0:15

Pushkin. Not

0:20

long before he died, Steve Jobs

0:22

made this big, sweeping,

0:25

very Steve Jobs claim.

0:28

He said, the biggest innovations

0:30

of the twenty first century will be at the intersection

0:33

of biology and technology. A

0:35

new era is beginning. If

0:38

Steve Jobs was right, if biotech

0:41

over the next fifty years develops like computers

0:43

did over the past fifty years, then

0:45

we are about to see wave

0:48

after wave of just extraordinary

0:50

innovations in medicine. Very

0:53

high on that list of innovations human

0:56

body parts made in the lab. I'm

1:04

Jacob Goldstein and this is What's Your Problem, the

1:06

show where I talk to people who are trying to

1:08

make technological progress. My

1:11

guest today is Nina Tandon, co founder

1:13

and CEO of EpiBone. Nina's

1:16

problem is this, how do you grow

1:18

human bone in a lab and

1:21

do it at a price that makes economic

1:23

sense. In our conversation

1:25

we talked about how EpiBone is growing

1:28

human bone that's being used even

1:30

now to treat patients, but also

1:33

we talked more broadly about the field

1:35

that EpiBone is part of. It's

1:37

a field called tissue engineering.

1:41

Maybe just to start, like, what is tissue

1:43

engineering? Well, tissue

1:46

engineering is a

1:49

branch of engineering that's devoted

1:51

to the creation

1:53

of surrogate body parts.

1:57

Okay, the future, Yeah,

2:00

one stop body shop for human prepare

2:03

to what extent is tissue engineering

2:06

the present? What tissue engineering is actually

2:08

happening in mass

2:10

production, normal medicine. Now, that

2:12

is a good question, and I think you

2:15

know an easy way to think about it is, you know, if

2:17

you and I were to do a thought experiment of

2:20

what would be an easy tissue to grow, what

2:23

might you say? None? I would

2:26

say it sounds crazy hard to grow tissue, all

2:28

right, right, Well, maybe something flat, okay,

2:31

maybe something with a single cell type. Maybe

2:33

a tissue then regenerates on its own.

2:36

Skin okay, boom rites

2:39

a skin is a flat tissue, single

2:41

cell type, and regenerates

2:45

on its own. Okay, has a lot

2:47

of stem cells in it, and so regenerates

2:49

on its own. Like you get a cut, you get a

2:51

scrape, and magically a

2:53

week later or whatever, you have new skin there.

2:56

Yeah. And so in the early two

2:58

thousands, we saw

3:01

two products in the late nineties

3:03

early two thousands be released to the

3:05

market, I believe, for burns

3:08

and diabetic foot ulcers

3:10

something like that. And so that's the first

3:13

that's easy. So you have this

3:15

moment twenty years ago, people

3:17

are making skin graphs in the lab

3:20

and there's sort of big dreams. So if we can do skin,

3:23

maybe we can regrow everything in the lab.

3:25

And so when do you get into the field, When

3:27

do you walk into the story. I

3:31

was an electrical engineer coming out of undergrad

3:33

and I had worked as a software programmer

3:36

for a telecom company. So this was

3:38

not what I thought I was going to be doing with my life.

3:41

But nine to eleven happened. I was

3:43

living in the suburbs for the first time in my life,

3:45

and I got a

3:47

little bored and started taking

3:50

classes at the local community college

3:53

in anatomy and physiology. And

3:55

I think because I was so lonely, because

3:57

I was so kind of starved

4:00

for that type of engagement, I really

4:03

got into this class and

4:07

I decided I was gonna,

4:09

you know, I had to follow this. So I applied to

4:11

the bioelectrical

4:14

engineering track at

4:16

MIT and got in for

4:18

a PhD for a PhD program, And

4:21

so it's at MT that you sort

4:23

of discover this

4:25

emerging field of tissue engineering.

