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NOVA ScienceNOW

RNAi: Expert Q&A

  • Posted 07.28.05
  • NOVA scienceNOW

On July 28, 2005, molecular biologist Greg Hannon answered questions about RNAi and its potential applications combating viruses, delaying aging, and treating various diseases.

Greg Hannon

Greg Hannon

Dr. Gregory Hannon is a researcher on the forefront of the field of RNA interference, a powerful new tool for gene analysis, discovery, and suppression. Full Bio

Photo credit: Zack Seckler/AP © HHMI

Greg Hannon

Dr. Gregory Hannon is a researcher on the forefront of the field of RNA interference, a powerful new tool for gene analysis, discovery, and suppression. He works on RNA biology and cancer biology at Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, where he is also a professor. Dr. Hannon's particular focus is cancer development and the potential for using RNAi against cancer. He received a B.A. in biochemistry and a Ph.D. in molecular biology at Case Western Reserve University in Ohio. Dr. Hannon was selected as a Howard Hughes Medical Institute investigator in 2005.

Q: If the RNAi system in our bodies already is so powerful that it has the ability to silence a disease or virus gene, why do we get sick or have diseases at all? Jonathan Hall, Iowa City, Iowa

Greg Hannon: The RNAi system has to be triggered by something. If a gene is mutated or mis-expressed, the system won't really pick that out and shut it off. Viruses are, of course, another story. First, it's good to realize that viruses are very smart—at least from an evolutionary standpoint. Just about as fast as we figure out a way to combat them, viruses tend to evolve a counterstrategy. This is especially evident in plants where most all viruses have proteins that shut off the RNAi response. Our response to viruses uses our immune system—which is distinct from RNAi. Whether or not we explicitly use RNAi to combat viruses remains to be seen. We can, however, fool the cell into using RNAi to attack a virus or any foreign pathogen whose RNAi the system can get access to.

Q: Are there any cons to potential RNAi therapy? Could there be any medical side effects that go along with otherwise effective treatment? Alvaro, Los Angeles, California

Hannon: Like any treatment, there is always the possibility of side effects. These can come from two sources. The first is our incomplete understanding of biology. We might not be able to predict exactly the right target for RNAi (or a drug for that matter) and suppress it to just the right level to get a therapeutic benefit without causing other problems. The more we know about a disease or process and the more we can test our ideas in model systems such as mice, the better off we are in this respect.

The second possible source for side effects comes from not having a perfectly specific therapeutic agent. Most drugs, for example, actually hit more than one target. For good drugs, secondary effects are tolerable. Designing a perfectly specific RNAi trigger might also prove a challenge, since the RNAs that confer specificity to the process are so short (22 nucleotides long as compared to our genome, which has about three billion nucleotides of sequence). Since not all 22 nucleotides have to match perfectly to shut down a target gene, we might get some of what are called "off-target" effects. However, with good design and thorough testing, there is no reason to think that RNAi will not be at least as specific as conventional drugs.

Q: I don't understand exactly how RNAi could treat or cure HIV/AIDS or other viruses. Would RNAi target the patient's genes, or would it work on the genes of the AIDS virus in order to suppress it? Anonymous, Brooklyn, New York

Hannon: Both. In fact, there are studies in the scientific literature that have shown good effects—creating virus resistance or reducing virus replication—in cultured human cells that have used either strategy. The problem with targeting the virus is that it could mutate or evolve in such a way that its sequence is changed so that the RNAi machinery can no longer recognize it. A better way might be to target one of the co-receptors that HIV uses to enter cells. One of these, CCR5, is known to be dispensable in humans, and, if you get rid of this, cells can no longer be infected by the virus.

Q: RNAi sounds great but what are the potential risks we face with the abuse of the power it could bring? It seems like RNAi could be used for controversial purposes just like cloning in order to change a person's genetic makeup. Dr. Carlo Gilez, Eastpointe, Michigan

Hannon: RNAi really doesn't change a person's genetic makeup. It simply turns down the expression of a specific gene. This is similar, in concept, to using a drug to inhibit the activity of a protein that might be encoded by that gene. Furthermore, if you were to treat someone with an RNAi-based therapy, the most likely way of doing it would not cause the change to be inherited in the next generation.

