00:00Precision delivery of medicine
00:02entertainment franchise games absolutely
00:05exploding small modly reactors and the
00:07nuclear Renaissance plus AI moving into
00:11very complex workflows now these were
00:14just a few of the major Tech innovations
00:16that Partners at a16z predicted last
00:19year and our partners are back we just
00:21dropped our list of over 40 plus big
00:24ideas for 2024 a compilation of critical
00:27advancements across all our verticals
00:30from Smart energy grids to Crime
00:31detecting computer vision to
00:33democratizing Miracle drugs like gp1s or
00:36even AI moving from blackbox to clearbox
00:40you can find the full list of 40 plus
00:43Builder worthy Pursuits at a16 z.com
00:47bigideas 2024 or you can click the link
00:50in our description below but on Deck
00:53today you will hear directly from one of
00:55our partners as we dive even more deeply
00:58into their big idea what what's the why
01:00now what opportunities and what
01:02challenges are on the horizon and how
01:04can you get involved let's dive
01:07in as a reminder the content here is for
01:10informational purposes only should not
01:12be taken as legal business tax or
01:14investment advice or be used to evaluate
01:16any investment or security and is not
01:18directed at any investors or potential
01:20investors in any a6z fund please note
01:24that a16z and its Affiliates may also
01:26maintain investments in the companies
01:28discussed in this podcast for more
01:30details including a link to our
01:31investments please see
01:38disclosures hi my name is Jorge K I'm
01:40one of the general Partners here at ad
01:42Dre and Horwitz I'm on the Bion health
01:44Team where I focus on investments in the
01:45Life Sciences my big idea for the year
01:49is programming medicine's final frontier
01:52where are the reusable rockets for
01:53biotech traditional drug development is
01:56pain takingly timec consuming risky and
01:58expensive it's highly bespoke too one
02:02molecule has no bearing on the next
02:03molecule that gets developed like
02:05traditional Rockets they're onetime use
02:10changing spacex's rocket reusability has
02:12transformed space travel lowering costs
02:15and Expanding Horizons similarly
02:18potentially Curative programmable
02:20medicines like gene therapy can reuse
02:22components like the de delivery vehicles
02:25used to Target specific cells while
02:28swapping out the genetic cargo the next
02:30mission uses the same rocket to deliver
02:32a different payload to a new
02:34destination the FDA is looking to the
02:36skies and taking a page out of the faa's
02:39approach to Aviation safety rigorous yet
02:41adaptive recently launching its own new
02:44office for therapeutic products and
02:46pilot piloting operation warp speed for
02:49rare disease to create more transparent
02:51and flexible processes for evaluating
02:53and approving programmable medicines
02:55imagine a future where we redeploy not
02:58reinvent innovation it will
03:00revolutionize how we make medicines and
03:03where these medicines can take us all
03:05right so Jorge I feel like this big idea
03:07is so compelling this idea of
03:09programming medicine um certainly sounds
03:12like something that uh the whole world
03:15could benefit from but before we get
03:17into that maybe you could just break
03:19down a little bit further why
03:20traditional drug development is as you
03:22say so painstakingly timeconsuming risky
03:26and expensive and maybe also just put a
03:29number to that like how long does it
03:30really take for drugs to be developed in
03:34terms sure um so first of all the reason
03:37why it's so painstaking it's so timec
03:40consuming it's risky and expensive is
03:42because we're putting something into
03:44human beings and so of course the bar of
03:46what we're going to do should be and is
03:49exceedingly High uh in terms of how long
03:52it takes um you know these are averages
03:54of averages of course but on average it
03:57could take anywhere between 10 to 15
04:00years to develop a drug uh to get it to
04:03patients and that's obviously a very
04:05very long time especially in diseases
04:07where people are desperately in need for
04:09better treatments so why does it take 10
04:12to 15 years typically well typically
04:14there there are three stages in in
04:16developing a medicine right the first
04:18one is what we would call you know the
04:20actual drug Discovery stage which is you
04:23know the work that goes into you know
04:25finding a Target in a disease that you
04:28would like to hit with a medicine um in
04:32some cases that Target is already known
04:34in some cases you're looking to discover
04:37new targets to go after to have better
04:39treatment options for a given disease
04:41that can take many many years even in
04:43that first phase the second phase is
04:46what we call preclinical development so
04:48now it's this work of once you have a
04:51Target you think is worth hitting and
04:53you have a molecule that you think hits
