RNA Interference: Nobel Lecture by Fire & Mello | Gene Silencing

[00:00:00]well andrew fire craig miller welcome to stockholm uh when we spoke a couple of months ago just after you'd heard the news that you've been awarded the nobel prize you both sounded quite surprised that it had come as quickly as it has done has that surprise subsided at all i'm still surprised by the whole thing i mean it's uh it's obviously a really major honor to be honored by one's colleagues in such a way but at the same time there are a lot of other scientific discoveries and other contributions to the field we're in that are probably no less deserving and so it's a it's an interesting situation to be in i agree it's uh it's just been really you know every day i i'm still not sure it's really me that's the recipient of this recognition i i really feel it's more the prize is this is awarded for the science and in in that respect we're representing many researchers and and it's a great honor to be here to be spokespeople for the discovery really and and to bring the some attention to the science and the fun of science and how the last couple of months been have they been whirlwinds or very much so yeah i mean we each have our scientific day-to-day lives and intertwined with that has been um a lot of interesting other things and also planning a trip to sweden so the combination thinks it's made for a busy couple months for both of us i think imagine um the prize was awarded for a very concrete discovery a very a single event if you like is there a moment you can recall when the penny dropped that rna interference was what you were looking at and you understood how it worked certainly not because we still don't understand how it works i think it's been very very exciting and fun to be part of this field because of all of the you know the interesting interrelationships between you know the rna interference phenomenology and then the developmental mechanisms that are related to it and i think we have so much still to learn about the basic mechanism of gene regulation even going beyond rnai as a playing a role in that process but we i honestly i feel that it it's been exciting at many steps along the way but i can't think of a single point where we felt we understood the mechanism really i mean i i still feel we don't understand the mechanism fully um that we have a great much better idea about the underlying mechanism now but but we have so much more to learn that um it's i think it's just still a lot of fun it's very exciting field but there was an insight gained that it was double-stranded rna doing this and it's interesting to think about the path that led to your ability to come up with that insight would you put it down to the fact that the two of you came together perhaps to work on this problem certainly a major part of it the other major part of it was that the groundwork that had already been laid in the puzzle by by primarily by other people um a major part of it was the people that worked with us that all had very significant contributions to it it was really a matter of being in the right place at the right time particularly the work that had been done in in plant systems and in fungal systems and some of the work that was done elsewhere in the worm system by for instance suguo and other people really set it up so that we could just inject rna that we would make in the lab and then get a result in a couple days or a day what happened and that made a very sort of efficient system to begin to test hypotheses i think that the understanding that there was an organismal response to the injected material was part of what was very exciting to me even though i didn't understand certainly what was happening the the the observation that the silencing signal could spread from cell to cell and even be transmitted in the germline were extremely exciting and yet we didn't understand how the silencing was triggered and in fact we were not focused on double-stranded rna in my case we were thinking more in terms of double-stranded rna as a potentially as a replication intermediate or something that was produced during the amplification process that was necessary for the inheritance to occur and we thought more of double-stranded rna therefore as an intermediate in the silencing and andy really deserves credit for the you know thinking well perhaps the double-stranded rna is an important trigger as well because in some organisms like ourselves there's clearly a double-stranded rna response that had been studied previously that's involved in an antiviral mechanism so we were uh thinking more of it as an intermediate which it really is as well it's it's interesting they're more than it's double standard darning is not only it is a trigger but it's not the only trigger for this type of silencing so i think that also at was was an element that added to the confusion in the literature on the earlier work done in plants because it wasn't clear when a virus or a trans gene was introduced into an organism what the trigger was and i think the reason some of that confusion exists is because there are more than one trigger triggers for this so it's it's an interesting twist really that we still don't understand all the different ways that you can trigger the silencing but double-stranded rna is in fact an intermediate in many of these related silencing pathways so that's one of the elements we still are very much in need of understanding you you emphasize the basic science aspect of all this and there's a lot still to be understood i suppose it the world has really embraced rnai as a technology and an application do you do you find that worrying that people leap on it in its partially understood form and want to use it i i don't find it a worry i think it's natural for people to want to use i mean hope is especially when you have a sick family member you know this this this sincere desire for some sort of a treatment or a cure and i think it's important for the scientists to make sure that that doesn't get blown out of proportion that that hope