Pushkin. You're listening to Brave New Planet, a podcast about amazing new technologies that could dramatically improve our world or if we don't make wise choices, could leave us a lot worse off utopia or dystopia. It's up to us. On October 8th, 1769, James Cook, an explorer and captain in the British Royal Navy, became the first European to set foot on the islands that are today known as New Zealand. His arrival would have dramatic consequences for the Maori people that had inhabited the land for hundreds of years.

It would also radically alter New Zealand's ecology because when Cook disembarked, so too did some of the rats that had hitchhiked on his ship previously unknown to the Pacific Islands. These rodents grew in population over the centuries and wreaked havoc on the environment.

We're in the middle of a rodent nomy. You've seen the headlines. Rats as big as cats, rats everywhere and is a problem.

It is everywhere like you wouldn't believe they know through things.

We've probably got the most rat, the double the mice rats we've ever had. Shocking to say, shocking.

And it's not just unpleasantness. That's the problem. The rats and other invasive mammals have been decimating New Zealand's birds.

They devoured tens of millions of eggs and baby birds every year, causing the extinction of one quarter of the nation's unique bird species. New Zealand has long tried to get rid of these invaders.

The traditional answer has been to spread rat poison all over the islands, often by helicopters.

But rat poison is indiscriminate. Native animals can also die from eating it.

Sometimes humans accidentally consume it as well, and it hasn't solved the problem.

Recently, scientists have proposed a much more targeted solution. It's called a gene drive, a genetic engineering trick that guarantees that when two animals meet, a specific gene will be inherited by 100 percent of their progeny in time.

Any gene, even a disadvantageous gene, would spread through the population if New Zealand were to release genetically engineered rats with a gene drive to dramatically decrease the rats fertility, well, the rat population would shrink.

In effect, evolution could be directed to vote the rats off the islands. And it's not just rats. Gene drives might be used against any invasive animal or plant that uses sexual reproduction, and they might also be used to save species, for example, by helping them survive the effects of climate change.

Most importantly, gene drives might save millions of lives by eliminating or modifying the mosquito that's primarily responsible for spreading malaria throughout sub-Saharan Africa. Now, no one is yet deployed. Gene drives in the wild, but they've been shown to work in the laboratory.

Reshaping nature, it's a heady concept. Scientists are exhilarated by the possibilities for improving the world.

At the same time, they're wondering what could possibly go wrong. Today's big question, should we use gene drives to correct the past introduction of invasive species, protect species from the ravages of climate change and save humans from serious infectious diseases? Or is it too risky? Evolution and ecology, after all, can be strangely unpredictable. When might the risks be justified? And when you're proposing to release things into nature, who needs to say yes? My name is Eric Lander, I'm a scientist who works on ways to improve human health.

I helped lead the Human Genome Project and today I lead the Broad Institute of MIT and Harvard. In the 21st century, powerful technologies have been appearing at a breathtaking pace related to the Internet, artificial intelligence, genetic engineering and more. They have amazing potential upsides, but we can't ignore the risks that come with them. The decisions aren't just up to scientists or politicians, whether we like it or not. We all of us are the stewards of a brave new planet.

This generation's choices will shape the future as never before.

Coming up on this episode of Brave New Planet. We speak to scientists who played a key role in inventing gene drives, this is potentially a much more elegant way of solving ecological problems than poisons and bulldozers. We talk with people trying to balance the benefits and risks.

OK, so people are looking at using genetic engineering to alter wild species. This is really exciting. And at the same time, literally in the same breath, I was also just like, holy crap, if this isn't used properly, this could be really damaging to our planet.

We hear from a scientist in Burkina Faso who wants to use gene drives to get rid of malaria.

This is really my dream and my hope that I can come up with something that can really help not only Burkina Faso, but the entire Africa and a journalist from Kenya who's pretty skeptical.

It's very nice to think that people really care about the lives of Africans, but I think the story is a lot more complex than that.

Stay tuned. Hey there, I'm Bill Nye, host of Science Rules, where we talk about all the ways in which science rules our universe, you never know what you might learn on our show.

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Chapter one, snail's the size of baseballs. To understand the reasons why people might want to use gene drives, I talked with someone who's thought a lot about them.

My name is Dr. James Collins. Go by Jim, my professor in the School of Life Sciences at Arizona State University.

Jim is an evolutionary ecologist who co-chair to study on gene drives for the U.S. National Academy of Sciences for an evolutionary ecologist. He has a bit of an unusual upbringing.

I grew up in New York City, Queens, and always just had a love of of plants and animals in New York City, in New York City.

Queens at the time was different than Queens. Today, I could go fishing. I could catch turtles and snakes and frogs, all kinds of insects, bring them home to my very tolerant parents.

Jim knows a lot about how ecosystems can be disrupted by the introduction of new species for microbes to mammals.

He told me that Captain Cook was responsible for more than just introducing rats into New Zealand.

Think about Hawaiian birds where they're endangered by avian malaria. And that's as a result of a mosquito being introduced by Captain Cook. Then the colonists brought chickens and they brought avian malaria. The mosquitoes begin to feed on the chickens, acquire the malaria and then begin to feed on native birds, transmit the malaria to native birds and they are being diminished in terms of population sizes and even species.

In fact, Hawaii has become the bird extinction capital of the world since humans arrived 95 142 bird species found.

Nowhere else in the world have become extinct in Hawaii. Even small scale introduction of a new species can lead to massive problems. In 1966, a young boy who was vacationing in Hawaii decided to take a few of the giant land snails that live there back to his home in Miami to keep them as pets in the family garden. The snails, which can grow larger than the size of baseballs, reproduced quickly, they soon began to cause economic damage to local farms, and they also carry dangerous parasites slithering along at quite literally a snail's pace.

