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Geraldine Hamilton 談人體器官晶片

Geraldine Hamilton: Body parts on a chip

 

Photo of three lions hunting on the Serengeti.

講者:Geraldine Hamilton

2013年6月演講,2013年12月在TEDxBoston 2013上線

 

翻譯:洪曉慧

編輯:朱學恆

簡繁轉換:洪曉慧

後製:洪曉慧

字幕影片後制:謝旻均

 

影片請按此下載

MAC及手持裝置版本請按此下載

閱讀中文字幕純文字版本

 

關於這場演講

構思新藥及較佳療法十分簡單,難的部分在於進行測試,這個過程或許會讓可行的新療法延遲數年上市。在這場通俗易懂的演講中,Geraldine Hamilton展示她的實驗室如何在晶片上建構器官和人體部位,構造簡單的晶片擁有所有測試新藥必備的元件-甚至可為特定對象量身打造治療方法。(攝於TEDxBoston)

 

關於Geraldine Hamilton

Geraldine Hamilton將器官和人體部位建構於晶片中-以測試新型、客製化療法。

 

為什麼要聽她演講

Geraldine Hamilton的職業生涯跨足學術研究、創新生物科技及醫藥產業。她的研究著重於與藥物開發有關的人類體外模型開發及應用。她是某間初創生物科技公司(CellzDirect)的創始科學家之一,擔任科學技術副總裁及細胞產品主任,成功將學術研究技術移植及商業化,提供製藥工業肝細胞產品,用於安全評估及藥物代謝研究。

 

Hamilton獲得與葛蘭素史克公司合作的英國Hertfordshire大學細胞生物學/毒理學博士學位,隨後在北卡羅萊納大學進行博士後研究。她目前的研究興趣和以往經歷包括:器官晶片、毒理學和藥物代謝、肝細胞生物學、基因表現及分化機制調控、外源物質對細胞核受體及肝細胞轉錄活化之調控、人體細胞分離及冷凍保存技術。

 

Geraldine Hamilton的英語網上資料

Home: wyss.harvard.edu

 

[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。

 

Geraldine Hamilton 談人體器官晶片

 

我們正面臨全球性健康挑戰:目前研發新藥的方式太過昂貴、耗時,且失敗機率往往大於成功機率;這根本行不通。這意味著亟需新療法的病人得不到治療,疾病也無從醫治。我們花的錢似乎越來越多,因此每十億美元的研發支出所獲得的核准上市新藥越來越少。更多的錢、更少的藥,嗯。

 

這是怎麼回事?好,其中存在許多因素,但我認為主因之一是:進入人體臨床試驗之前,用來測試藥物是否有效或是否安全的工具無法滿足我們的要求;它們無法預測人體內發生的事。目前可使用的主要工具有兩種:細胞培養及動物試驗。

 

我們先討論第一種-細胞培養。好,細胞在我們體內快樂地運作,我們將它們從原生環境中取出,放入其中一個培養皿中,期待它們能如常運作。結果呢?並非如此。它們不喜歡那樣的環境,因為這和體內環境大不相同。

 

動物試驗呢?好,動物確實能提供相當有用的訊息。它們使我們明白複雜有機體中發生的情形,我們藉此學習到更多生物學相關知識。然而,大多數情況下,動物模型無法預測使用特定藥物時發生於人體內的情況。

 

因此我們需要更好的工具。我們需要人體細胞,但我們必須找到使它們快樂地在體外運作的方法。

 

我們的身體是動態環境,持續地運轉,我們的細胞亦是如此。它們處於體內的動態環境,持續感受機械力,因此-如果我們想讓細胞快樂地在體外運作,我們就得成為細胞建築師。我們必須替細胞設計、建設、打造另一個家。

 

這正是我們在Wyss研究所進行的工作,我們稱它為晶片上的器官,這裡恰好有一個。很美,不是嗎?卻令人不可思議。我手中是一個位於晶片上、正在呼吸的人類肺部。

 