4:27

Yeah. Yeah, And when

4:30

you discover it, like, what

4:32

do you think, oh, my gosh,

4:34

it's so cool this woman,

4:37

Gordona, who was one of the professors, and

4:39

I just connected with her as a person. To

4:41

discover that one of

4:43

the nicest people that I knew at MIT

4:46

also happened to be experimenting

4:49

with using electrical signals to grow

4:51

hearts, and that I

4:54

was like, wow, I need to

4:56

know if maybe she might want to work

4:59

with someone who's an electrical engineer on that, and

5:01

she did, And that was

5:03

really felt like destiny to me because

5:06

I thought to myself, I mean, I'd already fallen

5:08

in love with the heart at that point through

5:11

my studies, so it really

5:13

spoke to me. And the idea that

5:15

we could copy those electrical signals to

5:17

try and coax embryonic stem

5:19

cells into becoming heart cells

5:21

or you know, to essentially

5:24

coax the tissue to form

5:27

that to me was intoxicating. So

5:29

how do you get from there? I mean, you fell

5:31

in love with the heart, but you didn't end up starting

5:34

EPI Heart, You started EPI bone, Right,

5:38

how do you get from from there to starting

5:41

your company? Cardiac tissue is on the

5:43

end of the spectrum in terms of difficulty. There's

5:46

a lot of intermediate hard end

5:48

of growing tissues mechanically at

5:50

most metabolically active tissue in the body,

5:53

multiple cell types arranged in a very

5:55

specific manner. So really the most

5:58

difficult you could possibly imagine, and bone

6:01

is in the middle. It's a complex

6:03

shape, but we could solve that using digital

6:05

fabrication, and we

6:08

could use a single cell type to engineer a pretty

6:10

high quality bone. So it was clear to me

6:12

that if I wanted to be involved in translating

6:15

that's the word we use in the field, translating

6:19

science towards the clinic in

6:21

my lifetime, I should

6:23

probably you work on a tissue that's

6:26

closer to the skin side of the spectrum

6:28

than cardiac. Right, so you

6:31

start epic bone, you decide to work on bone.

6:34

That's like almost ten years ago now, and

6:36

today you do have this engineered

6:39

bone. You're doing a clinical trial and

6:42

as I understand it, right, this is bone

6:44

that is going into people's jaws,

6:46

where typically a surgeon would cut a piece

6:48

of a patient's own bone out of some other part

6:51

of their body. But you're growing the bone

6:53

in a lab basically from scratch.

6:56

So tell me about the clinical trial that's going

6:58

on right now. Okay, so patient I

7:01

think I'm allowed to say this. Patient

7:04

one suffered a traumatic injury

7:07

due to a car accident, and

7:09

so we provided bone to help reconstruct

7:11

the jaw. Patient two had

7:14

suffered from a degenerating jaw resulting

7:17

in airway obstruction, so we provided bone

7:19

to help elongate the jaw and

7:22

relieve that airway obstruction. Patient

7:24

three, he was born with facial asymmetry

7:27

that would only be correctable

7:29

by taking bones out of some other part of his body

7:31

to reposition his jaw, and

7:34

we were just able to grow bones for

7:36

him using a small sample of his fat tissue.

7:38

So you know, whether it's

7:40

for cancer, trauma, or congenital defects, people

7:43

need bone. It's bone is the most transplanted

7:45

team in material after blood. And so he

7:47

is three. The number of patients in the trial,

7:50

that's the we've done six. Oh,

7:52

he's done six, Okay, yeah,

7:54

And what is the total number of patients

7:56

you plan to enroll? That's the fully enrolled.

7:58

So that was our phase one too. That was our phase

8:00

one two, first in human, first

8:03

in class. Basically safety

8:05

and a little bit of efficacy. That's what phase one

8:07

two, that's right, Yeah, yeah, in

8:09

a little bit of efficacy, and hopefully

8:11

we'll move forward with a phase three in the not too

8:13

distant future where we'll be able to

8:17

help a few more patients. And

8:19

so how does the process work.

