Good morning, students, staff and colleagues.
I'm Doctor Ethel Gordon from the Department of Biology.
It is my pleasure to introduce Doctor Kevin Esvelt as the inaugural speaker for
today for this week's Earth Day program.
Doctor Essfelt would have addressed you last month during the annual Darwin
Festival had it not been for inclement weather.
Doctor Essfelt received his bachelor Bachelor in Chemistry and biology from
Hobby Mudd College in Claremont, CA, and he received his PhD from Harvard
University.
Dr.
Essfelt is an associate professor of Media Arts and Sciences at MIT and
director of the Sculpting Evolution Group.
He is his lab is working to develop technologies that allow for local
alteration of organisms.
They also are are developing systems that would allow genetic changes in the wild
to be overwritten or reversed.
An outspoken advocate of sharing research plans to accelerate discovery and improve
safety.
Doctor Esfil's lab seeks to promote beneficial advances while safeguarding
biotechnology against mistrust and misuse.
He is here to describe some of his recent work.
This talk is entitled Should we?
Should we engineer ecosystems?
Please welcome Doctor Kevin S Scott.
Thank you for the very kind invitation and introduction and as well for the
oddly appropriate mouse microphone.
I love it.
So I thought I would, in honour of Earth Week,
give a talk focused on this question of what should we do with our new found
power.
So the question might be restated as why engineer living things to begin with?
Not necessarily out there in the environment, but just across the board.
Curiosity.
Is it wanting to understand the world and how other creatures experience it,
understand how they work, understand how they came to be,
how we came to be.
But to draw on Darwin Day, Darwin's bulldog,
Thomas Huxley had a different idea.
So responding in part to the development of Social Darwinism,
the movement that says that we should reconfigure society to be more like
natural selection in the wild, Huxley said this is nonsense.
Let us understand once and for all the ethical progress of society depends not
on imitating the cosmic process like social Darwinism,
still less in running away from it, but in combating it.
That is, he is saying, evolution happens out there and we don't
approve, so we should do something about it.
And he says, it may seem an audacious proposal thus to
pit the microcosm against the macrocosm and to set man to subdue nature to his
higher ends.
But I venture to think that the great intellectual difference between the
ancient times with which we have been occupied and our day lies in the solid
foundation we have acquired for the hope that such an enterprise may meet with a
certain measure of success.
Now, it's been 131 years since he wrote that,
and we were in fact quite far from doing anything in his day,
But we do in fact have a solid measure of foundation for success.
So what would we use it on if we decided to?
I submit Cochleo Maiya Hamanevorax has to be one of the best named creatures out
there in South America.
It's commonly called the bischera or Gustano Berndodor da granado.
We call it the New World screwworm.
I submit that at least by back of the envelope,
eradicating this Organism from the wild, removing every last every last screwworm
botfly, would relieve more animal suffering
integrated over the future than any other single possible human action.
Why is that?
Well, this Organism lays its eggs, its primary myiasis.
It lays its eggs in open wounds, anything as small as a tick bite,
and the larvae then drill their way in.
That's why they're called, they're screw shaped,
that's why it's called the screw room.
And they devour the Organism, the healthy tissue, not just diseased.
And they culture microbes that emit volatiles that summon in new gravid
females to lay more eggs.
It solely preys upon mammals and birds which we know can suffer warm blooded
things and it often ends with the host being devoured alive by flesh eating
maggots.
So Darwin lost his faith over the Icnum Onidae which just do this to insects.
This is mammals and birds.
We're much more confident that they suffer and by back of the envelope.
Based on habitat density in South America, it sure looks like this happens to
probably something on the order of a billion mammals and birds every year.
Typical lifetime of an insect species is several million years.
When you do the math this is 10 to the 15th mammals and birds being devoured
alive by flesh eating maggots.
For comparison, factory farming is about 10 to the 11th
animals per year.
So if if we were to continue at 100 years before we stop then that would be 10 to
the 13th.
So stopping this is probably more important than enduring factory farming
immediately, unless it is 100 times worse to be a
broiler hen than it is to be devoured alive by flesh eating maggots.
It's also a horrific burden on some of the poorest people in South America,
causes tremendous amount of of economic damage to herders in particular because
they have to constantly treat their animals for infestations.
So I went down to Uruguay and they have now launched a project to build a gene
drive system in these organisms.
So CRISPR based gene drive basically says let's introduce the CRISPR system and a
desired change CRISPR introduce this into the reproductive cells.
CRISPR cuts and introduces itself into the genome, but then it's in there,
it cuts the other chromosome, copies itself over such that now when
this mates with a, with a wild type Organism,
then in each generation in the reproductive cells,
you get CRISPR copying such that it's always inherited.
So generation after generation it spreads.
So the net effect then is me having to drop out of the presentation and to deal
with that video.
So you end up with the whole population in principle being engineered.
If this works well, this works great in the laboratory,
it probably works great in the wild, but thankfully no one has actually
released them yet because it will spread to all populations connected by gene flow.
So Huxley was pretty optimistic back then.
Now we really can engineer entire species.
This probably could get rid of the New World screwworm because we already
eradicated it from an entire continent, North America,
just by irradiating the larvae enough so that they became sterile.
They still developed and then releasing 100 times as many sterile screwworms as
there were wild screwworm flies.
And we did this to push them out of up through Florida,
West down through Texas to the Mexican border.
USDA, then US then made agreements with Central
American countries and pushed them South.
And so that now our tax dollars go to releasing 10 million irradiation
sterilized screw room flies every week in a living wall across Panama to prevent
them from reinvading North America.
