TED2015
Siddhartha Mukherjee: Soon we'll cure diseases with a cell, not a pill
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Current medical treatment boils down to six words: Have disease, take pill, kill something. But physician Siddhartha Mukherjee points to a future of medicine that will transform the way we heal.
Siddhartha Mukherjee - Cancer physician and writer
When he’s not ferreting out the links between stem cells and malignant blood disease, Siddhartha Mukherjee writes and lectures on the history (and future) of medicine. Full bio
When he’s not ferreting out the links between stem cells and malignant blood disease, Siddhartha Mukherjee writes and lectures on the history (and future) of medicine. Full bio
Double-click the English transcript below to play the video.
00:12
I want to talk to you
about the future of medicine.
about the future of medicine.
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But before I do that, I want to talk
a little bit about the past.
a little bit about the past.
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Now, throughout much
of the recent history of medicine,
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
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
but we happen to be celebrating
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the hundredth year of the introduction
of antibiotics into the United States.
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.
was nothing short of transformative.
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Here you had a chemical,
either from the natural world
either from the natural world
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or artificially synthesized
in the laboratory,
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.
exquisite specificity.
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And you would end up taking
a previously fatal, lethal disease --
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.
into a curable, or treatable illness.
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You have a pneumonia,
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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
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.
and hypertension and heart disease.
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And it's worked,
but it's only worked partly.
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,
in the human body,
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every chemical reaction
that your body is capable of,
that your body is capable of,
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most people think that that number
is on the order of a million.
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 pharmacopoeia,
all of medicinal chemistry?
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
of all chemical reactions in your body
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are actually targetable
by this lock and key mechanism.
by this lock and key mechanism.
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You know, if you think
about human physiology
about human physiology
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as a vast global telephone network
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with interacting nodes
and interacting pieces,
and interacting pieces,
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then all of our medicinal chemistry
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is operating on one tiny corner
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at the edge, the outer edge,
of that network.
of that network.
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It's like all of our
pharmaceutical chemistry
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.
10 or 15 telephone lines.
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So what do we 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
that the natural world
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gives us a sense of how one
might think about illness
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,
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.
semi-autonomous unit called a cell.
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These self-regulating,
semi-autonomous units
semi-autonomous units
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give rise to self-regulating,
semi-autonomous units called organs,
semi-autonomous units called organs,
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and these organs coalesce
to form things called humans,
to form things called humans,
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and these organisms
ultimately live in environments,
ultimately live in environments,
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which are partly self-regulating
and partly semi-autonomous.
and partly semi-autonomous.
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What's nice about this scheme,
this hierarchical 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
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,
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we've tried rather desperately to apply
this lock and key model to cancer.
this lock and key model to cancer.
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We've tried to kill cells
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using a variety of chemotherapies
or targeted therapies,
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,
of breast cancer,
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but eventually you run
to the ceiling of that approach.
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,
about using the immune system,
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remembering that in fact the cancer cell
doesn't grow in a vacuum.
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?
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.
spectacular new medicines in cancer.
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And finally there's the level
of the environment, isn't there?
of the environment, isn't there?
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You know, we don't think of cancer
as altering the environment.
as altering the environment.
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But let me give you an example
of a profoundly carcinogenic environment.
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,
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,
white sheet of paper,
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one of the most potent neurostimulants
that we know, called nicotine,
that we know, called nicotine,
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and you add to that one of the most potent
addictive substances that you know,
addictive substances that you know,
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and you have
a pro-carcinogenic environment.
a pro-carcinogenic environment.
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But you can have anti-carcinogenic
environments too.
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.
for breast cancer, for instance.
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We're trying to change the metabolic
milieu for other forms of cancer.
milieu for other forms of cancer.
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Or take another disease, like depression.
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Again, working upwards,
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since the 1960s and 1970s,
we've tried, again, desperately
we've tried, again, desperately
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to turn off molecules
that operate between nerve cells --
that operate between nerve cells --
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serotonin, dopamine --
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and tried to cure depression that way,
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and that's worked,
but then that reached the limit.
but then that reached the limit.
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And we now know that what you
really probably need to do
really probably need to do
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is to change the physiology
of the organ, the brain,
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
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
has shown that talk therapy
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combined with medicines, pills,
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really is much more effective
than either one alone.
than either one alone.
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Can we imagine a more immersive
environment that will change depression?
environment that will change depression?
