How do we control mosquito populations?

23:56So, for example, I used to go sample fish and I would use what's called fight nets. You essentially put a net that goes, one side of it is in like the middle of a lake. The other side goes to the shoreline. As the fish swim along the shoreline, they hit the net that hits the shoreline and they follow it essentially into a funnel that they can't get out of. and then you sample that once a day. Does that make sense? Mm-hmm. Okay, so we trap fish. We take the fish out. We tag the fish in a way where we will know if we've seen them before or not and then we release them back into the environment. And then a week or two later, we go out again and we use another technique to catch as many fish as we can.

24:33In this case, we're using an electrofishing boat where you stun the fish temporarily. You bring them into a live well on the boat where it's got a lot of water circulating so that they can like come to and stay safe. And then you count how many fish you collected and you look to see how many of them you're catching for the second time. So how many of them showed up in both of your samples? And so then you're making this assumption that the proportion of animals that you re-caught in your second sample is similar to the proportion of animals that you caught the first time in the entire population.

25:09So, for example, if I caught 50 fish in my first sample and marked them all, and then I went out and I caught 100 fish in my second sample, 10 of which were already marked individuals, the way that I would capture this is I would say 50 times 100, which is the number of fish I captured in both of my samples, and divide by 10, which is the number of individuals I caught twice. And that would give me an estimate that there's 500 fish in the population. All right. So the goal here is to get a sense for how many animals there are total. Of course, you can't measure all of the animals. And so you measure twice and then you look at the overlap because if you have 100 % overlap between your two measurements, that means you have a smaller population.

25:50If you have no overlap between your two measurements, then you have a bigger population because you're getting different subsets of the whole population. Is that the way to think about it? Exactly. Yes. Yeah. If you mark 100 fish and then the next day every single fish is marked, it suggests there's not really any other fish out there. But if only 10 % of them are marked, then it suggests that the population has another 90 % out there. Right. Cool. All right. So that's how mark and recapture studies work to get a sense for like, how many birds are there or how many cheetahs are there? But what do you do for mosquitoes?

26:22You can't capture and mark mosquitoes, can you? So first of all, thanks team. It was very helpful to have your input on that. Yeah. So marking and recapturing mosquitoes would be kind of nuts because they're so small and so delicate that when you go to catch them and count them, well, maybe not unfortunately, you usually kill them in the process of counting them. And so how could you mark a mosquito and release it? And the answer is they usually don't. So when a lot of companies are trying, for example, to see how many mosquitoes are out there, what they'll do essentially is grow males in the lab and they'll throw out all of the females because you don't want to put any extra mosquitoes out there that will be biting anybody and taking blood meals.

26:59But since the males don't take blood meals. They hatch them out of eggs in the lab. And then when they go to emerge to go from the water to their like air phase, they put a powder on the surface of the water and it's a fluorescent powder. So as the mosquitoes emerge through it, they get covered in this fluorescent dust. Wow. And you get fabulous mosquitoes. And you get fabulous mosquitoes. You can also genetically modify them so that they fluoresce green based on a protein that they're making themselves. But one way or another, you're making it so that the animals that you've released into the wild are detectable in some way that didn't require you to like handle them, which could kill them.

27:38So now instead of doing mark and recapture, you mark in the lab. And then when you go out, you can put, for example, a giant tub with dry ice, which releases CO2 that attracts the mosquitoes. And so you find a way to capture them. And then you look at the proportion of mosquitoes that you recapture that fluoresce when you look at them and you'll say, okay, those are the ones we added to the environment from the lab. And then you compare that to the number that didn't fluoresce, which were the wild animals that you're catching for the first time. And this process does kill them while you're doing the counting.

28:12Does that make sense? Yes. So if you attract and capture a bunch of mosquitoes and they're all your fluorescent ones, this suggests that your fluorescent ones are dominating the population. And if they come back and you see almost none of your fluorescent ones, it means that they're a tiny fraction of the population. So there's a bunch out there. What I wonder is like, how many other crazy ideas did they come up with before this crazy idea that they made work? Like, I love the experimental creativity of science this way. You know, like this is a hilarious idea, but I would really love to see the whiteboard where they came up with all sorts of bizarre ideas, including like, you know, laser pointers or who knows what.

28:51There are some more complicated methods. So, for example, you can look at how many batches of eggs appear to have been laid in some water that you put out, and then you can try to extrapolate from the batches of eggs how many females likely came by to lay those eggs. And it's much more complicated, and there's a lot more guesswork because you have to have an estimate for the average number of eggs laid by a female, for example. But yes, I think it is a beautiful technique to release fluorescent mosquitoes who can't bite you and then see how many of them you get back. And this is important because it's like a basic element of mosquito science.