04:55that Target you have to do all of the
04:58work to develop that
05:00molecule into a medicine to ensuring
05:02that it has all the qualities of what
05:04you want a medicine to have in terms of
05:06How It's absorbed and how it's
05:07metabolize and where it goes to into
05:09body um and whether or not it's toxic
05:11and if so you know how much of it is
05:13toxic all of that work we we do in in
05:16what we call preclinical development
05:18outside of humans we do this in in in
05:20dishes and cells we can do this in
05:22animal models like mice or even monkeys
05:25uh and that as you can imagine also
05:26takes many many years and then of course
05:29there's the third phase which is the
05:30most important phase which is what we
05:32call clinical development uh which is
05:35the you know the terms that uh many
05:38would be familiar with uh in terms of
05:39human clinical trials where there's a
05:41phase one trial a phase two trial and a
05:43phase three trial and that process can
05:46take anywhere between five to seven
05:48years and so when you add up all of
05:51those phases the drug Discovery phase
05:53the preclinical development phase the
05:55clinical development phase that's how
05:56you get to these 10 to 15 years and I
05:59should add that once you're done with
06:01clinical trials you now have to file for
06:04regulatory approval so here in the US
06:06you file with the FDA the process by
06:09which these applications get rev
06:11reviewed by the FDA You know despite the
06:13fda's best efforts can take one
06:16sometimes even two years to go through
06:18so again when you sum all of that up
06:20it's um it's you can see why it can
06:22often take well over a decade to make a
06:26medicine absolutely and to your point
06:30is a very reasonable concept but where
06:32does programmable medicine come into
06:35play here and how does that maybe change
06:36the Paradigm across each of those stages
06:39or where does it have the potential to
06:41really reshape that Arc yeah so I think
06:44this is where um the concept of a
06:46programmable medicine potentially could
06:48be um very transformative to how we
06:50think about developing drugs uh and that
06:53is uh because in a programmable medicine
06:55there are multiple components that could
06:57be uh as I as I described redeployed for
07:01different applications so let me give
07:02you an example um a gene therapy is this
07:06idea that you can deliver a a genetic
07:10payload in other words you can deliver a
07:12gene to a cell um that has a defective
07:17Gene if we're able to make a medicine
07:20that does that that can deliver one gene
07:23to a given cell type it becomes
07:25increasingly likely that we'll be able
07:27to deliver a different Gene to a
07:30different cell type for a different
07:31disease and that's very different than
07:34the way we traditionally make medicines
07:36if you think about a traditional
07:37medicine like a chemical a molecule that
07:40is a chemical that is tested and
07:43designed for a specific disease at a
07:48Target the second you switch the target
07:51we don't reuse the atoms in the molecule
07:53and try to fit them into a new Target we
07:55just design a different molecule and
07:57that's why I say you know in traditional
07:59drug development one molecule has very
08:02little bearing on the next molecule you
08:04design but in the case of these
08:06programmable medicines where all the
08:07components can be reused uh you just
08:10have to essentially redirect or
08:13redeploy um components like you know
08:16delivery vehicles for Gene therapies or
08:19in the case of a gene editing medicine
08:22just redirect what edit you want the um
08:25the enzyme or the protein to make and
08:28that is where the programmability comes
08:31in and that sounds huge right just so I
08:34understand you correctly when you're
08:36talking about the re the reusability of
08:39um these medicines it's basically the
08:42equivalent of the reusable rocket is the
08:46um almost like the um you basically
08:50would have already gotten a certain drug
08:53approved to be able to deliver something
08:56each time you're reiterating on that
08:58would you then need to have the the
09:00specific genetic um almost like payload
09:03in there reapproved but most of that leg
09:06work has already been done am I thinking
09:08about that correctly that's right in
09:10this analogy what we what we would love
09:14possible is that you know the rocket in
09:17in this case is the vehicle by which you
09:19ensure that your payload is delivered
09:22right and and some of the most common
09:24ones that we know in terms of what would
09:25be Rockets here are uh the l&p uh
09:29molecules that all of the covid vaccines
09:31that many of us received were delivered
09:33right the covid vaccine was mRNA mRNA
09:36had the instruction for what it wanted
09:38your body to make and that was
09:39encapsulated in this LNP uh particle
09:43lipid nanoparticle it's like a little
09:46ball of fat similarly for a lot of Gene
