00:00:00
next up is Nicole Paul I'm really
00:00:02
excited for this talk I think you guys
00:00:04
will find a lot of optimism in where
00:00:07
technology is playing out in um in
00:00:10
biology and bioengineering to cure
00:00:13
fundamental human disease
00:00:15
for nearly 20 years she's been
00:00:17
developing Next Generation aav platforms
00:00:20
for Gene repair Gene transfer and Gene
00:00:22
editing and chief directed Evolution for
00:00:24
novel engineered capsids and comparative
00:00:27
multiomic approaches to interrogate
00:00:29
translational aav biology she's going to
00:00:32
share a little bit about her work with
00:00:33
her startup siren biotechnology which
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came out of stealth last year please
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join me in welcoming Dr Polk to the
00:00:40
stage
00:00:42
we'll let your winners ride
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Rain Man
00:00:47
[Music]
00:00:49
[Applause]
00:00:51
we open source
00:00:52
and they've just gone crazy
00:00:56
[Music]
00:00:59
all right quick show of hands how many
00:01:00
of you have ever even heard of the
00:01:02
phrase gene therapy or viral gene
00:01:04
therapy before Oh My Gosh would you guys
00:01:07
read in Wall Street Journal and The
00:01:08
Economist all right pretty good usually
00:01:10
it's like two hands
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um so who the heck am I why am I up here
00:01:14
talking to you about this so like I said
00:01:16
my name is Dr Nicole Paul come until
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like a hot minute ago I was a professor
00:01:19
of viral gene therapy at UCSF in San
00:01:22
Francisco and decided to spin out a
00:01:24
company based off some work in my lab
00:01:25
and I'm here to talk to you guys a
00:01:26
little bit about using viruses as
00:01:28
medicine so so what is gene therapy
00:01:31
broadly speaking uh this is using
00:01:33
viruses as medicines so historically we
00:01:36
have used these to treat single Gene
00:01:38
genetic disorders but we can use these
00:01:40
much more broadly now and I'll share a
00:01:41
little bit about that but historically
00:01:43
we've used these when you were born
00:01:45
either missing a gene in your genome or
00:01:48
you had a mutation in a particular Gene
00:01:50
in your genome and all you needed in
00:01:52
order to be completely healthy was to
00:01:53
have a functional copy of that Gene
00:01:55
given back to you or to have
00:01:58
um that the particular mutation in that
00:02:00
Gene corrected and restored for you and
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we can do all of these with viruses
00:02:04
and so if that sounds a little bit crazy
00:02:06
and a little bit new and a little bit
00:02:07
revolutionary it's because it is we're
00:02:09
kind of quite literally living through
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um one of the most recent and kind of
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newest eras of modern medicine and so in
00:02:16
order to talk about where we are we kind
00:02:18
of need to understand where we came from
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so nearly every one of you in this room
00:02:22
this first era of modern medicine
00:02:24
started probably with your either your
00:02:26
parents or your grandparents this is
00:02:29
with chemical medicines this is when we
00:02:30
realized that gosh every time I have a
00:02:33
stomachache I can go eat this one
00:02:34
particular Leaf from a tree
00:02:36
and when I eat that leaf I feel much
00:02:38
better and then the scientists realize
00:02:40
well we don't have to eat the leaf we
00:02:42
could isolate the chemical compound that
00:02:43
comes from that leaf and then we could
00:02:45
produce that in mass synthetically in
00:02:47
large Vats in the lab and that way we
00:02:49
don't have to all go outside and eat and
00:02:50
eat leaves all the time
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um and so the Advent of chemical
00:02:54
medicines and realizing that we could
00:02:55
isolate these and synthesize these in
00:02:57
Mass was an absolute transformation this
00:02:59
is nearly every drug you've ever taken
00:03:01
in your life these are all the pills you
00:03:03
can go find at your local pharmacy uh
00:03:05
particularly the ones that are over the
00:03:06
counter and so this is the vast majority
00:03:08
of medicines you've ever taken in your
00:03:09
entire life
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and the way these chemical medicines
00:03:12
work right you take that pillow you
00:03:13
swallow it it goes into your stomach it
00:03:16
gets dissolved by the acids in your
00:03:17
stomach it then gets absorbed into the
00:03:19
bloodstream in your GI tract and then
00:03:21
goes throughout your entire body and it
00:03:23
will bind to and affect kind of either
00:03:25
the shape or the function or the ability
00:03:27
of various proteins in your body in a
00:03:29
way that's useful to reduce your
00:03:30
symptoms
00:03:31
and so then in the next kind of era of
00:03:34
medicine we had the brilliant idea well
00:03:36
