Evening with Actor Richard Gere who has a fascinating new movie out called time out of mind about a man homeless. It really is a movie i wanted to make but by the end of it i forgot the man was homeless. That wasnt the issue. I was a deeper kind of yearning for a place that i was interested in, a more spiritual, cosmic voyage towards a yearning for place, for connection, for family, for tribe. Where is my place where i am valued, where i am precious . Rose lasker laureates and richard gere, when we continue. Rose funding for charlie rose has been provided by american express. Additional funding provided by and by bloomberg, a provider of multimedia news and Information Services worldwide. Captioning sponsored by Rose Communications from our studios in new york city, this is charlie rose. Rose the lasker awards are among the highest honorsiin science. They recognize individuals from major advances in understanding, treating and preventing disease. Lasker laureates have won nobel prizes in the last seven years. Evelyn witkin is joining us, Ground Breaking search on dna that helped shape modern genetics. Also Stephen Elledge of harvard university, he built on witkins work uncovering dna repair, a mechanism that protects the human genome. Pleased to have both at the table. Welcome. Thank you. Rose great to have you here. Pleasure to be here. Rose you will receive the awards tomorrow. Yes. Rose tell me about you and how your career, why this direction . I was a graduate student at columbia. In 1943, i read a paper that came out by two scientists and they established in that paper that bacteria have genes like other organisms, and that hadnt been known before. Rose in 43, they did not know . They did not know bacteria had genes. And i got very excited when i read that paper because it seemed to me that bacteria would be a wonderful material for genetics. Rose to study genes. To study genes, because they divide every 20 minutes, and you can hold a billion of them in one little test tube in your hand, and that my advisor, my professor at columbia, saw i was so excited about the bacterial developments, he suggested that i do my ph. D. Dissertation research with e coli instead of fruit flies, and ealso suggested i should go to Cold Spring Harbor for the summer because thats where bacterial genetics was being born, and i could learn to handle e coli and come back to columbia and do my research with e coli. So i went to Cold Spring Harbor, and it was a wonderful place to be at that time. And you could feel the stirrings of the revolution in molecular biology beginning, and there was much excitement about the new developments both in bacteria and in badg in bacteriaphageh exciting genetics coming out of those studies. So i started out by discovering a radiationresistant mute pt, and it was unexpected and diverted me from my original plan looking to induce mutations with chemicals, and that became the subject of my ph. D. Thesis. Rose you would induce the mutation by radiation . No, i had planned to study radiationinduced mutation, but my first day in Cold Spring Harbor, the very first experiment i did, i discovered a radiationresistant mutant. Rose i see. Why was that important . Well, this was in 1944 and some of the physicists involved in the Manhattan Project were quite interested. Some were in Cold Spring Harbor. A few of the physicists who had worked on the atomic bomb decided that they were disenchanted with what they had brought and switched to working in biology. Rose and their interest and curiosity was in the effect of radiation . Well, the fact that a single mutation can increase resistance of an organism 100 fold, they knew i didnt know i didnt know, but they knew the bomb was coming and the use of the bomb would expose populations to a huge amount of radiation. Rose as it did. So the idea that you can have a single gene mutation that greatly increases resistance to radiation was interesting to them. At any rate, i studied that phenomenon. I got my thesis, i got my ph. D. Then i started to think about how mutations happen. The first thing well, one of the ways that i worked was to start out with strains that require something to grow, like an amino acid or some other component of their nutrition, and look for mutations that no longer required that growth factor, that was easy to select, because if you just leave out the growth factor, the ones that have lost that requirement will be the only ones who could grow. And, so, that was a system that i used. And the first thing i did i was using ultraviolet light as the source of my radiation, and we didnt know yet, but we found out in the 50s well, a little bit later than that, in the late 50s that what ultraviolet light does to dna is to fuse or connect two of the dna Building Blocks that we call bases, and theyre normally not connected to each other in the fact that they get connected stops the recommendation of the dna. The copying enzymes that usually go quickly through dna making a copy, theyre stopped by that kind of damage. Thats the kind of dna damage that is lethal unless something either repairs it or tolerates it somehow. And what i was trying to well, what i did begin to find out was that there was a repair mechanism that i couldnt identify biochemically at this point, but i could see the effect of it. I could see that it was eliminating the mutations very rapidly under certain conditions. And a few years after that, a repair mechanism was identified biochemically. It turned out to be the same ine i had more or less observed in action, and thats called excision repair. Rose so from that discovery about dna repair, what happened between that time and today . What do we know now thats on the course of learning . We know there are very many different kinds of repair. I wont describe them all. But i guess what im known for, what the prize relates to is work i did thats called the s. O. S. Response for my part in discovering the s. O. S. Response. The s. O. S. Response and the term s. O. S. As used in its usual meaning to have the International Distress signal, a bacterial cell that has this kind of ultraviolet damage that stops the copier is in distress. What i learned was