 Thank you and good morning Gustavus office college honors Nobel laureate J. Michael Bishop Chancellor and Arthur Rock and Tony Timberock distinguished professor of the University of California at San Francisco Dr. Bishop shared the 1989 Nobel Prize in Physiology and Medicine with his colleague Harold Varmas for discovering the cellular origin of retroviral oncogenes Which control normal growth in cells but can turn renegade and cancerous under certain conditions Their work was based upon a hypothesis that growth of all cancer cells is not the result of an invasion from the outside But rather retroviral exploitation of a normal gene These findings allow the understanding of how malignant tumors are formed from changes to normal cell genes This work eventually led to recognition that all cancer most likely arises from damage to normal genes and Provided new strategies for detection and treatment of cancer Dr. Bishop born the son of a Lutheran minister and raised in rural, Pennsylvania Sites his passion for fostered Sites his passion for music fostered by his parents as a deeply grateful legacy from what he characterizes as his pastoral years Career testing in high school predicted a future in journalism forestry or music teaching as likely vocations However after befriending the family physician during a summer in high school an Interested medicine and the fundamentals of human biology arose within Dr. Bishop is a product of a private church related liberal arts college like Gustavus Adolphus He earned an undergraduate degree in chemistry from Gettysburg College in 1957 intent on intending medical school However, not without being tempted along the way by history philosophy and other liberal arts influences With little interest on practicing medicine. He entered Harvard Medical School with a hope of becoming an educator During an independent study where he was free to read and think Dr. Bishop developed an interest in molecular biology and thus completed his medical degree in 1962 After two years on staff at Massachusetts General Hospital and postdoctoral work at the National Institutes of Health and in Hamburg, Germany He joined the Department of Microbiology and Immunology at the University of California at San Francisco in 1968 where he still resides Albeit with ever-increasing involvement and responsibilities In 1981 he was named the director of the GW Hooper Research Foundation and program in biological sciences at UCSF A year later. He added the university's Department of Biochemistry and Biophysics to his faculty affiliations Then in 1998 he was selected as Chancellor He now has a unique perspective as a researcher practitioner Teacher Administrator and observer of the greater medical scene Bishop has received numerous awards for his teaching and research in addition to the Nobel Prize including the Albert Lasker Award for basic medical research in 1982 The Alfred P. Sloan Jr. Award from the General Motors Cancer Research Foundation and the Armand Hammer Cancer Research Award in 1984 the American Cancer Society Medal of Honor in 1985 The American College of Physicians Award in 1987 and the National Medal of Science in 2003 An inveterate reader. He has also authored more than 500 research publications and reviews and the book How to Win the Nobel Prize in Unexpected Life in Science a Science scientist who did not specialize in basic research until he was well into his 30s Bishop is finally a fervent supporter of taking the large of view of science of Allowing one's self to follow one's instincts rather than the conventional paths of specialization In the end Dr. Bishop states if Offered reincarnation he would choose the career of a performing musician with exceptional talent Preferably in a string quartet One lifetime as a scientist is enough great fun, but enough For his research into cancer and the promise of preventing it and for his efforts to improve the public understanding of science and federal support for research Gustavus Adolphus College is both honored and privileged to bestow an honorary degree upon J. Michael Bishop Upon recommendation of the Gustavus Adolphus College faculty. He is presented for the degree of Doctor of Science honoris causa Dr. Bishop it is within the tradition of the Nobel conference here at Gustavus To confer an honorary doctorate degree on individual Nobel Prize awardees who participate in this conference In doing so we honor your scientific achievements We recognize the influence your efforts have had on the disciplines within which you work and we express our appreciation for your presence and Participation in this 42nd annual Nobel conference And so by the authority vested in this institution by the state of Minnesota and Upon the recommendation of the faculty and the board of trustees of Gustavus Adolphus College I hereby confer upon you J. Michael Bishop the degree of Doctor of Science Honoris Causen with all the rights privileges and honors pertaining thereto As Dr. Bishop gets ready for his talk Let me begin with just a couple of announcements. We don't ordinarily Do continuing education credits for the Nobel conference, but in response to requests from you I have arranged for continuing education credits for Physicians physicians assistants sociologists marriage and family counselors Psychologists and some other groups that I've probably forgotten at this point We have a registration desk in the back of the room there you may register To participate in this if you'd like right after the close of the ceremonies here I'd also like to encourage you to visit a display that was organized by Larry Cusisto from Life Sciences Alley of medical Devices in progress in Minnesota. It's in the forum next door to us there We have the virtual heart from the Lily High Heart Institute from the University of Minnesota as a display here Very interesting alternative. It's in the building right next to us here. And now it is my pleasure to Turn the podium over to dr. Michael Bishop. Good morning, and thank you very much for being here I am honored and pleased to be here It's a a sort of pleasant recollection of my own beginnings My father was a Lutheran minister as you heard I acquired my enduring love of music while singing in the church choir. I had no choice And I came of age intellectually while attending Gettysburg College Like Gustavus a small liberal arts college with a venerable Lutheran tradition And from that experience, I also acquired a lifelong belief in the importance of liberal arts education to our culture and so I went to personally honor Gustavus for sustaining that tradition in such a fine way in February of 1865 the Austrian monk rigor Mendel delivered two lectures to the are inherited Mendel had discovered James But he knew nothing of their physical nature and he gave them no name Instead he simply published the lectures in a journal called transactions of the Bruin Natural History Society Circulation of about 50 under the title experiments in plant hybridization Hardly charismatic No one seems to have noticed Yet Mendel's work represents one of the seminal advances Perhaps in this day and age I should say ovarial advances in the history of human discovery The significance Mendel's discovery was not understood by his contemporaries and the results were ignored by those few who knew of them Well a lot has happened since then The science of genes has become so powerful and pervasive that biomedical scientists now refer to our time as the genomic era Some even say that we have entered the post genomic era a distinction that in my view for the moment remains more semantic than substantive I am going to speak with you about the science of genes What that science might offer to human welfare and the challenges that that science poses to our society? To begin with how did we find our way to the genomic era and that story begins with cells Cells are the microscopic living bricks that compose our bodies We each began life as a single cell the fertilized egg That multiplied trillions of times over to form an organism of profound complexity That miraculous achievement is governed by