I'd like to tell you about a patient named Donna. In this photograph, Donna was in her mid-70s, a vigorous, healthy woman, the matriarch of a large clan. She had a family history of heart disease, however, and one day, she had the sudden onset of crushing chest pain. Now unfortunately, rather than seeking medical attention, Donna took to her bed for about 12 hours until the pain passed. The next time she went to see her physician, he performed an electrocardiogram, and this showed that she'd had a large heart attack, or a "myocardial infarction" in medical parlance.
我想要跟各位聊聊 一位叫做唐娜的病人。 在這張照片中, 唐娜大約七十五歲, 精力充沛又健康, 是個大家族的家長。 不過,她的家庭有心臟病史, 有一天,她的胸口 突然痛到讓她站不起來。 不幸的是,唐娜沒有 尋求醫療協助, 而是選擇在她的床上躺了 十二小時,直到胸痛過去。 後來她去看她的醫生時, 醫生幫她做了心電圖, 結果顯示她之前的狀況是 重大的心臟病發作, 用醫學用語來說, 就是「心肌梗塞」。
After this heart attack, Donna was never quite the same. Her energy levels progressively waned, she couldn't do a lot of the physical activities she'd previously enjoyed. It got to the point where she couldn't keep up with her grandkids, and it was even too much work to go out to the end of the driveway to pick up the mail. One day, her granddaughter came by to walk the dog, and she found her grandmother dead in the chair. Doctors said it was a cardiac arrhythmia that was secondary to heart failure. But the last thing that I should tell you is that Donna was not just an ordinary patient. Donna was my mother.
在這次心臟病發作之後, 唐娜變得不一樣了。 她的精神日漸萎靡, 她無法繼續做很多 她以前很享受的身體活動。 後來到了她追不上 孫子孫女的程度, 就連走到家門口的車道前 去取郵件都是件費勁的事情。 有一天,她的孫女正出去遛狗時, 發現她的祖母在椅子上過世了。 醫生說(死因)是心臟衰竭 所伴隨的心律不整。 但,在最後我想告訴各位一件事, 唐娜不是一般的病人。 唐娜是我母親。
Stories like ours are, unfortunately, far too common. Heart disease is the number one killer in the entire world. In the United States, it's the most common reason patients are admitted to the hospital, and it's our number one health care expense. We spend over a 100 billion dollars -- billion with a "B" -- in this country every year on the treatment of heart disease. Just for reference, that's more than twice the annual budget of the state of Washington.
很不幸的是, 像這樣的故事其實很常見。 全世界排名第一的殺手 就是心臟疾病。 在美國, 心臟疾病是病人住院 最常見的原因, 且相關的醫療照護花費也最高。 在美國,每年我們要花 超過一千億美元,是「億」喔, 來治療心臟疾病。 這個數字比華盛頓州 年度預算的兩倍還高。
What makes this disease so deadly? Well, it all starts with the fact that the heart is the least regenerative organ in the human body. Now, a heart attack happens when a blood clot forms in a coronary artery that feeds blood to the wall of the heart. This plugs the blood flow, and the heart muscle is very metabolically active, and so it dies very quickly, within just a few hours of having its blood flow interrupted. Since the heart can't grow back new muscle, it heals by scar formation. This leaves the patient with a deficit in the amount of heart muscle that they have. And in too many people, their illness progresses to the point where the heart can no longer keep up with the body's demand for blood flow. This imbalance between supply and demand is the crux of heart failure.
這種疾病為什麼這麼致命? 一切都始於,心臟是人類身體中 再生性最差的器官。 心臟病的發生是由於 給心室壁供血的冠狀動脈中 形成了血凝塊。 這會造成血流被阻塞, 而由於心肌的新陳代謝十分活躍, 血流只要被中斷幾個小時 就足以致死。 因為心臟無法重新長出新肌肉, 它癒合的方式是形成疤痕, 而這樣的結果會讓病人 沒有足量的心肌。 許多人的病發展到後期時,他們的 心臟無法及時供應身體需要的血流。 這種供需之間的不平衡 是心臟衰竭的關鍵所在。
So when I talk to people about this problem, I often get a shrug and a statement to the effect of, "Well, you know, Chuck, we've got to die of something."