something happens in that cell that the damage itself and the stalled replication generates a signal that turns on a bunch of genes. We didnt know how many, yet we now know its at least 43 different genes that are in the healthy cells but they dont make the product, they just sit there. Rose in the healthy cell. In the healthy cell. But in a damage cell, they get turned on and they make all their Protein Products and they go into action, and what they do is, in a number of very diverse ways, they help the cell survive. They repair damage. They get the replication going again, and the way they do that, one of the gene products thats induced at that point in the s. O. S. Response is another dna copier that isnt stopped by this damage. Its one of the scientists who worked on it calls it a sloppier copier, and its not so fes festidious. It gets by the damage by inserting any base in that position, and chances are that it will be a mistake and a mutation if the wrong base is inserted in the dna, that is a mutation. Rose and the consequence of all that is for us . The consequence is, first of all, we learned that there is the phenomenon of induction of many genes when you have genetic damage and, of course, what happened after we developed this system and described it in detail that Steve Elledge who is going to speak after me picked up where we left off rose saw what you had done. He didnt just see what we had done, he took part in what we were doing. Hes about 35 years younger than i am, were of different generations but have the same interests. He was a graduate student at the same time i was working on the s. O. S. Response and he was working on the s. O. S. Response in his graduate work. He did valuable work that rose let him pick up the story from there. Okay. Rose go ahead. Because the way he picked it up will answer your question about what the significance is now he brought ut to the human level. Rose congratulations. Thank you. Rose so youre there as a graduate student. Right. So i did my ph. D. In graham walkers lab and graham worked on the s. O. S. Response and, in fact, i was the person who identified the gene for the sloppier copier. That was my thesis, so i was very familiar with evelyns work and the whole concept of the s. O. S. Response as a graduate student. And then i got my ph. D. , and i went to stanford, and i was going to work on something completely different. I was interested in plants, i was interested in trying to figure out how to m manipulate human genes, also, so i had multiple interests. I was going to follow up on graduate work, i never intended to, always seems like you should do something different. So i started looking for genes that might be involved in letting us manipulate human genes. Rose right. Something thats very exciting now. And i failed to find that gene that i was looking for but i accidentally cloned another gene, and this other gene that i found turned out to respond to dna damage and recommendation problems. It was a gene involved in making nucleotides to make dna, those are the Building Blocks. And i realized that, well, you know, at the beginning, you know, there was all this great work in bacteria, but people in bacteria, you know, sort of didnt work on eukaryotes, the cells that we worked on. It wasnt at all clear that the same pathways would actually be functioning there. Rose were they . Similar, but different. So it wasnt this take it here and put it over here. What we found was that they had developed a competely orthoginal, sort of different system to sense problems at dna recommendation forks and transmit that into information. So what i discovered were the genes and the pathway in human cells, eventually, starting in yeast, but that actually are scouring your genome looking for problems and when they find the problem they set up a signaling apparatus thats sort of like sending out radio signals to the ambulances that come in to try to deal with these problems. As evelyn had discussed earlier, u. V. Light makes a specific type of damage and there is a specific type of pathway that can snip it out and fill it in like a pothole and move on, excision repair. But if you have a problem thats in the process of duplicating the dna, and that means youre taking the dna apart and copying it, thats a much more severe problem, and when that kind of a problem happens, you need a very sophisticated response. So the response that i found was sort of the equivalent of the response in bacteria which we know existed at the time, and that turns out to alert and activate a lot of different sorts of pathways that result in the survival of the cell. They do a lot of other things, too. For example, you know, since were working on humans now, we know what the effects of losing these genes are. So if you dont take care of your genome, you get mutations you get rearrangements and you can get cancer, you can get developmental defects. Rose how do you take care of your genome . You have a monitoring system. The dna has the ability to sense its own integrity. It has evolved the ability to know when it has a problem. Rose a malfunction. A malfunction. And it calls in the troops. Some of these troops are very dangerous. Some of the enzymes that you dont really want around all the time. So you have to turn them on at the right time in the right place. Cells cant see. They have to feel their way around things. So there has to be something that says, okay, theres a problem here i need you guys over here now to fix this, not yesterday or tomorrow, now. And they get through. Because the human genome is very, very complex. Rose this is all an Automatic Process in the human body or is it from outside . Its an Automatic Process in the sense that we carry all these genes that have evolved to sense the presence of dna damage, called the dna damage response and to alert the rest of your body. Now, i said earlier that, you know, in terms of human health, some very subtle changes in the pathway can lead to serious developmental disorders. But the you take the pathway altogether, you cant even duplicate a cell. Its that important. Every time you duplicate a cell, there are problems. This pathway is always monitoring