a genetic program Now I presume that there may be poets lawyers and physicists in the audience So I feel obliged to give a brief dissertation on the nature of that genetic program and how it's implemented The command center for our cells is located within a compartment known as the nucleus Shown here in diagrams of both a plant and an animal cell Within the nucleus the commands are carried within structures known as chromosomes These are individual human chromosomes released from the nucleus of the cell and magnified many hundreds of times over They have been stained so that each displays a distinctive pattern of bands by which the different chromosomes can be identified a sort of microscopic fingerprint We have homo sapiens possess 48 chromosomes two copies each from 24 different chromosomes one copy from mom One from pop and each set of two has a different geographic fingerprint of the sort shown here Embedded within chromosomes are the instructions that dictate the structure and activities of our cells and of our lives These instructions are inscribed on that remarkable molecule known as DNA This is a mic electron micrographic picture a very small pieces of DNA magnified more than 100,000 times and incidentally They're not always yellow though. This was an artistically oriented scientist who colored them by hand The DNA illustrated here occurs naturally as a circle as you've seen a photo But our DNA is actually a consists of immensely long strings That are linear with two ends rather than circular and there is one string bearing a particular set of genes on each chromosome Several yards of DNA are crammed into each human cell divided among the individual chromosomes To dramatize if the DNA from a single human cell were magnified as in this picture It would be more than a million feet in length Whereas the cell would be not much larger than the screen itself We know very little about how that cramming is achieved The instructions carried by DNA are composed of a molecular vocabulary that we call genes the vocabulary that men will discover There are roughly 10 genes situated along these short pieces of DNA The chemical details are much too small to be seen even at this magnification In contrast the several yards of human DNA harbor perhaps 30,000 genes and a lot more as you'll hear momentarily Genes are the molecular instructions for the lives of ourselves in the words of one particularly devout gene scientist the language of God Incidentally, he has parlayed that provocative phrase into a book on the New York Times best-seller list The instructions for the lives of ourselves are assembled from a chemical alphabet whose components Are called nucleotides Small molecules that are linked together to form the strands of DNA rather like Lego units assembled into long linear strings The order in which the nucleotides are arranged along DNA in turn creates the genetic vocabulary The alphabet dictates the vocabulary and the complete assemblage instructions all of our genes taken together is what we call the genome Now instructions must be read to be understood and implemented Genetic instructions are read by universal molecular pathway found in every living organism This pathway first copies DNA into a smaller molecule called RNA and then the RNA into even smaller molecules known as proteins DNA to RNA to proteins Proteins are important to our story. They are the executors of the genome the handmaidens of genes The molecules get most of the job done the pieces from which much of the cell is built the engines that drive the chemical reactions of life It has taken more than a century to assemble the knowledge that defines the genomic era And it was fair to begin as I did with Grieger Mendel's description of the discreet manner in which particular traits are inherited In his case it was the shape color and other properties of pea seedlings and pods Mendel's discovery attracted little attention. He sent a copy of his publication to Charles Darwin a Contemporary Darwin apparently never even opened the reprint the pages remain uncut to this day Darwin would have been well served to look at those pages Because they contain the answer to one of the great puzzles that vexed him until the end of his days What exactly is the material substrate on which his natural selection plays during the course of evolution? It is in fact genes discovered by Mendel The existence of genes was rediscovered by other scientists at the turn of the 20th century over a hundred years ago And the word gene was then coined Mendel had been dead for more than two decades But his old publication was brought to light and he was duly honored as the original discovery of what came to be called Mendelian genetics Now just three years after Mendel's discovery of genes Friedrich Mischer working in Tubig in Germany Isolated a gooey substance from the nuclei of pus cells taken from infected wounds The goo was first called nucleon, but it was in fact DNA In the decades it followed suspicions arose that DNA might be the carrier of genetic information Those traits discovered by Mendel But those suspicions were not proven until 1944 almost a century after Mendel's discovery of genes and Mischer's discovery of Nucleon or DNA Soon thereafter James Watson and Francis Crick deduced the three-dimensional structure of DNA a double helix that was pregnant with biological meaning It was a momentous discovery that gave Watson and Crick name recognition among the general public Equivalent to that of Albert Einstein Will any of you here who have not heard of Watson and Crick please raise your hands? No one had the courage The double helix was followed by the decoding of the molecular alphabet that composes our genes So that we could begin to read the instructions they contain the molecular equivalent of deciphering the Egyptian hieroglyphic script linear B Which incidentally was accomplished in 1952 just had before the molecular decoding By the British architect Michael Ventress in this instance archaeologists and molecular biologists were working in the same time frame Now we were not able to manipulate these instructions even though we now had them in front of us until the invention of recombinant DNA in 1972 Recombinant DNA allows scientists to splice fragments of DNA from different sources together and To replicate the spliced molecule endlessly in a microorganism Creating little factories that churn out immense quantities of the recombinant DNA and any proteins that it might encode This set the stage for the biotechnology industry made it possible It also made possible the human genome project which gave us the complete Sequence of the genetic alphabet in our DNA 3 billion units 3 billion nucleotides all arranged in their correct order The language of God had been laid bare Although we are still translating it into the mundane realities of everyday life Genomic error was truly launched by a technology advance that made possible the sequencing of the human genome And we are steadily getting better at this It can be done now in a matter of weeks And we will soon be able to do it in a matter of days or even hours And there's been a concurrent reduction in cost for billions of dollars for the first Human genome project down to tens and even just mere thousands of dollars We may very soon regard the sequencing of an individual's genome as little more than measuring their blood cholesterol The human genome project was unlike any previous undertaking in biological research a truly disruptive innovation It was big science rather than rather like particle physics involving thousands of scientists and entirely unlike any Experimental biology that had preceded it. It had strictly defined goals deliverables in corporate speak in contrast to the helter-skelter form of discovery practiced in most biomedical laboratories It involved many research institutions in multiple nations. It was highly organized in a top-down configuration Now that's anathema to the typical academic scientist Ask any Chancellor or Dean how their faculty would feel about instructions from the top of the command chain and