它不僅美觀,也具有許多功用。我們將活細胞放入這個小晶片中,處於動態環境的細胞可與不同種類的細胞作用。許多人嘗試在實驗室中培養細胞,他們試過許多不同方法,他們甚至嘗試在實驗室中培養迷你器官;這並非我們嘗試的做法。我們只是嘗試在這個小晶片中建立最小的功能單位,呈現細胞於體內所經歷的生化反應、功能及機械張力。它是如何運作的?容我向各位展示。我們運用電腦晶片製造工業技術,打造與細胞及其生長環境相仿的結構。其中有三條液體通道,中間是多孔彈性膜,我們可在其上放入人體細胞,例如肺細胞。下層是微血管細胞,即血管中的細胞。然後我們可對晶片施加機械力,使膜伸展及收縮,因此細胞將受到與我們呼吸時相同的機械力,如同身處體內的情形。上方通道有空氣流過,然後使含有養分的液體流過血液通道。好,晶片很美,但我們能如何利用?我們可藉由這些小晶片獲得不可思議的功能,我來做個展示。例如我們可模擬感染過程,將細菌細胞加入這個肺模型中,然後加入人類白血球。白血球是人體抵抗細菌入侵的防線,當它們偵測到因感染引起的發炎反應時,它們將由血管進入肺部、吞噬細菌,現在你將在晶片上看見真實發生於人類肺部的過程。我們已標記這些白血球,因此你可看見它們流過。當它們偵測到感染時,就會開始黏附。它們開始黏附,然後試著從血管進入另一側的肺部。如你所見,我們能確實呈現單一白血球。它進行黏附、鑽入細胞層、通過孔洞、從膜的另一側穿出。就在這裡,它將吞噬標示為綠色的細菌。在這個小晶片上,你目睹人體對感染的最基本反應之一,這就是所謂的免疫反應。相當令人興奮。

 

現在我想分享這張圖片,不僅因為它很美,也因為它讓我們得知許多細胞在晶片上發生的情形。它告訴我們,這些來自肺部微小氣管的細胞,事實上擁有你印象中肺部所見的毛髮狀結構。這些構造稱為纖毛,它的作用是將黏液掃出肺部。是的,黏液,十分噁心,但事實上它十分重要。黏液會吸附顆粒、病毒、潛在過敏原,這些小纖毛會將黏液清出肺部。當它們受到香菸之類的物質破壞時,它們無法正常作用,無法將黏液清除,這將導致支氣管炎之類的疾病。纖毛及黏液清除作用也和某些嚴重疾病有關,例如囊狀纖維化。但現在,藉由這些晶片的功能,我們可開始探索潛在新療法。

 

我們研究的不僅是肺晶片,我們也有腸晶片,就是這個。我們將人類腸細胞放入腸晶片中,它們持續蠕動,逐步傳導至所有細胞,我們可模擬許多你在人類腸道中所見的功能。現在我們可開始建立疾病模型,例如腸燥症-這是一種令許多人困擾不已的疾病;它令人虛弱,而且好的療法不多。

 

目前我們實驗室正在研發一系列不同的器官晶片,然而這項技術的真正力量在於:我們能藉由液體流動使它們連結。液體於細胞間流動,因此我們可將多種不同晶片彼此連接,形成所謂的虛擬人體晶片,這讓我們興奮不已。我們並不打算在晶片上重建整個人體,我們的目標是重建足夠的細胞功能,使我們對體內發生的情形進行更佳預測。例如現在我們可開始探索使用噴劑型藥物時發生的情形。那些和我一樣有氣喘的人,當你使用吸入劑時,我們可探索藥物如何進入肺部、進入身體,如何影響-例如心臟等器官。它會改變心跳嗎?它有毒性嗎?它會被肝臟清除嗎?它會經由肝臟代謝嗎?它會經由腎臟排泄嗎?我們可開始研究身體對藥物的動態反應。

 

