9:59:59.000,9:59:59.000 I want to talk to you[br]about the future of medicine, 9:59:59.000,9:59:59.000 but before I do that, I want to talk[br]a little bit about the past. 9:59:59.000,9:59:59.000 Now, throughout much[br]of the recent history of medicine, 9:59:59.000,9:59:59.000 we've thought about illness and treatment 9:59:59.000,9:59:59.000 in terms of a profoundly simple model. 9:59:59.000,9:59:59.000 In fact, the model is so simple 9:59:59.000,9:59:59.000 that you could summarize it in six words: 9:59:59.000,9:59:59.000 have disease, take pill, kill something. 9:59:59.000,9:59:59.000 Now, the reason for[br]the dominance of this model 9:59:59.000,9:59:59.000 is of course the antibiotic revolution. 9:59:59.000,9:59:59.000 Many of you might not know this,[br]but we happen to be celebrating 9:59:59.000,9:59:59.000 the hundredth year of the introduction[br]of antibiotics into the United States, 9:59:59.000,9:59:59.000 but what you do know 9:59:59.000,9:59:59.000 is that that introduction[br]was nothing short of transformative. 9:59:59.000,9:59:59.000 Here you had a chemical,[br]either from the natural world 9:59:59.000,9:59:59.000 or artificially synthesized[br]in the laboratory, 9:59:59.000,9:59:59.000 and it would course through your body, 9:59:59.000,9:59:59.000 it would find its target, 9:59:59.000,9:59:59.000 lock into its target -- 9:59:59.000,9:59:59.000 a microbe or some part of a microbe -- 9:59:59.000,9:59:59.000 and then turn off a lock and a key 9:59:59.000,9:59:59.000 with exquisite deftness,[br]exquisite specificity, 9:59:59.000,9:59:59.000 and you would end up taking[br]a previously fatal, lethal disease, 9:59:59.000,9:59:59.000 a pneumonia, syphilis, tuberculosis, 9:59:59.000,9:59:59.000 and transforming that into a curable,[br]or treatable illness. 9:59:59.000,9:59:59.000 You have a pneumonia,[br]you take penicillin, 9:59:59.000,9:59:59.000 you kill the microbe, 9:59:59.000,9:59:59.000 and you cure the disease. 9:59:59.000,9:59:59.000 So seductive was this idea, 9:59:59.000,9:59:59.000 so potent the metaphor of lock and key 9:59:59.000,9:59:59.000 and killing something, 9:59:59.000,9:59:59.000 that it really swept through biology. 9:59:59.000,9:59:59.000 It was a transformation like no other, 9:59:59.000,9:59:59.000 and we've really spent the last 100 years 9:59:59.000,9:59:59.000 trying to replicate that model[br]over and over again 9:59:59.000,9:59:59.000 in noninfectious diseases, 9:59:59.000,9:59:59.000 in chronic diseases like diabetes[br]and hypertension and heart disease. 9:59:59.000,9:59:59.000 And it's worked,[br]but it's only worked partly. 9:59:59.000,9:59:59.000 Let me show you. 9:59:59.000,9:59:59.000 You know, if you take the entire universe 9:59:59.000,9:59:59.000 of all chemical reactions[br]in the human body, 9:59:59.000,9:59:59.000 every chemical reaction[br]that your body gets, 9:59:59.000,9:59:59.000 most people think that that number[br]is on the order of a million. 9:59:59.000,9:59:59.000 Let's call it a million. 9:59:59.000,9:59:59.000 And now you ask the question, 9:59:59.000,9:59:59.000 what number or fraction of reactions 9:59:59.000,9:59:59.000 can actually be targeted 9:59:59.000,9:59:59.000 by the entire pharmacopia,[br]all of medicinal chemistry? 9:59:59.000,9:59:59.000 That number is 250. 9:59:59.000,9:59:59.000 The rest is chemical darkness. 9:59:59.000,9:59:59.000 In other words, 0.025 percent[br]of all chemical reactions in your body 9:59:59.000,9:59:59.000 are actually targetable[br]by this lock and key mechanism. 