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Quyen Nguyen 談利用顏色導航的外科手術 Quyen Nguyen: Color-coded Surgery
講者：Quyen Nguyen 2011年10月演講，2011年12月在TEDMED 2011上線
翻譯：甘貞珍博士 編輯：朱學恆、洪曉慧 簡繁轉換：洪曉慧 後製：洪曉慧 字幕影片後制：謝旻均
關於這場演講 到目前為止，外科醫生均藉由將不同組織以顏色明白標示的教科書學習，但組織的真實面貌並非如此。在TEDMED中, Quyen Nguyen展示了如何利用分子標記使腫瘤發出綠色螢光，準確地指引外科醫生下刀位置。
關於Quyen Nguyen Quyen Nguyen利用只會使腫瘤發光的分子探針，做為輔助外科醫生進行手術的非凡工具。
為什麼要聽她演講 Quyen Nguyen博士與諾貝爾化學獎得主錢永健博士 (Dr. Roger Tsien)合作研究的重點是研發螢光探針來為外科手術作精細的分子導航。他們的第一個合作成果是一種能使腫瘤外緣發出螢光或「發亮」的「智慧型」探針，使外科醫生更容易辨識並準確地切除腫瘤。他們最近的合作研發出另一種探針，它能使神經纖維「發亮」，幫助外科醫生修復受傷的神經，同時避免手術中不必要的誤傷。
Quyen Nguyen是加州大學聖地牙哥分校的外科手術教授及顏面神經診所主任。
Quyen Nguyen的英語網上資料 Home: drnguyen.
[TED科技?娛樂?設計] 已有中譯字幕的TED影片目錄（繁體）（簡體）。請注意繁簡目錄是不一樣的。
我今天要和你們談談醫學界一個最大的迷思，那個迷思就是，只要我們能有更多的醫學突破，之後所有問題都能迎刃而解。我們總喜歡幻想，有個獨行俠似的發明家，某個深夜在實驗室裡做出一項驚天動地的發現，就這樣，一夜之間改變了一切。這情景很動人，但事實並非如此。實際情況是，當今的醫療工作是一項團隊行動，從許多方面來說，一直都是如此。我想與大家分享一個故事，這是我在工作上的深刻體驗。
我是一名外科醫生，外科醫生跟光一向有一種特殊關係。當我在病人體內切了一個開口時，只見到一片漆黑，我們須要靠光的照明才能看清自己在做什麼，這就是為什麼古早以來手術總是在相當早的清晨開始，以利用白晝這段時光。如果你看一些早期手術室的歷史圖片，它們總是設在建築物頂端，例如，這是西方世界最古老的手術室，位於倫敦，這間手術室事實上設在一座教堂頂端，好讓陽光射進來。這張圖片是美國最著名的醫院之一，波士頓的麻省總醫院。你知道手術室在哪裡嗎？在這裡，位於有很多窗戶採光的樓頂上。
現今，在手術室裡，我們不再需要依賴陽光；因為我們不再需要依賴陽光，我們有特別為手術室安裝的燈光設備，我們有機會為手術室添置其他類型的燈光，一種能讓我們看見目前肉眼無法看見之物的燈光設備，我想這就是螢光的神奇之處。
我不妨從頭說起吧！當我們還在唸醫學院時，我們用像這樣的插圖來學解剖學，圖中一切都用顏色標明，黃色是神經，紅色是動脈，藍色是靜脈。還真容易，每個人都能當外科醫生，對嗎？然而，當我們面對手術檯上的病人，進行跟插圖中一樣的頸部解剖時，才發覺要分辨不同結構並沒有那麼容易。過去幾天我們已聽說過，目前癌症治療仍是個緊迫的難題，我們的當務之急是盡量保住病人生命，如果我們能盡早發現癌症，就可盡早以外科手術摘除病人的癌細胞，我不在意癌細胞裡有什麼基因或蛋白質，它已被丟進垃圾桶，手術完成，癌細胞切除，病人得救。
這就是我們對付癌症的方法。我們盡力而為，根據我們所學，也根據癌的外觀及觸感，以及它與其他結構的關係，還有我們的臨床經驗。我們會說，你知道嗎？癌症沒啦！手術圓滿成功，我們切除了癌細胞。當病人還躺在手術檯上時，外科醫生在手術室中總是這麼說。但事實上我們並不知道癌細胞是否完全被切除，事實上我們必須從病灶採取樣本，然後送到病理實驗室檢驗。這時病人仍躺在手術檯上，護士、麻醉師、醫生和所有助手們一起等待著，等待病理師收到樣本，將它冷凍及切片，在顯微鏡下一片片仔細檢視，然後將結果用電話通知手術室。每一件樣本大約需費時二十分鐘，所以如果你將三個樣本送去檢驗，一小時後才能得知結果。病理師常會這麼說，「知道嗎？AB兩處沒問題，但C處樣本還有癌細胞殘留，請你們將該處切除。」因此我們再拿起手術刀，重複以上步驟。
當全程結束後，病理室說，「沒事了，我們認為腫瘤全切除了。」但經常在幾天後，病人已經回家了，我們會接到一通像這樣的電話，「抱歉，當我們檢查最後的病理報告，看完最後一個樣本時，事實上我們發現有幾處樣本的邊緣地帶呈陽性反應，你病人體內還是有癌細胞。」所以現在你首先面臨的是，得對病人說，也許他們須要再次動手術，或須要接受更多的治療，例如放射性療法或是化療。所以如果你可以確實分辨，如果外科醫生可以在動手術時分辨是否還有癌細胞殘留，不是更好嗎？我的意思是，以許多方面來說，我們目前仍處於在黑暗中摸索動刀的階段。
所以在2004年，當我仍是一位外科住院醫師時，非常榮幸地遇見了錢永健博士，他是2008年諾貝爾化學獎得主。錢博士和他的團隊當時正研究如何檢測癌細胞，他們合成了一個非常巧妙的化學分子，這個分子有三個部份，藍色部份是最重要的，它是一種聚合陽離子，基本上它能吸附在體內每一種組織上。
所以想像你製備一種充滿這種黏性分子的溶液，將它注射到癌症病人的血管中，那麼身體裡每個組織都會亮起來。它沒有專一性，無法分辨正常細胞和癌細胞，所以他們在其上添加了兩個部分，第一部份是一種聚合陰離子，基本上它的功用就像非黏性背膠，所以當兩種離子結合時，分子呈中性，不會吸附任何組織。這兩個離子被某種只能被右式分子剪刀剪斷的分子連接在一起，例如腫瘤分泌的某種蛋白質分解酶，所以在這種情況下，如果製備一種溶液，其中混合了這種三合一分子及會發出綠色螢光的染劑，你將它注射到癌症病人的血管中，正常組織細胞無法將它剪斷，這個分子會經由代謝排出體外。但若體內有腫瘤存在，它分泌的分子小剪刀就會在切割點切斷這個分子，然後，蹦！這個腫瘤被染劑標記而發出螢光。
這是一張神經被腫瘤包圍的範例圖，你看得出腫瘤在哪裡嗎？我無法在進行手術時分辨出來，但它在這裡，發出螢光，呈現綠色。瞧，現在每位觀眾都能看出癌細胞在哪裡。因此我們在手術過程中能看出癌細胞的位置，以及醫生該做什麼處理，及切去多少組織才能將它切除乾淨。最奇妙的是，螢光不但很亮，事實上它也能透出組織。螢光散發的光芒可透出組織，所以即使腫瘤並非位於表層，你依然可以看見它。
你可以在這部影片中看見，腫瘤是綠色的，腫瘤上方是正常肌肉組織，看見了嗎？現在我將肌肉撥開，但在我將肌肉撥開之前，你已看見藏在下面的腫瘤，這就是利用螢光分子標示腫瘤的妙處。你不但能清楚辨視出腫瘤的邊緣，即使它不在表層，你也能看見它，即使當它落在視野之外時，它也能標示已擴散到淋巴結的癌細胞。
前哨淋巴結廓清術確實改變了乳癌和黑色素瘤的治療方式，以往乳癌病人必須接受非常傷元氣的腋窩淋巴結廓清手術，但當前哨淋巴結廓清術成為療程的一環之後，基本上外科醫生只尋找單一的癌症引流淋巴結。假如淋巴結中有癌細胞，病人將接受腋窩淋巴結廓清術，也就是說，假如淋巴結沒有癌細胞，病人就不需接受不必要的手術。
但目前前哨淋巴結的治療方式就像拿著地圖按圖索驥，就像在高速公路上開車，想知道下一個加油站在哪裡，地圖只告訴你它在路的前方，不會告訴你加油站是否還有汽油。你必須將它取下、帶回家、打開看看裡面，才能說，「啊！還有油。」，這太費時了。病人還躺在手術檯上，麻醉師、醫師也得在一旁等候，這太費時了。
