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.
我想跟大家探討醫學的未來。 未開始前,我要先講過去的醫學。 由從前一直到近代的醫學歷史, 我們愛用非常簡單的模式 來思考疾病和治療。 其實這些模式非常簡單, 可以用6個字總結: 染病、吃藥和除病。
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.
這個模式佔了優勢 當然是抗生素革命。 或許你不知道,我們剛剛 慶祝美國引進抗生素100週年。 但你必定知道 引入抗生素後,發展迅速。 這些化學物不是從自然界得來, 便是在實驗室人工合成。 它會進入人體, 找尋自己的目標, 然後鎖定目標—— 一種微生物或者它的一部分, 然後非常敏捷地、專門地 阻止細菌等像鎖鑰般結合。 最後把你從以前患的致命疾病—— 肺炎、梅毒,結核病, 變成可以治癒的疾病。 患了肺炎, 可以用盤尼西林 殺死微生物, 然後痊癒。
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.
這個概念很吸引人, 用鎖鑰結合的比喻,然後除病 非常有效。 而且這個概念已橫掃生物學界。 那種改變真是不同凡響。 科學家在以往的100年間, 竭盡所能不停複製這類模式, 應用在非傳染疾病,例如慢性疾病—— 糖尿病、高血壓和心臟病。 結果是可行的,但只是部分有效。 讓我告訴你為什麼會這樣。 如果以人體所有的 化學反應, 身體都能夠進行的每個化學反應, 大部分人都會認為大約有1百萬次 那就把它算作1百萬。 現在你會問, 其實所有藥物或醫學化學 可以鎖定的反應 有幾多次或幾多部分呢? 答案是250。 其他仍是未知數。 換言之,人體內的所有的化學反應 就只有0.025%是由 這個鎖鑰機制視為目標。 試想像人類的生理 就如全球的電話網絡, 佈滿互通的伺服器和其他組件, 然後所有的醫學化學 就在網絡的最外邊, 在那裡最小的角落運作。 好像所有的藥物化學 就在堪薩斯州威奇塔市 當電話接線生 笨拙地處理10條或15條電話線。
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.
我們根據這個概念要怎麼做? 要是改革這些方法又如何? 其實結果是大自然給我們的啟示, 跟我們以前對疾病的了解, 簡直是天淵之別, 不是由疾病,繼而藥物, 最後目標。 事實上,大自然的規則是下而上, 不是由上而下,而是由下而上, 首先由細胞開始,那是可以自我 調節和半自主的單位。 這些細胞造成器官, 也是自我調整和半自主的單位。 器官合併一起,造成人類, 這些生物是部分自我調整 和部分半自主, 最後在週圍環境生活。
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.
這種階級流程真不錯, 向上發展,而不是向下建立, 可讓我們思考疾病 有點不同。 就以癌症這種疾病為例。 自從1950年代以來, 我們竭力地把鎖鑰模式 來治療癌症。 探用多種的化療和標鈀治療, 嘗試消滅癌細胞, 而且多數人都知道,那是成功的。 它治療白血病這類疾病很有效。 對幾種類型的乳癌也有效。 但是利用這個方法 最終也到了極限。 只是到了最近10年來, 我們漸漸想到利用免疫系統治病, 還記起癌細胞其實 不是在真空生長。 而是在人體內生長。 因為人類有免疫系統, 可否用生物能力去攻擊癌症呢? 其實已經有好些驚人的 新癌症藥物因此硏製了。
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.
最後到了環境這一階段,是不是? 我們不認為癌症改變環境。 但讓我告訴你一個例子, 那是極度致癌的環境。 它叫做「囚禁」。 你如果孤獨、抑鬱、自我封閉, 再加上 捲起一張小小的白紙 把最強的神經興奮劑 叫做「尼古丁」放進去, 也加入了最易上癮的物質, 最後形成了致癌的環境。 但你也可以製造防癌的環境。 我們嘗試去創造周圍環境, 例如改變引致乳癌的激素環境。 還有不斷努力改變其他癌症的 新陳代謝環境。
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.
或者以另一類疾病如抑鬱來說, 又是從向上的方向治療。 自從1960到1970年代, 我們拼命地不斷嘗試 阻止分子在神經細胞之間運行, 如血清素,安多芬, 希望用這些方法治療抑鬱症, 雖然有效,但是很快到了極限。 我們知道現在可能最需要 改變器官和腦部的生理機能, 替它們重新接線,重新改造。 當然多次的研究證明 說話治療完全辦得到, 但經過不斷的研究證明說話治療 再加上藥物, 比接受單一的治療更加有效。 可否想像一個較為浸淫式 虛擬實境,將會改善抑鬱症嗎? 可否封鎖引致抑鬱症的 神經信號呢? 又再次沿著這條組織階級向上移。 最危險可能 不是藥物,而是比喻意義。 不要只是去消滅病菌, 以最慢性退化性疾病為例--- 腎衰竭、糖尿病、 高血壓和骨關節炎, 或許我們真的要把 這個比喻改為培養。 可能這就是答案, 改變我們對醫學的想法。
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.
