heritable human genome editing and when
will it happen and we’ll start off with
some definitions in the next 15 minutes
or so and then I’ll try and explain what
genome editing is and then I’ll
introduce you to some characters
throughout this talk
including the carpenter and then we’ll
finish with a summary so to those
definitions well by edit we simply mean
the standard dictionary definition of
edit where we’re going to make a precise
controlled change then it can be a very
large change or it can be a very small
change and what we’re changing is the
genome and the genome is really like an
instruction manual that tells us what we
are in a genetic terms and every one or
most of the trillions of cells in the
bodies of each of us contains two
instruction manuals one that we’ve
inherited from our mother and the other
that we’ve inherited from our father and
these instruction manuals each one is
huge it contains billions of characters
in fact 3.2 billion characters so if you
imagine that each one of these
characters is a ping pong ball to give
you an idea of how many characters there
are and in each of your cells if each
one is a ping pong ball there will be
enough in one cell to fill Wembley
stadium not once or twice or three times
or four times or five times but there
will be enough ping pong balls to fill
six Wembley stadium as you can see I’m
talking a lot of balls and if you wanted
to target just to make a change to just
one of those balls among six billion
that’s a big ask and the history of us
being able to do that before 1989 looks
like this nothing we couldn’t do it at
all and it wasn’t until the work of
these three geniuses came together about
10 years ago they were awarded the Nobel
Prize for Physiology or medicine in 2007
but we could do this for the first time
in the context of whole animals we did
it mostly for mice and this has been a
fantastically important method it’s
really enabled biomedical research but
although what we can now call the
classical method has been extremely
important its clunky its slow its
limited to one target it’s extremely
expensive it’s labor intensive
there’s restricted expertise not that
many people can
and it has a very variable efficiency
and so the search continued for better
more improved methods and that search
was rewarded in 2005 and 2010 by methods
that you may have heard of zinc finger
nucleases ear fens and talons and these
were better but still no cigar and the
search continued and then and then in
2012 and 2013 it was rewarded with Chris
Bachus 9 with these three publications
all in science at about that time that
reported what Chris Barker’s line does
and what it does is incredibly quick
it’s fast it takes weeks not years it
you can target many targets at one time
so you can make multiple edits it’s
economically it cost hundreds of euros
not tens of thousands it’s streamlined
it’s already widely practiced and it is
highly efficient you shoot you score so
although Chris Barker’s line doesn’t do
anything we couldn’t do before it just
does it so much better that it’s a
game-changer so how does it work well it
works in two ways the Chris Park has
nine first of all does its part which is
to make a break in the genome and then
the cell repairs that break and I’m
going to talk about each of these one by
one starting with the Chris Barr cast
nine part so this is the Chris Barker’s
line that’s going to do the genome
editing and in fact it works like a pair
of tiny molecular scissors and a
molecular sat-nav and the sat-nav that
you get to program exactly whereabouts
in the genome you want it to cut tells
the scissors which you’ve programmed
where to go and make the cut from the
genome and this is what it looks like
I mean it’s it’s an amazing system
really it’s a very simplistic and
simplified diagram but in the middle
here we have a representation of the
genome the genomic DNA and this is a
small part of these six billion
characters per cell and the sat-nav the
molecular sat-nav is actually looks
really boring really prosaic and it’s
this bit here it’s about a hundred and
ten characters long it’s called an RNA
molecule or a guide RNA molecule and
although it looks boring it’s amazing
because what it can do is interact with
two things one part of it can interact
with the pink blobby thing here
are actually the molecular scissors they
do the cutting and the other part twenty
characters worth can zip up with twenty
characters is specifically a twenty
character to stretch within that six
point four billion nucleotides of genome
sequence and that twenty characters is
enough to endow exquisite specificity to
the whole system so then once that’s
happened I’ve changed metaphors now so
now we’re moving from an instruction
manual to imagine the genome is like a
piece of string and we’ve cut the piece
of string exactly where we want with our
crisp our cast nine and now the cell has
to repair that cut because these
double-stranded breaks as they’re called
are bad news for cells they sometimes
occur naturally and if they’re not
rapidly repaired the cell can die and
indeed it can be even worse the entire
organism can die this is one way that
cancer is initiated so the cell quickly
has to repair this and the way it does
