Cancer Treatment Medicine

good afternoon. i'm george blumenthal, chancellor at uc santa cruz, and i want to welcome you to the 2011 foundation forum. this is a great event that allows us to have interesting discussions with a list of eminent panelists, i know because one year i actually did it myself as a panelist. tonight is a very special- or this afternoon is a very special program. we have some great guests, some great panelists including our own david haussler and artlevinson, the chairman of the board of genentech, and also my old friend mike bishop, the former chancellor at uc santa cruz.

mike is a very interesting guy because he wrote a book that i would encourage all of you to read, it's called how to win a nobel prize. mike is also the father of a banana slug, his son graduated from uc santa cruz. now we'll have the formal introductions in just a minute of our panelists but i want to introduce our host for this evening, ken doctor. ken is the president, actually the new president, at the uc santa cruz foundation. he is a noted journalist, a noted author, and a noted person being committed to uc santa cruz. formerly he was the head of the ucsc alumni association and as you might have guessed he is agraduate of uc santa cruz.

so without further ado let's welcome kendoctor. [clapping] thank you very much chancellor. on behalf of the uc santa cruz foundation we are very happy to welcome you all to the foundation forum. this has become an annual tradition and in fact it is the 10th annual foundation forum and i know a number of you have come for a number of years already. we have a great conversation today, and what this is about is a great public conversation place that we have every fall with passionate, creative and committed people. you'll have a moderator and three guests.

each one of these people is very distinguished in their field. among the panelists each one is already legendary in a field that is too near and dear to us, i would say, talking about newer approaches in the diagnosis and treatment of cancer. nobel laureate mike bishop is the chancellor emeritus of ucsf and professor of department- in the department of microbiology and immunology. art levinson is chairman of the board and former ceo of genentech and i have the great honor tonight on behalf of the foundation of presenting to both mike and art the foundation medal at our founder celebration dinner. that foundation medal recognizes individuals of exceptional distinction

whose work and contributions to society illustrate the ideals and vision of our uc santa cruz. both mike and art exemplify this outstanding level of leadership and we're delighted to have them here today to talk at length and at dinner. our third guest and panelist is ucsc's own distinguished professor of biomolecular engineering- these are very compound academic terms- david haussler. david is the center- is the director of the center for biomolecular science and engineering and an investigator for the howard hughes medical institute. we're also lucky to have a great moderator for our event. moira gunn is the host of two programs on national public radio: tech nation and biotech nation.

tech nation began i think almost twenty years ago, i think it's coming up on its 19th or 2oth anniversary at this point. it's heard on 200 public radio stations and technation.com. it chronicles the amazing twists and turns of tech, especially in our neighboring silicon valley, all the way back into the last century. moira recently won the national science board's 2011 public service award and she got a free trip to the state department. i'm not sure she'll tell you about that today. in her spare time she is an assistant professor of global information systems and biotechnology at the university ofsan francisco.

so please join me in welcoming all of these great guests for this year's foundation forum. it's great to see everybody here and it's really great irony now we havesome tech nation and biotech nation listeners. tech nation of course has been our full hour show and when biotech- i'm really an engineer, my phd is in mechanical engineering who needed biotech? what was that all about? so when it ran up and grabbed me by the throat we decided to do biotech nation. we put it right at the end of the show and we've never looked back. that was 2004. it's definitely the most popular part of the show because hey, who doesn't have dna?

it's very simple. it's very simple. and for those of you who listen to the biotech segment regularly, which you can do separately on the internet, the world we know is changing. welcome to biotech nation. now today it is really my pleasure to introduce to you some of the- all of the panelists today because they play such a role both in itspast, its current embodiment and its future. it's a very exciting time for us. first of all we have mike bishop, the chancellor emeritus of the university of california san francisco and university professor in the department of microbiology and immunology. in 1990- 89 rather mike bishop was awarded the nobel prize in physiology or medicine with harold varmus

for the discovery that growth regulating genes in normal cells can malfunction and initiate the abnormal growth processes of cancer. under his chancellorship at ucsf it has become a premier institution with leading professional schools of dentistry, medicine, nursing and pharmacy, a top ranked biomedical research graduate division, and two of the nation's leading hospitals. this includes its innovative mission bay campus with state-of-the-art biomedical research facilities. he continues to teach medical students and supervises a research team at ucsf studying the molecular pathogenesis of cancer. and as a nobel prize winner he has his own parking place,

so if you weren't motivated before- lets have a big round of applause just get on that nobel train now because there are many rewards, many rewards. next we have art levinson. he is the chairman of the board and former ceo of genentech. coincidentally, as a postdoc art worked in the lab of mike bishop and harold varmus at ucsf in 1980. he joined genentech where he began as a researcher and ultimately became the ceo in 1995. genentech is considered the founder of the biotech industry. it works- it uses human genetic information to discover and manufacture medicines to treat patients with serious or life-threatening medical conditions. oncology remains the major focus of genentech's research. art levinson.

it's also my great pleasure to introduce ucsc's distinguished professor of biomolecular engineering, david haussler. david is the director of the center for biomolecular science and engineering and an investigator for the howard hughesmedical institute. tomorrow he flies oxford to receive theweldon prize in genetics. thank you. now i understand you should have cards available to you, if you don't you will see people walking the aisles, and what we'll do is as we're going forward, if you would fill out questions on cards at about, oh, a quarter to four, something like that or a little after, i'm going to get a selection of them and then put them together and ask questions directly from the audience.

in the meantime we'll have a conversation ourselves but starting, each of our panelists will make a presentation. so let's start, let's ask mike bishop to start. thank you moira. about that parking space, i chose it in 1989, way in the back of our facility very close to my lab. when i became chancellor it was assumed i would want to move to the front of the facility close to my office. i kept the one in the back. i never had to cross a picket line, i never had to confront an animal rights demonstrator, and i was equidistant to my two offices.

we're going to talk with you about cancer. this is certainly one of the most fearsome adversaries of humankind. one person in three in this room will develop the disease, one in four will die of it and when i began my research career in 1968 we knew nothing about the genesis of cancer. we knew only of a few causes and we had not a clue about why cells would suddenly run rampant and create a cancer. over the last thirty decades, science has produced a fundamental understanding of what's wrong in cancer cells and that understanding is now in forming the development of therapeutics, the analysis or the examination of cause,

the development of new prognostics and diagnostics and detection devices. it has revolutionized our approach to cancer, and that's what we're going to talk to you about. i'm going to start the story in 1970 when for the first time a gene was shown to be able to cause cancer. of all places, this gene was found in a chicken virus, a virus that causes sarcomas, tumors of tissues like muscle, in chickens and was discovered by peytonrous in 1909, so it's called rous sarcoma virus. now the gene is called src because it causes cancer and we soon learned that there are only four genes in this virus. it's a very simple creature.