29:27It's just like to know what are the populations and where are they, right? Because without basic knowledge, you can't do anything. But I think a lot of people underestimate how much work goes into just getting some basic information. We had our episode about weather and just knowing what is the temperature everywhere on the earth would be hugely helpful. And we can't know that, We don't know that. And so just like knowing where the mosquitoes are would be massively beneficial, I imagine. Yeah. And actually, I don't know if you guys have ever talked about the citizen science projects that are the reason we have information about insect population size.

30:02But for example, many of us have noticed that our windshields are not covered in bugs when we go on a road trip these days. And that's because the insect populations have declined so much. And there are citizen science projects where people will like put nets kind of like the one you described on the top of their cars and drive around and just catch all the insects and count them. And there were people that were doing that in Germany throughout the 20th century. And that is a big part of why we know about the insect decline. Like if they hadn't done that, we just wouldn't even know. Wow. I didn't know about that.

30:31Yeah. That's amazing. Thank you, weird German insect capturing people. There are people out there who have enthusiasm for everything. It's incredible. It is. Well, I need a break from all these mosquitoes. I got to go scratch some itches. And when we come back, we're going to talk more about how mosquitoes do what they do and how we do what we do best, which is kill mosquitoes. Wow. Thank you for those answers, Daniel and Kelly. What a relief knowing that mosquitoes aren't able to coordinate their attacks. Let's hope they do not evolve that ability anytime soon. Also, so amazed that biologists have figured out a way to estimate mosquito populations.

31:11Sorry, Kelly, I will never doubt biologists again. Let's get whoever came up with that idea working on quantum gravity soon. Love the show. Thank you guys so much. Shout out to my Spring Street students.

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34:14Okay, we're back. And I'm very excited for this segment of the podcast where we get to take scientific revenge on all the mosquitoes that have caused me to suffer so much. All right. So we have this question from a listener, James, and let's go ahead and listen to James's question. Hi, Daniel and Kelly. I was wondering if you could cover gene drives. It seems like this technology has been out for a long time, but hasn't been deployed. It seems like a magical technology for wiping out invasive species. When you have invasive mosquitoes wiping out the last native Hawaiian songbirds with avian malaria, you have to ask why you wouldn't test this out on such isolated islands.

34:49What terrifying scenarios are keeping them from deploying gene drives in the outside world? Are those scenarios realistic? Or is the pesticide industry just bumping off gene drive researchers? Thanks. All right, so we have tried lots of things to kill mosquitoes with varying success. One of the things we tried initially was spraying a bunch of insecticides, and that worked for a while. But eventually the mosquitoes that happened to be resistant to the insecticides had a lot more babies, and now we have populations of insecticide-resistant mosquitoes. How does that even possibly work? I mean, I see, like, trucks driving around spraying insecticides, but I'm like, you know, what fraction of the mosquitoes are they going to be hitting with that?

35:30It seems like, you know, shooting individual pigeons in the park or something. It's like hopeless, right? Yeah. And sometimes they release it airborne. Other times they'll specifically release insecticides into like waterways where mosquitoes are breeding. And that's a little bit more targeted. Either way, you're probably killing a bunch of stuff you don't intend on killing as well. Because a lot of these things are not specific just for mosquitoes. And then aren't people going to end up drinking insecticide? Yeah. Or breathing it in. I remember whenever the insecticide trucks would come through in California, I would run inside the house or I'd bring my baby inside of the house.

36:05And yeah, so you breathe it in, presumably. I mean, they try to make it so that these chemicals are specifically focusing in on things mosquitoes and other insects do and not things that happen inside the human body. I don't know how well we're often able to do that. Katrina, do you have any insights there? Yeah. Oh, exactly. That's the idea. But I think that's extremely hard. I mean, when it comes to viruses and microbes, it's easier to come up with targets that are totally orthogonal to what would happen to a person. But that's so much harder for insects. Like, we're a little more closely related, believe it or not.

36:37To insects than we are to microbes. Yeah. Yeah, exactly. So it's harder to come up with distinct targets. But yeah, that's definitely the goal. But I think there's all kinds of off-target impacts. Like I'm sure you guys remember hearing about the peregrine falcons and the compromised egg structure that came from all the insecticides being sprayed in the 60s. Yeah, right. The DDT. Yeah. I think Rachel Carson wrote about that in Silent Spring. Yes. So we use these insecticides and we're trying to use them in a little bit more specific ways. So, for example, you can dip a bed net in insecticides and then you can put the bed net over your bed.

37:12And then at the time of day when mosquitoes are most likely to bite, you're protected inside of the bed net. and because it has already soaked into the bed net, you're not breathing a lot in or you're not drinking it in water. But the problem is that there's very strong selection pressure for mosquitoes to find routes around this. So for example, if you've got mosquitoes that bite at night, if there's variability and some mosquitoes are biting a little bit earlier in the day, the ones that bite earlier in the day are going to catch the early birds and then they're going to have a lot more babies that go early in the day and now the bed net isn't as helpful.

