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Business of Biotech in the dropdown . Welcome

0:41

back to the Business of Biotech . I'm Matt Pillar , and

0:43

it's a special day here in the

0:45

studio because we're going to be talking in circles , circular

0:48

RNA , that is , with Orna

0:50

Therapeutics CEO , Dr Thomas

0:53

Barnes , and if you're watching , you

0:55

can see that as such , I've brought along with

0:57

me my dear friend and colleague

0:59

, Anna Rose Welch , who

1:01

is editorial and community director

1:03

for our relatively new Advancing

1:06

RNA Community at Life Science

1:08

Connect . Welcome , Anna Rose .

1:10

Thank you .

1:10

Matt , awesome to have you here . It's awesome

1:12

to be here . We're uncomfortably close right

1:14

now .

1:15

We share a wall , and now we share a wall , now we

1:17

share nothing .

1:18

Yeah , yes , collectively

1:20

, dr Barnes and Anna Rose have likely

1:23

forgotten much more about RNA

1:25

than I ever knew or ever will know

1:27

, so you're in good hands today if

1:29

you're into RNA . For its part

1:31

ORNA , that is is

1:33

developing circular RNA therapeutics

1:36

delivered via lipid nanoparticles to treat

1:38

indications including B-cell lymphomas

1:41

and DMD , in addition

1:43

to some discovery stage , vaccine and

1:45

other therapeutic programs . Dr

1:47

Barnes , who's been at the helm there since

1:49

2020 , previously co-founded

1:52

or led a number of biotechs , including

1:54

Intelia and 11 Therapeutics

1:57

. It also serves as an executive partner at

1:59

the investment firm MPM

2:01

BioImpact . Dr Barnes

2:04

, welcome , thank you , pleasure

2:06

to be here . It's

2:12

our pleasure to have you , and I want to start out by getting to know you a little bit before

2:14

we kind of dig into the company and where you guys are going with your therapeutics

2:16

. Your academic experience in

2:18

genomics stands for itself . You've

2:20

got a Cambridge PhD , a

2:23

Harvard postdoc , a McGill fellowship

2:25

. Rewind

2:27

the clock quite a bit and tell us why

2:29

. I guess when and why

2:31

you decided to take that academic experience

2:33

into industry .

2:36

Well , the

2:39

story actually begins when I finished my undergraduate

2:41

. So my undergraduate in the University of Sydney was

2:44

majoring in genetics with a minor in

2:46

biochemistry , and that was cool what

2:49

I realized coming out . And the Australian program

2:52

is for a basic bachelor's degree

2:54

. It's a three-year program and the fourth

2:56

year is optional , which you spend in the lab if

2:58

you want to do that extra thing . So I was

3:00

very interested in doing that , but in coming out

3:02

of that I was pretty

3:05

sure I didn't want to be an academic . That

3:11

point in time represented the end of all the forward

3:13

momentum from high school and

3:15

you're going to university and it's

3:17

all on a track . And then it's like now what ? Yes

3:20

, so I could go do a PhD at that point

3:22

, but I wasn't sure that

3:24

that's what I wanted to do . That was the

3:26

direction I wanted to go in academia . So

3:28

I actually took a year off doing a variety of odd jobs

3:31

In fact , ranging from working in a department

3:33

store to being a taxi

3:35

driver , and

3:38

in the end there was a biotech

3:40

company that was starting in Sydney , australia

3:42

, just like they have in America . This

3:45

was a long time ago , so

3:47

it was in the early days , so this is in the 80s

3:49

, early 80s , and so I

3:51

thought , well , that could be interesting , let's try

3:53

that . So I got a job there and very

3:56

shortly after joining that I

3:58

was like , oh yes , this , I understand

4:00

this , I get , I love this . I

4:02

don't like academia and what is the

4:04

this that I was liking the this is

4:07

the teamwork , the fact that everybody

4:09

across the whole company is pulling together

4:11

at the same direction

4:14

and that the pace at which things

4:16

move are not limited by your own clumsy

4:19

fingers , but that ultimately , it's everybody's

4:21

hands working together that pulls things forward at an incredible pace

4:24

. So it's much more stimulating and there's a much stronger

4:26

sense of camaraderie across the whole organization , whereas

4:28

in academic labs you have these fiefdoms

4:30

you know my lab , you get your stuff

4:32

off my freezer shelf kind of mentality

4:35

, and so that

4:37

sort of team sport aspect of

4:39

science was instantly appealing . So

4:41

I was there actually for four years .

4:44

What was your role there , that initial first

4:46

blush with industry ? What was the role when you started

4:48

?

4:48

Well , I was a research assistant and I

4:50

got promoted to a senior research assistant at one point

4:53

. But it was back in

4:55

the cloning days where , you

4:57

know , ooh , you would clone

4:59

a gene and that was exciting

5:01

and that would be a big paper , that would be a big event . So

5:04

that's what we were doing , cloning and expressing

5:06

proteins in E coli

5:08

. That's what the world was

5:10

doing back then . So

5:13

at one point I thought all

5:15

right , maybe I want to do more than

5:17

this . You know what

5:20

would that be ? I considered various . I'm

5:22

doing this sort of career thing here . I

5:24

don't have to be going on quite so much about it , but I

5:26

think let's maybe Please do .

5:28

Yeah , it's good . It's good . I mean , you know

5:30

it's a frame of reference . We'll

5:32

fast forward if we need to . Okay .

5:37

So I was well , maybe I should

5:39

go do patent law , because there are very

5:41

few people who had a science and

5:43

patent law background . But in the end

5:45

I got some advice which is

5:47

some of the best advice I ever received in my life , which

5:50

is always pick the option that leaves

5:52

most options open . I've

5:54

used that piece of advice many times , and so I realized

5:57

that the answer to the puzzle then

5:59

was go get a PhD , because I

6:01

can still do everything I was contemplating on doing

6:03

. That was one of the things I was going to say I should go get

6:06

that , because it's also a terminal degree , there's nothing more

6:08

after that . So then

6:10

I launched off to do my

6:13

PhD and

6:15

then a postdoc at Harvard , but

6:17

the plan was to go back to biotech

6:20

. Originally

6:22

, when I left , I was going to back to sydney

6:25

, but then I kind of got stuck , ultimately

6:27

in the boston area , which is well , now there's

6:29

something up and coming , but it's now certainly the epicenter of

6:31

biotech in the world , and so , um

6:34

, basically I got stuck like a fly

6:36

to fly paper yeah , yeah

6:38

, so we'll talk about some of the

6:40

stops along the way , I think throughout the conversation

6:43

, uh , but but I'm going to hit the fast forward

6:45

button real quick here for a minute , because

6:47

you know you've had exposure to a lot of different

6:49

modalities , a lot of different areas of biotech

6:51

.

6:52

What was it that turned your interest toward

6:54

RNA ?