the answer Will not be pretty The human genome project was both high-tech and new tech and that's what steadily has been increasing the speed with which genomes are sequenced It required the utmost and computer manipulation of data spawning the field now known as bioinformatics And it even featured a competition between public laboratories and a private research enterprise The competition is credited with accelerating progress and it finished more or less in a dead heat What is the genome project taught us to date well first of all it has given us The entire Rosetta stone for human life the sequence of those three billion letters that spell out the program in the genetic vocabulary of the program Second there is other stuff in there lots of DNA that does not seem to carry what we are accustomed to calling genes We are just beginning to beginning to learn what if anything that DNA is doing it is one of the great mysteries of genomic science Third we have learned that there is not a simple one-on-one mapping between all our traits and genes one gene does not make an arm One gene does not make a pleasant disposition or for that matter an unpleasant one It is the combined action of many genes that creates these things They are what biologists call emergent properties because they emerge from an opaque complexity This has made necessary a new science systems biology devoted to explaining how the emergence occurs It is a nascent science virtually only born fourth it has become apparent that Much of the complexity of life is Based on the ability of cells to combine the actions of the genes in different ways to diversify the use of its genetic Stowering by this means the capabilities of a mere 30,000 genes is that's not so much if you think about it to make a human Being that that capacity Is due to the ability to combine and recombine the way genes are used and that is what creates the elegance of the human organism Fifth and least anticipated we have discovered a second form of genetic information Created by chemical modification of the DNA along its length a Modification that does not change the sequence of the genetic alphabet But does change the expression of the genetic vocabulary when and where it is deployed This second form of genetic information has been dubbed the epigenome. It is extremely important, but still only poorly understood But what promises does the genomic error hold it would be easier to list those that don't that it does not But I've taken a stab at listing the ones it does hold here are just a few It is laid out the script of evolution more clearly than the fossil record could ever hope to do By comparing the genomes of numerous species from the umblest to the most elegant We see irrefutable evidence that all those species have a common origin And we are learning the genetic means by which evolution occurred Second by scrutinizing the molecular language of our genes. We are gaining an ever deeper understanding of life's processes Third we can expect that the study of our genome will eventually resolve the nature nurture debate How much of our human genome is hardwired in our genes? How much of it is molded by experience? Fourth the genomic error will mean about improvements in health care much more about that in a moment agriculture animal husbandry Forensics already prominent in the press think of DNA evidence in the Duke Lacrosse team for example ecology demography In which we use genomics to trace the migration of human populations over the past centuries And even as an assist to trace the emergence of distinctive languages ascertainment of ancestry was Genghis Khan really your ancestor and Much more not the least of which will be abundant controversy a Brief aside on evolution The history of species is clearly recorded in DNA a record that spans more than a billion years Only the most obdurate opponents of evolution could now deny its existence So scientists reel in bewilderment at the refusal of the US public to join the rest of the world and accepting the nature of our origins In this survey illustrated here taken from the New York Times Residents in 34 nations were asked whether quote human beings developed from earlier species of animals closed quote as Virtually any biologists would tell you the correct answer is yes But well less than half of the US residents surveyed responded. Yes next to last Among the surveyed nations Buried between Cyprus and Turkey My main purpose today is to illustrate how genomic science and its derivatives might affect the advancement of human health And I will use three Context to illustrate the prospects our efforts to conquer cancer the human lust for longer life and The possibility that we would manipulate the human genome in ways that might alter and perhaps improve our species I've arranged these according to my personal view of their descending order of likelihood and ascending order of controversy and each of these chapters will be Progressively shorter because we have progressively less knowledge. We know a lot about cancer now We know much less about imitating with fusilla and we know very little yet other than the fearsome prospects of re-engineering the human genome And I begin with cancer One person in three in this room will develop cancer one person among the four of one person in four of all of us will die of the disease Within this very decade cancer will probably pass cardiovascular disease and stroke as the number one killer in the developed world The mortality rate for cancer has hardly changed over the past century Although we have seen a very small decline over the last five years as much the product of prevention as of therapy Now why has progress been so slow? We'll simply put cancer is a complex and versatile adversary Dramatized here by a cancer cell. This is the cancer cell Squeezing its way into a blood vessel between the linings of the blood vessel on its way to becoming a Metacis this is the only time this event has ever been captured by an electron micrograph It's a remarkable photograph and it's a dramatization of the adversary in its full bloom In greater detail the tumor cell fails to control its proliferation as it should Remains in a primitive state rather than maturing to adulthood. We call that failure to differentiate Has an unstable genome our genomes are remarkably stable, but the cancer cell genome can change at the drop of a hat and this Means it is abnormally prone to damage to mutations and other mayhem Are they they are cells of their cancer cells typically lost the ability to kill itself rather than become an outlaw One of the most recent discoveries in biology is that our cells have the innate ability to kill themselves If they become unwanted or dangerous to the organism the cancer cell has lost that ability which is an immense benefit to it Cancer cells can call forth the production of new blood vessels in order to sustain a growing tumor mass Cancer cells adhere less well to other cells and tissue matrix making easier for them to break loose and spread They are hyperkinetic They are invasive and so they are prone to disseminate to distant sites in the body the ultimate cause of death by cancer Now how does this complexity arise? Cancer has many causes only a few of which have been identified with any certainty There are particular viruses which cause cancer of the liver cervix some leukemias and some lymphomans There's a bacterium known as healobacter pylori that causes not only most stomach ulcers, but most stomach cancers Sunlight is the principal cause of skin cancer because of the ultraviolet radiation that it contains more about that later chemicals and cigarette smoke cause most lung cancers Diet may I emphasize the conditional may have a role in producing colon cancer and Reproductive hormones have been implicated in the genesis of breast and prostate cancer That leaves a lot To be learned it also suggests that things are extraordinarily complicated But underlying this immense variety is a single mechanism that accounts for most if not all tumors Because the causes of cancer Whatever their nature all seem to