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Can you lock out the signals
that elicit depression?
that elicit depression?
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Again, moving upwards along this
hierarchical chain of organization.
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 --
chronic degenerative diseases --
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kidney failure, diabetes,
hypertension, osteoarthritis --
hypertension, osteoarthritis --
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maybe what we really need to do is change
the metaphor to growing something.
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,
shift, as it were,
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came home to me to roost in a very
personal manner about 10 years ago.
personal manner about 10 years ago.
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About 10 years ago --
I've been a runner most of my life --
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.
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.
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.
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.
and it looked like that.
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Essentially, the meniscus of cartilage
that is between bone
that is between bone
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had been completely torn
and the bone itself had been shattered.
and the bone itself had been shattered.
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Now, if you're looking at me
and feeling sorry,
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,
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.
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.
cartilage degeneration.
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50 to 60 percent
of the men in this audience
of the men in this audience
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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.
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,
into the laboratory,
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and we began to do simple experiments,
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mechanically trying
to fix this degeneration.
to fix this degeneration.
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We tried to inject chemicals
into the knee spaces of animals
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,
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.
we had a research student from Australia.
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The nice thing about Australians
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is that they're habitually used to
looking at the world upside down.
looking at the world upside down.
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(Laughter)
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And so Dan suggested to me, "You know,
maybe it isn't a mechanical problem.
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."
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 --
as a skeletal stem cell --
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a skeletal stem cell that builds up
the entire vertebrate skeleton,
the entire vertebrate skeleton,
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bone, cartilage and the fibrous
elements of skeleton,
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.
in the nervous system.
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And two, that maybe that, the degeneration
or dysfunction of this stem cell
or dysfunction of this stem cell
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is what's causing osteochondral arthritis,
a very common ailment.
a very common ailment.
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So really the question was,
were we looking for a pill
were we looking for a pill
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when we should have really
been looking for a cell.
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.
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.
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.
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
and the yellow cells
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are cells that have arisen
from one single skeletal stem cell --
from one single skeletal stem cell --
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columns of cartilage, columns of bone
coming out of a single cell.
coming out of a single cell.
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These cells are fascinating.
They have four properties.
They have four properties.
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Number one is that they live
where they're expected to live.
where they're expected to live.
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They live just underneath
the surface of the bone,
the surface of the bone,
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underneath cartilage.
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You know, in biology,
it's location, location, location.
it's location, location, location.
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And they move into the appropriate areas
and form bone and cartilage.
and form bone and cartilage.
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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,
of the vertebrate skeleton,
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you can culture them
in petri dishes in the laboratory,
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?
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.
of cartilage around themselves.
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They're also, number three,
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the most efficient repairers
of fractures that we've ever encountered.
of fractures that we've ever encountered.
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This is a little bone,
a mouse bone that we fractured
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,
and repaired, in yellow, the bone,
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in white, the cartilage,
almost completely.
almost completely.
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So much so that if you label them
with a fluorescent dye
with a fluorescent dye
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you can see them like some kind
of peculiar cellular glue
of peculiar cellular glue
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coming into the area of a fracture,
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fixing it locally
and then stopping their work.
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,
decline precipitously,
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precipitously, tenfold,
fiftyfold, as you age.
fiftyfold, as you age.
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And so what had happened, really,
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is that we found ourselves
in a perceptual shift.
in a 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
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we had hooked ourselves
back onto this idea:
back onto this idea:
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cells, organisms, environments,
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because we were now thinking
about bone stem cells,
about bone stem cells,
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we were thinking about arthritis
in terms of a cellular disease.
in terms of a cellular disease.
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And then the next question was,
are there organs?
are there organs?
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Can you build this
as an organ outside the body?
as an organ outside the body?
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Can you implant cartilage
into areas of trauma?
into areas of trauma?
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And perhaps most interestingly,
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can you ascend right up
and create environments?
and create environments?
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You know, we know
that exercise remodels bone,
that exercise remodels bone,
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but come on, none of us
is going to exercise.
is going to exercise.
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So could you imagine ways of passively
loading and unloading bone
loading and unloading bone
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so that you can recreate
or regenerate degenerating cartilage?
or regenerate degenerating cartilage?
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And perhaps more interesting,
and more importantly,
and more importantly,
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the question is, can you apply this model
more globally outside medicine?
more globally outside medicine?