doesn't get over overstated and so you know i i can totally understand the excitement i i think that that if anything we really need to focus on you know the it really is an exciting discovery and there are many applications that that it can be put to um and i think we need to get that message out there's enough i don't think there's anything to fear except perhaps going too far and being too hyperbolic in in promoting it but i do think we we need to get the message out because it's very important as a research tool certainly and potentially as a therapeutic so i i think it's important i i think i mean it's it's almost a um a humorous thing but one of the things i found is that when i've gone to lecture in classical genetics which is the tool many of the tools of which were pre-existed us by several you know decades and 100 years or whatever one of the things i find is the students will suggest why not do everything by rnai and that certainly isn't there's still very much room for classical genetics it's really the basis for a lot of what we do and what we think about and so and and other techniques of genetics that are also have come up in the next the last few years targeted gene disruption which is extremely valuable technology and useful and a number of other things so i think that that students realize that when they when they get in to the depths of research problems that they really have to understand not only what's been developed in the last few years but also things that were developed 100 years ago do you think the funding climate is as accepting of basic research as it used to be is that well i i think that the funding climate is is is tight now in part because of the tremendous wealth of information that we have about the human genome for example the the sequence of every gene with more with that as background in the information technology that we have for searching that database i think it's harder to get funding to do the kind of work than andy and i did and quite often um it it's a priority that has to be made you know to fund this or to fund that and both really should merit funding but there just isn't enough funding money so in a way where i think we're being strapped in part through the success of the scientific enterprise as a whole creating you know more good science that can be done and i think that's enough it really can be looked at as an opportunity and the message that we have to get out to the uh the people who make the policy uh in terms of the politics and the funding decisions that there's a great opportunity with the advances that have been made in medical research you know the genome sequence and the information technology the gene profiling technology for looking at the expression of genes in cells and and things like rna interference that allow you to shut off genes to study their function these provide opportunities that you know make it actually harder to get basic science funding because now you can do a lot of these experiments in in human cells and that's not always good i mean the fact is if you're taking away the money from the very basic science that could lead to new technologies new discoveries that that would be very hard to get in in a vertebrate cell system so i think we as as in the peer review process we've seen this i know that i have uh where they're just you have to make a decision and they're they're just all you know several grants that should be funded and they're just not going to make it no matter what because there's all these others that need to be funded so these priorities it just becomes an impossible situation and we really in to fix that we just need to get the message to the public i think to support science more so that we can continue to get the funding we need does your funding come mainly from basic research funding from nih or from um is there also an industrial component to what you do where our funding comes from from non-profit sources both completely art my lab is funded completely by nih right i have funding also from the nih and howard hughes medical institute but the work that was done uh really was funded privately um some private grants other than than those mentioned as well so philanthropic support for disease-oriented grants like the acs the march of dimes funded some of my research and and also uh the pew charitable trust so to mention i think all of them right so those are all you know they're charitable organizations and their um and their um public organizations but but they're but they're all toward the goal of improving health care in a general way so when you bring new people to work on the problem into the lab i was interested to know what you look for in those students coming in i learned a lesson from a mentor of mine a gentleman named donald brown if someone walked up the door and said i want to learn that was a really major feature even if the person might not come in with the most spectacular of previous mentorship or whatever that was a really major thing and i think that's something that one looks for as someone that really wants to learn yeah it's very hard i i think sometimes students who are very bright um are not motivated enough and some mo i think so the major ingredient is motivation and a desire to follow through with an experiment and those are qualities frankly that you cannot glean in an interview so i think some of the best scientists struggle sometimes getting actually into the lab because the interview process might weed them out uh you know or they they may not have the patience for it you know or to go through it but but i i find it it's once once you work with someone you really get to know what they're like so most laboratories have what we call a rotation process so students will get an opportunity to work with you in the laboratory as they decide on which group they want to join during graduate work and so i think that's the been for me the most important aspect is having time to spend with the student in the laboratory if i know what they're like and i suppose that recommendation