this so made out we’ve made our break
here with the CRISPR cast line in a
specified place that now targets the
cellular repair machinery all of this
happens inside a cell each of your cells
has this machinery and what it does is
it kind of acts like it uses the good
instruction manual naturally to repair
the bad instruction manual to which the
damage has occurred but what we’ve done
is we’ve targeted the particular damage
the cut in the instruction manual or cut
in the genome and now we can flood the
whole system the cell with the
information to repair just that part and
we can get to write the page or the
sentences we can insert bits or we can
remove them and it looks a little bit
like if we homed in on this it looks to
me a little bit like a bridge so we’ve
got our extra piece of genome here just
a relatively small piece and it looks
like a bridge where the left foot of the
bridge perfectly matches the left-hand
side of the brake made by Chris Barker
slime and the right side foot of the
bridge matches perfectly the right side
of the brake but what’s in the middle
the span of the bridge you get to decide
what to put in so you can make a very
short span in fact it can correspond to
a deletion of the DNA or a very long
insertion you can put fouls
of characters in if you want to so all
of this really reminds me now of the
carpenter it’s as if we’ve given the
carpenter a molecular carpenter some
amazing new tools and of course like all
carpenters he or she has a vision for
what they want to make with these tools
and using their experience and expertise
they apply the tools to realize the
vision using the process so the vision
that they have in the context of Chris
bark has nine is likely to be clinical
so most people are thinking that we can
use this in the treatment or prevention
of heritable or disease that’s genetic
with a genetic component and to
illustrate what that might be I’d like
to introduce you to Chubb Shaw chop Shaw
was born on the 22nd of April 2013 by
the ages by the time he’s aged 17 he’ll
become a multi-billionaire and at 28
he’ll be the founder of chop Shawn lunar
mining Inc but when he’s 34 he’ll be
diagnosed with a heritable terminal
neurodegenerative disease what hope
might there be for trouble and people
liked rupture in 2047 well we might
combine several different technologies
including genome editing like this
rubbish all might go to his hospital or
clinic and give a simple cheek cell swab
to the practitioner to the clinician to
the doctor and they will take them away
and they will use something called
induced pluripotent C which we can now
do in humans as well as it was
discovered in mice initially and what
that happen cells and make them like
embryo cells they’re not embryos but
they’re like embryo cells and we can
cause these cells to proliferate we can
grow them in the dish and that gives us
an opportunity to do editing so we could
go in now we can add all of our other
CRISPR cache line components and we can
change the affected gene that
predisposes to truck shores condition
and now we can take those cells because
their embryo like cells we can ask them
to become neurons so we can ask them
this is called directed differentiation
to become like neurons and because it’s
all really derived from truck Shaw in a
way we can now transplant them back into
truck Shaw so that rupture is cured her
so off he goes and of course he’s very
rich he’s a multi-billionaire
all this stuff so that so the girls love
him but he finds the love of his life he
meets Mrs T and they decide but they
want to have they want to start a family
they want to have children the thing
about having children of course is that
truck Shaw’s gene that predisposed his
neuro degeneration might be inherited by
trouble jr. because we’ve only fixed
ruptures neurons so what hope might
there be for trouble jr. in the future
and this is where we come to heritable
human genome editing by Chris Park as
9so inheritable genome editing what
we’re talking about is a change and edit
that we make that can be transmitted to
future generations and there are two
hypothetical strategies in humans that
we might do this so we’re putting the
pieces together in mice and model
systems but so far everything I’m going
to say from now on is really
hypothetical we think that it’s in reach
and it’s foreseeable but it’s actually
hypothetical in humans but what we think
we’ll be able to do is we’ll be able to
either edit in the embryo or edit in
gametes or sperm and the egg and I’m
going to talk about these one by one
starting with the embryo so embryos of
the type that we’re talking about are
one cell embryos we all owe our origins
to the one cell embryo stage at some
point okay this is actually a mouse one
cell embryo but humanum one cell embryos
look very similar and you can see here
the maternal and mother derive and the
father’s instruction manuals before they
come together and we can inject into
this one so using a very gentle
injection protocol the Chris spark has
nine components that then can fix the
gene so that now the embryo can develop
and we can use standard assisted
reproductive technologies with a which
are current today in many fertility
clinics to transfer the embryo into mrs.