There's far too many in South America to get rid of them that way.
You really don't want to do sterile insect technique releases over the Amazon,
but gene drive gene drive could do it.
So the problem is, who gets to decide what should we do and
how?
Probably the most morally important application is to get rid of malaria and
then chestosomiasis.
But that probably shouldn't be the model of how we decide whether,
when and how to edit species just because it's really hard to deal with power
dynamics and complications and issues of education and equity in places like
Africa that suffer from those diseases.
So the screwworm is an interesting case because Uruguay is a high income country.
They've been engaging in the community discussions about whether or not to do
this.
And of course they would need to involve the rest of the Mercosur countries.
But we thought, well, at least I thought since CRISPR based
gene drive is my fault, we needed to a better guide to
engineering ecosystems with communities, with community input to help us decide
when to do this.
So I thought of a few general rules for engineering complex ecosystems,
which is number 1 is is to be humble because our power, I submit,
comes from reductionism.
It's simplifying the system, understanding the pieces extremely well
and how they fit together such that we can engineer a robust machine,
macroscopic or microscopic, that will function across a wide variety
of environments.
But to get that power, we simplified away all of the complexity,
which means we're much better at building things that change systems than we are at
understanding complex systems made of many different pieces.
So this demands some amount of humility in deciding are we ready to tinker with
that system.
So if you are going to tackle something, you should try to make the smallest
possible change that you think has a good chance of solving the problem.
Just because the most minimal change is the least likely to break something
important, you should always test it by starting
very small and local small scale.
Don't do something large.
Don't use a self propagating CRISPR gene drive that is not suitable for field
trials ever.
And then scale up only if the results look good in that ecosystem and in fact,
all relevant ecosystems.
And always, always seek advice from and defer to
others who know more because this is not nuclear physics.
If you're doing, if you're running a high energy super
Collider, there's probably no need to go to the
local community and say, hey, what do you think's going to happen?
Can you give us any advice on what we should do?
But if your engineering ecosystem people live out there and they know a lot and
may have noticed things that you haven't noticed.
And what we have found is that this is in fact true.
So where do you start?
Because like it or not, a lot of people are understandably leery
of our tinkering with the stuff of life.
A lot of people really don't like genetically modified foods.
A lot of people mistrust vaccines.
How can we avoid mistakes and backlash?
How can we build trust?
How can we earn that trust?
And I think the key is you got to address a problem obvious to everyone,
because honestly, tomatoes that go bad in the supermarket a
little faster than you might like is not exactly a great Clarion call to begin
tinkering with the stuff of life.
You should openly share your proposals before your experiments begin.
Note, this is not how we normally incentivize
folks to do science.
Normally, if you tell people your brilliant idea,
then someone else with more money in hands will get it done first, publish it,
scoop you and they get all the credit and you get none.
This is arguably fine for biomedical drugs,
because if my grab lab develops a drug and your doctor recommends it to you,
you can say no.
You can choose not to be affected.
You can opt out of being affected by our research.
But if we develop an eco technology intended to change the environment you
live in, even if it goes up for a vote in your
community, up or down and you get outvoted,
you're getting affected no matter what.
So if we developed that one in secret, we denied you a voice in decisions
intended to affect you, but you won't be able to opt out of.
So you need to actively invite concerns and community guidance openly before you
do anything and arrange for independent assessment of how it's going.
Because, of course, if you've developed the technology,
you are the single most biased person in the world when it comes to deciding
whether or not it should actually be used.
So how to test whether any of this is right?
This all sounds good in theory, but a lot of things sound good in theory
and don't actually work in the real world.
How do we test this?
And if it works, how do we actually change those
scientific incentives to something that might be more helpful?
Because I don't think anyone rationally engineering the scientific ecosystem from
scratch would set up the incentives for all of us to keep our best ideas a secret
from one another as long as possible.
So we decided that living here in New England, a possibly relevant,
sufficiently obvious problem is Lyme disease.
Now I'm from the Pacific Northwest, where we don't have horrific blood
sucking monsters lurking in the underbrush all the time,
ready to latch on and feed on your blood and give you nasty diseases.
So I found moving here a little traumatizing in that sense.
Had to be a little bit more cautious when it comes to hiking about.
But it is true that one could accurately claim that in the North East we have no
traditional natural disasters.
We don't really get serious hurricanes.
We don't have earthquakes or really serious tornadoes,
at least not near the coast.
Our natural disaster is Lyme disease.
It's the most common in vector borne infectious disease in the United States
by a long shot, and most cases go undiagnosed.
It's hardly malaria, but it ruins lives long term.
So we thought, is this something that you could
plausibly use in ecotechnology to fix?
So unlike Europe, which also has a Lyme disease problem,
we have one primary reservoir.
It's not the only reservoir, but the white footed mouse Paramiscus
leukopus is the primary reservoir.
And when it gets bitten by a tick, tick gets infected when it,
and when an infected tick bites it, the mouse gets infected.
So mainly you just have this cycle between the two of them.
And then most other species are secondary.
The problem comes when a tick that has just bitten a mouse and gotten infected,
then bites a person and infects them.
And we made this problem worse because we already engineered the local environment
to maximize the number of infected ticks.
Because of course, we love our trees.
We love living amidst trees.
The Northeast is more forested than it's probably ever been,
but we've carved it up with roads and houses,
so we've maximized the forest perimeter.
And as it turns out, the mice do best at the edges of
Woodlands.
Not in the open, not in the dense Woodlands,
but at the edges.
So we just turn the habitat to maximize the number of the primary reservoir.
We also got rid of most of the wolves, which allowed the deer population to
explode.