9:59:59.000,9:59:59.000 You know, if you think about[br]human physiology 9:59:59.000,9:59:59.000 as a vast global telephone network 9:59:59.000,9:59:59.000 with interacting nodes[br]and interacting pieces, 9:59:59.000,9:59:59.000 then all of our medicinal chemistry 9:59:59.000,9:59:59.000 is all operating on one tiny corner 9:59:59.000,9:59:59.000 at the edge, the outer edge,[br]of that network. 9:59:59.000,9:59:59.000 It's like all of our[br]pharmaceutical chemistry 9:59:59.000,9:59:59.000 is a pole operator in Wichita, Kansas 9:59:59.000,9:59:59.000 who is tinkering with[br]about 10 or 15 telephone lines. 9:59:59.000,9:59:59.000 So what do about this idea? 9:59:59.000,9:59:59.000 What if we reorganized this approach? 9:59:59.000,9:59:59.000 In fact, it turns out[br]that the natural world 9:59:59.000,9:59:59.000 gives us a sense of how one[br]might think about illness 9:59:59.000,9:59:59.000 in a radically different way, 9:59:59.000,9:59:59.000 rather than disease, medicine, target. 9:59:59.000,9:59:59.000 In fact, the natural world[br]is organized hierarchically upwards, 9:59:59.000,9:59:59.000 not downwards, but upwards, 9:59:59.000,9:59:59.000 and we begin with a self-regulating,[br]semi-autonomous unit called a cell. 9:59:59.000,9:59:59.000 These self-regulating,[br]semi-autonomous units 9:59:59.000,9:59:59.000 give rise to self-regulating,[br]semi-autonomous units called organs, 9:59:59.000,9:59:59.000 and these organs coalesce[br]to form things called humans, 9:59:59.000,9:59:59.000 and these organisms ultimately live[br]in environments, 9:59:59.000,9:59:59.000 which are partly self-regulating[br]and partly semi-autonomous. 9:59:59.000,9:59:59.000 What's nice about this scheme,[br]this hierarchical scheme 9:59:59.000,9:59:59.000 building upwards rather than downwards 9:59:59.000,9:59:59.000 is that it allows us to think[br]about illness as well 9:59:59.000,9:59:59.000 in a somewhat different way. 9:59:59.000,9:59:59.000 Take a disease like cancer. 9:59:59.000,9:59:59.000 Since the 1950s, we've tried[br]rather desperately to apply 9:59:59.000,9:59:59.000 this lock and key model to cancer. 9:59:59.000,9:59:59.000 We've tried to kill cells using a variety[br]of chemotherapies or targeted therapies, 9:59:59.000,9:59:59.000 and as most of us know, that's worked. 9:59:59.000,9:59:59.000 It's worked for diseases like leukemia. 9:59:59.000,9:59:59.000 It's worked for some forms[br]of breast cancer, 9:59:59.000,9:59:59.000 but eventually you run[br]to the ceiling of that approach, 9:59:59.000,9:59:59.000 and it's only in the last 10 years or so 9:59:59.000,9:59:59.000 that we've begun to think[br]about using the immune system, 9:59:59.000,9:59:59.000 remembering that in fact the cancer cell[br]doesn't grow in a vacuum. 9:59:59.000,9:59:59.000 It actually grows in a human organism, 9:59:59.000,9:59:59.000 and could you use the organismal capacity, 9:59:59.000,9:59:59.000 the fact that human beings[br]have an immune system, to attack cancer? 9:59:59.000,9:59:59.000 In fact, it's led to the some of the most[br]spectacular new medicines in cancer. 9:59:59.000,9:59:59.000 And finally, I mean, there's the level[br]of the environment, isn't there. 9:59:59.000,9:59:59.000 You know, we don't think of cancer[br]as altering the environment. 9:59:59.000,9:59:59.000 Let me give you an example[br]of a profoundly carcinogenic environment. 9:59:59.000,9:59:59.000 It's called a prison. 