snuff and the occurrence of cancer of the tongue, jaw, throat. We now call snuff by the disarming term “smokeless tobacco,” but its consequences can be just as onerous as illustrated by this figure. Soon thereafter, Percival Pott made a landmark observation. He recognized that scrotal cancer was very common in chimney sweeps in London. And he made a leap, an induction, and attributed this incidence of cancer to the soot that was accumulating on the skin of the chimney sweeps. With the emergence of the industrial revolution more and more external causes of cancer became apparent. Mainly from large industrial exposures, or in the case of X-rays, in the case of experimentalists who were working with X-rays in the early days after their discovery. To give you a sense of the power of these observations, consider the chemical 2-naphthylamine, which we now know can cause bladder cancer. Individuals who work with this chemical and have exposure for at least five years are almost guaranteed of having bladder cancer. Here is a list of some of the other examples, and the point of this list is to dramatize the great variety of cancers that can emerge from external causes, from exposure to industrial chemicals and physical agents. But could this be replicated in experiment? Could it be proven that these external agents were causing the cancer? In 1915, Katsusaburo Yamagiwa reported that he could induce skin cancer in rabbit ears by the repeated application of coal tar. This was a riveting discovery. It was the first direct demonstration that a chemical could elicit cancer. Yamagiwa was ecstatic over his discovery, so much so that he wrote a commemorative haiku in his own beautiful calligraphy. Roughly translated the haiku reads, “Cancer was produced. Proudly I walk a few steps.” By 1938 a great variety of external agents, mainly from industrial sources had been identified as causes of cancer. and the thought that there are external causes of cancer was well established. Now how do these agents work? Well, the first clue came from the work of one of America’s great scientists, H. J. Muller, who working with fruit flies discovered that X-rays caused mutations in the genes of the fruit fly. Some years later, American scientist Bruce Ames discovered using a very clever bacterial test that many carcinogens are mutagenic. Not all, but many. The third of our convergent paths to the genetic paradigm of cancer involved the study of abnormal chromosomes in cancer cells. In 1903, Walter Sutton was a PhD student working at Columbia University. Sutton was working with grasshoppers. And from his studies he was the first to reach the solid conclusion that chromosomes are carriers of heredity. He published that work, but never published another paper. Instead he became a surgeon and died prematurely at the age of 39. In 1914, the German biologist Theodor Boveri while studying worms and sea urchins had a vision. And in a famous monograph published an argument that the abnormalities of chromosomes might account for cancer. He anticipated the current form of the genetic paradigm with a remarkable prescience, but there was no evidence for his vision until 1959 when two scientists in Philadelphia, Peter Nowell and David Hungerford, the latter of whom was still a graduate student, discovered a miniature chromosome, an abnormal chromosome that was unique to the cells of chronic myeloid leukemia. The chromosome was dubbed the Philadelphia chromosome in honor of the city where it was discovered. Now the nature of this chromosome was not known until 1972 when Janet Rowley, working at the University of Chicago, demonstrated that the Philadelphia chromosome results from a reciprocal translocation between two chromosomes, chromosomes 9 and 22. Here is an image of what Janet Rowley had discovered. The two chromosomes essentially swapped pieces. In the end a piece of chromosome 22 is now on chromosome 9, and a piece of chromosome 9 is now on chromosome 22. That is the Philadelphia chromosome. We now know that abnormalities of chromosomes are common in human cancer, and sometimes there is sheer chaos among the chromosomes. Consider this example of colon cancer. Here are the normal human chromosomes arrayed and colored so you can distinguish one from another. And here are the chromosomes from the colon cancer. In some instances there are three instead of two. In some instances there you see what Rowley had found before. Chromosomes have swapped pieces. Here is a piece of a red chromosome on a blue gray chromosome. This kind of chaos suggests that havoc has been wreaked with the genes in the cancer cell. Now what might be the genetic consequences of both mutagenesis by external agents and the chromosomal mayhem that we find in cancer cells? The answer to this question came from the discovery that certain cancer genes carried in viruses are actually derived from normal cells, from cellular genes that we call proto-oncogenes. This story began in 1909 when Peyton Rous at the Rockefeller Institute discovered a virus that causes sarcomas in chickens, Rous Sarcoma Virus. It was a complete mystery as to how this virus caused cancer until 1970 when Steven Martin at the University of California, Berkeley, isolated a mutant of Rous Sarcoma Virus that demonstrated temperature sensitive transformation. In other words the virus could create a cancer cell at one temperature, but not at another. Here is an illustration of what Steven Martin had discovered. These are normal chicken fibroblasts growing in culture, and here’s what those fibroblasts look like near 24 hours after having