They certainly don't look menacing, but for the Florida Department of Agriculture, this is a horror movie. The problem with these things, they love just about anything that grows in Florida.

The eradication effort, which use poisons, took 10 years and cost over a million dollars. But despite all the work, the snail population eventually bounced.

Back in 2014, the Florida Department of Agriculture went door to door searching for the snails.

They found 150000 with two properties alone, harboring 700 of the critters with other invasive species.

The measures have been even more dramatic.

In the 1950s, Australia tried to exterminate an escalating population of European rabbits that had been introduced a century earlier by an English settler. Their solution was to release rabbits carrying a deadly myxoma virus, it killed millions of rabbits across Australia, but it didn't solve the problem. There are hundreds of invasive species that people would like to be rid of, zebra mussels in the Great Lakes, silver carp in the Missouri River, kudzu weed in Georgia, Burmese pythons in the Everglades.

But the species that cause the most harm to humans aren't recent invaders. They're indigenous mosquitoes that spread malaria in Africa. My name is Diane Wirth, I'm on the faculty at the Harvard School of Public Health. I work on malaria.

Diane is also a colleague of mine at the Broad Institute, and she studied malaria for over 35 years.

Malaria starts as a fever and chills. It has nondescript symptoms in the early stages. But then as the disease progresses, people can go into a coma, they get very sick and it spreads by mosquitoes.

That's right. The disease is transmitted by the anopheles mosquito in Africa. That's an awful anopheles. Gambia, a mosquito that's very efficient at transmitting malaria. The world has tried to eradicate malaria once before in the middle of the last century when they had DDT and chloroquine, DDT to kill mosquitoes and chloroquine to treat infected people. And that effort did lead to some successes. Malaria was eliminated from Italy, from most of southern Europe, from the United States, by a combination of those techniques and environmental activities, including putting oil on the top of water.

So it wouldn't be environmentally allowed now, but was done in the Tennessee Valley here in the United States in the 1950s.

And that effort failed in most of the world. And in fact, that effort really never included sub-Saharan Africa, because the experts at the time concluded that in sub-Saharan Africa, transmission was so intense that no effort could bring it under control.

How are we doing in the elimination of malaria today?

I think what's happened in the last decade is two things. One, there's been an overall reduction in the number of cases of malaria through increased distribution of bed nets, better diagnostics, better use of treatment, drugs.

We've dropped cases by 40 percent worldwide and deaths by about 50 percent worldwide. The other part of the story is really sub-Saharan Africa, where progress has slowed and in many cases reversed. For example, Nigeria has 25 percent of all of the malaria in the world, and 10 countries make up 70 percent of the burden of malaria worldwide.

All of these countries in Africa progress using our standard tools has stalled. In those countries. We're going to need innovation in order to actually continue the downward trend and in fact, in some cases reverse what appears to be a rebound in the number of cases.

The mosquitoes are rebounding, in part because they've evolved resistance to overcome traditional methods of control.

The major insecticide that we use to kill mosquitoes, there's resistance in almost all mosquito populations, and so we anticipate that the need to have new insecticides is urgent. And without that, we're unlikely to reach eradication girls, particularly in sub-Saharan Africa.

So scientists are constantly imagining new solutions to save ecosystems and to save human lives. Could gene drives be the answer?

Chapter two Selfish Genes. Instead of deploying poisons and viruses, what if we could just genetically reprogram pests to slow or even stop their reproduction? The strategy may sound simple, but it has a gaping hole, the logic of natural selection means that disadvantageous genes, ones that cause an organism to produce fewer offspring, should die out. But there's a loophole in theory, a gene could spread in a population even if it hurts, and organism's reproduction if it could find a way to ensure that it gets inherited by most of the offspring.

Could nature actually do that?

Nature does such things often again.

Evolutionary ecologist Jim Collins well-known example is a driving Y chromosome in some species of mice, which converts a population into all males. And of course, that population then would go extinct. It's one of those very interesting quirks of evolution in which you wind up with populations of all males basically blinking out of existence. And so you get one group can be converted into males that goes extinct. But there are other groups that still have males and females in them, and they'll they'll continue on when we think of how genes are passed on.

We usually think about the laws of Mendelian inheritance, first recognized by Gregor Mendel, a friar and scientist who studied plants in the Midwest.

Hundreds, Mendel figured out that in sexually reproducing species, each individual has two copies of each gene, one from their mother, one from their father.

They pass on one of those two copies to each child with the two copies, each having a 50/50 chance of being passed on. For example, imagine a gene that determines the sex of an offspring.

If you have a sexually reproducing species that has males and females in it, a baby would be predicted to be a male 50 percent of the time, female 50 percent of the time.

But what if a gene naturally evolved that could cheat, could greedily stack the deck so that it gets inherited 60 percent, 80 percent or even 100 percent of the time.

Biologists refer to such selfish behavior as a gene drive from a gene drive could do is change that ratio as far as any particular genetic trait is concerned.

So what was the first time anybody noticed the existence of a natural gene drive?

They were described in the very late hundreds, very early. Nineteen hundreds. So it's been known for a long time.

Over the 20th century, scientists discovered a vast array of gene drives in nature. But it was only in the beginning of this century that they began to seriously think about how they might harness the power of gene drives.

Austin Burt was the one who laid out in principle the idea that if there were a way to control this natural process, then indeed you would have in your hands something that could control the gene frequency in populations.

My name is Austin Burt and I'm professor of Evolutionary Genetics here at Imperial College London.