09:49therapies instead of using an l&p
09:51particle we use something called an aav
09:54which is an an adapted virus it stands
09:57for a dino Associated virus
10:00there have been examples in the clinic
10:02where uh payloads have been delivered
10:05with LMP or payloads have been delivered
10:06with aav for different applications all
10:09you're swapping out is the cargo the
10:11instruction in the of mRNA that's in
10:14that LMP or the instructions or the or
10:16the genetic cargo that's in that
10:18aab and this is very timely because the
10:22FDA is starting to signal that they are
10:26looking for ways to be increasingly
10:28adaptive to ensure that we can um they
10:31can adequately review these therapies
10:35that are reusing components but do so in
10:37a way that will be both rigorous but
10:39also adaptive and therefore hopefully
10:40more speedy and where people don't have
10:43to start from scratch because they
10:44already have that rocket um that is Rea
10:47applicable so tell us a little more
10:49about that where the FDA seems to be
10:51taking maybe some inspiration or at
10:53least that's what you um allude to with
10:55the FAA right so what can we what can
10:58they learn from the rocket reability in
11:01this analogy and what Also may be
11:03fundamentally different and what are you
11:05taking from some of the new
11:06announcements like the new office of
11:08therapeutic products yeah so I think
11:10there's a lot of things to take from
11:11this the first one is that I think
11:13there's there's there's real recognition
11:15here that um we are seeing meaningful in
11:19Innovation uh in terms of the kinds of
11:21medicines we can make and the FDA is
11:24appropriately uh trying to find ways to
11:27remain uh to main their rigor because
11:30again they have an extraordinarily high
11:32obligation to ensure safety and efficacy
11:34in patients but to um move um hopefully
11:39more quickly to attempt to keep up with
11:42all the Innovation we're seeing and so
11:44they've uh uh pushed forward on several
11:46fronts that I think are already uh
11:48pointing Us in that direction the first
11:51one is they've announced an office of
11:54therapeutic products whose uh mandate
11:57and mission is to to find ways to do uh
12:00exactly what we've been describing and
12:03so I think uh I think the industry the
12:05drug development industry now has a
12:07partner in the FDA in trying to find the
12:10best paths forward along the lines of
12:13what we talked about the second is they
12:15they are also uh trying to innovate
12:18themselves the FDA is looking to be more
12:20Nimble and is running experiments to uh
12:24find ways to do uh exactly that so for
12:27example um we all uh many of us would be
12:30familiar with operation warp spreed
12:32which was the effort by the government
12:34to try to ensure that the covid vaccines
12:36could reach all of us in a very very
12:39timely manner given the nature of the
12:40pandemic well the FDA has has said there
12:43are so many interactable diseases many
12:46rare genetic diseases that have no good
12:50therapeutic or treatment options so they
12:52are launching a pilot program mirroring
12:55the concept of operation warp speed uh
12:58but to apply apply that to rare diseases
13:01where they're going to run some
13:02experiments to see different ways that
13:04the agency can interact with industry uh
13:07to get these medicines uh more quickly
13:10to the patients that so desperately need
13:12them and so I think those are very very
13:14um promising signs that um both the
13:17industry and and the government are
13:18looking for ways to Ure ensure these
13:20Innovations reach patients in a in a
13:22timely and responsible Manner and
13:24there's also other proof points that we
13:25can point to that are happening um uh
13:28every day right now so for example um
13:31several companies that are developing
13:33cuttingedge Gene editing uh medicines
13:37are starting to get approvals by the FDA
13:39to move forward with some of their key
13:43uh clinical trials and there been a
13:45moment in time where the FDA was being
13:46more hesitant but I think as they as
13:48they've started to evaluate these
13:50Technologies more carefully they've
13:52started to U develop uh path forward for
13:55these uh medicines to continue to get
13:57developed and the breaking news
13:59is that the first crisper therapy has
14:02been approved uh this is a therapy for
14:05Cle cell anemia beta Thalia that was
14:08developed by a biote biopharmaceutical
14:11company called vertex Pharmaceuticals uh
14:13working with another company called
14:15Therapeutics um and this is a therapy
14:18for essentially curing uh a genetic
14:21disease in this case CLE cell anemia by
14:23taking the cells the relevant cells out
14:26of the body editing them uh
14:29with with the the crisper Gene editing
14:32technology and putting them back in the
14:35body in a way that results in a
14:38cure and this is a big deal for so many
14:40reasons the first one is it's the first
