(Crossposted from my Substack)

If you’ve been following biology news over the last few years, you might have heard of an interesting concept called a “gene drive”. The overall idea is to engineer a genetic allele that transmits itself to all offspring of a sexually reproducing organism, instead of being inherited by 50% as usual. This allele can also perform some other biological function (a relevant example is causing female sterility).


A gene drive spreads through a population. From Esvelt et al. 2014 (CC-BY)

In multiple trials, modern CRISPR-based gene drives have shown high efficacy in spreading through populations of caged Anopheles mosquitoes and completely suppressing their reproduction. Since Anopheles mosquitoes are the only ones that transmit malaria, causing their extinction would directly save hundreds of thousands of lives per year. Similar gene drives targeted to other types of mosquitoes (Aedes, Culex, etc.) could also eliminate diseases such as dengue fever, Zika virus, and West Nile virus.

However, in spite of promising laboratory trials, gene drives have not yet been deployed in the wild. But why not?

History of gene drives

Although the technology to build effective gene drives did not exist until recently, the idea has been around for a while. In fact, gene drives occur naturally. Some well-known examples are transposons in flies, homing endonucleases in algae, and segregation distorters in mice.

The idea of engineering a site-specific nuclease as a gene drive was developed as early as 2003, and in the decade that followed there were several efforts to develop these, with the labs of Austin Burt and Andrea Crisanti taking a lead role. These early systems showed some biased inheritance, but were not stable for more than a few generations.

The advent of CRISPR as a gene editing system opened up a new opportunity. A paper in 2014 by Kevin Esvelt and co-workers proposed Cas9 as a nuclease for a gene drive, with several properties making it ideal for the task.

From Esvelt et al. 2014 (CC-BY)

CRISPR-based gene drives quickly gained popularity in the field, and by 2018 the Crisanti lab had demonstrated a working gene drive that could efficiently suppress populations of Anopheles gambiae by targeting an exon of the doublesex gene required for female development. At the time this was announced, I was studying at the University of Cambridge, and attended a public lecture by Prof. Crisanti about his lab’s work. The overall mood in the room was almost euphoric: here was a technology that could save millions of lives, the best thing since Borlaug’s wheat!

Since that lecture, about 2 million people, mostly children in Africa, have died of malaria. Gene drive research has not stood still: the Crisanti lab tested their doublesex drive in larger cages of mosquitoes, and it again completely eliminated the populations. But given the millions of lives at stake, what’s taking so long for this gene drive to be released?[1]

See also: the battle against malaria in Africa has stalled

Why the wait?

There are two good arguments[2] against the immediate release of gene drives to eliminate mosquitoes.

First, nuclease gene drives have the possibility of generating resistant alleles, making future gene drives not work against the same target. Therefore, it’s important to get it right the first time, otherwise the potential of gene drives could be wasted. The goal of the large cage trials I mentioned earlier is to confirm that the doublesex-targeting gene drive is effective and does not cause resistance. Still, I think there are enough potential target sites in the mosquito genome that accidentally causing resistance at one of them would be only a moderate setback.

Second, in addition to resistance in the mosquitoes, we must also consider resistance by humans. Even if it benefited people in the short term, releasing a gene drive without consulting the local government would likely lead to a huge backlash, be perceived as “paternalistic colonialism”, and bring about massive restrictions on the development and use of other gene drives. It takes time to build community consensus, and although we should try to shorten this time, bypassing it entirely would be unwise.

But do these concerns really outweigh the roughly 1600 deaths, and many more cases of illness, that take place from malaria each day? I am honestly not sure. If I were Prof. Crisanti, I would be very tempted to release the mosquitoes.

For now, since renaming things is so popular these days, let’s change Anopheles gambiae to Anopheles delendae.

  1. ^

    I do not mean to imply Prof. Crisanti is stalling things; I hold him in high esteem and know he shares the same desire to eliminate malaria that I do. I also know that he recently spent a lot of time trying to stop COVID-19 and it’s hard to work on two things at once.

  2. ^

    There are also plenty of bad arguments, such as that mosquitoes are ecologically essential. They aren’t.

