WEBVTT

99:59:59.999 --> 99:59:59.999
I want to talk to you
about the future of medicine,

99:59:59.999 --> 99:59:59.999
but before I do that, I want to talk
a little bit about the past.

99:59:59.999 --> 99:59:59.999
Now, throughout much
of the recent history of medicine,

99:59:59.999 --> 99:59:59.999
we've thought about illness and treatment

99:59:59.999 --> 99:59:59.999
in terms of a profoundly simple model.

99:59:59.999 --> 99:59:59.999
In fact, the model is so simple

99:59:59.999 --> 99:59:59.999
that you could summarize it in six words:

99:59:59.999 --> 99:59:59.999
have disease, take pill, kill something.

99:59:59.999 --> 99:59:59.999
Now, the reason for
the dominance of this model

99:59:59.999 --> 99:59:59.999
is of course the antibiotic revolution.

99:59:59.999 --> 99:59:59.999
Many of you might not know this,
but we happen to be celebrating

99:59:59.999 --> 99:59:59.999
the hundredth year of the introduction
of antibiotics into the United States,

99:59:59.999 --> 99:59:59.999
but what you do know

99:59:59.999 --> 99:59:59.999
is that that introduction
was nothing short of transformative.

99:59:59.999 --> 99:59:59.999
Here you had a chemical,
either from the natural world

99:59:59.999 --> 99:59:59.999
or artificially synthesized
in the laboratory,

99:59:59.999 --> 99:59:59.999
and it would course through your body,

99:59:59.999 --> 99:59:59.999
it would find its target,

99:59:59.999 --> 99:59:59.999
lock into its target --

99:59:59.999 --> 99:59:59.999
a microbe or some part of a microbe --

99:59:59.999 --> 99:59:59.999
and then turn off a lock and a key

99:59:59.999 --> 99:59:59.999
with exquisite deftness,
exquisite specificity,

99:59:59.999 --> 99:59:59.999
and you would end up taking
a previously fatal, lethal disease,

99:59:59.999 --> 99:59:59.999
a pneumonia, syphilis, tuberculosis,

99:59:59.999 --> 99:59:59.999
and transforming that into a curable,
or treatable illness.

99:59:59.999 --> 99:59:59.999
You have a pneumonia,
you take penicillin,

99:59:59.999 --> 99:59:59.999
you kill the microbe,

99:59:59.999 --> 99:59:59.999
and you cure the disease.

99:59:59.999 --> 99:59:59.999
So seductive was this idea,

99:59:59.999 --> 99:59:59.999
so potent the metaphor of lock and key

99:59:59.999 --> 99:59:59.999
and killing something,

99:59:59.999 --> 99:59:59.999
that it really swept through biology.

99:59:59.999 --> 99:59:59.999
It was a transformation like no other,

99:59:59.999 --> 99:59:59.999
and we've really spent the last 100 years

99:59:59.999 --> 99:59:59.999
trying to replicate that model
over and over again

99:59:59.999 --> 99:59:59.999
in noninfectious diseases,

99:59:59.999 --> 99:59:59.999
in chronic diseases like diabetes
and hypertension and heart disease.

99:59:59.999 --> 99:59:59.999
And it's worked,
but it's only worked partly.

99:59:59.999 --> 99:59:59.999
Let me show you.

99:59:59.999 --> 99:59:59.999
You know, if you take the entire universe

99:59:59.999 --> 99:59:59.999
of all chemical reactions
in the human body,

99:59:59.999 --> 99:59:59.999
every chemical reaction
that your body gets,

99:59:59.999 --> 99:59:59.999
most people think that that number
is on the order of a million.

99:59:59.999 --> 99:59:59.999
Let's call it a million.

99:59:59.999 --> 99:59:59.999
And now you ask the question,

99:59:59.999 --> 99:59:59.999
what number or fraction of reactions

99:59:59.999 --> 99:59:59.999
can actually be targeted

99:59:59.999 --> 99:59:59.999
by the entire pharmacopia,
all of medicinal chemistry?

99:59:59.999 --> 99:59:59.999
That number is 250.

99:59:59.999 --> 99:59:59.999
The rest is chemical darkness.

99:59:59.999 --> 99:59:59.999
In other words, 0.025 percent
of all chemical reactions in your body

99:59:59.999 --> 99:59:59.999
are actually targetable
by this lock and key mechanism.

