Genetic Landscape: What is RNA Interference?

Good afternoon and welcome to today's meeting of the Common Wealth Club of California. I'm Jeff Bell, afternoon news co-anchor at KCBS AM in San Francisco and I will be your chair and moderator for today's program. We also want to welcome our listeners on the radio and want to remind everyone that you can find us on the internet at commonwealthclub.org. It is my great pleasure to introduce or distinguish speaker Dr. Andrew Fire today. It's not often that mere mortals like most of us get to share a room with one of the brightest minds of all time. Some what in fact whose contributions to our evolving knowledge base are so profound that they have been recognized by the highest honor possible, the Nobel prize such is our honor here today as we are privileged to share this room with Dr. Andrew Fire of Stanford University School of Medicine, 2006 winner of the Nobel prize in Physiology or Medicine. Dr. Fire and his co-recipients Dr. Craig Mello of the University of Massachusetts Medical School share the honor for their ground breaking discoveries regarding RNA interference. Now I'm not going to even pretend to understand the science behind the research, but I do know a couple of things. This research has literally turned the field of Molecular biology on its head. I also know that the RNAI-gene silencing technique that we are going to hear about is showing phenomenal phenomenal potential to treat 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 serendipitous connections to Stanford University, like the fact that he was born in there literally, and that he attended Stanford's bay area nemesis Cal, UC Berkeley, and you want to know the reason why? Because he was 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 to chat backstage if you will with Dr. fire in the other room and I can tell you that he is a sincere and down to earth, and unassuming and gracious as he has been made out to be certainly in the main stream press ever since his big honor last year with the Nobel prize. So ladies and gentlemen please join me in welcoming 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 am really looking forward to your questions and discussion. And I will tell a biology story, and but like any story many stories, it starts with a desire or a proposal for change. So in biology things change a lot, every organism every plant or animals are a little bit different from its parents. And as those differences are beneficial to their organism's growth you get evolution occurring. But I am talking about a different kind of change, its kind of change that we actually want to engineer as people. And these kinds of changes are things like if a person is sick, because the cells in the body aren't doing the right thing. We want to change them to be able to do the right thing, and that field is called medicine to some in some broad way or in the case of agriculture where plants aren't growing where you want them to or they not producing the right things, you have a desire to change them so they do what you want. And you can imagine that some changes are not what you want to have occur, most changes are probably neutral, some things are really important like the case of somebody who is sick or the case of a plant species which don't grow anymore because the temperature is changed, it's gotten warmer, and you need 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 any institution or for the whole world you have to understand how it works. If we understand how plants and animals work and why they are the way they are, we would have a better chance of being able to change them. And that proposal, that goal is really spurred by a discovery from the 1940s made by McLeod, McCarthy and Avery who discovered the DNA was the basic information resource that cells and organisms use. That's where we store what we are. And if you change the DNA sequence, DNA as a linear molecule it has got a lot of words laid out in it in a four letter alphabet, and if you change that sequence you can change the way of a person is, you can change the way a bacterium is, you can you can affect what happens. And so that was a major discovery as was discoveries later of exactly how that information 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 understanding how the DNA alphabet, how the DNA words are turned into an organism and then figuring out how to how to manipulate that to our to our benefits. And I guess a nice analogy since we are on the radio and some of people here can can imagine being on the radio is of a long monologue, you have a long monologue in the radio and you have a lot of information that's being given out and based on that monologue you are going to actually assemble either a human being or single cell or a bacterium or a plant or whatever. And so that the long monologue is a series of instructions. So you can imagine that if we had some desire to change what gets built from that monologue we would understand what these paragraphs mean and we will change specific paragraphs. So that the proposal that this whole scientific fields starts with came from people trying to make not necessarily humans that were different, but plants that do different things. And as a real test of their ability to do that a number of researchers said if we want to have a plant that's different, they wanted to to sort of test this idea out, that's what a 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 plant colored we can just put more of them into the plant, but put more of this the same paragraph, more copies of that paragraph into the monologue that's the plants DNA. And if it gets repeated enough times maybe we will have not just a little bit of the enzyme that makes the colored pigment, that makes the plant colored, but much more of it. So amongst the groups doing this actually was Richard Jorgensen who was then at a company called DNA Plant Genetics here in the Bay Area in Oakland. Another group in Holland was doing some other things, and they did this experiment of putting an extra copies in plant gene and what they observed was an opposite effect, not only that they not get more of the pigment they actually shutdown, not only the DNA the extra information they were putting in, but they also 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 in this biological system but it was exactly the opposite of what they expected. Their goal was to produce more of a specific enzyme. They put in the DNA the information from this enzyme and actually not only did the information not work they knock down the information that was already there. So one can go forward with the scientists who went forward, but think about it from the plant's perspective. If you are listening on the radio to this monologue well some of the information on the radio is actually not as valuable as other information, and how would you know what's the less valuable information? Well if every five minutes you hear commercial for something that information is over and over and, you want to ignore that, that is sort of selfish information that's there for its own benefit and not there to help you. And so in fact it turns out that our cells have a lot of ways of trying to filter useless information or sometimes deleterious information, bad information, from what we actually need in our DNA. Because we have a lot of junk there it turns out in addition to all of the paragraphs and all of the bits that monologue that we need to built our cells, it is also a tremendous amount of junk in there which is come up at various times because of the bits of information have inserted themselves into the genome, into the into the 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 that it there was something there that shouldn't be the experiments that Rich and John Milan Holland have done were putting external information into a system that shouldn't be there and the cell is capable recognizing and it shutting it down, and that's a very interesting field now. And it's a field that have sort of understanding how cell can recognize what's its own important information and what's coming in from afar. But what was very clear at that point as a as a research goal was that if we understood how the cell was able to see that this information that Rich is putting in was foreign. And if we could mimic that process we would be in a position to be able not to do what their original goal was which was to turn things on when they shouldn't be on or when they shouldn't be on but to turn things off. 