RNA Sandbox with Johns Hopkins RNA Innovation Center's Jeff Coller, Ph.D. and Michelle Kim, Ph.D.

Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Matt Pillar (00:04):
You don't need to be a full-time biotech analyst
to get a sense for theburgeoning RNA therapeutics
landscape.
The space has been sproutingnew company growth at a dizzying
pace, particularly on the heelsof the COVID pandemic, and it's
showing no signs of slowingdown.
While the development of RNAtherapeutics is arguably the
brightest spot on the biotechhorizon, you might also argue

(00:27):
that the public and privateresearch infrastructure required
to support the advance of RNAas a therapeutic modality has
some catching up to do.
I'm Matt Piller.

Anna Rose Welch (00:38):
I'm Anna Rose Walch no-transcript.

If you're into RNA, our guests likely need no
introduction.
Dr Jeff Collar is a BloombergDistinguished Professor of RNA
Biology and Therapeutics atJohns Hopkins University and he
serves on the boards of theSociety for RNA Therapeutics and
the Alliance for mRNA Medicines.
His colleague, Dr Michelle Kim,is Managing Director of the new
Johns Hopkins RNA InnovationCenter, the ambitious initiative
the duo are spearheading AHopkins molecular biology and

(01:29):
biochem PhD herself.
Dr Kim brings more than adecade of research experience,
earned at Howard Hughes MedicalInstitute, Circulomics and
PacBio, to the party.
Jeff and Michelle, welcome tothe show, Thank you.
Thanks for having us.
Thanks for joining us.

Happy to have you.

Yeah, super happy to have you.
Yeah, and we're excited to behere.
Yeah, we had the benefit of aconversation.
What a few weeks doing is goingto be awfully intriguing to the

(02:09):
folks who are interested in RNA, who are business biotech
listeners, and I thought maybe,which could be everyone.

Well, yeah, it could be everyone.

Yeah, you might not be an RNA developer, but
everybody's RNA curious right.

Should be.
Should be have RNA allthroughout them.
So yeah, everyone has rna weare mrna and come on, that's uh,
that's painting with a prettybroad brush on a t-shirt, right,
we'll go with it we'll go withit, all right.

I thought.
I thought maybe we'd start withthe, the origin story, um of
the of the johns hopkins r.
What was the?
What was the sort of thenucleus of thought, that, the
kernel of thought that sproutedthis, this initiative?

Jeff Coller, Ph.D. (02:53):
Yeah, you know, it really started back
during the pandemic, and so itgoes.
The origin story really goesway back to like 2012.
I first started working onmRNA-based therapeutics back in
that time and the space of mRNAtherapeutics was something that

(03:14):
most people just weren't payingmuch attention to, and I had
gone to some of these meetingsthat were very small at the time
only a couple dozen people andhad met some of the big players
in that field, in particular, aguy named Mike Houston who was a
CSO of a very small company outof Seattle called PhaseRx, and

(03:35):
I was talking with them and Mikeand I had some ideas about, you
know, how to improve mRNA-basedtherapeutics.
You know this was more than 10,15 years ago now and I started
working with FadesRx and sadly,they basically went under.
But during the pandemic, mikegave me a call and he was now a

(03:58):
CSO of Trilink Biotechnologies,which, as we all know, you know,
bloomed into this hugeorganization during the pandemic
because they were supplyingCleanCap for Comirnaty, or
Pfizer's version of the vaccine,and what was clear in some of
the conversations that Mike andI had was there's a lot of

(04:18):
interest in the RNA therapeuticspace, but there's only a few
dozen labs on the planet thatare even working on mRNA, mrna
translation, mrna stability, andso how are you going to develop
a new therapeutic modality,which has really become a pillar
of medicine now, and innovatethat, if the academic support

(04:42):
network just doesn't exist?
And you know, one of the ratelimiting steps, of course, with
getting academics interested inthis is feasibility and
accessibility to materials at areduced cost and at a cost, you
know point, where they can dorapid experiments and try to
innovate around the iterativeexperiments that they would do.

(05:02):
And Mike and I started talkingabout this and he put me
together with one of thefounders of Meriby, which is the
parent company of TriLink, aguy named Carl Hall, and Carl
and I had a conversation aroundthis where we thought wouldn't
it be great if we could get intoacademics' hands, at a very

(05:24):
reduced cost, rna basedmolecules that they could then,
you know, rapidly screen through, rapidly innovate their
technology around and then doexperimentations and and and
continue to to uh, uh, evolvefrom that, that standpoint and,
um, that's essentially what wedid is we created this

(05:47):
partnership with Trilink inorder to make mRNAs at a
clinical grade level and sorry,at a preclinical grade level so
that our investigators couldwork on it and really there's
sort of two hopes here.
One is that, since we'reworking with Trilink and we're

(06:07):
using their SOPs, that anymolecule that gets developed in
a laboratory would be easilymoved to a GMP type production
facility.
Be difficult to move thatbeyond the preclinical stage.
But the other side of it againis this idea that if we have

(06:29):
mRNAs that are at a reduced cost, it allows the investigators to
play with it and allows us totry different structures, try
different modifications, trydifferent arrangements of open
reading frames, whatever it is,in order to improve upon
whatever disease it is thatthey're after going after.
Because one of the clearramifications of what's happened

(06:54):
in the last five years is thatmRNA-based approaches work
brilliantly for vaccines.
But to get them to that nextstep, that promise of cancer
neoantigen therapy or genereplacement, of monogenetic
disorders, we really have toinnovate in ways to go beyond
the biology that is naturallylimiting to the mRNA expression

(07:16):
space.
So in a nutshell, that's reallywhere we're trying to go and
why we formed the center.
We're trying to go and why weformed the center.
The other aspect of that is,which I think is a very key
piece of the RNA InnovationCenter is that we are situated
right next to individuals thatare world expert in LNP delivery

(07:37):
, because it doesn't matter howmuch you innovate in the mRNA
space, if you can't get it tothe right cells, well then
you're just not going to be ableto do anything.
So by having our investigatorsin the INBT, the Institute for
Nanobiotic Technology, it reallyallows us to play these two

(07:58):
technologies off of each otherand then go after hard to solve
problems.

