Kind: captions
Language: en
flowing aging down might give us a
little bit of extra life
reversing aging even relatively
uncomprehensively
will give us essentially indefinite life
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impact theory enjoy the episode
hey everybody welcome to another episode
of health theory i am joined by somebody
who is really an incredible thinker when
it comes to anti-aging gerontology has a
very unique approach to that his name is
aubrey degray and he is the chief
science officer at the sends research
foundation aubry welcome to the show
well thanks for having me
great to be here i'm really excited you
you have um
keen insights into one of the areas that
i find most interesting in the world
which is can we live forever so i've
been telling people for years that i
want to live forever and they look at me
like i'm crazy
and i never understood that and
researching you i realized this is
something that you have come up against
a lot
um and you call it with the pro-aging
trance
so
i'd love to hear one do you actually
want to live forever
well to be honest i don't really think
very much in fact i don't really think
at all about
how long i want to live
i think it's really a pretty it's a
pretty strange thing to have an opinion
about to be honest because
it makes no sense to have any opinion
about something that you can change your
mind about in the meantime
you know i i compare it to having an
opinion about what time you would like
to go to the toilet next sunday
you know you may have an opinion about
what time how can that be possible it's
so like literally the difference between
existing and not existing you don't
think that
people are going to have a pretty strong
sense of whether they prefer one or the
other
uh again you know you're here you're
mixing up what people want and what
people expect
so of course one has an opinion about
what time one expects to go to the
target next sunday because of habit
right
so but having an opinion about what time
you want to go makes no sense because
you're going to have better information
on the topic nearer the time that is
going to you're going to be able to act
apart right so it's exactly the same in
my view for how long you want to live
that depends on your quality of life at
the time which in turn depend on all
manner of things that we don't know
about
you know like um
how good medicine's gonna be you know
whether there's gonna be a nuclear war
you know all manner of stuff i have
absolutely no idea how long i want to
live but i do know that i want to have
the choice i want to make sure that my
choice about how long to live and how
and of course how um
how high quality that life will be
is not progressively taken away from me
by aging so that's all really is that an
investment in having choice
that's really interesting and so now as
you're approaching the research and
looking at
how we extend sort of high functioning
life and i think that's probably
important um
to define so
let's get right into the idea that you
have that really differentiated you from
everybody certainly you know 10 years
ago when nobody was echoing your
sentiment what is different about
the
the approach that you have with sends
versus sort of the standard approach
before you presented that
so 10 years ago i'd more or less won the
argument
and um you know that became
really apparent
eight years ago
uh in 2013
when a group of my colleagues published
a paper that's very famous now it's
called the hallmarks of aging
and
it's pretty much exactly a restatement
of what i had published more than a
decade earlier
and it is
it is tantamount to holy scripture in
the field it is the paper that everybody
it's been
far more often than any other paper in
the whole of the biology of aging in the
past decade
and it simply describes this kind of
divide and conquer damage repair
approach to aging same as i did
so yeah by 10 years ago it was over i
had won the argument um
yeah so when i came along 20 years ago
and said listen we could do this damage
repair thing we could actually turn back
the aging clock and it might it should
be easier to do that
than
to slow the clock down which is what
people have been trying to do before
everybody you know first of all nobody
understood anything i was saying i was
bringing in a lot of
biology from areas that had not
historically been considered relevant to
the biology of aging and that of course
meant that the people who were studying
the biology of aging didn't know about
them so there was a lot of you know um
getting up speed involved in this
um
but yeah i mean just the general concept
even in the abstract that reversing
aging could be easier than retarding
aging just sounds wrong it sounds like
reversing aging is a bigger thing and
therefore it's got to be harder
and um so yeah the id all i had to get
across really was that
when we're slowing aging down we are
interfering with the processes that
drive aging
whereas when we are reversing aging we
aren't what we're doing instead we're
repairing the consequences of those
processes the damage that's already been
laid down that's completely different
from
retracing you know kind of running the
processes in reverse it's not like that
at all if it were then yes absolutely
reversing aging would be far harder than
retarding aging but it isn't
it's really interesting and so one do
you think that the early pushback on
that had to do with just they weren't
aware of some of the biology that you
were bringing into the debate um or was
it something
