The New Age of Medicine

Hi, everyone.

My name's Emily Mullin, and I cover biotech for WIRED.

It is my great pleasure to introduce

someone who really needs no introduction,

CRISPR pioneer, Jennifer Doudna.

She is a biochemist

at the University of California, Berkeley.

Dr. Doudna, of course, won the Nobel Prize in 2020

for her role in discovering the gene editing system

known as CRISPR.

She's also the founder of the Innovative Genomics Institute,

a joint effort between UC Berkeley, and UC San Francisco.

Please, let's welcome Dr. Doudna to the stage.

[bright music] [audience clapping]

Thank you so much for being here, Dr. Doudna.

It's been 11 years,

over 11 years since your landmark paper

appeared in the Journal of Science

first describing CRISPR as a novel genome editing system.

For all of us in the room, for all of our benefit,

can you remind everyone

what the acronym CRISPR stands for

and where CRISPR comes from?

Well, hi, Emily, it's a great pleasure to be here.

Hi, everybody.

So CRISPR is an acronym that stands

for Clustered Regularly Interspaced

Short Palindromic Repeats.

[audience laughing] Remember that?

I'm amazed I remember it.

But what it really is,

is a very powerful technology for editing genomes,

editing the code of life.

So imagine a tool that allows scientists

to literally go inside of a cell

and make a precise change to the DNA in the cell

that encodes all the information required for life.

And we can do this now with a precision

that allows us to program CRISPR

to target a particular gene,

I'm sure we'll get into what kinds of things are happening,

but it means that we can understand the function of genes

at a level that was never possible before.

And, most importantly,

we can actually manipulate those genes,

we can rewrite the code,

and that's what makes this technology so powerful.

Thinking back to the early days

of when you were studying CRISPR in the lab,

was there a moment either in the lab,

or maybe it was over your breakfast,

or driving home from work one day

when the potential of CRISPR

really dawned on you?

Well, you know, CRISPR came from fundamental curiosity

driven research into a bacterial immune system,

a mechanism that bacteria used to fight viral infection.

And it was by studying how that works,

that we figured out how to harness it

as a very different kind of technology

for manipulating DNA.

And, for me, I think it was really the moment

at which we recognized the mechanism

of this immune system,

and how it could be used to target DNA

in a programmable way,

and the understanding of how to program it

that, for me, was that moment

of kind of the aha moment of saying,

This technology is really going to change the world.

So for those of us who are not geneticists,

why edit genes at all?

You know, why not just give somebody

a small molecule drug, for instance?

Well, imagine that you had a way to manipulate genes

that cause disease or cause health.

It gives us a tool that means that in the future,

and the future is now by the way,

we won't have to take a drug

over a long period of time to treat disease,

but we can actually, for a genetic disease,

go to its source and make a corrective change

at the level of DNA.

So it fundamentally changes the way we think

about our health and the way

we think about the future of medicine.

And the hope is that these will be one-time treatments,

a one and done, correct? That's right.

So in mid-November, some of you might have heard

that the UK approved the first CRISPR-based therapy,

it's called Casgevy.

It is a one-time treatment

for people with sickle cell disease

made by Vertex Pharmaceuticals and CRISPR Therapeutics.

What was it like for you, Dr. Doudna,

when you found out this news

that CRISPR had essentially moved from an idea,

a concept in the lab to reality,

to treating patients to something

that doctors can now prescribe

to people with this terrible disease?

The reality of that, for me,

came home when I met Victoria Gray,

who is the first US patient to receive the CRISPR therapy

for her sickle cell disease.

Extraordinary story of a person

who had lived with this genetic disorder,

had affected her whole life,

made it difficult for her to be a mom to her kids,

to pursue her business interests.

And after receiving this therapy,

a one-and-done treatment,

it completely transformed her life.

She didn't have to deal

with the effects of sickle cell disease anymore,

and she was able to enroll in business school,

and she's starting a clothing company, it's amazing.

So, you know, seeing that kind of effect on somebody's life

and realizing that science and technology

are starting to enable people

to truly transform their future is extraordinary.

Right, I've spoken with sickle cell experts,

doctors who treat patients with this terrible disorder,

and they say this is truly

a transformative therapy,

these patients who have these terrible,

excruciating pain episodes

and now they don't have to deal with that anymore.

Here in the US, the FDA is now poised

to decide on whether to approve this therapy

by the end of this week,

and perhaps today we might hear actually, we don't know,

could happen Friday at 4:00 PM, like the FDA often does.

Some people are saying that this is a cure.