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 off when 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 the scientists to be able to turn off genes when they wanted to and the only missing part was knowing exactly how that occurred. And so about seven or eight years after Rich did those early experiments and many of the rest of us have made similar observations using slightly different biological experiments that things turned off when they shouldn't. We actually figured out why genes were being turned off in some of these circumstances. And it had to do with a type of another type of information its actually RNA and not DNA, but it was RNA information that had a specific form that was characteristic of being able to copy itself into new material, its called Double Stranded RNA. And when the cells sees that it actually knows that if there is something wrong going on, and when we made that sort of by accident and Richard turned out probably he had made some of that information by accident too. When we made this Double Stranded RNA by accident it turned out that that could be used as tool to be to turn off genes of a specific type in a specific cell. So now we have a enablement of 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 in the worm, it was still about three years before that became a general procedure that could be used in almost any cell. So let's do something, lets benefit mankind because we can now turn off genes. What kind of genes do we want to turn off that it is going to benefit mankind, and so there is a lot of proposals that have been made to use this, and I have to say that none of them are actually in the clinic yet, and there is lot of reasons for that. Just saying, here is a cool way to change a system, let's try it as therapeutic doesn't get 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 the consequences could be unintended and unwanted, you need to go through clinical trials you need to also be sure that if you want to change something and you and you know a Molecular Double Stranded RNA in this case they can affect that change. You have to deliver that to every cell that needs to be affected and the question of delivery is not one it's trivial, it's not something that, we normally do is to move this information around from cell to cell. So there is a lot of proposals that have been made to use this in a clinical setting and they're in various stages of either being tested pre-clinically which means using plants and animals as sort of pre-models to see what will happen, and some of them are being tested in clinical trials which means a very small number of people have signed on to not necessarily for their own benefits but for the benefit of mankind that they will participate in these clinical trials with the understanding that they will be very carefully monitored to make sure that no one really gets hurt and perhaps there is there can be an improvement there. And that's where the status is of them, now what kinds of diseases does this is involve, it turns out that almost any biological change that you want to engender, you can engender by turning something off, if you want to have more growth you turn off the components that normally regulate the system and prevent us from growing beyond a certain 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 been proposed, 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 essentially mitigate the symptoms of AIDS, and so that's certainly a known that's a known quantity, that is scientifically, extremely well supported hypothesis. Can we use RNA interference which is the technology that we all developed over these years to to prevent the HIV virus from growing? And the answer to that is yes, it can be used in sort of model systems. Should it be used is there a is there a reason to use that in a clinical system? That's a lot less clear, there are other drugs, other treatments that clinicians have to control the replication of the HIV virus. You don't really want to if , to the extent that those are successful. The impetus the reasoning and the justification for doing clinical trials 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 to another system Hepatitis C virus, that's also a very nasty virus, it creates its causes really significant pathogenic effects on people that are infected. There is no treatment for it, there are no drugs that can be used to control it in any reasonable way. That's a virus where there is been a much stronger proposals than to use this untested novel RNA as a potential therapeutic. But there is still many many hurdles that need to be gone through before it is considered to be safe enough and potentially effective enough 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 not being geared immediately toward finding new drugs finding new therapeutic treatments, but rather has been geared toward using this technology in a laboratory to explain what each gene does in a cell, and once we know that once we have the information we can begin to put together a much more detail picture of how the cell works, and perhaps to know exactly what buttons to push in a cell that might allow us to to more effectively intervene when something goes wrong like when a cancer cell is growing out of control of or when a virus is creating trouble. If we know exactly how that process occurs which of the many, many paragraphs in the cells monologue are required for the virus to grow or for a tumor cell to do its job out of control. Then we can actually know where we want to intervene in in such a way to improve things. And the other thing that's been exciting to lot of us in science is its been a window the whole discovery of Double Stranded RNA as a trigger for shutting off gene expression has been a window into all of the many ways that our cells have of sensing what's going on in there not only in their environment but in their own information flow and of using kind of general rules to be able to distinguish between what kind of activity what kind of genetic activity and information management is beneficial to the organism and what is likely to be harmful, and a lot of those processes turn out to involve this issue of here is a piece of information is saying I want more of me then it is a problem if a piece of information is saying I want to help out the cell then it might be more beneficial. It doesn't protect us completely from viruses and from tumors and things like that, but it actually has some advantages in in terms of the way we can deal with our environment and the challenges 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 will be able to stimulate some discussions.