But before I do that, I want to talk a little bit about the past.

Now, throughout much of the recent history of medicine,

we've thought about illness and treatment

in terms of a profoundly simple model.

In fact, the model is so simple

that you could summarize it in six words:

have disease, take pill, kill something.

Now, the reason for the dominance of this model

is of course the antibiotic revolution.

Many of you might not know this, but we happen to be celebrating

the hundredth year of the introduction of antibiotics into the United States.

But what you do know

is that that introduction was nothing short of transformative.

Here you had a chemical, either from the natural world

or artificially synthesized in the laboratory,

and it would course through your body,

it would find its target,

lock into its target --

a microbe or some part of a microbe --

and then turn off a lock and a key

with exquisite deftness, exquisite specificity.

And you would end up taking a previously fatal, lethal disease --

a pneumonia, syphilis, tuberculosis --

and transforming that into a curable, or treatable illness.

You have a pneumonia,

you take penicillin,

you kill the microbe

and you cure the disease.

So seductive was this idea,

so potent the metaphor of lock and key

and killing something,

that it really swept through biology.

It was a transformation like no other.

And we've really spent the last 100 years

trying to replicate that model over and over again

in noninfectious diseases,

in chronic diseases like diabetes and hypertension and heart disease.

And it's worked, but it's only worked partly.

Let me show you.

You know, if you take the entire universe

of all chemical reactions in the human body,

every chemical reaction that your body is capable of,

most people think that that number is on the order of a million.

Let's call it a million.

And now you ask the question,

what number or fraction of reactions

can actually be targeted

by the entire pharmacopoeia, all of medicinal chemistry?

That number is 250.

The rest is chemical darkness.

In other words, 0.025 percent of all chemical reactions in your body

are actually targetable by this lock and key mechanism.

You know, if you think about human physiology

as a vast global telephone network

with interacting nodes and interacting pieces,

then all of our medicinal chemistry

is operating on one tiny corner

at the edge, the outer edge, of that network.

It's like all of our pharmaceutical chemistry

is a pole operator in Wichita, Kansas

who is tinkering with about 10 or 15 telephone lines.

So what do we do about this idea?

What if we reorganized this approach?

In fact, it turns out that the natural world

gives us a sense of how one might think about illness

in a radically different way,

rather than disease, medicine, target.

In fact, the natural world is organized hierarchically upwards,

not downwards, but upwards,

and we begin with a self-regulating, semi-autonomous unit called a cell.

These self-regulating, semi-autonomous units

give rise to self-regulating, semi-autonomous units called organs,

and these organs coalesce to form things called humans,

and these organisms ultimately live in environments,

which are partly self-regulating and partly semi-autonomous.

What's nice about this scheme, this hierarchical scheme

building upwards rather than downwards,

is that it allows us to think about illness as well

in a somewhat different way.

Take a disease like cancer.

Since the 1950s,

we've tried rather desperately to apply this lock and key model to cancer.

We've tried to kill cells

using a variety of chemotherapies or targeted therapies,

and as most of us know, that's worked.

It's worked for diseases like leukemia.

It's worked for some forms of breast cancer,

but eventually you run to the ceiling of that approach.

And it's only in the last 10 years or so

that we've begun to think about using the immune system,

remembering that in fact the cancer cell doesn't grow in a vacuum.

It actually grows in a human organism.

And could you use the organismal capacity,

the fact that human beings have an immune system, to attack cancer?

In fact, it's led to the some of the most spectacular new medicines in cancer.

And finally there's the level of the environment, isn't there?

You know, we don't think of cancer as altering the environment.

But let me give you an example of a profoundly carcinogenic environment.

It's called a prison.

You take loneliness, you take depression, you take confinement,

and you add to that,

rolled up in a little white sheet of paper,

one of the most potent neurostimulants that we know, called nicotine,

and you add to that one of the most potent addictive substances that you know,

and you have a pro-carcinogenic environment.

But you can have anti-carcinogenic environments too.

There are attempts to create milieus,

change the hormonal milieu for breast cancer, for instance.

We're trying to change the metabolic milieu for other forms of cancer.

Or take another disease, like depression.

Again, working upwards,

since the 1960s and 1970s, we've tried, again, desperately

to turn off molecules that operate between nerve cells --

serotonin, dopamine --

and tried to cure depression that way,

and that's worked, but then that reached the limit.

And we now know that what you really probably need to do

is to change the physiology of the organ, the brain,

rewire it, remodel it,

and that, of course, we know study upon study has shown

that talk therapy does exactly that,

and study upon study has shown that talk therapy

combined with medicines, pills,

really is much more effective than either one alone.

