The video introduces the significant scientific discoveries made by Doctor Michael Bishop and Harold Varmus, which detailed the cellular origin of retroviral oncogenes. Acknowledged with numerous awards, this duo’s groundbreaking work stems from earlier research that started in Harvard Medical School and beyond. Discussed are the personal sacrifices and career paths of scientists, intertwined with rich anecdotes showcasing the pursuit and evolution of their research interests, particularly highlighting their contributions in understanding retroviruses and cancer.

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Key Vocabularies and Common Phrases:

1. retroviral [ˌrɛtroʊˈvaɪrəl] - (adjective) - Relating to or denoting a retrovirus, which is a type of virus that inserts its genetic material into the host's genome. - Synonyms: (viral, virologic, viral-related)

I'll try to give you a brief introduction to the discoveries of Doctor Michael Bishop and Harold Varmus...for important discoveries concerning the cellular origin of retroviral oncogenes.

2. oncogenes [ˈɒnkoʊˌdʒiːnz] - (noun) - Genes that have the potential to cause cancer, typically by regulating cell growth. - Synonyms: (cancer genes, tumor genes, malignant genes)

...they have been awarded the 1989 prize jointly for important discoveries concerning the cellular origin of retroviral oncogenes.

3. larynx [ˈlærɪŋks] - (noun) - The hollow muscular organ forming an air passage to the lungs and holding the vocal cords; the voice box. - Synonyms: (voice box, vocal cords, throat)

And I'm grateful to the medical attention of Stockholm for restoring my larynx to some semblance of function today.

4. procrastination [prəʊˌkræstɪˈneɪʃən] - (noun) - The action of delaying or postponing something. - Synonyms: (delay, postponement, deferral)

It's abundantly clear by now that the biographical theme today is procrastination.

5. neoplastic [ˌniːəʊˈplæstɪk] - (adjective) - Relating to the formation of tumors, especially cancerous tumors. - Synonyms: (tumorous, malignant, cancerous)

The genetic identification of Src was reported in the very same year as the biochemical discovery of reverse transcriptase...the data showed with luminous clarity that a gene within rouse sarcoma virus is responsible for the neoplastic transformation of infected cells.

6. pleiotropic [ˌplaɪəˈtrɒpɪk] - (adjective) - Producing or having multiple effects from a single gene or molecule. - Synonyms: (multifactorial, multifaceted, multifunctional)

How could this single protein elicit the pleiotropic change in cellular phenotype that we call neoplastic transformation, a change so numerous in kind that we could not count all of its components? Slide, please

7. hybridization [ˌhaɪbrɪdaɪˈzeɪʃən] - (noun) - The process of combining two different types of entities to form a new entity, especially in the context of molecules or DNA/RNA sequences. - Synonyms: (fusion, combination, amalgamation)

We now had a wedge with which to pry open the infected cell. The hammer to drive that wedge would be molecular hybridization.

8. transduction [trænzˈdʌkʃən] - (noun) - The process of genetic material transfer from one organism to another by a virus or viral vector. - Synonyms: (transmission, transfer, conveyance)

But our exercises with viral rna had a larger resonance because we had constructed the technical stage on which the discovery of retroviral transduction would eventually play out

9. enzymatic [ˌenzɪˈmætɪk] - (adjective) - Relating to or caused by enzymes, which are proteins that act as biological catalysts. - Synonyms: (catalytic, biochemical, enzymic)

This finding perplexed us and seemed abstruse, but it proved to be a harbinger of unanticipated enzymatic activities whose existence and functions are coming into view only now when the work was finally published, David Baltimore himself urged me to remain with polio virus, even to renounce my emerging interest in retroviruses

10. pathogenic [ˌpæθəˈdʒɛnɪk] - (adjective) - Capable of causing disease. - Synonyms: (disease-causing, harmful, virulent)

...numerous investigators, ourselves included, have spent the past decade documenting the sorts of genetic damage that can convert a harmless proto oncogene to a pathogenic oncogene.

Michael Bishop, Nobel Prize in Physiology or Medicine 1989 - Official Lecture

I'll try to give you a brief introduction to the discoveries of Doctor Michael Bishop and Harold Varmus. As you have seen from the official announcements, they have been awarded the 1989 prize jointly for important discoveries concerning the cellular origin of retroviral oncogenes. Together, doctors Bishop and Varmus have received a number of prestigious awards. Among them the Lasker Award in 1982. And the General Motors Foundation Cancer Research Award in 1984. The second installment will be given with the same title. Retroviruses and oncogenes.

But Doctor Michael Bishop, please. I do share all the gratitudes that Harold expressed to my family, whose embrace I form my original aspirations. To the small and large institutions that have helped me nurture those aspirations. To the many colleagues who've shared and pursued those aspirations with me. I'm grateful to the Nobel foundation and to all of Stockholm for exquisite hospitality. And I'm grateful to the medical attention of Stockholm for restoring my larynx to some semblance of function today. As I said last night in a more intimate setting. If the Nobel foundation required drug testing, as does the Olympic committee, I would not be before you today.

The english critic Cyril Connelly once remarked that the true index of a man's character is the health of his wife. My life in science has been rich and rewarding. I have sacrificed very little. May I have the first slide, please? But my partner in that life has sacrificed. No. The first slide. That's it. My partner in that life has sacrificed a great deal. Katherine, my wife of 30 years. May I have the next slide, please? There have been moments when I resolved. This was one of those moments when I resolved to be more attentive. But the realities are more properly shown in the next slide. Our coon. A cartoon that Katherine has seen once before. A decade ago. Right. You've got it. You're my best friend, my lover and my wife. Now I've got to get off the phone and get this finished. I take this moment of confession to speak my gratitude for her forbearance and to acknowledge that matters are not likely to improve. So the lights, please.

