0:00

Welcome to MIT Technology

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Review, Narrated. My name is Matt

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Honeen. I'm our editor-in-chief.

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Every week, we'll bring you a

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fascinating, new, in-depth story from the

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leading edge of science and

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technology, covering topics like AI,

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biotech, climate, energy, robotics, and

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more. Here's this week's story.

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I hope you enjoy it. Narrated by

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NOAA. Listen to more of the best

0:24

articles from the world's biggest

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publishers on the NOAA app.

0:29

or at newsover audio.com. Harriet

0:32

Brown writes, is this the

0:34

end of animal testing? In a

0:36

clean room in his lab, Sean

0:38

Moore hears through a microscope

0:40

at a bit of

0:42

intestine. It's dark squiggles

0:45

and rounded structures standing

0:47

out against a light

0:49

grey background. This sample

0:51

is not part of an

0:53

actual intestine. Rather, it's human

0:56

intestinal cells on a tiny

0:58

plastic rectangle, one of 24

1:01

so-called organs on chips his

1:03

lab bought three years ago.

1:06

More, a pediatric gastroenterologist at

1:08

the University of Virginia School

1:10

of Medicine hopes the chips

1:13

will offer answers to a

1:15

particularly thorny research problem. He

1:17

studies rotavirus, a common

1:20

infection that causes severe

1:22

diarrhea, vomiting, dehydration and

1:24

even death in young

1:26

children. In the US and other

1:28

rich nations up to

1:30

98% of the children

1:33

who are vaccinated against

1:35

rotavirus develop lifelong immunity.

1:37

But in low-income countries

1:39

only about a third

1:41

of vaccinated children become

1:43

immune. More wants to know why.

1:45

His lab uses mice for

1:47

some protocols, but animal

1:50

studies are notoriously bad

1:52

at identifying human treatments.

1:54

Around 95% of the drugs

1:56

developed through animal research fail

1:58

in people. Researchers have

2:01

documented this translation gap since

2:03

at least 1962. All these

2:05

pharmaceutical companies know the animal

2:07

model stink, says Don Inber,

2:09

founder of the Vess Institute

2:12

for Biologically inspired Engineering at

2:14

Harvard, and a leading advocate

2:16

for organs on chips. The

2:18

FDA knows they stink. But

2:20

until recently there was no

2:23

other option. Research questions like

2:25

Moore's can't ethically or practically

2:27

be addressed with a randomized

2:29

double-blinded study in humans. Now

2:31

these organs on chips, also

2:34

known as microphysiological systems, may

2:36

offer a truly viable alternative.

2:38

They look remarkably prosaic, flexible

2:40

polymer rectangles about the size

2:42

of a thumb drive. In

2:45

reality, they're triumphs of bioengineering.

2:47

intricate constructions furrowed with tiny

2:49

channels that aligned with living

2:51

human tissues. These tissues expand

2:53

and contract with the flow

2:55

of fluid and air, mimicking

2:58

key organ functions like breathing,

3:00

blood flow, and peristaltosis, the

3:02

muscular contractions of the digestive

3:04

system. More than 60 companies

3:06

now produce organs on chips

3:09

commercially, focusing on five major

3:11

organs. liver, kidney, lung, intestines

3:13

and brain. They're already being

3:15

used to understand diseases, discover

3:17

and test new drugs, and

3:20

explore personalized approaches to treatment.

3:22

As they continue to be

3:24

refined, they could solve one

3:26

of the biggest problems in

3:28

medicine today. You need to

3:31

do three things when you're

3:33

making a drug, says Lorna

3:35

Euet, a pharmacologist and chief

3:37

scientific officer of Emulate, a

3:39

biotechic company of Emulateec company

3:41

based in Boston. You need

3:44

to show it safe. You

3:46

need to show it works.

3:48

You need to be able

3:50

to make it. All new

3:52

compound... have to pass through

3:55

a preclinical phase where they're

3:57

tested for safety and effectiveness

3:59

before moving to clinical trials

4:01

in humans. Until recently those

4:03

tests had to run in

4:06

at least two animal species,

4:08

usually rats and dogs, before

4:10

the drugs were tried on

4:12

people. But in December 2022

4:14

President Biden signed the FDA

4:17

Modernisation Act, which amended the

4:19

original FDA Act of 1938.