這種改革思想, 產生認知的轉移, 是源於大約10年前, 我自作自受的後果。 大約10年前,我常常跑步。 有一個星期六,我去跑步, 回家,跟著一覺醒來 ,我簡直動彈不得。 右腳膝蓋腫起來, 可以聽到骨頭間嘎吱作響, 非常恐怖。 做醫生有一樣好處, 便是自己預約磁力共振。 我在隨後的星期照了磁力共振, 基本上,在骨中間的軟骨半月板 已經全部撕破,而且骨碎裂。
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.
如果你很同情我, 那麼讓我告訴你一些真相。 如果我替在座每位觀眾 照磁力共振, 將會有六成人的結果顯示 像這般的骨頭和 軟骨退化的跡象。 而女性到了70歲,便有85%的人 有中度到嚴重的軟骨退化。 而在座的男士有50至60% 也會有這些跡象。 所以這是很常見的疾病。 做醫生有第二個好處。 就是可以替自己的小病做實驗。 所以大約10年前,我們開始著手, 把這些方法帶到實驗室。 從做簡單的實驗開始, 呆板地想解決退化的問題。 我們給動物的膝蓋注射化學物, 想挽救軟骨退化。 經過冗長又痛苦的過程, 只可以用幾句總結。 基本上一無所收穫。 什麼事也沒有發生過。 跟著大約7年前, 來了一位澳洲研究生。 澳洲人的優點 就是他們習慣把世界倒轉來看。
(Laughter)
(笑聲)
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.
於是Dan向我提議說: 可能不是機械問題, 也不一定是化學問題, 可能是幹細胞問題。 換言之,他有兩個假說。 第一,真是有這樣的骨幹細胞-- 這些細胞建立整個脊髓骨架, 骨頭,軟骨和骨纖維。 就像血液裡有幹細胞, 神經系統有幹細胞一樣。 第二,這些幹細胞可能 退化或者失去功能, 引起骨關節炎這些常見的小病。 最有問題是我們本應 找尋幹細胞, 卻去找新藥物。 於是我們改變模式, 開始尋找骨幹細胞。 長話短說, 大約5年前,我們發現了這些細胞。 它們就在骨頭裡。 這幅是圖解,還有其中一張實照。 白色的東西是骨質, 見到紅色部分和黃色的細胞。 那是由一粒骨質幹細胞 變成的多個細胞-- 由一粒細胞洐生了軟骨和骨。 這些幹細胞非常有趣, 它有4種特質。 第一,它們就在適當的地方存在。 剛好在骨頭表面的底下, 在軟骨下面。 生物學非常重視位置、位置… 它們走到適當的地方 做成骨和軟骨。 那就是幹細胞 。 它有種有趣的特質。 你把它從脊髓抽出來, 放在實驗室的有蓋培養皿𥚃 做細菌培養, 它們渴望製造軟骨。 還記得我們怎麼不能因為 愛或金錢去製造軟骨嗎? 這些細胞卻極想製造軟骨。 製造自己的軟骨卷起來包圍自己。 還有,第三 它是我們所見過最佳 修復骨節的能手。 這是一塊小骨頭。 那是我們折斷的老鼠骨頭, 跟著任由它自己癒合。 這些幹細胞進入黃色的骨質丶 白色的軟骨裡,差不多修復一切。 它非常能幹甚至你用螢光染料 把它顯示出來, 可以見到它像一些特別的細胞膠水, 流入骨折的地方, 在那裡固定折骨,然後停止工作。 現在到了第四最不利的特點, 就是隨著年紀漸老, 幹細胞的數目以10倍, 50倍急劇減少。
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.
真正發生了的事情, 就是我們發現自己轉變了態度。 我們過去不停找尋藥物, 但是最後得出理論。 在某些方面 我們又再次抓緊這個概念: 細胞、生物丶環境, 因為我們想到硏究骨幹細胞, 把關節炎視為細胞疾病。
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?
跟著另一個問題是, 在器官有沒有幹細胞? 可否在人體以㚈,用它建成器官? 可否植入軟骨到受創傷的地方? 或者最有趣的 可否一直上階級頂部,製造環境。 大家都知道運動可以重塑骨質, 但是沒有人願意去運動。 試想像有那些被動的方法, 可以把骨裝上和卸下來, 讓退化的軟骨重生呢?
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. And it raises a series of, I think, some of the most interesting questions about how we think about medicine in the future. Could your medicine be a cell and not a pill? How would we grow these cells? What we would we do to stop the malignant growth of these cells? We heard about the problems of unleashing growth. Could we implant suicide genes into these cells to stop them from growing? Could your medicine be an organ that'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 system some of those organs had memory. How could we implant those memories back in? Could we store these organs? Would each organ have to be developed for 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 using environments 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 thoughts about model building. That's what we do as scientists. You know, when an architect builds a model, he or she is trying to show you a world in miniature. But when a scientist is building a model, he or she is trying to show you the world in metaphor. He or she is trying to create a new way of seeing. The former is a scale shift. The latter is a perceptual shift.