It's abundantly clear by now that the biographical theme today is procrastination. Peyton rous withdrew from medical school for a year to spend time on a ranch in Texas. Once back in medicine, he found himself, I quote, unfit to be a real doctor and turned to pathology for entry into research. Harold dallied with english literature before entering medical school, as you've heard. And I came close to abandoning medicine entirely at an early age. I entered medical school knowing nothing of research. But while at Harvard, I was awakened to research by newfound friends among my classmates. Classmates are always much more important than faculty. Two of them particularly important were John Menninger and Howard Berg, both now established scientists and academicians in their own right.

My interest in practicing medicine declined. I became ambivalent about continuing in medical school, yet at a loss for an alternative. Like Peyton Rous, I was rescued by pathology. Benjamin Castleman offered me a year of independent study in his department at the Massachusetts General Hospital, and Edgar Taft of that department took me into his research laboratory. Now, there was absolutely no hope that I could do anything of substance in research that year, but I found the leisure to marry, and I was riotously free to read and think, which led me to a new molecular biology.

I began my efforts to consummate that passion with two novitiates. May I have the next slide, please? I served the first novitiate with Elmer Pfefferkorn. Next slide, please. Yes, thank you. I had no credentials for this novitiate other than my desire. Yet Elmer took me into his laboratory, and Harvard Medical School excused me from the entirety of my fourth year so that I could try research unencumbered. Both of these were enlightened acts for which I am grateful beyond measure. I sought out Elmer and simbasvirus because I had perceived that the inner sanctum of molecular biology was closed to me, that I would have to find an outer chamber in which to pursue my passion. Through Elmer, I found animal viruses ripe for study with the tools of molecular biology yet still accessible to the innocent.

I was innocent, but I was also brash. I resolved to test the ability of the synbus rna genome to serve as messenger rna in vitro and to trace the fate of that genome as it entered the cell. Now, these were novel ventures in their time, 1961, and they were also technically foolish, but they sired an abiding interest in how the genomes of rna viruses commandeered the molecular machinery of the host cell, an interest that led me eventually, to retroviruses. Now, my work with Elmer was sheer joyous, but it produced nothing of substance. 20 years later, on the occasion of my 50th birthday, Elmer recalled my first novitiate in science with a quote from Th. Huxley.

There is great practical benefit in making a few failures early in life. May I have the next slide, please? Well, benefited by failure I may have been, but I also remained uncredentialed for postdoctoral work and research. So, on graduation from medical school, I entered an essential interregnum of two years as a house physician at the Massachusetts General Hospital, that magnificent hospital, admitted me to its training. Despite my woeful inexperience at the bedside and despite my candid admission to the chief of service that I had no intention of ever practicing medicine, I cherish the memories of my time there. I learned much of medicine, society, and of myself.

The lights, please. Clinical training behind me. I began my second novitiate by joining the research associates program. I was more serious than Harold. I went straight into the research associate program at the National Institutes of Health in Bethesda, Maryland, a program designed to train mere physicians like myself in fundamental research. In its prime, that program was a unique resource, providing us medical schools with many of their most accomplished faculty. Without the program, I, for one, would not have found my way into the community of science. Next slide, please.

My mentor at NIH was Leon Leventau, who has continued as an alter ego for me, and, I think it's safe to say, for Harold as well. To this day, my subject was the replication of polio virus, which had become a test case for the view that the study of animal viruses could tease out the secrets of the vertebrate cell. In my first publishable research, I obtained evidence that the replication of polioviral rna engendered a multi stranded intermediate, although my description of that intermediate proved flawed in its details, a flaw rectified later by a Nobel laureate in the making, David Baltimore.

Next slide, please. Midway through my postdoctoral training, Levental jumped ship. He departed for the faculty at the University of California, San Francisco, and in his stead I was joined by Gebhard Koch, who soon lured me to his home base in Hamburg, Germany. For a year and again I had an enlightened benefactor, Carl Habelae, who agreed to have NIH pay my salary in Germany, even though I would be in only the first year of a permanent appointment at NIH. I repaid the benefaction by never returning to Bethesda.

My year in Germany saw little success in the laboratory, but I learned the joys of romanesque architecture and german expressionism, probably a preferable outcome. Together, Gebhard and I continued to study multi stranded rna's, eventually showing that the double stranded form of poliovirus rna is infectious because the positive strand of the duplex can be expressed in mammalian cells, as if the duplex might be unraveling within the cell. This finding perplexed us and seemed abstruse, but it proved to be a harbinger of unanticipated enzymatic activities whose existence and functions are coming into view only now when the work was finally published, David Baltimore himself urged me to remain with polio virus, even to renounce my emerging interest in retroviruses. I took the advice as a compliment and ignored it.

May I have a slide, please? Next slide. Now. As my year in Germany drew to a close, I had two offers of faculty positions in hand, one at a celebrated university on the east coast of the United States, the other from Levantow and the University of California in San Francisco. I chose the latter easily because the opportunity seemed so much greater. I would have been a mere embellishment on the east coast. I was genuinely needed in San Francisco, and the decision proved providential beyond all measure.

May I have the next slide, please? In the laboratory adjoining mine at UCSF was Warren Levenson, who had set up a program to study rouse sarcoma virus, an archetype for what we now know as retroviruses. At the time, the replication of retroviruses was one of the great mysteries of animal virology. Warren, Leon, and I joined forces in the hope of solving that puzzle. But we had hardly begun before Howard Temmin and David Baltimore announced that they had solved the puzzle with the discovery of reverse transcriptase work. Of course, that brought them the Nobel Prize a scant five years later. The lights, please.