4:21

With a few small word

4:23

changes, the Act opened the

4:25

door for non-animal-based testing in

4:27

preclinical trials. Anything that makes

4:30

it faster and easier for

4:32

pharmaceutical companies to identify safe

4:34

and effective drugs means better,

4:36

potentially cheaper, treatments for all

4:38

of us. More, for one,

4:41

is banking on it. hoping

4:43

the chips help him and

4:45

his colleagues shed light on

4:47

the rotavirus vaccine responses that

4:49

confounded them. If you could

4:52

figure out the answer, he

4:54

says, you could save a

4:56

lot of kids' lives. While

4:58

many teams have worked on

5:00

organ chips over the last

5:03

30 years, the OG in

5:05

the field is generally acknowledged

5:07

to be Michael Shula, a

5:09

professor emeritus of chemical engineering

5:11

at Cornell. In the 1980s

5:14

Shula was a math and

5:16

engineering guy who imagined an

5:18

animal on a chip, a

5:20

cell culture, base seeded with

5:22

a variety of human cells

5:24

that could be used for

5:27

testing drugs. He wanted to

5:29

position a handful of different

5:31

organ cells on the same

5:33

chip, linked to one another,

5:35

which could mimic the chemical

5:38

communication between organs and the

5:40

way drugs move through the

5:42

body. This was science fiction,

5:44

says Gordana Vunek Novakovich, a

5:46

professor of biomedical engineering at

5:49

Columbia University, whose lab works

5:51

with cardiac tissue on chips.

5:53

There was no body on

5:55

a chip. There is still

5:57

no body on a chip.

6:00

God knows if there will ever be a

6:02

body on a chip. Shula had hoped

6:04

to develop a computer model of

6:06

a multi-organ system, but there were

6:08

too many unknowns. The living cell

6:11

culture system he dreamed up was his

6:13

bid to fill in the blanks. For

6:15

a while he played with the

6:17

concept, but the materials simply

6:19

weren't good enough to build

6:21

what he imagined. He wasn't the

6:23

only one working on the problem.

6:26

Linda Griffith, a founding professor

6:28

of biological engineering at MIT,

6:30

and a 2006 recipient of

6:33

a MacArthur Genius Grant, designed

6:35

a crude early version of

6:37

a liver chip in the

6:40

late 1990s, a flat silicon

6:42

chip just a few hundred

6:44

micrometers tall with endothelial cells,

6:47

oxygen and liquid flowing in

6:49

and out via pumps. silicon

6:51

tubing, and a polymer membrane

6:54

with microscopic holes. She put

6:56

liver cells from rats on the chip,

6:58

and those cells organize themselves

7:01

into three-dimensional tissue.

7:03

It wasn't a liver, but it

7:06

modelled a few of the things

7:08

a functioning human liver could do.

7:10

It was a start. Griffith, who

7:12

rides a motorcycle for fun

7:14

and speaks with a soft

7:17

southern accent, suffers from endometriosis,

7:19

an inflammatory condition where cells

7:21

from the lining of the

7:23

uterus grow throughout the abdomen.

7:26

She's endured decades of nausea,

7:28

pain, blood loss and repeated

7:30

surgeries. She never took medical

7:32

leaves, instead loading up on percocet,

7:35

advil and margaritas, keeping a heating

7:37

pad and couch in her office.

7:40

a strategy of necessity as she

7:42

saw no other choice for a

7:44

working scientist, especially a woman. And

7:47

as a scientist Griffith understood

7:49

that the chronic diseases affecting

7:51

women tend to be under

7:54

research, underfunded and poorly treated.

7:56

She realised that decades of work

7:58

with animals have... done a damn

8:01

thing to make life better

8:03

for women like her. We've

8:05

got all this data, but

8:07

most of that data does

8:09

not lead to treatments for

8:11

human diseases, she says. You

8:14

can force mice to menstruate,

8:16

but it's not really menstruation.

8:18

You need the human being.