three of those genes, as shown in this picture, are devoted to replicating the virus, so they're essential to the virus. the src gene causes cancer, but we know from a variety of experiments that it is not essential to the virus. you can take it away from the virus and the virus replicates just fine. harold varmus and i had just begun to work together in 1970 when we looked at this peculiar fact and wondered what it might mean. why would a virus have a gene that served it no purpose? that doesn't make any sense from the vantage point of evolution, of natural selection and it's- on a hunch we decided that perhaps the virus had acquired this gene from a normal cell,

in which it replicates. and after three or four years arduous experimentation with our young college doing most of the work, that turned out to be the case. there is a cellular src in every one of your cells and in the cells of every multicellular organism. it has a normal function in your body. it is vital. when it was transplanted into that virus by an accident of nature it suffered damage, which we call a mutation and that damage converted it to a cancer gene. it was not long before this was shown to be happening over and over again with a variety of normal cells. this kind of virus had a propensity for picking up normal cellular genes and some of these genes, if damaged or mutated, became cancer genes.

this led to a general scheme. we call the cellular genes proto-oncogenes. the word oncogene means tumor gene. we had a viral oncogene in src and thensuddenly dozens more, all of them aquired from cells. all of them pirating cellular genes that in the process become mutated or otherwise perverted and become viral oncogenes. the obvious next conclusion was perhaps you don't need a virus in the picture. perhaps all cancers arise in this way. but by contrast to the virus, the mutation is introduced by an external factor like the ultraviolet light in sun that causes skin cancer,

like the chemicals in cigarette smoke that causes lung cancer. that is now a fundamental tenet. we knowit is correct and we believe that all cancer arises from the malfunction of genes. although there are many causes of cancer and unfortunately we don't know many of those causes, they all seem to damage genes or otherwise disturb their function, and that is what gives rise to the malignant state of cells, of cancer cells. there are two kinds of genetic malfunction in cancer cells. one we can equate to a jammed accelerator. these are things that drive the cells to do what they have to do but can be controlled just as we control an accelerator.

the malfunction is that the accelerator has become jammed by mutation or some other change in the cell. the other sort of gene is a break and in a cancer cell the break is defective so we call the jammed accelerators oncogenes derived from proto-oncogenes and we call the defective breaks tumor suppressor genes and you will find those terms in the new york times so i am not embarrassed to present them to you. okay so that's it, that's exactly how cancer arises. all causes funnel into this genetic keyboard and cause its disharmony. so what do we need to exploit this knowledge? we need a complete inventory. we need to know every gene is capable ofdoing this

and every one that's malfunctioning in every type of human cancer, in every individual's cancer and we're going to get this information primarily by decoding all the genes in cancers and that's something you will hear about from david haussler. this is a huge enterprise well underway. it is already informing the way we manage cancer and it is going to eventually revolutionize. to dramatize this point here's a list of the different aspects of cancer that genome information is having animpact on. i'm not going to go into the details, i'll show you the list just so you have a feeling for how long it is and how it covers everything from the identification of cause to personalization of therapy

to the improvement of clinical trials. it's every conceivable aspect of cancer is going to have- is going to benefit from the genomic approaches that you'll be hearing about. but the one we're going to focus on today is therapeutics and this story begins at the turn of the 20th century with the young biomedical scientist named paul ehrlich. ehrlich had already developed an antitoxin for diphtheria for which he eventually received the nobel prize but after that he became interested in staining human tissues with organic dyes which you got from the farber corporation and he discovered that there were some dyes that stained germs, bacteria in human tissue, without staining the tissue cells

and this gave him a vision of what he called magic bullets. he coined the term. chemicals that might attack an infectious agent while sparing the normal cells of the organism. he proceeded to do the first drug screen and eventually found such a magic bullet for syphillis which made him world-famous, but his own objective was cancer and between 1904 and 1909 he put hundreds of chemicals onto cancer cells in test tubes and never found a magic bullet. he died in 1915 deeply disillusioned telling his wife on his deathbed that he had wasted his life. now we're in a position to create magic bullets, to fulfill paul ehrlich's vision because cancer genes create therapeutic targets that are not found in normal cells

and we can attack these cells preferentially, in principle and now in practice. that is to say we can attack the outlaw cell without necessarily harming the innocent bystander. there are three approaches to this dictated by the nature of the malfunction. one: we try to shut down the jammed accelerator. we're good at that, we know how to do that with drugs. it's a growth industry and you'll hear about that. second, you might hope to restore the defective breaks. we can't do that at the moment and i don't see any hope of doing it in the near future although we might be able to revive some of them based on the nature of the damage in them. and third, there's a newly emerging approach that i call attacking from the flank

and i'm not going to go into details on that. the virtue of this is it is effective, it can be used against both types of malfunction, accelerator and defective brakes. the point is we are making remarkableprogress in this direction. so the person who's going to tell you about how to inhibit jammed accelerators is my former young colleague and you've heard about him; art levinson. and there he is, on the left with me almost 40 years ago and if you look carefully at that petri dish, there's absolutely nothing on it. [lauging] so in the wake of the aftermath of this magnificent and monumental discovery by mike and harold

that in the genome of all of us lied the seeds of your potential destruction as it relates to cancer let's- i wanted to step back and ask wellhow have we done? i think the simple verdict is we've done pretty well but there's a lot more to do but certainly mike's work opened the pathway to intervene in an intelligent fashion in terms of cancer therapeutics. so let's judge this by a couple of different criteria. first of all this is a graph produced by the acs american cancer society. it's out of date but that's okay because i'm going to really spend the rest of my remarks talking about pretty much the work after 2000

but what this shows is the people that have survival, of women suffering from breast cancer and you can see as a function of time from the reoccurrence of breast cancer what the survival rates are by five year periods as a function on the x-axis of time. so you can see that we've made some very very good progress but obviously what we would like to do is really be up here and the progress before 1998 or 99 or so basically came about through the identification and application of very powerful poisons that kill essentially growing cells with a lot of bad side effects but because of mike and harold's work and the genetic revolution and the dissection at the really molecular level, atomic level, of the structure of genes inolved in cancer

