演講MP3+雙語文稿:我們可以用干細胞再生心肌嗎？
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【演講人及介紹】Chuck Murry
查克·莫里，醫(yī)生，科學家
【演講主題】我們可以用干細胞再生心肌嗎？
【演講文稿-中英文】
Translated by Lipeng Chen Reviewed by HomerLi
00:00
I'd like to tell you about a patient namedDonna. 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. Nowunfortunately, rather than seeking medical attention, Donna took to her bed forabout 12 hours until the pain passed. The next time she went to see herphysician, he performed an electrocardiogram, and this showed that she'd had alarge heart attack, or a "myocardial infarction" in medical parlance.
我想和你們講講一個叫唐娜的病人。在這張照片中，唐娜70多歲，一個精力充沛、健康的女人，也是一個大家族的領袖。但她有心臟病家族史，有一天，她突然感到胸痛。不幸的是，唐娜沒有尋求醫(yī)療救助，而是在床上躺了大約12個小時，直到疼痛過去。下次她去看醫(yī)生時，醫(yī)生做了心電圖，這表明她心臟病發(fā)了，或者醫(yī)學術語中的“心肌梗塞”。
00:33
After this heart attack, Donna was neverquite the same. Her energy levels progressively waned, she couldn't do a lot ofthe physical activities she'd previously enjoyed. It got to the point where shecouldn't keep up with her grandkids, and it was even too much work to go out tothe end of the driveway to pick up the mail. One day, her granddaughter came byto walk the dog, and she found her grandmother dead in the chair. Doctors saidit was a cardiac arrhythmia that was secondary to heart failure. But the lastthing 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(fā)作之后，唐娜就再也不一樣了。她的體能逐漸下降，她不能做很多以前喜歡的體育活動。逐漸到了她不能跟上孫子孫女的地步，而且要走到樓道盡頭去拿郵件也變得費勁了。一天，她的孫女過來遛狗，她發(fā)現奶奶死在椅子上。醫(yī)生說這是一種繼發(fā)于心力衰竭的心律失常。但我最后要告訴你們的是，唐娜不僅僅是個普通病人。唐娜是我母親。
01:09
Stories like ours are, unfortunately, fartoo common. Heart disease is the number one killer in the entire world. In theUnited States, it's the most common reason patients are admitted to thehospital, and it's our number one health care expense. We spend over a 100billion dollars -- billion with a "B" -- in this country every yearon the treatment of heart disease. Just for reference, that's more than twicethe annual budget of the state of Washington.
不幸的是，像我們這樣的故事太普遍了。心臟病是全世界頭號殺手。在美國，這是病人入院的最常見原因，這是我們最大的醫(yī)療費用。我們花了1000多億美元——1000多億美元——在這個國家每年用于心臟病的治療。順便說下，這是華盛頓州年度預算的兩倍多。
01:33
What makes this disease so deadly? Well, itall starts with the fact that the heart is the least regenerative organ in thehuman body. Now, a heart attack happens when a blood clot forms in a coronaryartery 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 heartcan't grow back new muscle, it heals by scar formation. This leaves the patientwith a deficit in the amount of heart muscle that they have. And in too manypeople, their illness progresses to the point where the heart can no longerkeep up with the body's demand for blood flow. This imbalance between supplyand demand is the crux of heart failure.
是什么使這種疾病如此致命？這一切都是因為心臟是在人體內再生能力最小的器官。當將血液注入心臟壁的冠狀動脈中形成血液凝塊時，心臟病就會發(fā)作。這會堵塞血流，心臟肌肉的新陳代謝非?；钴S，所以在血液流動中斷后的幾個小時內，心臟很快就死了。因為心臟不能長出新的心肌，它通過形成疤痕而愈合。這使病人在心肌數量上形成了短缺。在太多的人身上，他們的病情已經壞到心臟無法滿足身體對血液流動的需求。供求失衡是心力衰竭的癥結所在。
02:22
So when I talk to people about thisproblem, I often get a shrug and a statement to the effect of, "Well, youknow, Chuck, we've got to die of something."
所以當我和人們談論這個問題時，我經常會聳聳肩，然后說一句話，“好吧，你知道，查克，我們總會為某件事而死。”
02:32
(Laughter)
（笑）
02:36
And yeah, but what this also tells me isthat we've resigned ourselves to this as the status quo because we have to. Ordo we? I think there's a better way, and this better way involves the use ofstem cells as medicines.
