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  • I want to talk to you about the future of medicine.

  • 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.

  • So could you imagine ways of passively loading and unloading bone

  • so that you can recreate or regenerate degenerating cartilage?

  • And perhaps more interesting, and more importantly,

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

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

  • but growing something.