Disease Models & Mechanisms 3, 672-675 (2010) doi:10.1242/dmm.006882 A MODEL FOR LIFE © 2010. Published by The Company of Biologists Ltd

Targeting : an interview with Tyler Jacks

Tyler Jacks is one of the world’s foremost experts on mouse models of cancer and has pioneered the use of in the mouse to construct more accurate pre-clinical models. Here, he discusses his early influences and motivation, and his hopes for the future of cancer research.

he development and exploitation fond feelings towards MIT based on those of mouse models of human cancer early connections; it was somewhere very has led to fundamental break- familiar. My brother was an undergraduate throughs in cancer research. here as well. Throughout his career, first as a postdoctoralT fellow in Robert Weinberg’s And your mother was an actress? laboratory and then as an independent She went to Yale drama school and the researcher, Tyler Jacks has made key contri- American Academy in New York with the butions to this field. He made and studied intention of being a full-time professional mice lacking the (Rb1), neu- actress, and then got side tracked into rofibromatosis (Nf1) and p53 tumour sup- starting a family. But she lived out her pressor genes, and latterly engineered novel interests in the theatre by teaching drama

DMM mouse strains that accurately mimic human at the private school in our town and both in their and their directing and acting in community theatre. symptoms. Mice developed in his laboratory are used around the world to study different Were you never tempted to follow in her types of cancer, including lung, pancreatic, footsteps? colon and ovarian cancers, and his work has I did my share. Nothing that you would ever helped to define new approaches to studying have seen, I assure you! what we’re talking about is rooted in the cancer in an intact animal. In 2001, Jacks was work that has been done by us or by others appointed director of the Massachusetts What I’m leading up to is that there has in our lab, so it’s not made up, but never- Institute of Technology (MIT) Cancer always been a certain air of self assurance theless I think you do put on a performance. Research Center, and has overseen its recent about you, so my question is: is this real So, in that sense, the version of me that you rebirth as the Koch Institute. Under his or feigned? And if it’s real, where do you see is perhaps different from the day-to-day leadership, the Institute is moving into a new think it comes from? version – an amplified version. I don’t think building, scheduled to open in December Well, I would say that I do go into situations it’s a completely different person. At least I 2010, which will be home to a unique inter- with confidence that things are going to work hope it isn’t. disciplinary group of cancer biologists and out, but I’m not sure where that comes Disease Models & Mechanisms engineers. from. I guess I’ve had successes in school and Science is supposed to be a meritocracy, professionally, which built my confidence. I but the people who seem to be the most Tyler, you’re currently director of the don’t think it necessarily derives from the successful are often the good communi- Koch Institute at MIT, but you also have fact that my father was a university professor, cators. Do you think we should pay a lot a family connection to MIT, don’t you? although that probably did make me more more attention to that in training scien- My father was a professor here in the Sloan comfortable with academic life – I could tists? School of Management. He started in the envision what it would be like to move in There’s no doubt that being able to com- late 50s before I was born and was on the this direction. So, that may have influenced municate makes one’s visibility greater. faculty through the mid-80s. He retired my perception of things and people’s per- People who can communicate are asked to about the time I finished college. I didn’t ception of me. Your question about my present in different settings, and that gets grow up near the campus – our house was mother is probably relevant in that, in our their name and their work out there. I about 30 minutes away – but I did experi- business, communication – being able to learned how to organise material and ence the campus at some level and I had describe what you are doing, or performing, present it most effectively from both Harold if you will – is important, and I certainly Varmus, when I was a PhD student, and Tyler Jacks is Director of the David H. Koch Institute inherited a lot of that stuff from my mother. from Bob Weinberg, during my postdoc. for Integrative Cancer Research at Massachusetts Bob goes out of his way at the beginning of Institute of Technology (MIT), the David H. Koch So you’re a performance? Is there a each year to talk to the trainees about the Professor of , a Daniel K. Ludwig Scholar and a different Tyler somewhere? importance of giving a good talk, echoing Howard Hughes Medical Institute (HHMI) Investigator. I think that all of us are performing when what we’ve just been discussing. It’s really e-mail: [email protected] we give public presentations. Obviously, not meritocracy, it’s that plus those indi-