而當我和別人談到這個問題時, 他們卻通常會聳聳肩,並告訴我: 「查克,你知道的, 我們總會因為某種原因而死。」
(Laughter)
(笑聲)
And yeah, but what this also tells me is that we've resigned ourselves to this as the status quo because we have to. Or do we? I think there's a better way, and this better way involves the use of stem cells as medicines.
是啊,但這也讓我知道, 我們對這件事聽天由命, 是因為我們沒有別的選擇。 如果有呢? 我認為有個更好的方法, 這個方法是把幹細胞 拿來當醫藥用於治療。
So what, exactly, are stem cells? If you look at them under the microscope, there's not much going on. They're just simple little round cells. But that belies two remarkable attributes. The first is they can divide like crazy. So I can take a single cell, and in a month's time, I can grow this up to billions of cells. The second is they can differentiate or become more specialized, so these simple little round cells can turn into skin, can turn into brain, can turn into kidney and so forth. Now, some tissues in our bodies are chock-full of stem cells. Our bone marrow, for example, cranks out billions of blood cells every day. Other tissues like the heart are quite stable, and as far as we can tell, the heart lacks stem cells entirely. So for the heart, we're going to have to bring stem cells in from the outside, and for this, we turn to the most potent stem cell type, the pluripotent stem cell. Pluripotent stem cells are so named because they can turn into any of the 240-some cell types that make up the human body.
所以,幹細胞到底是什麼? 如果用顯微鏡來看幹細胞, 我們看不出什麽所以然, 它們看似只是簡單的小圓細胞。 但它們其實還有有兩項驚人的特性。 第一,它們能瘋狂地分裂。 我可以用僅僅一個細胞, 在一個月之内, 培養出高達十億個細胞。 第二,它們可以分化或特化, 所以,這些簡單的小圓細胞 可以轉變成皮膚、轉變成大腦、 轉變成腎臟等等。 我們體內的一些組織裡 充滿了幹細胞。 比如,我們的骨髓每天都會 產生出數十億個血細胞。 其他組織,如心臟,就十分穩定, 就我們所知, 心臟完全沒有幹細胞。 所以,我們必須從外界 把幹細胞帶入心臟。 為此,我們將目光轉向了 最強大的一種幹細胞, 多功能性幹細胞。 這種幹細胞被稱為多功能性幹細胞, 是因為它們能轉變為組成人體的 約 240 種細胞當中的任何一種。
So this is my big idea: I want to take human pluripotent stem cells, grow them up in large numbers, differentiate them into cardiac muscle cells and then take them out of the dish and transplant them into the hearts of patients who have had heart attacks. I think this is going to reseed the wall with new muscle tissue, and this will restore contractile function to the heart.
所以,我的想法是: 我想要取得人類的多功能性幹細胞, 大量繁殖它們, 將它們特化轉成心肌細胞, 接著把它們從培養皿中取出, 移植到心臟病病人的心臟裡。 我認為這樣就能夠在心室壁中 重新種下新的肌肉組織, 這樣就能恢復心臟的收縮功能。
(Applause)
(掌聲)
Now, before you applaud too much, this was my idea 20 years ago.
在各位給太多掌聲之前,我得 先說明,這是我二十年前的想法。
(Laughter)
(笑聲)
And I was young, I was full of it, and I thought, five years in the lab, and we'll crank this out, and we'll have this into the clinic. Let me tell you what really happened.