8:22

So we take two things from the patient. One,

8:24

we take an image a CT scan,

8:26

which is like a three dimensional X ray, so we can extract

8:29

three dimensional data out of that and

8:31

design a perfect puzzle

8:33

piece shaped biomaterial that will be the

8:35

eventual shape of the bone. We also

8:38

take a small sample of fat tissue from

8:40

the patient so we can extract the stem cells

8:42

out of it, so those cells can attach to the

8:44

scaffold, proliferate, lay down new matrix,

8:46

and essentially turn that biomaterial into living

8:49

bone. It takes about three weeks for bone.

8:51

So you take a CT scan to get

8:53

the image of the

8:56

shape of the bone you need, and

8:58

then from that you

9:01

make when you say a puzzle piece, you make basically

9:03

something that is the shape

9:05

of the bone you need made

9:08

of stick or something. What is

9:10

it made of? So we take a cowbone,

9:12

strip all the cellular material out of it, so we're

9:15

left with essentially protein

9:17

and mineral and it's

9:20

a very porous material. It looks like pumice stone

9:22

and you can infuse cells onto

9:25

that and the cells kind of recognize that matrix

9:28

as being a place that gives

9:30

them a cue towards differentiating them

9:32

towards bone. It feels bony

9:34

enough to these cells that they say, okay, let's

9:36

let's make the rest of this bone. So right, so you

9:38

have this puzzle piece made of cowbone

9:42

essentially, right, that's in the right shape.

9:44

So that's kind of one one track. And

9:46

then on the other track, you're taking fat

9:49

from the patient. You're

9:51

getting the stem cells out of that

9:53

fat, and stem cells are cells that can become

9:57

any kind of cell. Right, So, yeah,

9:59

we've got the cowbone

10:02

puzzle piece, we've got the

10:05

stem cells from the patient. What

10:08

exactly how happens next? Well,

10:10

this is our secret sauce. The bioreactor.

10:14

So a bioreactor is just

10:16

a fancy word for

10:18

a cell culture system, like

10:21

a place where you can culture cells in and so we

10:23

get those cells to turn to grow up and turn into

10:26

bone. So so just to be able to see

10:28

it, like, is the bioreactor

10:30

a metal box? What actually

10:33

does it look like? You know, you imagine a little bone

10:35

and then you imagine the reverse image

10:37

of that bone. So a little gasket that

10:40

like covers that bone perfectly, and that gasket

10:42

has holes in it so I can perfuse

10:48

liquid food through it as

10:50

it grows. And that gaskets contained

10:52

in kind of like another canister where

10:55

we can have fluid that comes in and fluid

10:57

that comes out. It's about the size of a coke

10:59

can, and

11:02

the fluid input and output are attached to a

11:04

pump, so it's constantly pumping.

11:06

And that whole contraption, which we've made

11:09

quite efficient in terms of sizes about a shoe

11:11

box in terms of size, and we

11:13

can stack them up so that we can

11:15

grow many at a time. Great,

11:18

So you take the cowbone

11:20

puzzle piece, how do you get the stem

11:22

cells to like go on

11:25

to the puzzle piece and grow. Yeah,

11:27

we perfuse them very slowly and

11:29

the cells attach. And that's part

11:31

of why the biomaterial is so important,

11:34

because you know, a piece of decellularized

11:37

bone has a lot of these nanostructure

11:40

attachment sites that cells

11:42

recognize and glom onto, and

11:44

so there's a period of time where the cells attach.

11:48

Most cells in our body are attached

11:50

to some sort of three dimensional matrix and

11:54

then they start to proliferate. And lay down

11:56

even more matrix. So they

11:59

proliferate around sevenfold and

12:01

they fill up that porous structure.