Austins, an expert in selfish genes, genes that cheat Mendelian inheritance, things that show gene drive or similar sorts of behavior and all the other sorts of weird and wonderful genes out there are able to spread through populations not because they increase the survival or reproduction of the organism, but because they're distorting transmission to their own advantage.

He became very interested in using gene drives for the benefit of public health.

So, for example, in 80s mosquitoes, which is the vector for yellow fever and dengue, there is a naturally occurring selfish element on the Y chromosome, the male determining part of the genome that gets into 95 percent or so of the progeny. And so it has the potential then to spread through a population and as it does so, distort the sex ratio of the population to be more and more male biased.

That's worth reiterating a naturally occurring gene drive in mosquitoes to 95 percent of the male.

And that caught people's attention because male mosquitoes don't bite people, they don't transmit the disease. And so the idea was that you might be able to use that sort of element to control the diseases spread by those mosquitoes, diseases like malaria.

Unfortunately, gene drives in animals tend to use specialized tricks, many of which still aren't fully understood. The best gene drive to engineer would be based on simple principles, and you'd most likely find them in simple organisms as luck would have it.

That's what Austin studied on my first grant was to study the selfish genetic elements of yeast.

The best known gene drive and yeast exploits the fact that chromosomes come in pairs. So here's the trick. The gene drive occurs at a specific spot on a specific chromosome, and it encodes the instructions for an enzyme called a homing Endou nuclease.

The sole purpose of that enzyme is to make a cut at the exact same spot on any other copy of the chromosome that doesn't already have the gene drive.

When a cell detects that cut, it fills it in with the genetic information from the matching spot on the uncute chromosome and presto change. So the cell inserts a copy of the gene drive into that spot on the chromosome.

When I was reading about this, I thought, well, OK, so if that was actually feasible, then we could instead use use that same sort of approach to change them, to recognize mosquito sequences and then using that to knock out a gene that's essential for the survival or reproduction of the mosquito and so suppress the population that way.

In 2003, Austin published a paper in the Proceedings of the Royal Society describing this brilliant idea. In principle, gene drives could be used to suppress a population, say, decreasing the fertility of mosquitoes or to alter a population, say, adding a gene that would prevent the malaria parasite from growing in the mosquito.

But there was one hitch. The homing in the nuclease in yeast recognizes only one specific DNA sequence. To engineer new gene drives, you'd need to be able to reprogram them to recognize different sequences.

It was difficult to get the enzymes, to recognize new sequences, to recognize Miskito sequences as opposed to sequences.

It would take another 10 years before the solution emerged. It turned out to involve another system that accomplished the same thing in a very different way. The system was called CRISPR. Chapter three, a shining, marvelous future. CRISPR is a kind of immune system that bacteria used to protect themselves against viruses, CRISPR uses an enzyme to cut the virus's DNA. But what's amazing is that the enzyme doesn't have a fixed target.

It's programmable. The bacteria create instructions based on past viral infections. The CRISPR enzyme uses these instructions to search for a matching DNA sequence and then cuts it.

It took 20 years and dozens of scientists around the world to understand exactly how CRISPR works. But once they did, scientists figured out how to use its ability to target DNA sequences to create a technology to edit the genetic code inside living cells from yeast to humans.

Genome editing has made a huge splash, including the award of a Nobel Prize last month to two scientists for their work on CRISPR.

CRISPR has so many potential applications, medical scientists realized that it held the prospect of fixing mutations in patients with severe diseases.

And Austin Burt realized that this new technology could turn his idea of gene drives from dream into practical reality.

Austin had been working for the last decade trying to engineer existing gene drives from organisms like yeast, and that was just a hideously complicated and difficult endeavor that wasn't getting all that far.

CRISPR was the perfect tool for enabling Gene Drive. This is biologist Kevin Esveld, who was the first person to propose a specific design for a CRISPR based gene drive.

I'm an assistant professor at the MIT Media Lab, where I direct the sculpting evolution group, and our job is to cultivate wisdom through ecological and evolutionary engineering.

Kevin's interest in sculpting evolution started early when he read Michael Crichton's 1990 novel Jurassic Park.

The mere notion that we might be able to resurrect dinosaurs through genetic engineering was just mind boggling. And even more so. There's this notion the park was a synthetic ecosystem built to host creatures that lived nowhere else in the world. That's an incredible idea that we can potentially make our own ecosystems. How old were you when your address book?

Oh, God, probably eight or nine at a very young age, you might say. I knew what I wanted to do with my life. I wanted to understand how genetics made organisms and ecosystems the way they are. And I was interested in tinkering with them in order to better understand the answer to that question.

Kevin remembers the moment when it dawned on him that CRISPR would make it practical to engineer gene drives. He immediately read all of Austin's papers.

The first day was pure elation, thinking about all the amazing things you could do. Everything that application's already one is human health.

Things like malaria, schistosomiasis, dengue. It spread by mosquito, Lyme disease, tick borne illnesses, mosquito borne illnesses, parasites, you name it. Number two is environmental preservation. And then there's agriculture because instead of spraying nasty poisons on our crops in order to get rid of the pest that eat them, how about we program the pests to dislike the taste? This is potentially a much more elegant way of solving ecological problems than poisons and bulldozer's.

In short, suppression gene drives aimed at suppressing the population of a dangerous or invasive species could provide a general approach to conquer terrible parasites and restore natural environments. To say that Kevin was excited would be an understatement.

The possibilities of a shining, marvelous future were just exploding all around me like fireworks.

Kevin published his proposal about how to build a CRISPR based gene drive in 2014. Within a year, scientific papers began reporting functioning gene drives first in yeast, then fruit flies, and then in mosquitos. Beyond Kevin's favorite applications, some people are thinking about gene drives as a way to help nature adapt rapidly to some of the devastating effects of climate change.