must become a very important part if you're looking for somebody's long-term commitment to problems you need to know that they've done that before it can be but they're so unreliable right it's hard because the recommendation letters often say as much about the person writing the letter and so you have to you have to factor two different two different um basically components into the equation and sometimes difficult to parse out which is which so you man many uh letters from asian laboratory heads are incredibly brief you know and it's hard to read into the line you know what what they really mean and i think it's a stylistic uh you know choice that they make not to over state anything and then sometimes in the u.s you get these letters that go on and on and on and you don't know uh how much is genuine either so it really i think the it's not there's no perfect way um i really feel that it's hard to tell in advance you mentioned mentorship and obviously you've both been the recipients of great mentorship what's that taught you about your own practice of mentor mentoring that's a that's a great i've had i feel so fortunate to have had uh great mentors um along the way and still colleagues really um that that i've learned so much from uh it's very very important but i could spend hours talking about mentors but you know that could you summarize just a couple of the things perhaps that you try and practice as a mentor for your students you want to take a crack at that yeah i think that um you know one tries to listen to what people are thinking because first of all that's part of the mentorship process and second of all it's part of the scientific process no matter who it is even somebody who's just walked into the lab with we've had high school students working in the lab the other thing is that you try and and work with work with people as colleagues for each other and get them to ask each other questions because again i don't necessarily provide the best mentorship for people in the lab the best the best advice and getting advice from each other has always been really critical and that's that's one of the nice things about about running a research lab in some cases that that the advice you can't just sit back and let the ship rot but on the other hand there are a lot of cases where the really important critical suggestions come because one person on one project suggests something to another person working another project so it's a really it's a really important aspect of it is to keep a collegial environment where people are comfortable talking to each other and and suggesting things to each other and i've just been very fortunate and having had people in the lab who are both you know outstanding scientists and also outstanding mentors to each other and to me as well in a lot of cases yeah i think it's so important uh you know the conversation that you have in the laboratory with your students or with your advisor as as i can recall in my own past those are so important as a way of learning and as a way of coming up with ideas it's interesting because the two people walk into the room and the idea is not there it's not it's not always brought there by one individual usually the idea materializes in the room or in the discussion group and the one thing that i really fear is coming in with my own idea that's wrong and pushing it too hard and so when you're mentoring it's important not to be too forceful about pushing your idea and to try to let people know that they should voice their ideas and sometimes that for me has been the most difficult part is getting the people in the lab to say what their ideas are and and a lot of times you know their idea is wrong and my idea is wrong and the other person's idea is wrong but you put them all together and all of a sudden there's a new idea that might also be wrong but it's still it's lots of fun at least maybe there's an experiment you can do that will distinguish that's the fun that is really fun part of the process and one thing i i fear and i've heard that once you have this kind of a prize that your students are too respectful and they won't question you know you say something and they'll actually believe it you know trust me science is all about you know questioning things and if you don't question it doubt it yeah and and so i think we need to reinforce that message to our students after we come back from this brief period of of celebration we need to go back and make sure that we get right back to the questioning well that neatly brings me on to the question of um your youth you're both very young and this is going to bring considerable the greater notoriety how do you think it's going to affect your future um research paths and that question of distance from your students is certainly one aspect well i hope it not too much in in that respect um i i feel you know that it's it's like having a new job you know an additional job um you know in addition to running a lab and trying to be a good advisor and leader for your group to have this new responsibility to to be a spokesperson for the science and to try to do the right thing in terms of you know promoting and the understanding of the science which you know we just had a very interesting discussion in parliament and i actually felt a little bit guilty during the discussion because you know scientists really haven't done a very good job of of educating the public about science and you know and that's partly because it's nobody's job i mean they don't really make that your job somehow it's supposed to be sort of part of your job but that's not the part that you get paid for you know you get paid for doing the research and publishing the papers which are read by your peers not by your neighbors so i think it's very it's an important responsibility i feel but i hope it doesn't distract uh too much from the science i'm very excited all the time by what's going on in the lab i want to get back to it yeah i think i mean i'm i really like my day-to-day life of teaching and research and family and that's a