The discovery of reverse transcriptase was sobering for me, a momentous secret of nature. Mine for the taking had eluded me. But I was also exhilarated because. Because the DNA synthesized by reverse transcriptase in vitro represented an exquisite probe for viral nucleic acids, a reagent that would give us unprecedented access to the lifecycle of retroviruses. To paraphrase a memorable simile from the Nobel lecture of Arthur Kornberg, we now had a wedge with which to pry open the infected cell. The hammer to drive that wedge would be molecular hybridization.

Slide, please. I became enamored of molecular hybridization even before Harald, and this is the proof of that, a slide I made while I was a second year medical student. From an article by Sol Spiegelman in Scientific American, I can see that I had much then to learn about audiovisual AIDS. And, of course, I had no access to color film either. hybridization was a tool that offered exceptional sensitivity and specificity in the pursuit of viral nucleic acids, a tool made to order for the study of retroviral replication, which proceeds in concert with, and is obscured by, the normal metabolism of the host cell.

Slide, please. Improvising assays. As we went, my colleagues and I soon had our first glimpse of viral rna in cells infected with retroviruses. These are early data portrayed in the quaint manner of the times, unrecognizable by most contemporary students, if for no other reason than that a grasp of math action is required for decipherment.

Slide, please. In due course, our analyses became more sophisticated, identifying individual viral rna's and the genes they carry. Here are representative data. Along with their architect, Nancy Quintwell, stalwart colleague for virtually all of my years in research. Next. Slide. And eventually the final sophistication, we were able to lay out the manner of viral gene expression in the detail illustrated here. The work produced one of the earlier examples of rna splicing and set the stage for the much later discovery of frame shifting in the translation of retroviral messengers, alluded to by Harold. But our exercises with viral rna had a larger resonance because we had constructed the technical stage on which the discovery of retroviral transduction would eventually play out.

Slide, please. I also picked up the study of reverse transcriptase itself, perhaps to exorcise my sense of failure at not discovering the enzyme in the first place. We began by working in vitro to explore the details of DNA synthesis by the enzyme. The most notable outcome was the demonstration that reverse transcriptase uses a cellular transfer rna as primer to initiate transcription from the retroviral genome. The transfer rna for tryptophan is, in the case of Ros sarcoma virus, the first one proven and shown. It's diagrammed here so as to highlight the portion of the rna that interacts with the template.

Now, to this day, I regard our efforts to identify the natural primer, the tRNA, for reverse transcriptase, as among the more imaginative work that we have ever done. But the reviews from the Journal of Molecular Biology were savage. The contemporary bias held that the retroviral genome itself served as both template and primer. And like all biases, it did not die easily. Nevertheless, we prevailed, as did our work. Priming by tRNA is now regarded as a generic feature of retrotransposons.

Lights, please. But what I most wanted to know was the course of events in the infected cell. Could we find the proviral DNA first imagined by Howard Timman and then foretold in substance by the discovery of reverse transcriptase? Where in the cell was this DNA synthesized following infection? What form did it take before and after integration into host DNA? Harold Varmus arrived to provide the answers and to alter my life and career irrevocably.

Now, truth be told, I remember my first encounter with Harold only dimly, as I learned just a few weeks ago, because I recall that he had a bearden. I even told the press that the beard swayed me in his favor. Harold says not to both suggestions. May I have this next slide, please? Yes. Well, he was certainly, well bearded by the time he joined us in earnest a year later. And if you compare this old image to the one that addressed you a short while ago, you can perceive how the achievement of international distinction can change tonsorial style. As he came into prominence, Harold removed his beard. And in contrast, I grew one to achieve the appearance of distinction.

I presume it took only a brief conversation with Harold, in a cursory inspection of his dossier, to know that I had found a kindred spirit. Bearded or not, I signed him on and encouraged him to write a fellowship proposal on the then mysterious transfer RNA's and the virions of retroviruses. What he wrote was good enough for funding, but none of it was ever done. By the time Harold took his place at the bench a few months later, the maelstrom of reverse transcriptase had struck, and the provirus was ripe for Harvest. Harold liked the look of the fruit, but he resisted the tools of Harvest point he omitted from his talk. In short, he wanted nothing to do with molecular hybridization. I had enough of that with Paston, he told me.

I persisted, more by neglect than by any effort to proselytize. Anyone who knows Harold knows how futile that would be. And Harold began a search for proviral DNA. And then fortune intervened in the form of a new technique. And this seemed to galvanize Harold into action. And within the year, his name became consubstantial, with expertise on the synthesis and integration of retroviral DNA. And in the process, I had lost a postdoctoral fellow and gained a splendid co equal.

Lights, please. Now, to this point we had thought little of cancer, a point that the press often finds difficult to come to grips with. But as the virus of Peyton Rous first lured me from polio virus, now it lured us to the study of neoplastic transformation. We were ready to follow the tenet enunciated by David Baltimore in his Nobel lecture of 1975. For a virologist interested in cancer, the problem is first to understand the molecular biology of retroviruses, and then to understand how they cause disease.

Slide, please. And what better place to begin than with Peyton Rouse? Although he could not have known it at the time, Peyton Rous gave us both reverse transcriptase and genetic purchase on neoplastic transformation when he isolated the chicken sarcoma virus that bears his name. It is common knowledge, of course, that for this remarkable discovery, Rouse was for many years criticized and disparaged. His finding was beyond the ken of most scientists of his time.