initiate a stepwise and usually Protracted chain of events that develops over the course of our lifespan and it is in principle the same sort of chain of events Irrespective of the initial cause of the cancer so the cause of the cancer is typically external But what is happening inside the cell is far more common to different tumors? So the sum of these individual events a plus b plus c etc is a malignant cell So I just call this tumor progression It takes time for all of this to happen and that accounts for the fact that cancer is typically although not always a disease of middle age and older We now know that most if not all of these steps represent changes in the human genome Each step is a genetic or epigenetic event This genetic paradigm for cancer arose from five clues First and this has been known for almost two centuries and literally ignored into the last two decades The malignant properties of cancer cells are heritable each cancer cell is rise to new two new cancer cells They do likewise odd infinitum such stable inheritance from cell to cell screams of genes signifies the involvement of genes second Substances that damage genes the damage DNA which we call mutagens can cause cancer A prime example are the chemicals and cigarette smoke third Many types of cancer cells contain microscopically visible abnormalities of chromosomes and The type of abnormality is specific to the kind of cancer in which the abnormality is found They differ from one kind of cancer to another and they differ in a specific way And of course chromosomes are the mechanical carriers of genes and an abnormality of a chromosome suggests that there will be Well be an abnormality of a gene underlying it fourth Some viruses contain cancer genes that actually originated for normal cells the viruses have accidentally plucked these genes from the cells in which they reproduce and Displayed them for our study In other words the potential for cancer does indeed reside in the genomes of normal cells And incidentally it is that discovery for which Harold Barmas and I received the Nobel Prize and fifth Cancers occasionally run in families. This is not typical only about 10% of all human cancers are familial as we say Coal cancer the breast and colon are probably the most familiar examples for an audience like this and The transmission from one generation to the next typically obeys Mendel's rules It is now clear then the damage to genes does indeed underlie cancers and we have uncovered the nature of those genes There are two sorts and they have bizarre names, but we're stuck with them One is called a proto oncogenes. There are hundreds of these in ourselves and these Serve normal functions for us, but in cancer cells. They're hyperactive The geneticists calls this gain of function and then there's something called tumors suppressor genes which speaks for itself These are deficient in tumor cells. They are loss of function changes in the genome There are hundreds of these in ourselves going about their work day by day Serving the normal purposes of the cell But what are these genes? Why can they give rise to cancer? Well, the behavior of ourselves is governed by an elaborate network of molecular interactions that Roughly resembles an electrical circuitry, but it's probably far more complex than the circuitry's you're familiar with Indeed the complexity of the circuitry is staggering Some computational biologists say that it must contain billions of interconnections within each of our cells Proto oncogenes and tumor suppressor genes are switches at some of the interconnections. It's displayed here in this sort of cartoonish style Proto oncogenes and tumor suppressor genes specify proteins their handmaidens which are switches at some of these interconnections Now first we thought of this circuitry in simple two-dimensional terms such as in Broadway boogie-woogie by Montréal but by now Knowing the complexity of this circuitry the artist who comes to mind is Jackson Pollock Since scientists are not proficient at drip painting or any painting Most of us they are worse other than house painting They We're resorting to molecular experiments and computer analysis to take the circuitry apart And let me tell you it is a daunting task and actually that new discipline I mentioned systems biology is where this will probably ultimately happen Despite the immense complexity of this circuitry we do have some sense of how genetic damage throws at a rye Some portion of the circuitry mobilizes the cell to necessary actions Proliferation is dramatized here, but we call that the cell division cycle We're just talking about the ability to divide to continue to reproduce Now some portions of this circuitry within the cell mobilize this reproduction and There are many other such things in cells each of which has to have a start signal Proto oncogenes are the switches in this activating part of the circuitry and Damage to proto oncogenes in cancer cells creates molecular short circuits The network now signals relentlessly driving the cell to unwanted action You could also think of these as jammed accelerators Other portions of the circuitry in our cells rain in the actions of cells Tell them to stop doing something or other such as proliferation tumor suppressor genes are part of these Negative switches these repressive switches and in activation of these genes loss of these genes in cancer cells Deprize the cell of the bridle unleashing it to unwanted actions. So here you would think of a defective break And that is exactly how we think of these two forms of normal genes that become cancer genes when they are damaged One when it is unleashed the other when it is lost or defective So the story of cancer reduces to these fundamentals gain and loss of genetic functions diametrically opposite maladies that combine to maim and kill We have at last laid bare the secrets of the cancer cell and they are rooted in the double helix of DNA Knowing the genetic anomalies underlie all cancers We need to develop an inventory of those anomalies in every form of cancer And this need has sired the cancer genome project sponsored by the National Cancer Institute The objective is to sequence the complete genome of many cancers many types of cancers and many numbers of each type of cancers Spot the true genetic abnormalities in those cancers the ones that differ from the normal tissue and deduced by compilation and comparison those abnormalities that are most likely to have been involved in the genesis of each type of cancer This is an immense undertaking Opposed by some cancer scientists because of the expense and the concern that it might not be the most effective way to get the answers we need and This is a vigorous debate but the work has begun the National Cancer Institute firmly believes that we should get a start on this and The start is on a relatively modest scale which will test the feasibility of the entire scheme but I think you can grasp the potential here that we might actually have in front of us a Complete picture of what's wrong with the genome and every type of human cancer and in every individual's cancer more about that in a moment now can we bend our Exposure of the genetic secrets of cancer cells to our advantage Well, we believe so The identification and characterization of cancer genes offers new approaches to diverse aspects of the management of cancer and given enough time I could authenticate each of these with the results, but let's just take the list first these include Identification of the many still unknown causes of the disease the necessary prelude to effective prevention It's hard to prevent a disease if you don't know what's caused it Evaluation of individual genetic risks for cancer our risk vary immensely We don't know why or how and we don't know how to ascertain that yet, but it is a fact Evaluation of individual Sorry early detection Which is deemed vital for maximum benefit for therapy and is not readily possible for many cancers Prediction of outcome prognosis so vital to the patient's peace of mind development and evaluation of new treatments urgently