利用這個技術，我們立即就能辨別。你們可以看見這一大堆小圓球，有些是腫脹的淋巴結，看起來比其他組織稍微大些。誰在感冒時淋巴結不會腫脹？這並不代表其中有癌細胞。利用這個技術，外科醫師一眼就能辨別哪個淋巴結含有癌細胞。我就不再深入探討這個部分了。但我們的技術除了可以用螢光標示腫瘤及癌細胞轉移的淋巴結外，還可將這個巧妙的三合一分子加上釓，用於進行無創傷性診斷。例如病人得了癌症，你想在手術前知道淋巴結中是否有癌細胞，可藉此利用核磁共振顯影術得知。
因此，進行外科手術時，知道該切除什麼是很重要的。但同樣重要的是保留那些有重要功能的組織，所以避免不必要的誤傷非常重要。現在我要談論的是神經。如果神經受傷了，可能導致癱瘓，引起疼痛。以攝護腺癌來說，多達百分之六十的病人在手術後可能發生尿失禁和性無能，很多人對這些問題深感苦惱，這些情況甚至發生在所謂神經保留式手術中。這是指外科醫生注意到這些問題，盡量避免傷害神經。
但你知道嗎？這些神經非常纖細，在攝護腺癌中根本無法看見，只能根據已知的血管解剖路徑追蹤它們的位置。能知道這一點是因為目前我們仍在進行這方面的研究，這意味著我們仍在探索它們確切的位置。多麼瘋狂啊！我們進行外科手術，試圖切除癌細胞，卻不知道它在哪兒；我們試著保留神經，卻看不見它們在哪兒。
所以我想，如果我們能想個辦法，用螢光標示神經的位置，不就太好了嗎？起初這個想法沒得到太多的支持，人們說，「我們多年來都這麼做手術，有什麼問題嗎？我們沒看見很多併發症啊！」但我還是堅持從事這項研究。我得到錢博士的協助，他帶著整個團隊一起參加，再一次地，這是一項團隊合作，最後我們終於發現了能準確標示神經的分子。我們將它配成溶液，加上螢光標籤後注射到小白鼠體內，牠們的神經成功地亮起螢光，因此你能看見它們的位置。
這張圖顯示的是小白鼠的坐骨神經，粗大的部份顯而易見，但它的尖端處，我正在解剖的位置，事實上有一些非常纖細的分叉神經，肉眼無法看見。你們可以看見，它們就像女妖梅杜莎的蛇髮。我們能看見各種神經，控制臉部表情、顏面運動和呼吸的每一條神經，以及攝護腺周圍控制排尿的神經，每一條都清晰可見，當這兩種探測分子加在一起時。這是腫瘤，你們能看清這個腫瘤的外緣嗎？現在你們能看見了。至於那些腫瘤中的神經呢？白色部份清晰可見，但腫瘤中的部分呢？你們能看清它的走向嗎？現在你能看清了。
基本上我們找到一種方法，在手術中為不同的組織染色標記，這是個小小的突破，我認為這將使外科手術改觀。我們將這項成果發表在美國國家科學院期刊及自然生物科技期刊，《發現》和《經濟學人》雜誌也評論了我們的工作，當我們將這項成果展示給眾多外科同儕時，他們說，「哇！我的病人可從中受益，我想這辦法能使我的手術更成功，減少併發症。」
我們現在需要努力的是，使這項技術進一步發展，研發能讓我們在手術室中看見這種螢光標誌的儀器，最終目標是將這項技術用在病人身上。然而，我們發現，事實上並沒有一個直接管道能開發這種一次性使用的化合物。這是可理解的，主流醫療工業將研發重點放在多次性使用的藥物上，例如需要長期服用的藥物。我們的目標是使這項技術更完美，我們將重點放在增添藥物與生長因子，殺死引起病痛的神經，而非病灶周邊的正常組織。我們知道這是可行的，也全力以赴地進行這項工作。
我最後想讓大家瞭解的是，成功的創新絕不是靠單一的突破，它不是一場短跑，不是短跑選手的獨角戲。成功的創新需要團隊合作，它是一場接力賽，它須要一個團隊創造發明，也須要另一個團隊將創造發明推廣並落實應用，完成它須要持續不斷的毅力和勇氣，堅持日復一日的奮鬥，透過教育和勸說，贏得大眾的採納，這就是我今天演講目的，希望大家瞭解醫療保健的重要。
感謝各位。
（掌聲）
以下為系統擷取之英文原文 About this Talk Surgeons are taught from textbooks which conveniently color-code the types of tissues, but that's not what it looks like in real life -- until now. At TEDMED Quyen Nguyen demonstrates how a molecular marker can make tumors light up in neon green, showing surgeons exactly where to cut. About the Speaker Quyen Nguyen uses molecular probes that make tumors -- and just the tumors -- glow, as an extraordinary aid to surgeons. Transcript I want to talk to you about one of the biggest myths in medicine, and that is the idea that all we need are more medical breakthroughs and then all of our problems will be solved. Our society loves to romanticize the idea of the single, solo inventor who, working late in the lab one night, makes an earthshaking discovery, and voila, overnight everything's changed. That's a very appealing picture, however, it's just not true. In fact, medicine today is a team sport. And in many ways, it always has been. I'd like to share with you a story about how I've experienced this very dramatically in my own work. I'm a surgeon, and we surgeons have always had this special relationship with light. When I make an incision inside a patient's body, it's dark. We need to shine light to see what we're doing. And this is why, traditionally, surgeries have always started so early in the morning -- to take advantage of daylight hours. And if you look at historical pictures of the early operating rooms, they have been on top of buildings. For example, this is the oldest operating room in the