6:57

Well , it was basically

6:59

that every time I change jobs , I like

7:01

to do something different , and

7:04

the

7:06

opportunity came up to join Intelia

7:08

. I was working with Nesson Birmingham

7:11

, the original CEO of Intelia , on

7:13

another project this is

7:15

associated with Atlas Venture when

7:18

the possibility of getting Intelia going came

7:20

up and that was just a very appealing . You

7:23

know , editing was very new , it was very cool and

7:33

so it still is . It still is he , uh , was it was ? I would say it was so cool , it

7:35

was white hot um back then . Um . So yeah , I had the opportunity to join

7:37

a cso , which I did , but interestingly , everyone

7:41

in that space was thinking about doing cell therapy

7:43

ex vivo manipulated cells , because

7:46

that was technologically tractable

7:48

or doing some sort of viral

7:50

delivery editing and

7:53

so you had CRISPR therapeutics . That picked the first

7:55

one and Editas

7:57

was an exemplar of the second one . Now

8:00

, we certainly had at Intellia we had an alliance with

8:02

Novartis on the cell therapy , but we also

8:04

were trying something a bit kooky , which

8:06

is to try and do RNA delivery

8:08

through a lipid nanoparticle where

8:10

the editor

8:12

was encoded in a messenger RNA . The guide

8:14

RNA was also in the mix and

8:16

they would all get sorted out once they

8:19

got into a cell . One would get expressed . The protein

8:21

would find the short RNA . The two of them would

8:23

trundle off to the nucleus . Get expressed

8:25

, the protein would find the short RNA . The two of

8:27

them would trundle off to the nucleus , cut some DNA and do some

8:30

damage literally . And so that seemed science

8:32

fiction-y . But we thought we'd give it

8:34

a shot . And again now I'll press

8:36

fast forward . We got it to work

8:38

some years later and I think

8:42

ultimately when the first clinical results

8:44

came out in the summer of 21, . Obviously

8:48

it was international front page news

8:50

editing in vivo for the first

8:52

time , and we were the ones who showed

8:54

that such a thing is possible . Now of course everybody

8:57

thinks , well , of course you want to do editing that way . All

8:59

the other ways are so fiddly . But

9:01

before we started it was science

9:04

fiction . So

9:07

I wasn't drawn to RNA so much as I fell into

9:09

it .

9:10

Yeah , I'm curious about that , the science fiction

9:12

, white , hot , cutting edge , brand

9:15

new kind of attraction

9:17

. What is it about

9:20

Tom Barnes that makes him

9:22

how

9:28

tom barnes ? That makes him , uh , not like what's the opposite

9:30

of of a verse like embrace ? What is it about you that that that uh makes you want

9:32

to , yeah , drawn to , like how it takes a special person to embrace

9:34

something that is , so you

9:37

know , more dramatic than nascent right

9:40

, and make a career of it . I

9:42

mean , you could , yeah . Well , I guess I guess my point is you could

9:44

have done a bang-up job in antibodies , for instance , but

9:51

no , you chose to go do some

9:53

cutting-edge gene editing and get

9:56

into the RNA space . What is it about your

9:58

makeup that makes you embrace that ?

10:00

Well , I'm a risk-tolerant person , firstly

10:02

, and I understand biotech

10:04

. In other words , I don't

10:06

in my mind require each

10:09

attempt to be

10:11

. It doesn't have

10:13

to be a home run . I understand that we'll give this

10:15

a go , and

10:18

if not , if what I call a noble failure

10:20

ultimately , then you can

10:23

pick up and do something else . At least that's

10:25

my approach . So that's one reason why I'm risk tolerant to

10:27

that . But the other thing is I'm

10:29

very curious . I'm interested in a lot of things

10:32

, and so I do

10:34

. I think it's a bit of my makeup too . Maybe

10:36

I'm a sort of a science hipster . I

10:38

kind of go off the mainstream

10:41

and I like going counter-culturally

10:43

, cross-current or something

10:45

I don't know .

10:48

Yeah , that's interesting and

10:50

that feeds some of the questions I have around how

10:52

you establish a business here

10:55

in this space when you have sort

10:57

of a counter-culture approach

10:59

, like what perhaps difficulties

11:01

that might create for you ? Before we get

11:03

to that , tell us the gen

11:05

story of Orna . By the way , anna Rose , it's really

11:07

nice to have you here , because when I can't think of a word , anna

11:10

Rose is a I'll be your thesaurus . She's

11:12

a trained poet , so

11:14

she's very wordy yeah .

11:16

You're like a living . Sometimes wordy is not

11:18

great , though .

11:19

A living breathing thesaurus sitting

11:21

next to me in the studio . Yeah

11:24

, so tell us Orna's founding story . What got

11:26

things started there ?

11:27

Yeah , so Orna

11:29

has a very traditional start

11:31

in the sense of , if you go back to how biotech

11:33

companies used to go , so

11:45

it used to be that academics would discover something and they would start a company

11:47

and pull some sort of nascent team together and then try and get venture interested . Now , of course , these days , venture typically

11:49

goes and scours science directly from universities

11:52

and so on and builds the company to their own sort

11:54

of preconception . But all of it was really in

11:56

that old mold . So our

11:59

story goes back to 2016

12:01

or 2017 , dan Anderson of MIT

12:03

is listening to a talk on naturally

12:06

occurring circle RNA in China and goes , huh

12:08

, I wonder if that could be an

12:11

interesting variant on a theme . Of

12:13

course , moderna already existed at that time . 11

12:16

was coming through and it

12:18

had already been known for attempting at least

12:20

the RNA-based editing

12:23

, and Dan had a long history

12:25

in LNPs and RNA in any

12:27

case , and so he gave the task to

12:29

a graduate student , alex Wesselhoft

12:31

, who completely

12:34

blew it out of the water PhD

12:36

finished in three and a half years

12:39

, green thumbs at the bench and

12:41

solved the fundamental problem , which is

12:43

how can you make circles efficiently

12:45

at scale and large enough

12:47

to be useful and figure

12:49

out how to make them useful by getting them

12:51

to express things . So he did all that and

12:54

so that was the basis of IP

12:56

that was filed . And then they thought , well , there

12:59

should be some value here , and

13:02

so a company was formed . It wasn't called

13:05

, or called at the time , and um

13:07

, and they basically encountered

13:09

npm . Capital is now npm

13:11

biopact and uh , this

13:13

is in the 2019 , so

13:16

the first funding came in in mid 2019

13:18

, but part of that funding was a , a conception

13:20

that what this company

13:22

should do with its circles is

13:25

to see if it could figure out a way of doing an

13:27

in vivo thing , but

13:29

not editing at this time , because the RNA is going to

13:31

be transient . But can we get the RNA

13:33

into immune cells ? And

13:35

if we could , could we disrupt or

13:37

displace CAR-Ts and cell

13:40

therapy completely , because it would be so much more

13:42

convenient . So , in other words , there's a very high

13:44

science concept that

13:46

predates me , and it was really an idea

13:49

that came from NPM . And so money came

13:51

in and they started building

13:53

the team immediately

13:55

, with Alex on board , and

13:57

I started talking to NPM . I had left Intelia

14:00

earlier in 2019 . I was scouting

14:02

about things to do and I started talking to them in October

14:04

or so and we kind of sealed the deal in 2019 . I was scouting about things to do and I started talking to them in October or so and we kind

14:06

of sealed the deal in December , so I started

14:09

early 2020 .

14:11

And you had no idea that the world was about to

14:13

blow up and become all RNA all the time

14:15

.

14:16

Exactly , it was fated . I

14:19

like to think I had a crystal ball , but I did not . Nobody did

14:21

, yeah , I did not .

14:22

Nobody did .

14:23

Yeah .

14:25

It is RNA all the time

14:27

. And how many

14:30

letters now precede RNA

14:32

across the spectrum ? Quite a few . There's

14:34

quite a few , yeah .

