February 2, 2021 • 59 mins
In one sentence: Unlocking new mRNA treatments will save lives, but it's not as simple as that.
—————
Overview
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Jake Becraft of Strand Therapeutics is an expert in designing and programming mRNA, critical strands of genetic material that provide instructions for making proteins. As one suite of tools in the emerging synthetic biology toolkit, mRNA is a twenty-first century harbinger of life.
Yet, with all powerful tools, there are risks of accidental or intentional misuse. It is this shared responsibility among the scientific, private, and public realms that Becraft advocates for thoughtful, anticipatory stewardship of these influential technologies. Stunningly, it's no longer science fiction to consider pre-making vast numbers of vaccines for every conceivable pandemic vector and their mutations. This, the 'Manhattan project for vaccines', is a matter of national defense, Becraft argues.
We are joined by contributing expert Malvika V. Miller for an episode featuring a wide-ranging discussion on synbio, STEM advocacy, national security policy, and more.
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Topic Timecodes
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[01:04] What Strand Therapeutics does
[03:24] Using messenger RNA technology for cancer and other rare diseases
[07:20] What is unique about Strand’s tech and its therapeutic delivery mechanism
[11:31] Targeting mechanism for constantly-changing heterogenous targets
[16:18] Biohacking and open-source science
[20:32] Biohacking security and regulation
[24:46] Increasing importance of biotech security
[29:33] Starting Strand Therapeutics
[32:14] mRNA vs. DNA
[35:38] Current challenges of synthetic biology field
[37:56] Prioritizing at Strand across many use cases of mRNA, a platform therapeutic
[40:41] Making medical developments more efficient and quicker
[42:28] Cancer as a key focus at Strand & strategy outlook
[43:20] Different perceptions of justifiable speed in developing consumer products vs. biotech
[46:23] Perception that COVID-19 vaccine was “rushed” & trusting regulatory agencies
[50:22] “Manhattan Project for vaccines”
[57:13] Who supports and pays for such a defense project
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Show Notes
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- Episode page, transcript, and podcast listening links: https://toughtechtoday.com/programming-mrna/
- Jake Becraft on LinkedIn: https://www.linkedin.com/in/jacob-becraft-biotech/
- Malvika V. Miller on LinkedIn: https://www.linkedin.com/in/malvikavmiller
- Strand Therapeutics (company): https://www.strandtx.com/
- A National Strategy for Synthetic Biology (publication): https://www.jstor.org/stable/26937411
- Subscribe with your favorite podcast service: https://www.buzzsprout.com/1169378/7631545-programming-mrna-with-jake-becraft
- Watch this show on Youtube: https://youtu.be/6NAyFuCkC-U
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:00):
Time is a critical factor. Andif you advance your drug a year
faster, and that drug is thedrug that would have cured or
put her into complete remissionwith that breast cancer as
opposed to succumbing to itwithin two years, then that year
that you could have advancedthat drug is incredibly,
incredibly important.
(00:22):
Welcome to Tough Tech Today withMeyen and Miller. This is the
premier show featuringtrailblazers who are building
technologies today to solvetomorrow's toughest challenges.
Welcome to Tough Tech Today withMeyen and Miller. We have the
honor of having on the show,Jacob Becraft, CEO, Co-founder
(00:47):
of Strand Therapeutics. And wealso have with us our guest
biotech expert, Dr. Malvika V.
Miller. So welcome both of you.
Nice to be here.
Jacob, let's launch into this.
Tell us what you're working onwith Strand Therapeutics.
Yeah, so, Strand Therapeutics isa next generation messenger RNA
(01:10):
gene therapy company. That's alot of words to say that what we
focus on are diseases that canbe that can be fixed or really
cured by transfer of some sortof therapeutic gene to correct
an underlying genetic issue. Andso this technology really came
to a head or really came intomedia's attention in 2020, as
(01:35):
the same technology was used tocreate the COVID vaccines,
really using a messenger RNA,and rather than delivering a you
know, synthetic protein for thecoronavirus. To train the immune
system, we were able to encode apart of the coronavirus onto
that messenger RNA and deliverit into patients and then
patients bodies can learn how tofight off the coronavirus. In
(01:56):
much the same way, we can usethat same underlying idea that
we can encode any protein wewant. And rather than encode a
piece of the coronavirus, we canencode proteins that direct the
body to kill cancer cells thatdirect different tissues to
function correctly again, andall of that can be done with the
(02:18):
same what's called thisplatform, messenger RNA therapy
is known as a platform, you canplug in any sort of encoded
protein on it, and then expressthat from the messenger RNA. And
so what Strand does that's alittle bit different is we build
messenger RNAs, not forvaccines, but for these other
sorts of chronic and deadlydiseases. And we use this type
(02:43):
of technology that was spun outof the Massachusetts Institute
of Technology that allows us totake that next step that allows
us to go from vaccines, whichare relatively simple, in kind
of mRNA therapeutics terms intothese these cancer and rare
disease therapies, which are abit more complex.
(03:04):
So to clarify then for all ofour listeners or viewers, this
is saying that what we've beenhearing in the news for a year
in terms of the rapiddevelopment of sort of
mRNA-based vaccines that we canrepurpose that kind of same
inspired technology to go aftercancer.
(03:24):
Exactly. So a lot of the currentmRNA companies, they are going
after cancer in another way. Sowhere cancer is really seeing
this renaissance right now is inan area called immunotherapy. So
immunotherapy, or cancerimmunotherapy rather, is the
idea that since cancer istechnically different than your
(03:48):
body that cancer is when yourbody has kind of gone beyond
itself; it's jumped the sharkand it's begun attacking itself
or growing out of control. Sincethat change actually indicates a
separation from what you wouldconsider yourself, your immune
system should be able torecognize when those cells
change over. And so the ideawith immunotherapy is that you
(04:11):
can train the immune system toattack cancer cells the same way
that you would train your immunesystem to attack the
coronavirus. And so what thecurrent vaccine mRNA companies
like Moderna or BioNTech havehave focused on doing with their
mRNA therapeutics are buildingwhat they call cancer vaccines.
(04:32):
So they've built coronavirusvaccines, they've built
influenza vaccines, and they'realso building cancer vaccines,
which is where instead ofputting a viral protein on the
mRNA and delivering that in acontext to the patient, they put
a cancer protein on the mRNA andthen deliver that into the
patient, which is also afantastic approach and really
(04:53):
represents a revolution in bothour ability to do gene therapy
and the therapeuticunderstandings of how we treat
cancer, the difference that thatstrand takes is that our
technology allows usessentially, to take a given
piece of messenger RNA, a pieceof messenger RNA will go into
(05:14):
any cell in the body and expresswhatever you encode onto that.
But in order to use mRNA, in amore rigorous therapeutic
context, what you have to do istake that messenger RNA and
engineer it with certainfeatures, so that it will only
express in the tissues that youwant it to, for example, if I
(05:34):
have a drug that I want to gointo a tumor cell, and directly
tell that tumor cell to startkilling itself, I don't want
that same RNA to go into theliver and tell the liver cell to
start killing itself, that wouldbe really unacceptable. And so
what what we do in order to gobeyond vaccines, is to engineer
(05:57):
these messenger RNAs with this,you know, cell type specificity
with all of these different kindof control mechanisms over
themselves. And then they can bedelivered into the body, they
can get into the tissue thatthey need to whether that's a
tumor, whether that's thekidney, whether it's really
wherever we can program it, andthen they can actuate their
(06:18):
therapeutic in any number ofways.
That's really fascinating. SoMalvika, I'd like you to react
to that because you haveexpertise in drug delivery. And
the way that these... could gowrong, which is in the medical
community... usually what we'relooking at is how to keep people
(06:39):
from getting worse.
I've loaded some self-destructcodes to my body.
It's a complex problem makingsure you get the right cargo to
the right place at the righttime, right? That's the holy
grail in drug delivery. And so,Jake, my question for you is, of
course, we have the mRNA, whichis the ultimate therapeutic, and
then we have the vehicle bywhich it's being delivered. And
(07:01):
for example, Moderna, BioNTech,Pfizer, they're using these
lipid nanoparticles and a lot ofpeople have heard about, you
know, lipid nanoparticleparticles, some people are
scared about them. And so justdecoupling the actual
therapeutic from the cargo, howare you approaching this
specificity of where you'retargeting? What is that
technical pillar that's behindStrand's technology.
(07:25):
Yeah. So I come from abackground of synthetic biology,
and synthetic biology is thisfield that has emerged over the
past 20 years to say that whatwe can do with any piece of
nucleic acid, whether that'sDNA, or RNA, or whatever, it
(07:47):
inherently has what's calledfeedback loops, or feedforward
loops in it, the same sort ofprogramming technologies that we
put into computer code can beput into genetic code. In your
body at any given time, thereare thousands of genes that are
turning on, and then some of thegenes are turning others off and
they form these very complexregulatory circuits. And what
(08:09):
synthetic biology says is we cantake that circuitry, that
regulation, and we canre-engineer orthogonal systems
to fit our own accords, right?
So we can build synthetic genecircuits now that rather than in
your body, a gene circuit mightbe responsible for responding to
a spike in glucose, and some ofthe genes in your body need to
(08:30):
respond and make extra insulinand, and yada yada yada like
that, what we can do is we canmake a gene circuit that goes
into a cell and can sense thetype of cell that it's inside
of, and kind of have this thiscircuitry, this algorithm that's
encoded onto it, that can giveyou this specificity. But
Malvika, you bring up a reallyfantastic point, which is kind
(08:52):
of specific to the messenger RNAspace, which has to do with
delivery. And delivery isthishuge problem that all gene
therapies have faced, whetherthey're viral based or whether
they're synthetic like lipidnanoparticle based. And so the
way that we approach this issueis that we develop and partner
(09:12):
and license, a number of firstrate lipid nanoparticles from
great groups that have developeddifferent sorts of technologies
that can help our therapeuticsget to around where they need to
be. As anyone who's studied thelipid nanoparticle field knows,
people have tried tofunctionalize particles, right?
(09:36):
They've tried to stick different
sorts of targeting (09:39):
make a lipid nanoparticle that has a
targeting antibody or somethingon it so that it will bind to a
given tissue. The problem isthat every targeting technology
that I have come across isfundamentally not specific
enough, right? There's alwayssome amount of leakage if you
(10:01):
deliver it into the bloodstream,the lipid nanoparticle, maybe
60% of it ends up in the tissuethat you want it to, and 40%
still ends up in the liver. Andso what you're facing there is
this next level of specificitythat you need. You need to still
have a nucleic acid, anmessenger RNA in our case, that
(10:22):
is specific to whatever yourultimate goal tissue is. And
so... the way to think about itis, if you think about the body
as an entire city, the lipidnanoparticle gets you into the
correct neighborhood, you choosethe correct nanoparticle to get
to the right tissue or organsystem. And then the engineering
(10:44):
of the messenger RNA gets youinto the correct house.
When you say (non-expert here),lipid nanoparticle, I'm thinking
of lipid in terms of like thelipid bilayer of soap or a cell
or something, and then thatthese are like magic dust that's
able to somehow go... it seemslike it's a case of Whac-A-Mole,
(11:06):
but somehow you've been able tomake these little nanoparticles
be able to be more broad in agood way with the way that they
target. Like something that'sgoing to be shifting around like
to me like a cancer cell isinherently going to not look
like a normal traditional cell,right? And so I don't understand
(11:26):
quite how you're able to keep upwith, with the changing face.