we now have, as mike mentioned, underexposed most of the targets allowing us to at least see if we can potentially intervene at a very specific level maybe even on a patient by patient level to stop the growth of the cancer and that's where i'm going to take this from now and i'm going to go through just a few slides quickly. clearly the observation that got all this going was the work that led to mike and harold's nobel prize. i need to credit mike in an additional way here. as his postdoc, one of many postdocs, mike was always extremely generous at providing his students all the research tools that they employed as postdocs in his lab so that when they went off on their careers they would have the ability to at least have the tools

to allow them the possibility of being successful unlike a lot of people arm who took a different approach and didn't necessarily make all these reagents available. mike was just unbelievably great in that regard and gave us essentially every probe from these viral oncogenes to me, to others at genentech, to see whether or not they could be useful at exposing or unraveling these latent genes that are in all of us in a form that obviously and hopefully always never will cause cancer. so one of the first things that i did when i joined the company we used one of the probes, one of the many probes that mike provided and it was a probe that represented the cancer-causing gene of one of these chicken viruses

that cause a type of cancer called erythroleukemia and we asked whether or not, way back then, there was a human version of that gene, did that gene basically reside in some earlier or primitive or native form in human cells and the answer was yes, we found it right here. this was a great technician in the lab and in 1982 these are the sequence and you can see his little comment here: "this is it. number five. woof woof" this is his version i guess of eureka. but that was that sequence. skipping a lot of other steps, some wonderful work by lisa cousins in actual oryx lab, they were able to take that little piece of that gene and kind of bootstrap their way up

and get the entire gene that was expressed and it turned out, lo and behold, jumping ahead many years that that very gene was the her2 gene about which i will now speak a bit. another important observation that was made in 1987 by slayman and ehrlich is that women with breast cancer, about a quarter to a third of them, have way too much of the protein that's incoded by that particular gene and it turns out that that protein existson the surface of these cancer cells and if a woman had this high level of this particular protein on the surface of the cell, then her prognosis was a lot worse and more dire than a woman with breast cancer who didn't make too much of this protein.

so just in a nutshell we decided then to see if we can make an antibody, these are molecules that you make to fight infections, for example, and could we target that particular protein on the surface of these breast cancer cells and if so might that slow or stopthe growth of the cancer, and i'm just gonna show you one of many, many clinical slides here we show that in women withlate-stage disease it increased survival - this particular antibody - by about 50 percent but we were interested also in askingwhether or not if applied earlier in the course of the diseasemight that antibody even be

more effective since you'retreating an earlier stage cancer there's reason to think why thatmight be the case and we think it is the case so what you'relooking at here now is what's called the treatment in the adjuvant settingadjuvant meaning really upon diagnosis surgery the earliest presentation of the disease and you askwhether or not this drug which is called herceptin,in addition to chemo, so chemo alone is this blue line andchemo plus this herceptin drug whether not improves outcomes for womenwith breast cancer who make too much of

this protein and this is the years from the trial um uh, entry and the percentage of womenwho are alive without disease. if you have diseaseafter the surgery and chemo and and you fail thoseapproaches, the disease is a very serious a very seriousconsequence. so this is the percentage of people who are alive with no disease, and you can see the addition of herceptin makes a dramatic difference and typically theway this curve is now running out since

we have this that if the disease - you can see these curves start to flatten - if by five or six years your free of disease you essentially arealways going to be free of disease, so it does seem like there's a dramatic improvement in survival by theadministration of this particular antibody that targets in a very specificway the aberrent nature that protein and i won't read this but a the newengland journal chose to write an editorial on theeffectiveness and the design of this particular trial, and the outcome ofthis trial, and i should also add that

because this is a very targeted approach um, that the side effects sideeffects associated with this drug are actually they're not non-existent but they're reallyquite mild relative to typical chemotherapy that basically goes after andkills every dividing cell. now i'm just going to end with a couple ofslides on a second uh type of cancer, and that's malignant melanoma.there about 70,000 people in the united states every year diagnosed with withwith melanoma and about 60 percent of patients have

a defect, a one nucleotide defect out ofthree billion nucleotides in the cell change in a gene that incodes aprotein called braf. doesn't really matter what it does,but it causes this protein to be extremely active in what's called the signal transductionpathway in the pathway that basically tells a cell to divide so it's kinda like this masteron switch that mike was talking about, and plexicon in collaboration leverage with roche and genentech worked very hard on the development ofcompounds that might latch onto that

altered protein and a shut it down. here's that protein right there it'scalled raf, there's the mutation that occurs and here's the the drug that wasdeveloped that shuts down that protein and the question is so what might that help people withmelanoma, and this is all... and the drug was just actually approved so i'm telling you the answer here about a couple months ago, but i wannashow you because if this projects, um, kind of a

dramatic demonstration of how this can work when it works, and it works about fifty or sixty percent of the time in melanoma patients with this mutationso this is a patient who first presents and you can see i hope, um, all thesedifferent nodules from the metastatic dissemination ofthis melanoma throughout the body. it's a very serious condition atthis point. this is after 15 weeks on the drug so we looked at this and we said, you know, unbelievable! this is like almost miraculous. here's the problem: as good of a drug as it is, look whathappens...

almost all the patients, um, regenerate their disease and and maybe we can talkabout this during a discussion just a bit. you can almost on a one-for-one basis,you know, match the nodule in the panel a with panel c so its kinda roaring back as if thecancer can overcome the very dramatic effect of the drug butfigures out ways to become resistant, so you know i wannaleave you with the sense that we're making good progress, it's notenough, but clearly we have the foundation's from the science, you'll hear moreabout this from david i'm sure,

to give me a lot of optimism if not in three to five years certainlyover the next 10 to 20 years that we'll be able to turn cancer into really a chronic disease. my last slide here is just onesentence from a recent, kind of editorial mini-reviewfrom three important investigators in the field, and the sentence i extracted here was that at this time of unparalleled promise incancer biology the biggest risk to progress may be economic. their thrust here thatin this time of really declining resourcesfor r&d,