37:45And we've actually been finding that in some parts of the world, mosquitoes are changing the time of day when they're most active so that they are now going after people when they're outside of the bed nets. Wow. And this is why when I came back from a trip to Tahiti where we had to sleep with bed nets every night and I loved waking up without any bites, I just set up the bed net on our couch. And then for weeks, I just like, anytime I'm hanging on the couch, I'm under the mosquito net. No big deal. I'm like impervious. I'm like laughing at all the mosquitoes. It was a very interesting sight, Daniel, like watching TV while sitting inside the bed net.

38:22It's amazing. Amazing. Because I don't feel any social pressure to be bitten by mosquitoes so I don't look like a weirdo under a bed net. I was happy. It was great. And now I know that ecologically I was suppressing mosquitoes in a balanced way. So yeah, I was being responsible. Way to go, Daniel. Thank you. Pat on the back. All right. That's what I wanted. Thank you very much. So mosquitoes essentially are constantly providing a moving target where there is selection for them to route around whatever methods that we are using to try to keep them at bay. People also use things like they'll dump mosquito fish into waterways.

38:55These are tiny little fish that eat the aquatic stages of the mosquito. My new favorite fish. Yeah, but then the problem is they also outcompete a bunch of native fish and they cause problems in the ecosystems that you introduce them into because they're not native there. So it's not a perfect method, but it's a method you can use in some areas. At your own house, now that you know that there's an aquatic stage, maybe you already knew that, but you can make sure that you dump any standing water. And if you want to, like, have a bird bath, just dump it out every day or two and then refill it because that won't give the mosquitoes time to hatch.

39:26But trying to, like, up the complication level a little bit, the next thing that we started in the 1950s was using sterile insect technique. And folks might remember that we talked about this a bit for the screwworm episode. And the idea here essentially is that you blast mosquitoes with gamma rays or other chemicals that sterilize them. And then you release just the males into the environment. Female mosquitoes mate once, and they'll mate with one of these sterile males. And then if they're able to lay eggs, those eggs won't hatch. And so essentially you are taking females out of the population reproductively by having them mate with males where it won't result in successful offspring.

40:06But this method has a couple problems. First of all, if you are just like randomly bombarding insects with gamma rays, yes, you're going to sterilize them, but you also might beat them up in a bunch of other ways. And so sometimes these males that you release into the environment aren't as good at attracting the ladies as the wild males because these males have all sorts of other things wrong with them. But Kelly, I read a bunch of comic books, and if you blast something with gamma rays, it usually gives it superpowers, right? Yeah. Are you telling me that particle physics isn't really connecting with biology there?

40:38Is that what's happening? I think that's what's happening, Daniel. I'm really sorry. Or maybe it's a statistical thing. Sometimes it works out that way, but the mosquitoes just, there hasn't been the Spider-Man equivalent for mosquitoes yet. Yeah, I'm glad that we haven't turned any of these mosquitoes into the Incredible Hulk mosquito. That would be really a sight to see. That's a nightmare. That would be bad. Yeah. I bet the fabulous mosquitoes do great, though. Yeah. The ultraviolet mosquitoes. Yeah. And actually, I have a colleague at the University of Hawaii who's working on the microbiome.

41:09It's actually in the context of gene drives, but they are working on making the microbiome of the mosquitoes robust to help the mosquitoes that they're engineering to go out there and succeed with the ladies, as it were. Nice. Is this Wolbachia? No, it's mosquitoes. It's a malaria project. It's Nicole Hinson at the University of Hawaii. By Wolbachia, I meant the bacteria that they're adding. But anyway, we'll get back to Wolbachia soon. Oh, no, I think that they are like more roundly making the microbiome of the mosquito robust so that in general the mosquito is robust. I'm not sure. But again, with this method, I wonder like how many males do you have to put out there to have this have any efficacy?

41:46It's not like the males are reproducing and making more of themselves, right? So like every one you put out is one that you essentially manufactured. Is it really possible to have an impact on the population? Yeah, great question. So there was an experiment done in Havana, Cuba. Sorry, I said that wrong, but that's what we expect out of me. Where about one and a quarter million irradiated mosquitoes, in this case the species was Aedes aegypti, were released. And again, all males. And they did a 20-week trial and they looked at a 50-hectare area, so a pretty big area. And they put out what they called ova traps, essentially just like areas where mosquitoes could lay eggs.

42:22And they didn't find any eggs in that 50-hectare area, suggesting that one and a quarter million mosquitoes, which is a lot of mosquitoes, is enough to essentially knock a population down in an area. But the problem is you got to keep doing that over and over and over again every year. So it's an expensive process that needs to be maintained. But it turns out it doesn't work well for Anopheles mosquitoes. So we talked about Aedes mosquitoes. There's another genus of mosquitoes called Anopheles that also tends to have a lot of species that transmit diseases to us. And that species, it looks like it's a little bit harder at the early stages of their life to figure out which ones are males and which ones are females.