我當時很年輕,很自滿,我心想, 在實驗室中研究五年, 我就能完成它, 我們就能在臨床上使用了。 讓我告訴各位真正發生的實情。
(Laughter)
(笑聲)
We began with the quest to turn these pluripotent stem cells into heart muscle. And our first experiments worked, sort of. We got these little clumps of beating human heart muscle in the dish, and that was cool, because it said, in principle, this should be able to be done. But when we got around to doing the cell counts, we found that only one out of 1,000 of our stem cells were actually turning into heart muscle. The rest was just a gemisch of brain and skin and cartilage and intestine. So how do you coax a cell that can become anything into becoming just a heart muscle cell?
我們開始努力嘗試 將多功能性幹細胞轉成心肌。 我們的第一次實驗成功了,算是吧。 我們在培養皿中得到了這些 小塊狀物,會跳動的人類心肌。 這很不錯,因為原則上,這就意味著 (這件事)是有可能辦到的。 但,當我們去計算細胞數量時, 我們發現,我們的幹細胞中 只有千分之一 實際轉變為了心肌。 其他的都成了大腦、 皮膚、軟骨、腸子的混合物。 所以,你要如何誘使 能變成任何東西的細胞 只轉變成心肌細胞?
Well, for this we turned to the world of embryology. For over a century, the embryologists had been pondering the mysteries of heart development. And they had given us what was essentially a Google Map for how to go from a single fertilized egg all the way over to a human cardiovascular system. So we shamelessly absconded all of this information and tried to make human cardiovascular development happen in a dish. It took us about five years, but nowadays, we can get 90 percent of our stem cells to turn into cardiac muscle -- a 900-fold improvement. So this was quite exciting.
為此,我們轉向胚胎學的世界。 一個多世紀以來, 胚胎學者一直在探索 心臟發展的謎團。 他們給了我們像 Google 地圖一樣的資訊, 讓我們知道如何從單一受精卵 一路走到人類心血管系統。 所以我們很不要臉地 帶走了這些訊息, 嘗試把人類心血管發展的過程 在培養皿中重現。 我們花了大約五年,而如今, 我們可以讓九成幹細胞 轉變成心肌—— 這是九百倍的改善。 所以,這很讓人興奮。
This slide shows you our current cellular product. We grow our heart muscle cells in little three-dimensional clumps called cardiac organoids. Each of them has 500 to 1,000 heart muscle cells in it. If you look closely, you can see these little organoids are actually twitching; each one is beating independently. But they've got another trick up their sleeve. We took a gene from jellyfish that live in the Pacific Northwest, and we used a technique called genome editing to splice this gene into the stem cells. And this makes our heart muscle cells flash green every time they beat.
這張投影片上的是 我們目前的細胞產品。 我們在小小的 3D 團塊中 培養我們的心肌細胞, 這一團塊叫做「類心臟器官」。 每一塊當中都有五百 到一千個心肌細胞。 如果再靠近看,可以看到這些 小小的類器官其實正在抽動; 每一個都獨自在跳動。 但,它們還有另一項技能。 我們從美國西北部太平洋岸 附近的水母身上取得基因, 我們採用了一種叫做 基因組編輯的技術, 把這個水母基因結合到幹細胞中。 這麼做就能讓我們的心肌細胞 每跳動一次就閃爍一次綠光。
OK, so now we were finally ready to begin animal experiments. We took our cardiac muscle cells and we transplanted them into the hearts of rats that had been given experimental heart attacks. A month later, I peered anxiously down through my microscope to see what we had grown, and I saw ... nothing. Everything had died. But we persevered on this, and we came up with a biochemical cocktail that we called our "pro-survival cocktail," and this was enough to allow our cells to survive through the stressful process of transplantation. And now when I looked through the microscope, I could see this fresh, young, human heart muscle growing back in the injured wall of this rat's heart. So this was getting quite exciting.