Others proved more perceptive. Henry James, among them the expatriate american author, toured the Rockefeller Institute and was introduced to Peyton Rouse in 1910, at a time when the youthful rouse was in the midst of his work on the chicken sarcoma virus. Whereas James was deep into the miseries of age. And but two years from his death, when James was told that Rouse was in charge of cancer research at the Rockefeller Institute, Rouse was in truth the only cancer researcher at the Rockefeller Institute, James responded fervently, how magnificent to be young and to have divine power.

Now, that has not been my experience of cancer research, although perhaps George client has come closer here at the Karolinska, but because in my case, youth is gone and power has eluded me. The opinion of Henry James notwithstanding, Peyton Rous also failed to achieve divine power. Instead, he waited until his 86th year of life before receiving the Nobel Prize, working in the intellectual shadow of Rouse. And as I do, I am grateful to the contemporary Nobel committee for acting more expeditiously on the case presented by Harold and myself. Slide, please.

Peyton Rous received his Nobel Prize two years before I first encountered his virus. The award dramatized the great mystery of how rousarcoma virus might cause cancer. It was a mystery whose solution lay in genetics, a story that Harold has told you. The data showed with luminous clarity that a gene within rouse sarcoma virus is responsible for cancerous growth of infected cells, that continuous action of the gene is required to sustain cancerous growth, and that the gene probably works by directing the synthesis of a protein. The oncogene Src had been cited when I describe the use of temperature sensitive mutants, which, of course, was what was used here. In the citing of Src to a general audience, or, alas, even to physicians, I am often asked whether the properties of these mutants underlie the use of heat to treat cancer. The listener has failed to see that the conditional mutant is an artifice, an invention whose properties nevertheless tell us something of nature's real ways. It is one of the great blights of our culture that the general public is so innocent of how science proceeds.

We in San Francisco, for example, pay a daily price for that innocence. The general public is inclined to distrust and resist almost any course that science might wish to take the lights, please. The genetic identification of Src was reported in the very same year as the biochemical discovery of reverse transcriptase. The two became themes that intertwined and nourished one another in the daily life of our laboratory, much as our deployment of molecular hybridization in the study of viral replication set the stage for the discovery of cellular SarC. So our ensuing success in isolating structural proteins of the virus from infected cells emboldened us to seek the protein encoded by SrC. We were in the midst of efforts to prepare antisera that would recognize the Src protein. When news of success came from Denver, Erickson and his colleagues had produced persuasive evidence that the oncogene encodes a 60 kilodolton protein of which you have heard, once the product of Src was a physical reality, the puzzle of its action loomed larger than ever. How could this single protein elicit the pleiotropic change in cellular phenotype that we call neoplastic transformation, a change so numerous in kind that we could not count all of its components?

Slide, please. The answer came quickly. Sr encodes a protein kinase whose amino acid substrate later proved, unexpectedly to be tyrosine. By phosphorylating numerous cellular proteins, the enzyme could rapidly change myriad aspects of cellular structure and function. By being the first exemplar of protein tyrosine kinases, it gave notice of a previously unappreciated regulatory device we now realize is second to none in the signaling pathways of the cell. The ways in which these answers emerged are illuminating. In Denver, the answer came from an inspired guess based on the pleiotropism of Src. Protein phosphorylation ranks among the most versatile agents of change known to biochemists in our laboratory.

Enzymalogical reasoning by Art Levenson led the way. Phosphorylation of the src protein in cellular extracts displayed properties suggestive of a unimolecular reaction, as if the protein were phosphorylating itself, as indeed it was. And at the Salk institute, Tony Hunter used an erroneous buffer and fortuitously separated phosphotyrosine from phosphothreanine for the first time in recorded history, the only example of productive laziness that I have ever seen. Acknowledged with gratitude by Tony in the annual reviews of biochemistry. The next slide, please.

The sighting and subsequent characterization of Src paved the way for a biological cornucopia. We now know of more than 20 retroviral oncogenes whose diverse specificities in tumor genesis provide experimental models for most forms of cancer that afflict humankind. Each of these genes encodes a protein, whose biochemical action provides distinctive purchase on the mechanisms of neoplastic growth. An astonishing repository of experimental models. Slide, please.

The proteins are deployed to the various reaches of the cell, including the nucleus, the cytoplasm, the plasma membrane, even the exterior beyond the cell, and they act in different ways, which for the moment are subsumed by three genre first, the phosphorylation of proteins with either serine and threonine or tyrosine as substrates. The immediate role of the oncogene product may be the induction of the phosphorylation, as in the case of growth factors, or catalysis itself, as with the receptors for growth factors secondly, the transmission of signals by gtp binding proteins, as exemplified by the products of ras genes, whose exact position in signaling pathways remains unresolved and third, the control of transcription from DNA in a positive or negative manner. Indeed, many of the proteins are probably capable of either of these under different circumstances.

It seems likely that this list of biochemical strategies will diversify in the future, since the functions of many oncogenes have yet to be elucidated. But the list displays an economy of style that may survive because it reflects the need for pleiotropism. Nature may have only a limited number of ways to achieve the manifold changes that create the neoplastic phenotype. Slide, please.

At first, it seemed that the lessons to be learned from retroviral oncogenes might apply only to the cancers that viruses induce in animals, that the oncogenes of retroviruses might be alley cats of evolution with little importance to humankind. The discovery of cellular src and the inference that the gene gave rise to the oncogene of rouse sarcoma virus inspired hope that this narrow view might be wrong. If cells contain genes capable of becoming oncogenes by transduction into retroviruses, perhaps the same cellular genes might also become oncogenes within the cell without ever encountering a virus.