Q: Could RNAi have an application for preventing overall aging of the body? Trint, Springfield, Missouri

Hannon: Conceivably, RNAi could be used to modify the behavior of stem cells, for example giving an instruction for expansion of stem cell pools. To the extent that this might be able to rejuvenate a tissue or organ, one might imagine that RNAi might be useful for combating symptoms of aging. Of course, a trade-off of manipulating stem cell populations could be an increased risk of those cells giving rise to cancer. RNAi has proven useful in extending the life span of some model organisms (worms and flies), but you should bear in mind that we really don't have a good understanding of the complex processes that give rise to organismal aging in mammals. Without such a knowledge, it would be difficult to know what an intervention to retard the process should be.

Q: Can RNAi be used to turn genes on that should be on, or can it only be used to turn genes off that should be off? John, Lancaster, Pennsylvania

Hannon: So far, it really looks like RNAi can only turn off genes. This is because it works either by destroying the RNA instructions that are made by the genome (messenger RNAs) or by blocking the translation of those instructions into proteins.

Q: I have heard of something called Zinc Finger Protein Transcription Factors (ZFP TF). I am curious if this technology could work in conjunction with RNAi and/or stem cell therapy to create a blockbuster approach to curing many diseases. My understanding is that ZFP TFs have the ability to turn genes on or off and even to modify DNA. In your opinion, which of these three approaches—ZFP, stem cells therapy, or RNAi therapy—is the most viable for future treatment of disease? Anonymous, Garfield Heights, Ohio

Hannon: The proteins that you mention and RNAi work in completely different ways. My feeling—and bear in mind that I may be biased here as someone that works on RNAi—is that RNAi would supersede this previous approach for controlling the expression of genes, particularly in terms of the potential for use in therapy.

Q: Hello, Greg,

My name is also Greg. I'm wondering what classes you think I should take in high school and what major to choose in college in order to pursue a career in RNAi research. Greg Towle, Age 14, Colfax High School, Alta, California

Hannon: Good question. Many high schools have advanced classes in biology, chemistry, and math that would be good preparation for a career as a biological scientist. However, I would really caution against becoming too narrow too early. Education becomes increasingly specialized as you move forward, and you should take advantage of your ability in high school and early in your undergraduate career to study a broad range of topics. Believe me, nothing you learn will ever be wasted. As an undergraduate, majors in biology, biochemistry, and similar topics are a good preparation for a Ph.D. course in the biological sciences. I would also suggest that you involve yourself in extracurricular activities that expose you to lots of different topics in science, including science clubs, science fairs, and the like. Most of all, continuing to watch NOVA seems like a pretty good idea too.

Q: Where can patients with diseases go to volunteer for clinical trials that come on the heels of RNAi discoveries? Is there a national clearinghouse for human trials where we can find out if a particular disease is being studied Bob McKissick, Anchorage, Alaska

Hannon: RNAi is really in its infancy as a therapeutic. The biggest hurdle right now is our ability to deliver the molecules that specifically trigger RNAi to the right cells in the body. Lots of work and significant progress are being made in this direction, but it may be a few years before you see a lot of clinical trials using RNAi that are really founded upon solid science.

Q: Dear Greg,

In the program you seemed bullish that RNAi could one day be used to combat almost any disease. Are there any kinds of diseases or viruses that RNAi wouldn't work for and why not? Shelly Stern, Boston, Massachusetts

Hannon: There are diseases that won't be suitable for treatment by RNAi. Several things come to mind. First, we might not be able to get inducers of this pathway into every type of cell in the body. That might restrict the kinds of diseases we can treat. Delivery of inducers of RNAi in a therapeutically meaningful way is an area of very intensive work in the field right now. The other kinds of diseases that would not be suitable would be those that are caused when we lose the function of a gene. Adenine deaminase deficiency is one example. Here, people are trying to put back a gene to counteract the effects of not having a functional copy. Finally, organisms that we really can't access with RNAi, such as drug-resistant bacteria, won't be suitable for this type of approach.

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