Kevin Esvelt, Harvard
Listen Now Download as mp3 from the show eLife Episode 13: Making blind mice see and mosquitoes resistant to malaria
A process called a gene drive could be useful for propagating desirable characteristics into the entire population of a species. For instance, malaria resistance could be engineered into mosquitoes, insecticide sensitivity conferred on plant bugs or even herbicide sensitivity being restored to resistant weeds or crops. Harvard’s Kevin Esvelt explained how it works to Chris Smith...
Kevin - One particular animal that we would love to alter in the wild is the mosquito, so they can't spread malaria. It is a terrible disease that kills 650,000 people a year, most of them children under 5. We know about particular genes that we can put in the mosquitoes that render them unable to transmit malaria effectively. The question is, how can we spread those genes through wild populations? We started by looking at some results from the laboratory of Austin Burt in Imperial College London. We ran some simulations suggesting that we might be able to spread genes through wild populations if the gene can benefit itself. Now, there are some genes in nature that can do this by biasing the odds that they will be inherited by offspring.
Chris - How did they do that?
Kevin - This particular class does it by cutting the competing version of the gene, such that the cell will then copy over the cheater. Austin Burt suggested that we might be able to adapt these genes to spread traits that we want to through the wild organisms.
Chris - So, if we look at your malaria example then, if you had genes which are capable of suppressing malaria in a mosquito, and you confer this technology on that gene, then it’s going to copy itself within the individual mosquito and then propagate through the population because it strongly selects itself.
Kevin - That’s exactly right because it is inherited almost twice as often as a normal gene. In fact, that single gene advantage is strong enough that it can even spread if it reduces the ability of the organism to survive and reproduce. The problem was that we didn’t have the molecular scissors necessary to make the cuts. We needed really good molecular scissors that could not only cut whatever sequence we wanted but can also cut multiple sequences right next to each to reduce the odds that evolution could come up with mutations that would block the ability of the scissors to cut.
Chris - So, do you mean in the same way that when we have an infection and we use antimicrobial drugs, bacteria can mutate to surmount the effect of the drug. But if we give multiple drugs at once, because we’re hitting different independent targets, it’s much harder to mutate each of those targets independently and simultaneously to make an organism that’s resistant, and you could do the same thing with a malaria mosquito with this technology?
Kevin - That’s exactly right. If we can target multiple sites within the original gene that we want to replace then we can make it that much harder for it to evolve resistance to our ability to copy over it.
Chris - Let's just look at the nuts and bolts of this a second then. So, what this would take then is, you have to have a set of these molecular scissors which are going to cut genes. You’ve got to plumb that into the genome in the correct genetic place - or locus - which you want it to target so it then copies itself with the ability to delete any opposing gene and then copy itself in there, but you're going to have to do that not just in one, but multiple places in the genome, can we do that?
Kevin - We can. Over the last couple of years, we’ve been developing a technology called CRISPR that is essentially molecular scissors that can target almost any sequence in the genome, even multiple sequences in the genome. We’ve used it to-date to edit the genomes of a wide variety of organisms because it seems to work in just about everything. The way we do it is we introduce the CRISPR system into the cell we want to edit along with an altered version of the gene. So, the CRISPR system cuts the original version and the cell repairs the damage by copying the altered version. So, our idea was, how about we simply encode the CRISPR system right next to the altered gene such that when the cell repairs the damage to the original gene, it will copy both the altered gene and the CRISPR system. That way, the offspring of that organism will inherit the altered gene and the CRISPR system. And they’ll also inherit from the other parent a copy of the wild type gene, the original version. CRISPR will then have again to cut the original gene and copy over the altered gene and the Crispr system. This way, the Crispr system effectively makes that same edit in every generation even in potentially the wild.
Chris - Based on your own modelling studies, how quickly could that propagate through a population because that will be an absolutely critical thing if this is to be an effective control against malaria?
Kevin - So, it depends on how many altered organisms we release, relative to the size of the original population and also, on how fast the organism reproduces. Insects like mosquitoes that breed very, very rapidly, we could potentially alter all of them in a span of only a few years.
Chris - What about the environmental consequences, negative impacts, and also, the rebound of the strong selective you're going to put on the pathogen? Will it not come back with a vengeance with some strategy to surmount your CRISPR system? It could evolve an anti-CRISPR gene for example.
Kevin - It could. Fortunately, we have 2,000 or so different variants of the Crispr system that bacteria have provided us so we could probably simply switch to a new one. But in many cases, what really prompted us to write these papers, before, we actually demonstrated this in the laboratory was because we realised that malaria was well, an excellent target. It’s really only got one potential application. We know that CRISPR works in every species we’ve tested throughout all the kingdoms of life. And this is a very general strategy that can be applied to alter almost any sort of gene. So, what this potentially means, these CRISPR gene drives, we could alter almost any sort of sexually reproducing populations in the wild. And that could have some pretty profound ecological effects. That's why we’re going to have to use it very, very carefully, and we’re going to have to be sure that we involve everyone who might possibly be affected because we all rely on healthy ecosystems and we all share responsibility to pass them on intact. So, if we have an ability to alter them by changing entire populations then we’re going to have to be very certain that we do this as safely and responsibly as possible...