How do you feel about the C-word?

Well, how do I feel about the C-word?

I feel very excited about it.

I think we have to be cautious,

because it's still the early days of CRISPR.

But so far it looks like people

that receive this one-and-done treatment

truly are cured of the effects of their disease.

What are the biggest safety concerns

with CRISPRing cells

that are put into a person's body,

like with this therapy,

or as we're talking about future therapies

that might actually have the CRISPR mechanism

right in the body where you're CRISPRing

people's tissues, organs,

injecting this gene editing treatment right into the body?

Well, I have to say I love your use

of the word CRISPR as a verb, Emily, that's great.

To CRISPR. [laughs]

But I think, you know, when we think about safety,

it's important to recognize that this tool

is being used today to make permanent changes to DNA,

but it's also possible to use it in a way that makes changes

that are reversible.

So I think going forward there will be a whole toolbox

of CRISPR tools that allow the kind of manipulation

to genes that is appropriate

given a particular disease or application.

But it is critical to maintain a focus on safety,

and, of course, that's what the whole

clinical trial process is all about.

Right, so with this therapy, and with others,

we hear about off-target effects.

Can you talk about what off-target effects mean?

And if we're talking about a precise genome editing tool

that's programmed to target

a very small place in a gene,

what could go wrong?

Well, we don't want it to target the wrong place

in the wrong gene.

And so the goal really is to ensure

that CRISPR is as accurate and safe as possible.

There's been a huge effort in the field over the last decade

to understand, you know,

when and how does CRISPR make a mistake?

And when it does, what can we do about it?

And also, most importantly, how do we avoid that?

And I think what's very interesting

is that looking at the clinical data

that are coming from these trials that are ongoing,

it's turning out that in clinically relevant cells,

using the type of validated CRISPR tools

that are being deployed in the clinic,

it appears really very safe.

It doesn't mean that we shouldn't continue

to work on this and pay very close attention to it,

but I think so far that issue has really not been a problem

in the application of CRISPR in humans.

The process of administering this sickle cell treatment

for patients is complex.

It's complicated, it's not as simple as taking a pill

or getting an injection.

It involves extracting patient's stem cells

from the bone marrow.

Then in the lab you have to CRISPR them,

to use it as a verb again.

And then, those cells are then returned

to the patient eventually.

But in order to do that,

the patient is in the hospital for many, many weeks.

They have to go through chemotherapy

to get their body ready to receive these cells.

There are all sorts of side effects

that they might have because of this process.

So it's not something that I think patients

are gonna go into lightly,

even though it does carry the promise of the C-word, a cure.

So I'm wondering, in the future,

do you think that this process could be simplified,

especially for patients who really, really want this,

but maybe the prospect of this complicated,

complex therapy, it's too much maybe for them

to think about and to undergo.

So how are scientists like yourself thinking

about simplifying this process

so that it's not so arduous,

I guess, for the patient to go through?

Well, it's not only arduous to go through,

but it also is expensive.

And that's one of the real challenges currently

is that this therapy is expected to be priced

somewhere between 1.3 and $2 million a patient.

So that's a price point that just,

you know, will make it out of reach for most people globally

that could benefit from it.

So I've been very interested in the expansion of CRISPR,

you know, into the world in a way that makes it affordable

and accessible to people that can benefit from it.

That was a very important reason we started

the Innovative Genomics Institute

at the University of California here in the Bay Area.

I think, you know, the Bay Area

has always signified innovation.

It's been a place that inspires creativity

with all of the people here, many of them here,

that are thinking about the future

and how do we create the future.

And so in terms of thinking

about the future of genome editing,

I really want to be working to ensure

that we make this technology

widely available and accessible.

And the question is, how do we do that?

And I feel that it's very important

to be working in the context of a nonprofit, which we are,

but also partnering as much as we can

with all kinds of companies, entrepreneurs,

investors, various stakeholders,

to build the technology of the future

that will enable, at some point in the future,

a sickle cell patient to receive a one-time injection,

maybe even that's a pill at some point that they take,

that is curative of their disease.

And today that sounds a little bit fantastical,

but I think it's very achievable.

And we have some concrete ways

that we're working towards that goal

at the Innovative Genomics Institute

to make sure that it becomes a reality.

Can you elaborate on that? I can.

So one of the big challenges right now

I think with CRISPR, and you alluded to it,

is how we deliver the CRISPR editors into cells,

how do we get them into a patient?

And today that's being done primarily by an approach

that for sickle cell disease, for example,

involves taking stem cells from a patient.