12:04

So even though it was porous at the beginning,

12:06

it looks like bone at the

12:08

end of huh. So you take

12:11

the puzzle piece, you put the puzzle

12:13

piece into the reactor, and then you

12:15

send the patient stem cells

12:17

into the reactor and they attached to and

12:20

grow over the puzzle piece in

12:22

within as well, they're filling up the three

12:24

dimensional YEA, yeah, it's not a pancake. It's

12:27

not a pancake. It's it it's like

12:29

a honeycomb or something. It's

12:31

really important to get the cells in three D. You

12:34

know, a lot of people can grow cells on a Petrie dish, but

12:36

grow cells in three D is a that's a big

12:38

challenge. But we've seen

12:40

that the bones perform their mechanical

12:43

duties on

12:45

day one. You know, patients are able to eat, speak,

12:48

drink, all the things that you'd

12:50

want to do after

12:54

the break. The problems Nina and her teams

12:56

still have to solve to get lab grown

12:58

bone approved and into widespread

13:00

use. Also, how should

13:02

we think about the pace of progress in tissue

13:05

engineering and in biotech More broadly.

13:14

Now back to the show. So I

13:17

want to talk about sort of the future and what you're

13:19

working on next in a minute. But before

13:21

we do that, I mean, you've been

13:23

in the field now for twenty years. Your

13:26

company has been around for nine years, and

13:29

so tell me about the progress

13:31

of the field in the time you've been in it. Tell me about

13:33

the progress of the field in the twenty years. What has what

13:36

has happened faster than you might have expected, what

13:38

has happened slower? And like where are we now?

13:40

What is happening in

13:42

tissue engineering right now? There was a technology

13:44

developed for cartilage, cartilage

13:47

in a couple of generations of cartilage,

13:51

so that's been established as

13:53

like another tissue that can be engineered.

13:56

There's another company called hum Site

13:58

which makes tissue engineered vasculator. They

14:01

are very close to getting

14:04

in approved for commercial

14:07

use. They are hope within about

14:09

a year or so. They're a publicly traded company. So

14:11

so vasculature, Just to be clear, like blood

14:13

vessels, they're making blood vessels. Blood vessels.

14:16

That seems hard. It's hard.

14:18

Yeah, it's hard. It seems hard. You gotta get the

14:20

tube. It's a tube. I don't know why that seems harder to

14:22

Me's a that. Yeah, hollow organs are

14:24

a step above flat tissue for sure. And

14:27

UM and there's their founder, Laura Nicholson.

14:30

What she learned in growing vasculature

14:32

was that cells needed flow, not

14:35

just flow of liquid, but pulsatile

14:38

flow. Be interesting, you're

14:40

moving like pulsatile, like like the way

14:42

the heart beats. And it's

14:44

not like a river. It's like, yeah,

14:46

exactly, it's not a river. And so

14:49

that's that was her genius discovery. And they

14:52

are you know, they've treated UM soldiers

14:54

and civilians in the Ukraine who need who

14:57

need blood vessels. UM. They are close

14:59

to commercials. Has the progress of

15:01

tissue engineering been slower than you would have

15:03

thought twenty years ago? Yeah,

15:05

I think my notion of time was very different following

15:08

years ago. You know. Now

15:10

I'm like, oh, twenty years okay, that's

15:12

nothing. A human lifetime, that's nothing. You

15:14

know, what can be done in a human lifetime? Not much?

15:17

You know, that's like more my kind of gallows

15:19

humor. Now, things move slowly, slash

15:22

wisdom, slash wisdom. Yeah,

15:25

sure, but like yeah,

15:28

things it's a glacial I like to

15:30

tell people this is like a slow motion marathon

15:32

in a way like this past twenty years have you know, blinked

15:35

and been gone in a heartbeat. But

15:38

yeah, it takes a long time to do things.

15:40

I think I've gotten better at being

15:42

more honest or realistic

15:45

in terms of estimating how long something's going

15:47

to take, because you can't rush

15:49

the science. And it's

15:51

really, you know, interesting, you say, oh, it sounds so futuristic.