是的，但這也告訴了我，我們已經對這個現狀自我放棄了。真是這樣嗎？我覺得有更好的方法，這種更好的方法包括使用干細胞作為藥物。
02:54
So what, exactly, are stem cells? If youlook at them under the microscope, there's not much going on. They're justsimple little round cells. But that belies two remarkable attributes. The firstis they can divide like crazy. So I can take a single cell, and in a month'stime, I can grow this up to billions of cells. The second is they candifferentiate or become more specialized, so these simple little round cellscan 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 likethe heart are quite stable, and as far as we can tell, the heart lacks stemcells entirely. So for the heart, we're going to have to bring stem cells infrom the outside, and for this, we turn to the most potent stem cell type, thepluripotent stem cell. Pluripotent stem cells are so named because they canturn into any of the 240-some cell types that make up the human body.
那么，究竟什么是干細胞？如果你在顯微鏡下觀察它們，太簡單了。它們只是簡單的小圓形細胞。但這掩蓋了兩個顯著的特征。首先，它們可以瘋狂地分裂。所以我只需要一個細胞，一個月后，我可以把它長到數十億個細胞。第二，它們可以分化或變得更具指向性，所以這些簡單的圓形細胞可以變成皮膚，可以變成大腦，可以變成腎臟等等?，F在，我們體內的一些組織充滿了干細胞。例如，我們的骨髓每天產生數十億個血細胞。心臟等其他組織相當穩(wěn)定，據我們所知，心臟完全缺乏干細胞。所以對于心臟來說，我們必須從外部引進干細胞，為此，我們轉向最有效的干細胞類型，多能干細胞。多能干細胞就是這樣命名的，因為它們可以變成構成人體的 240種細胞類型中的?任何一種。
03:54
So this is my big idea: I want to take humanpluripotent stem cells, grow them up in large numbers, differentiate them intocardiac muscle cells and then take them out of the dish and transplant theminto the hearts of patients who have had heart attacks. I think this is goingto reseed the wall with new muscle tissue, and this will restore contractilefunction to the heart.
這是我的想法：我想培養(yǎng)人類多能干細胞，讓它們大量分裂，進而分化為心肌細胞，然后把它們從培養(yǎng)皿中拿出來，再把它們移植到心臟病患者的心臟上。我認為新的心肌細胞會縫合心臟上的傷口，進而會恢復心臟的收縮功能。
04:17
(Applause)
（掌聲，歡呼）?
04:24
Now, before you applaud too much, this wasmy idea 20 years ago.
在你們鼓太多掌之前，我想說這是我20年前的想法。
04:27
(Laughter)
（笑）
04:29
And I was young, I was full of it, and Ithought, five years in the lab, and we'll crank this out, and we'll have thisinto the clinic. Let me tell you what really happened.
我很年輕，我充滿了這種想法，我想，在實驗室里呆五年，我們會解決這個問題的，我們會把這個想法在臨床上變成現實。我來告訴你們到底發(fā)生了什么。
04:40
(Laughter)
（笑）
04:41
We began with the quest to turn thesepluripotent 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 bedone. But when we got around to doing the cell counts, we found that only oneout of 1,000 of our stem cells were actually turning into heart muscle. Therest was just a gemisch of brain and skin and cartilage and intestine. So howdo you coax a cell that can become anything into becoming just a heart musclecell?
我們開始探索將這些多能干細胞轉化為心肌細胞。我們的第一個實驗差不多算成功了。我們在培養(yǎng)皿中放了一些跳動的人體心臟肌肉，這很酷，因為它表明，原則上我的想法應該可以做到。但當我們開始做細胞計數時，我們發(fā)現1000個干細胞中只有一個實際上變成了心肌細胞。其余的只是大腦細胞、皮膚細胞、軟骨細胞和腸道細胞的混合。那么你如何讓一個能變成任何東西的細胞?只變成心肌細胞呢？
05:20
Well, for this we turned to the world ofembryology. For over a century, the embryologists had been pondering themysteries of heart development. And they had given us what was essentially aGoogle Map for how to go from a single fertilized egg all the way over to ahuman cardiovascular system. So we shamelessly absconded all of this informationand tried to make human cardiovascular development happen in a dish. It took usabout five years, but nowadays, we can get 90 percent of our stem cells to turninto cardiac muscle -- a 900-fold improvement. So this was quite exciting.
