 First of all, thank you for Dr. Bishop for watching a marvelously informative and amazingly clear talk, just beautiful. Our customers to allow the other panelists to have the first opportunity to ask questions, so we have anyone on the panel with a question at this point. Dr. Callahan. I remember back in the 1970s sometimes the famous physician writer Lewis Thomas proclaimed the end of infectious disease and we would soon conquer the diseases of aging. Of course that didn't happen, he died of cancer. I guess my question is, what are we supposed to learn from evolution? It would seem to me with the difficulty with cancer, the diseases of aging is we seem to be actually fighting evolution which appears to want us dead sooner or later. And the question is, it is a fundamental question as to what extent should that process go on? Should we resist? Is it a lesson to be learned from evolution or can we ignore the lesson even if it's there? Well, there are many lessons to be learned from evolution. I'm not an evolutionary biologist but I think it's generally agreed that the central tenet of evolutionary quote, the theoretical part, is that evolution doesn't care how long we live, it cares how well we reproduce. And once we reproduce, we're left to our own devices. So the interesting question becomes, is that genetic, I took the line out of my talk. There was a line in my talk which says there was literally a genetic program for aging. That's a misapprehension actually I think. These genes are there to serve other purposes. They're there to sustain a vital organism so that it can reproduce. And once it's through the reproductive age, evolution has done a thing to protect us against type 2 diabetes for example, which is a disease of the aging. Nor has it done a whole lot to protect us against cancer, which is primarily a disease of the aging. So the lesson we learned from revolution, I think, is simply that if we're going to do things to the human organism that would extend its reproductive life, then we have to think very seriously about the impact on our species. I worry less about the impact on the evolution of the human species, and I worry about the impact on our society, some of the things I talked about near the end. Incidentally, the newest Thomas made a lot of predictions that were wrong. And I also illustrate some of my own fundamental beliefs which I violated a couple of times this morning, scientists should not make predictions. Any others? Dr. Osterholm. Thank you. In the terms that you laid out today, it's exciting from the standpoint of thinking our immortality or the potential thereof. And it's ironic, coming from the medical profession as you do, that the one thing that's really given, and I guess depending on your religious beliefs, this has been true, that death is inevitable. Death is going to be an eventual outcome. Everyone in this room will die one day. Given that, I would like maybe to think about or respond to the issue that, in fact, we're trying to avoid death at the cost of possibly creating a different death that may be much worse than the death we might otherwise have anticipated. Meaning, the top ten causes of death that exist today, if we eliminate them, there will be ten new ones. And I'm not so sure some of the new ones are going to be a lot worse than the ones we have now. How do you see the construct of genetic engineering, that whole issue you're talking about, playing into that discussion of maybe it is our time, maybe it is the way we want to go, and therefore we shouldn't monkey with it? I have my own reservations about monkeying with it. That's why I raised the issue at the end in a very telegraphic way. Do we really want to interfere with the natural human cycle of youth, reproductive life, and aging? Because we don't know what would lie ahead if we extend our lifespan so dramatically. But of course, we're doing that now. The incidence of mortality rate from cardiovascular disease is dropping fairly dramatically, and we'll probably continue to do so in a gradual way. And we do really do see the prospect of both being able to more effectively treat and eventually prevent the major cancer killers, which is the second most common killer in the developed world. So we're going to face that under current circumstances, and so we're going to have a population that is increasingly aging into the range of senility. Now one thing I didn't mention about, well I didn't mention it, but I didn't extrapolate. This course is highly speculative, so much of this. I just wanted to illustrate the possible prospects that the genomic era raises. The worm and the fruit fly, although it's not easy to assess their quality of life, there are certain features of them, certain properties that designate their aging. You can tell, if you take a random population of these old earthworms, you can tell the ones that are aging and nearing death. In manipulating these aging genes, the animals that live longer do not display those properties of impending death until very close to death. They remain properties of impending death. And very recently there's been some work, just one or two papers so far published in the journal Nature, which clearly link cancer with the aging program. And so the thought is that, it's a very provisional thought, that if you were to extend lifespan in a certain way, you could do it without these dreadful aspects that we associate without premature aging, if you will, what would become premature aging. But we just don't know enough to answer your question with any assurance. It's clearly on our minds, and I think we have quite a bit of time yet to think about it frankly. Dr. West? The question from the audience here, is 30,000 genes enough to code for a human being? Besides multifactorial inheritance and multiple protein encoding, is there another source for biological variability? Well I mentioned the epigenome, which is a very dramatic source for biological variation that we don't fully understand yet. But it's going to greatly increase the capacity for diversification of the genetic program, of expression of the genetic program. We're also coming upon other features of the genetic apparatus that are totally unanticipated. So the simplest answer to your question is, yeah, 30,000 genes is not enough, it confounded people, absolutely puzzled them when it was first discovered, but bit by bit we're finding it's only part of the story. So in essence the puzzle of how our complexity arises is unsolved. We have another question here. If we target adult stem cells that may be cancerous or precancerous, what