let's just cut out the middle man let's
00:03:37
not give you a chemical that alters the
00:03:39
shape or function of a protein let's
00:03:41
just give you the protein let's let's
00:03:43
advance to protein medicines and let's
00:03:45
now take a protein that has the
00:03:47
particular shape in the function that
00:03:49
you might need in order to provide some
00:03:50
kind of therapeutic benefit for the
00:03:52
disease state that you have and give you
00:03:53
that as a drug and so that's kind of
00:03:56
been the next kind of most recent wave
00:03:59
of modern medicine and so this is things
00:04:01
like enzyme treatments and antibody
00:04:02
therapies many of you in the room have
00:04:04
probably heard of the most successful
00:04:06
drug of all time anyone know what it is
00:04:09
anyone want to shout out a guess what's
00:04:10
the most successful drug of all time
00:04:12
that's raised the most money
00:04:17
it's not Viagra guys
00:04:22
Humira someone said it so this is an
00:04:25
antibody
00:04:26
that's used to treat a particular form
00:04:28
of arthritis
00:04:29
this antibody cells on average a little
00:04:32
over 21 billion dollars worth of just
00:04:34
that drug every single year and has been
00:04:36
the most successful drug for the last 20
00:04:38
years this is what we call a blockbuster
00:04:41
this is what everyone is shooting for in
00:04:43
their portfolio is a blockbuster drug
00:04:45
and it's an antibody
00:04:47
but now we're entering kind of this
00:04:49
newest third modern uh form of medicine
00:04:52
which is what we call living medicines
00:04:54
this is using things like viruses
00:04:55
bacteria cells things that are quote
00:04:57
unquote alive that we can now use to go
00:05:00
in and impart changes in your body why
00:05:02
would we do that well both chemical
00:05:04
medicines and protein medicines we
00:05:05
typically either give orally or we give
00:05:07
intravenously which means they're going
00:05:09
to go throughout your entire body but in
00:05:11
some cases we don't want a drug to go to
00:05:13
your entire body like for example when
00:05:14
you take chemo boy you feel like trash
00:05:16
right it's because it's also affecting
00:05:18
healthy cells in your body so sometimes
00:05:20
we want the medicine to only go into a
00:05:22
simple place in your body or a single
00:05:24
place so that way you only experience
00:05:26
the therapeutic effect in a single
00:05:28
location the other really cool thing we
00:05:30
can do with things like viruses and
00:05:31
cells is we can engineer I know many of
00:05:33
you here are like Tech or Tech adjacent
00:05:35
we can engineer in logic circuits so we
00:05:37
can add things like if then or and and
00:05:39
all these types of kind of Boolean logic
00:05:41
we can engineer those circuits into
00:05:43
viruses and cells and have them perform
00:05:45
those same types of decisions uh within
00:05:48
your body like if you experience this
00:05:49
release the drug If you experience this
00:05:51
don't
00:05:52
so you can engineer in these types of
00:05:54
circuits in order to get this really
00:05:55
really precise delivery of any
00:05:57
particular medicine that you're
00:05:58
interested in delivering and you can
00:05:59
package almost anything in a virus
00:06:01
and so a really common misconception is
00:06:04
that all viruses are bad for you all
00:06:05
viruses make you sick
00:06:06
couldn't be farther from the truth the
00:06:08
vast majority of viruses on the planet
00:06:09
are very good at getting inside of you
00:06:11
but very few of them make you sick I bet
00:06:13
most of you can't name more than 20
00:06:15
viruses and all the viruses you can name
00:06:17
are viruses that make you sick right
00:06:18
measles mumps small polio smallpox these
00:06:21
types of things we only know of them
00:06:22
because we study them because they make
00:06:24
us sick but the vast majority of the
00:06:25
viruses on the planet can actually kind
00:06:27
of be considered our allies they're
00:06:29
tools that we can use that don't make us
00:06:30
sick but they're still very good at
00:06:32
getting inside of us that we can use to
00:06:34
deliver all kinds of medicines
00:06:36
so all of this is talk much more fun to
00:06:39
look at as an actual video of this in
00:06:42
action and so what I'm going to show you
00:06:43
on this screen is a patient from a
00:06:46
clinical trial
00:06:47
from a patient that has a rare form of
00:06:50
inherited genetic blindness this is a
00:06:52
disease called Libra's congenital
00:06:53
amaurosis these patients are born
00:06:55
basically medically blind they cannot
00:06:57
see at Birth and you're going to see two
00:06:59
videos the one on the left is going to
00:07:01
be this patient pre-treatment attempting
00:07:03
to navigate a maze you can see that maze
00:07:05
on the floor at very very low light so
00:07:07
the reason that this looks very yellow
00:07:09
is because it's taken at one luminal
00:07:11
unit or low light all of us have much
00:07:13
poorer visual Acuity at low light than
00:07:15
we do at highlight so it's not that this
00:07:16
video is taken in 1985 it was just in
00:07:18
very very low light that's why it looks
00:07:20