My name is Didley Koffler. I'm a molecular biologist and I recently founded an initiative called Editing Nature, which tries to integrate diverse worldviews and perspectives to steer responsible development of genetic technologies for the environment.

Natalie first became interested in gene drives because she was frustrated with the methods that were being used to get rid of specific invasive species.

In Canada, where Nathalie's from, ash trees were disappearing at a frightening pace because they were being destroyed by invasive beetles originally from Asia. Ecologists had started considering ways to get rid of these beetles, and they pitched the idea of importing Russian wasps to prey on the Asian beetles.

I was like, are you kidding me? This doesn't make any sense. And so and so I just started thinking that there must be biotech options.

That very year, Kevin Roosevelt and his group had published reports on using CRISPR based gene drives to change wild species. And that was sort of the aha moment where I thought, OK, so people are looking at using genetic engineering to alter wild species.

This is really exciting because it could provide a solution for these really huge challenges that we're facing.

Among those challenges, Natalie, points to what's happening to coral reefs.

So we're seeing a huge decline in coral reef health right now, in large part because ocean temperatures are rising, oceans are becoming more acidic, and that's causing a lot of stress to the coral. It's happening really quickly and pretty extensively.

What a coral reefs matter.

I always think of them as almost like the force of the sea. So they create huge amount of habitat for many marine fish. Many people's livelihoods depend on the fish that depend on coral reef. And so there's been, you know, estimates in the trillions and trillions of dollars that would be lost if the coral were to continue to decline at the rates that they do.

So losing all the coral would be like losing all the forests in a way that's somehow I think about it.

In contrast to suppression gene drives, Natalie thinks that alteration gene drives ones that would spread beneficial genes throughout a population, could make some calls more resilient to climate change.

And there is research starting to come out showing that certain mutations in certain genes can be protective against things like acidification or high temperatures or allow the coral adapt better. And so the idea would be that you could use CRISPR gene editing to rewrite the genome of a coral to be able to express these resiliency inducing genes. If you were to introduce a gene drive as well, then that would also allow you to release into the wild, into the ocean and allow that to spread.

Chapter for Anopheles gambiae.

Of all the possible uses of gene drives, none is more compelling than Austin Bird's original idea of controlling the spread of malaria. According to the World Health Organization, more than 400000 people die from malaria each year. That's close to one death every minute. Most are children under five. Austin Bird ended up creating Target Malaria, a not for profit research collaboration with the mission of developing and sharing genetic technologies to help stop the spread of malaria in sub-Saharan Africa.

Target Malaria is targeting several mosquito species, including Anopheles gambiae, the mosquito responsible for most malaria cases in sub-Saharan Africa, which malaria expert Diane Wirth described earlier.

Among many possible designs, a simple approach would be to create a suppression gene drive that causes mosquitoes to produce mostly male offspring.

The strategy is actually a twofer. First, as Alston Bird noted earlier, male mosquitoes don't bite people, so they can't transmit malaria.

Second, the lopsided sex ratio should cause of the population to dramatically crash and perhaps be eliminated in some areas.

Targeted malaria is headquartered in the UK where Austen works, but it has research teams in many places, including Mali, Uganda and Burkina Faso.

I spoke via Skype with one of Target malarias, lead researchers in Burkina Faso.

My name is Abdul Jabbar. I'm a medical entomologist, Dr Abdulhadi Abati was born and raised in a rural area of southwest Burkina Faso, and he is intimately familiar with the disease.

Malaria is the leading cause of death in Burkina Faso. Absolutely. No doubt about that. This is really a very big issue for us as myself, as a kid. It's been several episodes of malaria. All my brothers and sisters, multiple, every single one got malaria. If you don't have a role in treatment right away, it's going to lead to death and even little myself when I was a kid a long time ago. I have to suffer from malaria and I can really see from the eyes of my parents that they were really very scared because they knew that any time they could lose me, fortunately I made it through.

But as a parent today, I have the experience of my kid.

Abdoulaye is dedicated his life to malaria prevention. He did his Ph.D. in France and post-doctoral research at the U.S. National Institutes of Health before returning to Burkina Faso.

Accidentally, I came to the U.S. to learn and I have to come back home, you know, to give back to my community and other places. This is my dream and my hope that I can come up with something that can really help not only the entire Africa to make sure that we can get rid of malaria.

When he first returned home, the most promising method of malaria eradication was to target mosquitoes by using insecticide treated nets.

And that tool was pretty successful, at least initially. We were really very excited when we saw the data because we had a really fantastic data showing that because the mission in Burkina Faso.

But soon researchers started to see problems with the method.

We started to see insecticide use coming in and we reached a point where mosquitoes are no longer susceptible.

As he began desperately looking for new tools, he came across the gene drive proposal from Austin Bird and Target Malaria and began working with the team.

My hope really that we are able to come up with some really good intervention tools that can help and then have a very good impact on malaria in Africa. Target malaria is still five to 10 years away from testing an actual gene drive in the field, but the excitement is palpable. Controlling malaria in Africa, saving 400000 lives a year would be a big, big deal. A gene drives clearly work in the lab. So what are people waiting for? Why aren't we just releasing gene drives against mosquitoes and lots of other targets as well?

What could possibly go wrong?

Chapter five, what could possibly go wrong? In thinking about what could go wrong, many scientists use terms like unintended consequences. Molecular biologist Natalie Koffler, well, she puts it differently.

OK, so people are looking at using genetic engineering to alter wild species, this is really exciting.

Huge challenges that we're facing and at the same time, literally in the same breath, I was also just like, holy crap, if this isn't used properly, this could be really damaging to our planet.