672 dmm.biologists.org Tyler Jacks A MODEL FOR LIFE

viduals who can most effectively commu- because I’d worked as a rotation student on work until winter ’91. There were incre- nicate what they are doing. a project about ribosomal frameshifting, I mental advances – we were able to make Parenthetically, I also think that scientists went off in that direction. To be honest, I ES cells with targeted mutations after some have an obligation to explain the impor- knew I wouldn’t be doing that long term. It time, and we were able to derive teratomas tance of their work, so not only should we worked like a charm and it was a great expe- from them, so we could do some work on be giving good talks to our peers, but we rience and I enjoyed it and learned a lot in those. Then we could make chimeric mice also need to be able to communicate in the process, but it was something of a from which we could derive fibroblasts, but order to convince the public in general stepping stone. It really wasn’t medically it took until the winter of ’91 to get germline about the importance of their investment oriented enough for me. transmission. I hadn’t published a paper in in research and the value of research to Bob’s lab when I went off on the job market. them. It’s certainly been said that we as a “I’d like to cure somebody! If community are not nearly as effective as we Was there a point when your resolve need to be in explaining to the lay public I could feel that I had cured faltered? and government officials why what we do just one person I would feel I didn’t lose hope. I was confident that we is important. I’ve tried to do that to a satisfied. I’m being slightly would get there. I knew that it should work, limited degree but, frankly, I need to be as there was no reason why it shouldn’t. doing a better job of it myself. facetious there but actually Others had succeeded with other genes by I’m serious” then. It was early days; it was one of those I’d like to turn to your career now. You situations where technical improvements started off as an MD/PhD student? After graduate work with Harold were likely to happen, and did. I simply Not exactly, but you’re almost right. When Varmus, you then went off to postdoc in employed the new methods – like using I left college I went into the UCSF PhD Bob Weinberg’s lab. What made you isogenic DNA, for example. Anton Berns’

DMM program, but, shortly after arriving there, I choose Bob? lab made the discovery that isogenic DNA started interacting with two people, Dave It relates in part to what we were just talking made a huge difference in targeting effi- Cox and Don Ganem, both of whom were about. You recall I had gotten very interested ciency, so we adopted that method and, involved in the MD/PhD program. The in tumour suppressor genes. The very first sure enough, we went from having 0 out of program was of interest to me because I had work from Web Cavenee came out in the 6000 clones screened by Southern blotting always been interested, if not in practising mid-80s, and then there was a flood of other to 10% targeting efficiency. medicine, in just learning about it. They both papers demonstrating the importance of encouraged me to apply to the program, and this new class. Weinberg’s lab had cloned the Have you any advice for someone in that I got in. However, by the time I was accepted Rb gene, and and Martin position now? I’d already begun my work in Harold’s lab Evans and others figured out how to target It’s a good question and I struggle with that and so, rather than jumping into the medical mutations in ES cells. I put those two things in my own lab, because there are plenty of school training, I decided I would finish my together, and decided I wanted to make an projects that are technically challenging PhD with the expectation that I would then Rb-. So, then I had to think and will never yield anything, and projects go to medical school. But when I finished about where to do that and, being from that are fraught with misfortune and will the PhD I was sufficiently happy with the Massachusetts, I was inclined to move back. never pull out of that downward spiral. In research that I decided to blow off medical Weinberg’s lab had just cloned the Rb gene, those situations, you want to tell the Disease Models & Mechanisms school and just do a postdoc. and Rudy Jaenisch’s lab upstairs in the postdoc to cut their losses and move on to Whitehead was setting off to use ES cells to something that will be more productive, So you never got to poke any patients make targeted mutations, so the environ- and I’ve done that on occasion. On the with needles or anything? ment seemed to be a good fit. I wrote to Bob other hand, I have postdocs and students No, I had zero exposure to patients. I did and met him at a meeting and discussed this who are stuck in a situation not unlike mine, have a name tag though: ‘Tyler Jacks, idea, which I later learned he did not think where I’ll give them a lot more latitude and Medical Student’. I wish I still had it but I had much merit, but he accepted me anyway. time to try to make it work. lost it. It was a rough road; it took quite some time to succeed technically, and I give Bob great Is it an intuitive thing then, with you? Did your interest in medicine inform credit for not pulling the plug and com- I think it probably is, yes. I think you use your research choices? pelling me to do something different. your best judgement. You have to take into I think so, definitely. I’m obviously inter- Fortunately, I really did want to do it, and consideration all the contributing factors, ested in basic biology, but for me the clinical we ultimately were successful in creating the including what the potential outcome or the relevance of what we do has always been Rb-knockout mice, and in time the p53- and potential value of the research is: if this important. My first several months in Nf1-knockout mice, and that then formed works will it really make a big difference? Harold’s lab were directed towards finding the foundation of my own lab. Will it be worth a couple of years of my life? the Rb gene, because I was already inter- In the case of the tumour suppressor gene ested in tumour suppressor genes and So you had a tough time as a postdoc? knockout project, I felt really committed to cancer genetics back then. The Rb gene- I arrived in the spring of ’88 and I left in it and wanted it to be the beginning of my cloning project failed miserably, and the spring of ’92, but things didn’t start to own independent career, so for me it made