yellow
00:07:20
so I'm actually going to start that
00:07:21
video
00:07:22
and I'll kind of talk over this this
00:07:24
patient while they're going so this
00:07:26
patient's medically blind they cannot
00:07:27
see the arrows on the ground that
00:07:28
they're being told to navigate nor can
00:07:30
they see the little obstacles that
00:07:31
they're being told like you should step
00:07:33
over so they're feeling for them with
00:07:35
their feet just like you would if you
00:07:36
were blind and you didn't have your
00:07:37
walking stick you would just kind of
00:07:39
feel in front of you to see what was
00:07:41
there so that you wouldn't manage to
00:07:42
trip and fall
00:07:43
so I'm not actually going to show you
00:07:44
this entire video because it took this
00:07:46
poor patient 214 seconds to attempt this
00:07:48
navigate this eight foot eight foot by
00:07:50
eight foot maze
00:07:52
and all this patient needed they were
00:07:54
missing a single protein in the back of
00:07:56
their eye all they needed was a single
00:07:58
viral infusion for that virus to express
00:08:00
a single protein that that patient was
00:08:02
missing in their eye
00:08:04
and this is that exact same patient
00:08:06
again this was a 10 year old just one
00:08:08
year after treatment they would have
00:08:10
been able to do this within seven days
00:08:11
though
00:08:13
so they have absolutely perfect vision
00:08:16
so we're able to
00:08:17
see pure blindness
00:08:21
this same young patient has now gone on
00:08:23
to get their driver's license
00:08:27
they are they are walking quite
00:08:29
literally they are walking amongst us
00:08:31
leading a completely normal life so this
00:08:34
feels crazy and revolutionary like oh my
00:08:36
gosh I hadn't heard about this when is
00:08:38
this when is this coming for the rest of
00:08:39
us and all of our indications
00:08:42
soon
00:08:44
where are we now this is a one-year-old
00:08:47
Slide the next prospectus from Wells
00:08:48
Fargo is expected to come out any day
00:08:50
now I was hoping it would come out
00:08:51
before this talk but it didn't but this
00:08:53
is the annual prospectus they put out
00:08:55
every year of kind of the advancement of
00:08:57
these gene therapy companies they do
00:08:58
this for every industry but this is for
00:09:00
gene therapy so this is all of the logos
00:09:02
of all of the companies that are working
00:09:03
in gene therapy for various diseases the
00:09:05
outer rings are kind of the earliest
00:09:07
stages of development those phase one
00:09:09
phase two trials and as you move towards
00:09:11
the center towards the bullseye that's
00:09:12
when you're FDA approved and you can
00:09:13
sell your drug for hopefully 21 billion
00:09:15
dollars a year and be a Blockbuster but
00:09:18
as you can see right there is a wave of
00:09:21
Gene therapies coming from so even those
00:09:22
few of you who didn't raise your hand
00:09:24
earlier that you had ever heard of gene
00:09:25
therapy before I promise you in your
00:09:28
lifetime no matter how old any of you
00:09:30
are in this audience in your lifetime
00:09:32
you are going to receive a viral gene
00:09:34
therapy as medicine
00:09:37
so there's a particular virus Dave
00:09:38
mentioned it earlier that I like to work
00:09:40
on this virus called aav and it's
00:09:42
typically used like we were mentioning
00:09:44
before to treat rare genetic disorders
00:09:45
some of the disorders that we've been
00:09:47
able to cure are the ones shown here on
00:09:49
this slide
00:09:50
and again we've typically only done rare
00:09:53
single Gene disorders and in my lab at
00:09:55
UCSF and now at the company we wanted to
00:09:57
ask a little bit Bolder question
00:09:59
typically we've only used these to treat
00:10:01
rare genetic disorders could we use
00:10:03
these to treat other indication spaces
00:10:04
ones with many more patients where the
00:10:06
need is much greater and the benefit to
00:10:09
humanity would be much more so we wanted
00:10:10
to ask a rather audacious question
00:10:12
rather than having a virus that might
00:10:14
cause cancer could you use a virus to
00:10:16
cure cancer Could you actually use a
00:10:17
virus as a medicine that could be used
00:10:19
to treat cancer
00:10:21
so we've been working on this for the
00:10:22
last seven years to try to go against
00:10:25
conventional gene therapy so every gene
00:10:27
therapy on the planet all the ones on
00:10:29
that Bullseye I just showed you on the
00:10:30
last slide whether they're from Academia
00:10:32
industry big Pharma doesn't matter
00:10:34
every one of those is bespoke and
00:10:36
personalized for a single indication so
00:10:38
that virus that you make can only be
00:10:39
used to treat that one disease and no
00:10:41
other disease and every one of those
00:10:43
viruses takes about 10 to 15 years to
00:10:45
develop so this is very time intensive
00:10:47
usually on average about two to three
00:10:49
billion dollars so maybe not necessarily
00:10:51
as expensive as the gentleman who just
00:10:52
left the stage but a very very expensive
00:10:54
technology nonetheless and typically
00:10:56
treat very very small patient
00:10:58