These are cells that are the progenitors

of our blood supplies, our blood cells,

editing them in the laboratory,

and then putting them back into a patient.

But we imagine a day when we don't have to do that,

that we actually have a tool

that will allow us to target the CRISPR molecules directly

to the cells that need editing in the body.

And we're doing this in a variety of ways

at the Innovative Genomics Institute,

but one of them involves taking the machinery

that viruses use to infect specific types of cells,

gutting that machinery

of all of the viral replication DNA,

so that you don't have a replicating virus,

but using the delivery vehicle

to deliver CRISPR molecules in a way that we can program

so we can program the vehicle

to go to the cells where editing is needed.

I think this is a very exciting future direction

of the field and something that will offer,

we hope, in the future patients the opportunity

to get a CRISPR therapy in a much more affordable fashion.

So let's bring it back to today.

And you mentioned the price of this sickle cell therapy,

the one that was just approved in the UK,

Vertex and CRISPR Therapeutics,

they have not announced a price for this therapy yet,

but as you mentioned, Dr. Doudna,

there are estimates that this could be upwards

of two to $3 million.

There are a lot of patients with sickle cell

in the US, over 100,000,

although not all those, of course, will be eligible

or may want this therapy.

But for those that do,

as a society, how do we make sure that these people

are going to be able to get this treatment?

I think one important conversation that needs to happen

is that we need to be working with payers,

insurance companies,

to understand how do you think about paying

for a therapy like this?

As we've been discussing,

ideally it's a one-and-done treatment

that cures somebody of a disease

that would otherwise recur over the course of their life,

which is obviously, you know, very, very expensive

to think about all of the hospitalizations,

blood transfusions, other kinds of treatments they need,

plus the economic impact on their ability to work,

and to support their family, to contribute to societies,

it's a huge cost.

And so I think that's a very important conversation

that, you know, is starting,

and needs to happen I think more intensively now

that CRISPR therapies are a reality.

This is a disease that mainly affects people

of African descent.

And it's a disease that scientists

have been studying for a long time

and have known the biological mechanisms behind,

since what, the 1950s I think?

It's taken a long time to get to this point

where we have a potential genetic cure for these people.

What do you think it's going to mean

for the patient community

to have something like this that is so revolutionary,

that could change the lives of so many people?

One of the things I'm excited about is that this is,

as you said, this is a therapy that's helping people

that have been traditionally not treated very well

by the medical community,

and so I think that's very appropriate.

I think it's very inspiring.

I really salute patients

that have been willing to go into these early trials,

that requires extraordinary bravery and willingness,

you know, to try something that's truly experimental.

But I also think they're blazing a trail for many others,

because the hope is that this will be the first

of many opportunities to use CRISPR

not only for rare genetic diseases,

but also for conditions that affect many more people.

And there are already pretty advanced clinical trials

that are looking into ways

to affect diseases of the liver,

but also to think about preventive medicine in the future.

So if we really wanna, you know, be futuristic

about where genome editing is headed,

I think that in the longer term

we're going to see applications that allow us

to protect ourselves from diseases

that we might be susceptible to due to our genetics.

And, on that note, let's shift to CRISPR's uses

in other areas of medicine.

So a biotech company called Editas Medicine

was developing a CRISPR treatment

for a rare type of inherited blindness

that it ended up benefiting I think one patient,

she had really good results,

but then it failed in the other patients

in this clinical trial.

What do you think that tells us

about the limitations of CRISPR?

Well, I think it tells us that in that trial

they were working with patients

who had very advanced disease of the eye

where it may have been too late in a way

for a genome editing technology,

or at least the way it was administered to them,

to be effective.

So, honestly, I don't think we can conclude anything

about CRISPR itself from that example.

I think it's more of a statement about the way

we need to think about treating diseases.

When we're talking about a genetic therapy,

we need to think about it from the perspective of,

what time points in the disease pathway

will this kind of approach be effective?

You mentioned this a little bit earlier

about the question of how to deliver CRISPR.

So I was hoping you could elaborate on this a bit

about what are the barriers

to applying CRISPR to other diseases?

I'm thinking about neurological diseases

when you're thinking about putting CRISPR in the brain,

or organs that are not necessarily easy to get to.

How do we edit those parts of the body?

Well, it's a big challenge, Emily, that's for sure.

I think when we think about putting CRISPR into the brain,

we face the same challenges

that any kind of neurological therapy faces,

which is that it's very hard to get molecules

across what's called the blood-brain barrier.

So with CRISPR today, what's happening is that people

are using a physical approach to do that.