這樣,我們終於準備好 要做動物實驗了。 我們把我們的心肌細胞 移植到老鼠的心臟中, 牠們先前已發作過實驗性心臟病。 一個月後,我很急切地 透過我的顯微鏡, 想仔細看看我們培養出了什麼, 而我看到…… 什麼都沒有。 一切都死了。 但我們堅持不懈,又做出了 一種生物化學雞尾酒, 我們稱它是我們的「助生雞尾酒」, 這足以讓我們的細胞 在很有壓力的移植過程中存活下來。 現在,當我透過顯微鏡觀察時, 我能看到這些新鮮、年輕的人類心肌, 在這隻老鼠受傷的心室壁中長回來。 這十分讓人興奮。
The next question was: Will this new muscle beat in synchrony with the rest of the heart? So to answer that, we returned to the cells that had that jellyfish gene in them. We used these cells essentially like a space probe that we could launch into a foreign environment and then have that flashing report back to us about their biological activity. What you're seeing here is a zoomed-in view, a black-and-white image of a guinea pig's heart that was injured and then received three grafts of our human cardiac muscle. So you see those sort of diagonally running white lines. Each of those is a needle track that contains a couple of million human cardiac muscle cells in it. And when I start the video, you can see what we saw when we looked through the microscope. Our cells are flashing, and they're flashing in synchrony, back through the walls of the injured heart.
下一個問題是: 新的肌肉會和心臟的 其他部分同步跳動嗎? 為了找出答案, 我們返回有水母基因的那些細胞。 基本上,我們是把這些細胞 當作「太空探測器」來用, 我們可以把它們 發射到陌生的環境中, 接著,透過閃光得到反饋, 來了解它們的生理活動。 各位現在看到的是放大的影像, 這張黑白影像上的是白鼠的心臟, 這顆心臟受過傷,接著接受了 三塊嫁接的人類心肌。 你們可以看到有一些 白色的對角線。 每一條極細的軌道 都含有數百萬個人類心肌細胞。 我開始播放影片時,各位就能看到 我們當時透過顯微鏡所看到的。 我們的細胞在閃爍, 且它們是同步在閃爍, 透過受傷的心室壁將閃光傳回來。
What does this mean? It means the cells are alive, they're well, they're beating, and they've managed to connect with one another so that they're beating in synchrony. But it gets even more interesting than this. If you look at that tracing that's along the bottom, that's the electrocardiogram from the guinea pig's own heart. And if you line up the flashing with the heartbeat that's shown on the bottom, what you can see is there's a perfect one-to-one correspondence. In other words, the guinea pig's natural pacemaker is calling the shots, and the human heart muscle cells are following in lockstep like good soldiers.
這意味著什麼? 意味著這些細胞是活的, 它們很健康,它們在跳動, 而且它們找到方式和彼此連結, 因此它們能夠同步跳動。 但這還不是最有趣的。 請看看最底部的描繪線, 那是白老鼠自己心臟的心電圖。 如果和呈現在底部的閃爍心跳 互相對照著看, 你會發現它們完美地一對一呼應。 換言之,白老鼠的 天然心臟節律器在主導, 而人類心肌細胞則是 亦步亦趨跟隨著, 就像優秀的士兵。
(Applause)
(掌聲)
Our current studies have moved into what I think is going to be the best possible predictor of a human patient, and that's into macaque monkeys. This next slide shows you a microscopic image from the heart of a macaque that was given an experimental heart attack and then treated with a saline injection. This is essentially like a placebo treatment to show the natural history of the disease. The macaque heart muscle is shown in red, and in blue, you see the scar tissue that results from the heart attack. So as you look as this, you can see how there's a big deficiency in the muscle in part of the wall of the heart. And it's not hard to imagine how this heart would have a tough time generating much force.
我們目前的研究已即將開始 用在我個人認為 最能模擬人類病人的動物身上, 也就是獼猴。 下一張投影片是顯微鏡的影像, 影像中的是獼猴的心臟, 我們讓牠發生過實驗性心臟病, 接著用沙林注射液來治療牠。 基本上,這就像是安慰劑治療, 用來呈現疾病的自然歷史。 紅色部分是彌猴的心肌, 藍色部分是心臟病 所造成的疤痕組織。 所以,各位可以從這張圖看到, 有一部分的心室壁非常缺乏肌肉。 不難想像,這顆心臟實在是 使不上力。
Now in contrast, this is one of the stem-cell-treated hearts. Again, you can see the monkey's heart muscle in red, but it's very hard to even see the blue scar tissue, and that's because we've been able to repopulate it with the human heart muscle, and so we've got this nice, plump wall.