populations the definition of a rare
00:11:00
disease in the United States is anything
00:11:01
that occurs in fewer than 200 000
00:11:03
patients a year but most of those Gene
00:11:05
therapies are going after indications
00:11:07
with like a hundred patients 200
00:11:09
patients so very very rare disorders
00:11:12
and so we wanted to go after something
00:11:13
that would help much more of humanity
00:11:15
and so we wanted to ask the question
00:11:17
could we make a single gene therapy that
00:11:19
could be used to treat millions of
00:11:20
patients across a variety of indication
00:11:22
spaces things like cancer where they're
00:11:24
often very similar to one another
00:11:26
could you make a universal gene therapy
00:11:29
is that even a thing
00:11:32
and so we wanted to kind of set out on a
00:11:35
fairly audacious project to not only
00:11:37
bring viral gene therapy to the oncology
00:11:39
world but to blend it with one of the
00:11:41
newest forms of oncology which is this
00:11:43
idea or this concept of immunotherapy
00:11:45
many of you have maybe even heard of
00:11:46
this before there's a variety of
00:11:48
different ways you can accomplish this
00:11:49
they all essentially work the same way
00:11:52
where they retrain your immune system to
00:11:55
fight cancer and I'm using that word
00:11:57
retrain very purposefully
00:12:00
every single one of you in this audience
00:12:02
has a tumor you've had a tumor every
00:12:05
single day of your life
00:12:07
it's usually a single cell you often
00:12:08
have many of them throughout your body
00:12:10
your immune system is doing what's
00:12:12
called background cancer
00:12:13
immunosurveillance your immune system is
00:12:16
circulating throughout your body every
00:12:17
single day and it's actually able to
00:12:18
detect and find and sniff out where
00:12:20
those tumors are and get rid of them why
00:12:23
they are while they are still single
00:12:25
cells
00:12:26
how do they do this so that single tumor
00:12:28
cell wherever it is in your body it
00:12:30
sends out little chemical cues to the
00:12:32
local environment as well as the immune
00:12:33
system and the healthy cells that
00:12:35
surround that tumor are also able to
00:12:37
detect something's weird about that guy
00:12:39
and they'll send a little message over
00:12:40
to the immune system and they'll be like
00:12:41
come over and do an investigation check
00:12:43
him out what's up with him
00:12:44
your immune system will come over sniff
00:12:46
it out and be like yeah I agree
00:12:47
something's up with him and they'll kill
00:12:50
that cell
00:12:51
and this is happening all the time
00:12:52
throughout your entire body
00:12:54
it's your immune system right now today
00:12:56
your immune system knows how to fight
00:12:58
cancer it's Exquisite at it so how in
00:13:00
the heck do you ever get a
00:13:01
baseball-sized tumor how does that
00:13:02
happen it happens because that
00:13:05
individual tumor cell through a variety
00:13:06
of different mechanisms there are many
00:13:07
ways this happens but typically somehow
00:13:10
through one or two mechanisms it will
00:13:12
end up basically randomly generating a
00:13:14
mutation that will give it essentially
00:13:16
an invisibility cloak that invisibility
00:13:19
cloak makes it so that those neighboring
00:13:21
healthy cells can't detect that
00:13:22
something's up with it so they don't
00:13:24
send a message to the immune system and
00:13:25
because it's a little bit invisible your
00:13:27
immune system also can't just like
00:13:28
randomly swim by and detect it and see
00:13:30
that something's wrong and so because it
00:13:31
can't be seen it can't be destroyed and
00:13:34
so then it starts to grow and become
00:13:35
your big baseball size mass and then you
00:13:37
become symptomatic right and then you go
00:13:39
to the doctor
00:13:40
but you can retrain your immune system
00:13:42
to be able to see that invisible tumor
00:13:44
and if you can do that with
00:13:46
immunotherapy then now you've got a way
00:13:48
to destroy a tumor that doesn't involve
00:13:50
chemo that doesn't involve radiation
00:13:52
but basically uses your own immune
00:13:54
system to fight Cancers and so we wanted
00:13:56
to blend the power of viral gene therapy
00:13:59
and the Precision delivery and kind of
00:14:00
those logic circuits around like do this
00:14:02
when you experience this these types of
00:14:04
things with immunotherapy to see if we
00:14:06
couldn't do something
00:14:07
important in the cancer space so we
00:14:09
developed a platform a variety of
00:14:11
different Universal Gene Therapies in my
00:14:13
lab at UCSF and spun those out into the
00:14:15
company and the name of the company is
00:14:17
actually based off the mechanism of
00:14:18
action here so we can take these viruses
00:14:20
have them deliver a variety of different
00:14:22
kind of cancer announcing payloads that
00:14:25
will announce to immune system the
00:14:27
cancer is here and so that way both the
00:14:30
cancer cell as well as the neighboring
00:14:32
cells will basically set off the fire
00:14:34
alarm pull the fire in and let the
00:14:37
immune system know this is where the