where they just couldn't accept that it
would one day be possible to rejuvenate
old tissues
well really there were three parts both
of those parts were
somewhat true
but
they understood that i was
you know i was basing my work on real
biology
they just you know it takes a while to
catch up biology is an enormous subject
and nobody knows more than a small a
tiny proportion of it so
really it was just a case of the
conclusion sound really
surprising therefore he's probably wrong
and i was um
you know i benefited a lot from the fact
that before i started talking about all
of this in about the year 2000 i had had
maybe five years in the field in which i
had been having good ideas other good
ideas that were relatively
uncontroversial and were well received
so everybody already knew that i was
smart and not knowledgeable and all that
so they they knew not to dismiss me too
easily
um but still you know it was tough but
the third thing which you haven't
mentioned was the really big one the
problem was that right from the
beginning
i was
perhaps a little bit too fearless in
the uh in what i said about the
consequences of all of this
in terms of how long people might be
expected to live
because that of course um
comes down to this thing i've mentioned
which i guess you're going to ask me
about coming up uh called longevity
escape velocity that leads me to the
conclusion that
whereas flowing aging down might give us
a little bit of extra life
reversing aging even relatively
uncomprehensively
will give us essentially indefinite life
uh so
you know
that's politically incendiary it sounds
like
i am not a scientist
and
scientists really do not want to
share a platform with people who sound
like they are not scientists however
smart they know that those people are
now were you getting out over your skis
from the biology perspective at that
time i mean obviously people have come
around now so something we've discovered
makes us far more plausible
were you intuiting that this could
become true or were you sort of
rationalizing from first principles that
there's there's nothing unrepairable
happening at the tissue level like how
did you come to that conclusion
um
yes i was saying well look the body is a
machine it's made of atoms and molecules
and stuff right um you know
its function is determined by its
structure
therefore
um you know
restoring the structure will restore the
function
therefore the only real question is are
there aspects of the structure that are
inherently even in principle impossible
to restore to how they were in young
adulthood
and
it seemed to me that no they're
obviously are not and nobody came along
and said yes there are
the the only real difference at the
beginning was in terms of the degree of
difficulty of this this thing and of
course even now
most people would be somewhat more
pessimistic than me in terms of that and
therefore in terms of the time frames
for developing this or that damage
repair technology for this or that type
of molecular or cellular damage but
we're within each other's range you know
um you know it's not it's not that we
think we're crazy about this and even
right back at the beginning when i was
first talking about all of this
um you know as i was bringing together a
lot of different ideas from different
areas of biology because of course the
damage repair approach is inherently a
divide and conquer one um you know the
people who what do you mean by divide
and conquer
oh simply that there are
lots of different types of damage we've
got to fix them all and each of them is
going to be
fixed by a different technology and
therefore um you know you've got to
apply the same technology a lot of
different things to the same people at
the same time in order to get the result
that's all i mean
right so yes so when i was talking to
the specialist in any given particular
area like for example mitochondrial
mutation
i would
generally not see very much pushback
from those people in regard to their
area you know i might be a little bit
more optimistic than them but i would be
basically talking sense and they would
understand that i knew where i was going
with this and you know they wish me luck
but when you ask these people about each
other's area
about which they knew very little
they would immediately throw out their
hand and say oh this is complete science
fiction there's no way this can work you
know so this was the kind of you know
consequence of the balkanization the um
siloing of of expertise in biology that
has happened increasingly over the years
and it took a while to break to break
that down
that's actually a really interesting
insight that the more somebody knew
about the area the more plausible your
take on things seemed but the less they
knew the more than they're sort of
defaulting to a base assumption that
they have about longevity itself um and
now is this where you see people
spilling into just sort of a dogmatic
approach about humans are never gonna
live forever i'm not willing to let
myself become optimistic about that
people for thousands of years have been
saying that they've cured it and people
are gonna live forever is that what
you're up against
yes um but in it it kind of
it's kind of more even more than that
because on top of the fact that this is
aging you know and everyone's been
saying this since the beginning of
civilization and therefore you know
everyone's been wrong therefore i'm
likely to be wrong as well
on top of that
there is the general fact that within
science overall
experts are
very reluctant to
risk