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53 comments, sorted by Click to highlight new comments since: Today at 6:13 PM

I think gene-drive mosquito control is in the same boat as nuclear power. It's perceived as having safety concerns, but the safety concerns can't be addressed by technological advancement because they're actually anxieties and misconceptions, not real problems. Laypeople seem to believe that ecosystems are fragile things that will spontaneously turn into wastelands if they're perturbed, which would mean that removing mosquitoes is risky, and that genomes are dark magic that will trigger zombie invasions if you do anything complicated with them.

The solution to this isn't progress and thoroughness, it's courage. Let the idiots believe what they will and do the right thing anyways.

I'm one of your aforementioned idiots.

To be more precise, I feel extremely uneasy about modern humans' ability to think through the actual consequences of acting on complex systems.

And I find myself utterly unpersuaded by "But here's a detailed model, with empirical backing!"

Like, nutrition is swarmed with this. As just one of a bazillion examples.

The only difference I see in this situation is that something like unilateral action is maybe possible. So just screaming "Tough shit, we're doing this" and pressing the big red button is more of an option.

Other than that power asymmetry, I don't get why this mosquito situation is so very different.

So I guess I'm an idiot? Eh.

Help me out here. Why is this case so clear to you? How do you know you're not basically just "That's my daughter's arm"-ing?

Nutrition is a bad example because it's an area with lots of known unknowns that have close causal connection to human health, and the prior on interventions is bad because the interventions disrupt an existing optimization process that is mostly aligned. That is: random perturbations on human biology are on average bad, because human biology has prior optimization that put it near a local optimum.

The same applies to interventions in economics: they have a high backfire rate because free markets are somewhat-aligned optimization processes.

Perturbations to mosquito biology, on the other hand, are on average good, because mosquito evolution points towards an attractor that's harmful to humans. And humanity is already spending lots of resources trying to eliminate them, and in the locales where this has been successful it's been positive.

You say nutrition is just one of a bazillion examples. I disbelieve. I think that once you've accounted for the presence of preexisting optimization processes in the environment, ruled out the possibility that you're dismantling an aligned process, and have a basic understanding of the domain, backfiring becomes rare.

I'm reminded of the old saying "the road to hell is paved with good intentions".

I think it is fundamentally wrong to just go so something for others even if they don't want it done just because one thinks, or even knows, it is good for them. It's a very bad precedent to set.

That's true that it could set a bad precedent. But it also could set a bad precedent to normalize letting millions of people die horribly just to avoid setting a bad precedent. It's not immediately clear to me which is worse in the very-long-run.

I think there is a rather large gap between saying it's wrong to force your solution on others to save them from themselves and normalizing letting millions of people die (for whatever reasons).

Work to offer the solutions and let them make their own, informed choice.

As has been noted by some already, it is not even clear that such forced actions are even required. Rushing to act without even bothering to try working with those being helped. That type of heavy-handed help seems completely uncalled for at this stage.

Work to offer the solutions and let them make their own, informed choice.

The problem is that the bureaucrats who make the decision of whether gene drives are allowed aren't the same people as the ones who are dying from malaria. Every day that you postpone the eradication of malaria by trying to convince bureaucrats, over a thousand people will die from the disease in question. Most of them, many of whom are infants, had no ability to meaningfully affect their political situation.

I am reminded of the old saying "don't let millions of people die because Robert Mugabe told you to".

Who do you think should have the courage and act? Should a few EA funders just fund a few biologists to do it?

If suitable biologists can be bought, then yes. I'm not certain how hard that is, though; most biologists are stuck in academic instutitions and ideology which tell them they need an IRB to sign off on their plan, and a lot of IRBs seem to be stuck in an ideology where they can't do cost-benefit analysis and veto everything. It's similar to the problem of organizing a COVID-vaccine challenge trial; the default outcome is that you try to find a grantee to do it, and they chicken out and do preliminary studies forever.

The information about how you would do a gene drive seems to be public information. CRISPR is public information. You don't need a prestigious Western academic. The black market finds doctors who are willing to do all sorts of things like transplanting organs without IRB approval. If you go to Africa, I would be very surprised if you couldn't bribe any local biologist into doing the experiment in a way where they wouldn't take public credit for it. 