00:14:38
tumor is come in and fight it and you'll
00:14:40
have these three different waves of
00:14:41
tumor killing that can happen both with
00:14:43
your innate and your adaptive immune
00:14:44
system
00:14:47
so while we were still at UCSF we were
00:14:49
like okay we have this really cool idea
00:14:51
we want to try this but we're agnostic
00:14:53
to any particular cancer type because
00:14:54
again we weren't an oncology lab we were
00:14:56
a viral gene therapy lab so we went over
00:14:58
to our colleagues at the Cancer Center
00:14:59
and we're like what's the gnarliest
00:15:00
cancer what's the one that nothing works
00:15:03
we love a challenge tell us something
00:15:05
that we can work on that will be
00:15:06
interesting and they said go after brain
00:15:08
cancer so we decided we'd start
00:15:10
collaborating with Folks at UCSF to
00:15:12
determine a brain cancer kind of path
00:15:14
but how do you test a drug
00:15:16
in order to make sure it works on human
00:15:18
brain cancer when you can't test it yet
00:15:19
on humans because the FDA wants you to
00:15:21
have a data package before you go up for
00:15:23
your clinical trial
00:15:24
so the way you test it is you actually
00:15:26
make mice with human brain cancer so you
00:15:28
can take brain cancer samples from
00:15:30
humans from biopsies and resections
00:15:32
Transplant those into mice they'll grow
00:15:34
a mini human brain tumor you can come in
00:15:36
and now treat them with your human drug
00:15:38
not your mouse drug your human drug to
00:15:40
test if it works and look to see whether
00:15:42
or not you get a response
00:15:43
and this is a quick little sample from
00:15:46
three Mice from a treatment group where
00:15:47
you can see uh those big colored blobs
00:15:50
or the tumors and the brains of these
00:15:51
myosis is live non-invasive
00:15:53
bioluminescent Imaging where the control
00:15:55
treated mice that receive either a
00:15:57
control virus or just receive sterile
00:15:59
saline have massive tumors these mice
00:16:01
die versus the mice that have been
00:16:02
treated with our virus where we can
00:16:04
completely eliminate these tumors as you
00:16:06
would imagine if you can eliminate the
00:16:07
tumors with imaging that might just
00:16:09
correspond to improvements and life
00:16:11
expectancy so this is the one and only
00:16:13
graph that I'm showing you very simple
00:16:15
it's a survival curve the line is
00:16:17
vertical you died the line is horizontal
00:16:20
you lived so we can massively improve
00:16:23
the lifespans of these animals and for
00:16:25
all intents and purposes cure these mice
00:16:27
of brain cancer and we're cueing up for
00:16:29
a clinical trial in 2025.
00:16:36
so we're excited to start our clinical
00:16:37
trial in 2025 and very quickly I'm going
00:16:40
to share with you guys maybe like 15
00:16:42
three little 15 second vignettes on what
00:16:45
else could we do with viruses so we see
00:16:47
a gentleman here sleeping
00:16:49
how many of you are short on sleep
00:16:52
every one of you raise your hands come
00:16:53
on uh so there is a rare mutation that
00:16:55
happens in patients these are people
00:16:57
walking amongst us who have a mutation
00:16:58
in a gene called dec2 these patients
00:17:01
again single mutation single Gene these
00:17:04
patients only need four hours of sleep a
00:17:06
night to be completely rested the same
00:17:07
way that we have the need for eight to
00:17:09
nine hours of sleep a night
00:17:12
you interested in getting this gene
00:17:13
therapy
00:17:15
we could do this today
00:17:16
we haven't yet but we could do this
00:17:18
today another example most of us in the
00:17:21
room pretty probably interested in
00:17:22
longevity
00:17:23
um we could use viruses to regenerate
00:17:25
the tissue in your in all of your joints
00:17:28
maybe get rid of things like cellulite
00:17:30
viruses brain fog all these types of
00:17:33
things this is probably a few more years
00:17:34
out where we're probably five to ten
00:17:36
years out on being ready to do this but
00:17:38
this is absolutely coming in your
00:17:39
lifetime you could get a Rejuvenation
00:17:41
gene therapy
00:17:43
you really want to talk far out we could
00:17:45
talk about maybe 30 years from now we
00:17:47
could absolutely engineer Humanity to
00:17:49
withstand life in much more drastically
00:17:52
harsh environments so we could alter
00:17:54
your skin color to be able to reflect
00:17:56
more UV light so you wouldn't get as
00:17:58
much damage if perhaps say you were
00:17:59
living on Mars we could engineer the
00:18:01
cells in your immune or in your gut and
00:18:04
the bacteria that live in your gut to be
00:18:05
able to metabolize foods that are more
00:18:07
easily grown on a martian environment
00:18:09
and these types of things so really your
00:18:12
imagination is the limit so could we
00:18:14
enhance human potential we absolutely
00:18:16
can it's just a matter of are you
00:18:17
interested in when
00:18:18
so happy to discuss the future
00:18:30
foreign
00:18:31
[Music]
00:18:40
[Music]
00:18:42
times yeah
00:18:45
can you just
00:18:48
um
00:18:49
help everyone understand the
00:18:52