Michelle, how did you end up joining Jeff here
at the RNA Innovation Institute?
I mean, was it?
How did this partnership arise?

Michelle Kim, Ph.D. (08:21):
Quite serendipitously, I was at PacBio
.
Yeah, I was at PacBio and I wasI should back up a little bit I
was at a startup that rolledout of Hopkins, which was
acquired by PacBio.
So I really love the startupenvironment and I really love
PacBio.
It was a great company, but Iwas searching for something more
akin to a startup environment.
I reached out to Jeff because Isaw that he is active in the

(08:45):
startup space, and we got totalking and he said you know,
actually I have this other thingthat's going on and you might
be interested in that.
So when was that.
I guess that was in thebeginning of 24, maybe around
January, that I reached out toyou.

Yeah, I think it was about January 2024.

So what did it look like to you, michelle, when
Jeff said well, I have thisthing.
What was the thing at thatpoint Like?
Was the thing an idea?
Were there bricks and mortarbehind it?

Oh no, I think, sorry.
Yeah, I think it was prettyclear even at that point that it
was going to be the RNAInnovation Center and what the
goal was and what the drive wasand the vision for how it would
grow and what it would become inthe future.
I think that was already inplace.
So I was very excited because Iwas trained in grad school as

(09:42):
an RNA biologist and going intomy postdoc I took RNA into a
translational research space andthen when I went to the startup
, I took a step away.
So I always wanted to come back.
So this just seemed like anamazing segue to go back to the
place I wanted to be.
So, yeah, very serendipitous.

Yeah, what was your charge, Michelle?
What did Jeff say?
All right, we're going to dothis thing and I want you to be
on board.
Here's what I'd like you to do.

Do you get to make it up as you go along what
are?

you doing Michelle?
What are you doing what?

are you doing, Michelle?

Jeff's listening with very piqued interest now.

I'm going to start taking notes, did I hire,
and what has she been doing?

I like to think of our arrangement and
Jeff, you should correct me, I'moff target like Jeff is like
the CEO right and the CSO andI'm like the COO right and I
think our Vision, our visions,are aligned on what we want to
do here.
And you know, I just I try tomake it happen in the broadest
sense.
That's how I describe it.
Yeah absolutely.

What would you?
What would you consider themission of the center Like at
this point?
You know you've got the, you'vegot the TriLink Association,
You've got the infrastructure inplace to pull things together
and we'll talk about morespecifically about funding here
in a minute.
But as you formed up, Jeff, howwould you sort of crystallize
the mission of the center now?

Yeah, I mean , the mission really is to try
again in an academic you know,it's really sort of a quasi
academic industrial relationship, and I think that's a very
critical piece, especially whenyou have a technology that
really is in its infancy, whereyou're trying to move it into
these new areas.
And so its mission is to dojust that.

(11:33):
It's to take on challengingproblems and work with
investigators who have expertisein whether it's cancer, biology
or some sort of monogenicdisorder, to work with them to
try and solve a problem.
So having experts in RNAbiology, experts in
manufacturing and then expertsin delivery and, of course,

(11:55):
experts associated with whatevereducation, to put those pieces
together in a way that isbeneficial and can go through
experimental reiteration, sothat we can learn from each
other and then gather thatinformation and then hopefully
make inroads into thistechnology.
And I really think this sort ofmodel is the only place this is

(12:16):
going to really occur, becauseby the time something gets spun
out at the biotech level,they're already set on their way
, right.
They have whatever product itis that they're thinking aboutch
level.
They're already set on theirway, right.
They have whatever product itis that they're thinking about,
their indication they're goingdown there, there's not much
time to go through experimentaliterations.
And in the academic setting, inthe pure academic setting,

(12:37):
there's not necessarily theroadmap in how to commercialize
and go after therapeuticdevelopment.
It's really this you know, it'salways been known as this
valley of death betweenacademics and industry and I
think what our center does issort of fill that void in a
unique fashion.
So our mission is really thatto put into the hands of our

(13:01):
investigators the power to beable to try different
therapeutic applications andtest them and then hopefully
spin those out, either to marketthem to other partners or to
make their own companiesassociated with Johns Hopkins.
So, and a long-termaspirational vision that we have

(13:22):
is to make our own, to startfrom ground zero some sort of
therapeutic and take it all theway to a clinical trial at Johns
Hopkins and have this sort ofwholly owned program that we've
developed and hopefully thatwould take advantage of some of
the novel science that we intendto explore.

Yeah, I'd like to add to that too.
I mean, hopkins has a very richhistory of taking research from
basic science to a therapeutic,and so we would like to be a
part of that narrative and we'rehoping to bridge the place
where people are at the point ofdiscovery which, as Jeff said,
is more challenging to do ifyou're in your biotech or pharma
setting so we can meet peoplewhere they're exploring things,

(14:06):
exploring ideas, and help themget to the point where they're
ready to try something larger ina clinical trial.

Yeah, it begs the question.
I'll let you, I know you gotone, but it begs the question,
just for a level set ofunderstanding.
You talked about these people,these discoverers, these
investigators.
Who are these people?
Who's invited to come play atthe RNA Innovation Center?

All are welcome.

Matt will be, there tomorrow.

I mean, right now we've started out
pretty small, meaning mainlyHopkins researchers, but that's
not really small.
We're a pretty big institution,but that's not really small.
I mean, we're a pretty big,pretty big institution.
Um, you know, once we get ouruh sort of the wind beneath our
wings, we'll expand from that Uh.
But as you know, as Michellesaid, all are welcome.

He seemed a little anxious.
I mean he was looking at us ina strange way.
Did you say that?
I mean he was?

looking at us in a strange way.
He's recognizing the power ofthis platform and he realizes
that when this episode drops,the floodgates will likely.

Well, to be honest with you, the reason I
say that is because I have beenworking on mRNA biology since
1993, for a very long time, andyou know know, up until 19 or
2019 nobody cared about any ofthat.
It was very esoteric and andstuck in academia.
And I've seen sort of how mylife has changed since 2019 and
the explosion of interest intothe research we do, into old

(15:44):
things that we had done in thepast, and there's just it's a
floodgate has opened since 2019,2020 of people wanting to get
into this, this game, becausewhen it comes to sort of
therapeutic development, as youguys know, you've been doing
this for a long time.
This podcast, you know,therapeutic development is
really very particular.