needed for cancer individualization of Therapies a wave of the future and Prompt evaluation of tumor response to treatment early enough to avoid futile exercises or to predict some success All of these should be facilitated by the genetic paradigm for cancer and most will rely upon what we call genetic testing So I want to do a brief aside on genetic testing Because it ranks among the most important and disruptive developments of the genomic era Three sorts of analysis are now being applied or developed for genetic testing the direct sequencing of individual genes and genomes Surveys of how vigorously active genes are within cells we call that their expression and Techniques capable of detecting all the proteins expressed in a particular normal or disease tissue This is a new field just developing called proteomics as opposed to genomics But they're all represent various forms of genetic testing Each gives a distinctive view of the state of the genetic program and together they Combined to give a powerful view of the state of the genetic program Now they give you a sense of how powerful some of the technology has become Here's an illustration of what the data looks like when we screen the activity of genes in ourselves Each bar each little bar of color Represents the relative activity of an individual gene red is high activity green is normal So this is what the data look like The data were obtained from an analysis conducted entirely on a piece of glass about one inch in length width and three inches in length And the analysis required about three hours With this technology it is possible to simultaneously assay the activity of tens of thousands of genes within a few hours Scanning and analysis of the data are computerized to obtain color charts like what you see here The technology is already in use limited use at least add a number of hospitals Now genetic testing can be done in three contexts in utero or during the course of in vitro fertilization or so-called assisted reproduction In order to test for the presence of certain inherited diseases in adult normal tissue in order to detect an inherited defect That might predispose to disease later in life breast cancer genes are telling and probably familiar example and Testing of disease tissue itself the best example is cancer to get a genetic fingerprint of the tumor that might assist in prognosis and treatment A genetic testing promises to be useful in a wide variety of settings here are some examples The identification of human remains recall 9-11 law enforcement determination of paternity prenatal detection of gender The detection of genetic susceptibility disease either in utero or at any time after birth The prediction of how individuals might respond to medical therapies the tracing of ancestry and in rapid diagnostics a Color array of the sort I just illustrated for you was used to identify the SARS virus a few years ago in an overnight experiment and at my University and a similar approach can be used to monitor for avian influenza virus So how might these technologies of genomics contribute to the study and management of cancer? And I'm good. I'm going to give you a limited number of examples first the prevention of cancer Provencher prevention is the principal hope for the eventual decisive control of cancer Progress towards prevention has been impeded by our failure to identify the causes of cancer If you do not know the cause of a disease prevention becomes almost impossible Yet, we do not know the causes of most major human cancers such as colon breast Prostate pancreas ovary brain and most leukemias and implements In the past we got most of our clues to cause from studying large populations for example The incidence of certain cancers the frequency of certain cancers changes dramatically when nationalities change Geographic or residents when Japanese move to Hawaii or the United States, etc In this illustration, we don't have to go into the details the red arrows denote migrations that have been accompanied by increases In certain forms of cancer big increases the blue arrows represent migrations that have been associated with decreases These findings suggest that there's something Different in the environment between a place where the cancer has a high incidence and the place where the cancer has a low incidence Because people change their incidence just by moving from one place to another Okay, so that's provocative But the data leave a lot to imagination too much to imagination So we're hoping to get some help from genomics Consider skin cancer We have believed for many years that excessive exposure to sunlight especially in childhood is the principal cause of Skin cancer a belief derived from studies of populations But more recently we've obtained molecular verification of that belief most skin cancers contain a damaged version of a tumor suppressor gene that's known by the dramatic name p53 as Illustrated by this excerpt from the New York Times the chemical nature of the damages characteristic of what happens to DNA when it is exposed to ultraviolet light Individual letters of the genetic code are changed in a predictable way that is characteristic of damage elicited by ultraviolet light So even without the previous evidence We would be almost certain that skin cancer is caused by the ultraviolet radiation in sunlight For cancer whose causes have yet to be established We hope that we might occasionally be able to reason backwards from the nature of the genetic damage in those cancers To the nature of what caused the damage and thus what caused the cancer? Second we have reason to believe that genetic portraits of tumors will improve our ability to detect cancer For example human excretions such as sputum breast fluid urine and feces carry cells shed from the interior of the body You're familiar with this certainly in the form of the pap test For cervical cancer it is now possible to screen those cells for genetic damage that signifies the presence of cancer This genetic cytology may be more sensitive and more revealing than currently established techniques and A retrospective look at the death of the American statesmen and native son of Minnesota Hubert Humphrey illustrates the point Hubert Humphrey died of bladder cancer Scientists have used genetic cytology to examine urine and tumor tissue taken from Humphrey and preserved after his death They found that the bladder tension cancer could have been detected six years earlier than it was Had genetic screening of cells in the urine been available Even the earliest samples had a mutation in the tumor suppressor gene P53 that I mentioned before and this is a telltale sign that ranks among the most common genetic changes in human cancer and a change that we know contributes to predisposes to malignancy Thus this analysis had it been available then could have prompted immediate aggressive therapy back here when his disease was deemed to be Not malignant Perhaps curing Mr. Humphrey of his cancer Indeed he spent 11 whole years at Increasing risk of his eventual fate Third genetic screening promises to improve our ability to predict the outcome of cancers Consider that double-edged sword of masculinity and it is a double-edged sword the PSA test Universally used in the United States to screen for prostate cancer the test embodies an uncertainty captured here pictorially some time ago in the New York Times You all know the conundrum the PSA test permits detection of tumors that would have gone unnoticed in the past Some of these tumors pose a mortal threat But others do not and would not need intervention for the moment. We do not know how to recognize one from the other But using new genomic technology Scientists have recently developed a complex genetic fingerprint that may identify Cancers of the breast lung and prostate with the potential to metastasize The results for prostate cancer are dramatized here where the test has been used to discriminate those tumors that recurred Following surgical removal. That's these from those that did not recur the genetic signature spots these tumors as ones in retrospect