i want to talk to youabout the future of medicine. but before i do that, i want to talka little bit about the past. now, throughout muchof 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 reasonfor 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 introductionof antibiotics into the united states. but what you do know is that that introductionwas nothing short of transformative. here you had a chemical,either from the natural world or artificially synthesizedin 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 takinga previously fatal, lethal disease -- a pneumonia, syphilis, tuberculosis -- and transforming thatinto 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 modelover and over again
in noninfectious diseases, in chronic diseases like diabetesand 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 reactionsin the human body, every chemical reactionthat your body is capable of, most people think that that numberis 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 percentof all chemical reactions in your body are actually targetableby this lock and key mechanism. you know, if you thinkabout human physiology
as a vast global telephone network with interacting nodesand 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 ourpharmaceutical chemistry is a pole operator in wichita, kansas who is tinkering with about10 or 15 telephone lines. so what do we do about this idea?
what if we reorganized this approach? in fact, it turns outthat the natural world gives us a sense of how onemight think about illness in a radically different way, rather than disease, medicine, target. in fact, the natural worldis 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 coalesceto form things called humans, and these organismsultimately live in environments, which are partly self-regulatingand partly semi-autonomous. what's nice about this scheme,this hierarchical scheme building upwards rather than downwards, is that it allows usto think about illness as well in a somewhat different way. take a disease like cancer.
since the 1950s, we've tried rather desperately to applythis lock and key model to cancer. we've tried to kill cells using a variety of chemotherapiesor targeted therapies, and as most of us know, that's worked. it's worked for diseases like leukemia. it's worked for some formsof breast cancer, but eventually you runto the ceiling of that approach. and it's only in the last 10 years or so
that we've begun to thinkabout using the immune system, remembering that in fact the cancer celldoesn't grow in a vacuum. it actually grows in a human organism. and could you use the organismal capacity, the fact that human beingshave an immune system, to attack cancer? in fact, it's led to the some of the mostspectacular new medicines in cancer. and finally there's the levelof the environment, isn't there? you know, we don't think of canceras altering the environment. but let me give you an exampleof 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 littlewhite sheet of paper, one of the most potent neurostimulantsthat we know, called nicotine, and you add to that one of the most potentaddictive substances that you know, and you havea pro-carcinogenic environment. but you can have anti-carcinogenicenvironments too. there are attempts to create milieus,
change the hormonal milieufor breast cancer, for instance. we're trying to change the metabolicmilieu 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 moleculesthat 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 youreally probably need to do is to change the physiologyof 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 studyhas shown that talk therapy combined with medicines, pills, really is much more effectivethan either one alone. can we imagine a more immersiveenvironment that will change depression?
can you lock out the signalsthat elicit depression? again, moving upwards along thishierarchical 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 greatchronic degenerative diseases -- kidney failure, diabetes,hypertension, osteoarthritis -- maybe what we really need to do is changethe metaphor to growing something. and that's the key, perhaps,
to reframing our thinking about medicine. now, this idea of changing, of creating a perceptualshift, as it were, came home to me to roost in a verypersonal 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 upand i basically couldn't move. my right knee was swollen up, and you could hear that ominous crunchof bone against bone.
and one of the perks of being a physicianis 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 cartilagethat is between bone had been completely tornand the bone itself had been shattered. now, if you're looking at meand feeling sorry, let me tell you a few facts. if i was to take an mriof every person in this audience, 60 percent of you would show signs of bone degenerationand cartilage degeneration like this.
85 percent of all women by the age of 70 would show moderate to severecartilage degeneration. 50 to 60 percentof 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 getto experiment on your own ailments. so about 10 years ago we began, we brought this processinto the laboratory,
and we began to do simple experiments, mechanically tryingto fix this degeneration. we tried to inject chemicalsinto the knee spaces of animals to try to reverse cartilage degeneration, and to put a short summaryon 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 tolooking 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 thingas a skeletal stem cell -- a skeletal stem cell that builds upthe entire vertebrate skeleton, bone, cartilage and the fibrouselements of skeleton, just like there's a stem cell in blood,
just like there's a stem cellin the nervous system. and two, that maybe that, the degenerationor 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 reallybeen looking for a cell. so we switched our models, and now we beganto 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 thena real photograph of one of them. the white stuff is bone, and these red columns that you seeand the yellow cells are cells that have arisenfrom one single skeletal stem cell -- columns of cartilage, columns of bonecoming out of a single cell. these cells are fascinating.they have four properties. number one is that they livewhere they're expected to live. they live just underneaththe surface of the bone,
underneath cartilage. you know, in biology,it's location, location, location. and they move into the appropriate areasand form bone and cartilage. that's one. here's an interesting property. you can take them outof the vertebrate skeleton, you can culture themin petri dishes in the laboratory, and they are dying to form cartilage. remember how we couldn'tform cartilage for love or money?
