These malaria drugs treat the mosquitos — not the people
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Welcome back to The Nature Podcast. This week, treating mosquitoes for malaria and understanding the genetics of pregnancy loss. I'm Nick Pachaciao and I'm Benjamin Thompson.

First up, we've got a story about efforts to improve the ability of anti-mosquito bed nets to prevent malaria transmission. Now, malaria is, of course, a scourge of humanity, with millions of cases seen each year, resulting in hundreds of thousands of deaths, with the burden of cases disproportionately seen in Africa.

Progress in tackling malaria had been seen since the year 2000, with the mass use of insecticide-treated bed nets being one of the key drivers. These bed nets prevent people from being bitten and also kill any mosquitoes that land on them, lessening the risk of further transmission.

But this control strategy has its limitation, as Flaminia Kataruccia from the Harvard T.H. Chan School of Public Health in the US explains. "Infanticides work very well for a while. So these bed nets are really effective for a while. We see a decrease in the number of mosquitoes and a consequent decrease in the number of malaria cases every time new bed nets are given to people. However, after a while,

Mosquitoes, they start developing new mechanisms of resistance, so they're not killed anymore, which means that they lose efficacy in terms of their ability to reduce the number of malaria cases. Indeed, widespread mosquito resistance to insecticides is thought to be an important factor in the plateauing in reductions of malaria cases. And so researchers have been trying to come up with alternative strategies to get around it.

We thought, why can't we, let's say, get out of this concept that we need to kill the mosquito in order to control malaria? After all, mosquitoes don't cause malaria. They transmit it. But the causative agent is the malaria parasite.

And in people, we killed malaria parasites with drugs. So couldn't we use the same strategy in the mosquitoes that transmit them? And this is what Flaminia and her colleagues have got a paper about in Nature This Week. Essentially, their method involves treating mosquitoes for malaria, using drugs to kill parasites before they can be transmitted to a human. They hope that these could be incorporated in bed nets to reduce the chances of malaria being spread.

Now, treating mosquitoes might seem like an unusual approach, but the team have shown it is a possibility. In previous work, they demonstrated that the anti-malarial drug atovaquone could work in mosquitoes to kill Plasmodium falciparum, the deadliest species of malaria parasite and the most prevalent on the African continent.

However, atovaquone is a drug used to treat malaria in humans, and the team wanted to find other compounds that could do the same job but weren't used clinically. This wasn't an easy task.

No compounds were known to target the parasite in the mosquito stages, so we had to perform a screen. We gave mosquitoes a number of chemicals and then we tested whether they would be affected against the parasite. Of course, the team didn't choose these chemical compounds at random. Instead, they tested ones that had shown promise in human blood experiments. Specifically, these compounds targeted parasites at a certain asexual stage in their life cycle.

The team reasoned that these compounds might show efficacy against a different asexual stage of the parasite's life cycle, one that takes place in the guts of female mosquitoes, specifically Anopheles galactos.

Gambier, the most important vector for malaria in sub-Saharan Africa. Sadly for the team, there isn't a lab model for this stage of the parasite's life cycle. So rather than test the activity of these compounds in a dish, the team had to manually test each of the 81 they looked at in this paper on live mosquitoes. I suspect that we did thousands and thousands of mosquitoes. But so

We take mosquitoes, we put them asleep and then we apply the compounds individually. Then when they wake up, we put them in a cage and we feed them with malaria parasites. After a few days, parasites are developing and then we dissect the meat gut, which is where the parasites develop, and we count parasites. Some of these compounds were absorbed through the insect's bodies and were effective at killing the parasites.

But the team needed to test whether these promising compounds also worked in a way closer to how these insects would be exposed to drugs in the real world. Namely, through their legs when they land on something. In this case, the team used glass slides. When we tested the compounds in this way, most of them did not work because the mosquito legs are covered by a waxy layer that is not easily penetrable by many compounds.

And that's where we had to do a lot of work in collaboration with chemists to modify the structure of compounds to make them more easily absorbed by the mosquito. Ultimately, the team developed two potent compounds that could be absorbed through mosquito legs. These targeted two different sites within the parasite's mitochondria, and the team hoped that using them in tandem will help lessen the chances of resistance arising.

But there was more work to do. We had these two compounds that were very potent in glass slides, but that doesn't really help us. We wanted to put them on surfaces that are more representative of mosquito nets. And so for that, we worked with material scientists that incorporated these compounds onto small surfaces. And these compounds retained full activity, even when incorporated onto materials that are very similar to actual mosquito nets.

These compounds, which Flaminia says are straightforward to synthesise and relatively cheap, maintain their activity after a year when incorporated into different sorts of plastic film, prepared in similar ways to how real bed nets are made.