rising health care costs, increasedcost of drug development here, that there's certainly a serious riskthat we might not be able to maximize you know all the the value that wereextracting from the science and i hope this won't be an obstaclebut it's certainly something else to think about thank you. (applause david. alright thanks, i hope the audienceappreciates that you're hearing the stuff of legend imean these these are huge, huge scientific breakthroughs that you're hearing about. (applause)

so, engineers like me are coming alonglate in trying to make a revolutionbased on the ideas that were that were generated out of that amazing time by mike and harold when it was first discovered that cancers are really caused bymutations in the dna, and here's a nice depiction of dna, it's thedouble helix the a's t's c's and g's with colored bars. it's important think about this fact that you start with a single cellthat contains the dna message that you got from your mom and your dad, and that cellcreates all the trillions of cells in your body

it's really a numbers game as we'veheard about some that those cells will undergo mutations and when one goes rogue in the fashion that was so eloquentlydescribed by the previous two speakers, then we get a disease that we know is cancer. the genome itself was a hidden mystery you know, mike could tell us the kind of ways that he approach it.you don't think about it anymore, but the the genome wastotally

terra incognita at the time that mikewas doing his work, and through art's earlier work and soit's it's exciting revolution that happenedin the year 2000 when we got our first glimpse of the genome we through theinternational consortium 20 sequencing centers all around theworld cranked through the genome sequence and produced ourfirst glimpses at this beautiful piece of work of naturethat is at the heart every one of our bodies.this was celebrated, you see this little picture here of

craig venter and francis collins withpresident clinton i won't go into the whole details, there's notime to tell the tell the side story, but there was a competition between aprivate corporation headed by craig venter inthe public effort and it was declared a tie at this meeting on june 26 when we both announced thatwe had sequenced the first draft of the humangenome. behind-the-scenes, and this is for santa cruz people, therewas a student at santa cruz, his name is jimkent who was furiously working on his computer,

and he was one of the first engineers tomake an enormous impact on genetics by puttingtogether the pieces. there were roughly six hundred thousand pieces ofdna that had come off the sequencing machines, and he assembled them into this first coherent version of the human genome, and it finished fourdays before this june 26th meeting that was prearranged.because of that, because of jim's extraordinary effort we are deeply honored at santa cruz to have been able to be the first to postthe working draft of the human genome, ourfirst glimpse

of three point seven billion years ofevolution and it was on july 7. now this chart isone of my favorite charts, and i'll say just one thing about it that green represents the total outgoinginternet traffic from the entire campus, (laughter) and you can see that what happened on july seventh was asingular event half a trillion bytes of data was transferred onto the internet inin that 24-hour period. so humanity was interested in seeingits

genetic heritage for the firsttime, and since then its become a very important basis for research in fact, jim's team and others at santa cruz have created a web-based interface to really make the genome part of the integrated web-based information exchange so thisbrings the original draft sequence up into thedigital age in a very strong way. there are hundreds of thousands ofscientists,

both basic researchers and appliedmedical researchers who access the genome. we get seventeen million hits on this web page per month so we are now a very importantpurveyor of information about this one referencedraft sequence which is now if considered finished atthis point and so it gives us a glimpse of onetypical human being. now that's a genome that's completelyintact and is the kind of genome you want in thecells in your body

but the genomes you've been hearingabout are quite dramatically different from that and so now we're in the process ofsequencing cancer genomes and we're sequencing them at a very veryhigh rate, and here's a picture of the enemy if you will, this shows how complicatedcancer genomes are the reference genome goes around likeclockwork, chromosome one, chromosome two, chromosome three and every time you see one of these redlines this means a piece... ...for example this red line means a pieceof chromosome one in this tumor is actually

attached to a piece of chromosome six, so the chromosomes have actuallybeen cut and pasted back together this line outside the red line that yousee here along the along the circle represents the numberof copies that we have for each of the geneticregions. now if it was a good genome you would have two copies. one from mom onefrom dad, so wherever this thing is not two, we havean abnormal copy number. you're looking at just one of the manymany genomes that we are now sequencing as part of the tumor genome

atlas project which we'll talk aboutin a minute, and in fact this one happens to be a brain cancer genome a glioblastoma which is a particularlydeadly disease. so what is the future? what can we learnfrom sequencing first hundreds then thousands of genomes like this? well, the hope as we've heard before, is to usethe information from these genomes to treat cancer better, and as mike said, it is an individualized problem. there areno two tumors that are exactly identical at the genetic level,so we have to think about this

in terms of looking at the molecularinformation from each tumor and making a decision, and that will notbe done one at a time. it's going to require avery large database of cases so in this picture we're illustrating the idea of personalized cancer treatment of the future in which the individual patient has a particulargenome sequence that is now obtained cheaply. the cost of genome sequencing isdropping at an astounding rate, and we're talking about a few thousanddollars now to obtain this information,

and that information is compared to avast number of other genomes that are been previously sequenced wherewe know the outcome we know what treatments were applied andwe know what works and what doesn't work and based on those comparisons the vastcomparisons in this large database we hope eventually that doctors will beable to make better decisions. now how big is this database? this is alittle bit of illustration of that we are now building a database that willbe five petabytes of data, and it's very hard, we struggled on how to visualize what does five petabytes of data really mean?well

if you take all of the written works of humanity from the very beginning of recorded history in all languages youget roughly 50 petabytes. we're one tenth of that already, ourdatabase of cancer genomes. so it is an enormous amount of data andthat's just the beginning... the project that i'm talking about whichwas mentioned by mike as well is the cancer genome project. this is theflagship project, the lead project out of the national cancer institute that's looking at ten thousand patientsit's much larger than all of the other cancer genome sequencing in the entireworld put together,

and it's organized nationally, and you seehere that there are data centers and now there's sequencing centers and analysis centers,and there's one data center and we're very very proud to be building thatright here at santa cruz. so that will hold the the data from this enterprise also from the target uh, project which is a project looking atthe five major childhood cancers and we hopethat that will grow beyond these initial flagship projects out of the nci. so in closing i think we have anextraordinary opportunity

cancer is caused by mutations in thegenome we now have the technology to read allof the mutations in the genome for the very first time, and with the community's help we canbring this information to bear on the battle against cancer. it's timethat the digital age meets cancer, and we can do this, we cando this head on at this point with the technology that we have. (applause) well now i'll actually have aconversation, (chuckles) and i'll look for some questions from the audience, but i really want to get back to this

baseline we only have to go you know thirty yearsago or so if someone had cancer there was this feeling it's your faultor uh, there was a lot of secrecy.people didn't talk about having cancer, and we've come a long way, but i think the latest change that people have is that this idea that given the role ofgenetic mutations in creating cancer, how true can we say itis that every cancer is different... ...every cancer evolved on its own withinthe individual?