To prevent that, Natalie founded an organization called the Editing Nature Initiative. For his part, Kevin Esveld came to a similar realization, although it took him just a little bit longer.

Soon after his day of euphoria, his vision of a shining, marvelous future with fireworks exploding, Kevin says he fell into utter despair, total paranoia of dark visions of horrible, horrific misuse and weaponization.

What worries Kevin, Natalie and others is the gene drives actually might be so easy to make and work so well that things might get out of hand, which means if a CRISPR based gene drive system will spread in the wild, probably to most populations of that species that are connected by any kind of gene flow, then that means that individual people could potentially single handedly edit entire species.

Suppose you release a gene drive into the rat population of a remote Pacific island. How can you be sure that it won't actually get off the island and the rodents got there in the first place?

Right.

It's we should all safely assume that they can also get off if one of those rodents goes away on a ship like the ones that stowed away on Captain Cook's ship.

It's possible that the gene drive could eventually spread throughout the entire species of black rats around the world, rats for invasive species in some places, but they're an important part of the ecosystem elsewhere.

So what happens if you unintentionally alter, suppress or in the worst case, wipe out a species? I asked evolutionary ecologist Jim Collins, who co-chair the U.S. National Academy of Sciences study published in 2016.

You do not want to be just reaching into ecosystems and arbitrarily removing species. Humanity has done lots of that, and there have been these unintended consequences that are not good.

Can you give us a couple of examples of of that?

There are any number of instances in which we've we've removed top predators, for example, in ocean systems in which the top predators have been fished out. And then you can wind up with the ecosystem that is greatly diminished. It's largely algae and jellyfish is by the time you've taken off the top predators in the system, what about unintentionally wiping out the mosquito species that carry malaria?

Could that disrupt an ecosystem?

Well, there are plenty of things that eat mosquitoes.

And so hypothetically, yes, there could be effects. Do we know exactly what they are yet? No.

Alston Bird, who founded Target Malaria, has thought a lot about the effects of suppressing mosquito populations. He's asked, are mosquitoes a keystone species on which other organisms depend? According to Austin, experts think not. Predators that eat mosquitoes appear to eat any flying insects.

He's also asked if mosquitoes disappeared from a region, would an insect transmitting an even worse disease take its place?

Well, it's hard to imagine because mosquitoes and malaria are amongst humanity's worst scourges.

Still, Austin says we should take nothing for granted, and mosquitoes are a relatively easy case. You'd have to answer the same questions for every possible use of gene drives. But as Jim Collins's National Academy report notes, there's another problem beyond unintended consequences. There's the disturbing possibility that someone might deliberately use gene drives to cause harm.

It could be used maliciously, a bad actor could decide to try to develop a gene drive system that might target some part of the food supply in the country, the individual could decide to introduce traits, undesirable traits and other other kinds of organisms and cause lots of mischief.

What would be the most likely targets for it? Organisms that reproduce sexually that have a relatively short generation time.

You'd want this thing to turn over pretty quickly.

So you're probably not going to use a gene drive system for for longer lived animals, larger vertebrates, let's say cattle's. But for smaller organisms that turn over pretty quickly, maybe poultry, you might be able to think about using something like a gene drive system.

In short, Jim says a bad actor might try to use gene drives as a bioweapon to devastate agriculture in a country.

Chapter six, Daisy Chains. As Kevin Esveld thought more, he stumbled across a big problem with his initial design for gene drives, it would be too risky even to run field trials to test the technology.

Why? Because if even a single organism escaped from the test area, well, the gene drive might invade the entire species.

The problem with the full power version is it has everything it needs to copy itself forever in every generation.

So Kevin got to work designing gene drives that couldn't spread forever, self exhausting gene drives. He designed something he named a daisy drive.

Every link in this daisy chain is the equivalent of like one gallon of genetic fuel and you burn genetic fuel over generations and when you run out, it stops.

Daisy drives involve a chain of genetic elements, say A, B, C, D, E, each inserted into a different chromosome. A copy's B to make sure it's inherited by all the offspring. B copies C, C copies D. and so on. But nothing's driving A it's inherited by only half the offspring. So when A is lost, there's nothing copying B, so it's eventually lost and so on. When you introduce a daisy chain into a large population, it should eventually peter out and Kevin has more tricks up his sleeve.

He's designed a gene drive that's engineered not to spread beyond the geographical area in which you released it. He calls it a threshold drive. It mimics one of the ways that reproductive barriers arise in the wild by using genetic rearrangements to make interbreeding less efficient.

Kevin thinks these tricks will make it possible to do much safer field trials, but still, what if a drive spreads despite these safety features? Well, Kevin says you can always create a new gene drive to spread and overwrite the first one.

He calls it a restoration drive.

Now, a lot of people say, wait a minute, you can't rely on the same technology that just went wrong. But hold on a second. If the problem is what we did to the species, then using another method that successfully spread a change to the whole species to successfully spread another change to the whole species is perfectly valid engineering. Even as Kevin works to devise solutions, Daisy drives, threshold drives, restoration drives, he knows he can't imagine everything.

I still assume that evolution is cleverer than we are. It's going to have some trick up its sleeve.

This is like you are fighting the tide or you're fighting a blind idiot alien God, to use my preferred conception of what evolution really is.

It's like the story that inspired Kevin to go into biotechnology. Jurassic Park in the classic 1993 film. Dr. Ian Malcolm, played by Jeff Goldblum, is a mathematician who specializes in chaos theory. Early in the film, he presciently calls out the park designers for the hubris in thinking they can control the dinosaur population.