The deer also prefer forest edges.
So we have many, many more deer.
And I know some people, having been influenced by Bambi,
see deer as these majestic creatures and they love seeing them in their, well,
maybe not in their gardens, but you know, in their backyards.
But I can't help but looking at look at a deer and think that's a million ticks in
the next generation.
So we maximize the number of deer and therefore maximize the number of ticks.
And then we maximize the number of the reservoir that transmits Lyme disease
more effectively than any other reservoir.
So we pretty much maximize the number of infected ticks in the environment
inadvertently.
So you can say This is why we have such a Lyme disease problem today,
whereas we really didn't say 80 years ago.
How do we fix it?
Well, one possible idea is to engineer the mice
so that they can't be infected, because then you break the cycle.
Fewer infected ticks means fewer infected normal mice or other reservoirs in the
next generation, and eventually it spirals down and down
and down to a much lower level.
Wouldn't completely prevent Lyme disease, but it would be much more like it was
historically by essentially removing the fuel in this fire.
So how could we do that?
Well, the idea we had back in 20/15/2016 was
look you can obviously vaccinate for Lyme disease through Aurelia burgdorferi,
OSPA works perfectly well or you can just infect a mouse.
It will develop immunity.
Some of those that immunity is mediated by antibodies.
Why not go in and find the relevant antibody encoding gene and move it into
the germline of the white footed mouse such that it's born expressing
neutralizing antibodies against Borrelia burgdorferi, the causative agent of Lyme?
If all of the mice were born with protective immunity, that would do it.
This seemed the sort of thing that we could do.
Folks have engineered various animals to secrete antibodies in their milk.
Why wouldn't it work if every cell or even just the liver cells say we're
secreting antibodies into the serum all the time?
But again, we wanted to go to communities before we
did anything labs, so we didn't test anything like that.
We actually said, look, this is probably going to work or
something like this is going to work.
We can make this work.
We don't know exactly how, but it seems very doable.
So let's go to communities and ask.
So we thought, well, OK, if you're going to change the environment
with organisms that can move, you should pick somewhere where they
can't move very far.
So the obvious choice was the islands, Nantucket and Martha's Vineyard.
So Nantucket is a little bit more organised than the Vineyard for those of
you who've ever been there.
And so they said yes, come out, speak at the Board of Health meeting.
And so I did.
And these are the original slides.
And the point that I said was, look, we're not doing this because Lyme disease
is the worst problem ever.
We can walk away if you don't want this.
This is primarily about pioneering a new way of doing community guided technology
development.
Intended to set this expectations for how eco technologies are developed in the
future.
And the idea here is that extremely extremely well off,
well educated communities with a tradition of New England town hall
democracy are perhaps best positioned to actually make this work.
In other words, if you can't get it to work in an English
speaking, well educated New England town hall
democracy, you probably can't get it working
anywhere.
So we should figure out the basics here where in the easiest environment and then
that can hopefully set expectations elsewhere.
So we emphasize that this is only a concept.
It will only move forwards if embraced by the community.
It would not be available anytime soon.
Lots of people have the idea that technology advances like this.
And while that is arguably true in AI right now,
it is not true in many other areas.
And so we said these are the key questions.
Do you want us to do this, yes or no?
Otherwise we walk away.
We haven't done anything, We haven't raised any money.
What are the criteria for release?
What do you want us to do, immunize them versus Lyme?
Should we try to engineer the mice to kill the ticks,
which we think we figured out a way that we could do that,
although we haven't actually done it yet, or both?
Where would you want the first field trials to be held?
Who should do the monitoring assessment because it can't be us.
And we went back again and again and again and again and again.
And we tried to get a lot of press to set an example,
which worked very well until the pandemic made everyone much more concerned about a
different kind of exponentially spreading biological construct.
So in the meantime, we decided to figure out, OK,
can we actually do this?
So we were able to raise some support both philanthropically and from NIH.
But as expected, with 25,000, 000 years between your standard lab mice
and white footed mice, they're actually more closely related to
hamsters.
And it turns out that reproductively, they're nothing like lab mice.
So engineering lab mice is now very standard, very straightforward.
Turns out if you encode antibodies in the germ line,
at least it looks like the mice end up resistant or lab mice.
But white footed mice, engineering them at all proved to be
extremely challenging.
So I'm primarily an engineer.
We do science and engineering, but my very strong preference is applied
science to engineering, not basic science.
So I'm frankly extremely miffed that we had to work out the reproductive biology
of white footed mice almost from scratch in order to engineer them.
Fortunately, I have very talented folks in the group
because what we ultimately needed to do was figure out when in heck these mice
and the females are in estrus because no one knew what the cycle was.
There is no mating plugs.
You couldn't tell when they had made it.
You couldn't tell when they had made it productively.
The actual colony expansion rate was terrible because when you just mix the
males and females, they actually the females don't get
pregnant very often, oddly enough.
And it was just a total mess.
You can't, you can't do pseudo pregnancy.
You can't do no, you couldn't do anything.
And also you can't just give the females hormones and have them produce a lot of
eggs, which is our standard practice for lab
mouse engineering Paramiscus.
Oh, they'll produce the eggs, it's just all the extra ones.
They're not viable.
So you get a lot of them on paper and like the number is high,
but then when you actually try to fertilize them and implant them.
So in order to solve this, we had we figured out eventually that
they're, the females exhibit a unique pattern of
movement that is temporal.
So when they're on the day when they're in estrus, they remain active much longer.
And this is just the females and only on the day when they're in estrus.
So we set up these Raspberry Pi based camera systems.