(16:05):
Right, you have an indication,somebody discovers a small
molecule or you know interestinggene therapy, whether that's
base editors or CRISPR orsomething.
But in the mRNA space, it's soeasy to really think about
things that you might want totry.

(16:26):
Easy to really think aboutthings that you might want to
try, whether that's creatingantigens or whether that's gene
therapies as an mRNA or baseeditors or CRISPR as an mRNA.
It's just really easy forpeople to imagine things they'd
want to do, and so that doesopen this floodgate of like well
, hey, I could try my favoritething now.
All I need to do is have sometools on how to do it, and

(16:47):
that's the piece.
Right now that a lot ofinvestigators are missing, but
they're eager to get involved.
You know, even before weofficially launched this, you
know the rumor mill in Hopkinswas brewing and we were getting
so much interest of people justcoming up and asking could we do
this?
And my lab in fact startedmaking RNAs for people just in

(17:08):
the bench, because there was toomany people asking us to do
this.
So you know, when I say that westart out small, we have to,
because I just think we will getflooded with a lot of requests.

Yeah, Jeff says he's been working in RNA since
1993.
I'm like what?
What?
Like you were coloring RNA withyour brains?
You don't look like you've been.
You don't look old enough tohave been doing anything since
1993.

Very kind, very kind of you, but it is a
fact.

Well, I think you know you've you've talked a
little bit about sort of thestate of the mRNA space, what it
was prior to the pandemic andnow where we are today, right,
but I think one of the biggestquestions I had, you know, when
hearing about the center is whynow?
Right, and so I think everygood origin story right has a

(18:01):
why now.
And you and Michelle and Jeffand you and I, we met just a
couple of weeks ago right at theAlliance for mRNA Medicine's
first Ascend conference, right,and so we were kind of privy to
a lot of the ongoing challengesthat the space is having.
But I'm curious, you know, howwould you answer the why now
question?
Why do you think that thecenter is so extremely necessary

(18:26):
today, given what's going on inthe mRNA space and what are
some of the biggest innovationsthat really you think need to be
made in the space that youthink the center will really
help pave the way towards?
So maybe we can start withMichelle and jump to Jeff.

So maybe we can start with Michelle and
jump into, jump to Jeff.
Yeah, yeah, I mean, I thinkthis also answers who we're
trying to serve.
Like we are starting with theHopkins community because, as
Jeff said, there are a lot ofresearchers here who are
interested in working in mRNA orwith RNA generally, but they
don't necessarily have exposureor molecular biology skillset in

(19:03):
their labs.
So we want to bridge thatdivide.
I think it's a time where a lotof people can start thinking
about this new modality.
It might spark some different,novel approaches to treating
things that previously were nottreatable.
So I'm so sorry, I just losttrack of your question.

No, I just what's the origin.
You know why.
Now, why do you think this?
Is an important time for thecenter and you know, given this
current state of the mRNA space.

Yes, and I think as I'm following up on
what Jeff said because of thepandemic, because of the
efficacy and the clearly provenvalue of using mRNA medicines, a
lot of people want to get intothis research area.
They don't have the skillsnecessarily, but we do.
We can offer them guidance, wecan offer them resources and we
can offer them a pathway totaking their ideas from

(19:54):
discovery stage to the pointwhere they might be ready to go
to a larger scale study.

And I'll just, you know, dovetail on that
is the the, when there's reallytwo mRNA based therapies that
are out there and they really dorepresent some of the most

(20:23):
widely understood and testedtherapeutics that have ever come
out, but they're based on sortof one set of rules in terms of
optimization of those and whenit would.
I mean, the manufacturing isone aspect, but then the biology
is another aspect.
And how many other things areout there that we haven't tried
yet?
Right?

(20:43):
I mean, they work really wellfor vaccines, but mRNA as a drug
is.
It is a good drug because it'scleared by the body.
It's cleared by the body veryrapidly and that's perfect in
some applications like a vaccine.
It's not great if you're tryingto do something like a gene

(21:03):
replacement or proteinreplacement therapy, and then
you know we're learning otherthings as we move along.
I mean, the pandemic fueled aneed to get these vaccines out
right away, and so both BioNTech, pfizer and Moderna linked you
know, decided to use, you know,m1 pseudouridine as their

(21:26):
modification.
Well, that might not have beenthe best choice now in
retrospect, because we'regetting data coming out in the
publication sphere that you knowthose modifications will allow
us for the vaccines to be useful.
There could be, you know,unintended read-through events
that you know we might not want,and there's over 150 unique

(21:49):
nucleotide modifications that weknow of.
Have we explored that entirespace?
Could we get to a point wherewe could improve the expression
profile of an mRNA and reduceits immunogenicity better than
what we already have?
And there's real examples wherewe might need that.

(22:09):
So, for example you know it'snot a case, it's not, it's not.
What we've heard from ourcolleagues in the government is
that the influenza outbreak isnot a when I'm sorry if it's a
when that there will beeventually a large scale
influenza outbreak and we'regoing to need viable vaccines

(22:32):
for that.
And in those cases you oftenhave to mix multiple mRNAs
together, but you get to a pointwhere you have too much mRNA
per dose, and so that creates animmunogenic response.
And so can we exploretechnologies, modifications or
alterations in mRNA structurethat can reduce the overall

(22:54):
amount of mRNA needed to get thesame amount of protein product
and that allows for us to gointo these more complex
therapeutic options.
And so I think, why now?
I mean that was your questionwhy now?
It's because we don't have this.
Technology is powerful, we needit.
We're going to need it forrapid responses to pandemics.

(23:16):
We're going to need it forother you know, rare diseases
that we might want to go after,or just simply reducing the
costs of already existingtherapeutics because it's cheap
relative to other therapeutics.
But the why now is because wedon't have the decades of
knowledge on how to improve uponthe efficacy in vivo, but also

(23:41):
the manufacturing, and you couldeven see from the event you
were talking about, the Alliancefor Amarni Medicine's event
there's so much interest in justthe manufacturing alone and how
we can reduce the cost and makethings better and safer, so it
really is an important moment.

