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I want to talk to you
about the future of medicine,

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

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Now, throughout much
of the recent history of medicine,

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we've thought about illness and treatment

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in terms of a profoundly simple model.

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In fact, the model is so simple

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that you could summarize it in six words:

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have disease, take pill, kill something.

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Now, the reason for
the dominance of this model

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is of course the antibiotic revolution.

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

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

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but what you do know

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is that that introduction
was nothing short of transformative.

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Here you had a chemical,
either from the natural world

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or artificially synthesized
in the laboratory,

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and it would course through your body,

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it would find its target,

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lock into its target --

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a microbe or some part of a microbe --

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and then turn off a lock and a key

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with exquisite deftness,
exquisite specificity,

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and you would end up taking
a previously fatal, lethal disease,

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a pneumonia, syphilis, tuberculosis,

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and transforming that into a curable,
or treatable illness.

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You have a pneumonia,
you take penicillin,

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you kill the microbe,

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and you cure the disease.

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So seductive was this idea,

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so potent the metaphor of lock and key

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and killing something,

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that it really swept through biology.

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It was a transformation like no other,

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and we've really spent the last 100 years

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trying to replicate that model
over and over again

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in noninfectious diseases,

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in chronic diseases like diabetes
and hypertension and heart disease.

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

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Let me show you.

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You know, if you take the entire universe

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of all chemical reactions
in the human body,

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every chemical reaction
that your body is capable of,

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

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Let's call it a million.

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And now you ask the question,

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what number or fraction of reactions

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can actually be targeted

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by the entire pharmacopia,
all of medicinal chemistry?

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That number is 250.

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The rest is chemical darkness.

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

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are actually targetable
by this lock and key mechanism.

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You know, if you think about
human physiology

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as a vast global telephone network

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with interacting nodes
and interacting pieces,

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then all of our medicinal chemistry

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is all operating on one tiny corner

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

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It's like all of our
pharmaceutical chemistry

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is a pole operator in Wichita, Kansas

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who is tinkering with
about 10 or 15 telephone lines.

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So what do about this idea?

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What if we reorganized this approach?

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In fact, it turns out
that the natural world

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gives us a sense of how one
might think about illness

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in a radically different way,

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rather than disease, medicine, target.

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In fact, the natural world
is organized hierarchically upwards,

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not downwards, but upwards,

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

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These self-regulating,
semi-autonomous units

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

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and these organs coalesce
to form things called humans,

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and these organisms ultimately live
in environments,

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

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What's nice about this scheme,
this hierarchical scheme

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building upwards rather than downwards

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is that it allows us to think
about illness as well

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in a somewhat different way.

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Take a disease like cancer.

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Since the 1950s, we've tried
rather desperately to apply

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this lock and key model to cancer.

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We've tried to kill cells using a variety
of chemotherapies or targeted therapies,

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

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It's worked for diseases like leukemia.

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It's worked for some forms
of breast cancer,

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but eventually you run
to the ceiling of that approach,

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

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

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

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It actually grows in a human organism,

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and could you use the organismal capacity,

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

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

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And finally, I mean, there's the level
of the environment, isn't there.

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

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Let me give you an example
of a profoundly carcinogenic environment.

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It's called a prison.

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

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and you add to that,

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rolled up in a little white
sheet of paper,

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

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

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and you have a pro-carcinogenic
environment.

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But you can have anti-carcinogenic
environments too.

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There are attempts to create milieus,

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change the hormonal milieu
for breast cancer, for instance.

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

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Or take another disease, like depression.

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Again, working others,

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

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to turn off molecules that operate
between nerve cells --

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serotonin, dopamine --

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and tried to cure depression that way,
and that's worked,

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but then that reached the limit.

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

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

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rewire it, remodel it,

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

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that talk therapy does exactly that,

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and study upon study has shown
that talk therapy combined

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with medicines, pills,

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really is much more effective
than either one alone.

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

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Can you lock out the signals
that elicit depression?

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Again, moving upwards along this
hierarchical chain of organization.

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What's really at stake perhaps here

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is not the medicine itself but a metaphor.

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Rather than killing something,

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in the case of the great
chronic degenerative diseases --

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kidney failure, diabetes,
hypertension, osteoarthritis --

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

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And that's the key, perhaps,

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to reframing our thinking about medicine.

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Now, this idea of changing,

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of creating a perceptual shift,
as it were,

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

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

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I went for a run, a Saturday morning run,

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

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My right knee was swollen up,

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

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

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

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Essentially, the meniscus of cartilage
that is between bone

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

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

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let me tell you a few facts.

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

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60 percent of you would show signs

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of bone degeneration
and cartilage degeneration like this;

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85 percent of all women by the age of 70

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would show moderate to severe
cartilage degeneration;

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50 to 60 percent of the men in
this audience would also have such signs.

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So this is a very common disease.

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Well, the second perk of being a physician

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

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So about 10 years ago we began,

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we brought this process
into the laboratory,

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and we began to do simple experiments,

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mechanically trying
to fix this degeneration.

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We tried to inject chemicals
into the knee spaces of animals

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to try to reverse cartilage degeneration,

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

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essentially it came to naught.

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Nothing happened.

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

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Now, the nice thing about Australians
is that they're habitually used

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to looking at the world upside down,
and so -- (Laughter) --

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

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

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In other words, he had two hypotheses.

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

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that builds up the entire
vertebrate skeleton:

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bone, cartilage,
and the fibrous elements of skeleton,

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just like there's a stem cell in blood,

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

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

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that is causing osteochondral arthritis,
a very common ailment.

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

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when we should have really
been looking for a cell.