14:34

Letters . Coding , non-coding

14:37

, that's one of the things I think that's cute about

14:39

the term we invented for what we do . I think that's cute

14:41

about the term we invented for what

14:43

we do . There's something that I noticed

14:45

early on is that up until that time

14:47

certainly

14:50

in the papers that Alex and Dan had published and in the early materials it was called Cirque

14:52

RNA , because C-I-R-C lowercase , because

14:54

that's what it's called , that's

14:56

the standard abbreviation . But I realized

14:59

almost immediately that people get confused . They look up

15:01

Cirque RNA and there's thousands of papers , there's

15:03

a lot of papers on circRNA , but none

15:05

of that is relevant to what we're doing , because

15:07

ours is completely synthetic . We're not

15:09

extracting circRNA cells

15:11

. We're making it in vitro , designed

15:14

to exactly encode exactly what

15:16

we want , and it's made in a different way than

15:18

it's made in vivo . It just in the end looks like a circle

15:21

. So we need a branding for

15:23

what this is , and I remember being

15:26

at a bar one Friday as one is .

15:28

That's where all the great ideas come from .

15:30

I was actually thinking of a name of the company as

15:32

well . Actually , really , that's what I was trying to do and I thought , you

15:35

know , moderna's kind of cute because it's like mode

15:37

RNA and they're abbreviated mRNA

15:39

and I thought we need something

15:42

, what

15:45

could be RNA , is there an RNA , something we could call the company ? And

15:48

I thought , well , I don't know , o-r-n-a

15:52

. I thought , oh , that's cute , because then

15:55

we could call it also O-R-N-A , where the O just means

15:57

circular . It doesn't stand for an O word , it just

15:59

means circular , and so that was just born

16:01

in a flash there , and so

16:03

we was just born in a flash there , and so we changed .

16:04

The important question is what were you drinking at the

16:06

time ?

16:08

I think , it was probably a beer , all

16:10

right , so

16:15

that's when the name came

16:17

in . So that was shortly

16:19

after I started there .

16:21

Yeah , I'm going to ask both of you

16:23

guys to unpack for me a little bit the

16:26

advantages , differences between circular

16:29

RNA , mrna and , specifically in Orna's

16:31

case , synthetically produced RNA

16:34

. We

16:36

could go long in this conversation . I don't want to go too long . This is

16:38

the business of biotech . It's not the science of biotech

16:41

. But for our listeners'

16:43

benefit , maybe just more color on

16:45

where O-RNA fits in

16:47

the landscape , the landscape that we've

16:49

seen linear RNA for quite some time

16:51

.

16:52

Yeah , well , the thing

16:54

that intrigued Dan back in the day

16:56

was that even to

16:58

this day , people don't really know what naturally occurring circles

17:01

do . There's a number of theories , but to

17:03

my instinct , I don't think any

17:05

of the theories have really nailed what they're circles do . There's

17:08

a number of theories , but to my instinct , I don't think any of the theories have really nailed

17:10

what they're there for . It doesn't quite feel right

17:12

. But the one thing that people know is that naturally occurring

17:14

circular RNAs hang out in cells a lot longer than the linear

17:16

RNA counterparts . Particularly , even , especially

17:19

, if it's derived from the same gene , the circular piece

17:21

is more long-lived than the linear piece

17:23

, so circles live longer than lines . Um

17:26

, and so that was really what dan said . Well , okay

17:28

, if you could do a whole technology based on circles

17:30

, you'd have , you'd be better . Well , you know

17:32

, longer half-life is better and that's

17:35

so . We've gone on to show that that's true and

17:37

I think it's been shown now in multiple people's hands

17:39

. Um , but what we

17:41

discovered along the way is that circular

17:43

RNA . I call it the gift that keeps on giving

17:46

, because it continued to

17:48

show these unexpected advantages

17:50

of mRNA and

17:52

the way . I would summarize it again , coming

17:54

back maybe to the business and less on the science is

17:57

that if , if

18:00

the world could make circular

18:02

RNA the way we make circular

18:04

RNA for products , nobody

18:08

would make linear RNA products

18:10

anymore , because

18:12

circles have advantage

18:15

upon advantage over lines and

18:17

no disadvantages . There's no trade-off

18:19

. There's basically fewer

18:22

better , more bits and

18:24

pieces to get a circle to work

18:27

than there is for

18:29

a line . It's funny because of course

18:31

the mRNA is our RNA

18:33

. It's how our structures are encoded . So naturally we try and mimic

18:35

that in the product and no one knows what circles do

18:37

. But as a biotechnology , as

18:39

a product , the correct answer is circles

18:41

. It's not the way we do it , but the

18:43

correct version of a product should

18:45

be a circle , because it's more stable

18:47

, it's easier to make , it's far

18:50

cheaper to make , it's made at high yield

18:52

, you can make them much larger , you

18:54

can express them much higher , they hang out in

18:56

cells much longer and they package much

18:58

more efficiently in the lipid nanoparticle

19:00

at the end of the day . So

19:02

they're just better

19:05

in every way .

19:06

Yeah , what's the take

19:08

on the market right now in terms

19:10

of other companies that are looking to

19:12

develop and capitalize on circular RNA

19:15

? I mean , are you one of a few , one of many

19:17

? You

19:20

can make him honest on this . Andrew , you

19:22

cover the space . You follow the space .

19:24

There's no one else like him . It's getting hotter and hotter

19:26

.

19:28

It's getting hotter and hotter . I think we were first

19:30

out there with these claims , and

19:32

then , I think , many people have come along and corroborated

19:36

the claims I think to their own satisfaction

19:38

, so I think we've got to get in on this action . The

19:45

thing is , though , that there's , as far as I'm aware , there's only one way

19:47

of making circles efficiently , and that's the way that Alex

19:49

discovered in . Dan's lab and we have

19:52

an exclusive license to that . So

19:54

now , having said that , there's more than one way

19:56

to make a circle and you can make it inefficiently if you wish

19:58

and if you in the end had a , you

20:00

know , one gram of circle made this way and one

20:02

gram made that way , it's still a gram of circle . At

20:05

that point , then it's what is in code . What are

20:07

the other differences in the molecule ? But

20:10

you know , in terms of ease and efficiency , I

20:12

would say ours is made in one step . To

20:14

be clear , there's no capping

20:17

, there's no tailing . There's a single

20:19

enzyme , which is the polymerase . There's no capping

20:21

enzyme or tailing enzyme . So there's

20:23

no mods . We

20:28

don't need mods because circles purify more readily

20:30

from the contaminants in the in

20:32

vitro transcription reaction , for which you

20:34

need the mods . So if you don't have

20:36

the mods as contaminants , then you don't need the mods

20:38

at all . And mods are much more expensive than regular

20:41

nucleotides . So our cost to make a

20:43

gram of finished stuff is like one-tenth to one-fifteenth

20:45

of mRNA .