最有趣又重要的是 可否在醫學以㚈, 把這個模式應用到全世界呢? 我曾經說問題不是消滅什麼, 而是培養什麼。 這樣喚起我們怎樣 思考未來醫學等 一連串的問題。 藥可否是細胞,而不是藥丸? 我們要怎樣培養這些細胞? 怎麼做才可以阻止 惡性幹細胞生長? 我們聽說過細胞 不受控制生長的問題。 可否把自殺式基因植入這些細胞, 阻止它繼續增生? 可否把體㚈製造的器官當成藥, 然後植入體內? 可否阻止身體一些地方退化? 如果器官需要有記憶呢? 就以神經系統疾病為例, 有些器官載有記憶。 怎樣才能把記憶植入 到那些器官呢? 我們可否儲藏這些器官? 個人的每副器官是否要先生長, 才放回人體內。 最令人苦惱的 是可否把環境當作藥物? 可否替環境買專利權? 每種文化, 薩滿巫帥一直用自然力量當作藥。 可否猜想得到未來的醫學呢? 我已經談論很多有關模式的問題。 我開始時講模式。 所以讓我總結也講創造模式。 這是科學家的分內事。 一位建築師建造一個模型, 這位建築師正把世界 變成縮樣給你看; 但是科學家建立一個模式, 是把世界變成比喻, 讓大家用新的眼光看世界。 前者是轉變比例, 後者是改變看法。
Now, antibiotics created such a perceptual shift in our way of thinking about medicine that it really colored, distorted, very successfully, the way we've thought about medicine for the last hundred years. But we need new models to think about medicine in the future. That's what's at stake.
現在發明抗生素, 成功地改變我們近百年來 對藥物的看法。 以前的看法是過度誇張 和歪曲事實。 但我們還是需要新模式 去硏究未來的醫學。 這是問題的癥結。
You know, there's a popular trope out there that the reason we haven't had the transformative impact on the treatment of illness is because we don't have powerful-enough drugs, and that's partly true. But perhaps the real reason is that we don't have powerful-enough ways of thinking about medicines. It's certainly true that it would be lovely to have new medicines. But perhaps what's really at stake are three more intangible M's: mechanisms, models, metaphors.
這𥚃有個流行的比喻詞 就是我們治療疾病 沒有轉移性影響 因爲缺乏威力的藥物, 有部分原因是對的。 或許真正的原因 就是沒有權威性的醫學思想。 如果發現新藥物, 真是最好不過了。 或者最麻煩是多了 3種無形的結局: 方法、模式、比喻。
Thank you.
多謝。
(Applause)
(鼓掌聲)
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 data and that medical treatments of the future will be for you specifically, your genome, your current context. Does that apply to this model you've got here?
Chris Anderson:我很喜歡這種比喻方法。 它是怎樣聯繫上來? 在technology land 有很多人討論 用藥個人化, 我們有全部資料描述未來的醫療 會替病人的基因組和 週圍的環境度身訂造。 這種療法是否適用於你的模式呢?
Siddhartha Mukherjee: It's a very interesting question. We've thought about personalization of medicine very much in terms of genomics. That's because the gene is such a dominant metaphor, again, to use that same word, in medicine today, that we think the genome will drive the personalization of medicine. But of course the genome is just the bottom of a long chain of being, as it were. That chain of being, really the first organized unit of that, is the cell. So, if we are really going to deliver in medicine in this way, we have to think of personalizing cellular therapies, and then personalizing organ or organismal therapies, and ultimately personalizing immersion 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's personalization all the way.
Siddhartha Mukherjee: 這個問題很有趣。 我們曾經認真思考過以基因組 來進行個人化醫學。 因為基因是如此重要的比喻, 我又再次用這個詞語 來談論今天的醫學, 基因組會推動個人化醫療。 當然基因組一如既往, 只是存在鎖鏈階梯最低一級 而細胞就是這裡 首個有組織的單位。 如果我們真是要這樣 表達醫學的概念。 那麼就從個人化細胞治療開始, 然後是個人化器官治療, 最後是個人化虛擬環境治療。 所以我想在每個階段 有這麼一個比喻,世界是龜駄著龜一路到無窮無盡。 而個人化治療也會一直發展下去。
CA: So when you say medicine could be a cell and not a pill, you're talking about potentially your own cells.
CA: 所以如果你說的藥 可能是細胞, 不是藥片, 可能是病人自己的細胞。
SM: Absolutely. CA: So converted to stem cells, perhaps tested against all kinds of drugs or something, and prepared.
SM:當然。 CA:於是轉向研究幹細胞, 或者檢測所有藥物, 然後製造出來。
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.
SM:沒有「或者」這回事。 我們正在做這些事情。 其實已經慢慢地發展, 不是放棄基因組,而是把它合併而成 所謂多重等級,半自動, 自我控制的系統, 例如細胞丶器官和環境。
CA: Thank you so much.
CA:多謝你接受訪問。
SM: Pleasure. Thanks.
SM:不用客氣。多謝大家。