43:01And if you can't be sure, then maybe you're releasing a bunch of extra females into the environment who are going to like go and start biting people and possibly transmit diseases. So it works okay for Aedes aegypti if you're willing to release it over and over again over a large area, but it works less well for anopheles because there's this step where you need to figure out if there are boy mosquitoes or girl mosquitoes. And because that's hard to do in the lab, that makes this technique a little harder to use. So next, let's talk about bacteria. So I suspect to have Katrina's attention. So Wolbachia is a gram-negative bacteria that's carried by a bunch of different kinds of insects.

43:39It lives inside of insect cells, and it only passes down the female line. And so it's found ways to manipulate a lot of different insect species to help it transmit from one generation to another. So if a male who has the bacteria mates with the female who doesn't, the eggs that she produces won't hatch. But if the female has Wolbachia and the male doesn't, then she will lay eggs that all carry Wolbachia. And so essentially the bacteria has a way of sort of manipulating things so that eggs are produced in ways where the bacteria can transmit. And in instances where the bacteria wouldn't be able to transmit, it just sort of like stops reproduction dead so that there's a line there where nothing's happening.

44:25So in this way, it can permeate the entire population. That's mind-boggling, this sort of like genetic engineering by the bacteria to ensure that only lines that have the bacteria continue. That's incredible. It is incredible. Yeah, I remember when I first learned about this. It's kind of like blood types or something, that there's like this incompatibility. But I know it's given people a real handle for engineering the populations, so I can only imagine what you're going to say next. So what I'm going to say next is that Scott O 'Neill at Monash University noted that a different lab had found that viruses and fruit flies have trouble growing when they're infected by Wolbachia.

45:04So this has nothing to do with reproduction. This is just if Wolbachia is there, it prevents the growth of viruses that otherwise would have killed the fruit flies. So O 'Neill was like, well, what if we take Wolbachia out of fruit flies and put it in mosquito eggs and then see if mosquitoes carrying this Wolbachia are less likely to transmit dengue, which is another mosquito transmitted disease that can be lethal. And so essentially they did the incredibly difficult job of extracting a teeny tiny bacteria from a fruit fly, sticking it into a teeny tiny little mosquito egg. Apparently they had to do this like thousands of times before it worked.

45:43But they eventually were able to get a strain of mosquitoes that were infected by the Wolbachia that was found in these fruit flies. So you're telling me that they found a strain of Wobakia that kills viruses. And since dengue is a virus, they were like, maybe this strain of Wobakia is going to also kill dengue. That's crazy. It doesn't necessarily kill the virus, but it makes it so the virus can't reproduce. And if the virus can't reproduce, it can't go from mosquito to mosquito. Right. And so they did some lab experiments and it was working well in the lab. And in fact, one of our listeners, Joe, sent us an email that included a link to an article where Wolbachia-infected mosquitoes had been released in Florida.

46:24So we're trying this like out in the wild. And so the question is, does it work? And I looked for a really long time to try to find studies that had quantified this working. And I was able to find one study. And it was in Indonesia. And they released Wolbachia-infected mosquitoes. And it reduced the spread of dengue by 77%. Wow. So not 100%, but like, man, those are much better odds. I'd take those odds. But then I found a 2024 review paper that was trying to aggregate all of the Wolbachia infected mosquito results. And they reported that essentially the only paper they were able to find was this paper from Indonesia.

47:03There were two other ongoing studies collecting data, but they hadn't published results yet. And so I would say at this point that this is super promising. I'd like to see evidence that it's working in some other areas before I could say like, oh, we, this is, this might be the key. But for dengue, there's some preliminary evidence that this method is promising. Well, I'm a big fan of anything that's anti-mosquito. And I'm a big fan of preventing dengue or other kinds of diseases. But the idea of like intentionally infecting mosquitoes with some kind of bacteria seems dangerous. Like, how do we know this thing isn't going to, like, mutate, and then all of a sudden it's some new horrible face-melting disease or something?

47:42So, you know, this bacteria is pretty widespread in nature, so it's not like we're introducing something super weird into the environment, but it is a different strain. I don't know. Bacteria expert, what do you think, Katrina? Well, I guess I was just going to say that this Wolbachia bacteria, I think it's present in, like, 40 % of insects. And so, of course, there's going to be very individual relationships that each bacteria has with its own insect. But I don't know. Of the things that humans do to manipulate the environment, this seems like a relatively innocuous one. I think it's really cool.

48:15It's like not so toxic to just kind of scramble things around a little and hope for a better outcome. All right. Well, if people's faces get melted, it's on you. Oh, no. Well, I think it's on Oxitec, which is a company that is releasing some of these mosquitoes. I don't know that we can blame Katrina. Trina, she didn't release them. But thank you for looking out for me, Kelly. Yeah, you're welcome. I like when we can team up against Daniel. So I'm sure. Well, you know, then maybe I need you to chime in on a topic that's been discussed heatedly at the Whiteson Institute board meetings recently, which is, you know, what is the source of all the mosquitoes at the Whiteson Institute compound that are biting Daniel?