Western world, in London, where the operating room is actually on top of a church with a skylight coming in. And then this is a picture of one of the most famous hospitals in America. This is Mass General in Boston. And do you know where the operating room is? Here it is on the top of the building with plenty of windows to let light in. So nowadays in the operating room, we no longer need to use sunlight. And because we no longer need to use sunlight, we have very specialized lights that are made for the operating room. We have an opportunity to bring in other kinds of lights -- lights that can allow us to see what we currently don't see. And this is what I think is the magic of fluorescence. So let me back up a little bit. When we are in medical school, we learn our anatomy from illustrations such as this where everything's color-coded. Nerves are yellow, arteries are red, veins are blue. That's so easy anybody could become a surgeon, right? However, when we have a real patient on the table, this is the same neck dissection -- not so easy to tell the difference between different structures. We heard over the last couple days what an urgent problem cancer still is in our society, what a pressing need it is for us to not have one person die every minute. Well if cancer can be caught early, enough such that someone can have their cancer taken out, excised with surgery, I don't care if it has this gene or that gene, or if it has this protein or that protein, it's in the jar. It's done, it's out, you're cured of cancer. This is how we excise cancers. We do our best, based upon our training and the way the cancer looks and the way it feels and its relationship to other structures and all of our experience, we say, you know what, the cancer's gone. We've made a good job. We've taken it out. That's what the surgeon is saying in the operating room when the patient's on the table. But then we actually don't know that it's all out. We actually have to take samples from the surgical bed, what's left behind in the patient, and then send those bits to the pathology lab. In the meanwhile, the patient's on the operating room table. The nurses, anesthesiologist, the surgeon, all the assistants are waiting around. And we wait. The pathologist takes that sample, freezes it, cuts it, looks in the microscope one by one and then calls back into the room. And that may be 20 minutes later per piece. So if you've sent three specimens, it's an hour later. And very often they say, "You know what, points A and B are okay, but point C, you still have some residual cancer there. Please go cut that piece out." So we go back and we do that again, and again. And this whole process: "Okay you're done. We think the entire tumor is out." But very often several days later, the patient's gone home, we get a phone call: "I'm sorry, once we looked at the final pathology, once we looked at the final specimen, we actually found that there's a couple other spots where the margins are positive. There's still cancer in your patient." So now you're faced with telling your patient, first of all, that they may need