Andrew Fire discusses The Genetic Landscape: What is RNA Interference?
Fire knows more than most people about the mysteries of genetics. Come learn about genetics and RNA interference from the winner of the 2006 Nobel Prize in medicine, for advances in gene silencing - a process that allows cells to selectively turn off specific genes. Research in this area jump-started a new biological field by opening the door to previously inaccessible lodes of genetic information- The Commonwealth Club
Jeff Bell has been working in radio for nearly two decades and has spent most of the past one anchoring news in Northern California.
Jeff attended U.C. Irvine to study civil engineering, and then to Cal Poly, San Luis Obispo, to get his M.B.A. Along the way, he began working in radio and set off on a circuitous path that first led him to KCBS in 1993. After two years as a part-time anchor/reporter for the station, Jeff left for fulltime work at KFBK in Sacramento, where he spent the next eight years anchoring drive-time news programs. He returned to KCBS in 2004.
Dr. Andrew Fire
Andrew Zachary Fire is an American professor of genetics at Stanford University.
Fire is one of the laureates of the 2006 Nobel Prize for Physiology or Medicine, along with Craig C. Mello, for the discovery of RNA interference (RNAi). This research was conducted at the Carnegie Institution of Washington and published in 1998. Fire is currently professor of pathology and of genetics at the Stanford University School of Medicine, which he joined in 2003.
Good afternoon and welcome to today's meeting of the Common Wealth Club of California. I'm JeffBell, afternoon news co-anchor at KCBS AM in San Francisco and I will be your chair and moderatorfor today's program. We also want to welcome our listeners on the radio and want to remindeveryone that you can find us on the internet at commonwealthclub.org. It is my great pleasure tointroduce or distinguish speaker Dr. Andrew Fire today. It's not often that mere mortals like most of usget to share a room with one of the brightest minds of all time. Some what in fact whose contributionsto our evolving knowledge base are so profound that they have been recognized by the highest honorpossible, the Nobel prize such is our honor here today as we are privileged to share this room withDr. Andrew Fire of Stanford University School of Medicine, 2006 winner of the Nobel prize inPhysiology or Medicine.Dr. Fire and his co-recipients Dr. Craig Mello of the University of Massachusetts Medical School sharethe honor for their ground breaking discoveries regarding RNA interference. Now I'm not going toeven pretend to understand the science behind the research, but I do know a couple of things. Thisresearch has literally turned the field of Molecular biology on its head. I also know that the RNAI-genesilencing technique that we are going to hear about is showing phenomenal phenomenal potential totreat everything from high cholesterol to HIV to Macular degeneration.You should also know that Dr. Fire is a bay area native with some rather unusual if not serendipitousconnections to Stanford University, like the fact that he was born in there literally, and that he attendedStanford's bay area nemesis Cal, UC Berkeley, and you want to know the reason why? Because hewas turned down by his only other college of choice and that would be Stanford University.You think they might be a little embarrassed by that all these years later? I had a brief opportunity tochat backstage if you will with Dr. fire in the other room and I can tell you that he is a sincere anddown to earth, and unassuming and gracious as he has been made out to be certainly in the main streampress ever since his big honor last year with the Nobel prize. So ladies and gentlemen please join me inwelcoming Dr. Andrew Fire.I want to thank Jeff for the kind introduction, and I guess I will start by talking a little bit, but I amreally looking forward to your questions and discussion. And I will tell a biology story, and but likeany story many stories, it starts with a desire or a proposal for change. So in biology things change alot, every organism every plant or animals are a little bit different from its parents. And as thosedifferences are beneficial to their organism's growth you get evolution occurring. But I am talkingabout a different kind of change, its kind of change that we actually want to engineer as people. Andthese kinds of changes are things like if a person is sick, because the cells in the body aren't doing theright thing. We want to change them to be able to do the right thing, and that field is called medicine tosome in some broad way or in the case of agriculture where plants aren't growing where you wantthem to or they not producing the right things, you have a desire to change them so they do what youwant. And you can imagine that some changes are not what you want to have occur, most changes areprobably neutral, some things are really important like the case of somebody who is sick or the case ofa plant species which don't grow anymore because the temperature is changed, it's gotten warmer, and youneed to you need to alter the plant to allow it to give you food.So we have this desire to change things and in order to really affect that as it would be for anyinstitution or for the whole world you have to understand how it works. If we understand how plantsand animals work and why they are the way they are, we would have a better chance of being ableto change them. And that proposal, that goal is really spurred by a discovery from the 1940s made byMcLeod, McCarthy and Avery who discovered the DNA was the basic information resource that cells andorganisms use. That's where we store what we are. And if you change the DNA sequence, DNA as alinear molecule it has got a lot of words laid out in it in a four letter alphabet, and if you change thatsequence you can change the way of a person is, you can change the way a bacterium is, you can you canaffect what happens. And so that was a major discovery as was discoveries later of exactly how thatinformation got translated into certain things happening into cells and the protein for