20:47

Yeah they're so real . Yeah , there's

20:49

some really nice supply chain benefits

20:51

to working with circular RNA and I think

20:53

, too , just the field talks

20:56

a lot about the clinical benefits as well , or

20:58

the hopes for clinical benefits

21:00

in the future , right , in terms of overcoming

21:02

some of this , just the stability , the durability

21:05

limitations that we've seen with linear mRNA

21:07

. So I've been watching it . Really

21:09

I've

21:16

been watching it with a lot of anticipation to see where it goes , because

21:18

I have been watching sort of the numbers of pipeline products

21:20

right start to creep up in the circular RNA

21:22

space . It's getting some more respect and some

21:24

more attention . And I really liked

21:26

what you were saying earlier too , because you

21:29

were talking about it , sort

21:31

of the iterative innovation that

21:33

the entire space is sort

21:35

of going through , and how you approach

21:37

failure and the challenge of

21:39

working in a potential area

21:42

that still has yet to really find its future

21:44

. I think the RNA space as

21:46

a whole , particularly on the encoding side

21:49

, right , your mRNAs , your self-amplifying

21:51

, your circular still have a long

21:53

ways to go , right , I think , in terms

21:55

of efficiency of development

21:57

and their biological impacts

22:00

, right . So I'm really curious

22:02

to kind of pick your brain on

22:04

how heading up in

22:06

a circular RNA company is

22:08

challenging today , right , especially

22:11

since we are still trying to figure

22:13

out I always kind of call

22:15

it the mRNA identity proposition

22:17

right Within the advanced therapy space

22:19

within the biologic sector . How

22:22

do you , you know , how are you navigating some

22:24

of the risks of working with a very novel

22:26

technology today , and how does that

22:28

impact your leadership

22:31

strategy of a company

22:33

that's kind of been paving the pathway for this

22:35

modality ?

22:38

Yeah , I mean , the risks we embraced

22:40

are substantially more

22:42

than the ones we've been talking about , because , as

22:45

I mentioned , the first thing we were meant to do was

22:47

go find a way

22:49

, a lipid , a particle , which would naturally

22:51

deliver to immune cells . Such a thing did

22:53

not exist , such a thing was never

22:55

suggested to have even been possible . Everyone

22:57

kind of thinks these things go to the liver as a default . So

23:00

not only were we trying to develop circles

23:02

as a novel payload and

23:05

promulgate the idea that

23:07

they don't need mods , which is iconoclastic In

23:09

fact , you know , a Nobel Prize has been given on

23:11

the need for mods and there we

23:14

are saying , well , you don't actually need them if

23:16

you use circles . I'm not saying

23:18

it wasn't a great idea . You know I myself

23:20

have received linear RNA vaccines

23:22

, but it's an interesting point . Technology

23:25

evolves , but we're trying to do this thing with delivery

23:27

as well . We were doing

23:30

two things . So you know , my feeling

23:32

was , yeah , this is not going to work . I

23:38

love the honesty , but you

23:40

know so , how do you do that ? Basically , it's exciting what you're

23:42

trying to do . The vision is there , yeah , and some people are always drawn . Basically , it's exciting what

23:44

you're trying to do . The vision is there , yeah , and some

23:46

people are always drawn to that , to that exciting possibility

23:49

. They're risk tolerant , I guess , like I am . That's always true in

23:51

the early stages of a startup . I mean , npm

23:53

was a very good , a very solid

23:55

name in terms of the venture banking , so there was good

23:57

funds available . But you

23:59

know , you also have to have a backup plan . Okay , what

24:01

do I do if this doesn't work

24:04

out ? And

24:06

so we had all that . But in the end we actually got it

24:08

to work and so

24:11

that was an amazing day that

24:13

we could deliver to immune cells and they

24:16

would take up the circles . The circles would

24:18

express , they would produce a CAR protein

24:20

on the surface of T's and NKs

24:22

and macrophages , and then those cells

24:26

would go and attack other cells in

24:29

the animal , just like a car T

24:31

does . So that was pretty , pretty

24:34

amazing and you know , we showed that . So

24:36

we , you know our innovations were not only academically

24:39

that we showed how to make . I'll be this

24:41

is a broader way . Of course , this is Dan's

24:43

lab , but you know Orna and its origin

24:46

story , you know , showed how to make circles . That

24:48

was possible . We showed how to express from

24:50

circles . We showed that it was possible to find

24:53

an immunotropic lipid . We showed the value

24:55

proposition behind doing that and what

24:57

you would do to get that to work . So we have

24:59

blazed a whole series of trails

25:01

as we've pushed into this

25:03

and you

25:06

know , one of the

25:08

challenges obviously when you start out is

25:10

also that it's very hard to be noticed

25:12

. And Squid Company is being started

25:14

all the time and when

25:18

I was at Intelia it was a luxury because

25:20

you'll notice editing

25:23

. You know everyone would

25:25

notice every single thing you would do People

25:27

lining up around the block to join the company

25:30

. It's like you could pick and choose whoever you want

25:32

to come . It was that

25:34

intense and

25:38

RNA was still very you know , it was very hot at the

25:41

time . As you know , the pandemic had started and there was

25:43

something with the vaccines , but

25:45

you still , you know you try

25:47

and be noticed and one of the things that

25:49

was surprising I still don't really understand to this day

25:51

is that the idea that the RNA could be circular

25:54

seemed to capture the

25:56

imagination of reporters

25:58

or people who like to write about it . It

26:01

wasn't like oh , we've got a different cap structure

26:03

or we do mods a different way , or

26:05

something like that . No , the RNA is circular . It

26:09

just seemed intriguing

26:11

enough that we got noticed early enough

26:13

, and because we were sort of the first one out there and

26:17

because it's right there in the name , we

26:20

kind of became I don't want to say synonymous , but

26:22

we certainly became like the name in the

26:24

space . So it was a little bit of luck

26:26

.

26:27

Yeah .

26:27

Being hot , a little bit of sort of marketing , yeah

26:30

, but there was also that inexplicable

26:32

. I don't know why circles capture the

26:34

imagination , but they just do .

26:36

They're so poetic .

26:37

They're so poetic , I mean yeah .

26:39

And you're ornicorns . I mean , come on

26:41

, you

26:45

know the and your ornicorns I mean come on . The myth is just baked

26:47

into your company .

26:52

You talked about being first on the scene . It's funny . I was just thinking about an episode that dropped

26:54

a few weeks ago , an episode of the Business and Biotech that I named the Innovator's Dilemma

26:56

. It was with a friend of mine , brian

26:58

Finrow , at Lumen Biosciences , and we talked about

27:00

that concept of being first

27:02

on the scene with a new technology or a new approach

27:05

and how it creates awareness

27:07

. Potentially inherently right

27:09

, it's something new , but

27:11

it can also create tension

27:13

. It can create challenges

27:18

. Have

27:21

a good , strong partner there , but I

27:23

guess take us behind the scenes a little bit around

27:26

. When you're revealing

27:28

something new to the community not just

27:30

the scientific community , but the investment community

27:32

what goes into

27:34

ensuring that you're winning

27:36

the funding you're going to need to move

27:39

forward and hit milestones ?