another surgery, or that they need additional therapy such as radiation or chemotherapy. So wouldn't it be better if we could really tell, if the surgeon could really tell, whether or not there's still cancer on the surgical field? I mean, in many ways, the way that we're doing it, we're still operating in the dark. So in 2004, during my surgical residency, I had the great fortune to meet Dr. Roger Chen, who went on to win the Nobel Prize for chemistry in 2008. Roger and his team were working on a way to detect cancer, and they had a very clever molecule that they had come up with. The molecule they had developed had three parts. The main part of it is the blue part, polycation, and it's basically very sticky to every tissue in your body. So imagine that you make a solution full of this sticky material and inject it into the veins of someone who has cancer, everything's going to get lit up. Nothing will be specific. There's no specificity there. So they added two additional components. The first one is a polyanionic segment, which basically acts as a non-stick backing like the back of a sticker. So when those two are together, the molecule is neutral and nothing gets stuck down. And the two pieces are then linked by something that can only be cut if you have the right molecular scissors -- for example, the kind of protease enzymes that tumors make. So here in this situation, if you make a solution full of this three-part molecule along with the dye, which is shown in green, and you inject it into the vein of someone who has cancer, normal tissue can't cut it. The molecule passes through and gets excreted. However, in the presence of the tumor, now there are molecular scissors that can break this molecule apart right there at the cleavable site. And now, boom, the tumor labels itself and it gets fluorescent. So here's an example of a nerve that has tumor surrounding it. Can you tell where the tumor is? I couldn't when I was working on this. But here it is. It's fluorescent. Now it's green. See, so every single one in the audience now can tell where the cancer is. We can tell in the operating room, in the field, at a molecular level, where is the cancer and what the surgeon needs to do and how much more work they need to do to cut that out. And the cool thing about fluorescence is that it's not only bright, it actually can shine through tissue. The light that the fluorescence emits can go through tissue. So even if the tumor is not right on the surface, you'll still be able to see it. In this movie, you can see that the tumor is green. There's actually normal muscle on top of it. See that? And I'm peeling that muscle away. But even before I peel that muscle away, you saw that there was a tumor underneath. So that's the beauty of having a tumor that's labeled with fluorescent molecules. That you can, not only see the margins right there on a molecular level, but you can see it even if it's not right on the top -- even if it's beyond your field of view. And this works for metastatic lymph nodes also. Sentinel lymph node dissection has really changed the way that we manage