Through accidental molecular piracy, retroviruses may have brought to view a genetic keyboard on which many different causes of cancer can play a final common pathway to the neoplastic phenotype. By 1982, that scheme was secure enough to deserve this cartoon in Scientific American, which in us circles represents the ultimate sanctification for a scientific finding. This scheme would not have set well with Peyton Rouse. Here is what he wrote in his Nobel lecture of 1966 no inkling has been found of what happens in the cell when it becomes neoplastic and how this state of affairs is passed on when it multiplies a favorite explanation has been that carcinogens cause alterations in the genes of cells of the body, somatic mutations, as these are termed. But numerous facts, when taken together, decisively exclude the supposition. Close quote.

Slide, please. The scheme did not sit well with some of our contemporaries either. Witness this cavil from 1985, which will be familiar to the cognoscenti among you at least. Even transduction itself was challenged, most notably in the keynote address at the 1979 Cold Spring Harbor Symposium on oncogenes, an imposing forum in which to find oneself assailed. But for us in San Francisco, the reality of transduction seemed inescapable.

Next slide, please. As Harold told you, our confidence began from this simple compilation, of which he showed you a more sophisticated version. This is my own homemade version. From those days, the cellular homologue of sark had been conserved through eons of evolution, whereas the other genes of rouse sarcoma virus could be found only in chickens. The ineluctable conclusion was that the two sorts of genes, an oncogene, on the one hand, and genes devoted to viral replication on the other, had separate origins. As Harold has explained, we would eventually muster many more sophisticated arguments, all of which pointed to the same conclusion.

The progenitor of SrC was a conserved, enhanced, vital cellular gene that found its way into Ralph's sarcoma virus by recombination. The images of cellular and viral sarc gained eventually from molecular cloning, sustained our argument in a gratifying manner. But for me, they were anticlimactic. Arguing for the cellular origins of SrC provided my first experience with the heuristic force of evolution. Quote, nothing in biology makes sense except in the light of evolution. To recall a famous aphorism from Dobzhansky. The aphorism embodies a truth that has been dishonored in the United States, where religious zealots continue. Their efforts to hound the teaching of evolution from public schools and men of little learning assail the truth of evolution under the fraudulent rubric of creation science.

Slide, please. The genesis of retroviral oncogenes by recombination with the cellular genome had been postulated by several observers at about the time we were doing our work. Here is a version from Howard Temmin, shown because it was in his Nobel lecture of 1975. He appears to have gotten it largely correct, except for his suggestion that SRC was mutated to an oncogene prior to transduction. I should point out that by the time this cartoon was drawn, the news of transduction from San Francisco had been widely promulgated.

Now, although it may sound self serving, I confess my ignorance of these speculations. When we began our work on cellular sarc in 72 73, I was motivated by a desire to test the virogene oncogene hypothesis of Huber and todaro, which Harold has explained not by an interest in the origins of oncogenes, but in due course. Howard Temmin provided a useful inspiration with his suggestion that all retroviruses arose by the cobbling together of disparate genetic elements in the cell with intermediates that he called proto viruses. The inspiration was for taxonomy, not experiment.

Slide, please. As transduction by retroviruses came into common discourse, the need arose for a generic term to describe the cellular progenitors of Src and other retroviral oncogenes. The first defined general usage was a term, cellular oncogene. Although I was a nominal member of the responsible committee on nomenclature, I was uncomfortable with this term because of its unwarranted implication that the native cellular genes carried intrinsic tumorigenic potential, that they need not be changed at all to cause trouble.

I did not like this thought. So, in playful homage to Howard Timman, I began to use the word proto sarc, as documented in this diagram from 1977, which I was using then to summarize the competing views of how viral Sark might have arisen. The generic term proto oncogene followed in short order. This is an amusing diagram because it embodies more than mere etymology. It exemplifies three intellectual generations of tumor virologists. The first, Renato del Beko, that's the one on the left. Renato only naturally brought a DNA tumor virus into the scenario. The second, Howard temmin, with protovirus and the third, the generation of Harold and myself. I emphasize that these are intellectual rather than chronological generations, because Howard Temmin is but two years my senior, albeit far my superior. After all, he came to this podium 14 years ago.

In the interim, proto oncogene has come into general use as the colloquial counterpoise to oncogene. It has also become an embarrassment because the precise connotation of the word is that of prototype rather than progenitor, which is not very far removed from the offensive connotation of cellular oncogene. But the intent of the taxonomic invention was clear. Numerous investigators, ourselves included, have spent the past decade documenting the sorts of genetic damage that can convert a harmless proto oncogene to a pathogenic oncogene.

Lights, please. The manuscript that announced our discovery of cellular sarc concluded with the speculation that the gene might be involved, I quote, in the normal regulation of cell growth and development or in the transformation of cell behavior by physical, chemical, or viral agents. Close quote. Chatting shortly after the announcement from Stockholm, Harold and I decided to we were very pleased with that last sentence. These words, however, were pure bravado, particularly because we then had no assurance that cellular Src was in fact a full fledged gene.

That assurance accrued over the ensuing two years, first in the form of evidence that cellular src was transcribed in normal cells, and then with the identification of the protein kinase encoded by the gene. Slide, please. What? I first saw this image of the protein encoded by cellular src presented to me one evening in this original autorideogram from Herman Opperman. All doubt about the substance of our beliefs dissolved in a moment of rapture. A single experiment had made the product of cellular src manifest in avian, mammalian, even human cells.