48:58And for example, I'm against having sources of fresh water near the house, but Katrina is growing vegetables hydroponically in our backyard. What do you think, Kelly? I need a ruling. There's no way for a mosquito to get into this hydroponic growth chamber or for a mosquito to get out. So I just really don't think it's possible for them to be in there. But there is sometimes like a bowl of water that collects from rain that I don't notice. And I'm sorry if that caused any mosquito growing to happen. I mean, I'm hearing all of your fancy engineering explanations for why this can't happen, but I'm taking measurements of mosquito bites and I'm telling you, it's high.

49:35It feels like there's been a lot of mosquitoes lately, but I thought we could blame that shipping container of the Port of Long Beach. Isn't that why? Well, what do you think, Kelly? I think that I like every opportunity that I can have to side with Katrina. But I don't really want to get in the middle of a marital spat. So I'm going to run away and call a commercial break and pretend none of this happened when we get back.

50:13Block Party is a can't-miss 4th of July concert happening at the Los Angeles Memorial Coliseum. Experience music performances by major artists, patriotic tributes, and the kickoff to Giving Fourth, helping to make July 4th the largest day of giving in American history. It's more than just fireworks. Join this landmark celebration and get your America's Block Party tickets now for$17.76 at America250.org. slash LA. Introducing the all-new Mazda CX-5. Featuring more connection. Hey Google, where's the nearest Pilates class? Safety that has your back. More discovery on the scenic routes. More passion in the details.

50:54And more control in changing weather. The all-new Mazda CX-5. More to move every side of you. See it in five films at mazdousa.com slash five sides. Google is a trademark of Google LLC. sequences shortened and simulated. Eczema is unpredictable, but you can flare less with Epglyss, a once-monthly treatment for moderate to severe eczema. After an initial four-month or longer dosing phase, about four in 10 people taking Epglyss achieved itch relief and clear or almost-clear skin at 16 weeks. And most of those people maintain skin that's still more clear at one year with monthly dosing. Epglyss, LibriKizumab, LBKZ, a 250 milligram per two milliliter injection is a prescription medicine used to treat adults and children 12 years of age and older who weigh at least 88 pounds or 40 kilograms with moderate to severe eczema.

51:40Also called atopic dermatitis that is not well controlled with prescription therapies used on the skin or topicals or who cannot use topical therapies. EBCLIS can be used with or without topical corticosteroids. Don't use if you're allergic to EBCLIS. Allergic reactions can occur that can be severe. Eye problems can occur. Tell your doctor if you have new or worsening eye problems. You should not receive a live vaccine when treated with EBCLIS. Before starting EBCLIS, tell your doctor if you have a parasitic infection. Ask your doctor about EBCLIS and visit ebgliss.lily.com or call 1-800-LILY-RX or 1-800-545-5979.

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52:49And we're back. And we are talking about genetic engineering techniques for controlling mosquito populations this time around. We're about to get to gene drives, which was the listener's question. This is the most roundabout way of getting there. But first, let's talk about some genetic engineering where essentially you take males and you make it so that if they don't encounter tetracycline, they will die. What is tetracycline? Tetracycline is an antibiotic. And essentially you make it so that the males are making a protein that when it's made, it messes up the cell's activity. But in the presence of tetracycline, that protein is suppressed so it doesn't get made.

53:29So males in the lab are given tetracycline. They act normal. But when they produce suns in the wild, the suns start producing this protein like crazy. It messes up their cell activity and they die. And so the females do lay eggs, but their eggs don't tend to survive. So you genetically engineer mosquitoes to be dependent on this thing that you can give them. So when they go out there in the wild, their bodies are making this protein. And since they don't have this magic powder, they end up killing themselves. They end up dying. Yeah. These are pretty complicated strategies, and they also are strategies that tend to make a lot of people uncomfortable.

54:05So, for example, this has been tried in the Cayman Islands, Panama, Brazil, and Florida. And in the Florida Keys, for example, the initial response was like massive backlash against the release of these GMO mosquitoes. They ended up getting released anyway, but there were people who were saying like, Like, I'm going to find the boxes where these mosquitoes are supposed to hatch from, and I'm going to dump them out or pour bleach in them. And I think in general, it's really important that you have public buy-in for these sorts of things because otherwise you just get – you know, you get people who are justifiably upset.

54:37They don't understand what's being released. They're worried that the genes that got put in the mosquitoes might jump into them. Is that what the concern is, that they're going to end up dependent on tetracycline also? Or is it just a generic like I'm scared of GMO stuff? I think it's more of a generic I'm scared of GMO stuff. You know, folks don't want GMO foods. I think they don't necessarily like the idea of getting bitten by GMO mosquitoes. I think they also don't like the idea of putting an engineered gene out in the environment and not knowing where it's going to end. So like these island capture experiments where, of course, the idea is that it's an island so it's somewhat contained are still unsettling because the world is so connected right now.