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What's at stake, as I said before,
is not killing something,
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
some of the most interesting questions
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about how we think
about medicine in the future.
about medicine in the future.
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Could your medicine
be a cell and not a pill?
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?
the malignant growth of these cells?
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We heard about the problems
of unleashing growth.
of unleashing growth.
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Could we implant
suicide genes into these cells
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
that's created outside the body
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and then implanted into the body?
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13:30
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.
some of those organs had memory.
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How could we implant
those memories back in?
those memories back in?
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Could we store these organs?
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Would each organ have to be developed
for an individual human being
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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You know, in every culture,
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shamans have been using
environments as medicines.
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.
I began this talk with models.
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So let me end with some thoughts
about model building.
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,
builds a model,
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he or she is trying to show you
a world in miniature.
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.
the world in metaphor.
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He or she is trying to create
a new way of seeing.
a new way of seeing.
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The former is a scale shift.
The latter is a perceptual shift.
The latter is a perceptual shift.
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Now, antibiotics created
such a perceptual shift
such a perceptual shift
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in our way of thinking about medicine
that it really colored, distorted,
that it really colored, distorted,
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very successfully, the way we've thought
about medicine for the last hundred years.
about medicine for the last hundred years.
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But we need new models
to think about medicine in the future.
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
a popular trope out there
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that the reason we haven't had
the transformative impact
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,
powerful-enough drugs,
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and that's partly true.
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But perhaps the real reason is
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that we don't have powerful-enough
ways of thinking about medicines.
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 M's:
are three more intangible M's:
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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.
I really like this metaphor.
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How does it link in?
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There's a lot of talk in technologyland
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about the personalization of medicine,
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that we have all this data
and that medical treatments of the future
and that medical treatments of the future
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will be for you specifically,
your genome, your current context.
your genome, your current context.
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Does that apply to this model
you've got here?
you've got here?
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Siddhartha Mukherjee:
It's a very interesting question.
It's a very interesting question.
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We've thought about
personalization of medicine
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,
is such a dominant metaphor,
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again, to use that same word,
in medicine today,
in medicine today,
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that we think the genome will drive
the personalization of medicine.
the personalization of medicine.
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But of course the genome
is just the bottom
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.
organized unit of that, is the cell.
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So, if we are really going to deliver
in medicine in this way,
in medicine in this way,
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we have to think of personalizing
cellular therapies,
cellular therapies,
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and then personalizing
organ or organismal therapies,
organ or organismal therapies,
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and ultimately personalizing
immersion therapies for the environment.
immersion 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.
there's turtles all the way.
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Well, in this, there's
personalization all the way.
personalization all the way.
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CA: So when you say
medicine could be a cell
medicine could be a cell
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and not a pill,
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you're talking about
potentially your own cells.
potentially your own cells.
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SM: Absolutely.
CA: So converted to stem cells,
CA: So converted to stem cells,
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perhaps tested against all kinds
of drugs or something, and prepared.
of drugs or something, and prepared.
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SM: And there's no perhaps.
This is what we're doing.
This is what we're doing.
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This is what's happening,
and in fact, we're slowly moving,
and in fact, we're slowly moving,
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not away from genomics,
but incorporating genomics
but incorporating genomics
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into what we call multi-order,
semi-autonomous, self-regulating systems,
semi-autonomous, self-regulating systems,
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like cells, like organs,
like environments.
like environments.
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CA: Thank you so much.
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SM: Pleasure. Thanks.
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ABOUT THE SPEAKER
Siddhartha Mukherjee - Cancer physician and writerWhen he’s not ferreting out the links between stem cells and malignant blood disease, Siddhartha Mukherjee writes and lectures on the history (and future) of medicine.
Why you should listen
While discussing a diagnosis with a patient, Siddhartha Mukherjee realized that there were no easy answers to the question, “What is cancer?” Faced with his hesitation, Mukherjee decided to do something about it.
Over the next six years, Mukherjee wrote the influential, Pulitzer-winning The Emperor of All Maladies, a 4,000-year “biography” of cancer. He collaborated with Ken Burns on a six-hour documentary for PBS based on his book, updating the story with recent discoveries in oncology.
In his new TED Book, The Laws of Medicine, he examines the three principles that govern modern medicine -- and every profession that confronts uncertainty and wonder.
Siddhartha Mukherjee | Speaker | TED.com