breast cancer, melanoma. Women used to get really debilitating surgeries to excise all of the axillary lymph nodes. But when sentinel lymph node came into our treatment protocol, the surgeon basically looks for the single node that is the first draining lymph node of the cancer. And then if that node has cancer, the woman would go on to get the axillary lymph node dissection. So what that means is if the lymph node did not have cancer, the woman would be saved from having unnecessary surgery. But sentinel lymph node, the way that we do it today, is kind of like having a road map just to know where to go. So if you're driving on the freeway and you want to know where's the next gas station, you have a map to tell you that that gas station is down the road. It doesn't tell you whether or not the gas station has gas. You have to cut it out, bring it back home, cut it up, look inside and say, "Oh yes, it does have gas." So that takes more time. Patients are still on the operating room table. Anesthesiologists, surgeons are waiting around. That takes time. So with our technology, we can tell right away. You see a lot of little, roundish bumps there. Some of these are swollen lymph nodes that look a little larger than others. Who amongst us hasn't had swollen lymph nodes with a cold? That doesn't mean that there's cancer inside. Well with our technology, the surgeon is able to tell immediately which nodes have cancer. I won't go into this very much, but our technology, besides being able to tag tumor and metastatic lymph nodes with fluorescence, we can also use the same smart three-part molecule to tag gadolinium onto the system so you can do this noninvasively. The patient has cancer, you want to know if the lymph nodes have cancer even before you go in. Well you can see this on an MRI. So in surgery, it's important to know what to cut out. But equally important is to preserve things that are important for function. So it's very important to avoid inadvertent injury. And what I'm talking about are nerves. Nerves, if they are injured, can cause paralysis, can cause pain. In the setting of prostate cancer, up to 60 percent of men after prostate cancer surgery may have urinary incontinence and erectile disfunction. That's a lot of people to have a lot of problems -- and this is even in so-called nerve-sparing surgery, which means that the surgeon is aware of the problem, and they are trying to avoid the nerves. But you know what, these little nerves are so small, in the context of prostate cancer, that they are actually never seen. They are traced just by their known anatomical path along vasculature. And they're known because somebody has decided to study them, which means that we're still learning about where they are. Crazy to think that we're having surgery, we're trying to excise cancer, we don't know where the cancer is. We're trying to preserve nerves; we can't see where they are. So I said, wouldn't it be great if we could find a way to see nerves with fluorescence? And at first this didn't get a lot of support. People said, "We've been doing it this way for all these