為了這個，我們轉向胚胎學的世界。一個多世紀以來，胚胎學家一直在思考心臟發(fā)育的奧秘。他們給了我們一張類似谷歌地圖的東西，這指示如何從一個受精卵一直發(fā)展到人類心血管系統(tǒng)。所以我們貪婪地使用了所有這些信息，并試圖使人的心血管發(fā)育發(fā)生在一個培養(yǎng)皿里。我們花了五年時間，但現在，我們可以讓90%的干細胞變成心肌細胞——提高了900倍。所以這很令人興奮。
05:56
This slide shows you our current cellularproduct. We grow our heart muscle cells in little three-dimensional clumpscalled cardiac organoids. Each of them has 500 to 1,000 heart muscle cells init. If you look closely, you can see these little organoids are actuallytwitching; each one is beating independently. But they've got another trick uptheir 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 stemcells. And this makes our heart muscle cells flash green every time they beat.
這張幻燈片向你們展示我們當前的細胞產物。我們的心肌細胞在被稱為心臟類器官的三維結構中發(fā)育。它們每個都有500到 1000個心肌細胞。如果你仔細觀察，你會發(fā)現這些小的類器官實際上在運動；每個類器官都在獨立地跳動。但它們還有另一個小奧秘。我們從太平洋西北部的水母身上提取了一個基因，我們使用了一種叫做基因組編輯的技術把這個基因拼接到干細胞中。這使得我們的心肌細胞每跳動一次都會閃爍綠色。
06:29
OK, so now we were finally ready to beginanimal experiments. We took our cardiac muscle cells and we transplanted theminto the hearts of rats that had been given experimental heart attacks. A monthlater, 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 wecame up with a biochemical cocktail that we called our "pro-survivalcocktail," and this was enough to allow our cells to survive through thestressful process of transplantation. And now when I looked through themicroscope, I could see this fresh, young, human heart muscle growing back inthe injured wall of this rat's heart. So this was getting quite exciting.
現在，我們終于準備好開始動物實驗了。我們取了我們的心肌細胞，把它們移植到有實驗性心臟病發(fā)作的老鼠的心臟里。一個月后，我焦急地透過顯微鏡觀察，看看我們長出了什么，我看到…沒有什么。一切都死了。但我們堅持不懈，想出了一種生化雞尾酒，我們稱之為“助生雞尾酒”，這足以通過移植的壓力，讓我們的細胞存活下來?，F在當我通過顯微鏡看的時候，我能看到這些新鮮的、年輕的人類心肌?在受傷的老鼠心臟壁上生長。這變得非常令人興奮。
07:13
The next question was: Will this new musclebeat in synchrony with the rest of the heart? So to answer that, we returned tothe cells that had that jellyfish gene in them. We used these cells essentiallylike a space probe that we could launch into a foreign environment and thenhave that flashing report back to us about their biological activity. Whatyou're seeing here is a zoomed-in view, a black-and-white image of a guineapig's heart that was injured and then received three grafts of our humancardiac muscle. So you see those sort of diagonally running white lines. Eachof those is a needle track that contains a couple of million human cardiacmuscle cells in it. And when I start the video, you can see what we saw when welooked through the microscope. Our cells are flashing, and they're flashing insynchrony, back through the walls of the injured heart.
下一個問題是：這種新的肌肉會與心臟的其他部分同步跳動嗎？要回答這個問題，我們回到了含有水母基因的細胞。我們基本上就把這些細胞當做太空探測器一樣來使用，我們把它們放到一個陌生的環(huán)境中，然后我們通過返還給我們的閃爍信號，來了解它們的生物活性。你們現在看到的是一個放大的豚鼠心臟的黑白圖像，這顆心臟受了傷，然后接受了三輪的人體心肌移植。你們可以看到那些斜行的白線。每個都是針線，里面有幾百萬人類心肌細胞。當我開始放視頻的時候，你們就可以看到我們透過顯微鏡時看到的景象。細胞在閃爍，而且它們在同步閃爍，透過受傷的心臟壁傳回來。
08:03
What does this mean? It means the cells arealive, they're well, they're beating, and they've managed to connect with oneanother so that they're beating in synchrony. But it gets even more interestingthan this. If you look at that tracing that's along the bottom, that's theelectrocardiogram from the guinea pig's own heart. And if you line up theflashing with the heartbeat that's shown on the bottom, what you can see isthere's a perfect one-to-one correspondence. In other words, the guinea pig'snatural pacemaker is calling the shots, and the human heart muscle cells arefollowing in lockstep like good soldiers.