instance.And so we actually can can describe the problem that's being addressed as one of understandinghow the DNA alphabet, how the DNA words are turned into an organism and then figuring out how tohow to manipulate that to our to our benefits. And I guess a nice analogy since we are on the radioand some of people here can can imagine being on the radio is of a long monologue, you have a longmonologue in the radio and you have a lot of information that's being given out and based on thatmonologue you are going to actually assemble either a human being or single cell or a bacterium or aplant or whatever. And so that the long monologue is a series of instructions. So you can imagine thatif we had some desire to change what gets built from that monologue we would understand what theseparagraphs mean and we will change specific paragraphs. So that the proposal that this whole scientificfields starts with came from people trying to make not necessarily humans that were different, butplants that do different things. And as a real test of their ability to do that a number of researcherssaid if we want to have a plant that's different, they wanted to to sort of test this idea out, that's whata proof of concept by making taking a plant that was colored and making it more colored.If we find out the genes, if we find out the bit of the monologue that's important for making a plantcolored we can just put more of them into the plant, but put more of this the same paragraph, morecopies of that paragraph into the monologue that's the plants DNA. And if it gets repeated enough timesmaybe we will have not just a little bit of the enzyme that makes the colored pigment, that makes theplant colored, but much more of it. So amongst the groups doing this actually was Richard Jorgensenwho was then at a company called DNA Plant Genetics here in the Bay Area in Oakland. Anothergroup in Holland was doing some other things, and they did this experiment of putting an extra copiesin plant gene and what they observed was an opposite effect, not only that they not get more of thepigment they actually shutdown, not only the DNA the extra information they were putting in, but theyalso shutdown the information that was already there of that paragraph.And so it was interesting and strange, they were making a difference. They were creating a change inthis biological system but it was exactly the opposite of what they expected. Their goal was to producemore of a specific enzyme. They put in the DNA the information from this enzyme and actually notonly did the information not work they knock down the information that was already there. So one can go forwardwith the scientists who went forward, but think about it from the plant's perspective. If you are listening on theradio to this monologue well some of the information on the radio is actually not as valuable as otherinformation, and how would you know what's the less valuable information? Well if every fiveminutes you hear commercial for something that information is over and over and, you want to ignorethat, that is sort of selfish information that's there for its own benefit and not there to help you. And soin fact it turns out that our cells have a lot of ways of trying to filter useless information or sometimesdeleterious information, bad information, from what we actually need in our DNA. Because we have alot of junk there it turns out in addition to all of the paragraphs and all of the bits that monologue thatwe need to built our cells, it is also a tremendous amount of junk in there which is come up at varioustimes because of the bits of information have inserted themselves into the genome, into the intothe into that monologue information that we have.And so it turns out that what was going on in a broader sense is that they cell was recognizing and thatit there was something there that shouldn't be the experiments that Rich and John Milan Hollandhave done were putting external information into a system that shouldn't be there and the cell iscapable recognizing and it shutting it down, and that's a very interesting field now. And it's a field thathave sort of understanding how cell can recognize what's its own important information and what'scoming in from afar. But what was very clear at that point as a as a research goal was that if weunderstood how the cell was able to see that this information that Rich is putting in was foreign. And ifwe could mimic that process we would be in a position to be able not to do what their original goal waswhich was to turn things on when they shouldn't be on or when they shouldn't be on but to turn thingsoff. And it turns of both of those are scientific and medical goals as well as agricultural goals,sometimes you want to turn something on when its not on, some times you want to turn something offwhen it is on and shouldn't be.And so it turned out that the that set of experiments were really the initiating part of an ability of thescientists to be able to turn off genes when they wanted to and the only missing part was knowingexactly how that occurred. And so about seven or eight years after Rich did those early experimentsand many of the rest of us have made similar observations using slightly different biologicalexperiments that things turned off when they shouldn't. We actually figured out why genes were beingturned off in some of these circumstances. And it had to do with a type of another type of informationits actually RNA and not DNA, but it was RNA information that had a specific form that wascharacteristic of being able to copy itself into new material, its called Double Stranded RNA. Andwhen the cells sees that it actually knows that if there is something wrong going on, and when we madethat sort of by accident and Richard turned out probably he had made some of that information byaccident too. When we made this Double Stranded RNA by accident it turned out that that could beused as tool to be to turn off genes of a specific type in a specific cell. So now we have a enablementof a ability to do biological change where enabling us to turn off a specific gene in a specific place.And you can ask okay, so now that