And understanding too.
I think during that conferencethere was a really good quote
about how we know.
So we've done decades anddecades of research into protein
structure, right, but there'sstill very little understanding
of RNA structure in and ofitself.
And so you know a lot of thework that you guys are really
well suited to address.

(24:18):
Right is to help us sort ofanswer the questions that maybe
biotechs today are not quitecapable of answering yet, or
because of different risktolerance.
Right and regulatory tolerancethere can be some limitations
there commercially that aren'tnecessarily faced with academic
research, yeah that begs thequestion.

What Anna Rose was just mentioning begs the
question.
That begs the question.
What Anna Rose was justmentioning begs the question.
And, jeff, when you were sortof giving us the big picture
earlier in the conversationaround what the center intends
to do, you hinted at the centerbeing a support mechanism beyond
just creating a sandbox forscientific experiments.

(25:01):
You know.
You hinted at the translationalum capabilities, the, the
relationship with trial linkbeing sort of foundational to to
your point, being able to takesome of these ideas eventually
into the clinic.
Um, what, what does thatinfrastructure look like at the
at the center right now?
And what, what do you aspirefor that?
Uh, I guess, yeah,infrastructure functionality to

(25:25):
look like in terms of a businesssupport mechanism versus just a
?
You know some, some lab spaceand some you know sure highly
decorated scientists who canhelp you yeah

work on your science experiments I mean the
way I see it is so by the, therelationship with trial link
really gives us a lot of I don'tknow what I want to say.
Well, it's powerful becauseyou're using essentially their
SOP to make the mRNA and it'sessentially the same SOP that a

(25:55):
GMP mRNA would be made at, butit's not GMP.
Um, so what that means is thatif the researcher again I think
I've said this before, but theresearcher can take it from the
preclinical state to the, to theclinical market, without having
to do too much new optimization.
So I think that's an importantpiece, because things can break

(26:16):
between preclinical studies andclinical studies and you don't
want that to happen.
But I think, from sort of, thesupport and business structure
is it's really this reiterativeapproach where you know if you
can give an investigator an mRNAat cost, essentially for
materials, and then they'retesting it and they see whatever

(26:37):
it is that they want to see,they might come back to us and
then say, hey, we need a littlebit more, we need either we're
getting too much off-targeteffects or the immune reactions
are too high, toxins too high,something.
So we can try and play with thatto get to a point where they're
happy with the outcomes thatthey're getting.

(26:58):
That then might allow them tomove on to either new co-startup
or licensing it to apre-existing biotech and with a
product essentially that hasbeen very well vetted in the
academic clinical setting,hospital setting here at Hopkins
.
So I think that provides a lotof value, because you don't

(27:19):
often see that and it'scertainly I mean again.
This goes back to this valleyof death issue.
There's a lot of great ideasthat start in laboratories like
mine that just wither on thevine either because they can't
leap that valley or when they dotraverse that valley they die
of starvation because there'sjust not enough energy to keep

(27:42):
them going to get it into themarket space.
So I think we can help providesome of that by offering input
and looking at their data,helping to evaluate and then
really seeing what more leverscan we pull to get them to the
place that they really need tobe.

Yeah, that's exactly right, because if
you were to have a company makean mRNA for you, they might
charge you a lot of money.
So instead of getting one typeof mRNA molecule, they can get
10, right, and they would allvary in different ways that we

(28:31):
think might be beneficial to itsexpression or stability, and
then they can see which one isthe best in their assays.
So it's a much more powerfulapproach when they're working
with us.

More sagging and more affordable.

Yeah, and what we really hope to do is we
having all this under sort ofone clearinghouse is we learn
from each of these programs thatwe assist.
So if we have investigatorsthat are doing neoantigen
therapy in the pancreas, we takethat information back with us
and we learn something aboutwhat worked there and what

(29:07):
didn't work, and then the nextperson who comes up and wants to
start a program somewhere else.
We learn from that and overtime we're gaining expertise
about when you know, when do youneed to have ultra pure RNA,
when do you tolerate a littlebit less purity, when you know
would it be great to have thisparticular type of RNA

(29:29):
modification or this you knowparticular UTR or whatever it
might be, or LNP formulation.
By gaining that information,keeping it in our records and
then advising you know, we'reeducating ourselves, we're
educating our own community tohelp, and so it's creating value

(29:50):
to the center itself.

What are the resource like?
What's the resource picturelook like?
You know you talk about theexpertise and the research.
Is it?
Are you relying on JohnsHopkins uh personnel to to
contribute to uh assisting withthis research and playing a role
here, or does the staff?
Does the center have its own,its own staff Like?

what do?

those look like.

So in terms of, like the financial aspects,
um, this was a joint venturebetween Hopkins and the Whiting
school of engineering at JohnsHopkins Sorry, between TriLink
and the Whiting School ofEngineering at Johns Hopkins.
So TriLink and Johns Hopkinsput in equal amounts of money to
launch the center, and it's afive-year agreement currently.

(30:41):
So the employees of the centerare employed by Johns Hopkins
through that money.
But it's it's as with anyacademic center.
It's never a money-makingbusiness.
It's basically break-even.
That's it, and so we charge.
We charge for our services,enough to keep, you know, the
everything balanced, um, and?
But we are an academic unit, sowe also can apply for grants

(31:05):
and take donations.
If you want to send us a check,go ahead.

Just going to slide that little info in there.

Send it directly to my home.
It's a joke.

So Matt and I are supposed to show up at 8 am
tomorrow and also pay to play.

That's right .
That's exactly right.
I'll send you my Venmo account.

I'm on it.

But we anticipate that, you know, we
will have multiple, like anyother academic center.
We're going to be applying forgrants, we'll be applying for
grants with other investigators,with other investigators, and
eventually there'll be aproduction of IP that will come
back to the center and all ofthat sort of you know.

(31:50):
Hopefully in time becomesself-reinforcing and sustains
the, the uh, the operations.

Yeah, yeah.
That's a another question I hadfor you was uh, what, what
claim the center and JohnHopkins might stake in the uh,
the potential value of some ofthese assets that you're helping
to create?
What does that business modellook like?
Or is it sort of TBD?