Even if it benefited people in the short term, releasing a gene drive without consulting the local government would likely lead to a huge backlash

But has anyone asked a local government?

https://www.stop-genedrives.eu/interview-mit-ali-tapsoba/ suggest that local opposition in Burkina Faso stopped them from releasing GMO mosquitos where the males are sterline without a gene drive in 2020 which Target Malaria later managed to do in 2021. 

Target Malaria plans in their timeline that they have to first to five years of testing with those sterile mosquitos before they will afterwards release the gene drive mosquitos in Burkina Faso.

Their timeline seems to be the result of consultation with local government. 

Do you know if GiveWell or any other charitable orgs are funding research that could get us to a release day faster? This seems like possibly one of the most cost-effective public health interventions of all time.

EDIT: I realized Google is a thing, so I googled it and it looks like Open Phil made at least two grants for gene drive research.

Looks like they sponsored a $1.2 million grant all the way back in 2016 for research on gene drives.

Here's another grant for $17 mil from 2017

And it looks like the Gates Foundation has donated at least $10 million as well.

Yes, they are funding the Crisanti lab and others.

Something I didn't see mentioned: is there any concern that a sudden elimination of malaria could cause a population surge, with cascading food shortage effects? I have no idea how population dynamics work, so it's non-obvious to me whether there's a potential problem there. Even if so, though, that still wouldn't be an argument to not do the gene drive, but just to make the appropriate preparations beforehand.

It wouldn't. First the time it takes for population changes to happen is very slow compared tithe business cycles that drive adaptations to economic changes. Second, eliminating malaria is considerably more likely to reduce population growth than increase it.

Do you have any pointer to studies suggesting that eliminating fatal diseases generally reduce population growth relative to the observed growth with the disease?


So I'm just reasoning off the general existence of a really strong demographic transition effect where richer populations that among other things are way, way less likely to die in childbirth have way fewer children than poor populations.

The impression I get, without having looked into this very deeply, is that the two most common models for what is going on is a female education effect, which correlates with wealth and thus lower mortality, but where the lower mortality effect is not having a direct causal influence on having fewer children, and a certainty of having surviving children effect, where once child mortality is low enough, there isn't a perceived need to have lots of births to ensure having some kids who survive to adulthood.

I'm sure there are other theories, and I don't know the literature trying to disentangle from observational studies and 'natural experiments' exactly what component of the changes that are involved with becoming a rich industrialized society causes birthrates to collpase.

The basic point though is that whatever the causal story, empirically you will find an extremely strong association between low childhood mortality rates and low birth rates. This is why people who are concerned with overpopulation generally see reducing childhood death rates as a good thing from an overpopulation perspective: There is a good chance that it is causal for fewer people being born, and it definitely in the historical record doesn't seem to drive rapid population growth.

Having said that, when I was more interested in demographics ten years ago, I got the impression that Africa was seen as transitioning slower than Asia, Europe, Latin America or the Middle East had. 

As far as I am aware, mosquitoes don't respect international boundaries. If you use this method to eliminate mosquitoes in some random African country, it would just spread to their neighbours.


My point entirely ;) I realize that was not clear.

Do we know how much a mosquito travels during its lifetime to be able to estimate how fast such a process would happen? 


(that is a big link!)

You might find some points of interest and I didn't actually read the paper.

One point of interest here might be that the farther distance migration of mosquitos seems to be either wind driven or cases of human transportation. The current state of transportation with more controls on what is carried might slow the speed or wide spread. But in a number of less developed placed that probably will not come into play much and so be an aid in the spread.

Some other urls I looked at, just standard google search, seemed to say most mosquitos will (intentionally) only fly a few miles (3 to 7 were the specific numbers I saw mentioned) from its breeding location during its lifetime. 

They don't move very fast by themselves but can when helped by human transportation (source : some post doc at my lab worked on this a few years ago).

Is there an easy to understand explanation  about why a sterility causing gene drive will spread through the population?