Can we imagine a more immersive environment that will change depression?

Can you lock out the signals that elicit depression?

Again, moving upwards along this hierarchical chain of organization.

What's really at stake perhaps here

is not the medicine itself but a metaphor.

Rather than killing something,

in the case of the great chronic degenerative diseases --

kidney failure, diabetes, hypertension, osteoarthritis --

maybe what we really need to do is change the metaphor to growing something.

And that's the key, perhaps,

to reframing our thinking about medicine.

Now, this idea of changing,

of creating a perceptual shift, as it were,

came home to me to roost in a very personal manner about 10 years ago.

About 10 years ago -- I've been a runner most of my life --

I went for a run, a Saturday morning run,

I came back and woke up and I basically couldn't move.

My right knee was swollen up,

and you could hear that ominous crunch of bone against bone.

And one of the perks of being a physician is that you get to order your own MRIs.

And I had an MRI the next week, and it looked like that.

Essentially, the meniscus of cartilage that is between bone

had been completely torn and the bone itself had been shattered.

Now, if you're looking at me and feeling sorry,

let me tell you a few facts.

If I was to take an MRI of every person in this audience,

60 percent of you would show signs

of bone degeneration and cartilage degeneration like this.

85 percent of all women by the age of 70

would show moderate to severe cartilage degeneration.

50 to 60 percent of the men in this audience

would also have such signs.

So this is a very common disease.

Well, the second perk of being a physician

is that you can get to experiment on your own ailments.

So about 10 years ago we began,

we brought this process into the laboratory,

and we began to do simple experiments,

mechanically trying to fix this degeneration.

We tried to inject chemicals into the knee spaces of animals

to try to reverse cartilage degeneration,

and to put a short summary on a very long and painful process,

essentially it came to naught.

Nothing happened.

And then about seven years ago, we had a research student from Australia.

The nice thing about Australians

is that they're habitually used to looking at the world upside down.

(Laughter)

And so Dan suggested to me, "You know, maybe it isn't a mechanical problem.

Maybe it isn't a chemical problem. Maybe it's a stem cell problem."

In other words, he had two hypotheses.

Number one, there is such a thing as a skeletal stem cell --

a skeletal stem cell that builds up the entire vertebrate skeleton,

bone, cartilage and the fibrous elements of skeleton,

just like there's a stem cell in blood,

just like there's a stem cell in the nervous system.

And two, that maybe that, the degeneration or dysfunction of this stem cell

is what's causing osteochondral arthritis, a very common ailment.

So really the question was, were we looking for a pill

when we should have really been looking for a cell.

So we switched our models,

and now we began to look for skeletal stem cells.

And to cut again a long story short,

about five years ago, we found these cells.

They live inside the skeleton.

Here's a schematic and then a real photograph of one of them.

The white stuff is bone,

and these red columns that you see and the yellow cells

are cells that have arisen from one single skeletal stem cell --

columns of cartilage, columns of bone coming out of a single cell.

These cells are fascinating. They have four properties.

Number one is that they live where they're expected to live.

They live just underneath the surface of the bone,

underneath cartilage.

You know, in biology, it's location, location, location.

And they move into the appropriate areas and form bone and cartilage.

That's one.

Here's an interesting property.

You can take them out of the vertebrate skeleton,

you can culture them in petri dishes in the laboratory,

and they are dying to form cartilage.

Remember how we couldn't form cartilage for love or money?

These cells are dying to form cartilage.

They form their own furls of cartilage around themselves.

They're also, number three,

the most efficient repairers of fractures that we've ever encountered.

This is a little bone, a mouse bone that we fractured

and then let it heal by itself.

These stem cells have come in and repaired, in yellow, the bone,

in white, the cartilage, almost completely.

So much so that if you label them with a fluorescent dye

you can see them like some kind of peculiar cellular glue

coming into the area of a fracture,

fixing it locally and then stopping their work.

Now, the fourth one is the most ominous,

and that is that their numbers decline precipitously,

precipitously, tenfold, fiftyfold, as you age.

And so what had happened, really,

is that we found ourselves in a perceptual shift.

We had gone hunting for pills

but we ended up finding theories.

And in some ways

we had hooked ourselves back onto this idea:

cells, organisms, environments,

because we were now thinking about bone stem cells,

we were thinking about arthritis in terms of a cellular disease.

And then the next question was, are there organs?

Can you build this as an organ outside the body?

Can you implant cartilage into areas of trauma?

And perhaps most interestingly,

can you ascend right up and create environments?

You know, we know that exercise remodels bone,

but come on, none of us is going to exercise.