That's the human protein there in the far right cleanest result. I was as thrilled by this image as I had been by the initial detection of src in cellular DNA. We were dealing with a functional gene, but in order to share our rapture, we had to circumnavigate two referees who argued that the peptide maps of the viral and cellular versions of src protein were too similar to be credible, that we must have made a mistake. We had not. Molecular cloning and nucleotide sequencing eventually revealed an astonishing kinship between the cellular and viral versions of Src, a kinship marred only by the subtle mutations required to render Src into an oncogene.

Slides, please. As our confidence in the reality of cellular sarc grew, a new challenge took shape. Could we generalize the principle of transduction? Had the oncogenes of other retroviruses also originated from cellular genes? To pursue the generality of transduction, we turn first to a retrovirus known as Mc 29, which attracted our attention because it offers a model for the induction of carcinomas, the most prevalent of human cancers. In searching for an oncogene in MC 29, the impatience of molecular biologists held sway. The rigor of formal genetics was cast aside.

Some investigators, ourselves included, use molecular hybridization to detect nucleotide sequences unique to the genome of McDezden. Others, most notably Peter Duisberg, used chemical procedures to identify the same sequences and to map their position on the viral genome. Slide, please. You should understand that both these strategies took liberties that we had not allowed ourselves. With Src lacking a deletion mutant that might define the oncogene. We and others made the assumption that the genomes of Mc 29 and its necessary helper virus were congenic, except for the presence or absence of the oncogene.

The assumption is exemplified by the cartoon in the slide. The same assumption had been applied previously in an effort to define the oncogene of a murine sarcoma virus and had led to a molecular quagmire. But now the lessons from Stark told us in more detail what we might be seeking. So Diana Shinus forged ahead and soon had a molecular probe that represented nucleotide sequences found in Mc 29 and other retroviruses with similar tumor genicities, but not in the related helper viruses. The newly found locus was taken to be the oncogene of Mc 29 and eventually designated Myc in deference to the form of leukemia genesis myelocytomatosis, from which the virus acquired its original name. Over the next several years, the authenticity of Myc would be ascertained by molecular cloning, nucleotide sequencing, and gene transfer, and to this day, the gene has never been defined by the strategies of classical genetics, and there is now no need to do so. The new biology is upon us.

Lights, please. The lessons of Src were powerful. We were able to argue that our molecular probe for the oncogene of Mc 29 was legitimate because the probe also detected nucleotide sequences in the DNA of normal vertebrates, sequences that were transcribed into rna in normal cells and that diverged among species in rough accord with phylogenetic distance. No other portion of the Mc 29 genome displayed these properties. The second, proto oncogene, had been cited. The example of cellular Src was not an exotic anomaly it was an archetype.

We were nevertheless rebuffed by two referees for a fashionable journal who took stances diametrically opposed to one another. One argued that the story of Mick was boring, that the genesis of all oncogenes had become self evident from the results with Sark. The other referee argued that we could not claim to have generalized the principle of transduction unless we could provide yet another example. Mick alone would not suffice. Imagine how bored the first referee must have been and how pleased the second as other examples began to tumble out, in particular those of the avian retroviral oncogenes, erb and Mib, both of which were described essentially in parallel with Myc, both of which proved to have cellular homologs.

In the years that followed, Myc proved to be a great provider, a vehicle for several seminal discoveries, the activation of cellular genes by insertional mutagenesis, the involvement of proto oncogenes and chromosomal translocations, and the amplification of proto oncogenes in human tumors. These discoveries had exceptional logical force because they involved a gene whose tumorigenic potential was already known from the study of retroviruses. Slide, please.

No sooner had the bounty of transduction become apparent than other routes to proto oncogenes took shape. Some serendipitous, others designed the ability of retroviruses to mutate cellular genes, creating oncogenes at their place of resonance within the cell the dissection of chromosomal abnormalities in cancer cells, such as translocations and amplifications, the use of gene transfer to detect mutant proto oncogenes by means of their biological activity, and the pursuit of phylogenetic kinships. The definition of proto oncogene had now become more expansive, subsuming any gene with the potential for conversion to an oncogene by the hand of nature in the cell or by the hand of the experimentalist in the test tube.

Lights, please. The tally of proto oncogenes has now reached 60 or more. Most are genes never glimpsed before by any other means. What are these genes? What are these genes in their normal guise? What purposes preserve them through 1000 million years of evolution? Why do they harbor the potential to wreak cellular mayhem? We formed our hypotheses from the lessons of transduction. The properties of retroviral oncogenes must echo the functions of proto oncogenes. Three properties seemed especially telling the stimulation of cellular proliferation the specificity of tumorigenesis.

As if each gene might be designed to work only in certain cells and the ability of many oncogenes to interrupt or sometimes reverse cellular differentiation. Like father, like son, it seemed possible that the actions of viral oncogenes are merely caricatures of what proto oncogenes are normally intended to do. Retroviruses may have revealed to us not only touchstones of tumor genesis, but clues to the nerve center that governs the normal cell cycle and the differentiation of cellular function.

Slide, please. Eager to explore these thoughts in a living organism, we turn to drosophila melanogaster, the fruit fly, represented here by a more attractive proxy at chinese grasshopper. Now, why the fruit fly? Why the fruit fly? I pose and answer this question principally for the benefit of my brother, a physicist for whom the ways of biologists are both mysterious and crude. First, the fruit fly. First, because the full collection of genes in this creature is within our scope. Second, because we have in hand a rich catalog of normal and mutant genes from the fruit fly, the products of almost a century of labor. Third, because the fruit fly is, for the moment, the only metazoan organism in which we can manipulate genes with reasonable facility, although a soil worm on the one hand and the laboratory mouse on the other are now making a strong bid for our favor.