over-promising and under-delivering
they really really want to
go
you know whenever they have the
misfortune to be talking to the general
public they want to say um we are we
don't know
you know uh in most in most walks of
life
saying you don't know is the opposite of
what you want to do you want to pretend
you do know stuff that you don't know in
science it's the other way around you
pretend that you don't know stuff that
you actually do know
that that's actually fascinating and
there is something to that sort of level
of humility that i like but it can
obviously distort in itself become
pathological
uh so i think now it's a good time
because i want to frame we're going to
get into the weeds of like what the
seven types of damage are and what the
sort of
antagonistic thing that we apply to that
to repair will be but now i think we do
need to get into what the escape
velocity is here and
what you think will ultimately happen i
don't want to put words in your mouth
but when i hear you speak uh maybe i
hear what i want to hear but i i hear
sort of the ultimate hope um so but
before i put words in your mouth
what when you talk about escape velocity
what do you mean
right yeah okay so let me give a nice
like a bit of background to it
so
at the end of the day because as i
mentioned earlier the human body is a
machine
and therefore its function is determined
by its structure
um
we can therefore say
that
the health of the body and therefore the
likelihood that the body will cease to
function at all in other words that we
will die anytime soon
is determined by
the
amount of damage that the body is
carrying around
and this damage the damage we're talking
about anyway
is
a result of the body's normal operation
in other words he is self-inflicted
we are inflicting this damage upon
ourselves throughout life even starting
before we're born because this is simply
consequences of things that the body
needs to do and it's really intrinsic
consequences there's no way that we can
have the body actually you know keep us
alive without the body also creating and
inflicting this damage upon itself in
that sense aging of the human body or of
any other living organism is no
different than aging of a simple man may
be seen like a car or an airplane or
whatever you know that accumulates rust
as a result of you know the rain what
this means is that
we
could in principle improve the
likelihood of living a bit longer just
by repairing some of the damage
but it's better than that
the key thing that we have to take into
account and again this is just as true
for living machines like you and me as
it is for inanimate machines like cars
is that machines are set up to tolerate
a certain amount of damage without
any really appreciable decline in
function
so this is why
the
health problems of late life are
problems of late life and we do not see
them at all until after middle age
there is a certain threshold below which
we are fine
even a 20 year old or 25 year old has
some quite a bit actually of damage in
their body but you wouldn't know it
so
this means that if we take someone who
is let's say 60 or 70 and they've got
plenty of damage in their body
and
they are getting sick or they're about
to start declining in health
and we fix even only half of the damage
that they have in their bodies
then they will be back to the same
amount of damage as they were when they
were let's say 30 or 40.
and
that is fine they will be restored to
absolute function both mental and
physical of course we need to do better
so
supposing we try to develop therapies
that repair that
and suppose we become fairly good at it
so that we can indeed repair half of the
damage let's you know partition the
damage into two categories two buckets
we call them easy damage and difficult
damage the easy damage is by definition
the stuff that we can repair with
the first generation damage repair
therapies that are perhaps not very far
off now and the difficult one difficult
damaging the stuff that we cut
then we can restore somebody from the
age of let's say 70 to the age of let's
say 40
biologically of course
now what's going to happen
after that what's going to happen is
they're going to of course carry on
being alive and damaging themselves more
and eventually they're going to get back
to
the um
the amount of damage in their bodies
that they had before they were treated
now here's the tricky part though
even if we continue to give them these
damage repair therapy
every year every day even
they're still going to get back to
the amount of damage that they had
before they were first treated because
the difficult damage on its own is going
to add up to that amount after a certain
amount of time maybe when they reach the
age of 100 or 110
even though there is a negligible amount
of easy damage because we're constantly
getting rid of it
here's the the critical thing though
by that time when they reached 100 you
know this is 30 years after they were
first treated and we the scientists will
have been busy during that time
we will have been figuring away
improving the therapy
and that means that when someone is 100
they won't be getting version 1.0 of
this damage repair
they will be getting therapies that not
only repair the easy damage but they
also repair some still not all but some
of the difficult damage which means that
the 100 year old will be able to be
re-rejuvenated
um so that they have the damage of a
40-year-old again or 30-year-old
even though the inherent difficulty of
doing so is greater than it was when
they were originally 60 or 70.