14:42time that a crisper therapy has been
14:44approved um as a medicine yeah um the
14:47second reason why this is a big idea a
14:49big deal is I think it's an important
14:51Milestone on this to this point about
14:54the future of what programmable
14:55medicines could look like now that you
14:57have a first approval
14:59could you you've demonstrated that a
15:01crisper uh editor could be safely used
15:04as a medicine so now if it edits
15:05something differently the the process
15:08for getting that approved should
15:10hopefully be you know shorter and
15:12faster and the third reason I think that
15:15this is a a big deal in terms of a
15:17milestone is how relatively speaking how
15:19quickly this has happened so you asked
15:22me at the beginning how long does it
15:23take uh make to how long does it take to
15:26make a drug and I said about 10 to 15
15:29average it's barely been 10 years since
15:32the concept of crisper was discovered
15:35and described in the scientific
15:36literature right so we went from the
15:38initial discovery of crisper as a
15:41potential uh use as a medicine all the
15:45way to an approval in just over 10 years
15:47that is lightning fast uh in this world
15:51so it's just an exciting moment in time
15:53I think for for for the industry and
15:55hopefully for for all the various
15:57patients that are looking for better
15:58Solutions uh and treatments for their
16:00diseases maybe you could just speak a
16:02little more to that like if we are able
16:04to see this Confluence um that you're
16:07discussing and this idea of programmable
16:10medicine becoming a reality what does
16:11that really mean in in terms of like the
16:15the speed of therapies um Coming the
16:17number of them the new business models
16:19that might be unlocked how this might
16:21ultimately end uh end up impacting
16:24patients any just kind of high level
16:25thoughts about this if we are moving to
16:27this new paradigm what that really means
16:30yeah I think it means a couple of things
16:32uh the first one uh is I think it means
16:35that U for the benefit of patients every
16:37time we run a clinical trial with these
16:40types of medicines we're not starting
16:42from from Square zero or from square one
16:46because we already know something about
16:48the various components in the therapy so
16:51that's the first thing the second thing
16:54is that generally speaking these
16:56programmable medicines are going after
16:58diseases where the cause of the disease
17:01is very well known in other words it's a
17:05mutation and it's the ability to
17:07intervene has been uh in an effective
17:10way has been what's been elusive for us
17:12so in in a lot of ways these new
17:14programmable medicines are just a
17:15fundamentally new superpower we can go
17:18after diseases that we weren't able to
17:19go after before and as a result the
17:22third thing that I think this means for
17:24all of us is that we may be on the cusp
17:26where you know the elusive c-word is a
17:30reality that we might actually have
17:32cures for lots of very intractable
17:34problems and that is a very new day
17:37indeed right like that is something that
17:39just has not been very common in in in
17:41our industry so I think there's lots of
17:43reasons to be excited yeah I mean I as
17:45you're talking I'm like actually smiling
17:47because it's it is there is it's hard
17:50it's impossible not to be excited but I
17:52guess just to close things off you've
17:53painted this beautiful picture of what
17:55may be to come could you share a little
17:57bit more about the blockers if any
18:00whether regulatory whether it has to do
18:02with the the fundamental science that's
18:04coming on board what would you say if
18:07this reality that you're painting uh
18:10were to not come to pass what would
18:13those reasons be and also maybe for
18:15those listening how can builders get
18:17involved how can they actually help make
18:19this reality come true yeah so first of
18:22all in terms of the blockers I think
18:24there are several um and I think they
18:26are important um and some of the blocker
18:28should be there um so the first one is
18:31uh everything I'm describing in terms of
18:33these programmable medicines has another
18:35side of it has another side of the coin
18:37to it which is these are largely
18:41permanent medicines as well so you know
18:44if if you take a pill and you have a bad
18:47you know a reaction or adverse event or
18:50toxic reaction to that pill you just
18:52stop taking the pill and eventually your
18:55body will clear it and you know
18:56hopefully um you know the the toxicity
18:58has been addressed in the case of making
19:03DNA if there is an error if there is a
19:06toxicity that comes from making that
19:08edit something inadvertent it's
19:11permanent or at least it has the
19:13potential to be permanent and so for
19:16that reason the FDA appropriately has
19:18extraordinarily High bar for how they
19:20think about um evaluating the safety of
19:22these medicines and um how they think
