I'm Kevin Esvelt.
I'm an assistant professor at the MIT Media Lab and Leader of the Sculpting Evolution group.
Now, my group works on engineering organisms, not just in the laboratory but also in the wild.
Now, humanity has been engineering organisms for a very long time.
We have, of course, selectively bred wolves into a tremendous variety of different dog breeds.
All of our crops have been selectively bred.
But what we need to realize is that when we alter an organism, we are diverting its resources
for our benefit, and away from its need to survive and reproduce in its ancestral habitat.
Darwin said "Man selects for his own good, Nature for that of the being which she tends."
And this is absolutely true.
Now that we have precise genome editing tools, such as CRISPR, the same rules apply.
That is, even though we can now use CRISPR to cut a particular site in the genome
and insert a desired sequence that allows us to change a particular trait of the organism,
we're still altering that organism to benefit us.
And that typically reduces its ability to survive and reproduce in the wild.
In other words, no matter how we edit an organism
-- the traditional selective breeding or modern genome editing --
we still expect it to be outcompeted by wild counterparts.
That is, our default expectation for any organism altered by humans is that,
in the ancestral habitat, natural selection will eliminate the altered genes.
But, that's only true for genes that play by the rules.
Some genes cheat at inheritance.
So, even though they might reduce the odds that the organism will reproduce,
they're more likely to be passed on to all of the offspring.
When this happens, we call it "gene drive".
Gene drive is a naturally occurring phenomenon that happens when a vertically transmitted genetic element
-- that is, something transmitted exclusively from parents to offspring --
reliably increases in frequency in a population, even though it does not help individual organisms
to survive and reproduce.
Gene drive is ubiquitous in nature.
Evolution invented it hundreds of millions of years ago.
Prominent examples include the gene drive responsible for the fact that the cow genome
is 25% snake, due to an ancient gene transfer event mediated by a virus in a tick that moved
a "jumping gene" gene drive that copies itself within genomes from snakes into cows.
Which then replicated until it was a quarter of the cow genome today.
More than half of the human genome comprises broken gene drive elements,
as well as a few active ones.
It's nearly impossible to find the genome of any species that doesn't have any signs
of an active or broken gene drive element within it.
They are utterly ubiquitous within the natural world.
And now, thanks to technologies such as CRISPR, we're on the verge of effectively harnessing them
to deliberately change wild populations.
CRISPR can be used to build a self-propagating gene drive.
Instead of simply delivering DNA encoding the change we want to make in that organism,
we also encode the CRISPR system and the instructions for making that change.
That is, we deliver into the reproductive cells DNA encoding the change and the CRISPR system.
CRISPR then cuts the target site in the genome and the entire DNA cassette is then inserted.
So now, this reproductive cell of the organism has the instructions for doing genome editing
on its own.
So, CRISPR components are produced.
They cut the other chromosome and copy over the DNA.
So now, there are two copies.
Any organism with two copies of a gene in its reproductive cells is guaranteed to
pass that gene on to all of its offspring.
So, when this engineered gene drive organism mates with a wild counterpart,
all of the offspring are guaranteed to inherit the drive system.
And in the reproductive cells of those offspring, editing happens again.
CRISPR cuts the wild type version inherited from the wild parent, and copies over the edited DNA.
That means that those organisms are guaranteed to pass it on to their offspring.
And editing happens again and again and again, down through the generations, until, in principle,
all organisms within that population have inherited the altered trait.
So, the key difference between a normal engineered gene and a standard self-propagating gene drive
is that, whereas our default expectation for a standard gene is that natural selection
will eliminate it from the wild,
our default expectation for a standard gene drive is that it is likely to spread in wild populations.
There are some requirements for gene drive systems.
The kind... this kind, the kind that we can make with CRISPR, requires sexual reproduction.
It doesn't work in bacteria and viruses.
Its ability to spread, and how fast it spreads, depends on the generation time of the organism.
Again, it's transmitted parents to offspring exclusively.
It also requires gene flow between different populations of the organism.
Gene drive can be used either to alter or, in some cases, to suppress populations.
And these have different potential uses.
So, can this really work?
Well, CRISPR-based gene drive at this time has been conclusively demonstrated
over multiple generations to work in four different species:
yeast, fruit flies, and two species of mosquito.
But we have every expectation that it will work in most organisms in which
CRISPR genome editing works, which is most sexually reproducing organisms.