I well, I think their standard that's all
stuff that's controlled by ourtech transfer office at Johns
Hopkins, which at Hopkins iscalled uh Tech Venture, so
J-H-T-V, and with anything thatcomes out of Johns Hopkins that
has that's Hopkins IP, they havethe rights over that.

(32:41):
And when a new code is started,then there are, you know, the
license has to be negotiatedwith Johns Hopkins.
That's a very standardoperational procedure for any
university and how they spin outcompanies and that's that's
really.
It is that if we develop thingsat Johns Hopkins, then if the

(33:05):
investigator wants to patentthat, then they're welcome to do
that.
Then it's all done through theterms of Johns Hopkins
University.

What about the Trilink influence there?
Are there any strings attachedto Trilink for these
investigators who are coming inand have the potential to take
something into a manufacturablestate?

I mean Trilink.
They're very generous in thisregard.
I mean they'd like to write,they would like the right to
look at it, but that'sessentially it meaning that they
have the right to look at itand potentially offer, you know,
licensing terms, but you knowour investigators can say no and
so it's very generous, they'revery supportive.

An important point for any would-be players who are
like what would I be tyingmyself down to?

Well, I think, from TriLink's
perspective, what they reallyare hoping for is because the
investigators are entering inearly in their development and
we're using their SOP, so it'sthe clean cap and the clean
strip protocol that you know.
They're putting more shots ongoal to get molecules into their
GMP.
We, we don't really want tostart making GMP mRNA at Hopkins

(34:24):
.
It's a whole different ballgame, different ballgame, yeah.
And and since we are usingtheir, their, their protocols,
the we would be sending businessto them and so that's what what
they get out of it more thananything.
So a lot of the de-risking isdone.
What they probably see is thatmost of the de-risking is done

(34:45):
with us through the academiccenter and then they get the
good stuff that they can make.
But in terms of IP, there's notether.

So go ahead, Michelle.

I was just going to say.
Trialink is extremelysupportive of this endeavor and
in fact they had a small teamhere last week walking us
through their SOPs.
So they're there, they answermany questions and they're
offering their help all the time.
So, yes, the idea is, becauseof this relationship, the

(35:23):
transition to larger scaleproduction should be seamless
relationship, the transition toa larger scale, production
should be seamless.

So you know, jeff, you'd mentioned that in
the past.
You know your lab had beenmaking quite a bit of RNA right
as things were coming up andquestions were being raised and
folks were.
RNA was getting a lot hotter.
I'm curious to kind of get atrajectory here of some of the
innovations that your lab hasbeen involved with right on the
scientific side for RNA Leadingup to this point.

(35:55):
First of all, you know wherehave you been particularly
active in mRNA and next-gen RNA.
You know prior to the launch ofthe center and then also how
you see that supporting some ofthe work right that you're going
to be doing moving forward withthe center.

Yeah, I mean , my lab has really for a very
long time worked on stability ofmRNAs.
That's kind of what our breadand butter is, and so when
people have asked us to workwith them on therapeutic RNAs,
we try to integrate all of ourteachings that we've learned on
mRNA stability into thosemolecules.

(36:33):
And that's sort of ourknee-jerk reflex is to make sure
that we design it the way wethink it should be designed,
which is not necessarily asintuitive as you might think,
Because we know a lot more aboutall the various little features
that control stability.
And it's not as simple as justlike going to some web protocol

(36:55):
and hitting like optimize my RNAand poof, there it is.
Yeah, there's a lot more thatgoes into it.
The other side of it is I'mreally fascinated by the RNA
modification space, because thatis an area we just simply have.
Like I said, we're in N of 1here, where it's M1.

(37:16):
Pseudo U is what everybodythrows in for the most part.
I mean, there are a few others,but there's so many other RNA
modifications out there yet tobe explored that could really be
used for particularapplications.
And then, lastly, the one thatyou know Matt was laughing and I
said I was been working on thissince 1993.

(37:38):
It's true, and back then wewere.
You know when somebody would say, cause we used to program cells
with mRNA.
Back then we would inject mRNAsinto oocytes and stuff and
reprogram cells and people wouldplay with this idea could you
use it as a therapy?
Well, no, because it wasdelivery, Delivery, delivery.
Delivery Delivery is always theproblem.

(37:58):
How do you get the transcriptto the cell that you care about?
And back then nobody was reallyeven thinking about the LNP
space as start exploring thatspace together, Because it is

(38:31):
true that we're not going toinnovate unless we can do that.
So that's another place wherewe've had some success, you know
, on this sort of individualbasis of you know, here's an RNA
, here's an application.
Let's talk to our colleagues Dothey have an LNP that might
work?
And all of this will have to besort of combined as things

(38:52):
change.
For example, if you startchanging modifications on an
mRNA, that's going to change itschemical property and so how
that gets packaged into the LNPis going to be different.

Huge question yeah, yeah.

So how do you?
You know you have to optimizein that space.
You can't just say, hey, I justdiscovered this novel way of
modifying an mRNA that reallyworks, great.
But try to package it into ageneric LNP and it doesn't do
anything.
So having those pieces togetheris really important.

An integrated approach for drug development
yeah.
Michelle, did you have anythingto add?
You have a background in theRNA world, right?
So I mean, are thereinnovations that you are most
excited to see the center tacklein the upcoming year or two, as
you set out to be COO right Tooperationalize all of these, uh,

(39:48):
all of the goals you guys have,are you most excited about
anything that you guys are goingto be working on in particular?

any innovations you want to see made
well, I mean we'll start withmrnas, and jeff's lab has made a
lot of very valuablediscoveries in how to increase
the stability and, as Jeff hasoften said, if stability is
increased then you're going tohave expression.
So this is going to be reallyimportant.
There were a lot of things thatI saw at the meeting in Boston

(40:19):
last week.
Was that last week?

Two, weeks ago.
It was like it was two weeks.

Yeah, a lot of people doing work on
self-amplifying rnas, um, sothat's an intriguing area that
we don't have experience inhands-on yet, but a lot of
people are asking about that.
Yeah, um, and that also isgoing to have issues with
packaging, because those tend tobe much larger molecules.
I'm really eager to see whathappens in that space, just how

(40:55):
mRNAs are used in areas wherethey haven't been used before,
such as new antigen therapySorry, I'm getting a cold.
No, no, you jinxed me.
I wonder where that came from.
Yeah, or for delivering enzymesand base editing and perspiring
.
So I think a lot of people aretrying to switch to that.