Right. And that's actually oneof the problems with relegating
the targeting to just the lipidnanoparticle kind of what
Malvika had brought up here thatif you just take the approach
that you're going to take alipid nanoparticle and put some
targeting technology on theoutside of it so that it can
(11:51):
bind to a cancer cell, forinstance, you have a incredible
heterogeneous target that'sconstantly changing. And that's
actually the same for tissuesthroughout the body... your
tissues are very heterogeneous,they're very hard to pin down
with a single target that youcan reduce and then put that on
the outside of a particle. Andso we don't really take that
(12:11):
approach. We use a number ofdifferent lipid nanoparticles
that can get us near the tissue,knowing that if that lipid
nanoparticle also goes into someother tissue, that's okay,
because the RNA is not going tobe active in that tissue, it is
going to have circuitry insideof it, once the RNA enters the
cell, it will still not beactive. And so it'll pretty much
(12:34):
be inert, and it'll just getdegraded in those what's called
non-specific targets. But whatyou said right there about the
lipid bolayers... That'sactually the exact point. So a
cell, the outside of a cellmembrane, going back to kind of
high school biology, is made ofthese lipid bilayers. Right,
(12:57):
these long chain, polarlycharged lipids polar and
nonpolar lipid species that formthese these bilayers as the
membrane of our cell. And sowhat a lipid nanoparticle is
essentially is a similar type ofmolecule still made of charged
lipid species, that then canencapsulate something like a
(13:19):
messenger RNA. And when thelipid from the nanoparticle
interacts with the lipid bilayerof the cell, you then can have a
sort of fusion or endocytoticevent where the cell kind of
takes that lipid and gobbles itup into itself. And then that's
how you facilitate the transferof this synthetic material that
(13:41):
is outside of the cell into theinner workings, the cytoplasm of
the cell.
So once it once it gets gobbledup, Strand Therapeutics is
really working on that extra setof instructions, once it's
inside the cell that is specificto the cancer cell or whatever.
So then, then it'll encode itand if it's a healthy cell, it
(14:04):
won't read the self-destructcode. And if it's a cancer cell,
it'll read the self-destructcode and be gone, tight? That's
your key portion of the chainthat you're working on.
Yeah, 100%.
I really liked that analogy youused of the neighborhood and
finding the house. And so nowlike Forrest mentioned, you're
now in that neighborhood, youfind that that house and now you
(14:26):
want to self-destruct or notself-destruct, depending on that
house, how good is theinformation that we have on the
specificity from tissue totissue or from house to house?
Like that's really what we needto make sure that this
technology would work. And soyeah, how good is that
information out there?
Yeah, I mean, that's a greatpoint. And so there's a wealth
(14:50):
of information out in the worldaround these sorts of different
biomarkers and it kind ofdepends on what you are
specifically targeting, right?
How are you discerning a cancercell, or any type of cell from
another type of cell... you needto find something that is
differentially expressed orsomething that is fundamentally
changed. And then you also haveto have a sensor for whatever
(15:12):
that's changing. It's a lot likethe early days of computer
science where you had to almostbuild a custom computer chip,
for any sort of case that youwanted, because all of the
different sensory components anddifferent actuators, nothing was
was kind of individuallyunified. And so what we're doing
(15:34):
now is we profile thesedifferent cells, we look for
different biomarkers, thingsthat we can differentiate the
cells based on these thesedifferential expressions, and
then we feed those in. And we dothat... originally when we were
at MIT, we were doing that usingdifferent databases. NIH and NCI
(15:56):
have a lot of fantasticdatabases on all of this
different information it'smind boggling the sort of
information that people haveaccumulated. But you know, since
then we've developed, inside thecompany, a lot of different sort
of proprietary techniques of howdo we identify these biomarkers
that we care about?
(16:18):
What do you think about some ofthe work in the biohacking space
where it's maybe not quite as aprofessional shop as as you may
be running with Strand, butnevertheless, because of.... the
commoditization of some of theequipment, that techniques, the
fact that now we can take anysort of living organism or a
(16:41):
virus, which is sort of like azombie state entity, and be able
to digitize its constitution,like what it is, and then easily
share that around the world?
What do you feel about the workof these groups?
So I'm very pro, open sourceopen source science, open source
publications. I believe thatscience should be accessible to
(17:02):
more people, I believe we shouldhave more community oriented
science centers. But wherebiohacking kind of runs up
against this... You know, a lotof times the today's current
biotech industry and the currentgenetics revolution is
juxtaposed with the technologyrevolutions of the late 20th
(17:23):
century, the computer clubs andthe hacking clubs that birthed
Steve Wozniak and Steve Jobsrunning off with Apple computers
out of kind of one of thesehacking groups, that hacked
together something that could...
I think the story of Apple is,that was the hack and jobs built
this chip that you could plugonto a phone, and it would allow
you to make long distance phonecalls. And I think Jobs like
(17:45):
called the Vatican, from the SanFrancisco area, and called all
the way to the Vatican. This wasin the 70s, when that costs
hundreds of dollars. And it's avery funny story, right? And a
lot of the early hacking, peoplewere able to pull pranks in
computer science, people werepulling pranks and the most
(18:05):
damage you could do.... I meanthere are stories of people
trying to attack like AT&T'sinfrastructure, or mess with
those mega corporations. But themost damage you could do was
limited to what technology wasrelied upon at that time. And
then as technology got moreadvanced, and we became more
reliant on technology, thehacking obviously got better.
(18:29):
But the defenses against hackinggot better. And now when you
know everyone's life andpersonal data, and health data
and banking data, and prettymuch everything you have is
online and there are hackers andnation states and such that are
attacking that.... there's alsoa lot more defense, we've
matured in the way that we candefend against this hacking, and
(18:52):
you don't see nearly as many atleast, of these sorts of bad
things that happen. And again,that's because the hacker
culture that started in theearly tech industry could only
hack into whatever we were usingtechnology for. And here's the
problem with completeopen-source, unregulated
(19:13):
biohacking, is that we'redealing with the end system,
right? Like the biohacking ishacking of the body, right? So
whatever sorts of problems oroversteps that biohacking may
cause could immediately impactpeople's lives. If you're
(19:35):
messing around with making somesort of therapeutic that's going
to give someone like ... you'rejust you're doing something that
you think is going to be funny,and then ends up causing a huge
problem that will immediatelyimpact people's lives. It's not
like it's the '70s and the onlything I have on the computer is
(19:55):
like a game of Tetris, right?
It's a lot more serious now. SoI think we have to be careful
how we juxtapose the tworevolutions and understand that
while science should be moreaccessible and should always
strive to be completely open, wealso have to think about what is
(20:18):
responsible.
So do you think in the future,there's gonna be biohacking
security companies that evolveout of this? Like virus scan and
an encryption...?
Well, I mean, so right now, wealready have a number of these
defenses in place, right? So forexample, if you order synthesize
(20:39):
DNA from any supplier in theUnited States, and you go onto
the IDT website, integrated DNAtechnology, one of the main
suppliers of synthesize DNA, andyou enter a sequence, that
sequence immediately gets runthrough a number of algorithms
that try to pin it down towhether or not it is a viral or
(21:00):
pathogenic origin immediately.
And if it is, it will flag itand they'll ask for a number of
different credentials, you know,where are you ordering from? Are
you ordering from a trustedcompany or ordering from a
university and even when you'reat the university you have to go
in and sign waivers and sayexactly what you're using this
(21:23):
sequence for. So that existstoday. I think that in the
future, we're definitely goingto have to get way more serious
about biosecurity, and thwartingbio hacking, because as fun as
biohacking is in a trailer inthe Cambridge, Massachusetts
(21:46):
neighborhood or someone sets upa trailer, and does some
biohacking to turn some bacteriagreen. That same technology can
now be used by someone with morenefarious purposes, to create
engineered super COVID. Andwhile the technology is not
(22:07):
there yet, we need to take thatthreat seriously today, because
again, if we look back at thetechnology sector and this
juxtaposition between biotechand technology, we clearly are
behind the gun on cybersecurity,right? I said, we have great
defenses but you know, peopleare trying to hack our
elections, people are trying tohack into everyone's systems
(22:27):
constantly. And Equifax islosing everyone's social
security information. So we'renot there. We weren't there on
technology... the hackers wereable to stay in front of us. In
biotech, we don't have thatluxury. Again, it's much more
serious. And we need to takethat biosecurity threat
seriously from day one.
(22:48):
So it sounds like we absolutelythen would benefit by having a
national defense policy onsynthetic biology, right? On
cyber biosecurity... I'll read abrief passage from a proposition
that's on a national defensestrategy around this. And it
says that, for the listeners andviewers who are interested in
(23:12):
this is that in in 2017,researchers at the University of
Washington were able to encodemalicious software into a string
of DNA, that when sequencedallowed them to take control of
the underlying computer system.
And this vulnerability providesa sophisticated attack vector
into academic and commercialoperating systems enabling
traditional cyber threats, suchas data exfiltration, or
(23:34):
industrial sabotage. So couldyou both of you react to that?
Yeah, I mean, I think the pointsthat have been made are
absolutely spot on. We want tostrike the right balance between
having access to these tools andmaking sure there's open
science, open communication, butalso balancing of the fact that
(23:56):
we need that oversight. And Iabsolutely agree that there
needs to be more done on thefederal level to have a
security program that's reallymaking sure that these tools are
being genuinely used forscientific research or
innovation or creating thingsthat are actually going to be
useful. I mean, I thinkdefinitely we need this now. And
(24:18):
I think a lot of what Jake hasalso been writing about in his
advocacy on the side outside ofStrand is getting at that to
really making sure we have anational defense biosecurity
program that's not just beingreactive to potential threats
but proactive in detecting themor making sure we have an
arsenal of tools to go afteranything that could come our
(24:41):
way. So absolutely agree that weneed something like this.
It's true. For instance, whenAndrew Yang ran for president
now in 2020, he talked aboutcreating a cabinet position for
technology right? Secretary ofTechnology, and that was this
(25:03):
revolutionary idea, right? It'slike oh my God, this forward
thinking guy. And we've been onthis technological war path for
50 years, right? Since the 70s,we've been trucking up in
technology to where today, youinteract with a number of
technology devices, and yourentire life, again, is contained
(25:24):
inside of that. And we're onlyjust now starting to talk about
a cabinet level position fortechnology. Luckily, the current
administration of the lastcouple of weeks, has already
prioritized genetics andsynthetic biology as a key
interest area, and elevated EricLander who is a professor at at
(25:47):
Malvika and my alma mater, atMIT, Eric has been not only made
the a Director of the Office ofScience and Technology Policy,
they have then elevated thatscientific advisor level from an
advisory level to a cabinetlevel position. That shows great
promise, I think that that isthe first of many steps in the
(26:11):
correct direction. What wereally need is a full
encompassing department, right?