How do you know they're all female? We control their chromosomes, it's really not that difficult to kind of control your attempting is it's not possible. If there's one thing the history of evolution has taught us, that life will not be contained. Life breaks free, expands to new territories, and it crashes through barriers painfully, maybe even dangerously. But know there it is, you're implying that a group composed entirely of female animals will breed.

No, I'm simply saying that life finds a way. Life finds a way.

Yet Kevin knows if we want the potential benefits the gene drives offer, we have to work hard to be sure that life doesn't find a way.

What I'm worried about is the loss of public trust when scientists accidentally engineer a whole species, whatever they do can be undone, except for the fact that it would become very well known through the media that scientists accidentally turned a species into GMOs.

So that's why you're very concerned to get this right.

You don't think that this really will go wrong and you do have this ultimate safety switch, which is send another gene drive to go after the first gene drive.

But if we have to do that, we've already lost public trust in the technology, so we'd better never have to do that. Chapter seven skeptic's. Well, everyone is in favor of eradicating malaria, which kills 400000 people a year. Some people are pretty skeptical about using gene drives to do it.

I personally would not be in favor of gene drives. This is Zahra Mallu.

I'm a journalist and documentary filmmaker from Kenya and I'm currently based in Montreal.

Zahra has covered a wide range of topics that affect Africa, including an investigative portrait of a multinational gold mine in Tanzania. Recently, she began collaborating with an organization called the Etc Group.

It's a small organization that works with civil society across different parts of the world, and they they do work on the impact of new technologies on biodiversity and human rights and agriculture. And so I came to learn about gene drives through such a group, through collaborating with them.

In 2018, Zaara made a short film and wrote an article casting Doubt on Target Malarias efforts in Burkina Faso. For starters, she challenges the motives of people working on gene drives.

The question to ask is, oh, gene drives really about public health and conservation or other other interests and other, you know, other ways that agribusiness companies can make profit from gene drives. Why do we really need gene drives? What are they really for? And who is going to benefit ultimately from the development of this technology? It's very nice to think that people really care about the lives of Africans, but I think the story is a lot more complex than that.

Zaara also argues that Africa doesn't really need gene drives to conquer malaria.

I come from a country where people contract malaria regularly. People die in my country from malaria. We do need to fight malaria and it's a terrible disease. No one's going to disagree with that. However, it's also important to know that Paraguay eliminated malaria. Recently, Sri Lanka eliminated malaria. Algeria and Argentina have just been declared malaria free. And so there are ways in which countries have successfully eradicated malaria without having to employ very risky technologies like gene drives.

I asked malaria expert Diane Wirth whether she thought malaria eradication in those countries provided a useful model for sub-Saharan Africa.

She was skeptical. Algeria. It's a desert. Mosquitoes need water to breed Paraguay. Very small number of cases are probably eliminated years ago, but finally certified Argentina's same story relatively little malaria ever. Sri Lanka is an island.

They don't have to deal with importation from surrounding countries. They have a very strong health care system.

So they're able to identify early every case of malaria and they have a mosquito vector that isn't very robust. Diane argued that malaria in sub-Saharan Africa represents a very different challenge.

There are different mosquitoes, there's different ecology. There's different burden of disease in the population. In many places in sub-Saharan Africa, children have malaria for half the year and serve as reservoirs for transmission.

The mosquito in Africa is a mosquito that only bites humans. That means that's the most effective transmitter in most of Africa. And so therefore, detecting early, preventing and getting treatment for the disease represents a challenge.

Whatever you think about the need for gene drives, Zora's key issue is very important. It's in the title of her film, A Question of Consent. Before gene drives get released into the wild, who needs to say yes? Chapter eight, Sharm el-Sheikh to Nantucket.

What to do about gene drives is a question that's been hotly debated by the governing body for the Convention on Biological Diversity in International Agreement among 196 countries on preserving, sustaining and sharing the benefits of biodiversity in December.

Twenty eighteen. The group met in Sharm el-Sheikh, Egypt.

Natalie Koffler, the founder of Editing Nature, traveled to Egypt to deliver a talk at the meeting.

Many representatives from Tagget Malaria were present and then met many representatives from several environmental groups. And those include environmental justice, advocacy of technological white watchdogs, groups like etc group.

The group of the NGOs at the meeting, including the etc group called for a total moratorium on gene drives, not just on deploying them, but even studying them in the laboratory. They are calling for a moratorium on research, so basically for all research to halt, which I believe is just somewhat ridiculous, I don't think there's a way you to stop people trying to understand more. And if the point is that this could be something that could be of great benefit, you would want to be able to study it more and make sure you can understand what those benefits or risks could be.

Stopping research to me seems irresponsible.

The governing body eventually rejected the call for a moratorium. Nonetheless, Zahra Mulu saw the meeting as a partial victory, pointing to the closing statement by the governing body, which she said requires organizations seeking to release gene drive organisms to obtain the, quote, free prior and informed consent of potentially affected communities.

So it has to be free prior and informed consent before these releases go ahead. So who exactly do you ask for consent? Elected officials, anyone who might potentially be affected?

How do you even know everyone who might be affected? Well, Kevin Esveld has been wrestling with these issues and a project he's working on to fight Lyme disease in New England.

Lyme disease is awful. Lyme disease is disgusting. I don't like ticks. So I figured, well, what if we decide to prevent Lyme disease caused by a bacteria?

Lyme disease can lead to serious long term symptoms, including pain, severe headaches and numbness. Humans get Lyme disease from being bitten by infected ticks. And how of the ticks pick up the bacteria? Most ticks get infected when they bite a white footed mouse. So what if the white footed mice were immune?