So you can see one here between all of these cages and we wrote some software.
So now we have our mouse app that keeps track of every mouse in the facility is
on camera.
We saw the females so that we can actually know what they're up to.
And so here you can see now these are days from mating.
So these are this is these are cycling females and you can see every four days,
boom, boom, boom.
This is the hours from lights off activity pattern.
They extends longer and then up until a meeting you actually add a male on the
day of estrus and then they will reliably reproduce.
And then we can do all the Embryology and see how yes indeed there is very
different developmental timelines of the embryos and the like.
So when we had to test out, OK, putting them in which horn of the uterus
is actually worthwhile and or can you do both?
And we did eventually get some engineered pups.
So now we can in fact engineer the germline of white footed mice.
This is one of those cases where the planning fallacy always applies.
Turns out took us better part of seven years to figure out how to engineer the
mice at all because there was nothing and they were just not very similar.
So now the next question is how many antibodies do we put in because we want
this to be evolutionarily stable resistance.
So one of our collaborators has now isolated Paramuscus leukopus antibodies
against Borrelia Osbay that binds to different epitopes and they all appear to
be neutralizing.
So we want to express ideally at least 4 antibodies so as to ensure that Borrelia
doesn't evolve to escape.
And then the other question is do we want to add something to localize them?
So the communities were very clear on one thing, do whatever you can,
but do not add genes from any non mouse species and not even a non mouse,
any non Paramiscus leukopus.
That is, you're allowed to go in and rearrange
genes as much as you want if it's already been in there, but don't add anything new.
This is an opinion that is held almost exclusively by people who did not have a
formal education in STEM.
The community divides almost perfectly.
People with a STEM background do not care where the genes came from,
they care what they do.
People without a STEM background say no.
Just as a general rule of thumb, don't go mucking with moving genes across
species boundaries.
We're worried that things might go wrong, Which is a pretty good heuristic,
actually.
When you think about how much can I get away with engineering an Organism using
only its genes versus nature's entire toolbox,
you really are tying my hands behind my back if you're saying only that species.
So it's actually pretty good for this.
And since we can solve the problem, fine, but that does mean we can't use CRISPR
based gene drive, which is fine.
We didn't want to do that immediately anyway.
And in fact, that's the one thing we told the
community is no, we won't do that for you.
But here is something that we could do.
And so this is what's called under dominance.
And the idea here is if you engineer mice to express these protective antibodies,
they sure don't.
Looks like they only need one copy of the antibody expressing locus to be resistant,
as you would expect.
But if you don't want those mice to spread outside the area of interest,
if you wanted, say here in if Salem wanted them but
Ipswich didn't or something like that, or Peabody didn't,
how do you keep the genes where the people want them,
who want them to actually live?
How do you keep them from crossing the border?
And the answer is you give the genes the right to vote.
You set up a majority wins dynamic that favors whichever genes are in the
majority.
So this is what happens in under dominance where you have when you have
something like a reciprocal translocation between two chromosomes,
whereby if you need to inherit either 2 translocated copies or two original
copies.
Because if you inherit the wrong mixture, if you're if you're 3 in one of any
combination, you're toast.
And So what this does is it says if you mate with the other kind,
half your grandchildren will die because that's what happens to the children of
hybrids.
That's a huge fitness penalty.
So in effect what you do is you favour whichever allele is in the majority.
And this would then lead to effective separation between the mouse populations
in different communities.
So we're working on doing that too.
We have to drop in Cree recombinase and in order to get the translocation to work.
So both looks like we're going to try.
So in summary, the communities set up steering
committees to guide research and development.
We suggest that they include one dedicated skeptic,
someone who actually opposes releasing the mice and is known to do that publicly,
but still supports the project because they like the way that we are going about
it.
That is, a lot of people support the process.
They really like the idea of community guided ecotechnology development.
They recognize they're probably going to lose that vote,
but they like the idea of setting the standard that this is how it's done to
capture community voices early.
Again, they prefer systgenic mice, so no genes across species.
And they have actually suggested some things that might have gone wrong that we
hadn't thought of primarily for the if we had made mice that actually kill the
ticks and how they're released.
So now we can get started on this.
So these are our our colleagues from various universities and all of the folks
in my lab who actually did the work.
So that was easy mode.
So far it seems to be going pretty well, albeit on the technical side.
But what do you do when the government, not you,
wants to use the technology that's a little bit more complicated.
Can you do anything?
I mean, you have a voice.
If you're known to have invented it, you what?
What do you do when the relevant communities are more challenging to work
with then New Englanders and when those communities possess a lot of relevant
ecological knowledge?
How do you understand it?
So these were all questions that we faced because the government of New Zealand
decided that they wanted to get rid of all invasive mammals by 2050 using
whatever technology was acquired.
Well, what what technologies do you think they
started looking at?
So we thought maybe, perhaps we should go and see what the
Maori thought about this and whether they thought it was a good idea.
Among other things, the Treaty of Waipengi gives them the
sovereignty over the natural environment in AUP Arora, not the government,
but also they have among the most well conserved bodies of traditional knowledge
of their environment of any indigenous community in the world.
So we thought we would should find out before tackling these mice or these mice
and rats, particularly the rats, is what they're most interested in.
Is this a good idea?
How should one go about it?
Is it OK for scientists to begin doing this?
Should the government be pursuing it or not?
And what would they want?
And we wanted to ensure that there was Maori and local guidance of these
technologies.
So the caveat slide was that none of this exists in mammals.
Don't expect this anytime soon.
And for our part, we're interested in suppressing rodents
for other reasons that are pests around here.