So, how does the one build this kind of gene drive, a standard gene drive?
Well, in order to make it stable, you need to identify an important gene,
a gene that's important for the fitness of the organism.
Then you build a drive construct that recodes the tail end of that gene and inserts guide RNAs
that instruct CRISPR to cut the wild type version.
You also encode the CRISPR nucleus and whatever genetic cargo you want this gene drive
to spread through the population.
Then, in the cell, this gene drive system will produce the CRISPR components that then
cut the important gene at multiple sites.
Then... this creates a double-strand break within that important gene,
and then the cell has to repair that before it divides.
It can do so using one of two mechanisms.
If it goes through homology-directed repair, then it copies the gene drive cassette.
We call this homing, when this copying event occurs.
And this is how you go from one copy of the drive system to two copies.
This is how it cheats inheritance.
But there is another repair pathway.
The cell can also just jam the broken ends of DNA together.
But this is why we're cutting an essential gene at multiple sites.
If it jams the ends together, it will delete a section of this important gene.
And that means that this product will be costlier than the gene drive.
That is, natural selection will favor the correct gene drive over this broken product.
And this is required to build a stable gene drive system.
This has been backed up by three studies by independent groups,
as well as a couple of preprints suggesting that
using multiple guides cutting different sites will in fact
preclude this form of resistance.
So, what can you do?
Again, we mentioned that gene drives can alter populations.
If that's used to delete existing genes, then the result is evolutionarily stable.
No matter what happens, if CRISPR cuts that target gene and replaces it with itself,
or if it's deleted, the gene is gone either way.
This can be done reliably.
It can also be used to add new genes, new cargo genes, or to edit pre-existing genes.
But these kinds of changes are not necessarily stable, because they're not linked to
the function of the drive system.
The drive can spread a broken version just as well as it can an intact version.
So there is no selection pressure for maintaining the exact change that we want to spread.
Gene drives can also be used to suppress populations.
For CRISPR-based drives, two methods were put forward.
These were originally posited by Austin Burt in the pre-CRISPR era.
In version 1, you ensure that all organisms that inherit the gene drive system
develop as one particular sex.
So, as the gene drive spreads through a population, all of the organisms become that particular sex
until the population crashes.
In the second method, the gene drive system is constructed such that inheriting one copy
results in a fertile organism that typically will pass on the gene drive system to all of its offspring.
But inheriting two copies -- one from each parent -- produces organisms that are
either not viable or, better yet, are not fertile.
So this means that the gene drive system spreads rapidly when rare.
And when it becomes common, most organisms are sterile and the population crashes.
Crucially, however, models predict that gene drive organisms can crash populations to low levels
but cannot remove them entirely without additional human help.
And this is because the gene drive system is not introduced into every subpopulation simultaneously.
Even if it succeeds in removing one small subpopulation, that area is likely to be
recolonized by organisms that have not yet been affected.
So, the net outcome is that the population is maintained at a very low level over time.
So, what are the potential benefits of gene drive?
That is, why would we want to alter wild organisms?
The main reason is our current methods for dealing with wild creatures that pose problems
are not very environmentally friendly.
We tend to rely very heavily on large-scale environmental engineering, using bulldozers
draining swamps, and other sorts of methods.
Or we use chemicals that have been tuned to attack entire classes of pests,
as well as most organisms reasonably closely related to those pests.
With gene drive, we could conceivably alter wild organisms in ways that are very precise,
and make the smallest possible change that we think could solve the problem.
For example, we might immunize animal reservoirs of human diseases so that they could not serve
as reservoirs for those diseases.
We could tweak vectors of human disease so they're no longer interested in biting humans,
but otherwise go about their ecological role.
We could precisely suppress populations of invasive species.
We could, similarly, reduce fecundity in animal populations, thereby reducing starvation
and predation and animal suffering, especially for organisms that we introduced.
And finally, in agriculture, instead of spraying toxic pesticides throughout our fields,
we could instead tweak the pests so they no longer like the taste of the crop.
This is far away.
We still need to learn a great deal more about how, for example, insect olfaction works.
But in the long run, this is a much more eco-friendly way to go about solving ecological problems
in the wild, if it can be done cautiously and carefully.
So, what are the potential risks?
What could go wrong?
Well, this is very hard to talk about because, ecologically speaking,
the effects are going to depend entirely on the nature of the species and the particular ecosystem
in which that change happens.