so that so you get the idea now that um
in order to keep the level of damage in
this person's body down to the level
that would naturally exist in a 30 or 40
year old
all we need to do
is progressively improve how
comprehensive the damage repair therapy
arsenal that we have is
people are getting the state of the art
therapy at any point they can stay one
step ahead of the problem as fund we get
closer and closer to being able to
repair all the damage
in other words the damage that's still
not repairable gets less and less it
takes longer and longer
to become problematic and therefore
we um can even slow down in the rate at
which we continue to improve the therapy
so this is why i believe that once we
get even the first generation therapies
that give us only 20 or 30 years of
additional healthy life we're done we
will never fall below this threshold of
minimum rate of improvement that i've
called longevity escape velocity
so yeah sorry that was a long answer but
i felt i need to go into every step of
it in order to get it through to people
who may not have had it before
no i love it i think that's really
helpful and this is what makes your book
so interesting and um you as sort of a
leading personality so useful
is you really give people an
understanding of what's happening and so
i actually want to go into these seven
types of damage and the intrinsic nature
that to me is one of the key insights
that i got from you is look yes you can
slow things down and you should i've
heard you talk about that before
absolutely eat better don't smoke
exercise but recognize that you know
we've we've been running uh whatever 200
000 year experiment and no one ever has
managed to live forever doing just that
so we know that there's gonna have to be
more
and the way that you look at how that
intrinsic damage is done i found
incredibly interesting so if you can
like walk us through just like quickly
what the seven types are and then we'll
sort of dip into some key moments in
each of them
all right so yes damage about so um
think about damage repair that makes it
so
um attractive as a therapeutic modality
therapeutic concept
is that all we need to do
is to identify what the damage is to
characterize the nature of the damage
the differences in molecular and
cellular composition between older
people and younger people
and
then figure out ways to reverse that to
to to restore that to the young young
state
now let me first first of all clarify
one thing that
people do often get wrong which is i am
not saying that there are only seven
types of damage there are hundreds and
hundreds of types of damage what i'm
saying is that those hundreds and
hundreds of types can be classified into
seven categories and that this
classification is a useful thing to do
because it corresponds to
therapeutic
modality so for example um one of the
categories is loss of cell so what does
a lot of cells mean it means cells dying
and not being automatically replaced by
the division and differentiation of
other cells simple idea right and of
course this happens in various different
tissues that happens in the brain it
happens in the heart applicant
assignment
and in order to fix this you would need
to do different therapies of course
but all those therapies come under one
heading they are all stem cell therapies
of one sort or another
and stem cell therapies all have a lot
in common of course there are
differences in detail sure but that's
really important because it means that
if you've got one or two stem cell
therapies working for one or two tissues
then you've learned a lot about how to
get stem cell therapy in general to work
so getting the next one to work and the
one after that is going to be far easier
and faster than the first one was
this is the general principle that
underlies the whole of the approach
we're going to end up with a lot of
therapies that will be applying to the
same people at the same time but the way
we develop those therapy will not be one
therapy at a time um okay so that's the
first there that's the first category
cell life
then there are two categories that
uh
they're all about having too many cells
of a bad thought of a bad type of one
kind or another
one
of those categories is cancer in other
words having cells that are bad in
as a result of the fact that they divide
uncontrollably when they're not supposed
to and they take over
and the um of course there are many
different ways that people have thought
about to address cancer uh cancer
immunotherapy has exploded in the past
10 years which is of course much more
recently than um when i first started
thinking about all of this
back when i first started thinking about
this the only approach that i felt was
sufficiently generic for cancer was to
address telomere maintenance the ends of
the chromosomes which are which get
shorter with cell division and cancers
um circumvent that by typically by
turning on a gene called telomerase um
so i'm all about trying to stop that
from happening there are various ways to
do that there's actually been some
massive progress in that area recently
with the development of a drug that
essentially turns telomerase into a
suicide gene so basically
when
cells are expressing a lot of telomerase
and you give them and you give the body
this drug those cells just kill over at
once which is much better than the
version that i first put forward in
2002.
