Transcriber: Arthur Manookian Reviewer: Ariana Bleau Lugo
It's great to be here
with old friends and new ones.
Each of the logos on the slide represents voices, like yours,
voices of pragmatism and practicality,
and I think it's extremely important to have convened meetings like this
that are projected out into the world, not just into this room,
so we can gather those voices
and prioritize the sort of things that we're talking about here today.
We're trying to recreate species from information alone.
The're are 2 organisms
that have been recreated from information alone.
They're both hybrids,
they are not perfectly exact copies of what went extinct.
One of them was recreated from our own genomes,
meaning that every one of us contains lots of pieces of retroviruses,
and these are reconstructed into a living retrovirus --
long extinct.
And the other was rescued
from a human who had died from 1918 flu virus
and was buried in the permafrost
and this was brought back to life.
And the study of these viruses
could save millions of lives in the future.
Now, how do we predict the cost of this project?
This comes up a few times.
How do we predict the cost of any technology
that is changing rapidly?
The best way to predict the future
is to change the future.
and we've noticed at the end of the genome project
the cost improvement
which had been going along at a slow clip
could have flat-lined because of the loss of the genome project funding
or it could have gone on this aggressive exponential
similar to computers, pretty aggressive.
6 decades we could've brought the cost down
from 3 billion dollars
to the current cost around 2,000 dollars.
By giving our way the current cost
arrived not in 6 decades, but in 6 years.
We can only hope that such things happen
to bring down the cost of projects like this
and that they do it because we're drafting behind
this incredible powerhouse of human medical genomics
to deliver into environmental habitat, preservation and species
de-extinction.
I'm going to break the process down into 3 very simple steps.
One of them is Raw DNA synthesis,
trying to get those basic information out of the computer and into DNA.
Then the next step is DNA delivery,
on the next slide and on the third slide will be,
once the DNA is delivered to the roughly right place
of splicing it into the genome perfectly,
not just putting it in some extra random place.
So the best, the cheapest we can do for raw DNA synthesis
is on the order of 100 to 200 base pairs,
millions of those things on a chip
made similar to chips in your phone,
on the order of hundreds of dollars per chip;
so you can make 600M base pairs on a chip for hundreds of dollars.
But then you have to do steps 2 and 3.
You have to deliver the DNA.
We can deliver single base changes scattered all over the genome,
or we can deliver big chunks of DNA up to 10 million base pairs
by either a process called 'cage'
or by Microcell-Chromosome Transfer.
This is where we stand right now -
and it's probably adequate,
but will improve by factors of 10,
just as sequencing and synthesis have.
Now, the third step is splicing this in very precisely.
In 1990 the first human trials on gene therapy
were approved by the FDA,
they were not precise.
They approved putting in random pieces of DNA
that added to your genome to fix rare genetic disorders.
That had the unfortunate consequence of causing cancer in some people,
so it was short lived.
6 years later, they introduced the first really amazing way
of doing targeted change
which was the Zn finger nucleases
and these have dominated for the 17 years since.
But a new actor has appered in the field.
My group and others have introduced this CRISPR technology
and I could spend an entire hour or two on this,
but just one second --
It's now not just protein guided
with the 3 fingers of the Zn Finger illustrated,
but it's RNA guided nuclease;
the nuclease cuts the DNA and then you can either
get rid of the DNA or introduce something new.
So those are the 3 ways that we see changing rapidly
in a very positive way for human gene therapy.
Now, here's an application.
How does HIV get into humans and what can we do about it?
It gets into humans via the CCR5 gene
which is present on almost all of our T-Cells
and it gets in and causes
one of the greatest epidemics in human history -- extremely sad.
And many of these are multidrug resistant
and vaccine resistant.
Here's those fingers again.
Now, not 3 fingers, but 8 fingers,
binding in the nuclease in the middle.
This is a hybrid molecule.
It's a hybrid between a mammalian set of Zn fingers
and a bacterial nuclease,
and it's going in and it's making a hybrid genome.
You can go on to patients, take out the T-Cells,
delete both copies,
both their mother's and father's copy of the CCR5 gene,
put them back into the AIDS patient,
the AIDS patient is cured and is resistant to future AIDS infection
and HIV.
So this is an example of the kind of motivation
for developing this technology
which will have spin-offs in exactly the fields
we're talking about here today.
This is example, that surface of cell where the AIDS virus is binding.
This is one of the first patients in a previous study,
but this is now inspired and expanded to a full phase 1
and now phase two clinical trial from the company Sangamo
which makes these Zn finger nucleases
that cleave and alter both copies of the CCR5 gene.