And I feel like the federalgovernment or the executive
branch of the government has notadded a new department since a
lot of us were a lot youngerwhen we added the Department of
Homeland Security. And in thewake of 9-11, but we can't
(26:34):
really be reactionary anymore,we need to both prioritize
technology, because clearlyhacking and social media
influences and things likeCambridge Analytica, and
Facebook influences and fakenews are having a real negative
impact, a real, measurable,toxic impact on the culture and
(26:55):
the stability of Americansociety. And much the same, we
need to be in front of thatcurve on biotech. Because again,
the risks are just that muchmore compounded. And there's a
thought that I hear, you know,to some people to take the
Luddite kind of approach tobiotech, where we say, well this
(27:19):
is dangerous or this iscomplicated so we should just
cease all research. And ofcourse, that's insane because
even if America chooses to ceaseall research, because it's
scary, China won't, Russiawon't... these other global
superpowers won't be stoppingtheir research. And so we have
(27:41):
to find a way to continue to notonly push research, but really
accelerate our research, but atthe same time, accelerate all
sorts of different mitigationand planning strategies, and my
advocacy, what you'rementioning, and some of the
things I've written specificallyon pandemic responses, but
should be taken into an allencompassing view of how we
(28:02):
think about biotechnology is toview things through a defense
lens. For whatever reason, humanbeings, and Americans especially
view things through a defensivelens and through a
preservation-of-self lens thatlends itself to thinking of
preparation, right? When wethink about, preventative
(28:24):
health, we don't do so well. Butwhen we think about preventative
defense, and how do we build...
building aircraft and aircraftcarriers and different sorts of
missile systems, we devote overhalf of our federal budget to
that sort of a thing. So I thinkthat we should start thinking
about that in terms of biotech.
(28:45):
So now that we have Space Forcemaybe the next thing we need is
Bioforce.
Yeah. 100%, that's it...
President Biden if you'relistening, call me up, let's
make Bioforce.
Bioforce join today, enlist. Iwould totally sign up that
(29:07):
sounds interesting anddefinitely would be helping
prepare us for the future.
We already have the uniforms ifwe just look to the Captain
Planet cartoon we already know.
There we go. Perfect. One onething I really wanted to hear
and give our viewers a littleview into the founding of your
(29:32):
company. Talk to us a little bitabout this process as you're at
MIT and thinking about startingan awesome new venture and what
that journey has been like sofar.
An "awesome new venture," yesthat's what I told myself every
day. I was like, "I'm gonna doan awesome new venture." No, so
(29:56):
the way that I think greatcompanies get started in the
science realm or in the deeptech realm is from a point of
inquiry first. And that's why Ithink academia can be so
powerful and why I think thatallowing or creating roadmaps
for graduate students orpostdocs are really researchers
(30:19):
at the academic level or at theresearch lab level, to spin that
technology into into companiesor even into nonprofits is
really what we should beenabling. And so I say that
because of how my company cameabout. So when Moderna first
started becoming more of amainstream company and I say
(30:42):
"mainstream" not on CNN likethey are today, but really just
as they achieved morepublications in the trade
presses of biotech, as morepeople became aware that there
were people like Moderna andBioNTech and such working on
mRNA. This is 2012, let's say,what we were doing at MIT in my
(31:04):
synthetic biology lab, we'rethinking about all right, this
is a new area of scientificresearch, a new area of
therapeutics. And we know that,other types of gene therapy from
engineered cell therapies tooncolytic viruses, all of those
genetic based therapies, at thetime were starting to...
(31:26):
synthetic biology was startingto innovate on them. It was
starting to program higherspecificities into cell
therapies and into engineeredviruses. But mRNA didn't have
any of the tools that DNA-basedapproaches like viruses and cell
therapies have. So for a decadebefore this even happened,
(31:46):
synthetic biology had beenbuilding all of these tools to
program the DNA of anything youwanted. And those tools were
able to be ported into theseviral engineered gene therapies.
mRNA didn't have any of thosetools. And so it was a 2012...
mRNA is more complicated or likehigher hanging fruit? Why was
(32:11):
mRNA lesser served?
Yeah, there are a number ofreasons, one of which is that no
one saw the reason, right? Sowith DNA, most of the genetic
circuits in your body that we'reat least aware of right now are
based on DNA. They're based onthese proteins called
transcription factors, they bindto the DNA, they turn genes on
(32:34):
and off. And it makes it a loteasier to build synthetic
systems, when you already havethat sort of technology. From
what we know of how mRNA isregulated, mRNA is a very
transient molecule, it degradespretty fast once it's into the
body. And that also limited itsability, early on as a gene
(32:56):
therapy platform, because it isso short lived, it's very hard
to build a robust gene therapyplatform around a number of
innovations that have beencovered by the press now such as
Catalin Carico, Andrew Weissman,at UPenn, their breakthroughs
with engineering messenger RNAsto get us to where we are today,
(33:17):
changed that thought process alittle bit. But again, there
were both no natural systems tobuild off of for mRNA regulation
and there was also no reason tobuild them because unless you
are delivering your gene therapyon a messenger RNA, you are
delivering it via DNA. And sothere's no real reason to build
(33:38):
all of this genetic circuitry towork at the mRNA level, if you
have DNA there, and you have awhole toolbox to play from, but
in 2012, with the legitimizationof the mRNA companies like
Moderna and BioNTech, we wereable to take an academic
approach because again, we wereacademics, we were at MIT, Ron
(34:02):
Weiss is the director of theSynthetic Biology Center and one
of the pioneers of syntheticbiology, one of the people who
really created the field ofsynthetic biology. And Ron and I
and my co-founder of Strand,Tasuku Kitada, along with a
number of other scientists atthe time, got to sit and perform
(34:23):
this academic exercise, whichwas if this technology is
successful, if mRNA is asimpactful as Moderna and
BioNTech and these othercompanies claim that it's going
to be, what will we need to takeit to the next level, what will
be the next step of hurdles thatwill impact the technology and
(34:46):
the ones we identified werespecificity and duration of
expression and all of thesethings that required synthetic
biology to add this next layerof expertise on top of it.
So you found some opportunity byjust thinking two steps ahead?
There's this new thing, what'sthe new thing for the new thing?
(35:08):
Yeah, exactly.
Malvika, with your perspectiveon synthetic biology and some of
the shared colleagues on thiscould you outline some of the
challenges that will need to beaddressed, perhaps for the
industry overall, but also thatStrand and Jacob maybe facing
(35:32):
down the road, and we can talkthrough... establishing of
priorities to address some ofthose challenges?
Sure, Jake, might be the best onthat. But I'll definitely take a
stab at taking the bird's eyeview of synthetic biology as a
whole. Jake hit on a few ofthose points... it comes down to
(35:52):
some of the transient nature ofmRNA, specifically for the field
he's working on. And like he'ssaying, making sure that this
mRNA molecule is... it comesdown to like, it's at the right
place, right time. And so that'ssome of the core pillars that
are going to have to beovercome. I mean, on a broader
level, there's a lot ofregulatory challenges. This is a
(36:15):
new therapeutic technology thatwould have to go through the
FDA, and I'm sure he can tellyou about some of the clinical
trials that they're planning torun, but as with any new
molecule, there are manyhurdles, and it could take
somewhere between five to tenyears to even get approval to
get into the clinic. So that'slike that's one notable thing.
(36:36):
And I mean, as he's probablyalready building... working
towards making sure this is aplatform technology. And so with
that word "platform," what thatmeans is that there are many
different indications that thistechnology could be used for,
but picking the first one tostart with is something that is
(36:58):
probably on top of many people'sminds in this space how do we
prove that our synthetic biologytechnology works? What is that
first sort of indication that weshould go after where there's a
sizable unmet need from aclinical perspective, but also
(37:19):
that you can actually get paidfor it. So someone's going to be
actually willing to pay for thistherapy down the line, whether
it's insurance, companyhospital... just understanding
that whole ecosystem. And sothat's something that I'd love
to hear more about from Jake ishow he thought about planning
what is that first market? Imean, it sounds like oncology.
(37:39):
What, specifically? And how didyou select that as the first
sort of indication to go aftergiven that what you're working
on can apply to so manydifferent areas?
It seems disorienting, yeah.
Yeah, how did you do that Jake?
It's a challenge to prioritize.
So where do you start?
Yeah, Malvika is completelycorrect on all of those points
(38:01):
really. I think, from aregulatory perspective, it's
interesting, because when Istarted the company, we knew
that mRNA was going to be thisnew frontier of medicine. And
there were, a number of phaseone trials that were ongoing,
with Moderna, and with BioNTech,and CureVac as well. mRNA
(38:22):
companies had been around for adecade at that point, doing
early stage clinical trials andtrying to get the science to a
level that it would beacceptable. Where we're at now
is actually in a little bitdifferent arena, because mRNA
has now become a, much morewidely used therapeutic
(38:45):
modality. And by the end of2021, my company strand will
enter the clinic in 2022. But bythe end of 2021, there will be
billions of people that havebeen injected with messenger
RNA, at least as a vaccine andthat's very powerful I think...
(39:08):
to talk about the comingfrontier of a drug. When you get
to the levels of hundreds ofmillions or billions of people
that have been administered adrug that lowers the bar, of
what's acceptable, or at leastit raises... the rising tide
raises all ships and whatnot...
because the FDA now will be lesslooking at the fact that it is
(39:31):
messenger RNA, in my opinion;they'll be looking less at the
fact that it's messenger RNA,and more at what are you doing
specifically and how are youdifferent? How have you changed
this molecule? What are youdelivering with the molecule?
What is it encoding? So thoseare all classic drug hang-ups
that you need to get throughwith the FDA, but now that we're
(39:56):
past the novelty of the platformitself the novelty of the
messenger RNA in that hundredsof millions of people and
potentially billions worldwideare going to receive mRNA. You
know, we're at kind of adifferent perspective there.
Malvika, you brought up clinicalindication selection... We
mapped out where the highestunmet medical need was and what
(40:21):
our technology could do in thequickest amount of time because
if anyone has ever spoken to mebefore, they know my number one
goal is to make medicine movefaster. And that doesn't mean
irresponsibly... it doesn't meanthat the FDA should not do its
due diligence. But we've seen in2020 that medical innovation and
(40:42):
regulation and clinical trialsand such can move faster when
people are motivated, when wedeploy resources and when
agencies are incentivized tomove with time as a deciding
variable. And with COVID, it wasbecause with time picking up
more people were dying everyday, the economy was at least
(41:02):
for small businesses, maybe notthe public markets, but for
small businesses... was gettingcrushed. And we understood that
time was the most importantfactor. And my argument is that
time will always be an importantfactor for someone, for that mom
who's just gotten diagnosed withbreast cancer, right? Time is a
(41:24):
critical factor, and if youadvance your drug a year faster,
and that drug is the drug thatwould have cured or put her into
complete remissionwith thatbreast cancer as opposed to
succumbing to it within twoyears, then that year that you
could have advanced that drug isincredibly, incredibly
(41:44):
important. And so I believe thatmedicine needs to move faster,
we need to innovate in the FDA,and the FDA has been incredibly
innovative with new genetherapies, they are on track.
But I believe that our researchinfrastructure, our clinical
trial infrastructure, and ourregulatory infrastructure can
all move faster. Because themedical technology, the
(42:07):
messenger RNAs, and otherengineered platforms that are
coming to the market now allowus to move faster in the drug
discovery and the drugdevelopment realm, which has
historically been the longestprocess that we need to move
through. And so we chose ourcancer as a first indication...