這將造成革命性改變。不僅對於製藥工業,也將影響許多不同產業,包括化妝品工業。我們有機會利用目前正於實驗室中研發的皮膚晶片,測試產品中的成分對皮膚是否安全,不需藉由動物試驗。我們可測試日常環境中所接觸的化學物質安全性,例如一般家庭清潔劑中的化學物質。我們也可將器官晶片應用於生物反恐或輻射暴露。我們可藉由它們對疾病進行深入瞭解,例如伊波拉病毒或其他致命疾病,例如SARS。

 

器官晶片也可改變未來臨床試驗方式。目前來說,參與臨床試驗的對象多半屬於「一般型」:往往是中年人、往往是女性。你不會看見太多臨床試驗對象包含孩童,但每天都有孩童接受藥物治療。我們擁有的藥物安全資料僅來自成人;孩童並非成人,他們的反應或許不同於成人。還有其他因素,例如族群間的遺傳差異,可能導致危險族群面臨不良藥物反應的風險。想像一下,如果我們將不同族群的細胞置入晶片,製造族群晶片,這確實能改變臨床試驗方式。這就是進行這項研究的團隊和成員,其中包括工程師、細胞生物學家、臨床醫師,大家攜手合作。我們在Wyss研究所確實目睹了相當不可思議的成果,這確實是各門學科的集合。生物學影響設計、策畫及建造方式,確實令人興奮不已。

 

我們正著手建立重要的產業合作。例如我們與一家專精於大規模數位製造的公司合作,他們將協助我們製造-不僅一片,而是數百萬計的晶片,使我們能盡可能提供給多數研究人員,這就是這項科技的重要潛能。

 

現在讓我展示一下我們的儀器。這是我們的工程師目前在實驗室中打造的原型機。這台儀器能提供所需的工程控制,使十個以上的器官晶片彼此連接。它也能進行其他重要工作。它擁有簡單的使用介面,因此像我這樣的細胞生物學家可進入實驗室,拿起晶片,放入卡匣中,如你所看見的原型機。將卡匣放入機器中,就像放CD一樣,就這樣。插電、啟動,輕而易舉。

 

好,我們想像一下未來可能的情況。若我能將你或你的幹細胞置入晶片,這將成為替你量身打造的個人化晶片。

 

在座每個人都是獨立個體,個體差異意味著我們對藥物的反應可能天差地遠,有時甚至無法預測。幾年前,我深受頭痛所苦,無法擺脫,我想:「好吧,試試不同的藥好了。」我吃了點Advil。十五分鐘後,我因嚴重氣喘發作被送進急診室。好,顯然這沒要了我的命。但不幸的是,有些負面藥物反應是致命的。

 

因此我們該如何防範?好,我們可想像,某天將出現Geraldine的晶片、Danielle的晶片、你的晶片。

 

個人化醫療,謝謝。

 

(掌聲)

以下為系統擷取之英文原文

About the talk

It's relatively easy to imagine a new medicine, a better cure for some disease. The hard part, though, is testing it, and that can delay promising new cures for years. In this well-explained talk, Geraldine Hamilton shows how her lab creates organs and body parts on a chip, simple structures with all the pieces essential to testing new medications -- even custom cures for one specific person. (Filmed at TEDxBoston)
 
About Geraldine Hamilton
Geraldine Hamilton builds organs and body parts on a chip -- to test new, custom cures.
 
About the transcript
We have a global health challenge in our hands today, and that is that the way we currently discover and develop new drugs is too costly, takes far too long, and it fails more often than it succeeds. It really just isn't working, and that means that patients that badly need new therapies are not getting them, and diseases are going untreated. We seem to be spending more and more money. So for every billion dollars we spend in R&D, we're getting less drugs approved into the market. More money, less drugs. Hmm.
 
So what's going on here? Well, there's a multitude of factors at play, but I think one of the key factors is that the tools that we currently have available to test whether a drug is going to work, whether it has efficacy, or whether it's going to be safe before we get it into human clinical trials, are failing us. They're not predicting what's going to happen in humans. And we have two main tools available at our disposal. They are cells in dishes and animal testing.
 