9:59:59.000,9:59:59.000 You take loneliness, you take depression,[br]you take confinement, 9:59:59.000,9:59:59.000 and you add to that, 9:59:59.000,9:59:59.000 rolled up in a little white[br]sheet of paper, 9:59:59.000,9:59:59.000 one of the most potent neurostimulants[br]that we know, called nicotine, 9:59:59.000,9:59:59.000 and you add to that one of the most potent[br]addictive substances that you know, 9:59:59.000,9:59:59.000 and you have a pro-carcinogenic[br]environment. 9:59:59.000,9:59:59.000 But you can have anti-carcinogenic[br]environments too. 9:59:59.000,9:59:59.000 There are attempts to create milieus, 9:59:59.000,9:59:59.000 change the hormonal milieu[br]for breast cancer, for instance. 9:59:59.000,9:59:59.000 We're trying to change the metabolic[br]milieu for other forms of cancer. 9:59:59.000,9:59:59.000 Or take another disease, like depression. 9:59:59.000,9:59:59.000 Again, working others, 9:59:59.000,9:59:59.000 since the 1960s and 1970s,[br]we've tried, again, desperately 9:59:59.000,9:59:59.000 to turn off molecules that operate[br]between nerve cells -- 9:59:59.000,9:59:59.000 serotonin, dopamine -- 9:59:59.000,9:59:59.000 and tried to cure depression that way,[br]and that's worked, 9:59:59.000,9:59:59.000 but then that leads to the limit. 9:59:59.000,9:59:59.000 And we now know that what you[br]really probably need to do 9:59:59.000,9:59:59.000 is to change the physiology[br]of the organ, the brain, 9:59:59.000,9:59:59.000 rewire it, remodel it, 9:59:59.000,9:59:59.000 and that of course, we know[br]study upon study has shown 9:59:59.000,9:59:59.000 that talk therapy does exactly that, 9:59:59.000,9:59:59.000 and study upon study has shown[br]that talk therapy combined 9:59:59.000,9:59:59.000 with medicines, pills, 9:59:59.000,9:59:59.000 really is much more effective[br]than either one alone. 9:59:59.000,9:59:59.000 Can we imagine a more immersive[br]environment that will change depression? 9:59:59.000,9:59:59.000 Can you lock out the signals[br]that elicit depression? 9:59:59.000,9:59:59.000 Again, moving upwards along this[br]hierarchical chain of organization. 9:59:59.000,9:59:59.000 What's really at stake perhaps here 9:59:59.000,9:59:59.000 is not the medicine itself but a metaphor. 9:59:59.000,9:59:59.000 Rather than killing something, 9:59:59.000,9:59:59.000 in the case of the great[br]chronic degenerative diseases -- 9:59:59.000,9:59:59.000 kidney failure, diabetes,[br]hypertension, osteoarthritis -- 9:59:59.000,9:59:59.000 maybe what we really need to do is change[br]the metaphor to growing something. 9:59:59.000,9:59:59.000 And that's the key, perhaps, 9:59:59.000,9:59:59.000 to reframing our thinking about medicine. 9:59:59.000,9:59:59.000 Now, this idea of changing, 9:59:59.000,9:59:59.000 of creating a perceptual shift,[br]as it were, 9:59:59.000,9:59:59.000 came home to me to roost in a very,[br]very personal matter about 10 years ago. 9:59:59.000,9:59:59.000 About 10 years ago --[br]I've been a runner most of my life -- 9:59:59.000,9:59:59.000 I went for a run, a Saturday morning run, 9:59:59.000,9:59:59.000 I came back and woke up[br]and I basically couldn't move. 9:59:59.000,9:59:59.000 My right knee was swollen up, 9:59:59.000,9:59:59.000 and you could hear that ominous crunch[br]of bone against bone. 9:59:59.000,9:59:59.000 And one of the perks of being a physician[br]is that you get to order your own MRIs. 9:59:59.000,9:59:59.000 And I had an MRI the next week,[br]and it looked like that. 9:59:59.000,9:59:59.000 Essentially, the meniscus of cartilage[br]that is between bone 9:59:59.000,9:59:59.000 had been completely torn[br]and the bone itself had been shattered. 9:59:59.000,9:59:59.000 Now, if you're looking at me[br]and feeling sorry, 9:59:59.000,9:59:59.000 let me tell you a few facts. 