They're also invasive here, actually, but they've been here for long enough
that I'm not sure what would happen if we completely got rid of them.
That doesn't seem very feasible, but it sure would be nice to have better
methods of rodent control in urban areas, ideally just by suppressing their
reproduction.
It'd be much more humane.
Lot of animal suffering caused by our using poisons against rodents and glue
traps and other things.
But what about Altaroa?
Should it be used there at all?
So we effectively said, look, we want Maori Co governance over any
proposals to use stuff that's our doing in Alta Arora,
and we won't support it if Maori aren't broadly supportive.
And we're interested because, well, we feel that folk who don't share Maori
values and expectations regarding ecological outcomes should still take
their concerns seriously, even if it can't be translated.
And this is crucial because we've seen over the past few decades that there's a
lot of traditional ecological engineering arrangements really,
that we've gone in and said, hey, look, this crop grows really much better,
much faster.
You can get an extra, whole extra crop cycle in,
you should start planting it.
And it's just completely destroyed this culturally evolved natural way of
managing the local ecosystem because we didn't understand how it worked.
And it took us decades to figure out how it worked.
And there have been some predictions in Alta Arora that practitioners of the
Mataranga traditional knowledge made that took over a decade for a Western PhD
ecologists to verify.
Yes, indeed, that is in fact how it works.
So we know it takes a long time to translate,
and that's just not a feasible thing to expect.
So we just have to take their word for it.
But here is where I really screwed up.
In the 1st paper describing CRISPR based gene drive I had to make the pretty Venn
diagram showing all the possible applications.
You will note controlling invasive species and pest management are on there.
Now in the main text I noted that since this was referred to the self propagating
form, that since rats are still always and
there is gene flow between all the populations pretty much everywhere in the
world, if you use this on invasive rats
somewhere, the gene drive will itself prove invasive
and go back to the native habitat.
So you can only do it if there was.
If you tried to do it globally, the whole world decides that you're going
to get rid of all the invasives and protect the native populations.
It's probably hard to coordinate internationally.
So all of that is in the main text now.
How many of you read the main text of all the papers as opposed to looking at the
figures?
So a lot of people got really excited because if you're a conservationist,
you don't have a lot to be excited about of late.
It feels like doom and gloom all the time and so promising new powerful tools that
could actually make a difference, you're really keen on going for it.
So a lot of people got really excited about using in particular self
propagating CRISPR based gene drives against invasive rodents in al Tearoa,
including folks who advising the government.
So problem is these things are super invasive.
So we modeled a drive system that only copies itself half the time and the rest
of the time it makes a resistant allele that can never be copied over.
So it caps out at 37% of the population ish,
and then the drive just goes down after that.
But this plots the peak allele frequency reached of this very terrible gene drive
against the number of organisms released and the probability density.
So you can see that the probability that it will not in fact spread goes down very,
very, very rapidly in the single digit number
of organisms.
These things are super invasive and if people will make money from moving
something, they will move something.
And we know this from Al Tarawa.
They smuggled in rabbit hemorrhagic fever virus, rabbit hemorrhagic disease virus,
excuse me, from Australia after that test went wrong
and they spread off of the island that it was used as a test site to the mainland
and the government of New Zealand said that was not a well run test.
No importing it yet and the farmers smuggled it in any way.
Rats cause a lot of economic damage.
Someone would move it.
So with Neil Gemmell of the University of Otago,
I wrote a paper saying conservation needs to use localized forms of gene drive.
We outlined a form of a Daisy Dr.
that splits up the elements so it can't spread indefinitely.
And there are various toxin antitoxin versions and things like the under
dominance trick and that you could use private allele targeting various
proposals.
But the point is you need to not use the self propagating full power version.
But because Neil, Neil wanted to use Au Taro as an example.
And we wrote this and then I reached out to the Maori and then this came back to
the revision stage.
And I just didn't think to send it to them because we'd already written it.
It was revision stage.
We did run it by a pocket here scientist in Al Tarawa,
but turns out when you show people in power that they are wrong and they cannot
do the thing that they wanted to do and had invested some political capital into
doing, and then you take that away from them.
They are not happy.
And it is hard to strike against me because I am here on the other side of
the world.
So who do they take it out again?
The folks on the bottom.
So as one of my Maori collaborators said, his meaning,
my naivete of the political situation Maori are in and publication of this
paper without talking to the other partner more than likely to have
consequences for a Maori that the author did not consider.
And she is entirely correct.
I was thinking of engaging with the Maori as drawing knowledge of their local
natural ecosystems such that nothing would go wrong.
I didn't think that there's a local political ecosystem.
So I apologized because I really screwed up.
And they generously invited me back at a large hooey on the local Tonga species
and how best to preserve them.
And I told this story and the most heartbreaking comment from the audience
that I've ever gotten was after I gave this talk and described the ways that it
might be done and asked for their guidance,
a woman and explained that I thought I'd learned from this,
but I'd already failed them.
And so I would completely understand if they said no,
we don't want anything like anything to do with this.
A woman of probably 60 something rose to her feet and she said,
I have never heard a Pakaya scientist apologize to us for anything before.
So they did decide that they were still interested in working with us because I
mean, that's a very low bar to clear, but.
So we engaged in further discussions and went back numerous times pre pandemic,
brought the lead Maori coordinator at the New Zealand Environmental Protection
Agency, who's in charge of integrating the
mataranga into assessments, came out to MIT on a fellowship and
joined us.
That's him right there, Doug.
And we continued this until the pandemic prevented us from going back.