27:42

Yeah , I think it has to be milestones

27:49

. Yeah , I think it has to be the logic of the idea , I might

27:51

even say the logical ineluctability of

27:53

the idea . The premise here was that cell

27:55

therapy is fantastic from an efficacy

27:58

perspective , but

28:00

it's so cumbersome , so difficult , so challenging

28:02

for patients that have to be managed so intensively

28:05

, that there's the cost of the therapy and then there's the

28:07

adjunct costs of just administering and

28:09

managing the patient during the administration

28:11

of the therapy and the risk associated with

28:13

that . And so the idea

28:15

was well , if you could just

28:17

do the manufacturing inside the

28:19

patient not at the bedside

28:21

, actually , just in the patient that

28:24

would make everything go away , and that's self-evidently

28:27

true . The idea that if

28:29

only you could , then that would be

28:31

great . That's an easy sell , because

28:33

that's obviously true . The question is well

28:35

, how the heck do you do that ? At

28:38

least our attempt , which in some

28:40

ways didn't have to work , but it was a shot

28:42

on goal , and there are , but there was

28:44

no name for what we're trying to do Now the field is called

28:46

in vivo CAR or in

28:48

vivo CAR-T , so there are some groups

28:51

that are trying to do it through adapted viruses

28:53

, where the viruses will deliver

28:56

, will do the job of delivering . Now , of course , they

28:58

tend to then integrate into

29:00

the genome . Some viruses don't , but

29:02

, like lentivirus , vectors

29:04

will integrate and ours is um

29:06

, transient , but it's redosable

29:08

, which a lentivirus is not . So

29:11

, um , uh , when

29:15

you um get to that point

29:17

of showing

29:19

that it works , the value

29:21

proposition is self-evident . Okay

29:23

, it's like , if only you could do this like teleportation

29:26

, yeah , that could be useful . Okay

29:28

, can you do it ? It's like you do a

29:30

little demo . I don't have to explain what you would

29:32

do with teleportation . You can take your mind

29:34

, can take it from there . So I just have to show you

29:36

look , particle , animal boom

29:39

, cells gone , tumor gone

29:41

, people go , I like

29:43

um

29:48

tumor .

29:48

Uh , people go , I like um here's money . Yeah , here's money , matt . We , we really

29:50

picked the wrong career .

29:52

I feel like I picked the wrong question . Dr

29:58

Barnes's answer was like well , I mean cause it works , dummy people

30:00

. You're

30:25

millions of dollars . To me that's kind of mind-blowing . Like you know , car-t

30:27

is still new and if you talk to CAR-T people they're telling you like

30:29

, oh , we haven't yet scratched the surface of the indications that we can

30:31

tackle . We're making great progress

30:34

in solid tumors and so on and so forth . So

30:37

I'm curious about your perspective of how the CAR-T

30:39

community might , I

30:41

guess , receive Orna's news

30:44

that

30:47

Orna thinks it can kind of leapfrog Carti

30:49

. And specifically , how would Dr Carl June

30:51

feel about the prospect

30:54

.

30:55

Our Series A was interesting because

30:58

every new

31:00

investor we had venture investors up until that point , but

31:02

every new investor we had in the Series A

31:04

was a pharmaceutical company

31:06

that was doing cell therapy Interesting

31:10

. So in other words they were saying

31:12

we too see

31:14

the value proposition and we wish

31:16

to be close to this story in

31:19

case it works out . So

31:24

I would say embracing the potential

31:26

. And obviously

31:28

, in some ways it's a competitive

31:30

technology to CAR-T

31:32

and it's much more

31:35

pharmaceutical in a way . Whereas

31:37

CAR-T is a living drug , it will expand . You can't

31:39

really control it , whereas this you can

31:41

control the dose . It has a a half-life

31:43

, it has a maximum concentration

31:45

which then fades over time and

31:47

that's a function of the dose that you give . So

31:50

there's much more like a traditional pharmaceutical

31:52

in that way , and

31:54

so many . So there's

31:56

car t companies that of course want to defend

31:58

their turf and their franchises , but

32:00

there's also many things about um this

32:03

that would be appealing to a

32:05

pharma player that isn't in cell therapy

32:07

, because those who might have found cell

32:09

therapy a bit fiddly would

32:11

probably find LNPs , whilst more fiddly

32:13

than a small molecule , a lot less fiddly than

32:15

a cell therapy .

32:17

I think that's an interesting point too , because

32:20

we live therapeutically

32:22

within the AT&P space right now

32:24

. Right , and so everything's

32:26

kind of been marketed or positioned

32:29

as this one and done right , which I think

32:31

can have sort of a sexy

32:34

bit of allure . Right , especially for a

32:36

therapeutic that can be very expensive

32:38

. Right , the prospect of a

32:41

durable , you know , potential

32:43

cure . Right , it's not everything approved

32:46

has been curative , but that one and

32:48

done does have some appeal to it . I'm

32:50

curious to you but the fact

32:52

that I think too

32:54

, investors can be aware

32:56

of if RNA is a chronically dosed

32:58

therapy that fits , similar to a biologic

33:01

. Right , that sort of that risk

33:03

proposition is understood . Right

33:05

, it's well known . But I'm curious

33:08

, do you find that navigating

33:10

the funding today has changed

33:12

at all ? Right , I mean , as more players come

33:14

into the space , with RNA as

33:17

the space , we're not mature by

33:19

any sense of the word , right , but as we

33:21

have moved beyond the pandemic

33:23

realm , you know , are you finding

33:25

that you know there

33:27

is investors are interested in different

33:29

types of information or data ? Or

33:32

, you know , has getting funds become

33:34

more challenging in any way ?

33:38

um , it's an interesting question

33:40

, I think . Um , you know

33:42

, as a company progresses through

33:44

its stages as this , as its own

33:47

story advances , its pipeline advances

33:49

, then what you want from or need

33:51

from the funding , uh , and the scale

33:53

of funding you need , it inherently changes

33:55

. So you're not appealing to the

33:57

same necessarily . You start with a

33:59

venture , uh appeal , and

34:02

then later on you're

34:04

appealing to different kind of later stage

34:06

investors and ultimately pre-public

34:08

investors and ultimately public investors

34:11

, and these investors

34:13

are all looking for different things , different

34:15

proof points . They

34:17

typically you can probably distinguish them based

34:19

on their own risk tolerance

34:21

profile , where they feel their sweet spot is and where they like

34:24

to get in . In

34:27

terms of our story , our story resonates

34:29

. In the case of Orna it resonates pretty well

34:31

. What we're trying to do is

34:36

relatively differentiated , so it's

34:38

not just the name that people remember , but they do

34:41

tend to recall that we're doing

34:43

what we call now pan car , because

34:45

our , our lipids don't

34:47

just deliver to t cells . So if you have a lentivirus

34:49

it's going to find the t cells because it's a t

34:51

cell tropic virus , whereas our

34:54

particles are , um , pan

34:56

lineage , they go to t's , nks

34:59

and macrophages and so

35:01

, uh , to the point that uh , people feel

35:03

cell therapy have only scratched the surface . Yes

35:05

, you have some people doing CAR-T's . You have some people doing

35:07

CAR-NK's Our whole company

35:09

is doing CAR-MAX CAR-M's

35:11

. Well , we do

35:14

all three with one injection . We

35:16

create all three with one injection

35:18

. So

35:22

that's why we call it pan-CAR rather than and we call it in vivo-CAR rather than in vivo-CAR-T

35:24

, because we're reaching all the effective

35:26

lineages in the immune system . So

35:29

you know , people like that and the

35:31

potential that we could do

35:33

something in solids is there without having to change

35:35

anything of what we do , because we're in the macrophage

35:38

already

35:40

. We just have to think

35:42

about what the target is . What

35:44

does the car target ? But

35:47

there are companies out there already trying to

35:49

blaze a trail in car max space . We're

35:52

content right now to be looking at relatively

35:55

tried and true targets . This is one of the

35:57

, I think , rules of bringing

35:59

new technology forward is you don't want to stack

36:01

your risk , you don't want to try new biology

36:03

and new technology . So

36:05

our technology is new . So we are

36:07

using a fairly vanilla target Helps

36:10

us compare and contrast , but it also helps

36:13

everybody understand what

36:15

you have in that way .

36:19

That's an interesting point . We've been

36:21

spending a lot of time talking about upshot . I'm

36:23

curious , dr Barnes , what , what you're like if you

36:25

do a risk analysis , uh , of

36:27

of the company between now and your next

36:29

, like big , important milestone , what , what

36:31

could go wrong ? I

36:34

mean she laughs Cause

36:36

, like you know , a lot

36:39

.