T she can carry the pregnancy and so
when rubbish or jr. is born all of his
cells now contain that edit so he will
not be predisposed to the
neurodegenerative disease that his
father had in the same way and there are
in fact many single gene conditions that
this kind of approach would would apply
to and although they are so there are
probably about 6,000 probably more than
6,000 that are known and although each
one of these is individually quite rare
together they really add up to something
and in the UK where I’m from there are
probably a million people who are
affected in this way so it’s really very
important but actually most disease has
a genetic component from multiple
different genes and this includes all of
our many of them all of our old
favorites cardiovascular disease
diabetes obesity cancer
irritable bowel disease multiple squares
a very long list which affects many many
millions of people so the thing about
these diseases is that although they are
of course massively important because
they have a different contribution from
the environment and from multiple
different genes we don’t understand them
we don’t understand the genetics and so
they’re often overlooked but that’s
going to change and it’s going to change
with one particular technology in
particular and that is whole genome
sequencing so the first human whole
genome sequence was published in 2001 at
a cost of approximately a hundred
million dollars u.s. dollars and this
chart here you can’t see the details but
it doesn’t really matter
shows how the cost of sequencing a whole
genome from humans has decreased in the
years since 2001 now if this cost had
decreased according to Moore’s law so so
Gordon Moore was was one of the
cofounders of Intel and he came up in a
1965 paper with the idea that the number
of he predicted that the number of
transistors that you could fit on a on
an integrated circuit would double more
or less every year the computer power
would double every every year and there
have been different iterations of that
idea but basically he’s been right but
if we followed with genome sequencing
this trajectory the cost today would be
about just under a million u.s. dollars
per genome per human genome sequence in
fact something different has happened if
you look at this just graph this graph
here which plots logarithmically the
last ten years the cost has been coming
down five times per year fivefold per
year every year it gets a fifth of the
cost so that means if we project forward
in five years time it will cost just 25
cents to sequence your genome so what
you’ll be able to do
is you’ll be able to go to your local
supermarket too the whole genome
sequencing counter give a swab from your
cheek cell they’ll take it off in a
drone and it will be sent to a
sequencing center and then they will
produce the information it’ll go up to
the cloud and the cloud and they’ll send
it to your healthcare provider or doctor
or insurer or whoever fantastic but what
does this mean well I think what it’s
going to mean is that we’re going to
identify new disease genes because these
sequences at 25 cents each we’ll be able
to sequence people with from addis ababa
or a delayed or thessaloniki or wherever
and we’ll be able to say well if you’ve
got that character that character that
page there that paragraph there that
paragraph there then you’ve got a 78%
chance of having hypertension by the
time you’re 62 and so then people are
going to say well you know that this is
and they’re gonna we’re going to find
out these associations possibly for all
diseases and indeed health if you’ve got
these things then you’re more likely to
be healthy so the other corollary of
this of course is that every embryo is
going to have some genes or some
sequences that predispose to bad things
happening perhaps many years in the
future so what hope will there be for
editing to fix these multiple changes
and we return here to our two methods we
could edit in the embryo but this is
unlikely because the white window of
opportunity is quite short to do
multiple editing and to confirm what’s
happening and there’s a risk that we
might end up with scrambled eggs so it’s
more likely that we’ll use the second
method here gamete editing where edit
sperm and eggs and very recently we’ve
started to develop the technology to do
this in mice so what it’ll happen in the
future with mr. t for example is that
mr. t will go along and generate IPS
cells from his cheek cells but instead
of turning these into neurons which we
did before after we’ve done the editing
we can do editing check it’s okay more
editing check it’s okay of the IPS cells
in the dish then we can turn them into
sperm cells and using standard
reproductive technology inject these
into eggs then mrs. T becomes pregnant
so that now chop saw jr. has multiple
genes edited from the paternal germline
similarly with Mrs T mrs. T might have
some so-called problem genes and we
can address those too we could do
similar kind of edits except this time
we can ask the IPS cells derived from
Mrs T to become eggs so now we can match
them both together and we can produce
truck sure that’s got edits on both
sides multiple edits so now the
carpenter is really given a fantastic
toolkit with which to realize his vision
the problem is that his vision and the
vision of other people might not be
quite the same as troubles vision trap
Shaw might not be satisfied with
repairing disease predisposing genes he
might want to have a family of you know
Lara Croft’s and Jason Bourne’s right so
then that brings the idea of enhancement
using genome editing for enhancement and
this is where we’re altering traits
genetically that are not necessarily
directly related to disease things like
I’ve listed some of them it’s quite good
fun to just think of the lists strength
endurance IQ for example this is a kind
of transhumanism light and it kind of
introduces the notion of designer babies
but there’s also transhumanism not so
light which is much more fantastic where
we’re thinking about adding traits to
humans right you want your kid to be
able to fly to school in the morning
madam no problem well give him or her
wings but there’s a problem with this ok
there are several problems with it but
the one problem that I want to focus on
is that we’re forgetting the process so
the carpenter is in his or her workshop
with the tools which we’ve given him he
or she has the vision but we’re
forgetting the process by which he or
she applies those tools to realize the
vision and this is the same problem that
beset Charles Babbage Charles Babbage
was born in 1791 and he’s credited with
being one of the pioneers of the modern
computer but he was asked his computer
his calculator was called a difference
engine and he was asked more than one
time in his lifetime mr. Babbage if I
put the wrong values into your
calculating machine will it still give
me the right answer now we can laugh at
this question but it’s the same mistake
that many people are making
today I think because we may not know
the correct sequences or the correct
values we may not know the correct
sequences to edit we probably do for
some single gene conditions but for the
multiple the complex gene conditions of
the complex traits we almost certainly
do not know them but until we do know
them until we know the correct sequence
is to edit we cannot reliably get the
right answer
and so if at the end of this talk I
return to the questions that we asked at
the very beginning what is human
heritable genome editing and when will
it happen I think that what we can say
is that it will probably be involved
Chris Bachus 9 so that heritable human
genome editing is the use of the CRISPR
cast line system to make prescribed
changes in gametes and sperm or egg or
early embryos and that then the when
there is some tension here to accelerate
the development there is there will be
rapid advances in sequencing technology
and they will drive demand for sequences
for the for editing but on the other
hand technical legislative political and
social considerations may push human
genome editing years perhaps even
decades into the future thank you very much