well david just told you. david you wannasay it again? (mumbling) ...well that's true but.... we look at the genomes and no two arealike, there's no question about that. but there is an important point: there are no two that are identical, but there's overlap. yes there arepatterns that reoccur. there are common jammed accelerators and some common defective brakes that occur in different kinds of cancers and thatshould be where we'll focus first to try to to hit thosebecause you get the biggest bang for your buck out of that.

and we know of at least 25 or so suchthat are sufficiently common, but there are hundreds... ...well i guess that just the sample, and how many mutations are in a cancer genome it can be as high asone hundred thousand. one hundred thousand... but in that there are maybe 25 or 30 that really count and manyof those are shared from one tumor to another, so that's the ray of hope here in the face of this extraordinary diversity. that's right itisn't just random out there it's a question of what particularsequences are malfunctioning.

now you and i could have the samemalfunctioning sequence but you dropped one letter and i droppedanother letter, it rendered it inoperable, and so that's the specific thing, so we've got some commonality but we also have some differences.now one man's genetic mutation may be another man's geneticinheritance. is it possible to be simply cancer prone just from yourgenetic inheritance? well i think we can all answer that. yes, there are two kinds of, uh, susceptibility. one is what we callstrong single gene. so you

many of you, perhaps all of you, heard of the brca gene... this is a break, and if it's defective and inherited, it creates an absolutely awesome predisposition to breast cancer,ovarian cancer, and incidentally prostate cancer. so that's a strong inheritance. every generation if there are at least a fewsiblings with women, (stumbles) one or more of them is going to have breast cancer. it's a powerful predisposition, and wehave a genetic test for analyzing families to see whether that

is responsible for a family history ofbreast cancer but then we have another moreproblematic set of genes which david could comment on too i think. these are called weak predispositions and uh, every issue of the journal called naturegenetics has got ten papers with, each has forty authors, and another five weak predisposition genes for diabetes, or cancer, or hypertension, or whatever, whether we'll ever be able to use theseis a moot point at the moment i think.

there's a company called decode iniceland which several years ago came up with a rather limited, i think about seven... seven geneticchanges that they argued: if they occurred together in awoman's, uh, among a woman's genes, that they had maybe a twenty-percent risk of developing breast cancer. now that's amodest increase, but it's a level of increase that clinicians believewould justify an mri examination. the problem is that this is only present in about five percent of

women. the bigger problem is thestatistics are not good, the sample sizes have not been largeenough, the test has gone nowhere. it's highlycontroversial if not dead. david, which is it? controversial ordead? i wouldn't want to judge this one, buti agree with you that we are seeing much stronger effectsin terms of the somatic changes, the changes that weren't inherited, but thechanges that happened during the course of a patient's lifetime. that's going tocontribute the larger amount apart from these already known strong cases where there'sa strong effect.

the only thing i'll say in defense ofthese so-called genome-wide association studies, is that they often point topathways or interrelated sets of genes that, thatweren't known to be relevant at all in cancer in if they're statistically soundnow we know that they are relevant in cancer even though one of them or twoof them that are actually investigated by themselves don't have a big effect. iagree and i didn't mean to totally... i just meant torepresent the state of art. i think it's entirely conceivable that we'llcome to a point where given the power of our computation,

we'll be able to say: "oh yes! if a womanha these 400 weak changes, she better have a mammogram every year!" uh, absolutely that day may come it's just nothere yet. not here yet. thank you for indulging me, because iwanted to be (at that all) back in one line here, because now we get onto some new thingswe're doing whole genomes, whole-genome, people who've got a lot of companies now in the race to produce whole genomes so fast and socheaply, in economic terms they're saying we'llactually give you the genome

if we can sell you some services, and diagnosing and analyzing them afterward so early diagnosis is extremelyimportant in cancer and i think a lot of people want to knowwhat are the opportunities now that we're going to be able to getmore data on people, are we going, how are we goingto be able to do early diagnosis in cancer before we have a tumor? if you look at the impact of earlydiagnosis and better therapies from the last, from 1988 to 2000, which is the last segment that i've been able to comeup with, it shows that

cancer patients added four years totheir life. and part of that again is early diagnosis,because if you can catch a tumor before it is disseminates or metastasizes and you have a good chance of surgically removing it and the outcome,the prospects are generallyvery very good. and of course on top of that they're muchbetter therapies these days, not perfect but better therapies, but maybe something that we could touch onthat has received a lot of notoriety and publicity just even in the last couple ofweeks is the psa, the test for

prostate cancer. this came, this test, uh, thisis a marker of prostate cells, i mean when you have prostate cancer you have more prostate cells than if you don't have prostate cancer, and these prostatecells make a particular... secrete a certain antigen protein calledpsa that you can measure in your blood and the test was put into wide use sometime in the mid 1990s, and as result of that, the incidenceof prostate cancer

increased by so much that it actuallyaffected the overall incidence of all cancers of all type of men and women in theunited states and you look at the incidence of cancer which isactually in the last 15 years coming down slightly there's it was a nice spike in 95 1996clearly just due to what was thought to be earlier diagnosisnow the dilemma is that if you look to see how usefulthat test is even though it can be specific for prostate cancer

the the best clinical thedata says that for every fourteen hundred men to get tested in screen with psa you save onelife okay so it's not like your help in twenty or thirty or eighty percentpeople it's 1 out of 1400 and at that level you know you wanna, have to question the math at a very fundamentallevel but on the- further downside to that is it, italso generates 48 unnecessary pretty intensive operationsthat could be a surgical

removal of the prostate, it can be, you know, weeks of radiation for no benefit but a lot of cost andanguish and and no benefit. so we have to be, ithink, very careful and that i think, illustrates the the earlydiagnosis is good there's suggestions now in there'sindications that by using very sophisticated dna measurements that we can actually finda circulating tumor cell of a lung cancer or colon cell in the blood and if you find a cell or two okay you probably have cancer but where isthe cancer how do you treat it

uh... we're still a ways away, ithink, from being able to, in a general, sense exploit this earlier diagnosis by some of the more recentmolecular techniques you're just holding, you're holding themic for him. "oh yes, he always has something more interesting to say." (laughter) i just want to be able to pass the batonto the next generation repeatedly during this program uh i agree with what art said um and i can dr... but i think there really issome hope, i mean the genome may come to the rescue here because umlet me give you an example