36:39

All of the things that can

36:42

go wrong can go wrong . Yeah

36:44

, there's a large number of them , you

36:48

know , I think LNPs are no different

36:51

. Rna is no different . You

36:54

can have timing delays , you can have manufacturing

36:56

snags , you can have translation

36:59

issues . You know , ultimately , whatever

37:01

you've seen , you get a different result in

37:04

people . Um , you know

37:06

, it's it's drug development . Yeah

37:08

, it's , it's a . It's

37:10

a low probability business , from

37:13

where you start to the chances that you'll

37:15

get an approval . Um , right , you

37:17

have to start so many threads

37:19

so that one of them is going to make it all the way

37:22

through . But you

37:24

know , you try and shorten your rods by getting

37:27

the right kind of proof points in animals in

37:30

vitro ahead of time . You

37:32

shorten your rods by using a known biology

37:35

. But yeah

37:37

, there's many things that can go .

37:39

I probably should have qualified the question a little more

37:41

. I liked it , it was a good question . It probably should have qualified the question a little more . I would

37:43

I mean , you know Liked it , it's a good question .

37:44

I mean , it's a great question With a lot of different answers

37:46

. We don't know enough about it , that's for sure .

37:48

Yeah , If I were

37:50

to narrow that question , though , I probably would have

37:52

asked like organizationally structurally

38:16

.

38:16

you know , in terms of people , talent , manufacturing

38:19

capacity , like assuming the science goes as well as science does during

38:21

drug development what that's within your control as the captain

38:23

of the ship , are you potentially anticipating a challenge around

38:25

? Well , there's a lot of good companies competing for talent , so everything that

38:27

happens is done by the people in the company . So you have to be good

38:29

at I mean as a group , as a company , as attracting talent

38:31

, and when people are here , it's

38:33

got to be an environment where they like to stay . They

38:36

can always leave . You know

38:38

, the best retention

38:40

tool that you have is have people not

38:42

want to leave , not , you

38:45

know um , golden handcuffs

38:47

or other sort of perks . Just create

38:49

an environment where people feel um

38:52

, seen , heard , appreciated

38:54

, where they feel they um

38:57

, you know , they participate

38:59

, they understand what's going on . Something I've

39:01

always striven for is transparency , as much

39:03

as I can , so that everybody

39:06

has a common sense of what we're doing , where

39:08

we are , what's going on . I

39:10

mean , obviously there are limits , but as much as I can

39:12

, and I think that tends to

39:14

help people buy into the

39:16

mission . One of the things that people often say after

39:19

they've interviewed here is that everybody

39:21

said exactly the same thing in

39:23

terms of what we're doing , what the mission is . There's

39:26

no duality or multiplicity

39:28

of views , because we

39:30

all have the same , we have a common view

39:32

. So I

39:34

think that's . People talk about culture

39:37

as being important . I think it often comes across sounding

39:39

very platitudinous , but I think culture

39:41

is very important in terms of retaining

39:43

people , because when you're in a good one , you

39:45

know it , and then you know

39:47

things do go awry or sideways

39:50

from time to time , and that is that

39:52

is when the true value of culture emerges

39:54

, because that's if , if , if , like

39:56

. Well , I'm here because you know the

39:59

pay is good and we're on a ride . I'm'm waiting for my stock

40:01

to vest . Then it goes south . It's like , oh , my

40:03

stock isn't worth anything . Well , everybody's out the door

40:05

. I mean , if it's a place that people don't want to be

40:07

at , but if it's a place that people

40:09

do want to be at , they say well , you know what , I'm

40:11

going to stay , I'm going to see this through .

40:26

And that I think of having a place where people like to work . You mentioned it's a competitive space

40:28

to find talent . Is that more specifically so when you're

40:30

dealing with circular RNA

40:32

? Or are there transferable

40:34

skills , perhaps from people who've

40:36

worked in other labs and other modalities

40:38

?

40:39

Oh sure , there's

40:43

plenty of transferable skills . Um rna is rna

40:45

is still um hot . So you , you know it still

40:48

, I think attracts um talent

40:50

. Circular rna perhaps a

40:52

little better um than

40:55

regular , another regular

40:57

linear rna company , unless it's an editing company

40:59

. I think editing still has cachet in

41:02

that way . But

41:05

yes , it would be different

41:08

if we were doing a

41:10

new kind of small molecule , a new kind of chemistry

41:13

, or it's an old kind of chemistry but

41:15

a new kind of target that we've chosen here to take

41:17

biological risk because , hey , we found new

41:19

targets . That's what we're going after , that's the what

41:21

we're going after . That's the hypothesis we're going

41:23

to test when we get to the clinic . That

41:29

is , I think it's just unless

41:31

you're good at telling the story or there's something really compelling

41:33

that tends to inspire

41:36

a little bit less readily than

41:38

you know . Gee , whiz technology

41:41

, yeah .

41:45

I'm going to shift gears here . A little bit , time flies when you're having fun . You

41:47

know we are going to run short on time , so I'm going to

41:49

shift gears . I I'd like to give you an opportunity

41:51

to talk a little bit about your partnership strategy

41:53

. I think you mentioned you found you

41:55

found solid support from pharma

41:58

. You know biopharma companies and you've

42:00

got specifically partnerships with Merck and

42:02

Renegade Therapeutics , maybe others . So

42:06

share a little bit about those partnerships and what sort of

42:08

your strategy , as the leader at Orna

42:10

, has been in establishing those partnerships

42:12

.

42:14

Yeah . So the strategy ? I think that

42:17

noise is not coming through . The

42:20

strategy

42:22

really derives from the fact that we have

42:24

a true platform . People

42:27

like to say they have platforms and investors like

42:29

to invest . Everybody , everybody

42:31

, says they have a platform . Investors like to invest in platform

42:33

because it means if the first thing doesn't work , you've got a second

42:35

thing . The alternative to a platform is a single

42:38

asset play , but it turns out

42:40

that's not a binary thing . Platforms

42:43

, or at least an approach , which give two or three products

42:46

okay , that's most things . It's

42:49

less common to have a platform that could really do

42:51

a vast number . Editing was one , certainly

42:53

, because a lot of the liver targets

42:55

were all picked over , but in the early days it was all

42:57

there . It was all there to be done , and

43:00

it's almost like this embarrassment of riches , of the number

43:02

of things you can do . And the same is

43:04

true for RNA , for our approach . I

43:08

mean , we have fewer people than Moderna

43:10

, but we are doing fundamentally the same

43:12

thing as Moderna . We are putting a long

43:15

coding RNA into a particle and administering

43:18

an IV . That's what they're doing . Our

43:20

RNA has a different shape and we have other

43:23

advantages . We think that we can do it , and their

43:25

delivery is different than our delivery , and that's a fundamental

43:27

thing . The

43:30

topology of the payload matters . Lines

43:32

versus circles , I argue

43:34

circles are better , but they're not necessarily

43:36

the killer app . Back here , I

43:38

think the real killer app is the delivery

43:40

. We were the first to show immunotropic

43:42

lipids . Now everyone's looking for them and trying

43:45

to replicate what we've shown . But until we

43:47

showed it it was possible , no one was really doing

43:49

that . So , in

43:55

terms of partnerships , then you look across all

43:57

the things you could do and there's like

43:59

oh , there's so many things that you

44:01

can do and and you can't do it all . I think the mistake

44:03

a lot of companies do is say mine

44:05

, mine , mine , we're going to do it all . Um , but

44:08

uh , you know , I've one of

44:10

the things I like to say . I like

44:12

to challenge people is how many products

44:14

does it take to make a successful biotech company

44:16

? It's just one . So

44:18

you know , how many of these things do you really

44:21

need ? So it kind of defies the partner strategy

44:23

. We pick the area we declared we're

44:25

going for in vivo car . That's what we're going

44:27

to do and we will . This

44:30

doesn't mean the partner is off the table , but the kind

44:32

of partnership we're looking for is going to be very different , more

44:34

selective , narrower , and

44:36

everything else that we can do . We'll

44:39

partner that . We'll partner that out , we're opening

44:41

to partnering that out , and so

44:44

that is the basis of the Merck

44:46

relationship , which is primarily focused on infectious disease

44:48

. So

44:55

we weren't going to do anything in that space , particularly we were a little bit late