55:17So it's hard to know what the reach of an experiment like that will be. Exactly. And so while these releases do first have to go through like a complicated series of approvals through groups like the Food and Drug Administration, the United States Department of Agriculture, the Environmental Protection Agency, it is still the first time we're doing something like this. And so Oxitec did release mosquitoes that had this tetracycline thing happening. And some of the genes from the mosquitoes did end up being found in wild mosquitoes. So like those genes had escaped into the population. There were some headlines at the time that sort of were way overblown.

55:58They said things like these genes are going to make the wild mosquitoes even better at biting us. And now we've just made our problem worse. There wasn't necessarily any evidence for that. But there was evidence that genes that were essentially manufactured in a lab are now part of the wild population and might be there forever. And we don't really understand if that is going to do anything at all. I understand the concern that these genes that you've put into one mosquito might end up in a wild mosquito and you don't know exactly what's going to happen. Maybe it turns them into Incredible Hulk mosquitoes, whatever.

56:29But how does a gene go from that mosquito to the wild mosquitoes? Does it have to breed with those mosquitoes or is there some other weird horizontal thing happening? So I think what happened in this case is that one of the mosquito babies that was supposed to die did not. And so it survived, had some of the genes that it got from its genetically engineered dad. and then is passing that through the generation. Okay, so it's through breeding. Yeah, you could imagine some compensation that allowed it to survive with that toxic protein, and then the toxic protein would stick in the population. I mean, I guess in my mind, there's so much evolution and transfer of genetic material all the time that any tiny little drop that comes from a lab feels insignificant to me.

57:14But I do understand why it feels unsettling. That's my gut feeling also, like horizontal gene transfer happens between insects and our food and just all sorts of different transfers are happening all the time in nature. I'm less worried about a genetic sequence that seems pretty benign getting out into the wild. But on the other hand, I'm somebody who is totally fine eating genetically modified foods. But I understand that that's not true for everybody. And so I can understand why this would be upsetting to some people. And I think generally, you know, biologists don't know how everything works.

57:46And we're pushing buttons and pulling levers on a big complicated machine. And it does feel like one little button on a huge machine. But, you know, you release the right pathogen and it can definitely have a big impact on a population. Yeah, I think it's important to be humble. Yeah. So let's get to gene drives, which is probably the most ethically controversial thing that we'll be talking about today. And we bring Katrina on the show because we generally love Katrina's input. But she also understands gene drives. And I spent a day smashing my head against a paper I could not understand. And so Katrina, could you explain gene drives for us, please?

58:21So a gene drive refers to when you use genetic engineering to force a gene through a population at a really high rate. So normally our genes are inherited approximately 50-50, so the chances of inheriting a particular trait are not weighted in one direction or another. What a gene drive does is it ensures or drives that a particular trait will be more frequent in the population. And we've actually been using this technique in the context of mosquitoes with a few different strategies in mind. It could be something that affects fertility. So then you drive the population to extinction. So that would lead to fewer mosquitoes is the goal there.

59:04But then there's also strategies where you try to prevent the mosquitoes from spreading malaria. So there's some mosquitoes that are naturally resistant to carrying the malaria parasite. And so spreading that strategy is another gene drive technique. So can we dig a bit deeper? Like I understand sort of the basics of genetics at the sort of peapod level, you know, from Gregor Mendel, and you have a 50 % chance of getting the gene from one parent or from the other. How does the gene drive affect which genes you're going to end up with? Well, okay. The one really cool strategy that people use to make gene drives work is to borrow the phage defense system called CRISPR-Cas9.

59:44As you guys hopefully know all about, there are these viruses called phages that can infect bacteria. And the bacteria defund themselves in all kinds of interesting ways. And one of them has been co-opted for all kinds of genetic engineering. It's called CRISPR-Cas9. And it turns out whenever the phage infect the bacteria, the bacteria keep a little record of little snippets of the genes that the phage was trying to infect the bacteria with. And then they put a little pair of scissors, a gene that can chop DNA up next to the little memory bank of all the little phage genes that were left behind.

1:00:23And then when the phage tries to infect, the scissors, the gene that has the DNA cutting enzyme on it will match up with the pieces of the phage gene and it'll chop up the phage as it tries to enter. It was just the Nobel Prize last year to Jennifer Doudna and Emmanuel Charpentier because they had the idea of taking this tool and using it to engineer genes in any system. So just to back up and make sure we're understanding, the CRISPR idea is some sort of like bacterial immune system where it remembers the viruses it's seen before and has a bunch of guys floating around, which will recognize those viruses.