It's really hard to maintain relationships by a Zoom during a pandemic,
so we're hoping to raise the funds to to go back and continue this,
particularly in the event that our Y linked suppression research continues.
But the point of this story is that when we gain the power to act and we use it,
then we become responsible for the consequences.
Anything that goes wrong is on us, anything unexpected.
But if we gain the power to act, and we don't use it,
we choose to do nothing, then we become morally responsible for
the continued existence of the problem.
It's on you either way, as soon as you gain the power.
So now we increasingly have the power to intervene in natural ecosystems in
targeted and programmable ways.
And it's on us no matter what we choose to do.
Thank you.
Given the intimate setting of this room, we haven't got a microphone.
But this is a comment.
This is the most responsible talk I've ever heard about gene engineering.
And I appreciate what you're willing to to stand up and say.
And we as scientists need to listen very, very carefully to what you're saying
because there are all kinds of issues.
You just scratch the surface there.
But thank you.
Thank you.
There is definitely no easy answers to this one,
although this isn't what keeps me up at night.
Biology gets more harmful than this.
What does keep going you really want to know?
A lot of our colleagues are very interested in learning more about
pandemic viruses under the assumption that we can better prepare for them.
So logically, you want to know how is something like
COVID, once it jumps, going to evolve so that you can engineer
vaccines that will cover the future variants?
But as Richard Feynman said, what I cannot create, I do not understand.
Eventually, we will understand how pandemics work.
We will be able to predict antigenic evolution and cell entry of key receptors
for probably all the different families of viruses.
There's a lot of machine learning work on attempting to model these,
and we will learn how to make arbitrary pandemics.
And right now we cannot defend against pandemics pretty much at all in any kind
of effective way because of the logistics of vaccine production.
In other words, many of our colleagues very well meaning
trying to help are putting out their public tools for engineering pandemic
capable viruses.
That's but it's totally solvable.
It's just it's not solvable using our tools.
It's probably not solvable within biotechnology just because you can't get
the cure to everyone, you can't vaccinate everyone against
everything.
There are so many possible configurations of entry proteins, for example.
You can't vaccinate against all of them.
Even broad spectrum isn't broad enough against that kind of design capability.
And if you wait until The thing is spreading,
Omicron infected half of Europe and a quarter of Americans within 100 days of
being discovered in southern Africa.
Something spreading through airports, something deliberately released across
multiple airports would spread much more quickly.
And the National Bio Defense Strategy says have enough,
have a vaccine approved in 100 days and have enough doses available for all
Americans in 130 days.
It's just way too slow.
So biotechnology appears to favour offense.
It's just straight up offense dominant.
That doesn't mean that technology is offense dominant because we know
perfectly well how to build protective equipment that will perfectly keep us
from getting protect from getting infected.
The power purifying respirator, you're not going to get infected with
anything while that's on.
You know, you can't scratch your nose, but it's also not going to break the seal
when if you reach under it to scratch your neck because it's positive pressure.
And those cost $1000 each.
And if we had one of those for every essential worker,
then we could lock down and withstand and eliminate any pandemic.
Question is, will we invest in doing that before we
learn to make pandemics?
So that's the other thing that I worry about these days,
is that we're not thinking about the downstream consequences of just learning
more.
Because it's nice to believe that all knowledge is worth having,
but some knowledge is not worth having yet.
Not until you invest in the defenses first.
Yeah, There was a conference in the Sylmar when
the combat DNA started coming along and that actually was useful, I think.
I mean that my perception is that it was useful.
Do you think that we could have a similar kind of moratorium occur bluntly right
now?
No, we did have a moratorium on enhancing
transmissibility and virulence of pandemic capable pathogens during the
Obama administration, and then it was overturned.
But too many of our colleagues think it's a good idea to learn which mutations
might occur that would make things pandemic capable so that we can then
better try to prevent spillover, early detection, all that jazz,
which is a very reasonable thing to think.
It's just, it assumes there's nothing deliberate.
You've shown that that that thinking is not necessarily, but it's very intuitive.
You want to know Morse, because then knowing knowing about it
makes you feel safer.
And then you do have more options for responding.
It's just we spend so much of our time thinking about how to fight disease that
it's hard to conceive that someone might want to use it as a weapon.
But it only takes one person.
Sales date brands itself as Massachusetts Civil Engagement University.
I think that's the respect and we have an office here for an office of civic
engagement.
I have done work in Southeast Asia, tropical rainforest and Puerto Rican dry
forest and locally and I didn't have support for the 1st 2:00 but I have
support now through that office.
Do you?
And it's made a real difference.
I've had a community based participatory research project that follows certain
certain structure and I find it to be a structure that is working.
It doesn't.
It's not always smooth, but I feel like we've accomplished a lot
in four years.
Do you have that type of support at MIT, People you can go to to say this is the
next step I'm going to take.
Can you give me some feedback about the the right path forward like or I'm
running into an issue because this is what I do.
Like if I get to a new stage of the project, I reach out to them and I say,
this is where I am.
What are the pitfalls?
What do I need to watch out for?
I'm just wondering if you have something similar to you.
Actually, we really don't.
So we have, we have the lawyers that tell us what we
can't do.
Lawyers can be useful and we have and we have the committee that tells us what we
need to be careful of when it comes to national security and engagements with
China and so forth.
We don't really have that.
I mean, we have the Office of the Vice President
for Research handles weird things like that.
So whenever we we just develop some phage mid tracers to put into the sewerage
system at different points, just flush them down different toilets
with different barcodes to then figure out how long does it take different
pathogens flush down a toilet to get to Deer Island treatment plant.