timing and the regulatory hurdles
00:18:55
um
00:18:56
viral gene therapy had a moment where
00:18:58
there were setbacks
00:19:00
and just share that with everyone how
00:19:03
that's affected how this technology has
00:19:06
been held back how it's progressing now
00:19:08
and what timelines generally look like
00:19:10
for getting these uh these uh
00:19:13
breakthroughs to Market
00:19:14
absolutely so today if you were to start
00:19:17
a brand new gene therapy company called
00:19:19
siren biotechnology or anything else and
00:19:22
you wanted to develop a viral gene
00:19:24
therapy and you wanted to get to Clinic
00:19:25
you're still probably looking for that
00:19:27
first program in like a 10 to 15 year
00:19:29
mark and it's not because it's going to
00:19:31
take you that long to run the clinical
00:19:32
trials it's not because it's going to
00:19:33
take you that long to grow up the Vats
00:19:35
of the drug it's it's mostly going to be
00:19:38
a regulatory timeline so in between each
00:19:39
one of these clinical trials even before
00:19:41
you do your very first ones I mean we're
00:19:43
ready today we could start our brain
00:19:44
cancer clinical trial today but we're
00:19:46
looking at 18 months of paperwork in
00:19:48
order to file to do that first phase one
00:19:50
and then you need to do your data
00:19:51
readouts in between each one of those
00:19:52
trials there's this kind of massive
00:19:55
amount of paperwork that goes in front
00:19:57
of the FDA that needs to be reviewed and
00:19:59
there's back and forth and so the
00:20:01
regulatory hurdles both from
00:20:03
if you weren't even doing anything you
00:20:04
know really drastic like those last
00:20:06
three vignettes that I talked about is
00:20:08
still going to be 10 to 15 years but if
00:20:10
you wanted to propose something like the
00:20:12
Sleep one that I mentioned that I think
00:20:13
we'd all I'm certainly interested in
00:20:16
um there you're probably looking at an
00:20:17
ethical review board and whether or not
00:20:20
they let you do something like that
00:20:21
because that's not a disease so fun fact
00:20:23
the FDA only lets you queue up clinical
00:20:26
trials to test drugs that are for
00:20:28
diseases but aging is not a disease
00:20:32
state
00:20:34
wanting to sleep fewer hours is not a
00:20:37
disease State insomnia is but wanting to
00:20:40
just sleep fewer hours and be fully
00:20:42
rested is not a disease state so we kind
00:20:44
of have to get to this moment where
00:20:47
does the FDA start changing their
00:20:49
definition of disease do we have a new
00:20:52
regulatory body who will review these
00:20:54
types of things that are more like
00:20:55
augmentations and enhancements how are
00:20:58
we going to Grapple with this as a
00:20:59
society are we are we okay with this and
00:21:03
let me just ask one more question it's a
00:21:05
great it's a great question you pose
00:21:06
because there is
00:21:07
increasing consensus that maybe we
00:21:10
should think about aging itself as a
00:21:11
disease obviously and that there's a lot
00:21:13
of approaches now to addressing that
00:21:16
what about the other challenges to
00:21:19
completing the research and the trials
00:21:21
and scalability what are the bottlenecks
00:21:24
we've talked about I've talked on our
00:21:26
show about car T therapy and the
00:21:28
challenge and getting manufacturing
00:21:30
scaled up to treat enough patients each
00:21:32
year even though the Technologies here
00:21:33
it's FDA approved those drugs are in
00:21:35
Market we just can't make enough what
00:21:37
are the chat and I've heard a lot about
00:21:39
uh lentovirus production and all these
00:21:41
other kind of viral vectors being 18
00:21:43
month delay super bottleneck how
00:21:45
bottleneck are we in being able to do
00:21:47
the research that you guys are doing and
00:21:49
ultimately to get these products to
00:21:50
Market make enough of the stuff to treat
00:21:52
patients so the single biggest
00:21:53
bottleneck is actually not technological
00:21:55
at all it's Financial it's access to
00:21:57
Capital
00:21:58
um right so these are like I said very
00:22:00
very Capital intensive the average viral
00:22:02
gene therapy is about two to three
00:22:03
billion dollars that's about three times
00:22:04
more than making one of those chemical
00:22:06
medicines some of that has to do with
00:22:08
time how long that process takes right
00:22:10
every year your company is operating uh
00:22:13
that GNA oh it's expensive
00:22:15
um it adds up really fast and so some of
00:22:17
this is just access to Capital and
00:22:19
there's right the any company every one
00:22:21
of us in this room this has a company
00:22:22
there's depending on your sector there's
00:22:24
a valley of death for some of you it's
00:22:26
very very early stage for some of you
00:22:27
it's a little bit more later stage but
00:22:28
there's a valley of death where you just
00:22:30
can't access Capital before you hit this
00:22:31
like big de-risking milestone where the
00:22:33
bigger checks will come in and private
00:22:35
equity and those types of groups and
00:22:36
crossover funds in your IPO so there's a
00:22:39