that were going to recur and spotted these tumors that were ones that would not recur It is thought that this distinction may prove to be generally predictive of how individual prostate cancers will behave in other words You could do it prospectively rather than retrospectively now These are still early days in the development of Technology, but there can be no denying the potential and similar tests for the prognosis of breast cancer are well underway And have been we widely reported in the media For does the genetic paradigm promise new therapies for cancer? It is unlikely that we will be able to directly repair or replace the damaged genes of cancer cells in the foreseeable future We have not yet learned how to operate on the DNA of living human beings with the necessary accuracy and efficiency We may never learn to do that If we focus on the protein handmaidens of genes, however, we see more cause for hope Given sufficient information about how these proteins act We should be able to direct our therapies accordingly The hope is to develop magic bullets of the sort first envisioned by Paul Ehrlich for bacteria Early in the 20th century and eventually achieved for bacteria But directed instead at cancer cells in other words, although cancer cells are born of normal cells We have it last found a way to attack the bad progeny without harming the good parents Here are four examples in which the protein products of damaged proteal oncogenes have been targeted successfully for therapy In each instance the target is a malfunctioning switch Created by a genetic anomaly that is unique to the cancer in question They're listed in the chronological order in which they were introduced and the first example emerged in 1987 When Chinese scientists discovered that the deadly disease acute pro-myocytic leukemia Here to for uncurable could be cured for the first time by supplementing the use of cellular Poisons with retinoic acid a relative of vitamin A We now know how this therapy works a genetic malformation in blood cells has created an abnormal protein that engenders the leukemia When used at therapeutic doses retinoic acid binds to the abnormal protein and reverses its effects It has no substantive effect on normal cells which do not contain the outlaw protein For this cancer retinoic acid is a magic bullet a targeted therapy When used in combination with other more conventional therapies, it is curative The targeting was fortuitous But nevertheless exquisitely specific it is a proof of principle in advance of its time Regrettably retinoic acid is useful for only that one leukemia a testimony to the specificity that underlies its efficacy In other words you can't have it both ways specificity precludes panacea The second example is widely known Perceptin a therapeutic antibody designed to attack the protein switch produced an abnormal amount on the surface of about 30% of breast cancers Perceptin has proven to be a valuable adjunct in the treatment of breast cancer, but it is not curative The third example is Gleevec a genuine poster child of medical research a drug aimed at a renegade chemical activity Spawned by a distinctive genetic malformation found in chronic myelogenous leukemia The course of chronic myelogenous leukemia begins with a chronic relatively indolent stage that can last for several years But eventually the disease evolves to a rapidly progressing acute phase that can kill within months Gleevec has demonstrated remarkable efficacy in the first phase of leukemia But it is disappointing in the treatment of the acute disease in part because the cancer cells quickly developed genetic resistance to the action of the drug Resistance to Gleevec however may be only a temporary problem We have new cousins of Gleevec that are effective against tumors that have become resistant to Gleevec itself And the use of Gleevec in combination with other therapeutics may offer more decisive results that possibility has yet to be explored The fourth and most recent example is a drug known as Eresa Eresa preferentially attacks a molecular switch on the surface of cells That is a relative of the target for Herceptin and this switch is Short-circuited in a variety of cancers and the ability of the Eresa to arrest such cancers is under active investigation And I'll return to that in a moment So in summary we have preliminary proof of principle that we will be able to target cancer therapy to individual genetic Malades by targeting the protein products of those maladies But we are far from running the table But given the ability to construct therapies which such exquisite specificity Genetic profiles of cancer hold the prospect for a complete individualization of cancer therapy There is hope that we will eventually be able to choose the most effective therapy for individual cancers of every sort based on genetic fingerprinting Just as we presently base the choice of antibiotic therapy on the specific sensitivities of the infectious agent The treatment of every cancer may someday be individualized and tailor-made According to the inventory of genetic lesions in the cancer. It may in other words become routine To sequence the genome of the cancer in question spot the responsible genetic abnormalities choose those which are Advantages targets for attack Tack several in combination and achieve a cure It is possible that we will do this within the next decade or two The largest impediment may prove to be cost Much will depend upon how many different genetic fingerprints there might be for any given form of cancer How diversified the tailor-made therapies might have to be if we have to devise a different therapy for every individual with colon cancer We have a problem The tailoring of treatments according to specific properties of cancer cells is not a new concept It probably originated with the recognition that breast cancer is containing the estrogen receptor and only those containing the receptor Would respond beneficially to treatment with anti-estrogens you probably all know about that But with the advent of genomics the strategy of targeting therapy to cancer cells has acquired a new elegance and precision Consider the example of Eressa in the treatment of lung cancer In lung cancer The surface of the cell carries an important switch known as the EGF receptors This is the surface of the cell and this is the switch this switch governs the activity of a vast network within the cell In lung cancer this switch is jammed Once again a short circuit that can wreak biological mayhem Eressa attacks the jam switch and shuts it off The original clinical trials of Eressa completed just a year or so ago Appeared to be discouraging The drug seemed not to have an effect on overall mortality of patients with lung cancer But still there were occasional Remarkable responses to the drug in patients with one common form of lung cancer known as non small cell lung cancer Here's the response illustrated the entire cavity lung cavity on the left side of this patient is filled with tumor Individual was put on Eressa three weeks later. This is what the scan looked like You can see why people got excited Recently scientists have found a way to identify Many of the lung cancer that will respond to Eressa in other words to identify this kind of lung cancer In most of the patients whose tumors respond to Eressa the protein target of Eressa that switch Contains characteristic changes in the DNA sequence So here the key part of the molecules been expanded and here are the changes at two very specific sites These changes signify that the switch will be responsive to Eressa and that the tumor will be responsive to Eressa We do not yet understand why these changes signify susceptibility But the results are dramatic for telling of what the future may hold for the treatment of cancer The group of patients who respond to Eressa are actually defined by several very different parameters This is interesting stuff that we don't fully understand yet For as I said before they all have a particular form of lung cancer known as non small cell lung cancer But only about 10% of this