(42:28):
well the specific cancers thatwe're looking at one of which is
breast cancer, because we knewwe could move very quickly and
provide real value to patientsin the fastest amount of time,
and also provide value to thecompany. We'd be able to move
quickly and that allows thecompany to demonstrate its
(42:48):
technology, which allows us tobuild value, and be able to
raise more capital, which we canthen put back into... all of the
capital we raise goes right backinto our our Research and
Development division, which isworking on building the platform
for new and exciting areas,which may have a longer research
time horizon. We're trying toinnovate on all sorts of
(43:12):
different areas now and sothat's kind of the the strategic
outlook that we took as aI think those are really good
points. And I want to sharecompany.
something that Malvika sharedwith me before recording the
episode, a post by a colleaguethat was saying how we
celebrate... the iPhone 11 wasreleased, and then a year later,
(43:34):
Apple releases the iPhone 12.
And that's celebrated as a superinnovative company, an amazing
product. And consumer tech iscelebrated for that speed,
though now we're starting tosee, on the biotech side of
things, where... about a yearand a half is when we have go
from the beginning of a pandemicto having potentially widely
distributed vaccines forthat.... I want to just sort of
(43:56):
bring up the point is that wemay celebrate the innovation of
consumer tech, one year from anamazing device to an amazing
device, year after year andsustaining that. With medical
land, it's a little bitdifferent, that there are
concerns of the safety or theintegrity of it... that there's
a perception that this isn'tsafe. And so...
(44:19):
The main issue being people arereacting to the fact that they
think things were rushed... thatit's easy to make an an iPhone
version. People are like, "Wow,that's amazing, new features."
And now of course everyone'ssuper impressed with the speed
at which mRNA vaccines got intothe clinic and ultimately are
(44:42):
now all over the world. Butthere's also that skeptical
nature... "Oh no, this wasrushed." How could we possibly
do it and that dichotomy of theconsumer tech versus the biotech
speed? How do we...? What wouldyou say to folks that think like
that that things are rushed? Imean, there's this huge backlash
(45:05):
that it's going to be difficultto overcome that.
That is a fantastic point. Andone thing it does is it
illustrates what I was sayingearlier, which is why biotech
and technology while similar,while you can talk about them in
the same vein, and you can talkabout the revolutions in
technology in the same veinwhy they need to be handled
(45:28):
differently, why we need to bein front of bio threats earlier
than we were in front of cyberthreats. That being said, I
think everyone should, shouldhave just the utmost faith in
our regulatory agencies. Andit's a hard thing to do in
today's society of massinformation, of social media,
(45:52):
and, frankly, of fake news,right? Because what ends up
happening is that folks whoaren't familiar with the
regulatory agencies, they aren'tfamiliar with the FDA and how
they operate and how clinicaltrials work are now very laser
focused on clinical trials. Andvery laser focused on vaccine
(46:13):
development and all thisdifferent technology, that in a
normal time, people outside ofthe industry aren't really
paying that much attention to.
And so now that people kind ofhave lasered in on it, they've
said things like, "well, thevaccine development was rushed."
I can tell you that, if wewanted to rush the drug through,
we could have had the drug readyin March. The vaccine that we
(46:38):
have today was designed actuallyat the beginning of 2020. We
spent the entire year of 2020,validating the safety of the
drug. And we spent the entire 10years before that validating the
safety and the efficacy of thistype of drug working with
messenger RNA as a platform. Sowe have a whole wealth of data
(47:02):
and a whole lot of science, thatunderlies exactly what this sort
of thing can do. And it shouldbe said that while drugs
directly go into your body andthey're designed to make some
sort of change, it's really themost amount of scrutiny that any
product that's consumed is putunder, because we have we have
(47:24):
no shortage of examples of wherea new a food company or an oil
company or anything startsaugmenting their product and
gets it out to the market. Andit has real health consequences,
because they're never reallylooked at, but at the drug
level, we look at these things,we look at these things so
(47:46):
incredibly intensely and witharmies of people whose only job
is to really be skeptical, andto know exactly how to review
and pay incredibly closeattention. I think that what
we're facing right now is whenit comes to getting the vaccine,
I advocate 100% everyone shouldget the vaccines. They are
(48:11):
incredibly safe. They're verymuch in line with what we would
expect from any sort of avaccine. And we should trust the
FDA to have done their duediligence, right? Because
there's a reason that we have anFDA and we don't put all drug
reviews to a popular vote,because it takes an incredible
(48:37):
amount of expertise to determinethese sorts of things like drug
safety and drug efficacy. So weneed to take a step back and
know that even though this drugdevelopment is in the center
line of the media, we reallyneed to have faith in the
agencies that we've built on theFDA being one of the most
(48:59):
effectively run organizationsdespite my qualms about the
speed at which... drugregulation happens outside of
the Coronavirus vaccine. FDA isone of the most fantastically
run organizations in the federalgovernment. And it's been
incredibly effective at managingthis sort of case. And I would
(49:21):
love to give everyone amasterclass in the ins and outs
of drug regulations and how weshould determine the safety of
these drugs, but that isn't whatpeople are necessarily
interested in. They're justinterested in knee-jerk
reactions and believing thatsomething has come to market
quickly.
(49:46):
So we'll have to do anotherepisode on the masterclass for
drug regulations. It'll be aspecial Tough Tech Today
episode.
Educational. So Jake I know oneof your personal motivations...
as you've mentioned many timesnow is to make medicines move
faster. I also wanted to makesure viewers of Tough Tech Today
(50:07):
also heard a little bit aboutthe advocacy side on the
proactive pieces you've beenpushing for: the Manhattan
Project for vaccines. Could youexplain what that is? And why
you think that's reallycritical?
Yeah. Love to talk about this.
So one of the things that themRNA vaccines enable us to do...
(50:27):
so the reason that the mRNAvaccine was able to move so fast
is.... mRNA is what's known as aplatform therapeutic. We've
mentioned this a little bit onthis, this podcast so far. A
platform therapeutic is reallywhere you have a given molecule,
(50:49):
so mRNA that is encapsulated ina lipid nanoparticle. And all of
the molecular species are kindof known. And the only thing
that you're changing withmessenger RNA is the sequence of
the... welll people are familiarwith ATGC. But in the case of
mRNA, it's actually AUGC,because thymine is switched to
(51:12):
uracil. And so with the AUGCsequence of the messenger RNA,
you can change that to be anysequence and that sequence can
match any viral protein. Thatsequence will code for a viral
protein through classic geneticsand you can then switch in the
sequence of any viral threatthat exists out there. And so
(51:36):
what I've been advocating for isthat, again, we take this
defensive look this idea ofvaccines for the national
defense knowing that one ofthe greatest threats that we
face as a nation and as aspecies is that of the
biological. Throughout history,biology and the microscopic and
(52:01):
the basically invisible to us,has been shaping our lives. It
changed how the Americas werefounded.... when the settlers
came and interacted with thenatives that lived here in this
country, how that proceeded hadto do with disease, infectious
(52:23):
disease that was that wasbrought along with those with
those settlers. So we've alwaysbeen shaped by this piece of
biology. And it's always been athreat, though for the past 100
years, we've enjoyed anunbelievable period of peace
time. Since Spanish influenza tothe current pandemic, we've had
(52:44):
our trials and tribulations,we've had polio, we've had HIV,
we've had a number of differentdiseases come out, but we
haven't had anything on thelevel of COVID. And so we have
to think about how do we preventthis from happening? And the way
we prevent this from happeningis by taking these platform
therapeutics, now that we knowthat this formulation works as a
(53:06):
vaccine; this particle with amessenger RNA inside of it can
be injected into the body andform immunity. And it's very
easy to now recode, that mRNArather than what it would take
to say build a traditionalvaccine, for every virus, which
would create, you'd have to makea new process, it'd take
(53:28):
multiple years for every singlesort of virus and understanding
it and building it, everythingwould have to be very niche.
With platform technologies, wecan just start encoding every
viral antigen sequence that wecan possibly think of. And so
what I believe we should do istake the proactive step, where
we create prototype vaccinesagainst every known infectious
(53:52):
virus, starting with the mosthigh risk viruses. And then we
create, even further vaccines,against other sorts of known
antigens that could emerge, wecreate a monitoring system where
we're constantly sequencing theviromes, the viral genomes that
(54:13):
are found in wild animal speciesthat are close to humans, such
as bats and pangolins, which iswhere coronaviruses mostly come
from. Sequencing these viruses,identifying new viruses and
making new vaccines in aproactive way, and taking each
one of these vaccines throughwhat we call early safety
(54:35):
trials. So the first six monthsof 2020, the first nine months
of 2020 even, were spent provingout that the vaccine was safe,
and you can do safety trialswithout an ongoing pandemic. You
need a number of volunteers. Youneed money to spend on that, but
it's a small amount of money.
(54:56):
It's single digit millions ofdollars to go from the mRNA
technology we have today to afully executed phase one safety
trial. And we could do that forevery single vaccine that we
could possibly develop. And sowhat this allows us to do is, at
(55:18):
the time of a new emergingpandemic, we can take this
arsenal of already de-riskedvaccines and begin right at the
phase three level, which thephase three is that efficacy
trial that was in the news inNovember and December, that has
to do with 95% of efficacy, thatwas all over every headline...
(55:39):
we can begin those trials, notin the fall, as we did in 2020;
but on the same timeline, we canbegin those in January, we can
start deploying vaccines and beready to roll out vaccines. By
the time we get to the spring orthe early summer, if we're
looking at a 2020 roadmap, wecan be ready to roll these out
(56:03):
and really take this proactivedefense, of course right now,
our health, our public healthdefenses are so reactionary. To
put it in context of the DefenseDepartment, imagine if we waited
until there was an attack on USsoil until we made any tanks or
(56:25):
any aircraft... we just waitedand then the moment someone
attacked us, we tried to spin upthe manufacturer of fighter jets
and aircraft carriers and buildthem all and deploy them then.
Imagine how bad things would getin that interim time where we
were we were waiting. So withdefense, we take a very
(56:45):
proactive role, and sinceinfectious diseases is clearly
one of the largest threatslooming, we live in a time of
unprecedented global peace forthe most part, so how do we now
talk about the these newthreats, such as biological...?
Both natural biological threatsand biological warfare, which
(57:09):
could also emerge in the future,we need to be prepared.
So, Jake, who do you think youneed to convince? Who's gonna
pay for it?
I mean, the protector of thepublic health is the public. And
so I believe that at thenational level, it needs to be
the country, right? The countryhas to pay for this, just like
(57:34):
we pay for our national defense.