The compounds also provided a lasting protective effect in the mosquitoes. What we found is that the duration of the effect is quite long and four days later the mosquito would have a much reduced chance of becoming infected with malaria parasites, which is something that is very promising for our control strategy where a mosquito bites today and then she gets infected in four days and she would still be fully protected from infection.

Fredros Okumu is a malaria biologist at the University of Glasgow in the UK and the Ifakara Health Institute in Tanzania. He was not part of this research and was impressed with what the team have shown.

He says that it could be a useful weapon to help bed nets maintain their impact, giving time for other economic or medical prevention methods, like vaccines, to be developed. Insecticide-treated bed nets are our best hope at the moment in terms of vector control, but they have a very clear challenge that from an evolutionary perspective we know we will not win. So what we've got to do is find options to delay that loss.

and preserve the efficacy of the impact of those bed nets as long as possible. And I think this group are providing just one of the many options that we could use to do that. And they're doing it unconventionally. I mean, most malignant deaths are happening in very rural places, far from reach of health facilities. And they're saying, well, mosquitoes still go to those villages. So why should we wait for these people in the clinics?

Why don't we bring the clinic onto their bed net? And they're doing it elegantly, and it seems to be working. Fredros says that boosting the ability of bed nets could reinvigorate their two-pronged benefits. Not just protecting the person under the net, but the wider community. Something that insecticide-treated nets do by killing mosquitoes, but are being hampered by the rise in resistance.

However, he thinks there remains important work to be done to investigate how well this approach ultimately works. Right now, we can't call it 100%. What we have to do is to wait until these bed nets are tested in a real field setting because we don't know what other problems might arise.

But I would hate to see it just stay in the lab, because from what I can read of this paper and from the work that this group has done before, it's not only an elegant way to do things, but it's also evidently very transformative. And I wish them well. Flaminia says that real-world testing is something that has recently begun, with a small trial using actual bed nets in Ethiopia and Burkina Faso.

The team are also looking to make the chemistry required to produce these compounds cheaper and come up with ways to speed up methods to develop and test other compounds to increase the pool available.

Only time will tell whether this strategy will help reduce the terrible impact of this disease. But Flaminia hopes it can be an important tool in the armory. This strategy is not a silver bullet that will eliminate malaria from the world, unfortunately. Malaria is a very complex disease and we have been trying to eliminate it for so long with many different tools and still here.

So I think that this is one strategy that can really contribute to bringing parasites to elimination in certain regions by targeting the parasite rather than the mosquito. That was Flaminia cataruccia. You also heard from Fredros Okumu.

To read Flaminia's paper, look out for links in the show notes. Coming up, a rare insight into the genetic mutations that cause pregnancy loss. Right now though, it's time for the Research Highlights with Dan Fox. A device powered only by sunlight can harvest drinkable water from the air, even in one of the world's driest deserts.

Researchers designed a device to capture moisture from the air using a spongy hydrogel, which they loaded with salt to boost its absorbency. The gel sucks water from the air during the cool nighttime. During the day, the device converts sunlight into thermal energy to heat the hydrogel.

The gel releases the moisture which then collects on a condenser. In tests, the system produced 0.6 liters of water per square meter per day in the extreme conditions of Chile's Atacama Desert. The researchers say that the device could cost around 150 US dollars per square meter and last for 20 years. You can absorb that research in full in Device.

The richest people in the world are disproportionately responsible for climate impacts such as extreme heat and drought. Wealthy people contribute to higher emissions by using more energy, buying more things and even through their investments. Researchers used climate models and statistics to link these higher emissions to temperature increases and trends in extreme heat and drought.

Their calculations suggest that from 1990 to 2020, the wealthiest 10% of the global population was responsible for two-thirds of the 0.61 degrees Celsius increase in average global temperature. They also estimate that these people contribute six times more to droughts in the Amazon than the average person.

Their results also reveal inequalities among nations. The wealthiest 10% of people in the United States contribute 17 times more to global warming than the worldwide per person average, whereas the wealthiest 10% in India contribute just 1.2 times the global average. You can find that research in Nature Climate Change. This next topic impacts millions of people around the world each year. Pregnancy loss.

When eggs and sperm are formed, a lot of genetic shuffling occurs. This is how genetic variation is created, but it can also lead to errors that mean an embryo can't develop.

A common problem is chromosomal errors. For example, having multiple copies of a chromosome, three instead of two, or a duplication of the whole set of chromosomes. It's known that chromosomal errors during meiosis are prevalent in pregnancy loss, but roughly like 50% of...