8:20

Or at least the human

8:22

cells. Shula and Griffith and

8:24

other scientists in Europe worked

8:27

on some of those early

8:29

chips, but things really kicked

8:31

off around 2009 when Don

8:33

Inber's lab in Cambridge, Massachusetts,

8:35

created the first fully functioning

8:37

organ-on-on-a-chip. That lung-on-a-chip was made

8:40

from flexible silicon rubber, lined

8:42

with human lung cells and

8:44

capillary blood vessel cells, that

8:46

breathed like the alveoli. tiny

8:48

air sacs in a human

8:50

lung. A few years later,

8:52

Inber, an MD PhD with

8:55

the tidy good looks of

8:57

a younger Michael Douglas, founded

8:59

Emulate, one of the earliest

9:01

biotech companies making micro physiological

9:03

systems. Since then he's become

9:05

a kind of unofficial ambassador

9:08

for in vitro technologies in

9:10

general and organs on chips

9:12

in particular, giving hundreds of

9:14

talks, scoring millions in grant

9:16

money. repping the field with

9:18

scientists and lay people. Stephen

9:21

Colbert once ragged on him

9:23

after the New York Times

9:25

quoted him as describing a

9:27

chip that walks, talks, and

9:29

quacks like a human vagina.

9:31

I quote, Inber says was

9:33

taken out of context. Inber

9:36

began his career working on

9:38

cancer, but he struggled with

9:40

the required animal research. I

9:42

really didn't want to work

9:44

with them anymore because I

9:46

love animals, he says. It

9:49

was a conscious decision to

9:51

focus on in vitro models.

9:53

He's not alone. A growing

9:55

number of young scientists are

9:57

speaking up about the distress

9:59

they feel when research protocols

10:02

cause pain, trauma, injury. and

10:04

death to lab animals. I'm

10:06

a master's degree student in

10:08

neuroscience and I think about

10:10

this constantly. I've done such

10:12

unspeakable, horrible things to mice,

10:14

all in the name of

10:17

scientific progress, and I feel

10:19

guilty about this every day,

10:21

wrote one anonymous student on

10:23

Reddit. Full disclosure, I switched

10:25

out of a psychology major

10:27

in college because I didn't

10:30

want to cause harm to

10:32

animals. Taking an undergraduate art

10:34

class led Inber to an

10:36

epiphany. Mechanical forces are just

10:38

as important as chemicals and

10:40

genes in determining the way

10:43

living creatures work. On a

10:45

shelf in his office he

10:47

still displays a model he

10:49

built in that art class,

10:51

a simple construction of sticks

10:53

and fishing line, which helped

10:55

him realise that cells pull

10:58

and twist against each other.

11:00

That realisation foreshadowed his current

11:02

work and helped him design

11:04

dynamic microfluidic devices that incorporated

11:06

shear and flow. Inbar co-authored

11:08

a 2022 paper that sometimes

11:11

cited as a watershed in

11:13

the world of organs on

11:15

chips. Researchers used Emulates liver

11:17

chips to reevaluate 27 drugs

11:19

that had previously made it

11:21

through animal testing and then

11:24

gone on to kill 242

11:26

people and necessitate more than

11:28

60 liver transplants. The liver

11:30

chips correctly flagged problems with

11:32

22 of the 27 drugs,

11:34

an 87% success rate compared

11:36

with a 0% success rate

11:39

for animal testing. It was

11:41

the first time organs on

11:43

chips had been directly pitted

11:45

against animal models and the

11:47

results got a lot of

11:49

attention from the pharmaceutical industry.

11:52

Dan Tagle, Director of the

11:54

Office of Special Initiatives for

11:56

the National Centre for Advancing

11:58

Translational Sciences, NCATS, estimates that

12:00

drug failures cost around two...

12:02

$2.6 billion globally each year.