um an example is hubert humphrey, um, herbert humphrey died of bladder cancer and when he first, when he was first seenfor his blatter complaints it was decided that he had some mildlocal disease and he was treated locally and thenabout three years later they decided well yes you actually do have um uh... a tumor, but its benign, it's not bad and about three years later they decidedthis is bad and did radical surgery and three years later he died okay if you do your arithmetic there'sover a decade, there's a lapse there

now some years ago this is all happening atjohns hopkins university some years ago, a young scientist at johnshopkins went back and got all the specimens from humphrey, including the cells from hisurine. and he looked in there for one of the premier bad breaks in cancer and it was in the very first specimensand if they had known that they would have known from the get-go toaggressively treat mister humphry and he might have survivedto run for office again so that's the sort of thing we hope willbe possible you know every

organ system in our body that hasaccess to the external world world releases cells. our bladder, our kidneys, our longs, our intestinal tract a breast fluid. so there's some hope that this so-calledmolecular cytology could be turned into a truly decisive detection but i wanna add a caveat there'semerging evidence that the, let's take breast cancer as anexample

there's emerging evidence that the mostaggressive tumors that inevitably kill matastasize at a very early stage in that even the earliest conceivabledetection maybe too late. now, i say that as a caveat not as a anestablished fact but it is something we have to bear inmind. now david there's lotta questions inhere about a databases as well as

tissue banks and that type of thing. one of the things i want you to be really clear about is the 10,000 cancer genomes you're getting,1are you getting tissue are you getting data and whatkind of data what are we talking about here? that's really important know. it's purely digital so we're talking about a digital libraryof cancer genomes no tissue the tissue is kept separately for thetcj project and other major cancer projects and that

actually frees us to be a littlemore creative on the other hand of course these arepersonal genomes from patients and and so we are enforcing thehighest level of security on these data so that only qualified researchers haveaccess to that. in this sense we are in extended armof the national institute of health in fact we are the first to it establish a relationship calledtrusted partner which is more or less invented so that we couldhave agencies like us could redistribute data

in a meaningful way to researchers. and that the gives us the bigresponsibility but it also allows us to replicate thesedigital data in a, in a way that makes it broadly all of them broadly accessible to thebest minds and and that's really the important thing wehave. when i when i talk like i go out and give speeches at atuniversities. i, you know i gave a speech at berkeleyfor example

just recently and i found colleaguesin areas of computer science in other areas of engineering just extremely excited by this. one of the most famous computerscientist in the world is dave patterson at at at berkeley and he's totallyengaged in analyzing cancer genomes at this pointand so it's a change in his career in a sense and that kind of mind thatbeautiful deep knowledge of how to deal with data,large amounts of data in the digital age is that's the mines we want to belooking at these data and working

closely with the national institute ofhealth and and the researchers who've spenttheir careers looking at data like looking thinking about cancer that those are the exactly the kind ofpeople we want to get looking at these data. ok, so, conceptually what we're talkingabout is they're not sending you any tissue we're taking tissue from, cancertumors or or cancers material if you will, whole-genome

that's right. all the dna sending andyou're storing the whole genome for digitally. there frequently should be a baseline.are we taking do we have the non-cancerous tissue? so we have the non-cancerous dna whole-genome, the cancers dna genome. yes. now we haven'ttalked about epigenetics, there's more than just thedna. who wan't to take that? that's true. well i'll just quickly say that from each patientwe get a blood sample

which tells us what the what the normalgenome is for that patient and then we get a tumor sample in whichtells us what what has changed in the tumor whetherthe mutations relative to the patient's normal genome in the tumor and then we also get informationabout the what's i think called dna methylationwhich is an epigenetic mark. it's a mark that occurs on dna that the cell puts theirand it has to do with whether this cell is going to use that piece ofdna or not.

so some genes are turned off bymethylation marks and some genes are are turned on and we can have thatinformation about each cancer patient as well. so just conceptually what's happeninghere is that we're taking a whole lot ofthings that used to be tissue or or just did a little bitwe're looking at this because of the technology we can only look at so muchthis gene or so much of this sequence. we're talking whole genomes we're talkingreference genomes, we're talking additional data

and i think what's so amazing is thatwhen you put it in a huge information-base that can beaccessed by people who have all kinds of capabilities you changeit. the very same person you're talking about, david paterson we, we forget that he and johnhennessy who is president of stanford wrote back where they were both justcomputer science types and friends wrote you know, structural architecture of computer systems text books and thingslike that gave me a couple there. john never thought he would bepresident at stanford and dave paterson

thought he would never be working inbioinformatics and so this is the kind of thing that canhappen. people who were doing things never related to that opens upthe entire process to working on things that hadn'thappened before. so when we're talking about where we going inthe future it's part of we have more people being able to workon it, not just more people doing the same thingsas ever. the nature has changed. now let'stalk about we have a lot of questions here and i'm justgonna put, throw out a few at the

different cancers so perhaps someone could pickone. we've got esophageal cancer, we've got ovarian cancer, we certainly have the prostate cancerquestion, we have many of those. on any of the thing's you're talking about are there, can anyone want to pick out a particularcancer to talk about to respond to that? go ahead art. so touching on that and also justlooking at the future of potential treatments, i'll use ovariancancer as an example.

so a lot of ovarian cancer genomes have beensequenced and one of the surprising and i think dauntingconclusions is that about one in seven women of with ovariancancer actually have a jammed accelerator. and as mike pointed out correctlythat it's in the world possibilities. it'srelatively easy to stop that jammed on we don't know how to stop thesuppressors and in the case of ovarian cancer relatively few are driven by that activeoncogene.