I also think and dream of a moreglobal coalition. We have the
World Health Organization, wehave these large scale global
cooperation treaties that peoplecome together... the Paris
agreement to fight climatechange, we could have similar
agreements of countries thatcome together and agree to fight
pandemics, to do environmentalmonitoring, to do global task
(57:57):
forces to have unified rules towhat happens when we identify a
novel virus. When COVID brokeout and they locked down Wuhan,
China, that actually took anamount of time before that
lockdown happened, and a numberof people left the city in that
(58:18):
time, because they knew thatthis lockdown was coming. We
need to have more unified sortsof ways of cooperating if we're
going to live in a globalsociety, if we're going to live
in a world where you can walkdown to the airport, pay, get on
a plane and be on the other sideof the world in less than 24
(58:38):
hours. That's the society welive in today. And it's
beautiful. But if we're going tolive there, then we have to have
global cooperation, we have tohave a way that the entirety of
the human species, or at leastthe vast majority, comes
together to say, these are ourpriorities, this is how we're
going to move forward, and thisis what we're going to build to
(58:58):
make sure that something ascatastrophic to the our way of
life as a species like COVIDnever happens again.
Thank you very much for joiningtoday.
Thank you guys for having me. Ireally appreciate this
conversation. This is a ton offun. Hi, I'm Jake Becraft, CEO
and Co-Founder of StrandTherapeutics. Stay tough.
(59:22):
We hope you enjoyed thediscussion with Jacob Becraft
and Malvika Miller. If youlearned something from this
episode, I invite you to say soin the comments, to ask a follow
up question, and we invite youto leave a five-star review or
like. Our next episode featuresEmily King, a global mining
expert. This is really importantbecause mining enables us to get
(59:45):
minerals, and there's a world ofminerals in every single
electronic gadget.
Click subscribe to be the firstto hear when the new episode
drops. Until then, stay tough!
Time is a critical factor. Andif you advance your drug a year
faster, and that drug is thedrug that would have cured or
put her into complete remissionwith that breast cancer as
opposed to succumbing to itwithin two years, then that year
that you could have advancedthat drug is incredibly,
incredibly important.
(00:22):
Welcome to Tough Tech Today withMeyen and Miller. This is the
premier show featuringtrailblazers who are building
technologies today to solvetomorrow's toughest challenges.
Welcome to Tough Tech Today withMeyen and Miller. We have the
honor of having on the show,Jacob Becraft, CEO, Co-founder
(00:47):
of Strand Therapeutics. And wealso have with us our guest
biotech expert, Dr. Malvika V.
Miller. So welcome both of you.
Nice to be here.
Jacob, let's launch into this.
Tell us what you're working onwith Strand Therapeutics.
Yeah, so, Strand Therapeutics isa next generation messenger RNA
(01:10):
gene therapy company. That's alot of words to say that what we
focus on are diseases that canbe that can be fixed or really
cured by transfer of some sortof therapeutic gene to correct
an underlying genetic issue. Andso this technology really came
to a head or really came intomedia's attention in 2020, as
(01:35):
the same technology was used tocreate the COVID vaccines,
really using a messenger RNA,and rather than delivering a you
know, synthetic protein for thecoronavirus. To train the immune
system, we were able to encode apart of the coronavirus onto
that messenger RNA and deliverit into patients and then
patients bodies can learn how tofight off the coronavirus. In
(01:56):
much the same way, we can usethat same underlying idea that
we can encode any protein wewant. And rather than encode a
piece of the coronavirus, we canencode proteins that direct the
body to kill cancer cells thatdirect different tissues to
function correctly again, andall of that can be done with the
(02:18):
same what's called thisplatform, messenger RNA therapy
is known as a platform, you canplug in any sort of encoded
protein on it, and then expressthat from the messenger RNA. And
so what Strand does that's alittle bit different is we build
messenger RNAs, not forvaccines, but for these other
sorts of chronic and deadlydiseases. And we use this type
(02:43):
of technology that was spun outof the Massachusetts Institute
of Technology that allows us totake that next step that allows
us to go from vaccines, whichare relatively simple, in kind
of mRNA therapeutics terms intothese these cancer and rare
disease therapies, which are abit more complex.
(03:04):
So to clarify then for all ofour listeners or viewers, this
is saying that what we've beenhearing in the news for a year
in terms of the rapiddevelopment of sort of
mRNA-based vaccines that we canrepurpose that kind of same
inspired technology to go aftercancer.
(03:24):
Exactly. So a lot of the currentmRNA companies, they are going
after cancer in another way. Sowhere cancer is really seeing
this renaissance right now is inan area called immunotherapy. So
immunotherapy, or cancerimmunotherapy rather, is the
idea that since cancer istechnically different than your
(03:48):
body that cancer is when yourbody has kind of gone beyond
itself; it's jumped the sharkand it's begun attacking itself
or growing out of control. Sincethat change actually indicates a
separation from what you wouldconsider yourself, your immune
system should be able torecognize when those cells
change over. And so the ideawith immunotherapy is that you
(04:11):
can train the immune system toattack cancer cells the same way
that you would train your immunesystem to attack the
coronavirus. And so what thecurrent vaccine mRNA companies
like Moderna or BioNTech havehave focused on doing with their
mRNA therapeutics are buildingwhat they call cancer vaccines.
(04:32):
So they've built coronavirusvaccines, they've built
influenza vaccines, and they'realso building cancer vaccines,
which is where instead ofputting a viral protein on the
mRNA and delivering that in acontext to the patient, they put
a cancer protein on the mRNA andthen deliver that into the
patient, which is also afantastic approach and really
(04:53):
represents a revolution in bothour ability to do gene therapy
and the therapeuticunderstandings of how we treat
cancer, the difference that thatstrand takes is that our
technology allows usessentially, to take a given
piece of messenger RNA, a pieceof messenger RNA will go into
(05:14):
any cell in the body and expresswhatever you encode onto that.
But in order to use mRNA, in amore rigorous therapeutic
context, what you have to do istake that messenger RNA and
engineer it with certainfeatures, so that it will only
express in the tissues that youwant it to, for example, if I
(05:34):
have a drug that I want to gointo a tumor cell, and directly
tell that tumor cell to startkilling itself, I don't want
that same RNA to go into theliver and tell the liver cell to
start killing itself, that wouldbe really unacceptable. And so
what what we do in order to gobeyond vaccines, is to engineer
(05:57):
these messenger RNAs with this,you know, cell type specificity
with all of these different kindof control mechanisms over
themselves. And then they can bedelivered into the body, they
can get into the tissue thatthey need to whether that's a
tumor, whether that's thekidney, whether it's really
wherever we can program it, andthen they can actuate their
(06:18):
therapeutic in any number ofways.
That's really fascinating. SoMalvika, I'd like you to react
to that because you haveexpertise in drug delivery. And
the way that these... could gowrong, which is in the medical
community... usually what we'relooking at is how to keep people
(06:39):
from getting worse.
I've loaded some self-destructcodes to my body.
It's a complex problem makingsure you get the right cargo to
the right place at the righttime, right? That's the holy
grail in drug delivery. And so,Jake, my question for you is, of
course, we have the mRNA, whichis the ultimate therapeutic, and
then we have the vehicle bywhich it's being delivered. And
(07:01):
for example, Moderna, BioNTech,Pfizer, they're using these
lipid nanoparticles and a lot ofpeople have heard about, you
know, lipid nanoparticleparticles, some people are
scared about them. And so justdecoupling the actual
therapeutic from the cargo, howare you approaching this
specificity of where you'retargeting? What is that
technical pillar that's behindStrand's technology.
(07:25):
Yeah. So I come from abackground of synthetic biology,
and synthetic biology is thisfield that has emerged over the
past 20 years to say that whatwe can do with any piece of
nucleic acid, whether that'sDNA, or RNA, or whatever, it
(07:47):
inherently has what's calledfeedback loops, or feedforward
loops in it, the same sort ofprogramming technologies that we
put into computer code can beput into genetic code. In your
body at any given time, thereare thousands of genes that are
turning on, and then some of thegenes are turning others off and
they form these very complexregulatory circuits. And what
(08:09):
synthetic biology says is we cantake that circuitry, that
regulation, and we canre-engineer orthogonal systems
to fit our own accords, right?
So we can build synthetic genecircuits now that rather than in
your body, a gene circuit mightbe responsible for responding to
a spike in glucose, and some ofthe genes in your body need to
(08:30):
respond and make extra insulinand, and yada yada yada like
that, what we can do is we canmake a gene circuit that goes
into a cell and can sense thetype of cell that it's inside
of, and kind of have this thiscircuitry, this algorithm that's
encoded onto it, that can giveyou this specificity. But
Malvika, you bring up a reallyfantastic point, which is kind
(08:52):
of specific to the messenger RNAspace, which has to do with
delivery. And delivery isthishuge problem that all gene
therapies have faced, whetherthey're viral based or whether
they're synthetic like lipidnanoparticle based. And so the
way that we approach this issueis that we develop and partner
(09:12):
and license, a number of firstrate lipid nanoparticles from
great groups that have developeddifferent sorts of technologies
that can help our therapeuticsget to around where they need to
be. As anyone who's studied thelipid nanoparticle field knows,
people have tried tofunctionalize particles, right?
(09:36):
They've tried to stick different
sorts of targeting (09:39):
make a lipid nanoparticle that has a
targeting antibody or somethingon it so that it will bind to a
given tissue. The problem isthat every targeting technology
that I have come across isfundamentally not specific
enough, right? There's alwayssome amount of leakage if you
(10:01):
deliver it into the bloodstream,the lipid nanoparticle, maybe
60% of it ends up in the tissuethat you want it to, and 40%
still ends up in the liver. Andso what you're facing there is
this next level of specificitythat you need. You need to still
have a nucleic acid, anmessenger RNA in our case, that
(10:22):
is specific to whatever yourultimate goal tissue is. And
so... the way to think about itis, if you think about the body
as an entire city, the lipidnanoparticle gets you into the
correct neighborhood, you choosethe correct nanoparticle to get
to the right tissue or organsystem. And then the engineering
(10:44):
of the messenger RNA gets youinto the correct house.
When you say (non-expert here),lipid nanoparticle, I'm thinking
of lipid in terms of like thelipid bilayer of soap or a cell
or something, and then thatthese are like magic dust that's
able to somehow go... it seemslike it's a case of Whac-A-Mole,
(11:06):
but somehow you've been able tomake these little nanoparticles
be able to be more broad in agood way with the way that they
target. Like something that'sgoing to be shifting around like
to me like a cancer cell isinherently going to not look
like a normal traditional cell,right? And so I don't understand
(11:26):
quite how you're able to keep upwith, with the changing face.
Right. And that's actually oneof the problems with relegating
the targeting to just the lipidnanoparticle kind of what
Malvika had brought up here thatif you just take the approach
that you're going to take alipid nanoparticle and put some
targeting technology on theoutside of it so that it can
(11:51):
bind to a cancer cell, forinstance, you have a incredible
heterogeneous target that'sconstantly changing. And that's
actually the same for tissuesthroughout the body... your
tissues are very heterogeneous,they're very hard to pin down
with a single target that youcan reduce and then put that on
the outside of a particle. Andso we don't really take that
(12:11):
approach. We use a number ofdifferent lipid nanoparticles
that can get us near the tissue,knowing that if that lipid
nanoparticle also goes into someother tissue, that's okay,
because the RNA is not going tobe active in that tissue, it is
going to have circuitry insideof it, once the RNA enters the
cell, it will still not beactive. And so it'll pretty much
(12:34):
be inert, and it'll just getdegraded in those what's called
non-specific targets. But whatyou said right there about the
lipid bolayers... That'sactually the exact point. So a
cell, the outside of a cellmembrane, going back to kind of
high school biology, is made ofthese lipid bilayers. Right,
(12:57):
these long chain, polarlycharged lipids polar and
nonpolar lipid species that formthese these bilayers as the
membrane of our cell. And sowhat a lipid nanoparticle is
essentially is a similar type ofmolecule still made of charged
lipid species, that then canencapsulate something like a
(13:19):
messenger RNA. And when thelipid from the nanoparticle
interacts with the lipid bilayerof the cell, you then can have a
sort of fusion or endocytoticevent where the cell kind of
takes that lipid and gobbles itup into itself. And then that's
how you facilitate the transferof this synthetic material that
(13:41):
is outside of the cell into theinner workings, the cytoplasm of
the cell.