Fourth, because when reduced to essentials, the fruit fly and homo sapiens are not very different. If that offends you, consult your local pastor or my father, who is available here for a few days and who wears the lutheran cloth of your official church. And fifth, because the fruit fly has a large complement of proto oncogenes with counterparts in mammals. Slide, please.

What we have learned of proto oncogenes from Drosophila vindicates some of the bravado in our first publication on cellular src mutant alleles have been identified for the counterparts of six proto oncogenes in the fruit fly to date. In two instances, the able and MIb proto oncogenes. The search for mutations was deliberate. In the remainder, mutations, recognized first in classical studies by their phenotypes, later proved to be Drosophila counterparts of mammalian proto oncogenes. All of the mutations elicit profound disturbances of development. Harold and I are represented here in two ways by intellectual acolytes.

First, the identity between the mammalian proto oncogene int one and the Drosophila gene wingless was brought to view by the work of rule Nussa in Amsterdam, who had earlier spearheaded the discovery of into one while working with Harold. And second, identification of the normal and mutant versions of Drosophila Mib is the handicraft of my student Elisa Katzen, who has now found that this gene is vital to cellular divisions during several portions of development.

Slide, please. The actions of proto oncogenes in development have their underpinnings in the elaborate circuitry that governs the behavior of cells. The junction boxes in this circuitry include polypeptide hormones that act on the surface of the cell, receptors for those hormones, proteins that convey signals from the receptors to the deeper recesses of the cell, and nuclear functions that orchestrate the genetic response to afferent commands, typically by regulating transcription.

Diverse lines of inquiry have brought these junction boxes to view, but the study of proto oncogenes has been among the richest sources, and time and again, the same lines, the several different lines of inquiry have converged on the same junction box. It seems that we may have more of the circuitry in view than we could have hoped. The cell is not infinitely complex. The cell can be understood.

Lights, please. But what of cancer? Are proto oncogenes among the seeds of this disease in all our cells? Are they a common keyboard for many different players in tumor genesis? As a physician, I found these questions attractive. As a scientist, I found them intimidating. Exploration of the cancer cell is akin to archaeology. We must infer the past from its remnants in the present, and the remnants are often cryptic.

But the first remnants to emerge from the proto oncogenes of human cancer cells told a vivid story, a story anticipated in a remarkable manner by Karolinska's own George Klein. Molecular dissections revealed that chromosomal translocations in human and murine tumors often affect proto oncogenes already familiar from the study of retroviruses, with Myc, that great provider prominent among them. Emboldened by these findings, Kari Alitalo and Munford Schwab joined us to mount a belated excavation for the genetic shards of tumor genesis.

We chose a neglected terrain in which to dig. Gene amplification amplified DNA slide, please. Focal amplification of domains within chromosomes is a scheduled and purposeful event during the life cycle of diverse organisms. In mammals, however, gene amplification is an unscheduled aberration that gives rise to karyotypic abnormalities known as double minute chromosomes and homogeneously staining reagents. When my colleagues and I began our excavations, gene amplification in cancer cells was known principally as a consequence of selection for chemotherapeutic of selection by chemotherapeutic agents.

But the literature also contained occasional examples of double manu chromosomes and homogeneously staining regions in untreated cancers. And when a limited sampling of these were examined by ourselves and others, they proved to involve previously identified proto oncogenes. Yet again, Myc was prevalent. In due course, it became apparent that gene amplification is relatively common even in untreated tumors, and that it affects proto oncogenes. Slide, please.

Intent on a more systematic study, we chose human neuroblastomas, in which gene amplification seemed exceptionally common. We resolved to ask whether the amplified DNA in neuroblastoma cells contains any of the proto oncogenes then known. When we got to Myc, we struck rich ore of an unexpected sort, a gene related to Myc cited in our work for the first time, and in parallel by Fred Ault and eventually designated enmic for neuroblastoma myc, or, if you prefer, not Myc. Quickly it became apparent that nmyc is an authentic proto oncogene, a close kin of Myc that apparently evolved to serve a separate purpose in the normal organism.

Slide, please. As the survey of neuroblastomas broadened, a fertile correlation became apparent. Amplification of NIC was found only in the more aggressive variants of the tumor, in perhaps one quarter of all the specimens examined. Moreover, within single tumors, nmyc was expressed abundantly only in neuroblasts, the least differentiated and presumably most malignant cells of the tumor. These correlations had two implications. First, that amplification of NMIC might embody a step in tumor progression, one of several events that exacerbate the malignancy of neuroblastomas and second, that we had brought to hand a prognostic tool, a device with which to supplement the conventional staging of the disease.

The passage of time has dealt kindly with these hopes. Last year, the New England Journal of Medicine, now known as the Journal of Molecular Biology for physicians in the United States. An editorial in this journal provided an imprimatur by arguing, I quote, in neuroblastoma, amplification of the NMiC gene is of greater prognostic value than the clinical staging of the disease. 30 years after deserting the bedside, I have found clinical relevance in my research.

You may have noticed that the excavation that unearthed NMYC was a pedestrian exercise in both concept and execution. Yet in one foul swoop it served up an important proto oncogene without the assistance of a retrovirus, hinted at a major role for gene amplification and tumorigenesis, foreshadowed the molecular dissection of tumor progression, and gave first notice that the emerging knowledge of oncogenes would eventually prove useful at the bedside. It is not only always wise to dismiss mundane experiments, and these themes have since found wider resonance. Slide, please.