12:05

The earlier in the process,

12:07

failing compounds can be weeded

12:09

out, the more room there

12:11

is for other drugs to

12:13

succeed. The capacity we have

12:15

to test drugs is more

12:18

or less fixed in this

12:20

country, says Shula, whose company,

12:22

Hesperos, also manufactures organs on

12:24

chips. There are only so

12:26

many clinical trials you can

12:28

do. So if you put

12:30

a loser into the system,

12:33

that means something that could

12:35

have won, didn't get into

12:37

the system, we want to

12:39

change the success rate from

12:41

clinical trials to a much

12:43

higher number. In 2011, the

12:46

National Institutes of Health established

12:48

NCATs and started investing in

12:50

organs on chips and other

12:52

in vitro technologies. Other government

12:54

funders, like the Defence Advanced

12:56

Research Projects Agency, and the

12:59

Food and Drug Administration have

13:01

followed suit. For instance, NIH

13:03

recently funded NASA scientists to

13:05

send heart tissue on chips

13:07

into space. Six months in

13:09

low gravity ages the cardiovascular

13:11

system 10 years, so this

13:14

experiment lets researchers study some

13:16

of the effects of aging

13:18

without harming animals or humans.

13:20

Scientists have made liver chips,

13:22

brain chips, heart chips, kidney

13:24

chips, intestine chips, and even

13:27

a female reproductive system on

13:29

a chip, with cells from

13:31

ovaries, fallopian tubes and uteruses

13:33

that release hormones and mimic

13:35

an actual 28-day menstrual cycle.

13:37

Each of these chips exhibits

13:40

some of the specific functions

13:42

of the organs in question.

13:44

Cardiac chips, for instance, contain

13:46

heart cells that beat just

13:48

like heart muscle, making it

13:50

possible for researchers to model

13:52

disorders like cardiomyopathy. Shula thinks

13:55

organs on chips will revolutionise

13:57

the world of research for

13:59

rare diseases. It is a

14:01

very good model when you

14:03

don't have enough patients for

14:05

normal clinical trials and you

14:08

don't have a good animal

14:10

model, he says. So it's

14:12

a way to get drugs

14:14

to people that couldn't be

14:16

developed in our current pharmaceutical

14:18

model. Shula's own biotech company

14:21

used organs on chips to

14:23

test a potential drug for

14:25

myosthenia gravis, a rare neurological

14:27

disorder. In 2022 the FDA

14:29

approved the drug for clinical

14:31

trials based on that data,

14:33

one of six hasperose drugs

14:36

that have so far made

14:38

it to that stage. Each

14:40

chip starts with a physiologically

14:42

based pharmacokinetic model known as

14:44

a PBPC model, a mathematical

14:46

expression of how a chemical

14:49

compound behaves in a human

14:51

body. We try and build

14:53

a physical replica of the

14:55

mathematical model of what really

14:57

occurs in the body, explains

14:59

Shula. That model guides the

15:02

way the chip is designed,

15:04

recreating the amount of time

15:06

a fluid or chemical stays

15:08

in that particular organ, what's

15:10

known as the residence time.

15:12

As long as you have

15:14

the same residence time, you

15:17

should get the same response

15:19

in terms of chemical conversion,

15:21

he says. Tiny channels on

15:23

each chip. Each between 10

15:25

and 100 microns in diameter

15:27

help bring fluids and oxygen

15:30

to the cells. When you

15:32

get down to less than

15:34

1 micron you can't use

15:36

normal fluid dynamics, says Shula.

15:38

And fluid dynamics matters because

15:40

if the fluid moves through

15:43

the device too quickly the

15:45

cells might die. Too slowly

15:47

and the cells won't react

15:49

normally. Chip technology, while sophisticated,

15:51

has some downsides. One of

15:53

them is user-friendliness. We need

15:55

to get rid of all

15:58

this tubing and pumps and

16:00

make something that's as simple

16:02

as a well-plate for culturing

16:04

cells, says Vounyakavich. The lab

16:06

and others are working on

16:08

simplifying the design and function

16:11

of such chips, so they're

16:13

easier to operate and are

16:15

compatible with robots, which do

16:17

repetitive tasks like perpetual in

16:19

many labs. Cost and sourcing

16:21

can also be challenging. Emulates

16:24

base model, which looks like

16:26

a simple rectangular box from

16:28

the outside, starts at around

16:30

$100,000 and rises steeply from

16:32

there. Most human cells come

16:34

from commercial suppliers that arrange

16:36

for donations from hospital patients.

16:39

During the pandemic, when people

16:41

had fewer elective surgeries, many

16:43

of those sources dried up.