So once it once it gets gobbledup, Strand Therapeutics is
really working on that extra setof instructions, once it's
inside the cell that is specificto the cancer cell or whatever.
So then, then it'll encode itand if it's a healthy cell, it
(14:04):
won't read the self-destructcode. And if it's a cancer cell,
it'll read the self-destructcode and be gone, tight? That's
your key portion of the chainthat you're working on.
Yeah, 100%.
I really liked that analogy youused of the neighborhood and
finding the house. And so nowlike Forrest mentioned, you're
now in that neighborhood, youfind that that house and now you
(14:26):
want to self-destruct or notself-destruct, depending on that
house, how good is theinformation that we have on the
specificity from tissue totissue or from house to house?
Like that's really what we needto make sure that this
technology would work. And soyeah, how good is that
information out there?
Yeah, I mean, that's a greatpoint. And so there's a wealth
(14:50):
of information out in the worldaround these sorts of different
biomarkers and it kind ofdepends on what you are
specifically targeting, right?
How are you discerning a cancercell, or any type of cell from
another type of cell... you needto find something that is
differentially expressed orsomething that is fundamentally
changed. And then you also haveto have a sensor for whatever
(15:12):
that's changing. It's a lot likethe early days of computer
science where you had to almostbuild a custom computer chip,
for any sort of case that youwanted, because all of the
different sensory components anddifferent actuators, nothing was
was kind of individuallyunified. And so what we're doing
(15:34):
now is we profile thesedifferent cells, we look for
different biomarkers, thingsthat we can differentiate the
cells based on these thesedifferential expressions, and
then we feed those in. And we dothat... originally when we were
at MIT, we were doing that usingdifferent databases. NIH and NCI
(15:56):
have a lot of fantasticdatabases on all of this
different information it'smind boggling the sort of
information that people haveaccumulated. But you know, since
then we've developed, inside thecompany, a lot of different sort
of proprietary techniques of howdo we identify these biomarkers
that we care about?
(16:18):
What do you think about some ofthe work in the biohacking space
where it's maybe not quite as aprofessional shop as as you may
be running with Strand, butnevertheless, because of.... the
commoditization of some of theequipment, that techniques, the
fact that now we can take anysort of living organism or a
(16:41):
virus, which is sort of like azombie state entity, and be able
to digitize its constitution,like what it is, and then easily
share that around the world?
What do you feel about the workof these groups?
So I'm very pro, open sourceopen source science, open source
publications. I believe thatscience should be accessible to
(17:02):
more people, I believe we shouldhave more community oriented
science centers. But wherebiohacking kind of runs up
against this... You know, a lotof times the today's current
biotech industry and the currentgenetics revolution is
juxtaposed with the technologyrevolutions of the late 20th
(17:23):
century, the computer clubs andthe hacking clubs that birthed
Steve Wozniak and Steve Jobsrunning off with Apple computers
out of kind of one of thesehacking groups, that hacked
together something that could...
I think the story of Apple is,that was the hack and jobs built
this chip that you could plugonto a phone, and it would allow
you to make long distance phonecalls. And I think Jobs like
(17:45):
called the Vatican, from the SanFrancisco area, and called all
the way to the Vatican. This wasin the 70s, when that costs
hundreds of dollars. And it's avery funny story, right? And a
lot of the early hacking, peoplewere able to pull pranks in
computer science, people werepulling pranks and the most
(18:05):
damage you could do.... I meanthere are stories of people
trying to attack like AT&T'sinfrastructure, or mess with
those mega corporations. But themost damage you could do was
limited to what technology wasrelied upon at that time. And
then as technology got moreadvanced, and we became more
reliant on technology, thehacking obviously got better.
(18:29):
But the defenses against hackinggot better. And now when you
know everyone's life andpersonal data, and health data
and banking data, and prettymuch everything you have is
online and there are hackers andnation states and such that are
attacking that.... there's alsoa lot more defense, we've
matured in the way that we candefend against this hacking, and
(18:52):
you don't see nearly as many atleast, of these sorts of bad
things that happen. And again,that's because the hacker
culture that started in theearly tech industry could only
hack into whatever we were usingtechnology for. And here's the
problem with completeopen-source, unregulated
(19:13):
biohacking, is that we'redealing with the end system,
right? Like the biohacking ishacking of the body, right? So
whatever sorts of problems oroversteps that biohacking may
cause could immediately impactpeople's lives. If you're
(19:35):
messing around with making somesort of therapeutic that's going
to give someone like ... you'rejust you're doing something that
you think is going to be funny,and then ends up causing a huge
problem that will immediatelyimpact people's lives. It's not
like it's the '70s and the onlything I have on the computer is
(19:55):
like a game of Tetris, right?
It's a lot more serious now. SoI think we have to be careful
how we juxtapose the tworevolutions and understand that
while science should be moreaccessible and should always
strive to be completely open, wealso have to think about what is
(20:18):
responsible.
So do you think in the future,there's gonna be biohacking
security companies that evolveout of this? Like virus scan and
an encryption...?
Well, I mean, so right now, wealready have a number of these
defenses in place, right? So forexample, if you order synthesize
(20:39):
DNA from any supplier in theUnited States, and you go onto
the IDT website, integrated DNAtechnology, one of the main
suppliers of synthesize DNA, andyou enter a sequence, that
sequence immediately gets runthrough a number of algorithms
that try to pin it down towhether or not it is a viral or
(21:00):
pathogenic origin immediately.
And if it is, it will flag itand they'll ask for a number of
different credentials, you know,where are you ordering from? Are
you ordering from a trustedcompany or ordering from a
university and even when you'reat the university you have to go
in and sign waivers and sayexactly what you're using this
(21:23):
sequence for. So that existstoday. I think that in the
future, we're definitely goingto have to get way more serious
about biosecurity, and thwartingbio hacking, because as fun as
biohacking is in a trailer inthe Cambridge, Massachusetts
(21:46):
neighborhood or someone sets upa trailer, and does some
biohacking to turn some bacteriagreen. That same technology can
now be used by someone with morenefarious purposes, to create
engineered super COVID. Andwhile the technology is not
(22:07):
there yet, we need to take thatthreat seriously today, because
again, if we look back at thetechnology sector and this
juxtaposition between biotechand technology, we clearly are
behind the gun on cybersecurity,right? I said, we have great
defenses but you know, peopleare trying to hack our
elections, people are trying tohack into everyone's systems
(22:27):
constantly. And Equifax islosing everyone's social
security information. So we'renot there. We weren't there on
technology... the hackers wereable to stay in front of us. In
biotech, we don't have thatluxury. Again, it's much more
serious. And we need to takethat biosecurity threat
seriously from day one.
(22:48):
So it sounds like we absolutelythen would benefit by having a
national defense policy onsynthetic biology, right? On
cyber biosecurity... I'll read abrief passage from a proposition
that's on a national defensestrategy around this. And it
says that, for the listeners andviewers who are interested in
(23:12):
this is that in in 2017,researchers at the University of
Washington were able to encodemalicious software into a string
of DNA, that when sequencedallowed them to take control of
the underlying computer system.
And this vulnerability providesa sophisticated attack vector
into academic and commercialoperating systems enabling
traditional cyber threats, suchas data exfiltration, or
(23:34):
industrial sabotage. So couldyou both of you react to that?
Yeah, I mean, I think the pointsthat have been made are
absolutely spot on. We want tostrike the right balance between
having access to these tools andmaking sure there's open
science, open communication, butalso balancing of the fact that
(23:56):
we need that oversight. And Iabsolutely agree that there
needs to be more done on thefederal level to have a
security program that's reallymaking sure that these tools are
being genuinely used forscientific research or
innovation or creating thingsthat are actually going to be
useful. I mean, I thinkdefinitely we need this now. And
(24:18):
I think a lot of what Jake hasalso been writing about in his
advocacy on the side outside ofStrand is getting at that to
really making sure we have anational defense biosecurity
program that's not just beingreactive to potential threats
but proactive in detecting themor making sure we have an
arsenal of tools to go afteranything that could come our
(24:41):
way. So absolutely agree that weneed something like this.
It's true. For instance, whenAndrew Yang ran for president
now in 2020, he talked aboutcreating a cabinet position for
technology right? Secretary ofTechnology, and that was this
(25:03):
revolutionary idea, right? It'slike oh my God, this forward
thinking guy. And we've been onthis technological war path for
50 years, right? Since the 70s,we've been trucking up in
technology to where today, youinteract with a number of
technology devices, and yourentire life, again, is contained
(25:24):
inside of that. And we're onlyjust now starting to talk about
a cabinet level position fortechnology. Luckily, the current
administration of the lastcouple of weeks, has already
prioritized genetics andsynthetic biology as a key
interest area, and elevated EricLander who is a professor at at
(25:47):
Malvika and my alma mater, atMIT, Eric has been not only made
the a Director of the Office ofScience and Technology Policy,
they have then elevated thatscientific advisor level from an
advisory level to a cabinetlevel position. That shows great
promise, I think that that isthe first of many steps in the
(26:11):
correct direction. What wereally need is a full
encompassing department, right?
And I feel like the federalgovernment or the executive
branch of the government has notadded a new department since a
lot of us were a lot youngerwhen we added the Department of
Homeland Security. And in thewake of 9-11, but we can't
(26:34):
really be reactionary anymore,we need to both prioritize
technology, because clearlyhacking and social media
influences and things likeCambridge Analytica, and
Facebook influences and fakenews are having a real negative
impact, a real, measurable,toxic impact on the culture and
(26:55):
the stability of Americansociety. And much the same, we
need to be in front of thatcurve on biotech. Because again,
the risks are just that muchmore compounded. And there's a
thought that I hear, you know,to some people to take the
Luddite kind of approach tobiotech, where we say, well this
(27:19):
is dangerous or this iscomplicated so we should just
cease all research. And ofcourse, that's insane because
even if America chooses to ceaseall research, because it's
scary, China won't, Russiawon't... these other global
superpowers won't be stoppingtheir research. And so we have
(27:41):
to find a way to continue to notonly push research, but really
accelerate our research, but atthe same time, accelerate all
sorts of different mitigationand planning strategies, and my
advocacy, what you'rementioning, and some of the
things I've written specificallyon pandemic responses, but
should be taken into an allencompassing view of how we
(28:02):
think about biotechnology is toview things through a defense
lens. For whatever reason, humanbeings, and Americans especially
view things through a defensivelens and through a
preservation-of-self lens thatlends itself to thinking of
preparation, right? When wethink about, preventative
(28:24):
health, we don't do so well. Butwhen we think about preventative
defense, and how do we build...
building aircraft and aircraftcarriers and different sorts of
missile systems, we devote overhalf of our federal budget to
that sort of a thing. So I thinkthat we should start thinking
about that in terms of biotech.