kind of cancer response The responsive tumors have those telltale abnormalities in that switch The responsive tumors are most typically a special form of non small cell carcinoma known as adenocarcinomas They are more common in women than men More common in individuals who have never smoked More common in individuals of Japanese extraction This all suggests that we're dealing with a very biologically special set of tumors, but we don't understand it And for the moment we do not yet know whether even that dramatic response to Eressa that I do Illustrate a few will actually eventuate in prolonged survival Now it's going to be a while before genomic guidance for therapy becomes common practice and extends to many malignancies But when that day arrives the prospects for the management of cancer will literally be transformed There's one further development that we need to consider briefly The development has emerged from a congruence of cancer research with our newfound knowledge of stem cells and in order to do the subject Justice I have to brief you just superficially on stem cells Anticipating by a tiny bit the lecture you'll hear tomorrow And then even I suspect you'll forgotten what little I have to say about stem cells by then First a brief biography of stem cells the ultimate stem cell is the fertilized egg Which embodies the capacity to eventually produce a complete organism in biological parlance the cell is totee potent There's a little Latin lesson here The fertilized egg divides into two cells these divide into four and so on and by the time the number of cells in the embryo It's reached about 200 they have been assembled into a structure known as the blastocyst Within the blastocyst or embryonic stem cells These have the potential to produce most if not all adult tissues each one of them They are either totally potent or at the least purry potent That completes the Latin lesson Now cells within the embryo continue to divide they become more specialized they differentiate eventually to produce adult tissue skin muscle bone heart blood and brain etc But embedded in many if not all adult tissues are still stem cells that can serve As an ongoing source of additional differentiated cells to continuously renew the tissue so-called adult stem cells It is generally thought that these adult stem cells are capable of producing only one tissue. They are unipotent. Sorry I slipped that in on you But the possibility that there may be more plastic that these cells may be able to do more things and just want make more Things this than one tissue under certain circumstances is still under study and is very controversial Examples of tissues that continuously renew themselves throughout our lives Include blood skin and the lining of our gut other tissues renew on demand deliver is a prime example And all this renewal is made possible by the persistence and activity of adult stem cells in our tissues Now in recent years it has become likely That cancers originate from a perturbation of an adult tissue stem cell or one of its first most primitive progeny This cancer stem cell as it's called Serves as a sort of taproot for the tumor mass It both renews itself producing another cancer stem cell and also throws off Cells that will become part of the tumor mass the mature tumor cell All current therapies for cancer are aimed at the mature cells of the tumor what we see in a full-blown breast cancer There is a strong chance that cancer stem cells are resistant to many of the therapies We presently addressed to the mature tumor cell and Thus serve as a reservoir of survivors that will spawn recurrence of the tumor once therapy is discontinued or even while it is underway We know this scheme is correct for leukemias We've known that for some years and it is probably correct for cancer of the breast brain skin among others The practical implication is that we should learn how to target our therapies to the stem cell Perhaps as well as the full-blown tumor cell if we are ever to routinely eradicate cancer by any means other than surgery prior to metastasis If we're going to eliminate metastatic cancer We will probably have to be able to eliminate the cancer stem cell wherever it is in the body But first of all we have to identify and characterize the cancer stem cells for each kind of tumor and then ascertain its susceptibility to therapeutics efforts to do this now constitute one of the most rapidly expanding fields in all of cancer research Even with therapies directed against tumor stem cells It is unlikely that any single therapy for cancer no matter how specific and elegant will ever become a panacea Because we have to deal with a large variety of damaged genes whose actions present great functional diversity So it is most unlikely that there will ever be one cure for cancer Instead it is likely that there will be many cures to match the many forms of cancer and the diverse genes that underpin the Genesis of these cancers So the message about cancer that I want to leave with you is one of hope The genetic paradigm has provided a powerful view of cancer the seemingly countless causes of this disease tobacco Sunlight asbestos chemicals viruses and many others all these may work in a single way by playing on a genetic keyboard By damaging some of the genes in our DNA an Enemy has been found we are beginning to understand its lines of attack and it can be only a matter of time before we have Invented ways to repel that attack In 1978 Susan Sontag published a widely read essay entitled illness as metaphor In that essay Sontag described cancer in the following terms. I quote this disease is overlaid with mystification It is a triumphant mutation charged with the fantasy of inescapable fatality a scandalous subject for poetry close quote Well over the past decade the force of science has taken some of the sting from Sontag The mystification of which she spoke is in retreat the triumphant mutations have been exposed We see new ways by which to confront that inescapable fatality. There may even be reason for poetry Methuselah is said to have lived 969 years What are our prospects for even approximating his prodigious survival? Might it be possible to significantly extend the human lifespan far beyond our current record of 115 years or so An early hint that we make be able to prolong lifespan by direct intervention came from experiments performed more than 50 years ago Rats were placed on diets that subjected them to severe caloric restriction a diet you would not want to tolerate The lifespan of the animals was extended by as much as two-fold and they were pretty good shape. They were pretty healthy And they seem not to age prematurely This sort of experiment has been repeated many times over with various rodents generally with similar results and Now experiments of this sort are in progress with monkeys But the results are not in and of course no one has tried it out in a deliberate way with a large population of humans Does longevity have anything to do with genes almost certainly First of all we know that certain isolated populations of humans who are highly inbred live to exceptional ages And that sounds like genes might be involved But second and far more dramatically recent experiments with simple creatures such as yeast bakers yeast worms and fruit flies Have shown that lifespan can be either prolonged or shortened by manipulating a limited set of genes in these creatures And we have the same genes in our genome Scientists are learning how to manipulate the circuitry controlled by these genes and as with caloric restriction The worms or fruit flies that live to exceptional age appear healthy until the very end of their days Although I confess it's not easy to assess the quality of life for a earthworm Now here's an example So here's the life here's here's the way the normal worm dies off, right less than 50 days And here the scientist Cynthia Kenyon at my institution has manipulated just two genes in this worm and extended the lifespan of the gene by a factor of six Six Extrapolate that to humans six times one hundred fifteen and you