(41:17):
So I think that's a reallyimportant area.
We're probably going to see alot of people asking us about
that.
But, yeah, I thinkself-amplifying rna is an
interesting space.
I know jeff and I have talkedabout that before.
It has its pros and cons, but,um, it's nice because you can

(41:37):
deliver less um and potentiallyget more expression.

but and potentially unmodified.
There's a lot of hope that youcan get the RNA to just simply
be unmodified and then andreduce the overall, because,
again, this whole idea ofreducing the effective dose is
very important.
You know, if you're stuck atlike 100 micrograms of RNA which

(42:04):
is what Moderna's was at, itreally kind of puts you at a.
That's a lot of RNA.
But if you can get it and whatI've heard from some of the
self-amplifying folks is thatthey're down to like 0.25
micrograms, so it's a prettysignificant you know difference
and you know, and that puts youinto a new realm of where you

(42:26):
can start mixing and matchingdifferent strands for complex
processes, whether that's likesome sort of gene editing or if
it is a pan viral vaccine thatyou want to generate.
So you can have five or sixdifferent transcripts in there,
you know, to try and get thebest response that you can

(42:50):
possibly get.
So those are all things that wereally need to explore.

Yeah, and these explorations I mean you know I'm
reading between the lines asyou talk about them and their
translation to the businessaspect, right Like this isn't
just a science experiment, thisisn't just doing cool stuff,
it's like these are the thingsthat we need to do in order to
move the business forward.
And I'm curious about that,cause I don't think it can be

(43:17):
overstated that this isn't justan academic exercise and that
you two both bring to the tablea bunch of industry and vendor
supplier experience.
You both worked in the biotechspace.
You've got, like I said, supplyexperience.
So I'm just curious about whatkind of mind share that industry

(43:43):
experience you're bringing tobear as you form the center up
and create the vision and, youknow, make it what you intend it
to be.
How, of those experiences thatyou've had in the industry the
business of biotech informed,the way that you're setting up
to help other companies buildand grow.

(44:05):
You want to start there,michelle.

Sure.

I think Jeff handles that at the macro
scale and I handle that at themicro scale, which is to say,
you know, jeff established thecenter.
There are a lot of playersinvolved, not just trial and get
Hopkins, but all the individualplayers within these two
different organizations.
So bringing the center inexistence was a, you know, that
was no small feat.

(44:30):
And then here gettingoperations going at the micro
scale, I think because of myexperience before in a small
startup and then in a largercompany, it was an eye opener to
me, coming from grad school anda postdoc, excuse me where
you're in a very academicmindset, it's very different

(44:50):
than when you're in a company,like when you are trying to sell
something or help people.
You have to be very customeroriented.
You need to know how to keepstakeholder engagement.
You need to know never to sayno or never to say it with that
word.
You need to understand likeyou're trying to understand what
do people need and then how canyou deliver to them and how can

(45:13):
you describe to them what youcan and can't deliver.
So I think those are the skillsets that I bring from my
previous experience and I hopeit pays off.
Yeah, I mean I can just add onthat and.

I hope it pays off.
Yeah, yeah, I mean, I can justadd on that, I mean, I think so.
I started my first biotechcompany back in 2018, 2017.
And it's Tevard Biosciences.
And I started that company withHarvey Lodish and he has really
been kind of a you know he he'ssort of an icon of biotech

(45:49):
development and I learned a lotfrom him.
But one thing you do learn intalking to investors and talking
to other players in the spaceleaders in the space and it goes
to why this center really isimportant is that you have to

(46:10):
hit the ground running.
When you start a new startup,you have a very limited time,
and so you have to identify aniche that you can occupy, that
you bring value to.
And that's really where I thinkwe can help in this arena is if
you have investigators that arecoming to us and they, hey,
they want to do this, that orthe other thing, you know it's.

(46:31):
It's fine if you're getting apublication, great, but if you
actually want to spin that outto make a company, well then
what is the real value of thatproduct?
What does it bring to the table?
And we can help with thatnarrative by saying well, you
know we understand the mRNAspace and we know that you know

(46:53):
that you have lots ofcompetition over here, but you
might have a singularity herethat could be explored and
provide value that investorswould be very interested in
seeing.
So you know we don't and wedon't work alone in that regard.
I mean we have the tremendoussupport of, you know, johns
Hopkins Technical Ventures andas well as our own, you know

(47:16):
contacts in the field.
So you know I anticipate thatthe center will provide.
You know we do more than justscience at the center.
You mentioned we're part ofthis alliance for mRNA medicines
and that is another aspectbecause it allows us to really
connect people with otherindustrial leaders and we have

(47:39):
over 60 to 70 members of thatalliance now that we're part of
and that network is veryvaluable and will be valuable to
our clientele as we moveforward.

Yeah, you'd mentioned something too about
how you can kind of help.
Your knowledge of the mRNAspace can help folks connect
their product or their researchright to some of the overarching
needs of that space.
And there's a lot of bestpractices, I think, in terms of
you know, how you can launch abusiness and best leadership
practices that are reallymodality agnostic.

(48:16):
But I'm curious, you know, withyour background, both of your
backgrounds being in this RNAworld- and having seen the RNA
world pre-COVID, when no onereally gave it the respect that
it was due right, are there anyRNA-specific insights that you
think are really important forfolks to keep in mind as they

(48:38):
are launching an RNA business?