15:54

I think a lot of people believe

15:56

that this should happen, and there's very few

15:58

people that have the skill set to make it happen.

16:01

You know, because if you watch science fiction,

16:03

and or if you watch I don't know, even Star Wars

16:06

or the Marvel movies, there's

16:08

always examples of people getting healed

16:10

with technologies like tissue engineering,

16:13

so people assume that that's going

16:15

to happen. Like Luke Skywalker

16:17

got a new hand, So why can't I get a new

16:19

hand totally? Totally? Or in

16:21

Waconda, you know, they just regenerated,

16:24

or you know, there's all these technologies

16:26

in pop culture. Even in Grey's

16:28

Anatomy they had episodes of tissue

16:31

engineering. And yet it's

16:34

very hard and it

16:37

takes a long time. And so

16:39

I'm glad that I've been working on this particular tissue

16:42

because you know, it's been ten

16:45

years as a company and we've brought it to where

16:47

it's never been before. And now

16:49

the challenges a lot more

16:52

with a lot of that technical de risking behind

16:54

us. The challenges are more or

16:56

less of will this work in a living system

16:59

and more towards will this work in a clinical

17:01

setting? Will this work in the economy? And

17:04

I find that to be extremely exciting when

17:06

you say will this work in the economy,

17:08

that's a big interesting question that

17:11

we really haven't talked about yet. So

17:13

so how do you think about that? How how are

17:15

you approaching that? You know, unit cost economics

17:17

need to work. That's where the biomanufacturing comes in.

17:20

Automation of cell culture is a big driver.

17:22

It's a very artisanal process, you know,

17:24

using our hand pipets and expensive,

17:27

right, artisanal and hand this that

17:30

that that is expensive, right. I

17:32

don't want an artisical bone. I want to mass producing

17:34

bone, right yeah, right. Creating

17:36

the infrastructure that allows for automated biomanufacturing

17:40

is a big piece of it. We're not the only ones that need to

17:42

be working on that um But

17:44

then also I think scientifically and

17:46

clinically being very clever in

17:48

terms of the end points you're measuring in your clinical

17:50

trials so that you can make the economic case.

17:53

For Look, if we're going to give you this

17:55

piece of tissue, it's going to

17:57

save you surgeries down the

17:59

line. That is very interesting, And

18:01

like, tell me specifically what that

18:03

means in the case of the of the jawbone

18:07

easy economic cost of avoided. What

18:10

is the economic cost avoided for evybone?

18:13

Well, if you had evybone, you don't have to do an

18:15

extra hour or half hour of surgical time,

18:17

you don't have to put the patient in the ICU for

18:20

as much time for recovery. What those

18:22

all are very easily calculatable

18:24

costs. So so that

18:26

economic case is as important

18:28

to me as as

18:31

the clinical case. So if things

18:33

go well, when do you think

18:35

you might actually be approved and

18:37

out in the world twenty six,

18:39

twenty seven? Okay, yeah,

18:42

not crazy if you had at maut a future but a while yet.

18:44

So for some people that's forever. For some

18:46

people they're like, oh, that's pretty soon. I

18:49

wonder if the sort of absurd

18:51

rate of development of basically

18:54

semiconductors right, basically if Moore's

18:56

law, and the development of computer

18:59

technology has messed up our sense

19:01

of the rate of technological development.

19:03

Like if we have come to expect so funny that you brought

19:05

up law, Well, you were an electrical

19:07

engineer, so you know than I do. Yes.

19:10

So in biotech

19:13

there's a joke called e Room's

19:15

law, which is if you spell

19:18

more backwards, what do

19:20

you get? Because we're sort of the opposite

19:22

of that, it gets twice

19:25

as expensive and twice as slow every year.