they have the suppressor mutations,deletions, they have these epigenetic changes and we don't really know how to dealwith that. but looking ahead the reason, that'sa, that's a pessimistic outlook. the reason for optimism, i drawback on the experience with with with hiv aids. the aids virus. like the viruses that mike wastalking about, the rna tumor viruses, that the aids virus is relativelysimple. it only encodes a few genes and the initial attempts at therapy involvedblocking

the activity of one of those geneproducts that was required for the virus to replicate and as i think everybody in the audienceknows, those therapies molecules work but not verywell. they would drop your viral load for three months six months a year but thevirus always would come roaring back because mutations. the virus would figure out how to get aroundthat particular inhibitor. we're now at the point where we havedrugs against essentially all the essential componentsof the

hiv virus, and when you hit a patient whohas hiv with, let's say, a triple combination,what's called a triple combination regimen cocktail where you're interfering right at thebeginning with three essential functions the outcome is really quitedramatic. it's, it's not a cure but people ya know, typically will live often theduration their normal life because the virus is so stopped in this replicative ability that youfor all practical purposes in many many cases

it's almost, it's effectively a cure. so, the same thing is gonna happen, ibelieve, with cancer. so we now know if some cancers, aml,all, a type of leukemia typically has very fewgenes that are activated but it's not one it it might be four or eight. other cancers likelung cancer from a smoker might have twenty or thirty years even sixty drivermutations but the way we're gonna solve cancer, in myopinion, is to simultaneously intercept three, four, or five of these essentialproteins at once

because that's gonna be able to shutdown not just one pathway but potentially two or three simultaneously but as importantly in the long run it'sgonna probably allow us to stop the resistance. because it's very easy when you have literally billions and billions of cancercells, we can go through some math but it's it's it's relatively straightforward,when you have that many cancer cells there are pre-existing cancer cells that essentially allow any given cancer thatmight be otherwise susceptible to a given treatment

to get around that treatment becausethere are so many cancer cells with inherent so if you blast it at multiple points notonly are you interrupting many of the pathways at oncebut you can then simultaneously suppress even the activity of thatrare potentially resistance l. so i think over the next 10-15 yearsthat's the way we're gonna really cure cancer but it will take some time. yeah, combination therapies, familiar to you folks,i'm sure, and this is just the latter day form of it, a form that's far more sophisticated

rational. and let me give aninteresting example there's a disease called cupra mileacidic leukemia. this disease was incurable until abouttwenty-five years ago when some scientists in shanghai discovered, we won't even go into the names, treatmentx that suddenly was able, was a was a treatment that would put thesepatients into remission but then they would relapse. so theycombined treatment x with some existing poisons

as they've been called rightfully and theygot eventually about 80 percent cures but the twenty-percent remainresistant. then they came upon another treatment, y, which actually was derived from achinese folk medicine it's a great story but there's no time to tell it. and they combined x and y and they'renow curing everybody. and you know what? x and y attacked the same molecule, the same accelerator. they justattack it in different ways so if you have to very small

risks of resistance arising in thatmolecule and you and you hit the molecule twovery different ways the risk of resistance becomesinfinitesimally small and that's why the combination cures. it'sit's combination therapy attacking a single molecule. now, art'stalking about what will usually be the case, we'll attack several molecules but remarkably this works byattacking one. and the drug glivec which isprobably known to most of you the so-called miracle drug

that is very effective against early-stage chronic myeloid leukemia butrather limited effect against the final acutephase of it. patients develop resistance to it but there are now drugs that overcomethat resistance because they hit the molecule a different way and experts like charles sawyers andal joyman are betting that when you combine the glivec andthe derivative that overcomes the resistance to glivecby attacking the molecule in a different way

you put those two together you may cure the disease just the wayapl was cured by attacking the same molecule. so the point is that we've got problems butwe also have some pretty smart people working on 'em. you know it's it's so interesting thatyou're talking about just this way because we have a number of cards here which whowere which really reacted to, people obviously reacted to your melanoma slide here and they're asking thingslike:

well is the is the protein mutating isthat dna what's what's mutating here? and if you'retalking about multiple attacks you could be, it couldbe changing was like but it's like we got to that way, turn your head again, we got to that waywe get to this way. is this sort of the the sense thatwhatever it's doing you're getting it? it's not as it's not as static, it's actually dynamic andtrying to fight back. it's darwinian. there you go. yeah it's darwinian. cancer cells

we call it they have an unstable genome. they are exceptionally prone to genetic damage and they are that way because one of the early steps in thegenesis of a cancer cripples the cell's ability to keep itsgenome intact to repair the dna when it's damaged, to to keep the cell dividing correctly,segregating chromosomes when the two cells divide correctly. thatmechanism is crippled

early in cancer and that that allowsmutations to occur more frequently and the problem just amplifies as as thetumor cell moves along its life span. as result you as art explained, in that mass large vast number of tumor cells there's probablyat any given time a change that will make it resistant tothe existing drug. it's not deliberate act, it's a randomact it's a random change in the genome butthe drug selects for it.

so this cell thrives while the others aredying and suddenly you've got a resistant tumor. and the point we're making is if you canhit the cell two or three different ways at the sametime you reduce the likelihood that one cell is gonna have resistance to all three orfour attacks that's what we're talking about. right, distinct different approach. art and then dave. so you end upwith a model for for personalize cancer therapy inwhich it's a strategy

game it really is a strategy game tonot only knock the cancer down immediately but toprevent the the recurrence the emergence of resistance and that will increasingly have complex consequencesfor for the analysis that these data also in in light of what mike was saying, yousee that once the cancer itself is prone to mutation that you'regoing to get an enormous number of decoy mutations or passenger mutationsthat as they're called. these are mutations that aren't reallydriving the cancer but can confuse a

computational algorithm that looking atall of the mutations in the genome and not and prevent it from may be seeing thetrue driver's so there there is an enormous amount of very deepalgorithmic strategy very deep computational strategy that'sgoing to have to be applied to these data before we can get real cancertreatments out of it. maybe i'll just add a little bit morecolor to the the patient the melanoma patient that i showed. mike wonderfully andcorrectly points out the examples to

the two examples of others that if you can hit a given activeaccelerator in two different ways you might very well have a much betteroutcome i completely agree with that what we're learning from some veryrecently published work in melanoma with this b raf mutation is that the resistance almost never in that particular case comes from asecond mutation or pre-existing mutation in b raf. it'salways coming fro- we can name the genes, it doesn't matter butthat they're popping up from somewhere

else and one of the, i think i'll maybe i'll justcome back to the point about the lesions the metastatic lesionsalmost like reappearing in every single case maybe it's always dangerous to do alittle bit of math the but this is simple math and it's really sobering. if you have a a diagnosis of acancer and let's say the mass is one cubiccentimeter. there's about two and half centimeters per inch, so