(28:45):
So now that we have Space Forcemaybe the next thing we need is
Bioforce.
Yeah. 100%, that's it...
President Biden if you'relistening, call me up, let's
make Bioforce.
Bioforce join today, enlist. Iwould totally sign up that
(29:07):
sounds interesting anddefinitely would be helping
prepare us for the future.
We already have the uniforms ifwe just look to the Captain
Planet cartoon we already know.
There we go. Perfect. One onething I really wanted to hear
and give our viewers a littleview into the founding of your
(29:32):
company. Talk to us a little bitabout this process as you're at
MIT and thinking about startingan awesome new venture and what
that journey has been like sofar.
An "awesome new venture," yesthat's what I told myself every
day. I was like, "I'm gonna doan awesome new venture." No, so
(29:56):
the way that I think greatcompanies get started in the
science realm or in the deeptech realm is from a point of
inquiry first. And that's why Ithink academia can be so
powerful and why I think thatallowing or creating roadmaps
for graduate students orpostdocs are really researchers
(30:19):
at the academic level or at theresearch lab level, to spin that
technology into into companiesor even into nonprofits is
really what we should beenabling. And so I say that
because of how my company cameabout. So when Moderna first
started becoming more of amainstream company and I say
(30:42):
"mainstream" not on CNN likethey are today, but really just
as they achieved morepublications in the trade
presses of biotech, as morepeople became aware that there
were people like Moderna andBioNTech and such working on
mRNA. This is 2012, let's say,what we were doing at MIT in my
(31:04):
synthetic biology lab, we'rethinking about all right, this
is a new area of scientificresearch, a new area of
therapeutics. And we know that,other types of gene therapy from
engineered cell therapies tooncolytic viruses, all of those
genetic based therapies, at thetime were starting to...
(31:26):
synthetic biology was startingto innovate on them. It was
starting to program higherspecificities into cell
therapies and into engineeredviruses. But mRNA didn't have
any of the tools that DNA-basedapproaches like viruses and cell
therapies have. So for a decadebefore this even happened,
(31:46):
synthetic biology had beenbuilding all of these tools to
program the DNA of anything youwanted. And those tools were
able to be ported into theseviral engineered gene therapies.
mRNA didn't have any of thosetools. And so it was a 2012...
mRNA is more complicated or likehigher hanging fruit? Why was
(32:11):
mRNA lesser served?
Yeah, there are a number ofreasons, one of which is that no
one saw the reason, right? Sowith DNA, most of the genetic
circuits in your body that we'reat least aware of right now are
based on DNA. They're based onthese proteins called
transcription factors, they bindto the DNA, they turn genes on
(32:34):
and off. And it makes it a loteasier to build synthetic
systems, when you already havethat sort of technology. From
what we know of how mRNA isregulated, mRNA is a very
transient molecule, it degradespretty fast once it's into the
body. And that also limited itsability, early on as a gene
(32:56):
therapy platform, because it isso short lived, it's very hard
to build a robust gene therapyplatform around a number of
innovations that have beencovered by the press now such as
Catalin Carico, Andrew Weissman,at UPenn, their breakthroughs
with engineering messenger RNAsto get us to where we are today,
(33:17):
changed that thought process alittle bit. But again, there
were both no natural systems tobuild off of for mRNA regulation
and there was also no reason tobuild them because unless you
are delivering your gene therapyon a messenger RNA, you are
delivering it via DNA. And sothere's no real reason to build
(33:38):
all of this genetic circuitry towork at the mRNA level, if you
have DNA there, and you have awhole toolbox to play from, but
in 2012, with the legitimizationof the mRNA companies like
Moderna and BioNTech, we wereable to take an academic
approach because again, we wereacademics, we were at MIT, Ron
(34:02):
Weiss is the director of theSynthetic Biology Center and one
of the pioneers of syntheticbiology, one of the people who
really created the field ofsynthetic biology. And Ron and I
and my co-founder of Strand,Tasuku Kitada, along with a
number of other scientists atthe time, got to sit and perform
(34:23):
this academic exercise, whichwas if this technology is
successful, if mRNA is asimpactful as Moderna and
BioNTech and these othercompanies claim that it's going
to be, what will we need to takeit to the next level, what will
be the next step of hurdles thatwill impact the technology and
(34:46):
the ones we identified werespecificity and duration of
expression and all of thesethings that required synthetic
biology to add this next layerof expertise on top of it.
So you found some opportunity byjust thinking two steps ahead?
There's this new thing, what'sthe new thing for the new thing?
(35:08):
Yeah, exactly.
Malvika, with your perspectiveon synthetic biology and some of
the shared colleagues on thiscould you outline some of the
challenges that will need to beaddressed, perhaps for the
industry overall, but also thatStrand and Jacob maybe facing
(35:32):
down the road, and we can talkthrough... establishing of
priorities to address some ofthose challenges?
Sure, Jake, might be the best onthat. But I'll definitely take a
stab at taking the bird's eyeview of synthetic biology as a
whole. Jake hit on a few ofthose points... it comes down to
(35:52):
some of the transient nature ofmRNA, specifically for the field
he's working on. And like he'ssaying, making sure that this
mRNA molecule is... it comesdown to like, it's at the right
place, right time. And so that'ssome of the core pillars that
are going to have to beovercome. I mean, on a broader
level, there's a lot ofregulatory challenges. This is a
(36:15):
new therapeutic technology thatwould have to go through the
FDA, and I'm sure he can tellyou about some of the clinical
trials that they're planning torun, but as with any new
molecule, there are manyhurdles, and it could take
somewhere between five to tenyears to even get approval to
get into the clinic. So that'slike that's one notable thing.
(36:36):
And I mean, as he's probablyalready building... working
towards making sure this is aplatform technology. And so with
that word "platform," what thatmeans is that there are many
different indications that thistechnology could be used for,
but picking the first one tostart with is something that is
(36:58):
probably on top of many people'sminds in this space how do we
prove that our synthetic biologytechnology works? What is that
first sort of indication that weshould go after where there's a
sizable unmet need from aclinical perspective, but also
(37:19):
that you can actually get paidfor it. So someone's going to be
actually willing to pay for thistherapy down the line, whether
it's insurance, companyhospital... just understanding
that whole ecosystem. And sothat's something that I'd love
to hear more about from Jake ishow he thought about planning
what is that first market? Imean, it sounds like oncology.
(37:39):
What, specifically? And how didyou select that as the first
sort of indication to go aftergiven that what you're working
on can apply to so manydifferent areas?
It seems disorienting, yeah.
Yeah, how did you do that Jake?
It's a challenge to prioritize.
So where do you start?
Yeah, Malvika is completelycorrect on all of those points
(38:01):
really. I think, from aregulatory perspective, it's
interesting, because when Istarted the company, we knew
that mRNA was going to be thisnew frontier of medicine. And
there were, a number of phaseone trials that were ongoing,
with Moderna, and with BioNTech,and CureVac as well. mRNA
(38:22):
companies had been around for adecade at that point, doing
early stage clinical trials andtrying to get the science to a
level that it would beacceptable. Where we're at now
is actually in a little bitdifferent arena, because mRNA
has now become a, much morewidely used therapeutic
(38:45):
modality. And by the end of2021, my company strand will
enter the clinic in 2022. But bythe end of 2021, there will be
billions of people that havebeen injected with messenger
RNA, at least as a vaccine andthat's very powerful I think...
(39:08):
to talk about the comingfrontier of a drug. When you get
to the levels of hundreds ofmillions or billions of people
that have been administered adrug that lowers the bar, of
what's acceptable, or at leastit raises... the rising tide
raises all ships and whatnot...
because the FDA now will be lesslooking at the fact that it is
(39:31):
messenger RNA, in my opinion;they'll be looking less at the
fact that it's messenger RNA,and more at what are you doing
specifically and how are youdifferent? How have you changed
this molecule? What are youdelivering with the molecule?
What is it encoding? So thoseare all classic drug hang-ups
that you need to get throughwith the FDA, but now that we're
(39:56):
past the novelty of the platformitself the novelty of the
messenger RNA in that hundredsof millions of people and
potentially billions worldwideare going to receive mRNA. You
know, we're at kind of adifferent perspective there.
Malvika, you brought up clinicalindication selection... We
mapped out where the highestunmet medical need was and what
(40:21):
our technology could do in thequickest amount of time because
if anyone has ever spoken to mebefore, they know my number one
goal is to make medicine movefaster. And that doesn't mean
irresponsibly... it doesn't meanthat the FDA should not do its
due diligence. But we've seen in2020 that medical innovation and
(40:42):
regulation and clinical trialsand such can move faster when
people are motivated, when wedeploy resources and when
agencies are incentivized tomove with time as a deciding
variable. And with COVID, it wasbecause with time picking up
more people were dying everyday, the economy was at least
(41:02):
for small businesses, maybe notthe public markets, but for
small businesses... was gettingcrushed. And we understood that
time was the most importantfactor. And my argument is that
time will always be an importantfactor for someone, for that mom
who's just gotten diagnosed withbreast cancer, right? Time is a
(41:24):
critical factor, and if youadvance your drug a year faster,
and that drug is the drug thatwould have cured or put her into
complete remissionwith thatbreast cancer as opposed to
succumbing to it within twoyears, then that year that you
could have advanced that drug isincredibly, incredibly
(41:44):
important. And so I believe thatmedicine needs to move faster,
we need to innovate in the FDA,and the FDA has been incredibly
innovative with new genetherapies, they are on track.
But I believe that our researchinfrastructure, our clinical
trial infrastructure, and ourregulatory infrastructure can
all move faster. Because themedical technology, the
(42:07):
messenger RNAs, and otherengineered platforms that are
coming to the market now allowus to move faster in the drug
discovery and the drugdevelopment realm, which has
historically been the longestprocess that we need to move
through. And so we chose ourcancer as a first indication...
(42:28):
well the specific cancers thatwe're looking at one of which is
breast cancer, because we knewwe could move very quickly and
provide real value to patientsin the fastest amount of time,
and also provide value to thecompany. We'd be able to move
quickly and that allows thecompany to demonstrate its
(42:48):
technology, which allows us tobuild value, and be able to
raise more capital, which we canthen put back into... all of the
capital we raise goes right backinto our our Research and
Development division, which isworking on building the platform
for new and exciting areas,which may have a longer research
time horizon. We're trying toinnovate on all sorts of
(43:12):
different areas now and sothat's kind of the the strategic
outlook that we took as aI think those are really good
points. And I want to sharecompany.
something that Malvika sharedwith me before recording the
episode, a post by a colleaguethat was saying how we
celebrate... the iPhone 11 wasreleased, and then a year later,
(43:34):
Apple releases the iPhone 12.
And that's celebrated as a superinnovative company, an amazing
product. And consumer tech iscelebrated for that speed,
though now we're starting tosee, on the biotech side of
things, where... about a yearand a half is when we have go
from the beginning of a pandemicto having potentially widely
distributed vaccines forthat.... I want to just sort of
(43:56):
bring up the point is that wemay celebrate the innovation of
consumer tech, one year from anamazing device to an amazing
device, year after year andsustaining that. With medical
land, it's a little bitdifferent, that there are
concerns of the safety or theintegrity of it... that there's
a perception that this isn'tsafe. And so...