I like to kind of dig into some of the
individual nuances right thatcome from modality, specific
learnings and running a business.
I mean, I think what we can seefrom what's happened over the
last five years, the use of mRNAin vaccines is never going to
go away.
That's never going to go away.
That's something that you know.
That genie's out of the bottleand there's a lot of issues
around vaccines and politicalthings, blah, blah, blah, but

(49:12):
it's not going to go away.
It's just too easy, works toowell, and not that it works too
well, it works great.
But I think where we're reallyseeing incredible promise is in
neoantigen therapy or mRNA.
Again, the idea that you candesign a personalized therapy

(49:34):
for an individual withpancreatic cancer and have that.
You know the successes thatwe're seeing in the last two
years in pancreatic cancer withneoantigen approaches is really
tremendous.
That you know this was adisease where it's really a
death sentence but was leadingat least to half the people in

(49:55):
that study were still aliveseveral years later and so
that's going to continue andthere's a very clear path to
using mRNA in the new antigenapproaches.
It's not going to work.
You know mRNA is anothermodality in our therapeutic
arsenal.
It's not going to work foreverything but it is going to

(50:18):
work for these otherapplications and I think and I
don't think this is a crazyvision, think this is a crazy
vision I think you're going tosee in the next five to 10 years
sort of point of caretherapeutic development where
you have major medical centerslike Johns Hopkins or Sloan
Kettering or Houston Methodistcreating their own programs to

(50:42):
make personalized medicines onsite.
Where you get diagnosed withsome rare disease or rare cancer
, you go there and they, theyhelp design a therapy in the
house and you, you, you get thattherapy.
Now how that all gets paid forthat's a different issue.

(51:02):
But you know the the technologyis such that we can do it as
point of care and you knowthat's going to expand.
That will expand beyond themedical community also into like

(51:27):
agriculture and starting totreat you know, our food supply
before some of these pathogensemerge into the human population
.
Mrna is a very low-cost, viableapproach to start using on some
of our livestock and animalproducts.

Yeah, wouldn't that be amazing If we
could decrease the use ofantibiotics and animal farming
and then maybe reduce the use ofpesticides?

yeah, exactly, it's something we often
don't talk about.
A lot in biotech is where youknow you have certain approaches
like mrna that can cross justfrom.
You don't necessarily have todeploy it just to humans.
That technology is just asviable in other animals.
So so, and because it's lowcost, that reduces that barrier.

So yeah, Jeff, you talked about the valley of death
earlier and you talked aboutthe likelihood of death.
Even if you make it across thevalley of death, You're a very
uplifting man, Jeff.

I'm just kidding.
There's a movie coming soon.

I'm curious though and you know you talked about
some of you know some of some ofthe causes of that mortality,
but I'm curious if you you'veseen a lot of this, like you've
seen a lot of academic exercisesthat showed glimpses of
commercial promise andopportunity, and you've seen
them, you know, go north and gosouth.
If and I'm going to ask you ahard question to answer right
now- and I apologize for it inadvance If you're going to put

(52:49):
your next paycheck on a bet.

We really are going hard here.
Michelle, you want in on thistoo, are you going to?

risk not feeding your family for a week.
You're raising the bar way toohigh for this question.
It's not that good Uh but, butit is challenging to answer.
If you, if you had to, you knowyou.
Let's say you got, you got.
You got six ideas in the labright now.
Each of them have their own uhyou know, own glimpse of of of
commercial promise down the road.
Um, but you got to put yourmoney on what's going to go
wrong, Cause you've seen it gowrong before.

(53:28):
Like what's that knowledge gap,or that you know that that
missing piece that that so oftendo dooms these projects early.
Yeah.

Yeah, well, the biggest thing that dooms
almost any biotech is efficacyversus tox, right, like, how
much benefit do you get for therisk and is that tolerable?
And we see this all the timewhere you know there's gene

(54:05):
therapies that are going to dogreat things, but then we get
them into the clinic and there'svery little success.
You know, we've as everybody'ssaid and you probably heard a
million times in this podcast isthat it's really easy to cure a
mouse.
There's you, we've eliminatedcancer and most genetic diseases
in mice a thousand fold, um,but applying academic research

(54:30):
to the human body is much moredifficult, and so getting good
efficacy and low talks is whatis critical.
Um, without that you, you don'tget out the door.
And um, so if I was betting, youknow, in the place where I
think a lot of people have madethese bets historically is
always in the cancer space,because the risk, the benefit

(54:53):
ratio is so different versusother places.
You know prophylactic vaccines.
You've got a huge risk benefitanalysis that has to be done you
cannot cause harm there at alland it has to be efficacious.
And there's a lot of politicalaspects about that too.
But in the cancer space, ohreally.

(55:14):
I haven't heard any politicalinfluence on the vaccine space.
We could go down a wholedifferent podcast for that one.

If you wanted to.

Coming soon.

Coming soon to a podcast near you.
But cancer is embedding.
Where the next sort of wildlysuccessful mRNA therapy is going
to be is in these really hardto get to cancers, these
recalcitrant cancers likepancreatic cancer, glioblastoma,

(55:51):
where we can try.
We can take a lot more riskthere because the benefit is so
high and that allows forinnovation that then can
eventually allow us to do thingslike monogenetic gene
replacement, and which has itshas its challenges.

(56:14):
You know, the challenge thereis the, the durability of the
mRNA, the mRNA.
The reason why I study mRNA isbecause it goes away.
That is my job.
I've studied mRNA stability fordecades and it goes away, and
it goes away fairly quickly.
And so for protein replacementstrategy, unless we improve the

(56:39):
durability, or we improve orhave, or if it's an indication
that allows for repeat dosing,then we're sort of limited there
.
So from a betting standpoint,if somebody had a really good
cancer neoantigen treatment,that's where I'd be betting.

All right, you heard it here first.

But these are just.
I provide no market advice.

Remember, there's a paycheck riding on
this.
If anyone's listening, who paysJeff's bills over here?

We'll put a disclosure on the show and
protect you from any legalresponsibilities.
We're going to need to landthis airplane.

I'd love to keep the planes flying.

I've got a couple more, but I don't want to give
you short shrift.

No Well, so I guess it's more of an
overarching question, just sortof.
You know we've talked about whyacademia is a great place to do
some of the R&D that we reallyneed today, Right, and so I'm
curious, just as we're lookingforward into the future and just
in your experience so far withthe center, you know, have you

(57:54):
seen an increasing amount ofinterest from industry in
partnering more closely withacademia over the past year, two
years, and do you see that?
You know, now that the center'sfully fledged and formed and
exists, do you see that interestcontinuing to increase?

Yeah, I think so.
Yeah, absolutely A hundredpercent.
Go ahead, Michelle.