44:57

to the party . But even before the pandemic we were founded not to do

44:59

vaccines . We were founded to pursue

45:01

in vivo care . That's what we're doing Now

45:05

. The relationship with Merck goes a little bit beyond infectious

45:07

disease as well . I think they have had relationships

45:10

with other linear RNA companies

45:12

and so they have an interest in this space . So it

45:14

goes a little bit beyond that . In

45:17

the case of Renegade , renegade was a company that also

45:19

came from the same stable . It's another

45:21

NPM company . It was founded

45:23

about two

45:25

years after us and it

45:27

was going to address the delivery question

45:29

. So it's going to be delivery focused

45:32

, not payload focused . It was going to be relatively

45:34

payload agnostic and

45:36

so you know , we thought

45:38

, well , okay , we could always use some cool

45:41

new delivery . So

45:46

that was the with Renegade , as they were building

45:48

things out . Now , of course , one of the

45:50

places they started to see is , could

45:52

they get a better vaccine

45:54

lipid ? And so

45:56

, you know , the relationship

45:58

with Merck came along at a time when we already had some

46:00

early hits out of that , and

46:04

so the Merck deal is actually a three-way deal

46:06

between Warner

46:08

, merck and Renegade . But

46:13

, yeah , we continue to work with Renegade on

46:15

other things . So there is another deal with

46:17

a Chinese company called Simnova

46:20

, which is a member of the Simsea family , and

46:23

that was an opportunity to , from

46:25

our perspective , firstly doing excellent work there , discovering

46:28

novel binders , novel CAR proteins

46:30

with their clinically validating cells , so

46:32

it was a way to potentially get access to that , but

46:34

also to get access

46:36

to accelerated clinical evaluation through

46:39

a particular setup that they have in

46:41

China called investigator-initiated trials

46:43

. It's something that

46:45

most Chinese companies do and

46:48

something that we could do with

46:51

them in our collaboration

46:53

, so that was appealing to us as well . I

46:56

like to think we were already thinking globally , but

46:58

actually there was a

47:00

practical angle to that

47:02

.

47:03

Yeah , yeah . What about clinical

47:06

opportunities in Australia ? That seems to be all the

47:08

rage right now .

47:09

Absolutely absolutely , in terms

47:11

of not so much the investigative initiator

47:14

in terms of formal evaluation . The

47:16

Australian environment

47:19

is obviously a top-notch medical

47:22

society , medical healthcare

47:25

society . It has typically

47:27

simpler review

47:29

processes , shorter times and

47:32

there's a particular interest in drawing

47:35

RNA investment into

47:37

Australia by governmental agencies

47:39

. So there are various financial

47:43

incentives of going down there as well .

47:45

Yeah , it's positioning

47:47

itself quite nicely as a hub . Over

47:50

the past couple of years , it seems

47:52

like there's a lot of really exciting mRNA stuff

47:54

going on in Australia .

47:55

We don't want to hype it too much . Well

47:58

, we drew Dr Barnes to Boston

48:00

. We don't want to lose him to Sydney

48:02

. In

48:08

the time that we have left , let's talk about where the space

48:10

is going .

48:13

I've been somewhat obsessed , so I'm going to selfishly

48:16

ask the next question because I'm really curious

48:18

to hear your answer . I feel like I might already

48:20

know it , just given your love of

48:22

RNA , circular RNA , but

48:24

I'd really love to . You know , I often

48:27

am talking about the RNA toolbox

48:30

, the identity proposition that

48:32

the different modalities can play within

48:34

the broader biologic space , even just within

48:37

the mRNA sector as a whole . Right

48:39

, you know , moving from , I think the space

48:41

in general is moving towards some of these next

48:43

gen modalities more regularly , away

48:45

from the linear mRNA for a number

48:48

of different reasons . But I'm curious

48:50

to hear you know how you

48:52

foresee circular RNA really fitting

48:55

into , or perhaps dominating

48:57

, you know , do you see it fitting into more as

48:59

one tool right in the toolbox

49:02

, applicable , you know , kind of , only

49:04

in very specific use cases ? Or do

49:06

you see it being used in

49:09

partnership with a lot of different mRNA therapies

49:11

and biologics ? Or do you just

49:13

kind of see it dominating the space

49:16

, right ? Does it become the one to

49:19

throw in a Lord of the Rings joke

49:21

, the one ring to rule them all ? I

49:24

mean , you're welcome to steal that as

49:26

well , by the way , but we might get

49:29

in trouble with the Tolkien .

49:35

You know it's an interesting question . So

49:40

right now there are certain IP barriers

49:42

to getting into circular RNA , but

49:44

in the academic world , of course , they're

49:47

free to do research , and

49:50

I think there's a lot of circular

49:52

research going on right now , using

49:54

the method that Alex and Dan invented , because

49:56

it's just so easy and they don't

49:59

have a constraint that way . It's just so easy

50:01

and they don't have a constraint that

50:03

way . So there's going to definitely be ongoing

50:05

research with circles

50:07

, on what you can do with circles . The main limitation

50:10

, though , the thing that will limit

50:12

its reach , is how many different delivery

50:14

solutions you can . If all you have

50:16

is liver delivery , it doesn't really

50:18

matter , at the end of the day , whether it's a circle or a line

50:20

. You might get slightly different performance . It doesn't

50:22

really matter , at the end of the day , whether it's a circle or

50:24

a line . You might get slightly different performance . But what

50:26

is really going to push things forward is the delivery

50:28

question , and

50:31

at that point , if you were forced

50:33

to suffer with a mere linear RNA

50:35

but you had a very , very cool new delivery

50:37

, you can make fine products with that , and nothing's

50:41

prevented in that way . Mind

50:46

you , if you had the circle , it would just be

50:48

easier and better

50:50

. So I think people are going to continue studying natural

50:52

circles . That still is a bit of a mystery what they're

50:55

doing there . I think people are going

50:57

to do some technical innovations . An

51:03

area where we've been focused technically on the circle side is how you get

51:05

expression , because there is no cap , there's no end to the RNA

51:07

, so you have to mark the start

51:09

of the protein with a different

51:12

sequence element . Now single-stranded

51:14

RNA viruses use a trick

51:16

to do that and that's where we're drawing our inspiration

51:19

from . But we've been doing I

51:21

think we've been leading in that that space . We've been the first to

51:23

really explore that in more of an omics way

51:25

, and so we're um

51:27

, we're really trying to define the universe

51:30

of possible ways

51:32

of expressing , at least as already

51:34

um instantiated in

51:36

nature . Obviously you could go to random

51:38

sequences , but amongst those that are out there and

51:41

there's a lot that are are out there . So it is a little

51:43

bit daunting and we use , you know , we

51:45

use omics approaches , we use machine

51:48

learning to get after all that . So

51:50

I think , notwithstanding

51:52

the IP barriers , I think there

51:55

will continue to be a lot of interest in circles and

51:57

there'll be a lot of people trying to you , you know , work the

51:59

way around those patents in

52:02

some way other . Maybe they'll just be straight

52:04

up very clever ideas

52:06

that are very different to the ones that we have . That get

52:08

you there , and once you have the circle , um

52:10

, you know you will enjoy all those advantages

52:13

. Now , of course , you still have to express

52:15

, and so that's why we think the expression system

52:17

might be another line of defense

52:19

. I know you're trying to think about opening

52:22

doors , and here I am talking about closing doors

52:24

.