been infected with Rous Sarcoma Virus. What Martin discovered was that if he infected the cells at 35 degrees with this mutant, the cells transformed, but as soon as the cells were shifted to a higher temperature, they reverted to the normal state. You could cycle the cells back and forth between the transformed and the normal state just by shifting the temperature. To geneticists, this meant that there was at least one gene that was clearly responsible for eliciting the neoplastic transformation. We came to call these genes oncogenes and the gene in Rous Sarcoma Virus was dubbed src because it elicits sarcomas. In due course we learned that Rous Sarcoma Virus has four genes, only four genes, arrayed along its RNA genome as illustrated here. Three of these genes are responsible for viral reproduction. The fourth, the src gene, is responsible for cancer but only the induction of cancer. It is not required for replication of the virus. The seeming irrelevance of src to the welfare of the Rous Sarcoma Virus inspired our research group in San Francisco to ask whether this gene might actually be acquired from a normal cell. That it is an accident of nature. That proved to be the case. At some time in the past during the course of replication, the virus that became Rous Sarcoma Virus acquired a cellular gene and inserted it into its own genome creating the viral oncogene src. At first it seemed that Src might be a mere curiosity. But many other retroviral oncogenes were identified, and in almost every instance these too were found to be acquired from the normal cell. The cellular genes that gave rise to the viral oncogenes became known as proto-oncogenes. This led to a larger hypothesis. If a change in a proto-oncogene can create a viral oncogene, why could not the same sort of thing occur within the cell without the intervention of the virus? Why couldn’t proto-oncogenes become the progenitors of cellular oncogenes? That thought was made a reality by the discovery that proto-oncogenes are affected by genetic abnormalities in human cancer. Three forms of abnormalities were involved in this discovery. The first was something known as gene amplification. A focus on a chromosome, the DNA at that locus, replicates many times over, sometimes giving rise to little chromosomes that are thrown off and called double minute chromosomes, which then can re-insert into a chromosome and create what is called a homogeneously staining region. This was first observed with a proto-oncogene known as MYC in human cancer cells. The consequence is gross overproduction of the gene product. The second abnormality involved translocation of the sort first described for the Philadelphia chromosome. Translocations of the MYC gene were the first to be seen, and these translocations alter the control of the expression of MYC and again create a gross overproduction of the gene product. Third, single point mutations were discovered in another proto-oncogene known as RAS in human tumor cells. This point mutation converted the protein from a controlled state to an uncontrolled state. The protein activity could now run rampant. We now know of several hundred proto-oncogenes that have been implicated in human cancer. Several hundred genes of the normal cell that if altered in one way or another can contribute to the genesis of cancer. Now, the malady here is exaggerated activity, which we can equate to a jammed accelerator. Formally speaking, it is a gain of function, and it is genetically dominant. You need have this happen to only one of the two copies in the cell for the difficulty to arise. Our fifth path to the genetic paradigm of cancer involved the study of congenital cancer and incidentally uncovered an entirely new form of cancer gene. This work departs from the fact that about 5% of human cancer is strongly hereditary. And it began with a study of a childhood tumor known as retinoblastoma, and here is an example. In some instances, retinoblastoma is inherited in a very strong manner, as illustrated in this family tree, where every red box or circle indicates a case of childhood retinoblastoma. The first hint to what was going on here was the discovery of a defective chromosome in familial retinoblastoma, inherited retinoblastoma. It involved chromosome 13, and it was discovered that in some cases of retinoblastoma, there was a focal deletion. A piece of this chromosome was missing. This band here had disappeared in the chromosome of the family. It was immediately apparent that this deletion segregated with the disease in families. And in due course through the use of molecular biology, a single gene was identified as the culprit. A gene that was known as the retinoblastoma gene, or RB1. And it was the loss of this gene that was causing the trouble. Here is how we understand the inheritance of retinoblastoma. One of the two chromosomes in the family is carrying this deficiency. And some time during the early life of the child, the corresponding normal copy in the other chromosome is also damaged for one reason or another. Now the cell is totally deficient in this gene, and that gives rise to the cancer. A retinoblastoma also occurs as a spontaneous tumor. And in that instance, there is no inherited abnormality. Both copies of the gene are damaged during early life, giving rise to the cancer. And both of these are rare events, so as a consequence, for two of them to occur in the same lineage of cells, it makes this a very rare tumor and one in perhaps 30,000 people. So this is a new form of cancer gene, a genetic deficiency that we now know is present in