Pregnant losses do not have a chromosomal error. That's Håkon Jönsson, a researcher at DECO Genetics in Iceland. Håkon, along with a team of researchers from Iceland and Denmark, were interested in those 50% of cases without chromosomal error, where there is a euploid set of chromosomes.

Reporter Shamni Bundel spoke to Haukon and asked what's currently known about why these pregnancies are lost. For the euploid ones, little is known because it could be the immune response or it could be also...

point mutations. It could also be perhaps you have genotypes in the father and the mother. When combined, it leads to the fetal demise. This can be really difficult, especially in cases of repeated loss. And often there isn't a way of understanding what's going on. So yourself and others wanted to

and figure out if there were sort of underlying causes in the genetics of how these fetuses were being made, how they were inheriting genes from the mother's side, from the father's side, how things were being mixed together, whether things were mutating, and try and get a handle on what kinds of things were causing the losses. Exactly. Because like you

The dogma was it's all chromosomal errors. So this sparked Henrietta Svare-Nielsen, who is the professor of gynecology at the University of Copenhagen, to look into this because the current treatment to a pregnancy loss is the cold advice just to try again.

But she was not satisfied by that answer. And she wanted to know what's the underlying cause of these pecme losses. So she recruited Eva, who is also a professor of molecular genetics at the University of Copenhagen. And this study demonstrates there are some sequence variants or genotypes that

You could select against in metrofertilization. There's something that you could do for these patients. So if they were having IVF and you could actually sequence the genomes of the embryos, you could pre-identify those cases where some sort of genetic feature is going to make that pregnancy non-viable. Exactly. And presumably...

there could be so many causes of pregnancy loss. How did you go about surveying all of this data? And where did you get this data from? Henrik, sorry, Nielsen and Eva, they asked the patients to collect the products of conception at the time of the loss.

And then they did like exhaustive testing on their blood work and questionnaires and etc. And so the main thing you were doing is then doing DNA sequencing on this material from the non-viable pregnancy or this product of conception. And then also on the parents as well, is that right? Yes. So we compare the genome of the fetus to its parents.

And then we identify mutations there. So new mutations that are present in the fetus that are absent from the parents, they have roughly like 20% more mutations. However,

They have around 300% higher number of pathogenic genotypes compared to adult controls. So pathogenic genotypes in this case are where there are mutations in genes that are already known to cause developmental disorders. You know these genes are important and you're seeing lots of mutations in those genes. Exactly.

So there are certain pathogenic genotypes that you found in this pregnancy loss study where it was already known that mutations in these genes cause developmental disorders. And then there are others in which

Because that never appears in the adult population, because you would never see this particular variant or loss of function mutation in this particular gene in an adult because they wouldn't survive. Now you're actually being able to identify that, yes, they are here in these fetal samples, thus sort of showing that these genes are key and errors are

can be one of the causes of pregnancy loss? Exactly. So this affects the clinical counselling of these patients. So if you know it's de novo mutations, so it's something new, the recurrence risk is low, like roughly like 1%. So when there are brand new de novo mutations, the advice to try again would probably be sensible because it's likely somewhat of a one-off.

But then you also have the case where the sequence variant is present in both of the parents. And it's just quite likely that you will inherit both copies from the parents. There you could apply screening of the embryos in in vitro fertilizations. And in completing the study, you were able to identify causes for

quite a lot of the cases that you were looking at. So you found pathogenic genotypes that you can pinpoint as a genetic cause of that pregnancy loss. We estimate roughly like 6% of these pregnancy losses are lost to these pathogenic genotypes.

So this is a substantial contribution. If you consider that there are roughly 140 million babies born every year in the world, we estimate that millions of pregnancies are lost to these pathogenic genotypes. And given that the adult population is rapidly increasing in age when having the first child,

So you estimate this contribution to increase because like 80% of the variance in the number of mutations transmitted to the offspring is explained by the parental ages at conception. So actually that 6% is a huge increase on what we knew before and a huge number potentially of pregnancy losses in cases that

if we had an idea of why they might be happening, that you could now identify and avoid that? Yes, definitely. And as the data sets increase, I think this will be a better and better resource for exploring the sequence diversity present in these fetuses. Because, okay, we explained 6% of these pregnancy losses with these denomitations, but when

When we have larger reference cohorts, then we can go back into these pregnancy losses and perhaps find more genes that do not tolerate mutations. And why has the genetics of pregnancy loss been so understudied up to this point? It's quite the operation to collect these because these pregnancy losses happen frequently.

some time of the day and you have to get the sample and you're asking people to collect the product conception and put it into a refrigerator and then come with that sample to the clinic. It's a big ask. Yeah, it's a big ask. And I just admire the people that participate in this. And I think this is key why this has been understudied.