First, we can point to a variety of human malignancies in which damage to one or another proto oncogene has been found with some consistency, and indeed, the list is now longer. The damage takes diverse forms, including translocations, amplifications, and point mutations, all of which appear to have dominant effects on gene function. The list of malignancies containing these lesions is impressive because of the diversity of tumors involved. Because of their identities, several can be counted among the principle nemeses of humankind.

And because the list has been assembled after only a few years of pursuit with imperfect tools, there is doubtless more to come beyond this list, there lies the burgeoning repertoire of recessive lesions in human cancers, whose nature and unquestionable importance are just now coming into focus. Slide, please.

Second, catalogs of genetic damage within individual tumors are taking shape, showing us how the malfunction of several different genes might combine to produce the malignant phenotype. For example, carcinomas of the colon contain no less than five different yet consistent lesions, some genetically dominant, others recessive carcinoma, the lung, at least four, carcinoma, the breast, five, neuroblastoma, at least three. Moreover, detection of the lesions is likely to provide information for prognosis, perhaps even for therapeutic management. Examples include neuroblastoma, as I said, and now carcinoma of the breast and ovary, and pre leukemias, and doubtless more to come. Slides, please.

For those of us who first studied cancer more than 30 years ago in medical school and then returned a decade or so later to the disease to find it little less a mystery, the contemporary image of the cancer cell is both thrilling and an unexcelled vindication for fundamental research. The image was forged from the vantage point of molecular genetics and with the tools of that discipline. The lines of discovery trace back to minuscule columns of hydroxyapatite, from which the molecular probe for Src first flowed to Src itself, which even now has not been persuasively implicated in human cancer, and to the lowly chickens in which Peyton Rouse first found his tumor and his virus.

From these humble roots, a great tree of knowledge has grown, and a great truth has been reiterated. We cannot prejudge the utility of scholarship. We can only ask that it be sound. Slide, please. Now what of treatment? Will we acquire new antidotes for cancer from our study of oncogenes?

There is little likelihood that we will be able to repair or replace damaged proto oncogenes in the foreseeable future, particularly in the individual already burdened with countless tumor cells. We are not capable of that sort of genetic engineering. There is talk of restoring functional copies of recessive oncogenes to tumors in which they are defective. But for me and many others, realization of this objective in human subjects seems many years distant as well.

But if we focus on the protein handmaidens of genes, we can see a little more cause for hope. Given sufficient information on how these proteins act, the pharmaceutical chemist, or perhaps the immunotherapist, may be able to invent ways to interdict the action of oncogene products, even to exploit the specificity of genetic damage and thus, to reverse the effects of oncogenes. We are not close to implementing these strategies, but they are reasonable hopes. The protein tyrosine kinases and the signaling proteins encoded by Rassonka genes are logical first targets for trial.

Now I'm eager not to appear naive. No single therapy against an oncogene product is likely to become a panacea. We must deal with a large variety of oncogenes whose products are deployed to the many reaches of the cell and whose actions present great chemical and enzymatical diversity. And we must be prepared to cope with evolving genetic damage within cancer cells that can bring a variety of oncogenes into place sequentially and stay one step ahead of our wits.

In 1983, a distinguished figure in american cancer research told the New York Times, I quote, scientists should learn how to manipulate oncogenes to protect or treat patients within the next five years. The words ring hollow now, except as a cautionary note. Well, truth be said, the last decade of cancer research has produced a fair share of hyperbole. Here's my favorite sampling.

The essential biochemistry of cells can be worked out within the next decade or two. JD Watson, 1972 the molecular details of carcinogenesis should be largely worked out by the end of this decade. Robert Weinberg, 1983 we're beginning to understand what a cancer cell is and how it works. We're in a new world. Louis Thomas, 1986 the human intellect has finally laid hold of cancer with a grip that may eventually extract the deadly secrets of the disease.

JM Bishop, 1983 and occasions thereafter. Perhaps we can be forgiven this hyperbole. Things have gone well. The search for genetic damage in cancer cells and the explication of how that damage affects the biochemical functions of genes have become our best hope to understand and thus to thwart the ravages of cancer. We have happened upon a biological roadmap that should eventually lead us to explanations of how normal cells govern their replication and why cancer cells do not.

At the beginning of this century, the austrian engineer and novelist Robert Musel offered a description of progress in science that foreshadowed modern views of epistemology and that now exemplifies the course of contemporary cancer research. I quote from the man Ona. Every few years, something that up to then was held to be error suddenly revolutionizes all views. An unobtrusive, despised idea becomes the ruler over a new realm. Harold Varmus I and our numerous colleagues in this field have been privileged to assist as a despised idea became a ruler over a new realm.

The notion that genetic changes are important in the genesis of cancer, has met strenuous resistance over the years from no less than Peyton Ralph. But now that notion has gained ascendancy. And in the event, I have learned that there is no single path to creativity, not even within the stern halls of science. Consider the extemporaneous course of Harold and myself. From the liberal arts to this exquisite moment, we are constrained not by the necessary discipline of rigorous, but by the limits to our imaginations and our intellectual courage.

In the words of an american sage, dare to be wrong, or you may never be right. Discovery takes two forms. The first is mundane, but nevertheless legitimate. We grope our way to reality and then recognize it for what it is. I liken that to parenting. Actually, the second form of discovery is legitimate, but also sublime. We imagine reality as it ought to be and then find the proof for our imaginings. I have been fortunate to know the first form of discovery and am thankful for the privilege. I have miscarried opportunities to know the second and am diminished by the failure. Redemption will lie in more imaginings. In the words of Carl Krause, the real truths are those that can be invented. Thank you.

Science, Technology, Innovation, Retroviruses, Cancerresearch, Discoveries, Nobel Prize