It only causes female sterility, so the males keep passing it on. It reaches the whole population because the gene encodes a protein that  affects the DNA and ensures it’s inheritance, rather than being a fifty fifty. If a modified and unmodified mate, then their offspring have only one copy of the modified DNA and one copy of the unmodified. They would have only a fifty fifty chance of passing that on. But if the gene has the effect of breaking other (nonmodified) copy, then the organisms natural DNA repair mechanisms will copy from the other chromosome to repair the damage. That copies the modified gene over! Now it has only the modified  DNA  and will pass it on with 100% chance. So will it’s offspring, forever, until there are no nonsterile females.

Could such a gene arise spontaneously in nature and be the final  reason for the elimination of a species?

Gene drives (I.e. genes that force their own propagation) do arise in nature. There are “LINE” genes that apparently make up over 20% of our genome: they encode RNA that encodes a protein that takes its own RNA and copies it back into your DNA at random locations, thereby propagating itself even more than our engineered gene drives do. With it taking up that much of our genome, I could imagine something like that killing off a species, though I’m failing to find a specific example.These are examples of selfish genes, so that might be where to read more.

Here is an example of something that comes close from "The Selfish Gene":

One of the best-known segregation distorters is the so-called t gene in mice. When a mouse has two t genes it either dies young or is sterile, t is therefore said to be lethal in the homozygous state. If a male mouse has only one t gene it will be a normal, healthy mouse except in one remarkable respect. If you examine such a male's sperms you will find that up to 95 per cent of them contain the t gene, only 5 per cent the normal allele. This is obviously a gross distortion of the 50 per cent ratio that we expect. Whenever, in a wild population, a t allele happens to arise by mutation, it immediately spreads like a brushfire. How could it not, when it has such a huge unfair advantage in the meiotic lottery? It spreads so fast that, pretty soon, large numbers of individuals in the population inherit the t gene in double dose (that is, from both their parents). These individuals die or are sterile, and before long the whole local population is likely to be driven extinct. There is some evidence that wild populations of mice have, in the past, gone extinct through epidemics of t genes.

Not all segregation distorters have such destructive side-effects as t. Nevertheless, most of them have at least some adverse consequences.

From the discussion of human-engineered gene drives, they would only cause sterility in one sex, which would help avoid the gene dying off as quickly.

Yes, definitely. Although we don't have any examples of this happening, since those species would have gone extinct, making them unable to be studied.

I think this is about superstition around genetics, lack of local populations understanding / trusting the likely outcomes, and most of all, unethical status quo bias. I hate the Copenhagen interpretation of ethics https://www.lesswrong.com/tag/copenhagen-interpretation-of-ethics, I hate status quo bias, and this whole issue makes me so mad. I've been mad about it for years. If I didn't think that AGI was about to come along and turn the whole world on its head, I'd go launch the gene drives myself and damn the consequences. To me it seems like this is institutional cowardice and responsibility-dodging causing these deaths. I very rarely in my life every raise my voice in anger about anything, but this type of scientific cowardice is one of the few subjects I can't talk about without unintentionally raising my voice. This is not the only example, it is only one of the most glaring of MANY. The problem occurs over and over again when reasonable hypotheses get IRB'ed to death and people are left to die as a result. My anger about this is a big part of why I left academia.

What are the others?

Even if it benefited people in the short term, releasing a gene drive without consulting the local government would likely lead to a huge backlash, be perceived as “paternalistic colonialism”...

Yeah, in that case count me in on the "do it yesterday" train.

I think the "local governments might say no" angle is entirely hypothetical anyway. Has any government said no, is it likely that any government will say no? Most malaria-prone countries dedicate significant government funding and resources to mosquito-destroying programs. I suspect most would very happily pay for a gene drive if it was offered to them.

[+][comment deleted]1y21

Although the technology to build effective gene drives did not exist until recently, the idea has been around for a while. In fact, gene drives occur naturally. Some well-known examples are transposons in flies, homing endonucleases in algae, and segregation distorters in mice.

The paper about the flies is from 1992. Drosophila melanogaster still seems to be around and was not driven to extinction. Is there something we can learn from that about gene drives?

Most gene drives wont render the females (and only the females) sterile.

A naturally occurring gene drive features a "selfish gene" rapidly spreading itself through the population of a species. For instance, we could engineer a gene drive that rapidly turns a whole mosquito species purple. Gene drives that lead to species extinction are a subset of all possible gene drives.