Kevin's big idea was to take the mice that had developed antibodies against Lyme disease, read out the genetic instructions that encode those antibodies and use a gene drive to spread those instructions throughout the entire white footed mouse population so that the mice get born immune.

For a number of reasons, Kevin decided the best place to test the idea would be Nantucket and Martha's Vineyard. Former whaling communities turned summer resorts in Massachusetts. First, they have high rates of Lyme disease. About half the people who grew up there have had acute episodes. Second, there islands, so a gene drive wouldn't spread as easily. And third, they had in place a mechanism for consent.

New England has this tradition of town hall democracy in which communities actually get together and discuss important problems.

So Kevin reached out to the Boards of Health on Nantucket and Martha's Vineyard and Nantucket, got back to us first and said, yeah, come to our meeting. So we took the ferry and I explained how we might be able to do this. But if we were going to do it, the community would need to tell us what to do.

Are they interested enough for us to bother? And if so, which option would they prefer when they say this sounds really interesting, we think you should begin research.

How many more meetings have you had after that first meeting? Oh, well over a dozen meetings on both islands. And as this changed the way you think about the experiment, it has.

So people who live there know much more about the environment than I do or in collectively more than any single scientist does. They could notice something that we haven't. And so if you want to make this kind of project as safe as possible, you invite everyone to poke holes in your pet theory. Kevin isn't actually proposing to start by releasing gene drives on the whole of Nantucket or Martha's Vineyard. Instead, he's hoping to try it on some very little islands nearby.

Fortunately, there are several owners of islands who have volunteered their islands for this project because they're tired of going out there over the summer and getting bitten by ticks and having to take doxycycline.

These tiny little islands uninhabited except for occasionally a few summer residents, all of whom have bought in.

So what's your scenario for releasing Gene Drive Mice on a little island? We're considering the possibility of using a form of threshold drive that might be the very first field trial target. Best case scenario would be three years if it turns out the standard methods in lab mice transfer pretty readily. According to a recent update from Kevin, most islanders are comfortable with the idea of releasing genetically engineered mice, provided that all the DNA components come from within the mouse species.

Many, though, are bothered by the idea of mixing DNA from different species, which would, of course, rule out a CRISPR based gene drive at least to start. Chapter nine, consent or consensus? So what to do about fighting malaria in West Africa? The problem is far more urgent than Lyme disease, which is almost never fatal, and the issues around consent are far more complicated.

Again, Zahra Mulu is highly critical of Target Malarias process, which she views as secretive.

So I guess a question pops for them is what constitutes consent to them? What have they done to ensure that the process of free prior and informed consent is in place in Burkina Faso following the decision at the Convention on Biological Diversity? When I spoke to people in Burkina Faso, they certainly were not informed. People need to be informed, not just at the village level where these releases are going to take place, but also in the city's civil society needs to be informed.

I would say the whole country and even the whole region needs to be informed because this is a very risky technology whose consequences are not known.

In Tsar's film, she interviews, about a dozen people in the regional capital were targeted. Malaria's lab is located.

And in small communities where Target Malaria someday hopes to test drives, the people interviewed mostly say they haven't been told about the research. Some say they distrust GMOs, citing Burkina Faso's experiences with genetically modified cotton. And some worry the gene drives will have side effects. According to one woman interviewed, quote, It will kill us. Sora's says Target Malaria hasn't accepted the concept of informed consent.

Target malaria talks about stakeholder engagement. They talk about community engagement, but they don't talk about consent.

She also says Target Malaria shouldn't be the only group providing information about gene drives because they're advocates for the new technology.

Information needs to be out there, information that's not just from Target malaria, but also independent information from researchers, from scientists.

I asked Abdul-Hadi Abati, the Burkina Faso native and target malaria scientist, about his organization's efforts.

It's really important that you have to work in full combat on these, you know, with the different community. What is the level and went community communities, not just about the villages where you're doing the work. It's, you know, the religious authority, the media, the also the civil society. So you can make sure that you have a lot to learn from these people.

Abdulai says that he and his colleagues meet regularly with local residents as well as citizens in other parts of the country to help people understand gene drives. They've developed a lexicon to translate the scientific words into the local languages.

They've also invited residents to visit the laboratory to see how they feed the mosquitoes and explain their experiments.

And he says they've put in place a grievance mechanism that these people are into in the villages I'm not happy about. Did they have any concerns? And now we come and we sit down with them and then we can talk. And and this is how you build us, you know, with the villages.

Target Malaria has also worked with the Burkina Faso government, getting permission from the National Biosafety Agency for small scale releases of non gene drive mosquitoes and with the African Union scientific arm, which issued a favorable report about the potential for gene drives.

Still, Abdoulaye acknowledges there will never be unanimity about gene drives. It's really extremely difficult for the new technology to have everybody having the same opinion. That being said, it's clear that the is really quite the boss. So we all know about 70 to 80 million people or so. You can reach out to anyone, anybody. So we have done what we can do face to face with people. And beyond that, now, we have been working also with the media, either through the TV or through also the weekend paper.

So to mix it up with information in the way that people can, you know, get the right information and then we open our door for anyone who may have concerns about anything. And so far, I can say that we have reached out to a lot of people feel we should have a lot of work to do given target malarias, engagement activities.

I asked Alston Bird about Zahra Molas criticism that the group doesn't talk about getting, quote, informed consent. Austin argued that informed consent is the right concept when you're performing a medical procedure on an individual patient. But he says public health interventions are decided by communities and governments. The practice is to work at the community level to seek community acceptance or approval. In fact, it turns out the statement by the governing body of the Convention on Biological Diversity also endorsed this approach.