Yeah, yeah, I mean I think that's
definitely evidenced here withour partnership with TriLink.
But when I was in PacBio, Imean they and other companies
that I had spoken with, likeeverybody, is understanding or
realizing the real value ofacademic centers for discovery,
right, because you know, aswe've talked about earlier, it's
just it's an inhibited prospectif you're at a biotech company

(58:41):
or pharma company when you havetimelines and deadlines and
programs, if you're a biotechcompany or pharma company when
you have timelines and deadlinesand programs.
So I think I think companiesare going to continue to grow
their interest in trying topartner with academic
institutions to help fosterthese early ideas and, you know,
with the idea that it's goingto come back to them so they can
work on the other end of theresearch pipeline.

Yeah, for sure.
Yeah, and this modality reallyis sort of unique among all
other modalities out there,because it's not like, if you're
doing a small molecule, how areyou going to reiterate that and
learn where?
Here, you know, it's a basicbuilding block.
It has to do one thing, whichis to make a protein, and so
there's a rule book for that.

(59:24):
And but we can, you know, it isthe messenger of the genetic
code and we can get it tocommunicate any information we
want.
And so that's where, um, whyindustry is so fascinated by
this technology and why they'reapproaching places like us in

(59:45):
order to say, well, what can wedo together?
And I only see that interestcontinuing to go up and up and
up in the next few years.
This is a technology that'ssimply not going to go away.
It's not.

Anna Rose Welch (01:00:01):
I like to hear that, at the helm of a
publication called Advancing RNA, we certainly hope it goes
nowhere.

Matt Pillar (01:00:13):
What's the next big agenda item for the RNA
Innovation Center in terms ofits growth and development and
go-forward plan?

Michelle Kim, Ph.D. (01:00:23):
Well as of Thanksgivinggiving.
We are fully operational.
So because we were in thebuilding stage until right now.
So we have a number of projectsthat are on deck.
We're gonna gonna be able todive into them now.
So that is.
That is the first step that isthe first step in that.

Jeff Coller, Ph.D. (01:00:44):
And as we grow these smaller, individual
faculty-based projects, we wantto expand out from there and we

(01:01:26):
have some conversations going onabout how to leverage this
technology in unique ways.
We're talking with the AppliedPhysics Lab here at Johns
Hopkins on.
Maybe there are things that wecan do outside of the individual
, but also of the biggerindustry as a whole.

So yeah, when should those, those groups,
those those potential partnersand researchers who are who are
interested in learning moreabout what you guys are doing?
Where can they learn more?
I think, we're going to be intouch with you.

They can either contact me or Michelle
directly, or we have a website.

We have a website and a LinkedIn page.
All right.
Many avenues.

Maybe some T-shirts in the future.

we're gonna get t-shirts.
We'll, we'll, we'll.

I'll help you, I'll help you come up with
slogans.
You're welcome in advance don'tforget that.
Don't forget the link to thevenmo, okay just personal venmo
at the bottom of each t-shirt.
I think she's a marketingofficer.

Send me your Venmo.
We'll put that in the shownotes.

Michelle, you want to get in on this too.
A hundred percent.

I guarantee the inbound interest in the offering
is going to far exceed theinbound Venmo.

But we'll put it out there, that's fine.

Well, guys, I feel like we've just scratched the
surface.
Michelle, to your point, you'refully operational.
There are some projects in theworks we're going to have to
revisit.
We're going to have to revisitdown the road and learn about
some of that project work andstay up to date with the
progress of the RNA InnovationCenter and any number of these

(01:03:06):
things.
You know the vaccineconversation.
I'd welcome that.
Vaccine politics there's a lot.

DNA's reputation is a hot topic.
I mean, I'm here for it.

I was sitting here dreaming up an episode dedicated
to the application of rnatechnologies and and veterinary
science as a as a as a means ofre-establishing public trust.

Yeah, I mean , there's a lot to talk about
there, right like there yeah,there is a lot to talk about and
you know, and there are peoplethat are trying to help in this
space.
That's's what, in part, themission of the Alliance for mRNA
Medicines is about to reallytry to, you know, change the
public narrative.
We have a lot of challengesahead of us and it's important

(01:03:57):
that the public realizes thatthese technologies are not there
.
As you know, they're not badtechnologies that are meant to
just make people money.
They, they are technologiesthat actually are saving
people's lives and, uh, they'regoing to become very important
in the next few years.

(01:04:18):
And it's a technology thatreally started with Operation
Warp Speed during the Trumpadministration, and it was
launched during that time, andwe have to embrace it and we
really have to rally around itas a technology.

It's here to stay.
It's here to stay.

Yeah, it's in us and it's here to stay.

Well, congratulations on the progress
you've made with the InnovationCenter to date and the role that
you're playing in thatmessaging and that work and,
like I said, we're definitelygoing to have you back on the
show.
I've heard that you and youguys and Anna Rose hang out on
the road quite a bit.

Next, time we do this, there will be
Manhattans and perfectManhattans and other forms of
bourbon involved, because that'swhen the conversation gets.

Well, let's do it in Manhattan.

Really.
Yeah, I'm there.
I'm there Traveling.

I wasn't going to bring it up, you just did, but
yeah she'll let me know, I'msure, when you guys are ready to
come back on and share anupdate, but in the meantime,
thank you all so much.

Thank you, thanks for having us.

Thank you, it was fun.
Thanks a lot.

So that's doctors Jeff Collar and Michelle Kim,
I'm Matt Piller and I'm AnnaRose Welch, and you just
listened to the business ofbiotech If you're working in the
RNA therapeutic space, orsimply, as I said earlier, rna,
curious.

Which you should be.

Which you should be .
Anna Rose and her work atAdvancing RNA are must follows.
So bookmark advancingRNAcom oryou can subscribe to Anna Rose's
newsletter and connect with heron LinkedIn.
Your subscribe anywhere.
You get your podcasts and go tothe videocast page under the
Listen and Watch tab atbioprocessonlinecom, where you

(01:06:08):
can not just listen to Anna Roseand I, but you can watch us.

I know it's really it's very exciting.

We drop a new episode every Monday morning, so
we'll see you then, and thanksfor listening you.

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RNA Sandbox with Johns Hopkins RNA Innovation Center's Jeff Coller, Ph.D. and Michelle Kim, Ph.D.

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