1:01:03Plus it comes with scissors so that when the viruses come near, it latches on and then it chops them up and then the viruses can't infect the bacteria anymore. Is that the basics of how the CRISPR system works? Yeah, that is exactly the basics. but the idea of using it as a tool is really cool because basically now you have a system that can go and find a particular DNA sequence and then it's got scissors right next to it so it can go cleanly chop things out exactly next to whatever sequence is next to it. So with the phages, the bacteria were using it to chop up phages. But now imagine you wanted to go in there and slice and dice a mutation that was causing sickle cell anemia.

1:01:44You can do that. That That actually is happening in people right now, which is amazing. So people with sickle cell anemia now can have some access to CRISPR-Cas9 genetic engineering technology where you use the same scissors, but this time you match it to the gene causing the sickle cell disease and you have the scissors go in there and snip out the problematic gene and replace it with a healthy gene. And I mean, that's to me amazing that that is actually working in people. The idea is not that old. I mean, the discovery is somewhat recent. And so that's the same strategy that's been used to build mosquito gene drives.

1:02:23So I understand how CRISPR can let you edit your genes, which on one hand sounds like, why is that hard? You know, you just like go in and edit the data. But like this data stored on DNA, you can't just go in there and like manipulate it with tweezers. You need some sort of like microscopic manipulation tools. And that's what CRISPR is giving you. But how does that connect to gene drives? How does CRISPR let you enhance which genes get passed down in the population? Well, you engineer mosquitoes that contain a CRISPR-Cas9 gene set in there. And so you could put the scissors right next to a gene that's important for fertility.

1:03:00Or you could put the scissors right next to a gene that controls whether the mosquito is able to be infected by the malaria parasite. And so if you put that in there, then the CRISPR-Cas9 scissors will go around spreading that gene even after the mosquito is born. So throughout the mosquito's life, the gene drive will be active and it will continue to spread that gene. So your opportunity for picking up your genetic traits will not end right at the moment of Mendelian inheritance. The gene drive will continue to be active after that. In the same way that you go in and edit somebody's genes when they're alive to remove the bit that's giving them some condition, you're basically giving these mosquitoes a little bit of genetic engineering during their whole lifetime.

1:03:52So it's not just what they inherit, you're like changing them after the fact. That's cool. Yeah. So basically, if that gene drive is in there, every time the little cassette that has the scissors on it encounters the gene that it can match to, it will swap things around. So you can, like one of the examples that I really loved that I read about was where they had a naturally malaria resistant mosquito and it was just caused by one snip in a gene, a single mutation, and they made a gene drive that forced that mutation through the population. But it's a naturally existing gene, so they're not making a Frankenstein mosquito here.

1:04:32And it made it so that the malaria infectivity rate of the mosquito population could go down. I found another paper where they were tinkering with the gene that they called double sex. And essentially what happened is they made sure, you know, that everybody got two versions of double sex. And if you're a female that has the double sex genes, you are sterile and you also look a little bit male-like. But males who get it are normal and they can go on spreading the gene drive. So essentially every baby that's produced that's a female is not going to make any more babies. And males that are produced are going to be able to go on and mate, but they're going to pass this gene drive on to their offspring.

1:05:13And so they'll create female babies that die and male babies that go off and continue to pass the gene drive until it gets through essentially the entire population, I think, is the goal. Wow. Yeah. And so this has not yet been released into the environment. And so as Katrina noted, there's two different methods. You could try to either kill the mosquitoes directly or you could do something to the mosquitoes so they can't transmit the disease anymore. There might be some other options, too. But those are the two things that people are working on right now. But this, I think this technique in particular is a little scarier ecologically because, you know, like what if that gene drive jumps to, I don't know, another mosquito species?

1:05:53Maybe having two mosquito species eradicated doesn't sound so bad. But what if somehow that gene drive is able to jump to, I don't know, a ladybug that helps control pests in agriculture or something? And now we've got this thing that could lead to extinction. And there's some concern that if you release it, you know, where is it going to end up? But how do these jumps happen? Earlier we were saying that the genetic engineering that you manufacture in your mosquitoes can spread to wild mosquitoes through inheritance. But we're not having mosquitoes like having babies with ladybugs. How does that jump possible?

1:06:27So as we're going to talk about in a future episode, the definition of a species isn't always entirely crisp. Sometimes you can get individuals that are in the same genus, for example, mating with each other. I don't know if they get confused or they have very particular interests, something they're looking for in a partner. No judgment, no judgment. No judgment, no judgment. But if, you know, the mosquito species you put the gene drive in mates with another mosquito species, now you're wiping out that species too. And you can imagine yourself jumping around the tree of life. And whenever you get some, you know, cross species mating, you've now got that species wiped out too.

1:07:04So CRISPR can move because species aren't crisp is what you're telling me. That's right. I mean, yeah, that's definitely one way is through mating partners that might be a little bit less related. But I mean, another big strategy is that sometimes there are big leaps in genes that get transferred across the tree of life. And that often is facilitated by viruses. So, for example, 8 % of the human genome is in the form of endogenous retroviruses. So that means that one of our long-ago ancestors had a virus infect one of their germline cells, one of their sex cells, and we have inherited that to the tune of literally 8 % of our genome.