there's this possibility and I should say from our initial experiments inthe worm, it was still about three years before that became a general procedure that could be used inalmost any cell.So let's do something, lets benefit mankind because we can now turn off genes. What kind of genesdo we want to turn off that it is going to benefit mankind, and so there is a lot of proposals that havebeen made to use this, and I have to say that none of them are actually in the clinic yet, and there is lotof reasons for that. Just saying, here is a cool way to change a system, let's try it as therapeutic doesn'tget you very far, especially if you are talking about human biology, if you are talking about medicine.You don't simply manipulate humans genetic information with out realizing the some of theconsequences could be unintended and unwanted, you need to go through clinical trials you need toalso be sure that if you want to change something and you and you know a Molecular DoubleStranded RNA in this case they can affect that change. You have to deliver that to every cell that needsto be affected and the question of delivery is not one it's trivial, it's not something that, we normally dois to move this information around from cell to cell. So there is a lot of proposals that have been made touse this in a clinical setting and they're in various stages of either being tested pre-clinicallywhich means using plants and animals as sort of pre-models to see what will happen, and some ofthem are being tested in clinical trials which means a very small number of people have signed on tonot necessarily for their own benefits but for the benefit of mankind that they will participate in theseclinical trials with the understanding that they will be very carefully monitored to make sure that no onereally gets hurt and perhaps there is there can be an improvement there. And that's where the status isof them, now what kinds of diseases does this is involve, it turns out that almost any biological changethat you want to engender, you can engender by turning something off, if you want to have more growthyou turn off the components that normally regulate the system and prevent us from growing beyond acertain point, if you want to have less cholesterol you turn down the enzymes that make cholesterol.But many of the possible and I should I should add one other really major application that's beenproposed, which is a question of controlling viral replication. HIV is a really characteristic case of this,HIV is the virus that causes AIDS, if you prevent the virus from replicating you actually essentiallymitigate the symptoms of AIDS, and so that's certainly a known that's a known quantity, that isscientifically, extremely well supported hypothesis. Can we use RNA interference which is thetechnology that we all developed over these years to to prevent the HIV virus from growing? And theanswer to that is yes, it can be used in sort of model systems. Should it be used is there a is there areason to use that in a clinical system? That's a lot less clear, there are other drugs, other treatmentsthat clinicians have to control the replication of the HIV virus. You don't really want to if , tothe extent that those are successful. The impetus the reasoning and the justification for doing clinicaltrials were something completely unknown that may not work and may actually have negative effects,is it really there? Something that may occur in the far future but something not immediate, you go toanother system Hepatitis C virus, that's also a very nasty virus, it creates its causes really significantpathogenic effects on people that are infected. There is no treatment for it, there are no drugs that canbe used to control it in any reasonable way. That's a virus where there is been a much strongerproposals than to use this untested novel RNA as a potential therapeutic. But there is still many manyhurdles that need to be gone through before it is considered to be safe enough and potentially effectiveenough to begin clinical trials on that.I should say also that there is been a whole dimension of the scientific interest in this, which is notbeing geared immediately toward finding new drugs finding new therapeutic treatments, but rather hasbeen geared toward using this technology in a laboratory to explain what each gene does in a cell, andonce we know that once we have the information we can begin to put together a much more detailpicture of how the cell works, and perhaps to know exactly what buttons to push in a cell that mightallow us to to more effectively intervene when something goes wrong like when a cancer cell isgrowing out of control of or when a virus is creating trouble. If we know exactly how that processoccurs which of the many, many paragraphs in the cells monologue are required for the virus to growor for a tumor cell to do its job out of control. Then we can actually know where we want to intervenein in such a way to improve things. And the other thing that's been exciting to lot of us in science isits been a window the whole discovery of Double Stranded RNA as a trigger for shutting off geneexpression has been a window into all of the many ways that our cells have of sensing what's going onin there not only in their environment but in their own information flow and of using kind ofgeneral rules to be able to distinguish between what kind of activity what kind of genetic activity andinformation management is beneficial to the organism and what is likely to be harmful, and a lot ofthose processes turn out to involve this issue of here is a piece of information is saying I want more ofme then it is a problem if a piece of information is saying I want to help out the cell then it might bemore beneficial. It doesn't protect us completely from viruses and from tumors and things like that, butit actually has some advantages in in terms of the way we can deal with our environment and thechallenges that come up as well as the challenges that coming from from with in the system.So with that sort of introduction to the science I think that I will take questions and hopefully we willbe able to stimulate some discussions.