99:59:59.999 --> 99:59:59.999
You know, if you think about
human physiology

99:59:59.999 --> 99:59:59.999
as a vast global telephone network

99:59:59.999 --> 99:59:59.999
with interacting nodes
and interacting pieces,

99:59:59.999 --> 99:59:59.999
then all of our medicinal chemistry

99:59:59.999 --> 99:59:59.999
is all operating on one tiny corner

99:59:59.999 --> 99:59:59.999
at the edge, the outer edge,
of that network.

99:59:59.999 --> 99:59:59.999
It's like all of our
pharmaceutical chemistry

99:59:59.999 --> 99:59:59.999
is a pole operator in Wichita, Kansas

99:59:59.999 --> 99:59:59.999
who is tinkering with
about 10 or 15 telephone lines.

99:59:59.999 --> 99:59:59.999
So what do about this idea?

99:59:59.999 --> 99:59:59.999
What if we reorganized this approach?

99:59:59.999 --> 99:59:59.999
In fact, it turns out
that the natural world

99:59:59.999 --> 99:59:59.999
gives us a sense of how one
might think about illness

99:59:59.999 --> 99:59:59.999
in a radically different way,

99:59:59.999 --> 99:59:59.999
rather than disease, medicine, target.

99:59:59.999 --> 99:59:59.999
In fact, the natural world
is organized hierarchically upwards,

99:59:59.999 --> 99:59:59.999
not downwards, but upwards,

99:59:59.999 --> 99:59:59.999
and we begin with a self-regulating,
semi-autonomous unit called a cell.

99:59:59.999 --> 99:59:59.999
These self-regulating,
semi-autonomous units

99:59:59.999 --> 99:59:59.999
give rise to self-regulating,
semi-autonomous units called organs,

99:59:59.999 --> 99:59:59.999
and these organs coalesce
to form things called humans,

99:59:59.999 --> 99:59:59.999
and these organisms ultimately live
in environments,

99:59:59.999 --> 99:59:59.999
which are partly self-regulating
and partly semi-autonomous.

99:59:59.999 --> 99:59:59.999
What's nice about this scheme,
this hierarchical scheme

99:59:59.999 --> 99:59:59.999
building upwards rather than downwards

99:59:59.999 --> 99:59:59.999
is that it allows us to think
about illness as well

99:59:59.999 --> 99:59:59.999
in a somewhat different way.

99:59:59.999 --> 99:59:59.999
Take a disease like cancer.

99:59:59.999 --> 99:59:59.999
Since the 1950s, we've tried
rather desperately to apply

99:59:59.999 --> 99:59:59.999
this lock and key model to cancer.

99:59:59.999 --> 99:59:59.999
We've tried to kill cells using a variety
of chemotherapies or targeted therapies,

99:59:59.999 --> 99:59:59.999
and as most of us know, that's worked.

99:59:59.999 --> 99:59:59.999
It's worked for diseases like leukemia.

99:59:59.999 --> 99:59:59.999
It's worked for some forms
of breast cancer,

99:59:59.999 --> 99:59:59.999
but eventually you run
to the ceiling of that approach,

99:59:59.999 --> 99:59:59.999
and it's only in the last 10 years or so

99:59:59.999 --> 99:59:59.999
that we've begun to think
about using the immune system,

99:59:59.999 --> 99:59:59.999
remembering that in fact the cancer cell
doesn't grow in a vacuum.

99:59:59.999 --> 99:59:59.999
It actually grows in a human organism,

99:59:59.999 --> 99:59:59.999
and could you use the organismal capacity,

99:59:59.999 --> 99:59:59.999
the fact that human beings
have an immune system, to attack cancer?

99:59:59.999 --> 99:59:59.999
In fact, it's led to the some of the most
spectacular new medicines in cancer.

99:59:59.999 --> 99:59:59.999
And finally, I mean, there's the level
of the environment, isn't there.

99:59:59.999 --> 99:59:59.999
You know, we don't think of cancer
as altering the environment.

99:59:59.999 --> 99:59:59.999
Let me give you an example
of a profoundly carcinogenic environment.

99:59:59.999 --> 99:59:59.999
It's called a prison.