Now let's talk about the first one, cells in dishes. So, cells are happily functioning in our bodies. We take them and rip them out of their native environment, throw them in one of these dishes, and expect them to work. Guess what. They don't. They don't like that environment because it's nothing like what they have in the body.
 
What about animal testing? Well, animals do and can provide extremely useful information. They teach us about what happens in the complex organism. We learn more about the biology itself. However, more often than not, animal models fail to predict what will happen in humans when they're treated with a particular drug.
 
So we need better tools. We need human cells, but we need to find a way to keep them happy outside the body.
 
Our bodies are dynamic environments. We're in constant motion. Our cells experience that. They're in dynamic environments in our body. They're under constant mechanical forces. So if we want to make cells happy outside our bodies, we need to become cell architects. We need to design, build and engineer a home away from home for the cells.
 
And at the Wyss Institute, we've done just that. We call it an organ-on-a-chip. And I have one right here. It's beautiful, isn't it? But it's pretty incredible. Right here in my hand is a breathing, living human lung on a chip.
 
And it's not just beautiful. It can do a tremendous amount of things. We have living cells in that little chip, cells that are in a dynamic environment interacting with different cell types. There's been many people trying to grow cells in the lab. They've tried many different approaches. They've even tried to grow little mini-organs in the lab. We're not trying to do that here. We're simply trying to recreate in this tiny chip the smallest functional unit that represents the biochemistry, the function and the mechanical strain that the cells experience in our bodies. So how does it work? Let me show you. We use techniques from the computer chip manufacturing industry to make these structures at a scale relevant to both the cells and their environment. We have three fluidic channels. In the center, we have a porous, flexible membrane on which we can add human cells from, say, our lungs, and then underneath, they had capillary cells, the cells in our blood vessels. And we can then apply mechanical forces to the chip that stretch and contract the membrane, so the cells experience the same mechanical forces that they did when we breathe. And they experience them how they did in the body. There's air flowing through the top channel, and then we flow a liquid that contains nutrients through the blood channel. Now the chip is really beautiful, but what can we do with it? We can get incredible functionality inside these little chips. Let me show you. We could, for example, mimic infection, where we add bacterial cells into the lung. then we can add human white blood cells. White blood cells are our body's defense against bacterial invaders, and when they sense this inflammation due to infection, they will enter from the blood into the lung and engulf the bacteria. Well now you're going to see this happening live in an actual human lung on a chip. We've labeled the white blood cells so you can see them flowing through, and when they detect that infection, they begin to stick. They stick, and then they try to go into the lung side from blood channel. And you can see here, we can actually visualize a single white blood cell. It sticks, it wiggles its way through between the cell layers, through the pore, comes out on the other side of the membrane, and right there, it's going to engulf the bacteria labeled in green. In that tiny chip, you just witnessed one of the most fundamental responses our body has to an infection. It's the way we respond to -- an immune response. It's pretty exciting.
 
Now I want to share this picture with you, not just because it's so beautiful, but because it tells us an enormous amount of information about what the cells are doing within the chips. It tells us that these cells from the small airways in our lungs, actually have these hairlike structures that you would expect to see in the lung. These structures are called cilia, and they actually move the mucus out of the lung. Yeah. Mucus. Yuck. But mucus is actually very important. Mucus traps particulates, viruses, potential allergens, and these little cilia move and clear the mucus out. When they get damaged, say, by cigarette smoke for example, they don't work properly, and they can't clear that mucus out. And that can lead to diseases such as bronchitis. Cilia and the clearance of mucus are also involved in awful diseases like cystic fibrosis. But now, with the functionality that we get in these chips, we can begin to look for potential new treatments.
 