these cells are dying to form cartilage. they form their own furlsof cartilage around themselves. they're also, number three, the most efficient repairersof 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 inand repaired, in yellow, the bone, in white, the cartilage,almost completely. so much so that if you label themwith a fluorescent dye
you can see them like some kindof peculiar cellular glue coming into the area of a fracture, fixing it locallyand then stopping their work. now, the fourth one is the most ominous, and that is that their numbersdecline precipitously, precipitously, tenfold,fiftyfold, as you age. and so what had happened, really, is that we found ourselvesin a perceptual shift. we had gone hunting for pills
but we ended up finding theories. and in some ways we had hooked ourselvesback onto this idea: cells, organisms, environments, because we were now thinkingabout bone stem cells, we were thinking about arthritisin terms of a cellular disease. and then the next question was,are there organs? can you build thisas an organ outside the body? can you implant cartilageinto areas of trauma?
and perhaps most interestingly, can you ascend right upand create environments? you know, we knowthat exercise remodels bone, but come on, none of usis going to exercise. so could you imagine ways of passivelyloading and unloading bone so that you can recreateor regenerate degenerating cartilage? and perhaps more interesting,and more importantly, the question is, can you apply this modelmore globally outside medicine? what's at stake, as i said before,is not killing something,
but growing something. and it raises a series of, i think,some of the most interesting questions about how we thinkabout medicine in the future. could your medicinebe a cell and not a pill? how would we grow these cells? what we would we do to stopthe malignant growth of these cells? we heard about the problemsof unleashing growth. could we implantsuicide genes into these cells to stop them from growing?
could your medicine be an organthat's created outside the body and then implanted into the body? could that stop some of the degeneration? what if the organ needed to have memory? in cases of diseases of the nervous systemsome of those organs had memory. how could we implantthose memories back in? could we store these organs? would each organ have to be developedfor an individual human being and put back?
and perhaps most puzzlingly, could your medicine be an environment? could you patent an environment? you know, in every culture, shamans have been usingenvironments as medicines. could we imagine that for our future? i've talked a lot about models.i began this talk with models. so let me end with some thoughtsabout model building. that's what we do as scientists.
you know, when an architectbuilds a model, he or she is trying to show youa world in miniature. but when a scientist is building a model, he or she is trying to show youthe world in metaphor. he or she is trying to createa new way of seeing. the former is a scale shift.the latter is a perceptual shift. now, antibiotics createdsuch a perceptual shift in our way of thinking about medicinethat it really colored, distorted, very successfully, the way we've thoughtabout medicine for the last hundred years.
but we need new modelsto think about medicine in the future. that's what's at stake. you know, there'sa popular trope out there that the reason we haven't hadthe transformative impact on the treatment of illness is because we don't havepowerful-enough drugs, and that's partly true. but perhaps the real reason is that we don't have powerful-enoughways of thinking about medicines.
it's certainly true that it would be lovely to have new medicines. but perhaps what's really at stakeare three more intangible m's: mechanisms, models, metaphors. thank you. (applause) chris anderson:i really like this metaphor. how does it link in? there's a lot of talk in technologyland
about the personalization of medicine, that we have all this dataand that medical treatments of the future will be for you specifically,your genome, your current context. does that apply to this modelyou've got here? siddhartha mukherjee:it's a very interesting question. we've thought aboutpersonalization of medicine very much in terms of genomics. that's because the geneis such a dominant metaphor, again, to use that same word,in medicine today,
that we think the genome will drivethe personalization of medicine. but of course the genomeis just the bottom of a long chain of being, as it were. that chain of being, really the firstorganized unit of that, is the cell. so, if we are really going to deliverin medicine in this way, we have to think of personalizingcellular therapies, and then personalizingorgan or organismal therapies, and ultimately personalizingimmersion therapies for the environment. so i think at every stage, you know --
there's that metaphor,there's turtles all the way. well, in this, there'spersonalization all the way. ca: so when you saymedicine could be a cell and not a pill, you're talking aboutpotentially your own cells. sm: absolutely.ca: so converted to stem cells, perhaps tested against all kindsof drugs or something, and prepared. sm: and there's no perhaps.this is what we're doing. this is what's happening,and in fact, we're slowly moving,
not away from genomics,but incorporating genomics into what we call multi-order,semi-autonomous, self-regulating systems, like cells, like organs,like environments. ca: thank you so much. sm: pleasure. thanks.