99:59:59.999 --> 99:59:59.999
You take loneliness, you take depression,
you take confinement,

99:59:59.999 --> 99:59:59.999
and you add to that,

99:59:59.999 --> 99:59:59.999
rolled up in a little white
sheet of paper,

99:59:59.999 --> 99:59:59.999
one of the most potent neurostimulants
that we know, called nicotine,

99:59:59.999 --> 99:59:59.999
and you add to that one of the most potent
addictive substances that you know,

99:59:59.999 --> 99:59:59.999
and you have a pro-carcinogenic
environment.

99:59:59.999 --> 99:59:59.999
But you can have anti-carcinogenic
environments too.

99:59:59.999 --> 99:59:59.999
There are attempts to create milieus,

99:59:59.999 --> 99:59:59.999
change the hormonal milieu
for breast cancer, for instance.

99:59:59.999 --> 99:59:59.999
We're trying to change the metabolic
milieu for other forms of cancer.

99:59:59.999 --> 99:59:59.999
Or take another disease, like depression.

99:59:59.999 --> 99:59:59.999
Again, working others,

99:59:59.999 --> 99:59:59.999
since the 1960s and 1970s,
we've tried, again, desperately

99:59:59.999 --> 99:59:59.999
to turn off molecules that operate
between nerve cells --

99:59:59.999 --> 99:59:59.999
serotonin, dopamine --

99:59:59.999 --> 99:59:59.999
and tried to cure depression that way,
and that's worked,

99:59:59.999 --> 99:59:59.999
but then that leads to the limit.

99:59:59.999 --> 99:59:59.999
And we now know that what you
really probably need to do

99:59:59.999 --> 99:59:59.999
is to change the physiology
of the organ, the brain,

99:59:59.999 --> 99:59:59.999
rewire it, remodel it,

99:59:59.999 --> 99:59:59.999
and that of course, we know
study upon study has shown

99:59:59.999 --> 99:59:59.999
that talk therapy does exactly that,

99:59:59.999 --> 99:59:59.999
and study upon study has shown
that talk therapy combined

99:59:59.999 --> 99:59:59.999
with medicines, pills,

99:59:59.999 --> 99:59:59.999
really is much more effective
than either one alone.

99:59:59.999 --> 99:59:59.999
Can we imagine a more immersive
environment that will change depression?

99:59:59.999 --> 99:59:59.999
Can you lock out the signals
that elicit depression?

99:59:59.999 --> 99:59:59.999
Again, moving upwards along this
hierarchical chain of organization.

99:59:59.999 --> 99:59:59.999
What's really at stake perhaps here

99:59:59.999 --> 99:59:59.999
is not the medicine itself but a metaphor.

99:59:59.999 --> 99:59:59.999
Rather than killing something,

99:59:59.999 --> 99:59:59.999
in the case of the great
chronic degenerative diseases --

99:59:59.999 --> 99:59:59.999
kidney failure, diabetes,
hypertension, osteoarthritis --

99:59:59.999 --> 99:59:59.999
maybe what we really need to do is change
the metaphor to growing something.

99:59:59.999 --> 99:59:59.999
And that's the key, perhaps,

99:59:59.999 --> 99:59:59.999
to reframing our thinking about medicine.

99:59:59.999 --> 99:59:59.999
Now, this idea of changing,

99:59:59.999 --> 99:59:59.999
of creating a perceptual shift,
as it were,

99:59:59.999 --> 99:59:59.999
came home to me to roost in a very,
very personal matter about 10 years ago.

99:59:59.999 --> 99:59:59.999
About 10 years ago --
I've been a runner most of my life --

99:59:59.999 --> 99:59:59.999
I went for a run, a Saturday morning run,

99:59:59.999 --> 99:59:59.999
I came back and woke up
and I basically couldn't move.

99:59:59.999 --> 99:59:59.999
My right knee was swollen up,

99:59:59.999 --> 99:59:59.999
and you could hear that ominous crunch
of bone against bone.

99:59:59.999 --> 99:59:59.999
And one of the perks of being a physician
is that you get to order your own MRIs.

99:59:59.999 --> 99:59:59.999
And I had an MRI the next week,
and it looked like that.

99:59:59.999 --> 99:59:59.999
Essentially, the meniscus of cartilage
that is between bone

99:59:59.999 --> 99:59:59.999
had been completely torn
and the bone itself had been shattered.

99:59:59.999 --> 99:59:59.999
Now, if you're looking at me
and feeling sorry,

99:59:59.999 --> 99:59:59.999
let me tell you a few facts.