19:25about which diseases are probably the
19:27most appropriate to go after with
19:30something that is potentially Ure but
19:32also potentially permanent yes so that's
19:34one blocker um uh that you know is just
19:37going going to need it's going to need
19:39to be addressed systematically and it
19:41should be a second blocker is you know
19:44one of the most the only medicines that
19:47work are the ones that get to patients
19:51and these programmable medicines have a
19:53couple of challenges in terms of
19:55accessibility the first one is um these
19:59are not pills you get over the counter
20:01these are very complex medicines and uh
20:04so therefore uh the process by which you
20:06get treated um can be um a very long and
20:11difficult process so I just described
20:14the approval of uh crisper therapy for
20:18Cle cell anemia y the process by which
20:21you get the treatment uh could take
20:24months because you have to go you have
20:28removed the cells get edited in this
20:31case you actually have to get a form of
20:34of of therapy to kill your internal
20:36cells so you can replace it with the
20:38corrected ones um afterwards and that
20:40whole and that could be a long stay at
20:42the hospital so that whole process could
20:44take several months so the accessibility
20:47of these therapies um will limit how
20:50many people can get them and when and a
20:53second element to accessibility is cost
20:56yes and today uh these therapies um can
21:00cost on the order of millions of dollars
21:04now on the one hand that millions of
21:06dollars of cost is Justified because a
21:10lot of R&D went into it they're very
21:12exens expensive to make and manufactur
21:14it's very expensive to manufacture all
21:16these components I'm describing uh and
21:18that's number two and then number three
21:20they provide a fair amount of benefit
21:23you know in the case of treating a baby
21:25that had you know something like sematic
21:26muscular atrophy that would have other
21:28died a oneandone gene therapy uh from
21:31nardis this is a a therapy that's worth
21:34about it's cost about 2.1
21:36million effectively um uh saves that
21:40baby's life so there's an incredible
21:41amount of value that comes from that
21:43absolutely but the cost of discovering
21:45developing manufacturing these therapies
21:48and the benefit that they come from also
21:49comes with a very Hefty price tag and
21:51that's going to limit
21:53accessibility so that's one of the other
21:56key blockers I would say that we're seen
21:58in this in this space now how can
22:00builders help I think Builders can help
22:02in a very important way which is if
22:04there is one technology on this planet
22:07that can scale better than anything else
22:10we know of it's biology and so all of
22:14the things I'm describing um in terms of
22:16blockers to access at some point can be
22:20addressed by improving our ability to
22:23engineer biology to address some of
22:25these limitations so improved biology
22:28can make manufacturing much more uh
22:31scalable and therefore um much less
22:33expensive uh improving the kinds of uh
22:37of interventions and the Precision by
22:39which these programmable medicines work
22:41can address some of these questions of
22:43permanence or toxicity so where the
22:46builders can really help is just become
22:49better program MERS of biology and from
22:51that we will get better applications at
22:54higher scale and at lower cost and
22:56hopefully get them in the hands of
22:58patients more quickly that's amazing and
23:00maybe one super quick question to end
23:02things off is you know a lot of our
23:04listeners are familiar with the idea of
23:07exponential uh exponentially decreasing
23:09cost in things like software um do you
23:11see that same uh kind of curve being
23:14applied here when you're talking about
23:16decreasing costs is that really the
23:17future that you're painting where these
23:19things instead of costing millions of
23:21dollars we're talking thousands is that
23:23really in the future that's the Hope um
23:26and the possibility is there because
23:28again you know biology can scale
23:30exponentially we all did come from one
23:32cell and here we are we're sitting here
23:34that's such a great Point yeah so I
23:36think um you know but there's work to be
23:38done there we haven't seen it yet
23:39absolutely but that's the promise and
23:41that's the hope all right I hope you
23:43enjoyed this big idea we do have a lot
23:45more on the way including a new age of
23:48Maritime exploration that takes
23:49advantage of AI and computer Vision Plus
23:52AI first games that never end and we
23:55voice first apps May finally be having
23:57their Moment by the way if you want to
23:59see our full list of 40 plus Big Ideas
24:02today you can head on over to az.com SL
![How To Succeed As A NEW & YOUNG Realtor [Deals Every Month + Luxury Listings]](/_next/image?url=https%3A%2F%2Fi.ytimg.com%2Fvi%2FrtrRghgTayc%2Fhqdefault.jpg&w=3840&q=75)