9:59:59.000,9:59:59.000 If I was to take an MRI[br]of every person in this audience, 9:59:59.000,9:59:59.000 60 percent of you would show signs 9:59:59.000,9:59:59.000 of bone degeneration[br]and cartilage degeneration like this; 9:59:59.000,9:59:59.000 85 percent of all women by the age of 70 9:59:59.000,9:59:59.000 would show moderate to severe[br]cartilage degeneration; 9:59:59.000,9:59:59.000 50 to 60 percent of the men in[br]this audience would also have such signs. 9:59:59.000,9:59:59.000 So this is a very common disease. 9:59:59.000,9:59:59.000 Well, the second perk of being a physician 9:59:59.000,9:59:59.000 is that you can get to experiment[br]on your own ailments. 9:59:59.000,9:59:59.000 So about 10 years ago we began, 9:59:59.000,9:59:59.000 we brought this process[br]into the laboratory, 9:59:59.000,9:59:59.000 and we began to do simple experiments, 9:59:59.000,9:59:59.000 mechanically trying[br]to fix this degeneration. 9:59:59.000,9:59:59.000 We tried to inject chemicals[br]into the knee spaces of animals 9:59:59.000,9:59:59.000 to try to reverse cartilage degeneration, 9:59:59.000,9:59:59.000 and to put a short summary[br]on a very long and painful process, 9:59:59.000,9:59:59.000 essentially it came to naught. 9:59:59.000,9:59:59.000 Nothing happened. 9:59:59.000,9:59:59.000 And then about seven years ago,[br]we had a research student from Australia. 9:59:59.000,9:59:59.000 Now, the nice thing about Australians[br]is that they're habitually used 9:59:59.000,9:59:59.000 to looking at the world upside down,[br]and so -- (Laughter) -- 9:59:59.000,9:59:59.000 Dan suggested to me, "You know,[br]maybe it isn't a mechanical problem. 9:59:59.000,9:59:59.000 Maybe it isn't a chemical problem.[br]Maybe it's a stem cell problem." 9:59:59.000,9:59:59.000 In other words, he had two hypotheses. 9:59:59.000,9:59:59.000 Number one, there is such a thing[br]as a skeletal stem cell 9:59:59.000,9:59:59.000 that builds up the entire[br]vertebrate skeleton: 9:59:59.000,9:59:59.000 bone, cartilage,[br]and the fibrous elements of skeleton, 9:59:59.000,9:59:59.000 just like there's a stem cell in blood, 9:59:59.000,9:59:59.000 just like there's a stem cell[br]in the nervous system, 9:59:59.000,9:59:59.000 and two, that maybe that, the degeneration[br]or dysfunction of this stem cell 9:59:59.000,9:59:59.000 that is causing osteochondral arthritis,[br]a very common ailment. 9:59:59.000,9:59:59.000 So really the question was,[br]were we looking for a pill 9:59:59.000,9:59:59.000 when we should have really[br]been looking for a cell. 9:59:59.000,9:59:59.000 So we switched our models, 9:59:59.000,9:59:59.000 and now we began to look[br]for skeletal stem cells, 9:59:59.000,9:59:59.000 and to cut again a long story short, 9:59:59.000,9:59:59.000 about five years ago,[br]we found these cells. 9:59:59.000,9:59:59.000 They live inside the skeleton. 9:59:59.000,9:59:59.000 Here's a schematic and then[br]a real photograph of one of them. 9:59:59.000,9:59:59.000 The white stuff is bone, 9:59:59.000,9:59:59.000 and these red columns that you see[br]and the yellow cells 9:59:59.000,9:59:59.000 are cells that have arisen[br]from one single skeleton stem cell, 9:59:59.000,9:59:59.000 columns of cartilage, columns of bone[br]coming out a single cell. 9:59:59.000,9:59:59.000 These cells are fascinating.[br]They have four properties. 9:59:59.000,9:59:59.000 Number one is that they live[br]where they're expected to live. 9:59:59.000,9:59:59.000 They live just underneath[br]the surface of the bone, 9:59:59.000,9:59:59.000 underneath cartilage.