(44:19):
The main issue being people arereacting to the fact that they
think things were rushed... thatit's easy to make an an iPhone
version. People are like, "Wow,that's amazing, new features."
And now of course everyone'ssuper impressed with the speed
at which mRNA vaccines got intothe clinic and ultimately are
(44:42):
now all over the world. Butthere's also that skeptical
nature... "Oh no, this wasrushed." How could we possibly
do it and that dichotomy of theconsumer tech versus the biotech
speed? How do we...? What wouldyou say to folks that think like
that that things are rushed? Imean, there's this huge backlash
(45:05):
that it's going to be difficultto overcome that.
That is a fantastic point. Andone thing it does is it
illustrates what I was sayingearlier, which is why biotech
and technology while similar,while you can talk about them in
the same vein, and you can talkabout the revolutions in
technology in the same veinwhy they need to be handled
(45:28):
differently, why we need to bein front of bio threats earlier
than we were in front of cyberthreats. That being said, I
think everyone should, shouldhave just the utmost faith in
our regulatory agencies. Andit's a hard thing to do in
today's society of massinformation, of social media,
(45:52):
and, frankly, of fake news,right? Because what ends up
happening is that folks whoaren't familiar with the
regulatory agencies, they aren'tfamiliar with the FDA and how
they operate and how clinicaltrials work are now very laser
focused on clinical trials. Andvery laser focused on vaccine
(46:13):
development and all thisdifferent technology, that in a
normal time, people outside ofthe industry aren't really
paying that much attention to.
And so now that people kind ofhave lasered in on it, they've
said things like, "well, thevaccine development was rushed."
I can tell you that, if wewanted to rush the drug through,
we could have had the drug readyin March. The vaccine that we
(46:38):
have today was designed actuallyat the beginning of 2020. We
spent the entire year of 2020,validating the safety of the
drug. And we spent the entire 10years before that validating the
safety and the efficacy of thistype of drug working with
messenger RNA as a platform. Sowe have a whole wealth of data
(47:02):
and a whole lot of science, thatunderlies exactly what this sort
of thing can do. And it shouldbe said that while drugs
directly go into your body andthey're designed to make some
sort of change, it's really themost amount of scrutiny that any
product that's consumed is putunder, because we have we have
(47:24):
no shortage of examples of wherea new a food company or an oil
company or anything startsaugmenting their product and
gets it out to the market. Andit has real health consequences,
because they're never reallylooked at, but at the drug
level, we look at these things,we look at these things so
(47:46):
incredibly intensely and witharmies of people whose only job
is to really be skeptical, andto know exactly how to review
and pay incredibly closeattention. I think that what
we're facing right now is whenit comes to getting the vaccine,
I advocate 100% everyone shouldget the vaccines. They are
(48:11):
incredibly safe. They're verymuch in line with what we would
expect from any sort of avaccine. And we should trust the
FDA to have done their duediligence, right? Because
there's a reason that we have anFDA and we don't put all drug
reviews to a popular vote,because it takes an incredible
(48:37):
amount of expertise to determinethese sorts of things like drug
safety and drug efficacy. So weneed to take a step back and
know that even though this drugdevelopment is in the center
line of the media, we reallyneed to have faith in the
agencies that we've built on theFDA being one of the most
(48:59):
effectively run organizationsdespite my qualms about the
speed at which... drugregulation happens outside of
the Coronavirus vaccine. FDA isone of the most fantastically
run organizations in the federalgovernment. And it's been
incredibly effective at managingthis sort of case. And I would
(49:21):
love to give everyone amasterclass in the ins and outs
of drug regulations and how weshould determine the safety of
these drugs, but that isn't whatpeople are necessarily
interested in. They're justinterested in knee-jerk
reactions and believing thatsomething has come to market
quickly.
(49:46):
So we'll have to do anotherepisode on the masterclass for
drug regulations. It'll be aspecial Tough Tech Today
episode.
Educational. So Jake I know oneof your personal motivations...
as you've mentioned many timesnow is to make medicines move
faster. I also wanted to makesure viewers of Tough Tech Today
(50:07):
also heard a little bit aboutthe advocacy side on the
proactive pieces you've beenpushing for: the Manhattan
Project for vaccines. Could youexplain what that is? And why
you think that's reallycritical?
Yeah. Love to talk about this.
So one of the things that themRNA vaccines enable us to do...
(50:27):
so the reason that the mRNAvaccine was able to move so fast
is.... mRNA is what's known as aplatform therapeutic. We've
mentioned this a little bit onthis, this podcast so far. A
platform therapeutic is reallywhere you have a given molecule,
(50:49):
so mRNA that is encapsulated ina lipid nanoparticle. And all of
the molecular species are kindof known. And the only thing
that you're changing withmessenger RNA is the sequence of
the... welll people are familiarwith ATGC. But in the case of
mRNA, it's actually AUGC,because thymine is switched to
(51:12):
uracil. And so with the AUGCsequence of the messenger RNA,
you can change that to be anysequence and that sequence can
match any viral protein. Thatsequence will code for a viral
protein through classic geneticsand you can then switch in the
sequence of any viral threatthat exists out there. And so
(51:36):
what I've been advocating for isthat, again, we take this
defensive look this idea ofvaccines for the national
defense knowing that one ofthe greatest threats that we
face as a nation and as aspecies is that of the
biological. Throughout history,biology and the microscopic and
(52:01):
the basically invisible to us,has been shaping our lives. It
changed how the Americas werefounded.... when the settlers
came and interacted with thenatives that lived here in this
country, how that proceeded hadto do with disease, infectious
(52:23):
disease that was that wasbrought along with those with
those settlers. So we've alwaysbeen shaped by this piece of
biology. And it's always been athreat, though for the past 100
years, we've enjoyed anunbelievable period of peace
time. Since Spanish influenza tothe current pandemic, we've had
(52:44):
our trials and tribulations,we've had polio, we've had HIV,
we've had a number of differentdiseases come out, but we
haven't had anything on thelevel of COVID. And so we have
to think about how do we preventthis from happening? And the way
we prevent this from happeningis by taking these platform
therapeutics, now that we knowthat this formulation works as a
(53:06):
vaccine; this particle with amessenger RNA inside of it can
be injected into the body andform immunity. And it's very
easy to now recode, that mRNArather than what it would take
to say build a traditionalvaccine, for every virus, which
would create, you'd have to makea new process, it'd take
(53:28):
multiple years for every singlesort of virus and understanding
it and building it, everythingwould have to be very niche.
With platform technologies, wecan just start encoding every
viral antigen sequence that wecan possibly think of. And so
what I believe we should do istake the proactive step, where
we create prototype vaccinesagainst every known infectious
(53:52):
virus, starting with the mosthigh risk viruses. And then we
create, even further vaccines,against other sorts of known
antigens that could emerge, wecreate a monitoring system where
we're constantly sequencing theviromes, the viral genomes that
(54:13):
are found in wild animal speciesthat are close to humans, such
as bats and pangolins, which iswhere coronaviruses mostly come
from. Sequencing these viruses,identifying new viruses and
making new vaccines in aproactive way, and taking each
one of these vaccines throughwhat we call early safety
(54:35):
trials. So the first six monthsof 2020, the first nine months
of 2020 even, were spent provingout that the vaccine was safe,
and you can do safety trialswithout an ongoing pandemic. You
need a number of volunteers. Youneed money to spend on that, but
it's a small amount of money.
(54:56):
It's single digit millions ofdollars to go from the mRNA
technology we have today to afully executed phase one safety
trial. And we could do that forevery single vaccine that we
could possibly develop. And sowhat this allows us to do is, at
(55:18):
the time of a new emergingpandemic, we can take this
arsenal of already de-riskedvaccines and begin right at the
phase three level, which thephase three is that efficacy
trial that was in the news inNovember and December, that has
to do with 95% of efficacy, thatwas all over every headline...
(55:39):
we can begin those trials, notin the fall, as we did in 2020;
but on the same timeline, we canbegin those in January, we can
start deploying vaccines and beready to roll out vaccines. By
the time we get to the spring orthe early summer, if we're
looking at a 2020 roadmap, wecan be ready to roll these out
(56:03):
and really take this proactivedefense, of course right now,
our health, our public healthdefenses are so reactionary. To
put it in context of the DefenseDepartment, imagine if we waited
until there was an attack on USsoil until we made any tanks or
(56:25):
any aircraft... we just waitedand then the moment someone
attacked us, we tried to spin upthe manufacturer of fighter jets
and aircraft carriers and buildthem all and deploy them then.
Imagine how bad things would getin that interim time where we
were we were waiting. So withdefense, we take a very
(56:45):
proactive role, and sinceinfectious diseases is clearly
one of the largest threatslooming, we live in a time of
unprecedented global peace forthe most part, so how do we now
talk about the these newthreats, such as biological...?
Both natural biological threatsand biological warfare, which
(57:09):
could also emerge in the future,we need to be prepared.
So, Jake, who do you think youneed to convince? Who's gonna
pay for it?
I mean, the protector of thepublic health is the public. And
so I believe that at thenational level, it needs to be
the country, right? The countryhas to pay for this, just like
(57:34):
we pay for our national defense.
I also think and dream of a moreglobal coalition. We have the
World Health Organization, wehave these large scale global
cooperation treaties that peoplecome together... the Paris
agreement to fight climatechange, we could have similar
agreements of countries thatcome together and agree to fight
pandemics, to do environmentalmonitoring, to do global task
(57:57):
forces to have unified rules towhat happens when we identify a
novel virus. When COVID brokeout and they locked down Wuhan,
China, that actually took anamount of time before that
lockdown happened, and a numberof people left the city in that
(58:18):
time, because they knew thatthis lockdown was coming. We
need to have more unified sortsof ways of cooperating if we're
going to live in a globalsociety, if we're going to live
in a world where you can walkdown to the airport, pay, get on
a plane and be on the other sideof the world in less than 24
(58:38):
hours. That's the society welive in today. And it's
beautiful. But if we're going tolive there, then we have to have
global cooperation, we have tohave a way that the entirety of
the human species, or at leastthe vast majority, comes
together to say, these are ourpriorities, this is how we're
going to move forward, and thisis what we're going to build to
(58:58):
make sure that something ascatastrophic to the our way of
life as a species like COVIDnever happens again.
Thank you very much for joiningtoday.
Thank you guys for having me. Ireally appreciate this
conversation. This is a ton offun. Hi, I'm Jake Becraft, CEO
and Co-Founder of StrandTherapeutics. Stay tough.
(59:22):
We hope you enjoyed thediscussion with Jacob Becraft
and Malvika Miller. If youlearned something from this
episode, I invite you to say soin the comments, to ask a follow
up question, and we invite youto leave a five-star review or
like. Our next episode featuresEmily King, a global mining
expert. This is really importantbecause mining enables us to get
(59:45):
minerals, and there's a world ofminerals in every single
electronic gadget.
Click subscribe to be the firstto hear when the new episode
drops. Until then, stay tough!
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