We didn't stop with the lung on a chip. We have a gut on a chip. You can see one right here. And we've put intestinal human cells in a gut on a chip, and they're under constant peristaltic motion, this trickling flow through the cells, and we can mimic many of the functions that you actually would expect to see in the human intestine. Now we can begin to create models of diseases such as irritable bowel syndrome. This is a disease that affects a large number of individuals. It's really debilitating, and there aren't really many good treatments for it.
 
Now we have a whole pipeline of different organ chips that we are currently working on in our labs. Now, the true power of this technology, however, really comes from the fact that we can fluidically link them. There's fluid flowing across these cells, so we can begin to interconnect multiple different chips together to form what we call a virtual human on a chip. Now we're really getting excited. We're not going to ever recreate a whole human in these chips, but what our goal is is to be able to recreate sufficient functionality so that we can make better predictions of what's going to happen in humans. For example, now we can begin to explore what happens when we put a drug like an aerosol drug. Those of you like me who have asthma, when you take your inhaler, we can explore how that drug comes into your lungs, how it enters the body, how it might affect, say, your heart. Does it change the beating of your heart? Does it have a toxicity? Does it get cleared by the liver? Is it metabolized in the liver? Is it excreted in your kidneys? We can begin to study the dynamic response of the body to a drug.
 
This could really revolutionize and be a game changer for not only the pharmaceutical industry, but a whole host of different industries, including the cosmetics industry. We can potentially use the skin on a chip that we're currently developing in the lab to test whether the ingredients in those products that you're using are actually safe to put on your skin without the need for animal testing. We could test the safety of chemicals that we are exposed to on a daily basis in our environment, such as chemicals in regular household cleaners. We could also use the organs on chips for applications in bioterrorism or radiation exposure. We could use them to learn more about diseases such as ebola or other deadly diseases such as SARS.
 
Organs on chips could also change the way we do clinical trials in the future. Right now, the average participant in a clinical trial is that: average. Tends to be middle aged, tends to be female. You won't find many clinical trials in which children are involved, yet every day, we give children medications, and the only safety data we have on that drug is one that we obtained from adults. Children are not adults. They may not respond in the same way adults do. There are other things like genetic differences in populations that may lead to at-risk populations that are at risk of having an adverse drug reaction. Now imagine if we could take cells from all those different populations, put them on chips, and create populations on a chip. This could really change the way we do clinical trials. And this is the team and the people that are doing this. We have engineers, we have cell biologists, we have clinicians, all working together. We're really seeing something quite incredible at the Wyss Institute. It's really a convergence of disciplines, where biology is influencing the way we design, the way we engineer, the way we build. It's pretty exciting.
 
We're establishing important industry collaborations such as the one we have with a company that has expertise in large-scale digital manufacturing. They're going to help us make, instead of one of these, millions of these chips, so that we can get them into the hands of as many researchers as possible. And this is key to the potential of that technology.
 
Now let me show you our instrument. This is an instrument that our engineers are actually prototyping right now in the lab, and this instrument is going to give us the engineering controls that we're going to require in order to link 10 or more organ chips together. It does something else that's very important. It creates an easy user interface. So a cell biologist like me can come in, take a chip, put it in a cartridge like the prototype you see there, put the cartridge into the machine just like you would a C.D., and away you go. Plug and play. Easy.
 
Now, let's imagine a little bit what the future might look like if I could take your stem cells and put them on a chip, or your stem cells and put them on a chip. It would be a personalized chip just for you.
 
Now all of us in here are individuals, and those individual differences mean that we could react very differently and sometimes in unpredictable ways to drugs. I myself, a couple of years back, had a really bad headache, just couldn't shake it, thought, "Well, I'll try something different." I took some Advil. Fifteen minutes later, I was on my way to the emergency room with a full-blown asthma attack. Now, obviously it wasn't fatal, but unfortunately, some of these adverse drug reactions can be fatal.
 
So how do we prevent them? Well, we could imagine one day having Geraldine on a chip, having Danielle on a chip, having you on a chip.
 
Personalized medicine. Thank you.
 
(Applause)

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