Disease Models & Mechanisms 673 A MODEL FOR LIFE Tyler Jacks

a big difference, and I think for the field it perfect; at best they’re going to address depending on the project, we also have was important as well. That wouldn’t nec- facets of the human disease, and for that they clinical collaborators. That makes a big dif- essarily be true for every project. should be quite useful. All of us in the mouse ference in thinking about aspects of trans- modelling field need to maintain that per- lation from our discoveries to potential Do you miss benchwork? spective. clinical uses. It’s something that’s happened I do miss it on occasion, although I’m not to a limited degree at present and really tempted to go back. At this point I I know from talking to clinicians that something that I would like to enhance in don’t think I would be very good at it and, they get very annoyed with basic the future. I actually think that the models practically speaking, it would be very hard researchers who produce mouse cancer are now pretty well developed and that to do. I’ve seen people try to do it in a part- models without reference to the human there are even more opportunities for that time way and it’s usually a disaster. And I disease. kind of clinical translational aspect. find running a lab is pretty fulfilling. I enjoy Well, I think I’m probably one of those basic watching the process unfold for students researchers! If you take lung cancer, which How should you go about advertising and postdocs, watching their results come we work on a lot, we’ve engineered mice with yourself to clinicians? in, watching them succeed in developing a mutations in lung-cancer-relevant genes, I think by making it clear in presentations project and making discoveries. I feel like like Kras, which is mutated in about 30% of at meetings and so forth that this is where I contribute to that at some level but really non-small-cell lung cancers, and p53, which we’re at and this is where we want to be. it’s about watching them do it. I find that is mutated in perhaps 50%. So, at one level, Being in Boston, we have a lot of clinical very satisfying. that answers your concern. But even so, colleagues in neighbouring institutions who we’re modelling only a subset of non-small- are also interested in these kinds of collab- Is there a secret to recruiting and cell lung cancers, and we’re not talking about orations. The new Koch Institute likewise running a good lab? lung cancers that have accumulated multiple has as a real focus the translational aspects