years. What's the problem? We haven't had that many complications." But I went ahead anyway. And Roger helped me. And he brought his whole team with him. So there's that teamwork thing again. And we eventually discovered molecules that were specifically labeling nerves. And when we made a solution of this, tagged with the fluorescence and injected in the body of a mouse, their nerves literally glowed. You can see where they are. Here you're looking at a sciatic nerve of a mouse, and you can see that that big, fat portion you can see very easily. But in fact, at the tip of that where I'm dissecting now, there's actually very fine arborizations that can't really be seen. You see what looks like little Medusa heads coming out. We have been able to see nerves for facial expression, for facial movement, for breathing -- every single nerve -- nerves for urinary function around the prostate. We've been able to see every single nerve. When we put these two probes together ... So here's a tumor. Do you guys know where the margins of this tumor is? Now you do. What about the nerve that's going into this tumor? That white portion there is easy to see. But what about the part that goes into the tumor? Do you know where it's going? Now you do. Basically, we've come up with a way to stain tissue and color-code the surgical field. This was a bit of a breakthrough. I think that it'll change the way that we do surgery. We published our results in the proceedings of the National Academy of Sciences and in Nature Biotechnology. We received commentary in Discover magazine, in The Economist. And we showed it to a lot of my surgical colleagues. They said, "Wow! I have patients who would benefit from this. I think that this will result in my surgeries with a better outcome and fewer complications." What needs to happen now is further development of our technology along with development of the instrumentation that allows us to see this sort of fluorescence in the operating room. The eventual goal is that we'll get this into patients. However, we've discovered that there's actually no straightforward mechanism to develop a molecule for one-time use. Understandably, the majority of the medical industry is focused on multiple-use drugs, such as long-term daily medications. We are focused on making this technology better. We're focused on adding drugs, adding growth factors, killing nerves that are causing problems and not the surrounding tissue. We know that this can be done and we're committed to doing it. I'd like to leave you with this final thought. Successful innovation is not a single breakthrough. It is not a sprint. It is not an event for the solo runner. Successful innovation is a team sport, it's a relay race. It requires one team for the breakthrough and another team to get the breakthrough accepted and adopted. And this takes the long-term steady courage of the day-in day-out struggle to educate, to persuade and to win acceptance. And that is the light that I want to shine on health and medicine today. Thank you very much. (Applause) |
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