What is being done?
And how might that affect the relationships of that species with all of the others?
It will vary entirely on a case-by-case basis.
But there are also social risks with gene drive because, to put it mildly,
people are not terribly fond of the idea of genetic engineering,
especially not when it comes to wild organisms.
So, there is a serious danger of a potential lack of public support and a loss of trust
in both science and governance should scientists attempt this in ways that are perceived
as unethical, or if anything should go wrong.
But one might wonder, why isn't gene drive of biosecurity risk?
That is, this is the ability to alter a wild population.
And a standard gene drive will spread indefinitely.
Isn't that a threat?
And the answer is, probably not.
Gene drive is a technology that inherently favors defense, for three reasons.
First, it's slow.
It necessarily takes many generations to spread.
Second, it's obvious if you look.
That is, if you sequence the genome, in the natural population you should never see eukaryotic
expression signals that turn on gene expression adjacent to CRISPR components,
because CRISPR comes from bacteria.
So, if you ever see a sequencing read that shows two of those elements together,
you know it is unnatural.
That signature cannot be hidden.
So, it's slow.
It's obvious if you look.
And it can be countered, and reliably so.
The first report of a CRISPR-based gene drive was in yeast.
And when we did this, we first built a gene drive that disrupted a target gene,
thereby changing the traits of the yeast.
We also built a second gene drive that cut the first one and restored a functional copy
of that broken gene, thereby restoring the broken trait.
And the first drive worked, nearly perfectly, at ensuring inheritance of the broken trait.
And the second drive, nearly perfectly, restored that broken trait to functionality.
So in principle, because CRISPR can target essentially any sequence, any gene drive that
one person makes and releases can be overwritten,
and its genetic effects undone by a second gene drive.
So, this should be able to restore the original phenotype of the organism.
But it can't necessarily restore the exact original DNA sequence.
Efforts to enable that kind of change are currently underway,
but they haven't yet been demonstrated.
And it's important to note that just because we can restore the population back to
the way it was originally -- in terms of its relationships with other organisms, its behavior and traits --
that doesn't necessarily mean that every ecological change that might have occurred
will necessarily be reversed, because ecosystems are very complex.
In summary, though, fortunately, gene drive does not seem to be a major biosecurity threat,
just because anything that is slow and obvious and easily blocked just isn't a major physical threat.
But the social risks of gene drive and the potential social threats are very, very high,
because people's perception of something doesn't depend on an actual physical change.
So, a very relevant question is, how many organisms carrying a standard gene drive
have to escape a laboratory or be released in order for that gene drive system to invade a wild population?
The answer, somewhat disturbingly, seems to be very, very few.
That is, if you have just two organisms released, there's a non-trivial chance that
that gene drive system will spread in that wild population.
And as the number increases, you can approach near certainty.
And the models that demonstrated this, that predicted it to be the case, took into account
a large number of factors that had been predicted to block this, including genetic level resistance
to the gene drives, whether pre-existing in the population;
the presence of inbreeding;
other barriers to gene flow.
All of these increased the number of organisms needed to invade, but they did not prevent it entirely.
Even gene drive systems that are not stable, that get outcompeted by their resistant alleles,
that can't spread above 40% of the organisms within one population, can still invade population after population.
Never rising above 40% in any one, but ultimately affecting every population.
In general, we can plot the relationship between how efficient a gene drive is
-- that is, how efficiently is it copied from one chromosome to the other --
against the migration rate between two populations
-- that is, out of the number of organisms in one population,
what fraction of them move to the adjacent population in each generation.
And what we find is that highly efficient gene drive systems, such as those
demonstrated in mosquitoes that are copied at 95% of the time room, or more often,
are predicted to invade all populations connected by gene flow
where you have one organism per million moving between those populations.
So, what this means is that models predict that a single laboratory accident that releases
just a handful of organisms bearing this kind of gene drive into a wild population
could devastate public trust in both science and governance.
And this would probably delay all applications of gene drive by many years, because one can
imagine terrible headlines such as "Scientists accidentally turn entire species into GMOs --
is CRISPR to blame?"
And that, in turn, would devastate public trust in applications of CRISPR and gene therapy,
gene therapy which already has been set back by over a decade due to a tragedy
in an unwise and ill-planned clinical trial.
An accident involving gene drive would be much worse.