about the susceptibility to normal adult stem cells? Might they also be susceptible? Well no, not if we're using targeted therapy. It's the same principle I illustrated for you with those four examples. The cancer stem cell in principle, again this is provisional but we have good evidence for it in leukemia. The cancer stem cell is different than the normal adult stem cell. It's carrying at least one if not more than one genetic abnormality and just as with the mature tumor cell, the ideas to develop therapies that attack the genetic abnormality in the cancer stem cell, the adult, and not the normal adult stem cell. So it's the same principle just applied to the cancer stem cell rather than to the mature cancer cell. We have another question. Your lecture focused heavily on the genetic components of cancer and cancer treatment. Can you comment on the immune system research being conducted as both a causative agent and potential disease therapy? The only role the immune system plays that we know can play in the genesis of cancer is when it is deficient. And I can illustrate that with patients who are immunosuppressed because they receive transplanted organs. They are susceptible to certain tumors that are caused by viruses and they're susceptible because their immune system is not counteracting the viral infection. One of these is forms of lymphoma that are caused by virus called Epstein-Barr virus that many of us are carrying in ourselves for the rest of our lives. And it doesn't bother us, but if our immune system is suppressed, then this virus can cause lymphoma in a certain number of us. Another example is Kaposi's sarcoma, which occurs mainly in patients with AIDS and because the immunosuppression of those patients has affected the ability of a certain herpes virus to infect them and elicit this tumor. The same thing is true of cancer of the cervix, which is the incidence of cancer of the cervix is elevated in women with AIDS. And that's because cancer of the cervix is caused by infection with papillomavirus. And these individuals are more susceptible to the infection and the consequences of the infection because their immune system is suppressed. Using the immune system as a therapeutic has been a dream for five generations. And until now it doesn't approach a practical reality. I think that's all I need to say about it. It's still under avid, it makes the press about once a year use the same tube or three people with yet another way to do it, but it doesn't approach a practical reality. That's another question. Are disease bearing genes present for a reason? Will elimination of these genes possibly have a deleterious effect? I would think that's unlikely. They're not that common. There's no evidence they've been selected for. In fact, from their rarity in the human population, it would appear that they've been counter selected. So I doubt very much that eliminating these genes is going to have anything but a beneficial effect. And let me repeat that we can eliminate this kind of gene in ways that are, for much of our population, entirely acceptable. Because it's done, it's already done by as part of what's called pre-implantation diagnosis. If a fertilization is done in vitro as an assisted reproduction, when little embryos reach the size of about eight cells, this has been in the press recently because people are making stem cells, trying to make stem cells this way too now. One day embryo reaches about eight cells, the reproductive scientist or physician just takes one of those cells and can do the diagnostic test to look for hemophilia gene if hemophilia is in the family. And if it's present and it's acceptable to the parents, that embryo can be discarded and another one tested until one is found that doesn't have the deleterious gene. So that's already a practice, pre-implantation diagnosis. So to sort of repeat, if you look at all of the evidence, it would appear that disease genes like that have been counter selected rather than positively selected. There are few exceptions. For example, there are certain blood diseases, the best being sickle cell anemia that provides some protection against malaria infection. And indeed, the frequency of that disease is of sickle cell is higher in areas where malaria infection is endemic. But we have ways to get rid of malaria if we were just willing to apply them universally and bear the expense. And then I believe probably that there would be no further selection of advantage to having sickle cell anemia. It's a dental disease and it's been counter selected in those populations that don't have to bear a malaria burden. Dr. Oster, how did you? No, actually the comment that Dr. Bishop just made about a good example of sickle cell anemia, there are those very rare instances where a deleterious gene does have a benefit and part of our job is going to be understanding when that occurs, but I agree with him. It's a very, very rare situation and it usually is an evolutionarily evident kind of gene situation. But let me point out that all of this you're questioning and the answers indicates how even in the consideration of disease and disease susceptibility, something that seems so pragmatic, evolution, the existence of evolution and our understanding of evolution is so important as a theoretical underpinning. There's a wonderful book written, you may remember Jim, about the evolution of disease and the role of evolution in generating disease and preventing it. Evolution underpins everything in biology and biomedicine. I think it was Dubjonsky once said that you can't think about biology without thinking about evolution, it's just impossible now. And in fact, just one follow up on that, when you think about it, if you trace back our human ancestry, we go back about 80,000 generations to the caves. And throughout that time, many evolutionary selections occurred that were related largely to a world of infectious disease as a life expectancy of less than 40. And it's only been in the last really 100 years that we've had this major change in who we are as humans, and yet that program has already been there. And I think that what Dr. Bishop is really pointing out to us is very important, that in fact we're monkeying with a lot of history that we don't really understand yet that occurred for a very specific reason, and now it's our job to figure that out. Even though we live in a world very different than we did even 5, 10 or 15 generations ago. Well, I think it's about time to give one last round of applause for our panelists. We will break for lunch, and we will reassemble here at one o'clock.