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So we switched our models,

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and now we began to look
for skeletal stem cells,

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and to cut again a long story short,

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about five years ago,
we found these cells.

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They live inside the skeleton.

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

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The white stuff is bone,

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and these red columns that you see
and the yellow cells

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are cells that have arisen
from one single skeleton stem cell,

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

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These cells are fascinating.
They have four properties.

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

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They live just underneath
the surface of the bone,

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underneath cartilage.

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

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and they move into the appropriate areas
and form bone and cartilage. That's one.

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Here's an interesting property.

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You can take them out
of the vertebrate skeleton,

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you can culture them
in petri dishes in the laboratory,

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and they are dying to form cartilage.

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

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These cells are dying to form cartilage.

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They form their own furls
of cartilage around themselves.

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They're also, number three,
the most efficient repairers

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of fractures that we've ever encountered.

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

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and then let it heal by itself.

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

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in white, the cartilage,
almost completely,

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

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you can see them like some kind of
peculiar cellular glue

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coming into the area of a fracture,
fixing it locally,

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and then stopping their work.

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Now, the fourth one is the most ominous,

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and that is that their numbers
decline precipitously,

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precipitously, tenfold,
fiftyfold, as you age.

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And so what had happened, really,
is that we found ourselves

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in perceptual shift.

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We had gone hunting for pills

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but we ended up finding theories,

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and in some ways, we had hooked ourselves
back onto this idea:

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cells, organisms, environments,

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because we were now thinking
about bone stem cells,

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

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And then the next question was,
are there organs?

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Can you build this as an organ
outside the body?

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Can you implant cartilage
into areas of trauma?

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And perhaps most interestingly,

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can you ascend right up
and create environments?

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You know, we know
that exercise remodels bone,

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

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So could you imagine ways of passively
loading and unloading bone

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so that you can recreate
or regenerate degenerating catilage?

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And perhaps more interesting,
and more importantly,

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the question is, can you apply this model
more globally outside medicine?

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What's at stake, as I said before,
is not killing something,

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but growing something.

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And it raises a series of, I think,
some of the most interesting questions

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about how we think
about medicine in the future.

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Could your medicine be a cell
and not a pill?

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How would we grow these cells?

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What we would we do to stop
the malignant growth of these cells?

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We heard about the problems
of unleashing growth.

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Would we have to implant
suicide genes into these cells

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to stop them from growing?

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Could your medicine be an organ
that's created outside the body

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and then implanted into the body?

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Could that stop some of the degeneration?

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What if the organ needed to have memory?

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In cases of diseases of the nervous system
some of those organs had memory.

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How could we implant
those memories back in?

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Could we store these organs?

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Could each organ have to be developed
for an individual human being

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and put back?

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And perhaps most puzzlingly,

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could your medicine be an environment?

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Could you patent an environment?

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In every culture, shamans have been
using environments as medicines.

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Could we imagine that for our future?

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I've talked a lot about models.
I began this talk with models.

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So let me end with some thoughts
about model building.

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That's what we do as scientists.

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You know, when an architect
builds a model,

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he or she is trying to show you
a world in miniature.

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But when a scientist is building a model,

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he or she is trying to show you
the world in metaphor.

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He or she is trying to create
a new way of seeing.

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The former is a scale shift.
The latter is a perceptual shift.

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Now, antibiotics created
such a perceptual shift

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in our way of thinking about medicine
that it really colored, distorted,

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very successfully, the way we've thought
about medicine for the last hundred years.

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But we need new models
to think about medicine in the future.

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That's what's at stake.

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You know, there's
a popular trope out there

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that the reason we haven't had
the transformative impact

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on the treatment of illness

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is because we don't have
powerful enough drugs,

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and that's partly true,

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but perhaps the real reason is
that we don't have powerful enough

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ways of thinking about medicines.

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It's certainly true that

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it would be lovely to have new medicines,

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but perhaps what's really at stake
are three more intangible ends:

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mechanisms, models, metaphors.

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Thank you.

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(Applause)

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Chris Anderson: I really
like this metaphor.

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How does it link in?
There's a lot of talk

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in technologyland about
the personalization of medicine,

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that we have all this data
and that medical treatments of the future

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will be for you specifically,
your genome, your current context.

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Does that apply to this model
you've got here?

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Siddhartha Mukherjee: It's
a very interesting question.

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You know, we've thought
about personalization of medicine

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very much in terms of genomics.

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That's because the gene
is such a dominant metaphor,

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again, to use that same word,
in medicine today,

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that we think the genome will drive
the personalization of medicine.

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But of course the genome
is just the bottom

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of a long chain of being, as it were.

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That chain of being, really the first
organized unit of that, is the cell.

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So, if we are really going to deliver
in medicine in this way,

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we have to think of personalizing
cellular therapies,

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and then personalizing
organ or organismal therapies,

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and ultimately personalizing
emersion therapies for the environment.

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So I think at every stage, you know,

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there's that metaphor,
there's turtles all the way.

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Well, in this, there's
personalization all the way.

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CA: So when you say
medicine could be a cell

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and not a pill,

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I mean, you're talking about
potentially your own cells.

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SM: Absolutely.
CA: So converted to stem cells,

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perhaps tested against all kinds
of drugs or something, and prepared.

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SM: And there's no perhaps.
This is what we're doing.

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This is what's happening, and in fact,
we're slowly moving,

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not away from genomics,
but incorporating genomics

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into what we call multi-order,
semi-autonomous, self-regulating systems,

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like cells, like organs,
like environments.

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CA: Thank you so much.
SM: Thank you.