it's not very much. it's like a little balllike that. there are about a billion cells in that ball. now if you ask how many divisions does it take to get to abillion cells it's at about thirty. so in other wordsyou one cell divided the two, that's a division, then it goes four and eight, dadada. two to the thirtieth is about a billion, so30 divisions. now you can ask what is the mutation rate at each division? and we know fromthe enzymes that copy dna there's a mistake made about one every100 million times david can probably

refine this a little bit. probably even higher in a lotta cancersbut i'm being conservative. there's three billion nucleotides inevery genome so that means that every division they're about thirty mistakes in the best cases so you go play it out 30 divisions and now you're talking acouple thousand mutations but you have a billion cells and the waythe math, if you just, you know the numerator denominator works it's it's frightening because it says that ina mass of a billion cells

you can expect that essentially everysingle nucleotide in at least 1 of those cells will be mutated and some of those mutations are gonnagive you resistance to whatever drug you have. be it in theprimary you know protein you're attacking or who knows what else that will allowthat cell to come back. so what's probably happening my guess in in these lesions allflourishing after some creative time is that in thosebillion cells per lesion there are pre-existing cellsthat are inherently

resistant to the therapy. after 15weeks looks like "oh fantastic" you know we all can celebrateand jump up and down cause 99.9999 percent the cells are dead, but there's that one or three cells inalmost every spot that doesn't care about your drug and itgrows and grows and after three months, six months, a year, year and a half, yousee that elaboration of the of the cancer almost recapitulates the firstyou know presentation. so this is tough stuff. go ahead!

wow art did it! i'm gonna ask you one quick question here i wasgonna ask just to wrap up but this is a very poignant question before we go to the wrap-up and itsays "i'm a cancer survivor. knowing what youknow today, doesn't matter what kind of cancer.how do you want me to think about my cancer?" i don't know how to answer that questionwithout knowing a lot more. yeah. i think it's an attitudinal question. i beg your pardon?maybe an attitudinal question

about attitude. if you're wondering about the risk of recurrence it depends entirely upon the nature of the original tumor and how long yousurvived already and if you're wondering about theprospects for future therapy should you have a relapse it would again depend on the type of tumorwe have as you've heard we have new magicbullets for some but not for others.

so there are many determinants there's nosimple answer to that question. do you have any contributions there? i, you know of course, i don't wanna giveany personal cancer advice but i would say as a community we need tolobby for larger sharing of these data, we need the government doesn't have enough moneyreally to explore enough that the mutations that are beingmanifest in in all of the tumor tissues that areflowing through our hospitals every day. and a lot of, a lot of potential

data that we could get from these, thesetumors is is not available simply for lack offunding. now that we can sequence the dna we havethe possibility of collecting an enormous amount of data so i would just say advocate and if you have a if through your advocates you canadvocate for for more deeper molecularcharacterization and for those data to be stored in the database so that thenext patient maybe it's your son or daughtercan benefit

from the knowledge of the molecularchanges that were in your tumor. that's something that you can do,everyone can do this if, but we need, we really need a, a publiceffort behind this. well we haven't gotten us some fabulousquestions here the antithesis of that issaying, saying if if i give my cancer cells and they they result in a successful treatmentdo i do i get some money back? i would say give unselfishly.

there are some really great questions in the air andsome other new technologies and specific questions on cancers and i'msorry we can't get each and every one of them because they're all very valid. so let me ask you each to give onelast sort of a wrap-up whatever your lastword, we'll start with david and come back here to mike.david. well i, i'm deeply honored to, to share the stage with these twodistinguished gentlemen and it's been a real experience for me beinghere

and i'm happy to be in a position maybe to provide some computer scienceskills engineering skills to this important problem at this stage. so i look forward to very dramaticchanges in our understanding at this diseaseover the next decade. it's the most exciting time to be in cancer research right now. well i'm flanked by two people who in theend will i think allow us to solve thedisease. from, you know, mike's pioneering

work allowing us to understand the basicnature of the, the genes in a both theoretical and apractical sense that opened the door for all of usfrom scientist like david and others who are doing these genome sequences i don't know what.wer'e getting i think pretty close to a hundred a thousand actually. [arthur] 10,000 at the thecancer genome atlas project. where are we at right now? how many? [arthur] we're at about 3,000 i think. okay well

it's going so fast i lost track at around800. but obviously this is gonna then at amolecular bases tell us exactly what genes are doing what. so those the two pillars that weneed to attack and it's just a matter of being able to figure out how toattack those jammed accelerators a more daunting task is we talkedabout is to figure out how to maybe restore the suppressor functionsthe way mike nicely presented hitting it from the flank. so i think there's every reason to be

optimistic but not necessarily next year the next year but my generalsense is that we're lagging maybe ten to fifteen years behind where we were with hiv butlook how far we've come there and i don't see any reason why will be differentwith this. i'd like to bring up somethingthat's been neglected in the discussion because we've beenfocusing on therapy which is understandable. for most of us cancer is an immediate issue. can it be cured? but in the long run

if we want to truly control this diseasewe will control it by prevention. now i'm a microbiologist originally and i know the history infectiousdiseases and antibiotics were miracle drugs when they first camein they're not so miraculously anymore some stuff you probably knowwhat has reduced the burden of infectious diseases by probably ten thousand fold around theglobe over the last three generations vaccines prevention smallpox polio easels on and on

i'm not saying we have a vaccine againstcancer i'm saying we did understand the causes cancer and then we understand it we can inprinciple act to prevent it and we don't know thecause most to the major killers that is themost challenging for cancer research in my i'm opinion and i'm hoping thatgenomics will drive that field as well but so at as you hear these cabbie ox aboutprediction a brisk caveats about will these magic bulletstherapy

not be limited in their efficacyremember that there's another ray hope prevent this disease stop smoking becareful about sunlight exposure and as we identify other causes act on we have two vaccines against virusesthat cause cancer water them the vaccine against espy'sthe virus has already reducing the incidence of liver cancer around theworld the other can prevent cervical cancer up if we give it to are young

next-generation i'm so don't forget prevention that is for thelong term i think great ray of hope before i turned over to your host mikebishop art levinson david haussler thank you rose so from hubert humphrey and the and chinese folk medicine thecombination drugs and ucsc becoming a first trusted data partner at it's been ainvigorating and i think

inspiring conversation for many of us iwanna thank to all our panelists one more time david art mike and lawyerfor wonderful moderation and thank you all for coming to this year's foundation for a min see younext year and hopefully in between