how do you selectively do that
oh you don't the point is the selection
is done by
the
cancer cell itself the cancer cell has
turned on telomerase expressing it at a
high level so cells that are not
expressing telomerase are not affected
by the drug but the ones that are
expecting telomerase they incorporate
this drug into their dna and that causes
them to kill over it's brain
are the only cells that are expressing
telomerase cancer cells i didn't think
that i thought that many cells
it's close enough so the stem cells of
rapidly renewing tissues like the blood
and the lining of the guts
they do express telomerase but only at
really trace level
far far lower than what cancers do
so there's plenty of therapeutic window
there um you know in terms of dose and
duration to be able to kill off the
cancer as well without having a bad
effect
a significant effect on the stem cell
population
and is that universal to cancer like all
cancer types express telomerase very
nearly not a great question not quite
um about 90 percent of cancers uh
maintain their telomeres using this
method the other 10 percent use a method
called alt which stands for alternative
lengthening of telomeres
and um
also still really very poorly understood
i'm afraid uh though actually there's
been massive progress over the past few
years and we may be close
um but yes we definitely need to
to address those cancers as well
and um in fact one of the main
weaknesses of my original
anti-telomerase anti-telomere approach
was that
if a cancer was expressing a lot of
telomerase
and you stopped it from doing so it
would switch towards
um
the great thing about this new um drug
is that the cancer won't have time to do
that the cells die too quickly um so um
the other way in which you can have too
many bad cells is if cells
are not bad by virtue of dividing too
much but they're just bad in some other
way um so they get into a state where
they are um
perhaps they're still doing what they're
supposed to do or maybe some of what
they're supposed to do but they're also
doing bad stuff
and the most um well-known category of
this well subcategory within this
category is cells that are called
senescent cells
these are cells that
get into a very characteristic state
where they secrete nasty chemicals that
are bad for the cells around them in
fact they some of those chemicals are
oncogenic so they can actually promote
cancer in neighboring cell
um but there are other ways in which
these cells can be bad so we'd like to
get rid of those cells now again this is
an area where there's been great
progress in the in the last 20 years
originally my view was that the only way
we were going to get rid of these cells
was by
essentially a a method that
was also to do with suicide gene so
essentially introducing a um
a an engineered gene with a virus which
in therapy into these cells that would
cause them to die as a result of the
other things they were doing already
and that's
still a perfectly reasonable approach
it's being pursued by at least one
company in this space
but
the remarkable thing that we've
discovered less than 10 years ago now
is that in fact we may very well be able
to do this just with pharmaceutical
there may be small molecule drugs that
can actually get in and selectively kill
off these narcissism cell
and there's a bunch of companies at
least half a dozen companies doing that
right now so that's all good news
all right so that's three things so far
and there's also to do with cell number
that was having too few cells and there
was two types of having too many cells
of a bad type
um now the other things are all at the
molecular level and two of them are
inside cells two of them are outside so
let's do the inside first
first one of these is mitochondrial
mutation so mitochondria are of course
the um machine within the cell that does
the chemistry of breathing it you know
they combine
oxygen with nutrients as a way of
extracting energy from those nutrients
and mitochondria have their own dna
they're the only part of the cell that
does outside of the chromosome to the
nucleus and uh
you know that dna is essential there are
only 13 proteins encoded in it but those
proteins are absolutely required
components of the machinery that makes
mitochondria do what they do
and um sure enough um that dna gets
mutated in fact it gets me taken really
fast as compared to
the dna and nucleus because the
mitochondria is a really bad place for
dna to be it's um
you know basically the process of
extracting energy from nutrients with
oxygen is a chemically very
hairy uh elaborate thing that has
byproducts in particular has reactive
toxic byproducts called free radical
which damage dna
um so yeah this this seems to be bad for
us and we'd like to fix it
but unfortunately fixing it is easier
said than done because it turns out that
even though i mean you think we're not
very good at gene therapy you know like
getting new genes into into the nuclear
dna we have no
way to do anything in the mitochondrial
dna the vectors just don't get there you
know it's just not going to happen
not for a very long time we need a
radical discovery to make that possible
um
but we can do something else
what we can do is we can put backup
copies of that mitochondrial dna
into the nucleus into the nuclear dna
with regular gene therapy
now you may think well that's not going
to work is it because you know the dna
is in the wrong place the proteins are
going to be in the wrong place that's
right that's done
but actually
it might not be set up because the