16:45

As micro physiological systems become

16:47

more mainstream, finding reliable sources

16:49

of human cells will be

16:52

critical. Another challenge is that

16:54

every company producing organs on

16:56

chips uses its own proprietary

16:58

methods and technologies. Inberg compares

17:00

the landscape to the early

17:02

days of personal computing, when

17:05

every company developed its own

17:07

hardware and software, and none

17:09

of them meshed well. For

17:11

instance, the microfluidic systems in

17:13

emulates in testin chips are

17:15

fuelled by micro pumps, while

17:17

those made by Mimetus, another

17:20

biotech company, use an electric

17:22

rocker and gravity to circulate

17:24

fluids and air. This is

17:26

not an academic lab type

17:28

of challenge. emphasises Inber. It's

17:30

a commercial challenge. There's no

17:33

way you can get the

17:35

same results anywhere in the

17:37

world with individual academics making

17:39

organs on chips, so you

17:41

have to have commercialisation. Namangay

17:43

Bonpus, the FDA's chief scientist,

17:46

agrees. You can find differences

17:48

in outcomes depending even on

17:50

what types of reagents you're

17:52

using, she says. Those differences

17:54

mean research can't be easily

17:56

reproduced, which diminishes its validity

17:58

and usefulness. would be great

18:01

to have some standardisation," she

18:03

adds. On the plus side, the

18:05

chip technology could help researchers

18:07

address some of the most

18:09

deeply entrenched health inequities in

18:12

science. Clinical trials have

18:14

historically recruited white men,

18:16

under-representing people of colour,

18:18

women, especially pregnant and

18:21

lactating women, the elderly

18:23

and other groups. And

18:25

treatments derived from those trials

18:28

all too often fail in

18:30

members of those underrepresented groups,

18:32

as in Moore's rotivirus vaccine

18:34

mystery. With organs on a chip

18:36

you may be able to create systems

18:39

by which you are very very thoughtful,

18:41

where you spread the net wider than

18:43

has ever been done before, says Moore.

18:45

Another advantage is that chips

18:47

will eventually reduce the need for

18:50

animals in the lab, even as

18:52

they lead to better human outcomes.

18:54

There are aspects of animal research

18:56

that make all of us uncomfortable.

18:58

Even people that do it acknowledges

19:01

more. The same values that make us

19:03

uncomfortable about animal research are

19:05

also the same values that

19:07

make us uncomfortable with seeing

19:09

human beings suffer with diseases

19:11

that we don't have cures for

19:13

yet. So we always sort of balance

19:15

that desire to reduce suffering in all

19:18

the forms that we see it. Lorna

19:20

Ewett, who spent 20 years

19:22

at the farmer giant AstraZeneca

19:24

before joining Emulate, thinks we're

19:27

entering a kind of transition

19:29

time in research, in which

19:31

scientists use in vitro technologies

19:33

like organs on chips alongside

19:36

traditional shell culture methods and

19:38

animals. As your confidence in

19:40

using the chips grows, you might

19:42

say, okay, we don't need two

19:44

animals anymore, we could go with

19:46

chip plus one animal, she says. In

19:48

the meantime, Sean Moore is excited

19:50

about incorporating intestine chips more

19:53

and more deeply into his

19:55

research. His lab has been funded

19:57

by the Gates Foundation to do what

19:59

he He describes as

20:01

a as a between intestine chips

20:03

made by made and and mammatus.

20:05

They're infecting the chips with

20:08

different strains of of

20:10

try to identify the pros

20:12

and cons of each company's design.

20:15

It's too early for any

20:17

substantive results but Moore says

20:19

he does have data showing

20:21

that organ chips are a

20:23

viable model for studying rotavirus

20:26

infection. infection. That could ultimately be

20:28

a real a real game in his

20:30

lab and in labs around

20:32

the world. world. There's more players

20:34

in the space right now,

20:37

says says and that competition

20:39

is going to be a

20:41

healthy thing. healthy thing. You were listening listening

20:43

to Technology Review, Harriet Brown writes,

20:45

is is this the end

20:48

of animal testing? This

20:50

article was published on the

20:52

21st of June the 21st of June

20:54

was read by Jane Wing Jane

20:56

Wing for Noah.