both congenital and sporadic cancer. And the affected genes are known as tumor suppressors because in their absence cancer is favored. Typically both copies of the genes are defective in a tumor, and that is how we usually spot them. And the deficiency is genetically recessive because both copies must be affected. Here are a few prominent examples. These examples were… almost all of them were discovered first by the study of inherited cancer. But with the latter day techniques of genomics, we can now identify tumor suppressor genes without any assistance from congenital cancer or heritable cancer. Now the malady here is loss of a gene or its activity, which we could equate to a faulty brake as opposed to the jammed accelerator of proto-oncogenes. So the geneticist calls this a loss of function, and it is genetically recessive. So we have identified two major culprits in cancer cells, proto-oncogenes, which suffer gain of function in tumor cells, and tumor suppressor genes which suffer loss of function in cancer cells. And these two collaborate in ways that we don’t fully understand just yet to produce the final malignant state. A variety of events can create the genetic malfunctions in cancer, and these all can affect either a proto-oncogene or tumor suppressor gene. They include: gain or loss of entire chromosome; focal amplification or deletion within a chromosome, as I illustrated for you with the retinoblastoma gene; chromosomal translocations, as I illustrated for you with both the Philadelphia chromosome and the case of the proto-oncogene MYC; a direct mutation in the gene product, which activates the gene product in the case of a proto-oncogene, but inactivates it in the case of a tumor suppressor gene; or defective control of expression, either up or down. Up for a proto-oncogene, down for a tumor suppressor gene. And all of these have been observed in human cancer. Now how can we authenticate the powerful circumstantial evidence that these genes are involved in cancer? And there are four general approaches. First, what I call guilt by association. If you find the Philadelphia chromosome in every case of chronic myeloid leukemia, which is essentially the case, surely it has something to do with the disease. We can also install replicas of the damaged proto-oncogene or tumor suppressor gene in mice, and this often leads to the production of tumors, and it often leads to production of the same kind of tumor in which the lesion was originally identified in human cancers. And finally, in very recent years, it has been possible to demonstrate that targeting at least a few of these abnormalities with therapeutics gives rise to a therapeutic response. Something I will talk about in greater detail in my second and third chapters. Now how many of these adverse events are required to produce a malignant cell? Epidemiologists were among the first to approach this problem. And by simply charting the incidence of a particular tumor against age, they reached the conclusion that multiple events were required, and by mathematical analysis of the data, they could assign a rough approximation of the number of events required to give rise to certain cancers. For example, childhood leukemia, only a few events were required which was probably the reason that these diseases occur in children. Lung cancer, 6 or more, and prostate, which we commonly associate with the late middle age and elderly, may involve 20 or more discrete events. If we look at this in a biological sense, we see evolution in miniature. An initial event occurs in a single cell, causing that cell to replicate. And then an event occurs in one member of that population, which changes the cell yet again. This happens multiple times, giving rise finally, to a tumorigenic clone. We call this tumor progression, and at the genetic level, the molecular level, we believe, and in fact we have been able to show that what is happening over the course of time is the accrual of independent genetic events. So that by the end there is a combination of these events that give rise to the malignant cell. Recently it has become apparent that sometimes a cataclysmic event can occur that shatters an entire chromosome, and the pieces are then stitched back together in a random order. This is a… and this single event can create more than one cancer gene along the array of the chromosome. We do not know how often this occurs but it obviously would be an accelerating event in tumor progression. So we have reached our genetic paradigm for cancer, and it has these components. There are many causes of cancer, but they all work by damaging genes or otherwise disturbing the function of the genes. Both gain and loss of gene function are involved, cooperate in some way in the production of the tumor. 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. There is a stepwise evolution of malignancy, probably resolving from the selection of favorable properties of the evolving malignant cell. And there is this cooperation among gain and loss of function. In 1978, Susan Sontag published a book entitled “Illness as Metaphor.” In that book she described cancer as “overlaid with mystification”, “a triumphant mutation”, an “inescapable fatality”. The emergence of the genetic paradigm for cancer has got the mystification in retreat, exposed the triumphant mutation, and rendered that inescapable fatality vulnerable. This is a triumph of modern science that offers great hope for the future management of cancer, and it is that hope that I will turn to in the second chapter of my story. Thank you for listening.