99:59:59.999 --> 99:59:59.999
If I was to take an MRI
of every person in this audience,

99:59:59.999 --> 99:59:59.999
60 percent of you would show signs

99:59:59.999 --> 99:59:59.999
of bone degeneration
and cartilage degeneration like this;

99:59:59.999 --> 99:59:59.999
85 percent of all women by the age of 70

99:59:59.999 --> 99:59:59.999
would show moderate to severe
cartilage degeneration;

99:59:59.999 --> 99:59:59.999
50 to 60 percent of the men in
this audience would also have such signs.

99:59:59.999 --> 99:59:59.999
So this is a very common disease.

99:59:59.999 --> 99:59:59.999
Well, the second perk of being a physician

99:59:59.999 --> 99:59:59.999
is that you can get to experiment
on your own ailments.

99:59:59.999 --> 99:59:59.999
So about 10 years ago we began,

99:59:59.999 --> 99:59:59.999
we brought this process
into the laboratory,

99:59:59.999 --> 99:59:59.999
and we began to do simple experiments,

99:59:59.999 --> 99:59:59.999
mechanically trying
to fix this degeneration.

99:59:59.999 --> 99:59:59.999
We tried to inject chemicals
into the knee spaces of animals

99:59:59.999 --> 99:59:59.999
to try to reverse cartilage degeneration,

99:59:59.999 --> 99:59:59.999
and to put a short summary
on a very long and painful process,

99:59:59.999 --> 99:59:59.999
essentially it came to naught.

99:59:59.999 --> 99:59:59.999
Nothing happened.

99:59:59.999 --> 99:59:59.999
And then about seven years ago,
we had a research student from Australia.

99:59:59.999 --> 99:59:59.999
Now, the nice thing about Australians
is that they're habitually used

99:59:59.999 --> 99:59:59.999
to looking at the world upside down,
and so -- (Laughter) --

99:59:59.999 --> 99:59:59.999
Dan suggested to me, "You know,
maybe it isn't a mechanical problem.

99:59:59.999 --> 99:59:59.999
Maybe it isn't a chemical problem.
Maybe it's a stem cell problem."

99:59:59.999 --> 99:59:59.999
In other words, he had two hypotheses.

99:59:59.999 --> 99:59:59.999
Number one, there is such a thing
as a skeletal stem cell

99:59:59.999 --> 99:59:59.999
that builds up the entire
vertebrate skeleton:

99:59:59.999 --> 99:59:59.999
bone, cartilage,
and the fibrous elements of skeleton,

99:59:59.999 --> 99:59:59.999
just like there's a stem cell in blood,

99:59:59.999 --> 99:59:59.999
just like there's a stem cell
in the nervous system,

99:59:59.999 --> 99:59:59.999
and two, that maybe that, the degeneration
or dysfunction of this stem cell

99:59:59.999 --> 99:59:59.999
that is causing osteochondral arthritis,
a very common ailment.

99:59:59.999 --> 99:59:59.999
So really the question was,
were we looking for a pill

99:59:59.999 --> 99:59:59.999
when we should have really
been looking for a cell.

99:59:59.999 --> 99:59:59.999
So we switched our models,

99:59:59.999 --> 99:59:59.999
and now we began to look
for skeletal stem cells,

99:59:59.999 --> 99:59:59.999
and to cut again a long story short,

99:59:59.999 --> 99:59:59.999
about five years ago,
we found these cells.

99:59:59.999 --> 99:59:59.999
They live inside the skeleton.

99:59:59.999 --> 99:59:59.999
Here's a schematic and then
a real photograph of one of them.

99:59:59.999 --> 99:59:59.999
The white stuff is bone,

99:59:59.999 --> 99:59:59.999
and these red columns that you see
and the yellow cells

99:59:59.999 --> 99:59:59.999
are cells that have arisen
from one single skeleton stem cell,

99:59:59.999 --> 99:59:59.999
columns of cartilage, columns of bone
coming out a single cell.

99:59:59.999 --> 99:59:59.999
These cells are fascinating.
They have four properties.

99:59:59.999 --> 99:59:59.999
Number one is that they live
where they're expected to live.

99:59:59.999 --> 99:59:59.999
They live just underneath
the surface of the bone,

99:59:59.999 --> 99:59:59.999
underneath cartilage.