52:24

I think that's an important conversation . To have to be

52:26

honest , you need to talk about some of the potential

52:29

door closers as well . Right , I mean , this

52:31

is new and there's a we

52:33

want to protect it .

52:34

I mean , that's where our value is . But

52:39

when you look across the modalities and there

52:41

are companies now doing tRNA , the

52:44

idea is that it's basically nonsense

52:47

suppression , stop codon suppression , so all those genetic

52:49

diseases which have a premature termination

52:52

, codon , you know maybe one therapy it's a very intriguing

52:55

idea and so on . So

52:57

there's going to be continuing approaches

53:00

with RNA , not , I think , less

53:02

about circles versus lines , but

53:05

creativity will emerge in other ways . So

53:08

you know tRNA or you

53:10

know we see RNA editing as something that's

53:12

out there now , or there'll be other kinds

53:15

of RNA splicing things that are going on

53:17

, I mean . So there'll be RNA this and

53:19

RNA that , for sure .

53:21

Yeah , a whole universe of opportunities

53:23

that will work in parallel , most

53:26

likely to each other , right , not just

53:28

. You know , one

53:30

ring to rule them all , right , one

53:32

solution .

53:34

Not if Dr Barnes has us . Dr

53:38

Barnes , what I mean ? 2020

53:40

was an interesting time to start a biotech

53:43

company . What do you wish

53:46

? You knew then that you know

53:48

now Whether that

53:50

answer is specific to just biotech

53:52

leadership in general or

53:55

specific to the RNA space um

54:06

.

54:06

So I'm a first-time ceo . So back when I was starting , you know , I I had to at least have

54:08

the courage of my convictions that I could do a half

54:10

decent , halfway decent job at it . Um and

54:12

um , you know , I learned what , uh

54:15

, it really feels like being a ceo

54:17

. I'm not sure I would . You know , just

54:19

get ready for the ride is maybe what I tell myself

54:22

, but

54:27

I'm not really sure my younger self would have even understood , you know . Oh

54:29

, it will be like this . Yeah , I think you have to sort of live through

54:31

it to really sort of sense . It's

54:35

a very central role , I think , at

54:37

the CEO level , particularly in the early days

54:40

you've got , you basically have to do a lot

54:42

of different things because

54:44

the team is not fully fledged . But

54:48

then , as it grows , then what you're trying to do

54:50

shifts and evolves and changes . And

54:53

there's raising money Is

54:56

the story good enough ? Polishing

54:59

your craft in terms of pitching and getting people

55:02

interested in what you're doing , getting the message

55:04

across succinctly or in an exciting

55:06

way , you

55:08

know . And there's your board

55:10

as well , making

55:13

sure everything is very

55:15

smooth and aligned there . I've been

55:17

in any number of board meetings before as

55:20

a participant , but not , as you know

55:22

, ceo , which is a far more central function

55:25

in that . So that was maybe the newest

55:28

thing to me , because

55:30

I'd done early stage startups before where

55:32

they didn't have the title of CEO . I was basically

55:35

doing everything anyway . So the early phases

55:37

of Honor were very familiar . Yes

55:41

, I don't know that there's , there's advice , um

55:44

, just to say that , uh , you know

55:46

, it's , it's , it's a lot , it's a big role .

55:48

Yeah , there's a , there's advice in all of it

55:50

. You know , I I ask questions like that all the time

55:52

of my guests , specifically like scientists

55:55

turned CEO , um

55:57

and . And the answers are

55:59

are wildly varying , but there's

56:01

, there's meat in all of them , right , like

56:03

someone's going to take something away from it . So

56:05

just one follow-up to that and then we'll

56:07

let you get on with your day . You

56:10

said get ready for the ride . Looking

56:19

back , what aspects of the ride .

56:20

Were you perhaps the least prepared for , hmm , least

56:22

prepared for ? Well

56:26

, we went through some interesting macro uh

56:28

factors . I mean , I've been in biotech long enough . I've

56:30

seen various macro factors and that employee

56:32

things go up , things go down , but it's other

56:35

people's responsibility in some ways to deal with

56:37

it or ensure the health of the company

56:39

. And , um , you

56:41

know , uh , there was you

56:43

. You know there was the big boom time in 21

56:45

and then it all sort of went south

56:47

and sort of the investment dried up

56:50

. So

56:55

that was , you know , that's really out of your control

56:57

, as you're presented with a scenario

57:00

and you have to solve for what you're

57:02

trying to solve for and then , if the conditions

57:04

change , you have to resolve for that . So

57:06

that's less . You know that's , and

57:09

that's not you . I mean , that's your team at that point

57:11

, that's everybody , from your board to

57:14

your executive team , to yourself , and

57:16

then everybody in the company is trying to create

57:19

value through what they do . I mean the

57:21

path to salvation is value creation

57:23

. I didn't mean for that to rhyme , but

57:25

it did .

57:26

You're a poet .

57:28

And I don't know it .

57:31

The conversation is coming full circle . Oh my

57:33

God , do

57:35

you see what I did there ? Oh my God .

57:39

So anyway , that's the ride . I would say in this

57:41

particular case it could

57:44

have been a very smooth , steady

57:46

period in biotech over

57:48

this last little while , but it's definitely been up and down

57:50

, yeah .

57:52

Prepare to wear many hats , in other words

57:54

right .

57:56

Well , I could selfishly continue

57:58

this conversation for quite some time , because

58:00

I've enjoyed it thoroughly . I

58:03

think co-hosting is fun .

58:04

It is fun we're going to do more of this .

58:08

I'm going to find R&A companies so that I can

58:10

just R&A companies pitch

58:12

Matt , You'll get this .

58:14

You'll get this .

58:17

Dr Barnes , we really appreciate you coming on . Thank

58:19

you for joining us .

58:20

Thank you , thanks very much for having me A

58:22

lot of fun . Thanks , matt , thanks , anna Rose .

58:26

We will revisit , maybe down the road

58:28

, when there's another inflection point to talk about . We'll catch

58:30

up with Orna , but in the

58:32

meantime , thanks again , thanks , thank

58:34

you . So that's Orna Therapeutics

58:36

. Dr Thomas Barnes , I'm

58:38

Matt Pillar and I'm Anna Rose Welch

58:40

, and you just listened to the Business of Biotech

58:43

. Listen and subscribe wherever

58:45

you listen to podcasts . Sign up for our Business

58:47

of Biotech newsletter at bioprocessonline . com/bob

58:52

. Drop us a line with your guest and

58:55

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58:57

always , thanks for listening .