1:07:46Most of them are pretty dormant and haven't really affected us that much. But some of them have led to the biggest innovations in biology. So like, for example, did you guys know that the gene that led to the placenta evolving came from a virus? So an endogenous retrovirus that infected one of our ancestors back before mammals existed had a gene in it that helps with membrane fusion. So like that gene in a virus is great for helping the cell membrane fuse. But in a mammal, it allows for the fusion between the uterus and the placenta. So cool. So those kind of jumps can happen. And to me, that's a really big question about gene drives, because what if this CRISPR gene gets transmitted farther afield?

1:08:35I think that's the real concern. But keep in mind, in your own gut right now, you have thousands of bacteria that contain all kinds of CRISPR systems, and I'm not worried about those transmitting into human cells. And I should note there are labs that are working on anti-gene drive techniques, like a gene that you could release into the population that would sort of stop the gene drive. And so there are some folks who are forward thinking about this problem and are trying to stop it. But then we can return to Daniel's earlier point, which is that biology is complicated and biologists don't necessarily know what's going to happen.

1:09:06So like, what if we knock out one mosquito species, a different mosquito species fills that niche, and that species is even better at transmitting the disease. Now we've, you know, maybe we can release gene drives again to control the problem. But like, it's hard to know what's going to happen to a system when you remove a an animal that has, you know, a large number of individuals out in the population. And we don't really understand the ecological impact. So Daniel mentioned that some mosquitoes pollinate chocolate. You know, what if you have a mosquito species that ends up being an important food source, for example, for a fish species that is an important source of protein for the local community?

1:09:45So like there's a lot of, you know, ecological stuff that might happen that we don't understand very well. And so making the decision to knock out a species because we've decided we wanted to do that, you know, could have some other implications. But if, on the other hand, you're talking about, you know, more than half a million people dying every year from malaria, my tolerance for taking risks goes up a little bit. But those risks should be well thought through, in my opinion. And I hope that you're including my itchy ankles from mosquito bites in your calculation. I'm not. I mean, that's got to weigh a lot.

1:10:13I'm not. Nope. And, of course, Katrina's going to vote with you, so I'm not voted again. So where we are on this right now is that some genetically modified mosquitoes have been released, and we're doing tests on those. But no gene drive mosquitoes have been released yet. There was Target Malaria was working in Burkina Faso to try to get community buy-in to get people on board with this idea of releasing gene drives. But recently their facility was essentially raided, and they were told that their project is being shut down. It was a little bit unclear what happened because it seemed like the target malaria group was in good with the local community, in good with the government.

1:10:53There have been some like think tanks that think that the problem actually is Russian disinformation where this message has been spread that we are using genetic modification to make people sterile and releasing these genetic mosquitoes will sterilize the local population. So it has become a complicated ethical geopolitical problem. And that's where we are right now. We are sort of trying to decide as a society what we're going to do when we have this technique that could be used to save a bunch of lives from malaria, but has, you know, potential implications, some of which we know about and some of which we might not even understand unless we were to actually try the experiment.

1:11:32So it's complicated because it's biology. But it's worthwhile because these are people's lives and it matters. Yeah, and I think it's so interesting that it's more controversial when we understand what we're doing better. I mean, for example, in agriculture, we've been selecting for traits for thousands of years that have all kinds of ecological impact, and we don't find that to be controversial. But as soon as we use molecular biology tools to genetically engineer things, it's less understandable and somehow scarier, although the implications could be the same. So I think that's really interesting.

1:12:03All right. So we have had a fun, complicated discussion about mosquitoes and genetic engineering. And Katrina, I have no doubt we'll bring you back on the show five or six more times before the end of the year, which is only a couple weeks off. Thanks for coming back on the show. Well, thank you for having me. Thank you to our listeners for submitting their questions. Let's hear what they had to say about the episode. I really appreciate you getting to my question and in the most relevant episode. I can't say that I'm entirely convinced that the reason gene drives haven't been tested yet aren't nefarious.

1:12:36After all, if your goal was eradication and you released enough mosquitoes on a small island, and considering the length of the mosquito life cycle, how long would it take to eradicate the species entirely? A short time period leaves very little time for the genes to jump. If the gene drive did jump species and eradicate another species of mosquito, Hawaii has no native mosquitoes to worry about. In fact, the 6 to 8 invasive mosquito species on the islands would make a great test case to see if the gene drives do jump species. Maybe some diligent pesticide use by the ports could keep any modified mosquitoes from leaving the island before total eradication.

1:13:11Overall, it seems much less risky than Uruguay's plan to use gene drives to eradicate screwworms, given the biodiversity of South America. Maybe the answer is in Wolbachia, which you covered. Perhaps it's just less risky. It looks like they've started attempting to use it to eradicate Culex mosquitoes on Maui to save native birds. Thanks so much.

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