So this is real, not science fiction, and is potentially applicable
to endangered and extinct species.
I think it is important to lump these together,
the endangered and the extinct and habitat preservation.
All of these synthetic biology has hopefully something good to say
and to contribute
if we all behave responsibly and meet as we're now.
The Tasmanian Devil
has kind of the opposite problem of humans,
it has too little immune diversity
and so, there is actually a transmissible cancer.
They kind of bite each other when they're fighting
and normally that would just cause a few cuts,
but this now transmits a cancer.
It's actually Tasmanian devil cells going from one to another.
And we heard in the earlier talk that we wanted Tasmanian devil
to help us bring back the thylacine,
so you might be able to get a little diversity
from existing Tasmanian devils
or you could go back and get from information
that we can get from extinct dead versions of these
and introduce that diversity.
So, as I said, humans have the opposite problem,
they have too much immune diversity
at least too much from the standpoint of transplantation.
If you want to get an organ donor
you have to search the world over to find somebody
and even then the lines are very long
and it's very unfortunate.
But we can increase or decrease diversity
by looking at this little set of genes on crhomosome 6 of humans.
And there's a corresponding chromosome in Tasmanian devils
and all the animals we're talking about here today.
You can go on and change as little as 2 to 5 of these genes
to increase the diversity of the Tasmanian devil
or a few more genes
and you can make the tissue that you want to transplant,
the stem cells that you want to turn into organs and transplant,
compatible with just about any human
without having to find a specific doner.
A small number of genes can make
amazing differences in both of these 2 species.
Sergey Zimov has been telling us at least since 2005
of the potential impending threat to the entire world
that comes from the threat to the arctic carbon.
There's more carbon
sequestered in the grasses and other things in the Arctic
than all of the rainforest burned to the ground,
I don't recommend this, but this is hypothetical,
times 2.5.
And it doesn't require burning the tundra
it just requires melting it which is currently happening,
as you can see in some of the slides from the other speakers.
So, this is a mammoth --
hypothetically a solution to this,
but we need to explore whether this is the only solution
or even an adequate one,
getting rid of the dead grass,
stumping down the trees
and stumping down the insulating snow in the winter
so the arctic freeze can get into the permafrost.
These are the sort of things that could be achieved
uniquely by mammoths.
So Sergey Zimov and his colleagues have created Pleistocene Park,
it's currently populated by much smaller mammals.
We would propose to make a hybrid elephant
that has the best features of modern elephants
and the best features of mammoths.
We have enough of the mammoth genome
and enough information in computers about many other species
to know the key physiological features
that we need to introduce in the elephants
that they will be happy year-round
in the Arctic regions of Canada and Russia.
Many of these have actually, maybe to some people's surprise,
have already been recreated.
5 different gene variants have been tested,
either molecularly or in cells,
including blood haemoglobin
and genes involved in hair colour.
And we want to get to the other ones even more vital to the cold,
having to do with subcutaneous fat
and sebaceous glands
which, amazingly, elephants don't have.
They have short stubby bristly hair
that causes cooling rather than
the insolation that we actually want.
Developmental biology
is currently one of the big pushes forward for synthetic biology
and it's going quite well.
Spectacular results already, even though we're just starting.
Here's an example of a mouse incisor
which with just 3 changes in the spry genes
can become very tusk like in the lower example
where you have the 3 mutations from UCSF.
We can learn from many animals,
not just from the mammoth DNA,
but from developmental biology in many animals, including humans.
Here are two human mutants that cover this huge range of hair
ranging from very sparse hair,
kind of like what you see in the elephant tail and legs
on the left hand side,
to very wooly and body covered hair,
as we see in the mammoth as well.
So we'd like to bring these back.
And then finally,
the 22 month gestation period of the elephant
is one of many small challenges that we need to overcome.
But we have various tools, you've seen some already,
not in just my talk, in others,
where can test a few genes at a time
molecularly, cellularly, or increasingly in organs and systems;
again being developed for human health,
we want to be able to develop organs in labs
so that we can use them for transplantation.
And you can test out whether what you think
is going to create that subcutaneous fat layer
or the wolly hair.
And these are examples of tests from stem cells,
actually from my own body,
in the case the ones on the right,
where you can generate almost every tissue in the laboratory
either in mice or in tissue culture.
So again, what's important
is for this community to come together
and hear your voices of practicality and pragmatism
and what you want to see done and how.
Thank you very much.
(Applause)