pretty full life for both of us and so adding as craig says an extra job to that i'm not quite sure how it's going to work but somehow we'll probably manage when you talk about education educating people about science is there a particular target group you think of is there one group of people who you think need this more than any other no i think it's a lifelong process to be educating yourself constantly because knowledge you know science is it's a fluid thing and it's not just science it's all realms of knowledge really there's all kinds of interesting things to learn in this world and i think we need to make our children into lifelong learners somehow you know get them you know don't lose them along the way to to the you know the in the interesting world that that you can expose them to and and you know it's very difficult there's no easy solution i think to this question of how best to educate that's what we also were talking about earlier today and be interested to know how the swedish people have solved that problem it's interesting to learn about different cultures and how they approach learning but it's very important to do what turned you on to being a lifelong learner what what was it that happened to you that made you was there a single event that made you want to learn i had to say it was a single event because it was a lifetime is a lifelong thing i think one one thing that um you know in terms of lifelong learning is that is that it's surprising how little you need to change a description of a piece of science between talking to the nobel assembly of the karolinska institute which is one of the highest audiences in science and people that are extremely knowledgeable about everything you're talking about down to kindergarteners and actually if you just change some of the language you can use almost the same discussion for both groups and have you know a significant fraction of them probably at least at least come away from with some understanding of what you talked about probably the same fraction in each case so yeah i think science as a process though it naturally tends to make you want to be a lifelong learner if you're going to enter into an enterprise where there really are no right answers i mean that's what science is all about it's it's testing ideas it's trying to disprove an idea once you once you have an idea the first thing you do is try to to test it to see if it's right and the the most fun thing is when it's wrong and and then you have to come up with a new idea so it's a constant process i mean if you ever thought that you would understand everything certainly that would be very boring to be part of a science that is now a complete understanding of a process and fortunately i don't think that's going to be our problem for many many many years to come so i think it's a natural process once you've decided that you would like to be involved in science the the nice thing is it's a it's an everyday it's an exploration it's a new discovery out there waiting to be made and it just the process itself i think is lends itself very well to the basic human nature of of liking to explore and to understand and to see new things that's what science is all about so i think we can do a lot better in terms of recruiting people into the sciences if we could somehow project that at an earlier level in education right now i think too much of our education is focused on memorizing facts and not enough on the exploratory process of science and what an what a real scientist does is some is so different from what you're exposed to when you take science in in high school or grade school you know i i feel that for me and my own understanding of what it would be like to be a scientist i had the i was fortunate to have a father who was a paleontologist so i was aware of science going on at the smithsonian where he worked the museum where he worked and and you know going on field trips with him so that getting to see that real scientists don't just read books you know they actually do things is so important i'm interested in this idea of being able to explain the work uh to any audience i think ernest rutherford said that you shouldn't be doing science if you couldn't explain it to your tobacconist just kind of antiquated concept nowadays perhaps especially in the us but the um [Music] the your field doesn't lend itself immediately to exp to simple explanations there's a lot of jargon associated with it so the fact that you feel that you can with few alterations explain it simply is a very encouraging message i think it takes a little bit of time you know one of the things that's um that's challenging is to explain things in a very short time you you need to be able to go back through some of what's been learned often with with a group that's not as aware of the history and go go through that i think i think with that it's it's it becomes more straightforward what i think is is is a challenge and you know it's often impossible is this when people say can you tell us in a few words you know that the the one that that struck me in the few days after the announcement of the award was thinking about the the scientists or the mathematicians who solved the poincare conjecture which is a very important conjecture of mathematics and thinking about someone walking up to them and saying well in a few words can you explain to the to the general audience the both the conjecture and the proof of it and of course that that that certainly is doable and a little bit of time but it's it's difficult in a short period and when i thought about that i was a little more relaxed about my somewhat ineptituded in one's occasion when i'm asked to explain things a few words and being able to do that totally clearly to everybody it's it can be a challenge i i think one of the the real interesting things about talking to people about your work is you know you're right there's a lot of jargon and in a lot of times that's just very distracting but you know i find that sometimes children even ask the better questions because they don't