Fortunately, the scientific community has been on top of this in agreeing to recommend the use,
and demonstrate the use, of laboratory safeguards that allows research on this kind gene drive
to be pursued safely.
And these include molecular forms of confinement... only program drive systems to cut sequences
that are not found in wild populations; separate the components so that not everything necessary
for copying is copied when the drive system spreads.
And you only do this research in laboratories far from populations of the target organism,
such that even if they do escape the lab there's no one to mate with.
Above all else, don't rely solely on barrier confinement, because people make mistakes,
and sometimes organisms can move.
So, what does that mean for scientists who are interested in working with gene drive?
It means they should probably only build this kind of standard gene drive system
if they're working on a problem for which the goal requires affecting an entire species.
And there are only a few such potential applications.
And of them, really only one has any kind of chance of international agreement to go ahead and use it.
And that one is the eradication of malaria, because malaria kills half a million people every year,
most of them children under the age of five.
And there are very few possible paths to eradication that don't involve some form of gene drive
targeting the African vectors.
So, here is a problem for which this kind of standard self-propagating gene drive
is almost certainly necessary.
And it's one that is eminently worthy.
And it's a problem that everyone understands.
That is, it's possible that the nations of the African Union will agree to deploy
this kind of gene drive against malaria.
There are very few other problems for which that is the case.
Most other work on gene drive should focus on different kinds of drive systems.
That is, don't work on the standard gene drive that will affect most populations of the target species.
Instead, work on different forms that are localized.
Local drive systems will be needed to accomplish all of the other goals outlined,
suppressing populations of invasive species, for example.
That is something where you don't want to build a drive system that will spread
into the native population, where the species may be playing an important ecological role.
More generally, you want to build drive systems that will not spread across international boundaries,
because it is much easier to get regulatory approval and popular support for
something that is confined within one nation, and ideally within one particular town.
So, scientists interested in drive systems and ecological engineering should instead
focus on ways of making those technologies localized.
But as they do, we need to keep in mind that this technology is very different
from conventional biomedical research.
Because if we're developing a new drug that can go through regulatory approval,
be put on the market, people's doctors can recommend the drug to them.
And they're free to say no.
They can decline.
They can opt out.
They can choose not to be affected by our development of this drug.
But if we develop a drive system intended to alter the shared environment,
people will not be able to opt out of its effects.
Even if they get to vote on whether or not it's used in their community, if they're outvoted,
they will be affected even though they don't want to be.
And that's why ecological engineering is a form of civic governance.
Just like passing a law, it will affect everyone within the region.
And that means that if we develop these technologies in a closeted manner, behind closed doors,
without telling people what we're doing, we're denying people a voice in decisions
intended to affect them.
And as the National Academies' report says, "The best course of action is to ensure that
those who would be affected have an opportunity to have a voice in decisions about it."
And that's why current efforts aim to change the scientific incentives governing gene drive research
to encourage scientists to pre-register the experiments they intend to perform,
and to make those pre-registration forms public so that people know about all gene drive research
that is going on, and can suggest improvements and changes that could influence
how the particular application ends up affecting their community.
This should not only increase the likelihood of public support
-- because people will then have a voice,
and will be able to shape the technology and the particular application in ways that they want --
but it's also the ethical thing to do.
More generally, gene drive research is an opportunity to initiate and pioneer
a new form of local, open, and responsive science.
If we're developing technologies intended to engineer the shared environment,
we should ensure that early applications only address problems that are obvious to all citizens.
We should openly share our proposals before experiments begin, so that communities can
weigh in on the direction the technology is going, and shape the particular application
in ways that suit them and their environment.
We should actively invite any and all concerns and community guidance, including inviting
skeptical voices to point out potential problems.
Because, first of all, it's their environment, and so it's their decision.
But second, local communities know more about their own local environment than we do.
And ecosystems are complex.
And when you're engineering a complex system that you don't completely understand,
you want to make the smallest possible change that can solve a problem.
And you want to start small, and local, with a field trial, before you scale up.
And that field trial needs to be evaluated by independent scientists, because try as we might,
those of us developing a technology will always be biased in its favor.
We need to make it clear to communities when we begin that independent assessment
of that technology will be needed.
Put this together and we have a chance not just to develop these technologies in an ethical manner
that is more likely to win public support and solve real-world problems,
but it's also a step towards changing how we do science in general, making it more open and aligned
with actual community needs and community wishes.