So just figure out how good is wastewater monitoring for pathogen detection in a
city environment.
But because that would involve putting something into the environment that is
engineered, then this is, you know, sort of trips the warning flags and is
you need permission from the vice president for researchers office.
And so they look at it and make sure.
And then they basically say, have you engaged with every relevant
regulatory authority already?
And I have learned that this is the thing you have to do.
You have to go to them and saying, Yep, here's here's the local,
state and federal regulatory approval.
And here is a letter from the Office of Science and Technology Policy at the
White House saying that they approve of this.
And then maybe you'll get it through MIT.
It's sometimes I can't fathom how it is, how we go full throttle on understanding
how pandemic viruses work and yet we're so constrained and cautious on things
like this.
So no, we don't have anything specifically for
supporting that.
It would.
It sounds lovely and it's amazing that you're doing it.
We don't have anything quite like that.
We do have the advantage of the city of Cambridge has a biosafety committee for
the city originating from the original recombinant DNA moratorium and the city
of Boston has one too.
So we often talk to them.
And the other resource that we have do have at MIT who are really great.
Our environmental health services group is which runs our biosafety committee
which I'm on.
And our, our biosafety officers are really great
and they talk us, talk to us about this to help us engage
with the EPA and so on.
So they're the closest equivalent, but they're not really about going out to
the community, except insofar as saying you should talk
to the city biosafety committee because they're the community.
I mean, I think it would be a lot harder for them
to support me if I were doing work in New Zealand.
Right, right, right.
They know they have, I'm doing the work in Salem.
So they have personal and professional connections throughout the city,
so with the community, but also with the mayor's office,
for example.
So those types of connections are really helpful.
But the other element here is that that makes the community based participatory
research should I don't mean to make this about me, sorry,
but the thing that really works well is that I have partners in a partner in the
city and a partner in the community and we are equals in the project.
And we always, I always consult with them before each
step and they do the same with me and they bring different types of expertise.
So, you know, that's that's super, super helpful because sometimes my
community partner will put on the brakes and say, yeah, no, no, no, no, you don't.
I'm like, but, but but I listen to her, you know,
so and and also if I have a need that from the city and she has a way of
figuring out how to get that, you know, so it's that sounds very like the
situation that we've established on Nantucket where just the board,
the Board of Health commissioner just just orchestrates things.
And then a former member of the Select board handles the ACT,
handles that side of government.
And then we have a local the local skeptic who's in tune with the people who
really don't like the idea of engineering life across the board.
You know, the are so important.
Absolutely.
Yeah, because even if they're wrong, they're going to influence other people.
So it will turn the yeah, you.
I had to do like some quick troubleshooting.
We had an article in the Globe and I there were I had to watch social media
because there were some of these like people who are like we're, you know,
they they they were, they're negative, right.
So there's maybe 2, but they were popping up all over the
place.
Yeah, it's, it's it's really hard because some folks
feel very strongly about these things.
And you have to ensure that everyone's voice is heard.
But at the same time, you try to avoid misleading and you have
to try to avoid letting other people mislead.
What's going on?
I mean, people, people call these Frankenmice.
Of course they do.
Like, that's just how it is.
I mean, but for the most part on the islands,
people hate Lyme disease enough that they're really interested in going for it.
Although the the derail is always, well, how about we just shoot all the deer?
It's like, you've tried that many times before.
They're like, no, no, no.
But I've never been on it before.
I am so charismatic and persuasive, and I will convince everyone that we will
shoot all of the deer.
Now it's like, you go do that and we'll be back in a
year and see how that's gone.
I remember hearing about that effort on Rahegan.
Yeah.
What was the outcome there?
It mostly worked.
Yep.
That's the that's the strongest evidence that in fact,
if you just shot all the deer, then the problem would mostly go away.
That's great.
Yeah.
So Sam, yeah, I think you were the first to kind of
associate the terms CRISPR and gene drive.
Can you say something about how other people use CRISPR and what linking that
gene drive actually means?
Yeah, So CRISPR is normally actually saying
what people normally use CRISPR for.
I mean, people use CRISPR for almost everything
now just because CRISPR is a protein that allows you to input an RNA and it will
then go and find some other DNA, some matching DNA sequence or RNA
sequence in the cell.
So you can the natively, it's scissors.
And so people use it to cut the DNA, which then triggers the cell to try to
find a way to repair it.
So if you provide the new version to be inserted,
then the cell will often input insert your new version to repair the damage as
though it were using copying it over from the other chromosome.
But you can also nick just one strand and cause other things to happen.
You can attach a base editor to change just one base.
You can nick 1 strand and then have a reverse transcriptase make a new single
stranded DNA sequence to be inserted.
That's prime editing.
You can break the scissors function and attach an activator or repressor to turn
genes on or off with CRISPR.
But the native form is just use the scissors to cut it and then introduce DNA,
new DNA sequence to be inserted.
So in a, in a mouse that's called a knock in,
but the gene drive is just using is encoding the editing machinery along with
the edit such that editing can happen every generation.
So that's the gene Dr.
aspect.
And gene Dr.
occurs very commonly in nature.
And that particular mechanism of just a of an endonuclease on one chromosome
cutting the chromosome that doesn't have it so that the gene encoding that
endonuclease gets copied over.
That's very common in yeasts in particular, also in some bacteriophages.
What's new about CRISPR is it's just a endonuclease that we can very easily
target.
And I was far from the one first one to suggest we use gene drive to engineer
wild organisms.
That was Austin Burt of Imperial College London,
and he actually launched a project trying to get it working in malarial mosquitoes
using an actual yeast homing endonuclease.