value of death for many of these early
00:22:40
stage companies where usually either
00:22:42
after your seed stage or your series a
00:22:43
but before you've got clinical trial
00:22:45
readouts where people are very nervous
00:22:47
to give you a really big check so that's
00:22:49
certainly the biggest hurdle right now
00:22:50
and why you see many companies going
00:22:52
under across the biotech space
00:22:53
regardless of if they're selling Gene
00:22:55
therapies and then from the
00:22:56
technological side it's still
00:22:58
manufacturing is just like the drum beat
00:23:00
being able to manufacture these things
00:23:02
at scale continues to be a challenge we
00:23:05
need folks who come from like the
00:23:07
mechanical engineering and these types
00:23:09
of backgrounds who don't historically
00:23:10
necessarily think of Biotech as a place
00:23:13
where they could apply their their
00:23:15
knowledge and Technologies to please
00:23:17
come over to biotech and help us make
00:23:20
you know new generations of bioreactors
00:23:22
and types of things that will allow us
00:23:24
to produce these at scale cleanly
00:23:26
cheaply and easily and it's just not
00:23:29
intuitive making chemicals at scale is
00:23:32
something that we've been doing for 40
00:23:33
years so we're really good at it genenta
00:23:35
can make kilos of drugs in an afternoon
00:23:37
with a robot but viruses are still
00:23:40
something like if I queue up the biggest
00:23:42
cdmo in the world
00:23:43
catalent Pharma and ask them to make us
00:23:46
a 5 000 liter bioreactor a virus they'll
00:23:48
absolutely say yes but they won't even
00:23:50
touch it for two and a half years
00:23:52
um because I wanted to double click on
00:23:54
the
00:23:55
concept of making life better for people
00:23:58
who aren't sick the Marty Seligman from
00:24:01
the American Psychological Association
00:24:03
actually posed this question 20 years
00:24:05
ago and he said well we try to make all
00:24:07
of psychology and Psychiatry is taking
00:24:09
depressed people and anxious people and
00:24:12
making them less depressed and anxious
00:24:14
what about meaning and fulfillment for
00:24:16
people who are content what about more
00:24:17
joy and so when you look at the field
00:24:20
and it's amazing the progress you're
00:24:23
making and thank you for doing all that
00:24:24
work aside from hey can we sleep less
00:24:27
what else is you know do you do you talk
00:24:31
about wow if we had the mandate to take
00:24:33
healthy people and and give them a gift
00:24:35
of augmenting them making them into
00:24:38
superheroes almost when we're talking
00:24:39
about like X-Men mutations here what are
00:24:43
the fun things that you dream about that
00:24:45
you could do for Humanity could we all
00:24:46
just have Vision like Hawks or oh night
00:24:49
vision is totally possible night vision
00:24:51
yeah easy
00:24:53
not literally without the goggles yeah
00:24:56
easy I mean a world in which that's just
00:24:59
an FDA like I need a I need the green
00:25:01
light but no that's easy
00:25:03
so okay that feels like Professor X kind
00:25:06
of level I like it what else you
00:25:08
got keep going
00:25:11
um night vision would be possible the
00:25:13
ability to metabolize
00:25:15
um you know a food that grows perhaps in
00:25:17
a different environment that not only
00:25:19
you can't get any nutrients from but you
00:25:21
can't even absorb it um so we could make
00:25:23
it so that you could you know pretend
00:25:25
pretend Soylent tasted good
00:25:28
um you know uh you could eat anything
00:25:30
and not only could it taste good to you
00:25:32
but it could provide you all the
00:25:33
nutrients that you need and be able to
00:25:35
grow with you know much less much less
00:25:37
water and in the types of environments
00:25:38
that we'll have in in the future planets
00:25:40
that you know given the climate change
00:25:41
challenges that we all have
00:25:43
um as far as other augmentations I mean
00:25:45
there's there's all of the obvious
00:25:46
Beauty applications uh that I think all
00:25:49
of us are already doing uh now this we
00:25:52
would just be doing this with a
00:25:53
different modality right so removing you
00:25:54
know there's a there's a gene therapy
00:25:56
company in San Diego working on male
00:25:57
pattern baldness uh there are folks
00:25:59
working on you know all the wrinkles and
00:26:01
cellulite and you know getting your hair
00:26:02
color back and like all of the normal
00:26:04
Beauty things that you would expect
00:26:05
that's absolutely coming but as far as
00:26:06
beyond the obvious Beauty things like
00:26:08
what other types of augmentations I
00:26:10
think the mental Health space is a huge
00:26:12
one because it's it's usually a very
00:26:14
very simple thing and it's complex but
00:26:17
it's simple they're usually missing a
00:26:19
single receptor or a single protein
00:26:21
somewhere in their brain and if we were
00:26:23
just able to restore that for them in
00:26:24
just that location and not everywhere in
00:26:26
their body
00:26:28
um you could restore Joy you could
00:26:30
restore happiness all of these types of
00:26:31
things do you want to talk about the