mitochondrion is a really complicated
big machine that is actually composed of
not just 13 proteins but more than a
thousand proteins all the others
are already encoded in nuclear gene in
our regular chromosome
and the machinery obviously therefore
exists to get those proteins into the
mitochondria after they've been
synthesized in the main body of the cell
without cell
so the
idea here is to hijack to co-opt that
machinery to essentially modify the dna
of these 13 13
um so that they become the proteins
become substrates for this standard
machinery and those proteins are
imported into the mitochondria along
with all the other thousands
and um you know assembled as if they had
been synthesized in the mitochondrion
already
now this even though you know i've shown
you that it's not merely so
you know implausible as you might have
thought initially nevertheless it's
still really hard and in fact people
people thought of this idea back in the
1980s and by the early 1990s they'd
given up
um but i said
yeah maybe you gave up a little too
easily and so we um started having a go
at this and sure enough we have made a
lot of progress
we are now at a point we haven't got it
working yet i'm not saying we have but
we're far far closer to getting this
working than anyone believe would ever
be possible so you know we're fairly
pleased with ourselves
all right if you're able to get that
first part to happen
do you think that cell now will out
compete that's one thing i've never
quite understood about gene therapy or
editing dna is how do you then get that
new version to win
all right great question so um
in in this particular case you're not
quite asking the right question because
it turns out that
mutant mitochondrial dna
generally
already doesn't win within the among
mitochondria
in cells that are dividing
cells that are dividing reasonably often
seem to purify away
the mutant mitochondria as fast as the
mutations rye
the ones that are problematic are cells
that are not dividing like muscle fibers
for example
those are cells in which the
mitochondria still are dividing and some
of them are being destroyed of course
and it turns out that the mutant
that they sometimes um some mutants
enjoy a selective advantage they
clonally expand and take over the cell
so the problem is to fix that
now of course if we're putting these
backup copies in the micro in the
nucleus then that whole problem of
selection between mitochondria goes away
because they've all got the same genes
because they haven't got the genes at
all the genes are common to the to all
mitochondria itself
the other type of damage in the cell
inside the cell is a much easier one to
explain
it's just garbage waste product
so the cell is doing a million different
things all the time and of course
different cells do somewhat different
things but they all do a lot of things
and those processes create byproducts
by products has to be eliminated
sometimes that happens by excreting them
into the circulation and having the
circulation take them away and excrete
them out of the kidney
or the liver
and sometimes the byproducts are simply
destroyed
now um that sounds great and it works
well for almost all of these byproducts
but
turns out that some of these byproducts
are created only very rarely and
therefore you know if you don't do
either of those things if you just store
them up rather than either excreting or
destroying them that's okay it doesn't
you know it doesn't kill you
until old age and of course old age is
what we're working on right but old age
is something that evolution doesn't care
about at all evolution only cares about
the propagation of genetic information
and therefore once you've had your kids
you know you you're
you're irrelevant to evolution that's
why we don't have genes to keep us
healthy late in life so
we have these waste products that
accumulate very slowly but eventually by
old age they start to matter and they
cause a lot of the things that are bad
for a slave in life like atherosclerosis
and macular degeneration
um so
what we want to do to fix this is we
want to get the cell to be better at
either breaking down or excreting things
that it not it can't it doesn't normally
do
and we've adopted both approaches
in the case of macular degeneration
the um particular
waste product that needs to be
eliminated is a kind of uh derivative of
vitamin a
that accumulates in cells at the back of
the eye in the retina
and we identified enzymes in bacteria in
fact
that are able to break these this stuff
down
these enzymes do not exist in human um
but they do exist in bacteria so we
figured out that if we could get those
enzymes into human cells then the
problem would go away the material would
not accumulate and people wouldn't go
blind
um and it worked we um we got to go
working in cell culture we were able to
spend the idea out as a startup company
a few years ago
and with a bit of luck it'll be a
clinical cloud in the eurozone
and the enzymes are so specific that
they only attack the unwanted
detritus for lack of a better word yeah
i mean enzymes are usually very specific
so that's not particularly surprising
and this molecule you know you don't
find this molecule
anywhere else there are no other
molecules in the body that look like
that that exists for good reasons and
that look anything like this molecule so
it's not particularly surprising that
the specificity
and what does the enzyme do if it were
to sort of get loose as it were and
encounter other tissue it just sort of
dies