這是什么意思？這意味著細胞是活的，它們很好，它們在跳動，它們已經成功的融為一體了，所以它們在同步跳動。但還有更有意思的事情。如果你看底部的線條，這是豚鼠心臟的心電圖。如果你把閃光和心跳排成一行如圖所示，你看到的是一對一的完美對應。換言之，豚鼠自身的心臟正在主導，而人體心肌細胞則是亦步亦趨的跟隨著，就像好士兵一樣。
08:37
(Applause)
（掌聲，歡呼）?
08:44
Our current studies have moved into what Ithink is going to be the best possible predictor of a human patient, and that'sinto macaque monkeys. This next slide shows you a microscopic image from theheart of a macaque that was given an experimental heart attack and then treatedwith a saline injection. This is essentially like a placebo treatment to showthe 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 asyou look as this, you can see how there's a big deficiency in the muscle inpart of the wall of the heart. And it's not hard to imagine how this heartwould have a tough time generating much force.
我們目前的研究已經進入了我所認為的和人類最相近的動物實驗階段，那就是獼猴實驗。下一張幻燈片是一幅顯微圖像，展示了一只實驗性心臟病發(fā)作的獼猴心臟，然后被注射了鹽水。這基本上就像安慰劑治療，顯示疾病的自然發(fā)生過程。獼猴的心肌呈紅色，藍色部分，你可以看到心臟病引起的疤痕組織。當你看著這張圖時，你會發(fā)現心室壁的一部分?肌肉有很大的缺陷。不難想象這顆心臟在起搏時會有多么大的阻礙。
09:25
Now in contrast, this is one of the stem-cell-treatedhearts. Again, you can see the monkey's heart muscle in red, but it's very hardto even see the blue scar tissue, and that's because we've been able torepopulate it with the human heart muscle, and so we've got this nice, plumpwall.
相反，這是顆接受干細胞治療的心臟。同樣的，你可以看到猴子的心肌是紅色的，但是很難看到藍色的疤痕組織，那是因為我們用了人類的心肌?去恢復了它，所以我們重新有了一扇漂亮豐滿的心室壁。
09:43
OK, let's just take a second and recap.I've showed you that we can take our stem cells and differentiate them intocardiac 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'veshown that we can scale them up into an animal that is the best possiblepredictor of a human's response. You'd think that we hit all the roadblocksthat lay in our path, right? Turns out, not.
好吧，讓我們花點時間回顧一下。我已經向你展示了我們的干細胞以及它們分化成心肌細胞的過程。我們已經學會了如何在移植后保持它們的活力，我們已經證明它們與心臟的其他部分同步跳動，我們已經證明我們可以在成為最能預測人類反應的動物身上進行實驗。你們會認為我們清除了所有阻礙我們前進的路障，對吧？事實證明，不是這樣。
10:12
These macaque studies also taught us thatour human heart muscle cells created a period of electrical instability. Theycaused ventricular arrhythmias, or irregular heartbeats, for several weeksafter we transplanted them. This was quite unexpected, because we hadn't seenthis in smaller animals. We've studied it extensively, and it turns out that itresults from the fact that our cellular graphs are quite immature, and immatureheart muscle cells all act like pacemakers. So what happens is, we put theminto the heart, and there starts to be a competition with the heart's naturalpacemaker over who gets to call the shots. It would be sort of like if youbrought 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 runthings, and it takes a while to rein everybody in and get people working in acoordinated fashion. So our plans at the moment are to make the cells gothrough this troubled adolescence period while they're still in the dish, andthen we'll transplant them in in the post-adolescent phase, where they shouldbe much more orderly and be ready to listen to their marching orders. In themeantime, it turns out we can actually do quite well by treating withanti-arrhythmia drugs as well.