Unfortunately, as someone in the directed evolution
field, you do not want to engineer homing
endonucleases.
They are a tremendous pain, extremely, extremely difficult to retarget and even
and if you only cut it one site, you run the risk of acquiring A mutation
that then would block cutting thereafter.
So that's the resistance that I referred to that capped out that poorly functional
gene drive.
What you want is to cut multiple sites and CRISPR lets us do that very easily.
And CRISPR also lets us ensure that the process is is reversible just because,
and this is in fact why CRISPR based gene drive is defence dominant,
which is rare in biotech because it is slow,
spreads only vertically over generations.
It's obvious the sequencing, you can't hide it.
You don't see CRISPR systems in sexually reproducing genomes,
and it's easily countered because any CRISPR based gene drive can be
overwritten by another CRISPR based gene drive that is identical except for the
addition of some extra guide RNAs that targets the first one and engineers it so
it doesn't target itself.
So that way you can just take one that is doing something wrong,
remove whatever it is about it that's doing it wrong,
and then program it to overwrite the first one.
And because of the dynamics of reproduction in the relevant organisms,
you effectively have a defender advantage.
You can always raise more mosquitoes and release them to counteract a gene drive
that is doing something wrong.
You can't actually turn the population to the exact genetic sequence it was before,
That is beyond us.
But you can ensure that the phenotype will go back to what it was before and
when we built the first ones.
Examples of CRISPR based gene drive in yeast.
We simultaneously built one version that was intended to knockout a native gene,
and then at the same time we built the countering version that overwrote the
first one and restored the gene.
And they both worked.
But we wanted to set the precedent of don't build the gene drive without
building the countering immunising reversal drive.
Not when everyone ignored, but we tried.
Yeah.
You had a question.
Yeah.
I was just wondering with a disease like Lyme or you're not relying on herd
immunity that comes not what, why is there a a preference?
Or maybe there isn't a preference.
Maybe there's another reason.
But why go to the vector?
Why engineer the vector and instead of just working on a vaccine for humans for
Lyme disease?
So there is so OK, so the history of the Lyme vaccine is
kind of a mess.
There used to be one for humans still available for dogs,
but it was withdrawn from the market because there was a backlash.
It was at the very beginning of the anti vax movement.
People were claiming that it would the vaccine was giving them Lyme arthritis,
and the FDA investigated and concluded that it was not in fact happening.
But people believed it was happening.
And there was a lot.
There was campaigns and lawsuits against the pharmaceutical company that produced
it and they, because it had only been approved for 15
and older and it wasn't very commonly taken up,
they weren't really making money on it anyway.
So then in the face of all these lawsuits and bad press,
the company just said well enough with that, we're just going to withdraw it.
So they still sell it in the veterinary market.
It's the literally the same vaccine.
So if you want a lime vaccine, you just have to have a friendly
veterinarian.
It's about 75% protective, which you know, that's better than nothing.
It doesn't get rid of the problem, but it would help a lot.
And thankfully, there is a new one being developed where
this time the strategy was to include coverage of the European strains.
So they would also be effective in Europe because the original 1 was only the North
American strain.
So they're hoping that the European market will help.
So hopefully that will come out.
But even that one is also still only about 75% effective.
So that would be much better, especially if kids can get it.
But they're probably not going to approve it for, you know, age 1 and up.
So there's going to be a window of vulnerable kids and still 25% is still
quite a lot of risk when it comes to how nasty Lyme disease can be in the chronic
form.
So, but the real, but the real answer is we needed some
problem sufficiently obvious to try to figure out how to develop eco
technologies.
And that's why we did this, not because we decided Lyme was the most
important thing that we should be working on in, in all honesty,
one or two more questions.
Yeah.
Is anyone there an immunologist?
So our primary immunologist is actually our collaborator at Dana Farber,
Wayne Morasco.
Yeah.
We don't have a primary immunologist in my group.
We have people with a wide variety of forms of expertise,
but not immunology is not one of them.
Can you say what is there about the hamster that made the white footed mouths
closer to that than to other types of Oh yeah, strains and all of the genetics?
So yeah, so it's just, yes, I was just noting that the oh,
where was that?
I was just noting that the there we go that they're more closely related
evolutionarily to hamsters than they are to lab mice and rats.
And reproductively they're also more similar.
So our, our activity monitoring trick actually
works in all of them, but it seems to actually work better in
in these.
And so we're making it easier to engineer hamsters as well.
So if you need one and if you want a glowing hamster, Cameron,
you told us a great story, a heartwarming story following your Maori
faux pas and your trips out to Nantucket and Martha's Vineyard Stand back to what
was it, 2016?
Yeah.
In your group, who was the impetus to let's go out and
be humble scientists to ask, was it you personally,
or was this a new movement in the guys that work in this particular field?
It was mostly me trying to figure out how to engage in this topic.
And then I was fortunate enough to be joined by Joanna Buckfall,
who's the project manager of Mice Against Tics.
She joined as a student in my lab not too long thereafter.
And Sam Telford, who's at Tufts, is our Lyme epidemiologist and ecologist.
And he and I invited him to just a preliminary discussion of how should we
go about this?
Is this a totally crazy idea before I go and talk to these communities?
And Sam's, Sam is amazing.
So he was very much oh, wow, this is actually a novel way of tackling
this recalcitrant problem.
And so he was very much on board with helping.
And he's just been honestly one of the best collaborators I've ever had.
So yeah, we've.
And then we were very fortunate to connect with the right people on the end
tucket very early.
Yeah.
Well, thanks very much for joining us and for
recent.