The participation rate is quite high. Henrietta has been surprised by this, but perhaps not because people want to know what's wrong and want to have answers. And what would be the sort of ideal next steps in sort of further uncovering even more of the causes of pregnancy loss?

What would you like to see happen? Back in Copenhagen, they have been studying using these non-invasive prenatal testing to assess the status of the fetus. In the future, you will perhaps just be able to assess the fetal status through the bloodstream of the mother, so you don't have to collect a product of conception

to know what's going on in the fetus. So hopefully that will be the future. Hauke Njonsen there talking to Sharmlee Bundell. And there's a link in the show notes to his paper with full details of the research. Finally on the show, it's time for the briefing chat where we discuss a couple of articles.

that have been highlighted in the Nature Briefing. Nick, why don't you go first this week? What have you been reading? Well, I've been reading this week in Nature about a world first, and this is the first bespoke, personalised CRISPR therapy given to a baby with a genetic disease. Right, so CRISPR, of course, long been hoped to be this kind of

Really amazing way to edit small bits of DNA to maybe correct errors that can cause disease. Yes, exactly. And this has been done in some cases. So there are perhaps dozens of people who have had CRISPR therapy to treat sickle cell disease, which is a particular error that leads to red blood cells not forming properly. But in this case, this was a very specific and very

rare genetic disorder, which meant that this baby, who's called KJ Muldoon, to not being able to process proteins properly. Which clearly is a problem. Yes, it is a problem because what happens if proteins are not processed properly in his case was that there was a buildup of ammonia.

And ammonia is not great for you and it can actually cause brain damage over time. So typically when this occurs, the only treatment is to have a liver transplant. But it's months before babies are able to have such a liver transplant.

So in this case, a team of researchers, along with a few companies and the US Food and Drug Administration, all sort of came together in a race almost to try and treat this baby boy with this condition. So I'm guessing they must have understood what was underlying this condition then to try and adjust the DNA to try and fix it essentially.

Yes. So what was happening in this case is one particular enzyme was not folded correctly. And so they needed to make a small change to the genetics to make sure that the protein that eventually became that enzyme was correct in the first place. And so would process the parts of the proteins that have been broken down effectively and stop this buildup of ammonia.

And so what the team did in this case is they used a type of CRISPR editing known as base editing. And you may be familiar with this. This is where single base pairs, so the A's, C's, T's and G's, those are edited and that can allow you to do sort of

precision editing and so they basically had to all come together and very quickly while you know there is perhaps ammonia building up in this baby boy try and come up with this and in within six months they actually managed to do this and come up with a drug for this bespoke treatment for baby moldy and

And baby Muldoon is doing a-okay now? Yeah baby Muldoon is 10 months old now and all indications are that he is doing well so of course doctors are carefully checking on him as he develops but it looks like that this condition seems to be at least fixed. It's too soon to say something like a

cure yet. There'll be a lot more testing and checking to actually find that out. But what they did was they did three rounds of treatments and at every round of treatment, they've been able to reduce the medications that they've been giving him to treat the ammonia buildup. Well, that is a good news story. But I'm wondering about how applicable this is more broadly. This was a bespoke treatment for one little lad.

And it required a huge number of people and teams to come together. Is this something that could be rolled out to other people? Well, that is the rub of this one. This is, as you say, a bespoke treatment. This was personalised for his particular genetics and his particular condition. So it's unclear how what they've done here could be expanded to treat other people with other rare genetic disorders. And even when it is something that can treat a lot of people, this is a very expensive process.

But this could also inspire people. This is basically a test case showing that this sort of treatment can work. So it may inspire people to look further into this, to do more sort of CRISPR treatments to try and treat these rare genetic disorders and more.

you know, for the parents as well. They said in this article that every milestone that baby Muldoon is reaching is a tiny miracle to them. Earlier last week, his mother walked into his hospital room and found him sitting up by himself. And she said, we never thought that this was going to happen. Well, fantastic stuff. And it blows my mind, Nick, that

These gene editing tools were essentially discovered in bacteria as a defense system. And really not that much time has passed that we are seeing this translational aspect and they are being used to help people in the real world. For sure. Well, let's move on to my story today, Nick. It's a very different one. It's about spicy food. Let's talk about spicy food. Are you a fan? I do love spicy food. I can tolerate a decent amount of spice, I would say. I will say I'm an enthusiast, but I think...