這些獼猴的研究也教會了我們，我們人類的心肌細胞造成了一段時間的心電不穩(wěn)。它們引起了室性心律失常或不規(guī)則的心跳，長達移植后幾個星期之久。這完全出乎意料，因為我們在小動物身上沒有看到過。我們對這進行了廣泛的研究，結果發(fā)現，發(fā)生的原因是我們的細胞圖很不成熟，未成熟的心肌細胞都像起搏器。所以當我們把它們放進心臟，它們便開始與心臟的自然起搏競爭決定誰來占主導地位。這就有點像如果你一下子把一群傻乎乎的青少年帶到你井然有序的家里，他們不想遵守你的規(guī)則和節(jié)奏，需要一段時間來控制所有人，讓人們以協調一致的方式工作。所以我們現在的計劃是當細胞還在培養(yǎng)皿里的時候，讓它們經歷這個麻煩的“青春期”，然后我們在“青春期”后移植它們，那時它們會更加的有序，準備好遵守它們的行軍命令。同時，事實證明當這種方法和抗心律失常藥物結合時，我們做的相當不錯。
11:27
So one big question still remains, and thatis, of course, the whole purpose that we set out to do this: Can we actuallyrestore function to the injured heart? To answer this question, we went tosomething that's called "left ventricular ejection fraction."Ejection fraction is simply the amount of blood that is squeezed out of thechamber of the heart with each beat. Now, in healthy macaques, like in healthypeople, ejection fractions are about 65 percent. After a heart attack, ejectionfraction drops down to about 40 percent, so these animals are well on their wayto heart failure. In the animals that receive a placebo injection, when we scanthem a month later, we see that ejection fraction is unchanged, because theheart, of course, doesn't spontaneously recover. But in every one of theanimals that received a graft of human cardiac muscle cells, we see asubstantial improvement in cardiac function. This averaged eight points, sofrom 40 to 48 percent. What I can tell you is that eight points is better thananything that's on the market right now for treating patients with heartattacks. It's better than everything we have put together. So if we could doeight points in the clinic, I think this would be a big deal that would make alarge impact on human health.
還有一個大問題，當然，這就是我們開始做這件事的全部目的：我們真的能恢復受傷心臟的功能嗎？要回答這個問題，我們研究了所謂的“左心室射出分率”。射出分率是每一次起搏時從心腔中擠出來的血液量。健康的獼猴，就像健康人一樣，射出分率約為65%。心臟病發(fā)作后，射出分率下降到40%左右，所以這些動物很快就會患上心力衰竭。在接受安慰劑注射的動物中，一個月后當我們掃描它們時，我們看到射出分率不變，因為心臟不會自動恢復。但是在每只接受人體心肌細胞移植的動物身上，我們看到心臟功能有了實質性的改善。從40%到48%，平均有8個點的提升。我能告訴你的是8個點比現在市場上的任何用于治療心臟病患者的東西都要好。這和我們把所有的東西放在一起比都要好。如果我們能在臨床上達到8個點，我認為這將會對人類健康產生很大的影響。
12:39
But it gets more exciting. That was justfour weeks after transplantation. If we extend these studies out to threemonths, we get a full 22-point gain in ejection fraction.
但是還有更令人興奮的。這只是移植后的四周。如果我們把這些研究延長到三個月，射出分率會增長22個點。
12:52
(Applause)
（掌聲，歡呼）
12:59
Function in these treated hearts is so goodthat if we didn't know up front that these animals had had a heart attack, wewould never be able to tell from their functional studies.
這些治療過的心臟功能很好以至于如果我們事先不知道這些動物有過心臟病發(fā)作，我們永遠無法從功能研究中將它們辨別出來。
13:12
Going forward, our plan is to start phaseone, first in human trials here at the University of Washington in 2020 -- twoshort years from now. Presuming these studies are safe and effective, which Ithink they're going to be, our plan is to scale this up and ship these cellsall around the world for the treatment of patients with heart disease. Giventhe global burden of this illness, I could easily imagine this treating amillion or more patients a year.
接下來，我們的計劃是開始第一階段，2020年首次在華盛頓大學進行人體試驗——兩年后。假設這些研究是安全有效的，我覺得它們是這樣的，我們的計劃是擴大規(guī)模，把這些細胞運到世界各地用于治療心臟病患者。鑒于這種疾病的全球性負擔，我可以很容易地想象，每年治療一百萬或更多的病人。
13:40
So I envision a time, maybe a decade fromnow, where a patient like my mother will have actual treatments that canaddress the root cause and not just manage her symptoms. This all comes fromthe fact that stem cells give us the ability to repair the human body from itscomponent parts.
我設想一個時間，也許十年后，像我母親這樣的病人會接受真正的治療，這可以解決根本原因，而不僅僅是緩解她的癥狀。這些都因為干細胞讓我們有能力可以從人類身體的組成部分來修復自身。
13:58
In the not-too-distant future, repairinghumans is going to go from something that is far-fetched science fiction intocommon medical practice. And when this happens, it's going to have atransformational effect that rivals the development of vaccinations andantibiotics.
在不久的將來，修復人類就要從牽強附會的科幻小說中走進普通的醫(yī)學實踐。當這發(fā)生時，它會產生一個顛覆性的效果，可以比肩疫苗和抗生素的發(fā)展。
14:18
Thank you for your attention.
謝謝你們的聆聽。
14:19
(Applause)
（掌聲，歡呼）