DMM Well, I vet my people very carefully. I think driver mutations in several genes over the of our work, so, in addition to bringing it’s important that one is careful in doing course of many years of exposure to cigarette science and engineering together for cancer, the homework, making sure that the person smoke. I can understand the concerns of the we’re also trying to move beyond discov- has the background and credentials and people who study the real disease, because eries to applications. We’re advertising the personality to succeed. It’s only a fraction what we have done is very different; we whole institute at that level, and that of the people who apply that eventually induce tumours in these models in a couple includes my own research. make it through. I’m pretty careful in of months, and it’s impossible for us to know choosing people I feel will be successful and exactly which aspects of the disease in What are your own remaining ambitions function well in a biggish, fast-paced lab humans our disease in the mice refer to. in terms of cancer research, and what with pretty high expectations. They’re not should those of the community be? going to get a lot of oversight from me, Do you think this will always be a limi- I’d like to cure somebody! If I could feel that direct oversight; they’ve got to be able to tation? I had cured just one person I would feel run their own projects. It’s not everybody It’s getting better now in the sense that satisfied. I’m being slightly facetious there who’s cut out to do that. people are now using a range of models with but actually I’m serious. a variety of initiating mutations. That’s In terms of the community as a whole, Turning back to research: what do you helpful, because it’s now representing a we need to translate all of our accumulated Disease Models & Mechanisms think the pros and cons of mouse models larger collection, but it doesn’t change the molecular-genetic information about the are? fact that the cancers in the mice develop in disease towards better therapy. The good I think that they’re getting better and better. a short period of time compared to the news is that we are seeing examples of that The tools that we have now for making human disease. All sorts of non-tumour-cell with some of the targeted therapies, but it’s compound mutants and inducing mutations autonomous effects might be influencing the still limited in the sense that the targets to in specific cell types, very specific kinds of development of the tumour in humans that which we’ve made drugs today are a tiny mutations, it’s all going in the right direction, we may or may not be capturing in the mice. fraction of all the things that we know are and I think that the models that have been We don’t know, for example, what the mutated and are contributing to cancer. For developed by us and by others are actually somatic mutations are in the models; that is, example, Kras is mutated in 30% of all quite sophisticated now. We’ve gone a long what happens beyond the initiating human tumours in aggregate, but we don’t way towards addressing some of the mutations that we’ve introduced. In my lab, know how to treat a Kras-mutant tumour. concerns that were there at the beginning, we’re just starting to study that. It’s clear that Also, as we develop therapies, we need to about whether one could effectively model there are some effects – but how many, and get a handle on how we’re going to human cancer in the mouse. I think we’ve how much they overlap with the situation in overcome resistance, because the mutabil- answered that question for now. That said, humans, we still don’t know. ity of cancer and its effects on treatment mice are not little people and the effects of response will be a constant problem that we mutations in genes in mice will not always Does your lab have contact with clini- have to address. cause the same effect as in humans. We have cians? A second area to invest in is metasta- plenty of examples of that, so we can’t fool We have MD/PhD postdocs who bring sis. We need to understand better the ourselves into thinking that the models are some of the clinical relevance and, process of metastasis and hopefully the

674 dmm.biologists.org Tyler Jacks A MODEL FOR LIFE

difference between the metastatic cell, the So what would inspire you scientifically cases cures. I believe that this will happen metastatic environment and the primary if you were 21 again? over the next 20, 30 or 40 years. In my view, tumour. If we could do that we might be I would hope that people will see the light that’s a very exciting prospect for a disease able to find new therapeutic approaches at the end of the tunnel at this point, and that’s been around for a very long time and to the disseminated disease, which is that young investigators would think that killed a lot of people. I hope that young clearly a huge problem, as 90% of cancer- the goal is achievable: we can actually get investigators will be inspired and want to related deaths are attributable to metasta- there, this is not just research for research participate directly in the solutions. sis. sake – we can actually solve the cancer Excerpts from this interview can be heard The last area, which is somewhat related problem. I said at a talk that I gave at the in the podcast associated with DMM Vol. to metastasis, is the whole issue of the AACR meeting in the spring, I consider that 3, Issue 11/12 at http://www.biologists.com/ tumour microenvironment and the the rising generation of cancer researchers DMM/podcasts/index.html. DMM greatly complex interactions that exist between are the ones who will in fact succeed. appreciates Prof. Jacks’ willingness to share the cancer cell and the cells that surround They’re not going to wipe cancer off the his unique thoughts and experiences. Prof. it. There’s some knowledge about what’s face of the Earth, they won’t cure every Jacks was interviewed by Kathy Weston, happening there, but it’s still quite limited. patient, but they’ll develop and deploy Consulting Editor for DMM. This piece has It’s probably very important and might lead treatments that are effective in leading to been edited and condensed with approval to new therapeutic opportunities. significantly longer survival and in some from the interviewee. DMM Disease Models & Mechanisms

Disease Models & Mechanisms 675