So you can do injections that cross the blood-brain barrier

and introduce CRISPR molecules

into particular parts of the brain.

And, in fact, I was at a meeting yesterday

where I was reviewing some data

from a scientist at Ohio State University.

He also has an appointment here at UCSF in the city

that allows targeting

of particular parts of the brain

with various kinds of molecules,

he wasn't using CRISPR, but, in theory, one could,

and seeing amazing effects on patients

that have really devastating neurological disorders.

So I think that, again, thinking about the future,

which is a theme of this meeting,

it's really exciting to think about the opportunities

to target genes that make people susceptible

to neurological disease,

Alzheimer's, neurodegenerative disease,

I think these are very important areas

of focus in the future with genome editing.

You're working on a new initiative

around using CRISPR to edit the microbiome.

What diseases might be treated that way

and why the microbiome?

Well, let's start with what is the microbiome?

The microbiome is the collection of microbes

that populate our bodies, our planet.

They affect really everything

about our health and our environment.

And what's really interesting with CRISPR is that,

as I mentioned earlier,

it's a technology that came from microbes.

And so what we're trying to do now

is to use CRISPR at its source,

going back into those microbes,

but not doing it traditionally the way scientists

have investigated one type of bacteria at a time,

but to really think about how we can edit whole populations

of microbes in their native environment.

And in terms of the impact there,

why would we want to do this?

There's increasing evidence that our own microbiome,

the microbiome that lives in the human gut,

affects a lot of the health and disease impacts

that we experience over the course of our lifetime.

And so we think that in the future it will be possible

to use CRISPR to fine tune that microbiome

so that it either doesn't produce disease-causing molecules

or does produce molecules that improve our health.

And in the environment, we have a project with folks

up at the University of California, Davis,

to impact the production of methane

by microbiome populations that live in cattle.

And you may know that methane

is one of the most powerful of the greenhouse gases.

So being able to reduce or even eliminate methane production

by cattle would actually have an enormous impact globally

on greenhouse gas production.

So we're actively working on this in the laboratory

to make sure that the technology is effective.

And then, of course, very importantly,

with our institute partnering

with farmers in other countries

to begin educating them about this technology

and, ultimately, to help them

begin to deploy it when it's ready.

So would this involve swallowing a liquid probiotic

with CRISPR molecules in it?

Or what exactly are you imagining?

Could be that, yeah, this is one of the things

we're researching right now,

is what is the best way to deliver,

again, this back to this question of delivery,

how do we deliver the genome editors into the microbiome?

And one of the approaches

that could be very interesting actually,

is using the viruses that infect bacteria to deliver CRISPR

back into a particular species of microbes,

so that's something we're exploring.

So, as you alluded to before,

there are several CRISPR therapies

being tested in clinical trials right now for HIV,

cancer, a hereditary form of high cholesterol.

What are you most excited

about when you look out at the CRISPR landscape?

Well, I'm certainly excited about expanding opportunities

to help people with rare disease.

I think that's very important.

It's an area that most traditional pharmaceutical companies

don't focus on, because it doesn't offer

the kind of economic payout that they might be looking for.

And yet, if we look collectively at people

affected by rare diseases, it's a large number.

And so the opportunity with CRISPR

is that because of its programmable nature,

once we understand how to use it for one disease,

we can, we hope, reprogram it fairly readily

to use the same molecules for a different disease.

And so I think that's one application that I'm very excited

about and is a focus of the Innovative Genomics Institute.

And then, of course, we already spoke

about the opportunities in climate change

with methane production.

And I think there are huge opportunities

in agriculture more broadly that, frankly,

many of us will experience, I think, CRISPR in our lives

in the agricultural world

before we might experience it clinically.

We could have a whole other conversation about that.

And I wanted to ask you to do a little bit

of a prediction for my last question.

And because you just mentioned

about people's lives being touched by CRISPR,

if you could look out into the audience

and give me a sense of, in 10, 20 years,

how many people out there will get a CRISPR treatment

in their lifetime?

Hmm, that's a hard question.

I think in 10 to 20 years, if you're talking

about somebody receiving an actual CRISPR therapy,

it's probably gonna be still a relatively small number.

I think that by a decade or more from now though,

most of us will be experiencing CRISPR in our lives

through the food that we eat,

through the environmental impacts that we're able to deploy

with CRISPR to reduce greenhouse gas emissions.

I think that will be the more broad global impact

in the near term.

Well, thank you so much, Dr. Doudna, for joining us.

This has been a great conversation.

Thanks a lot, Emily. Thank you.