Transposons don't stop if they have one copy per individual in a species. They continuously increase their copies per chromosome.

Most species have evolved ways to suppress transposon activity for the transposons that are native to that species. If you add a new transposon for which you don't have any suppression systems that can plausibly make the species extinct. 

The abstract of the paper does discuss this:

These results provide new insight into the process of a transposon's invasion into a new species and the potential risk of extinction such an invasion might entail.

Generally, it's quite surprising that we see a newly inserted transposon family in a species with 50 transposon families in one of our core model organisms if you assume that species survive a majority of insertions of new transposons.

To me, the idea of eliminating an entire species of insect that is part of a complex system sounds reckless. The consequences cannot be predicted and we continue the trend of destroying rather than adapting. Not to mention that DNA is complex in its own right and we cannot predict the consequences of introducing mutations at a faster rate than "nature" has stabilized coping with.

The objective is not to eliminate malaria, really; it's to eliminate the disease that is caused by malaria, for which there are many approaches that do not require messing with large ecosystems, such as improving the resistance of victims or keeping mosquitoes at a distance (heck, if we are determined to introduce mutations, why not add one that causes the mosquitoes to dislike a particular smell, for example, and then make towns smell like that? It would be less destructive, although still subject to the unpredictability of messing with DNA).

(Note that even in the article you share about mosquitoes not being ecologically important there is didn't among the experts)

Humans have driven to extinction tens of thousands of species, and continue to kill more every year. Whilst mostly bad, very few of them have had terrible impacts on the ecosystem.

To then hyperfocus on one particular species, specifically one which kills hundreds of thousands of people each year, is essentially an isolated demand for rigour. If we wanted to reduce our impact on the ecosystem let's focus instead on saving some of the species that don't cause extreme human suffering.

Much of the environmental destruction is directly caused by people living in unwealthy nations, as a way of trying to produce wealth. Elephant poaching and rainforest slash and burn are examples. Alleviating a major source of misery will probably help these countries become more economically successful. It will save ecosystem diversity on net.

But enormous resources are already used destroying local mosquito populations. In many countries water in swamps is covered with a layer of oil to stop mosquitos breeding in it. Helicopters and planes I think sometimes spray insecticides over forests. In Singapore and parts of Malaysia these kinds of measures have successfully eliminated the local mosquitos.

A gene drive might be cheaper and more effective (and with less side effects) than blanketing the water with oil and the air with insecticides.

Malaria deaths are a crazy high number. How bad would the ecological side-effects need to be to make it not worthwhile? 

if we are determined to introduce mutations, why not add one that causes the mosquitoes to dislike a particular smell, for example, and then make towns smell like that

Why would you expect those mutations to spread? 

Note that even in the article you share about mosquitoes not being ecologically important there is didn't among the experts

The question is not about whether or not mosquitoes in general are ecologically important but whether if you get rid of less than 0.1% of the mosquito species, the niches covered by them are not just filled by other mosquitos.

It does sound reckless doesn't it?  Even more so when you consider that over time you would likely have to eliminate many species of mosquito, not just one to achieve the effect you desire.  And, as the linked nature article noted, this could have knock on effects on other species which prey on mosquitos. 

I think your comment is important, because this is probably the heart of the objection to using gene drives to exterminate mosquitos. 

I think a few points are relevant in thinking about this objection:

(1)  We already take steps to reduce mosquito populations, which are successful in wealthier countries. 

(2) This shows the limited ecological effects of eliminating mosquitos.

(3)  The existing efforts are not narrowly targeted.  Eliminating malaria and other disease causing mosquitos would enable these other efforts to stop, possibly reducing overall ecological effects.

(4) Malaria is a major killer and there are other mosquito borne diseases.  If you are looking at this from a human-centered perspective, the ecological consequences would have to be clear and extreme to conclude that this step shouldn't be taken and the consequences don't appear to be clear or extreme.  (If there is another perspective you are looking at this from, I'd be happy to consider it.)

(5)  Humanity is doing its best to eradicate Guinea worm to universal praise.  It's a slow process.  Would you suggest reversing it? Why are mosquitos and Guinea worms different?

Fair points made, will take them and ponder.