you know they just don't know what a word means for example and they say well what is dna or what is rna uh you know what is a protein and you could then spend you know hours and hours discussing what it is and as long as the the child or the adult continues to ask questions you'll find this wonderful conversation that can go on for quite a while and really uh you know i think that i agree with andy it just takes time and it takes the audience also being curious enough to and not afraid of asking questions i i think most scientists are happy to spend some time you know discussing their work and quite often they wonder why no one asks a question well they didn't understand something very early in the talk and so they they stopped really listening and it's important to sort of raise your hand and say but can you explain this one thing and and quite often that's a really good question so that the hard part is losing people you know and it's a two-way thing so conversations with a child can sometimes be even easier because you know how to track the conversation to keep them engaged i suppose they lack the fear of asking the silly question which has which which science must suffer from a lot that people feel excluded from it and therefore don't feel they can they feel they'd make themselves look silly if they asked a question yeah there's very few there's very few really silly questions and some of the very silly questions that you might ask a scientist like how do we really know the world is flat for instance you know at some point in ancient history you know that that that kind of question is is is valuable at some point terrifying because they reveal the fact that one can't explain it oneself but yes yes so one of the things we did this year for the first time was to invite uh some of the public to ask questions to you of the internet and i'd like to if i may just pose a couple of those questions um [Music] so first of all the specific one from kerry austin in texas who says what application in genetics will offer the most effective use of rna interference i think there are probably lots of in in the field of genetics there are probably many different applications again combined with the tools of both classical genetics and the sort of more modern set of technologies that don't necessarily involve rna i like gene disruption i think all together they give us a really good toolbox not so not something that in 20 years we're going to say you were doing that you know that's these were the cruel crude tools we had in 2006 to do experiments and i think that they'll they'll also improve over time so i'm not sure they'll just there'll be one best application in in research genetics i think there'll be there'll be many applications but they'll be combined with all the other tools and will always be wanting better tools yeah i think it's certainly it's speeding i think the use of of vertebrate cells as genetic tools for studying uh the function of genes and and there's some really exciting technologies that have been developed that allow it to be applied fairly broadly in studying genes in cells in culture so i think that that's helping a lot but by itself it's really it's just the first step so i think it's being used primarily as as an inexpensive but fairly rapid way of doing genetics and really needs to be backed up ultimately with other kinds of genetic tools such as real knockout cells and perhaps even animals to test these ideas along with you know before you really understand what's happening you have multiple lines of of data or investigation that support your your work so but rna interference is important tool i think for doing that first round of genetics where there are you know 20 000 genes and you want to know which ones are important in in tumor or you know in some other disease uh so you have to sort through a lot and it's quick way of doing that maybe a new way that would have been uh fairly it would have been impossible earlier so i think it's providing an important function there there was a time when people were talking a lot about the need for standards for such experiments is that time passed are they now widely accepted for the publication of our end now i think there's still a need for it for standards there are there are publications that have a very high standard for for proving something and those cases you really are quite sure that what they're reporting is indeed due to a decrease in a specific gene and there there are some cases where because of the system in in a few cases where it's actually quite difficult to do the kinds of controls you'd want to do um and other for other reasons too you you come away not being as sure of the results you're certainly you're certainly sure that that the observations are correct but whether the results are indeed due to a specific gene i think that that there's a interesting give and take amongst amongst people writing and doing work in the field okay and finally bob found from calgary in alberta canada asked a question which we've touched a little bit on already has winning a nobel prize changed your work ethic at all well i i i guess certainly not if anything maybe getting less sleep is the main way it's changed my work ethic but you know it really is a tremendous honor to to have this kind of recognition and i think i lost a lot of sleep over you know trying to figure out how to deal with the issues of you know what what to say to policy makers and and so on and how to how to take on this new responsibility so i think there's a new type of work rather than a work ethic that's changed um hopefully we'll do well with that it's early to say yeah it's a it's an interesting challenge for us it wasn't we didn't go to school and some of these things it's that lifelong learning again yes it's the hard way okay well i see that we're running out of tape so uh i'm afraid we have to draw this to a close but thank you very much indeed for taking the time in a busy week to talk to us and once again many many congratulations thank you it's been a pleasure