相對的,這是用幹細胞治療的心臟。 同樣,紅色部分是猴子的心肌, 但幾乎看不見多少藍色的疤痕組織, 那是因為我們讓人類心肌 重新入住到這顆心臟裡, 才會有這種撲通跳的優良心室壁。
OK, let's just take a second and recap. I've showed you that we can take our stem cells and differentiate them into cardiac muscle. We've learned how to keep them alive after transplantation, we've showed that they beat in synchrony with the rest of the heart, and we've shown that we can scale them up into an animal that is the best possible predictor of a human's response. You'd think that we hit all the roadblocks that lay in our path, right? Turns out, not.
好,咱們花點時間來做重點回顧。 我已經讓各位看到, 我們能取用人類幹細胞 將它們特化,轉變成心肌。 我們也學會了如何 在移植時不讓它們死亡, 各位也看到,它們能 和心臟的其他部分同步跳動。 我們還能更進一步, 把它們放到最能預測 人類反應的動物體內。 你們可能會認為,我們該碰到的 障礙都碰過了,是吧? 然而,並不是這樣。
These macaque studies also taught us that our human heart muscle cells created a period of electrical instability. They caused ventricular arrhythmias, or irregular heartbeats, for several weeks after we transplanted them. This was quite unexpected, because we hadn't seen this in smaller animals. We've studied it extensively, and it turns out that it results from the fact that our cellular graphs are quite immature, and immature heart muscle cells all act like pacemakers. So what happens is, we put them into the heart, and there starts to be a competition with the heart's natural pacemaker over who gets to call the shots. It would be sort of like if you brought a whole gaggle of teenagers into your orderly household all at once, and they don't want to follow the rules and the rhythms of the way you run things, and it takes a while to rein everybody in and get people working in a coordinated fashion. So our plans at the moment are to make the cells go through this troubled adolescence period while they're still in the dish, and then we'll transplant them in in the post-adolescent phase, where they should be much more orderly and be ready to listen to their marching orders. In the meantime, it turns out we can actually do quite well by treating with anti-arrhythmia drugs as well.
這些彌猴研究讓我們認識到, 人類心肌細胞會造成 一段時間内的電流不穩定。 這些細胞會造成心室心律不整, 或心臟節律不整, 在移植後數週都會有這種現象。 這是我們沒有預料到的, 因為在小動物身上並沒有發生。 我們對這個狀況進行了廣泛研究, 結果發現,發生的原因 是因為我們的細胞圖 還不太成熟, 而不成熟的心肌細胞 都像是有自己的心臟節律器一般。 情況是,我們一旦把 這些細胞放進心臟, 它們就開始和心臟的 天然節律器競爭, 搶著要主導權。 這就有點像是 你把一群吵鬧的青少年 通通放到很有秩序的家庭裡, 而他們不想遵守規則 和你做事的節奏。 要花一點時間才能控制住每個人, 讓大家用很和諧的方式合作。 所以,我們此時的計畫 是要讓細胞還在培養皿中的時候, 就先度過這段麻煩的青春期, 接著,我們再把青春期後的 細胞拿來做移植。 這時候的細胞便會更有秩序, 且準備好聽命令來行軍了。 同時,我們也發現 使用抗心律不整的藥物 進行治療的效果也相當好。
So one big question still remains, and that is, of course, the whole purpose that we set out to do this: Can we actually restore function to the injured heart? To answer this question, we went to something that's called "left ventricular ejection fraction." Ejection fraction is simply the amount of blood that is squeezed out of the chamber of the heart with each beat. Now, in healthy macaques, like in healthy people, ejection fractions are about 65 percent. After a heart attack, ejection fraction drops down to about 40 percent, so these animals are well on their way to heart failure. In the animals that receive a placebo injection, when we scan them a month later, we see that ejection fraction is unchanged, because the heart, of course, doesn't spontaneously recover. But in every one of the animals that received a graft of human cardiac muscle cells, we see a substantial improvement in cardiac function. This averaged eight points, so from 40 to 48 percent. What I can tell you is that eight points is better than anything that's on the market right now for treating patients with heart attacks. It's better than everything we have put together. So if we could do eight points in the clinic, I think this would be a big deal that would make a large impact on human health.