00:26:34
capital markets piece because you
00:26:36
mentioned you need Capital yeah we're
00:26:38
fundraising hi yeah and uh tomorrow
00:26:41
maybe maybe you can help out here but
00:26:43
you know the biotech Market's been
00:26:45
decimated oh yeah since November of 21
00:26:47
and it's really intricately linked to
00:26:50
interest rates because of how far out
00:26:52
you have to make a bet on a biotech
00:26:54
company and so as a result the
00:26:55
valuations have plummeted 80 90 percent
00:26:57
in many cases a lot of stuff just not
00:26:59
getting funded right now
00:27:01
um maybe tomorrow you can share your
00:27:03
point of view on where things are headed
00:27:05
there and um Nicole maybe you can share
00:27:07
a little bit about what the experience
00:27:08
has been fundraising even though you
00:27:10
have a great technology that's got some
00:27:11
proof points how hard it is well I I
00:27:13
have a I have a kind of a technical
00:27:15
question but which is just
00:27:17
you had to when you picked aav
00:27:20
you had to make a decision about small
00:27:22
edits and not large edits I guess right
00:27:25
so just explain to these guys about what
00:27:27
payloads are actually possible in AV and
00:27:30
are you thinking about what happens if
00:27:32
you actually have to go beyond four KB
00:27:34
and how are you going to solve that
00:27:36
so because a lot of the diseases that
00:27:38
these guys will actually probably
00:27:39
understand are not small Snips they're
00:27:41
going to be large you know
00:27:43
cut and paste two types of gene therapy
00:27:45
there's Gene transfer gene therapy where
00:27:47
we give you the whole Gene that you were
00:27:49
missing like perhaps you were missing
00:27:50
that portion of your chromosome at Birth
00:27:52
so that's Gene transfer gene therapy
00:27:53
we're literally transferring a
00:27:54
functional copy of the gene back to you
00:27:56
and then there's Gene editing gene
00:27:57
therapy where we go in and actually
00:27:58
correct a mutation in place uh within
00:28:01
your genome and don't give you anything
00:28:02
extra so every virus on the planet has a
00:28:06
carrying capacity it has a size just
00:28:07
like a sedan can't carry as much as a
00:28:10
minivan and so aav viruses the viruses
00:28:12
that I work on are amongst one of the
00:28:14
smaller viruses so it can only package
00:28:16
about 4.75 KB so the numbers of
00:28:18
nucleotides that you can fit inside of
00:28:20
it and different viruses have larger
00:28:21
packaging capacities and can fit more
00:28:23
studs that's 4700 letters of DNA and so
00:28:27
different viruses will have different
00:28:28
packaging capacities and so if you're
00:28:30
doing Gene transfer gene therapy where
00:28:32
you need to provide the entire copy of
00:28:33
the gene you can only put in genes that
00:28:36
will fit with all of the other
00:28:37
regulatory elements for expression
00:28:38
within that virus so of all protein
00:28:42
coding genes since we're typically going
00:28:43
after diseases that are in influencing a
00:28:46
protein of all protein coding genes
00:28:47
eighty percent of those genes can fit
00:28:49
within my virus so actually the vast
00:28:50
majority of genetic diseases can be
00:28:52
treated with aav gene therapy with Gene
00:28:54
transfer gene therapy with Gene editing
00:28:56
gene therapy we can treat anything
00:28:57
because now we're not size limited we
00:28:59
only need to deliver either the knicker
00:29:01
or the cutter right many of you have
00:29:03
heard of things like crispr that's one
00:29:04
of the many tools we can use to Nick or
00:29:06
cut DNA and we can either make a Nick
00:29:08
and have your body repair the mutation
00:29:11
we can go in and make a Nick or a cut
00:29:13
and we can cut something out that wasn't
00:29:15
supposed to be there or we can go in and
00:29:18
Nick or cut something in your genome cut
00:29:21
something out and then put something
00:29:22
that was meant to be there the whole
00:29:23
time back in all three of those forms
00:29:26
those Gene repairs and Gene edits are
00:29:28
all kind of broadly classified as a lot
00:29:29
of Gene editing gene therapy and all of
00:29:31
those would fit within a lot of any
00:29:33
virus there's a high percentage of
00:29:34
disease I don't know the percentage you
00:29:35
probably know which is really just like
00:29:37
one point mutation right yeah huge
00:29:40
transcribe AC or something is typically
00:29:42
the biggest one right can you just
00:29:43
explain to folks in when you think the
00:29:46
tool chain will exist for us to do those
00:29:48
single point edits and actually just
00:29:50
today you can actually go in and
00:29:52
accurately rewrite an a to a c okay
00:29:55
today there's a yeah there's a few in
00:29:56
yeah there yeah
00:30:00
um guys we got to wrap and I want to
00:30:02
really thank Dr Nicole Paulk for her
00:30:05
amazing work
00:30:06
um
00:30:12
fantastic thank you so much thank you
00:30:15
thank you thank you
00:30:19
[Music]
00:30:19
[Applause]
00:30:21
[Music]
00:30:23
rain man
00:30:24
[Music]
00:30:27
we open source it to the fans and
00:30:30
they've just gone crazy
00:30:31
[Music]
00:30:37
I tried