have imitated in the fusilla has the little worm down here Finally and unexpectedly revealed the formula of youth the fountain of youth so sought by humankind We do not yet know but the results with simple creatures bring to mind several questions first Can the actions of lifespan genes be manipulated by drugs? Rather than by direct manipulation of genes as we do in worms and fruit flies the answer is likely to be yes Knowing what we know about these genes now, and there are actually several small companies already seeking such drugs I have not invested in any of them You will be pleased to hear even in this epistemiast state That one prominent candidate is the chemical resveratrol which is found in red wine so Drink up second that such drugs are found will they work in humans? Time will tell Third Well, let me just well, that's rights There's no question. We've got genes like the genes that were manipulated in the worm And some of those genes are involved in the machinery that allows a cell to respond to insulin. It's just that ordinary So I can assure you from what we now know that sugar is indeed bad Particularly if you're interested in imitating the fusilla Which brings us to two other questions First Should we find a way to prolong human life by chemical intervention? Will the extra years be spent in a fog of senility or will we like the worm remain robust until our end is near? We need to ask ourselves that We don't know and second there is a philosophical issue of whether we would really want to do this What might happen to the human species if we disturb the established rhythms of youth adulthood and old age? What might happen to both the biological and social evolution of our species which is ongoing? These are things to ponder and resolve before a longevity pill hits the marketplace or at least the FDA Now while some scientists seek to manipulate Lifespan with drugs others foresee the possibility of altering many and diverse aspects of human experience by directly recrafting the genes of our species designer jeans designer genomes the motivation is often aspirational rich with dreams a more vital productive capable creative and gratified Humanity can you all read the caption? I was wondering when you'd notice there are lots more steps. We're not all we're not home yet the basic idea But the details soon lead us into dubious territory The most immediate objectives are medical in nature and are fundamentally humanitarian to eliminate genes responsible for inherited diseases such as hemophilia taste acts disease and cystic fibrosis more remote is The prospect of endowing our species with genes that confer resistance to certain diseases AIDS is a case in point because genes have been identified that block either infection with HIV or a progression to disease after infection The more dubious territory of which I spoke involves a desire to design our offspring in ways that are social rather than medical Gender selection physical appearance talent of one sort or another Resilient temperament enhanced intelligence sexual preference We might each have a personal list of preferences were we willing to admit to them Is any of this even remotely? Conceivable well at first blush. Yes. Here's a list of traits that have been provisionally associated with the genome in various ways Obesity which is not simply a matter of self-indulgence Risk-taking my favorite example is mountain biking vulnerability to addiction Talent for dance Tennessee to anorexia relative sexual veracity and capability sexual orientation hot tempers altruism and the very essence of humanists of humanists in the form of genes that dictate the complex development of our brain Now I caution you that much of this remains tenuous But it deserves mention at least in cautionary terms because it has been widely reported in the media I took all of these examples for reports in either the New York Times a paper of great distinction Or the San Francisco Chronicle a paper of no distinction whatsoever These two papers have reported all of this in the last two years. I didn't make it up But by what means might we create designer genomes for certain medical reasons we already do We screen the products of in vitro fertilization for unwanted disease genes and retain only those that are free of these genes at Least for parents who are willing to have this done It is also likely that we could develop procedures to modify genes directly during the course of in vitro fertilization assisted reproduction And then there is reproductive cloning The technique that gave us the sheep dolly and that you will hear about more tomorrow from Dane Pollock If we were ever able to perfect and indulge in the reproductive cloning of humans We would achieve the ultimate opportunity to redesign genomes Reproductive cloning of humans is presently anathema to virtually everyone and I for one hope it stays that way Now there's one fundamental that gives pause all of this speculation Hemophilia is caused by single aberrant gene which we can eliminate from a family lineage with procedures now in use The same prospect applies to many other inherited diseases Traits such as musical talent and hot tempers are another matter entirely It appears that they arise from interactions among multiple genes in ways that we don't begin to understand So Mozart on demand seems remote and extreme The reality that genes have much to do with our nature and behavior And the possibility that we might someday manipulate genes to change our nature and behavior prompts two thoughts First we risk resignation to self-indulgence I've blown the whole thing. There we go First we risk resignation to self-indulgence the caption of this cartoon in the new york times was my dna made me do it And self-indulgence is the beginning of decline Second we risk denial of our better angels I quote judy nersigian co-author of our bodies ourselves Familiar at least to many of the women in the audience I quote as we increasingly come to see our children as commodities to be chosen like consumer products They will be devalued in ways that we will come as a society to regret Nersigian was speaking of gender selection But her statement extrapolates well to the much larger field of play I have just sketched Several years ago casio ishiguro published a novel entitled never let me go As the story unfolds the reader gradually comes to realize that the young woman who is the central figure and narrator of the novel Is in reality a human clone Created for a sole purpose to donate organs one after another until her capacity for life is exhausted Near the end of the novel an elderly woman who had opposed the introduction of cloning to create organ donors And was imprisoned for that mediates or meditates on how the practice achieved acceptance and I quote When the great breakthroughs in science followed one after the other so rapidly there wasn't time to take stock to ask the sensible questions Suddenly there were all these new possibilities laid before us all these ways to cure so many previously incurable conditions This was what the world noticed the most wanted the most By the time people became concerned about how these cures were being achieved It was too late There was no way to reverse the process How can you ask a world that has come to regard cancerous curable to put away that cure? Because of the way it is achieved There was no going back If we wish to avoid ever reaching the point of no going back We must all scientists and unscientists alike Reach a common knowledge of how we might get there And we must all reach a common understanding of why we might never want to arrive Having deciphered the language of god do we wish now to play god? I think not Our ambitions remain more modest and more humane Their spirit captured in these lines of verse from kitty hawk by robert frost The comfort is in the covenant. We may get control if not of the whole of at least some part. We're not too immense So by craft or heart Or art We can give the part wholeness in a sense Thank you for your attention to a demanding lecture and I look forward to your questions