It can be overdone. And this story I read about in New Scientist actually could be useful for me. It's about the discovery of an anti-spice compound. An anti-spice compound. So is this something that just has no spice at all or actively cancels out spice? Well, actively cancels it out. And what's more strange is it was found in chili peppers. Okay, so something to cancel the spice of chili peppers was found in chili peppers. Absolutely right. So let's go to it. So the heat in chilies comes from compounds called

capsaicinoids. Now, these bind to receptors in your mouth, and that's what makes you feel the fire, right, if you eat some spicy food. And different chilies have different heats, and the Scoville scale is used to compare heat, and that's based on the concentration of these capsaicinoids. And you have quite a wide range here. You have zero, which is like the bell pepper, the sweet pepper, and up to 2.6, 2.7 million for pepper and

X, which is currently the hottest chili pepper that you can get. That is quite a range. So does this new chemical come in the minus on this Scoville scale? Well, that's a great question. I don't know the answer to that. But I will say that this Scoville scale, there's been some discrepancy between...

Some peppers not being as hot as their Scoville rating suggests, right? The concentrations suggest they should be really, really hot, but they're not. And some researchers, and what they did was they gave people samples of different chili peppers, but adjusted so they should all have the same Scoville rating. But some perceived the heat from these different sorts of peppers differently.

So we have this discrepancy here. And what they've done is they've done some chemistry, gone in to look for that, and they've identified three compounds present in high quantities in the chilies that were not quite as intense as they should have been based on their Scoville scale. And these compounds are called glucosides. And...

I think they thought, well, hang on a minute, maybe this is what's going on here. This is the kind of anti-chili pepper. They had to test it, and they did so in a rather unusual way, which I think is very clever. They tested two chili samples at once, right? One with these potential spice-lessening compounds and one without.

And they tested it in people on either side of their tongue. So one half, I guess, was the control with the regular chili and the other half had this potentially active compound in it. And they did this to try and lessen the effect of, you know, if your tongue was inflamed after eating something hot, you might feel things differently. And what they showed is these compounds, these glucosides, seemed to lessen the intensity of

of the chilli. Oh, interesting. And did they work out how they were doing this? Are they like blocking the receptors of the capsaicinoids or something like that? Good question. Don't know yet how they're working, but this is one of the things that is being investigated. Are they blocking the path that stops these compounds making you feel the heat?

And the question now is, OK, that's interesting. What do we do with this information? And the article that I read about, it lists a few different things. Maybe there's dark side and light side here, Nick. I think the dark side is this could be used to breed hotter chilies. Great. What we need, more hot chilies. We need more hot chilies. Let's raise chilies that don't have these compounds.

The flip side of that is maybe you could use it to raise milder chilies with more of them in there. That's obviously the chili aspect, the chili angle, I suppose. There's also the idea that maybe this could be used as a sort of a first aid, either because you've eaten something particularly spicy and need some immediate relief. Maybe you've got kids who won't eat because something's too spicy.

But maybe also it could be used to block severe pain by blocking pain receptors. So, of course, when we feel the heat, we are feeling it as pain. So potentially, and this is obviously a long ways down the road, these could actually have a translational use.

That is very interesting and not something I'd really considered. I mean, when I think of anti-spice compounds, I just think of milk, but this seems a bit more advanced. It seems like that, but obviously milk is a good go-to, I think, and will remain so for the time being. But let's leave it there for this week's Briefing Chat. And listeners, for more on those stories, you can check out the show notes for some links of where you can find them and where you can sign up to The Nature Briefing to get even more stories like this emailed directly to your inbox. ♪

That's all for this week. If you want to keep in touch, you can follow us on X or Blue Sky, or you can even send an email to podcast at nature.com. I'm Nick Petrichow. And I'm Benjamin Thompson. Thanks for listening. In honor of Military Appreciation Month, Verizon thought of a lot of different ways we could show our appreciation, like rolling out the red carpet, giving you your own personal marching band, or throwing a bumping shindig.

At Verizon, we're doing all that in the form of special military offers. That's why this month only, we're giving military and veteran families a $200 Verizon gift card and a phone on us with a select trade-in and a new line on select unlimited plans. Think of it as our way of flying a squadron of jets overhead while launching fireworks. Now that's what we call a celebration because we're proud to serve you. Visit your local Verizon store to learn more.

$200 Verizon gift card requires smartphone purchase $799.99 or more with new line on eligible plan. Gift card sent within eight weeks after receipt of claim. Phone offer requires $799.99 purchase with new smartphone line on unlimited ultimate or postpaid unlimited plus. Minimum plan $80 a month with auto pay plus taxes and fees for 36 months. Less $800 trade-in or promo credit applied over 36 months. 0% APR. Trade-in must be from Apple, Google, or Samsung. Trade-in and additional terms apply.

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