nothing well the end yeah sure the
enzyme all proteins have a half-life the
enzyme just never finds its substrate
and nothing happens that's right and the
immune system doesn't attack it or
anything like that okay so so of course
that's a very important question the
immune system would generally attack
such a thing but because it is in the
eye we have a stroke of luck because
there's basically no immune system at
all in the eye so there are various
other early onset uh diseases of the eye
that are being addressed with various
other types of gene therapy already
involving either actual foreign genes
but more often human genes but
the human d is still foreign if
someone's got a congenital deficiency of
that
mutation in that gene right because then
they're not making the protein so yeah
so um
and also of course there's the viral
proteins itself you know the capsid or
whatever but yeah you can just do um
gene therapy much more easily in the eye
than you can in any other part of your
body
um all right then there's the idea of um
excretion so another of our spin-out
companies underdog pharmaceuticals is
looking at treating atherosclerosis
by that method essentially they've
developed a really cool molecule that's
able to go in and
infiltrate
atherosclerotic plaques and cells that
are
overly laden with oxidized cholesterol
which is the target in this case
um and they basically just extract it
they basically kind of solubilize it if
you like and bring it out into the
circulation so that it gets excreted
through the um through the kidney
and of course that's that's just as good
as breaking it down right it means it's
gone so yeah this is a really cool way
to address this problem we want to we
want to do other things other things
that we want to break down and sell
maybe more difficult we're just starting
a project
that breaks down proteins that
accumulate in the brain
there are various cases of this so one
of the most famous is what i call
neurofibrillary tangles in alzheimer's
disease these are made of mostly a
protein called tau which gets misfolded
and modified
and we
we've identified a way using a clever
type of antibody that can break this
stuff down at least in principle as i
said this is very early stage of the
project right now
um okay so i mentioned that i've done
five of my seven so far and i mentioned
that the other two
are outside the cell in the spaces
between cell
so what are they well the first one is
actually just like the one i just talked
about it's just waste product
and again we've got a case here in the
brain in alzheimer's disease these are
called senile plaques they're mostly
made of a protein called amyloid beta
and you know there's no question about
exactly which kinds of amyloid beta are
bad for you whether it's the big
aggregates that you see through the
microscope or whether it's the kind of
just a few of these things coming
together in what are called oligomers um
that that have damaging effect on for
example the permeability of cell
membrane but either way these are
misfolded and we want to get rid of them
and
um
turns out that getting rid of stuff like
this
outside the cell is a lot easier than
getting rid of stuff inside the cell why
is it easier
the reason it's easier is because the
machinery that we naturally have
inside the cell for breaking things down
is really really heavy duty but outside
the cell the machinery for breaking
things down is far more primitive
so lots of things accumulate there which
would not accumulate if only they were
inside the cell
um
they would be touched so all we have to
do is get them inside the cell and it
turns out that we can do that with the
immune system with vaccination we can
essentially trick the body into thinking
that the material is foreign and engulf
it like it with a bacterium and that
takes it inside the cell and then it's
tight
so that works now and people will be
able to get it working really well in um
alzheimer's disease there are actually
well there are variations on that scene
but
uh one way or another vaccination
against amyloid has been shown to really
get rid of analyte it doesn't have much
it's being used
now
kind of so it's been through clinical
trials all the way through phase three
unfortunately unfortunately if you want
to get something approved for medical
use you have to actually have a medical
benefit
rather than just a benefit that someone
can see down the microscope
and it doesn't or at least not to speak
up getting rid of amyloid in the brain
you know the people the people do not
get better
um or at least not much
so you have to ask why of course the
answer the one answer could be oh
amyloid doesn't matter i think that's a
dumb answer i think that the right
answer is that amyloid is not the only
thing that matters and that the other
thing we're not fixing with those
therapies like the tangles that i
mentioned earlier the synaptic density
and so on these things also matter a lot
and unless you fix them as well you're
not going to see a benefit but the
my bet is still that
if you fix all that other things you
didn't sex amyloid you'd still also have
only a mollusc benefit therefore it's a
fantastic thing that we have this
therapy in our back pocket
to be combined in the future with
therapies that are still being developed
man i'm really interested in what
happens as you begin to attack the
amyloid so when you know i think about
alzheimer's as sort of um a blood sugar
disease you know diabetes type 3 or
diabetes of the brain
and you think of the amyloid as sort of