things, saying, okay, we have to fix this and that, so life itself doesnt exist without this pathway in mammals. The other thing about it in terms of human health, this pathway, if there is too much damage, you make a decision to kill the cell, and that prevents cancer, and it can also cause another process called senescence and thats when the cells dont die but permanently quit dividing. These cells are controlled by our pathways that we discovered and accumulate as we get older and actually contribute to aging. Someone did an experiment where they eliminated the cells from the mouse that was rapidly aging and the mouse did not age. So its sort of the ying and i cant think sort of thing which is it takes a cell thats been damaged out of the chance of it becoming a cancer cell, but it leaves it there, and that leads to a problem thats involved in inflammation. These cells promote inflammation which is a problem for a lot of agingrelated diseases. So thats a pretty great experiment. Our pathway helps control that process. Rose whats the future of that . Well, its interesting. There have been companies that have sprung up around, trying to understand aging, calico out of google, and i have a paper coming out in science in two weeks that describes a new protein, its the switch that turns on the inflammation itself. Rose if you can cut that switch off thats why we have to ask the question does that stop things. Rose if there is something a cell that turns off or turns on inflammation, if we can figure that what happens there and can then turn off inflammation that presumably would help us a lot and we can prevent aging. This is still a theory but thats the theory people are working on now to try to test. If you get rid of the senescence cells, youre better off in a mouse. Isnt done it in a person yet. But if you just turn off the inflammation part, do you get better and thats what were trying to figure out. Are you still going to prevent the aging. Thats the theory. We found the switch that does that and we can genetically manipulate that in mice and sphee this is a part of the aging process or not and its a target we can potentially effect. Rose where might all this go . In other words, if we can repair genes, we can edit genes, some people look at that and they say, you know, lets look at this very carefully because what we could do you know, what do they mean when they say look at this very carefully . Well, tinkering with genes is not something we want to do per promiscuously. Rose because . Because we havent got the knowledge to be sure of the consequences. We have to take this very slowly and very carefully and be aware of the risks. Rose and who makes sure we do that . I think the field itself. Rose selfimposed. Yes. I think we have a pretty good record for regulating our own activities. In many tech notle that have been technologies that have been developed, theyre great in the lab. The question is what happens when we start doing it in people and thats where we have to be extremely careful. These tools are not perfect, and, so, they need to be very carefully managed and their consequences have to be looked at. Rose thank you and congratulations. Thank you very much. Rose thank you. Thank you, charlie. Great to be here. Rose back in a moment. Stay with us. Rose joining me now is James Allison of the university of texas. He found a lifesaving Cancer Treatment that harnesses the immune system. Glad to have him joining us as one of our lasker award recipients. Congratulations and glad to have you here. Thank you. Rose what is immune therapy. Using t cells to go after cancer and eliminate it. Rose what are t cells. The warrior of the immune system. They can attack cells affected by viruses and kill them and detect tumor cells as well that express things on their surface that are not supposed to be there. Rose and what drew you to them . Well, when i was in college, the t cells had just been discovered and nobody really knew how they worked and that to me was a fascinating thing that you could have these cells that travel all throughout your body and look for things that might hurt you. Rose and attack them . And attack them. Even though theyre things that theyd never seen before. Rose yeah. And, so, my first question which i meant to start with really is what drew you to medical research . As a boy growing up in south texas i was always interested in biology. My father was a country doctor. He did house calls. He encouraged me to be inquisitive and supportive. I thought about being a doctor for a while, but i realized from watching my dad and other doctors, that they have to be right all the time. They have to be able to diagnose and treat properly. I figured out early on, if youre a scientist you only have to be right some of the time. If youre wrong, you move on. Rose thats right. Immunotherapy, i hear this term in terms of lots of cancers. Its real serious. It comes with respect to some of the attacks on brain cancer now in terms of using polio virus. Yep. Rose is this the coming field in cancer . Well, i would say it is because the immune system can attack all cancers. The drugs i have developed, they unleash the immune system. They dont treat the cancer, they treat the immune system and unleash it to go and attack and conceivably can work against all kinds of cancer. Rose and remind me specifically why the lasker people and youre appearing at a Conference Im having later with a group of scientists, when you mention immunotherapy and Cancer Research your name is at the top of the list for a good reason. But explain to us exactly how you came to discover what you did. Well, i was interested in understanding how t cells, what turns them on, how its regulated. Rose let me interrupt you. Its a very interesting idea to me, and this is a nonscientific question, is the idea of cells being turned on and turned off. Mmhmm. Rose thats a remarkable idea that somehow cells which are allpowerful can be turned on or turned off. The immune system, you have to turn them on and you go from youve probably got 100 million t cells with different receptors kind of like the ignition switch, they can recognize different things. But when there i