It called on parties to seek either free prior and informed consent or approval and involvement of local communities. In other words, the international statement is open to both approaches. I asked Natalie Koffler what she thought about Target malarias efforts to inform the public. They also run a really significant public engagement initiative in the countries that they're looking to release these mosquitoes and eventually and that would be Burkina Faso and Mali and Uganda are sort of the three countries they're targeting. Target Malaria also has significant outreach with government officials and within the African Union.

I have to say, I'm and I'm impressed by the the amount of foresight they're using and the transparency they are they are using. They're going above and beyond what most technologists have ever done in the past.

Well, Natalie applauded Target malarias efforts. She agreed with Zahra Malou on one important point, namely that communities can't just rely on target malaria to provide information or to lead the discussions.

It's concerning to me when a large, well funded organization is able to sort of unilaterally steer the technologies progress. So there needs to be a third party neutral body that can help to mediate this sort of discussions and deliberation and information that would be needed to even come to any sort of decision.

Who is the independent third party who's not either a declared advocate trying to release the gene drive or the declared NGO opponent?

I mean, quite frankly, that's the sort of organization that I'm in the process of trying to create. These are really complicated issues and they really deserve time and reflection and engagement of a really diverse voices.

Natalie was the lead author of an unusual policy article entitled Editing Nature Local Roots of Global Governance, published in November 2013 in Science, the leading American Scientific Journal.

The article calls for the creation of a kind of honest broker organization that can convene parties ranging from local communities to technologists, NGOs and governments to deliberate about proposed uses of gene drives.

We call for the need to have really meaningful, locally based engagement around these technologies. But then we also call for the need for some sort of global coordinating body.

The article's great model of scientists grappling with how society might come together to make decisions about whether and when to deploy a new technology.

It has 16 co-authors, including Jim Collins, who led the National Academies study, and Kevin Esveld. I asked Jim Collins how something like a global coordinating body might work. For example, who would choose the representatives of the local communities?

I would be in favor of whatever governance structure the local community uses to pick its leadership or to pick representatives. And yet you're an optimist that this can be done. I am an optimist that it can be done. And furthermore, I think that we want to do it now. You want to do it now? You want to work through these problems now so that you're thinking you've got the time. The technology has not been perfected. So we have a little bit of breathing room.

So this is the time to develop these sorts of governance structures.

But scientists realize that achieving consensus won't be easy. The more people you have at the table, the harder it is to find consensus. Sometimes it's a paradox I think about a lot because I'm like full on. I want as many diverse voices at the table as we can have. I want historically marginalized voices at the table. I even want people speaking for nature at the table. And this is going to make things complicated. And so maybe we even have to think about again differently.

This isn't necessarily a yes or no. This is more of sort of an informing process that can help steer, at least steer the technology in a way that's reflective of a broader group of people.

Inventing wise ways to manage gene drives may ultimately take as much creativity as it took to invent gene drives in the first place. And it may take some time in that regard. I want to note that at the Broad Institute, the Research Institute I direct, we ourselves have had to grapple with what to do about gene drives.

I mentioned earlier that many scientists had contributed to the development of CRISPR, the key technology underlying modern gene drives, these scientists include some of my colleagues at the road.

And as a result, the institute is a co-owner of some of the foundational patents on CRISPR.

We've granted commercial licenses for the use of CRISPR for many purposes. But the question arose, should we let companies license our patents on CRISPR for use in gene drives? After a lot of discussion, we decided not to do so, at least not yet. We thought it would be better to wait before granting licenses to help buy time for society to decide whether and how to use the technology. Still, the clock is ticking, as I was finishing up this episode, I called Austin Bert to confirm my recollection.

The target, malaria was on target to release Gene Drive mosquitoes in about five years. He corrected me. He said Target Malaria expected to be ready in five years to submit an application asking for permission. What would happen next? He said, well, that would be up to society. Conclusion, choose your planet. So there you have it, gene drives, they could help us restore ecosystems disrupted by invasive species or help critical native species withstand climate change.

Most importantly, they might save millions of lives by suppressing the mosquitoes that spread deadly malaria. But the great power of gene drives to spread genetic changes throughout a population might make them very hard to control. They might spread beyond field tests or intended targets.

Can tamer versions of gene drives, daisy drives, threshold drives, restoration drives ensure safety, or are we kidding ourselves? Whatever we do, will life find a way? If we refuse to consider gene drives for any purpose, we'd be turning our back on a powerful way to tackle malaria. If we do want to consider gene drives communities in Africa, we'll need to answer some important questions. Who should be engaged and how? Who should convene the discussions and who gets to make the ultimate decision.

But it's not just Africa. Similar questions will arise throughout the world, including many places in the U.S. from Martha's Vineyard to Maui. So the question is, what can you do a lot? It turns out you don't have to be an expert and you don't have to do it alone, invite friends over virtually or in person when it's safe for dinner and debate about what we should do or organize a conversation for a book club or a faith group or a campus event.

You can find lots of resources and ideas at our website. Brave New Planet Dog. It's time to choose our planet. The future is up to us. Brave New Planet is a co-production of the Broad Institute of MIT and Harvard, Pushkin Industries and The Boston Globe with support from the Alfred P. Sloan Foundation. Our show is produced by Rebecca Douglas with Merridew theme song composed by Ned Porter, Mastering and Sound Design by James Gava, fact checking by Joseph Fridmann and a Stitt and Enchante.

Special thanks to Christine Heenan and Rachel Roberts at Clarendon Communications.

To Lee McGuire, Kristen Zerilli and Justin Levine. Our hands at the Road to Meal Lobell and Heather Fain at Pushkin and the Eliane Brud who made the Broad Institute possible. This is Brave New Planet. I'm Eric Lander.