going in and
grabbing on to particles that would
otherwise be problematic and sort of
encapsulating them
if you're taking that out i mean that
seems like it would really prolong the
sort of
health span even though you still have
the underlying condition or whatever
that's kicking off the things that have
to be grabbed a hold of
are were you surprised by how little
efficacy that has
not really no i mean a way of looking at
it really is that um
alpha ms is aging in microcosm
there are lots of different types of
damage accumulating and the crosstalk
between the processes that um create
different type of damage but they're
still semi-independent processes
so yeah i mean it's just like you know
if you fix five of the seven different
types of damage that i'm listing for you
at the moment then again you will not
expect to see all that much benefit
you've got to fix them all you haven't
got to fix any of them perfectly but
you've got to fix them all pretty well
incredibly interesting so
as we look into the future um the the
model sounds
it sounds really
useful because right now i feel like
we're still a long way away from really
understanding all of the biology even
just of something like metabolism
which in your book you talk a lot about
how a mass amount of the damage that
happens happens at the level of
metabolism but what's our timeline look
like are we
20 years away from escape velocity are
we 100 years away
so we are far enough away that i can't
give you a number in other words um you
know
if i mean because for any pioneering
technology right if it's even five years
away pretty much uh toss up
but i think we've got a 50 50-50 chance
of getting there within 15 years
i think um you know at least a 10 chance
that we won't get there for a hundred
years but who cares you know that's a
percent chance is quite enough to be
worth fighting for right
um
uh now of course how we get there you
have to break that down into you know
what steps need to happen
um
the big thing that's happened in the
past 15 years is basically um the
acceptance that this is a promising way
to go and the consequent arrival of a
lot of money especially in the past five
years from the private sector
um you know which is definitely speeding
things up a lot
um but there's a long way to go and uh
so i've already mentioned that there's
going to be a period where we take
therapies that work individually in
small small
patient populations and combine them
that's gonna that's bound to throw up a
few unanticipated interactions that we
have to address one way or another um
but even before then we've got to get
all the bits working some of them are
already working fairly well at least in
some examples so stem cells for
parkinson's disease for example or as i
mentioned already small molecules
addressing senescence cells and quite a
few of the other things are going to be
in clinical trials um in the next year
or two
but they've all got to get there
mitochondrial mutations for example i
can see that still being maybe five
years away from clinical trial
and so
looking at some of the like really
promising wins that have got you excited
um what are some like i know there's
been some big wins in parkinson's or at
least certain types of parkinson's um
what what are the things that you find
most exciting
well remember i don't work at the level
of clinical trials i'm focused on the
early stage stuff when something is even
within a couple of years of getting to
the clinic we've already spun it out
into a start-up company
um
so what excites me is typically the
breakthroughs that would take me half an
hour of background to describe why it's
even important right um
but honestly i'm excited about
everything i think that really the
difference between the answer i would
give to this question now versus five
years ago
is that five years ago if i was being
honest i would have to have said that
there were a couple of strands in which
progress was still imperceptible we were
really not making very much headway on
mitochondrial mutations we were also
making pretty much no headway on the one
that i never got to yet which is the
stiffening of the extracellular matrix
loss of elasticity
but around five years ago in both of
those cases we cracked it we got we
we've made a really
important
you know um log jam
breaking
um
breakthrough that essentially released
the bats and we got we started moving
much faster on both of those so now
there is nothing where we're really
stuck
aubry your world is is so
exciting and vast i mean it's crazy i
cannot believe that we've already been
going for an hour and we've like gotten
through chapter one of your book uh
it's really breathtaking man where can
people connect with you to learn more
about what you're doing um well of
course the right way to go to our
website uh sense.org septembery for
elephant enter november september.org
amazing man well this the conversation
has been so much fun i actually at one
point thought i may have misremembered
what time we started because it went so
fast uh your book is phenomenal all the
talks you've given are wonderful guys i
highly encourage you to engage with him
man you talk about hitting escape
velocity and where this is going and
somebody whose voice you know the more
that we can
get it out there i think the faster
things will progress so
um thank you aubry for being here and
speaking of preemptive thanks if you
haven't already i'll thank you now for
subscribing and until next time my
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