19:28

Yeah, and the FDA is backlogged

19:30

and there's just been so few

19:33

approvals over time,

19:35

it's really gone down. So I

19:37

think everyone understands

19:40

that no one wants to hurt people from

19:42

a regulatory standpoint, no one. They don't want to hurt

19:45

people. Entrepreneurs and companies, we

19:47

don't want to hurt people. But there's a risk

19:49

benefit to you know, if you if

19:51

you hold back innovation, sure

19:53

fewer people will get hurt, but also a fewer people

19:55

will will get these breakthrough treatments. There's

19:57

regulation, and that's clearly important, but

20:00

I feel like also the body is just super

20:02

complicated. Like I feel like, even independent

20:05

of regulatory bottlenecks,

20:07

it's just very hard problems

20:09

it's hard, but it does feel like, well,

20:11

I'm climbing a mountain that's worth climbing, and

20:14

you know we'll get there. We'll

20:18

be back in a minute with the lightning round, including

20:21

a very compelling argument that ourselves

20:24

are intelligent. Okay,

20:33

that's the end of the ads. Now it's done for

20:35

the Lightning round. What's one tip for

20:37

finding a mentor? M

20:40

who's your professional crush finding?

20:43

I'm run, sure, yeah, you're professional

20:45

crush. That's that's how that's Identifying

20:47

a mentor is like, who do you have a crush? How

20:50

do you find a mentor? How do you find a

20:52

mentor? Here's my answer. Good people lead

20:55

you to good people. I like all

20:57

of those answers. As a

20:59

former McKinsey consultant, do you think

21:01

McKinsey is overrated or underrated?

21:06

I think I think

21:08

neither appropriately rated.

21:11

They're appropriately powerful. I mean,

21:13

they do good work and they're

21:15

full of very earnest people, and

21:18

my goodness, do they know how to make a two by two matrix

21:20

out of any problem?

21:22

Um? Good? I

21:26

like broken down to do

21:28

a two by matrix? Um.

21:31

What's been the most surprising thing about running

21:33

a company? I think,

21:35

how much your psychology gets amplified.

21:41

You know, just think how much of the company

21:43

is a mirror, and if I'm having

21:45

a bad day, it amplifies

21:48

to the team. It just makes me have to

21:50

just really take my own mental

21:52

health and really seriously. Downward

21:55

dog or Warrior one, Oh,

21:57

down dog? I think I

22:00

love them? Well, yeah, Warrior one, I'd say Warrior

22:02

two. Okay, good,

22:05

I love yoga. I could talk about that for a long time. What

22:08

do you understand about human body that most

22:10

people don't That sells

22:12

are intelligent all of

22:14

our selves. Intelligence isn't

22:17

only in the brain. Intelligence is everywhere

22:19

in the body, at the cellular level.

22:22

What do you mean by that, Well,

22:24

we tend to think of intelligence as being

22:26

in our brain, and that places

22:29

like our heart are dumb. It's a dumb pump

22:31

that listens to the brain. But the heart

22:33

is thinking on its own. It's making a

22:35

lot of decisions about how much blood to pump

22:37

and send signals up to the

22:40

brain, but also does plenty of thinking

22:42

on its own. The eye isn't just

22:44

a camera. The eye contains

22:47

a lot of decision making processes

22:50

about what we're seeing before even

22:52

sending the image up to the brain. The optic

22:55

nerve is the largest

22:57

amount of data compression known in biology.

23:00

So intelligence is distributed

23:02

throughout the body. And I don't think a lot of people think

23:04

that, but I know that, and I

23:07

love that about the body. It makes me,

23:09

It makes living in a body fun for me.

23:17

Nina Tandon is the co founder and CEO

23:20

of EPIBOE. Today's show

23:23

was produced by Edith Russolo, edited

23:25

by Sarah Knicks, and engineered

23:27

by Amanda kay Wong. I'm

23:29

Jacob Boldstein and just one last quick

23:31

note. We're going to be off for the next couple

23:34

of weeks and we'll be back with a new

23:36

episode on Thursday, April twentieth,