但是,有個大問題仍然沒解決, 當然,那個問題也就是 我們動手做這一切的目的: 我們真的能夠幫 受傷的心臟恢復功能嗎? 為了找到答案, 我們轉向所謂的 「左心室射出分率」, 射出分率就是每一次心跳時, 從心室擠出的血液量。 健康的彌猴就跟健康的人一樣, 射出分率大約是 65%。 在心臟病發之後, 射出分率會下降到約 40%, 所以這些動物正在走向心臟衰竭。 針對接受安慰劑注射的動物, 我們在一個月後掃瞄牠們時, 發現射出分率並沒有改變, 因為,當然啦, 心臟並不會自己復原。 但,在所有接受 人類心肌細胞嫁接的動物身上, 我們都發現心臟功能 有了大幅的改善, 從 40% 增加到 48%, 平均有 8% 的提升。 我能告訴各位的是, 8% 的成果已經勝過 目前市面上用來治療 心臟病病人的任何東西。 比我們所有的療法加起來都還要好。 所以,若我們 在臨床上能達成 8%, 我認為,這會是件大事, 對於人類健康會有巨大的影響。
But it gets more exciting. That was just four weeks after transplantation. If we extend these studies out to three months, we get a full 22-point gain in ejection fraction.
但,更讓人興奮的還在後頭。 剛才談的只是移植後四週的狀況。 如果我們把這些研究 延伸到三個月, 射出分率能增加足足 22%。
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Function in these treated hearts is so good that if we didn't know up front that these animals had had a heart attack, we would never be able to tell from their functional studies.
這些接受治療的心臟, 功能變得非常好, 好到如果我們沒有事先知道 這些動物曾經心臟病發過, 光從它們心臟的功能上來看, 我們甚至不會知道它們有心臟病。
Going forward, our plan is to start phase one, first in human trials here at the University of Washington in 2020 -- two short years from now. Presuming these studies are safe and effective, which I think they're going to be, our plan is to scale this up and ship these cells all around the world for the treatment of patients with heart disease. Given the global burden of this illness, I could easily imagine this treating a million or more patients a year.
至於未來,我們的計畫 是要展開第一階段, 2020 年先在華盛頓大學 這裡做人體實驗—— 也就是短短的兩年後。 假設這些研究是安全且有效的, 我認為應該會是如此, 那麼我們的計畫就是把規模擴大, 把這些細胞運往全世界, 去治療心臟病病人。 這種疾病在全球都是很大的負擔, 我很容易就能想像,這個方法 每年可以治療至少一百萬名病人。
So I envision a time, maybe a decade from now, where a patient like my mother will have actual treatments that can address the root cause and not just manage her symptoms. This all comes from the fact that stem cells give us the ability to repair the human body from its component parts.
我的遠景是,將來, 也許十年之後, 像我母親這樣的病人 能接受可以根治的治療, 而不只是在處理她的症狀。 所有這些,都是因為 幹細胞讓我們有能力 可以從人類身體的 各組成部分來修復人類身體。
In the not-too-distant future, repairing humans is going to go from something that is far-fetched science fiction into common medical practice. And when this happens, it's going to have a transformational effect that rivals the development of vaccinations and antibiotics.
在不久的將來, 修復人類將不再是 牽強附會的科幻小說, 而會變成是常見的醫療做法。 當這一天到來時, 將會帶來轉化性的效應, 不輸給疫苗和抗生素 被開發出來的壯舉。
Thank you for your attention.
非常謝謝各位聆聽。
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