Can we regenerate heart muscle with stem cells? | Chuck Murry

譯者: Lilian Chiu 審譯者: Ziqing Ye

I'd like to tell you about a patient named Donna.

我想要跟各位聊聊 一位叫做唐娜的病人。

In this photograph, Donna was in her mid-70s,

在這張照片中， 唐娜大約七十五歲，

a vigorous, healthy woman,

精力充沛又健康，

the matriarch of a large clan.

是個大家族的家長。

She had a family history of heart disease, however,

不過，她的家庭有心臟病史，

and one day, she had the sudden onset of crushing chest pain.

有一天，她的胸口 突然痛到讓她站不起來。

Now unfortunately, rather than seeking medical attention,

不幸的是，唐娜沒有 尋求醫療協助，

Donna took to her bed for about 12 hours until the pain passed.

而是選擇在她的床上躺了 十二小時，直到胸痛過去。

The next time she went to see her physician,

後來她去看她的醫生時，

he performed an electrocardiogram,

醫生幫她做了心電圖，

and this showed that she'd had a large heart attack,

結果顯示她之前的狀況是 重大的心臟病發作，

or a "myocardial infarction" in medical parlance.

用醫學用語來說， 就是「心肌梗塞」。

After this heart attack, Donna was never quite the same.

在這次心臟病發作之後， 唐娜變得不一樣了。

Her energy levels progressively waned,

她的精神日漸萎靡，

she couldn't do a lot of the physical activities she'd previously enjoyed.

她無法繼續做很多 她以前很享受的身體活動。

It got to the point where she couldn't keep up with her grandkids,

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。

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,

有一天，她的孫女正出去遛狗時，

and she found her grandmother dead in the chair.

發現她的祖母在椅子上過世了。

Doctors said it was a cardiac arrhythmia that was secondary to heart failure.

醫生說（死因）是心臟衰竭 所伴隨的心律不整。

But the last thing that I should tell you

但，在最後我想告訴各位一件事，

is that Donna was not just an ordinary patient.

唐娜不是一般的病人。

Donna was my mother.

唐娜是我母親。

Stories like ours are, unfortunately, far too common.

很不幸的是， 像這樣的故事其實很常見。

Heart disease is the number one killer in the entire world.

全世界排名第一的殺手 就是心臟疾病。

In the United States,

在美國，

it's the most common reason patients are admitted to the hospital,

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。

and it's our number one health care expense.

在美國，每年我們要花 超過一千億美元，是「億」喔，

We spend over a 100 billion dollars -- billion with a "B" --

in this country every year

on the treatment of heart disease.

來治療心臟疾病。

Just for reference, that's more than twice the annual budget

這個數字比華盛頓州 年度預算的兩倍還高。

of the state of Washington.

What makes this disease so deadly?

這種疾病為什麼這麼致命？

Well, it all starts with the fact that the heart is the least regenerative organ

一切都始於，心臟是人類身體中

再生性最差的器官。

in the human body.

Now, a heart attack happens when a blood clot forms in a coronary artery

心臟病的發生是由於 給心室壁供血的冠狀動脈中

that feeds blood to the wall of the heart.

形成了血凝塊。

This plugs the blood flow,

這會造成血流被阻塞，

and the heart muscle is very metabolically active,

而由於心肌的新陳代謝十分活躍，

and so it dies very quickly,

血流只要被中斷幾個小時 就足以致死。

within just a few hours of having its blood flow interrupted.

Since the heart can't grow back new muscle,

因為心臟無法重新長出新肌肉，

it heals by scar formation.

它癒合的方式是形成疤痕，

This leaves the patient with a deficit

而這樣的結果會讓病人 沒有足量的心肌。

in the amount of heart muscle that they have.

And in too many people, their illness progresses to the point

許多人的病發展到後期時，他們的

where the heart can no longer keep up with the body's demand for blood flow.

心臟無法及時供應身體需要的血流。

This imbalance between supply and demand is the crux of heart failure.

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,

而當我和別人談到這個問題時，

I often get a shrug and a statement to the effect of,

他們卻通常會聳聳肩，並告訴我：

"Well, you know, Chuck, we've got to die of something."

「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

是啊，但這也讓我知道，

is that we've resigned ourselves to this as the status quo because we have to.

我們對這件事聽天由命， 是因為我們沒有別的選擇。

Or do we?

如果有呢？

I think there's a better way,

我認為有個更好的方法，

and this better way involves the use of stem cells as medicines.

這個方法是把幹細胞 拿來當醫藥用於治療。

So what, exactly, are stem cells?

所以，幹細胞到底是什麼？

If you look at them under the microscope, there's not much going on.

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。

They're just simple little round cells.

But that belies two remarkable attributes.

但它們其實還有有兩項驚人的特性。

The first is they can divide like crazy.

第一，它們能瘋狂地分裂。

So I can take a single cell, and in a month's time,

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。

I can grow this up to billions of cells.

The second is they can differentiate or become more specialized,

第二，它們可以分化或特化，

so these simple little round cells can turn into skin, can turn into brain,

所以，這些簡單的小圓細胞 可以轉變成皮膚、轉變成大腦、

can turn into kidney and so forth.

轉變成腎臟等等。

Now, some tissues in our bodies are chock-full of stem cells.

我們體內的一些組織裡 充滿了幹細胞。

Our bone marrow, for example, cranks out billions of blood cells every day.

比如，我們的骨髓每天都會 產生出數十億個血細胞。

Other tissues like the heart are quite stable,

其他組織，如心臟，就十分穩定，

and as far as we can tell, the heart lacks stem cells entirely.

就我們所知， 心臟完全沒有幹細胞。

So for the heart, we're going to have to bring stem cells in from the outside,

所以，我們必須從外界 把幹細胞帶入心臟。

and for this, we turn to the most potent stem cell type,

為此，我們將目光轉向了 最強大的一種幹細胞，

the pluripotent stem cell.

多功能性幹細胞。

Pluripotent stem cells are so named

這種幹細胞被稱為多功能性幹細胞，

because they can turn into any of the 240-some cell types

是因為它們能轉變為組成人體的

that make up the human body.

約 240 種細胞當中的任何一種。

So this is my big idea:

所以，我的想法是：

I want to take human pluripotent stem cells,

我想要取得人類的多功能性幹細胞，

grow them up in large numbers,

大量繁殖它們，

differentiate them into cardiac muscle cells

將它們特化轉成心肌細胞，

and then take them out of the dish

接著把它們從培養皿中取出，

and transplant them into the hearts of patients who have had heart attacks.

移植到心臟病病人的心臟裡。

I think this is going to reseed the wall with new muscle tissue,

我認為這樣就能夠在心室壁中 重新種下新的肌肉組織，

and this will restore contractile function to the heart.

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,

我當時很年輕，很自滿，我心想，

five years in the lab, and we'll crank this out,

在實驗室中研究五年， 我就能完成它，

and we'll have this into the clinic.

我們就能在臨床上使用了。

Let me tell you what really happened.

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.

我們開始努力嘗試 將多功能性幹細胞轉成心肌。

And our first experiments worked, sort of.

我們的第一次實驗成功了，算是吧。

We got these little clumps of beating human heart muscle in the dish,

我們在培養皿中得到了這些 小塊狀物，會跳動的人類心肌。

and that was cool, because it said, in principle,

這很不錯，因為原則上，這就意味著

this should be able to be done.

（這件事）是有可能辦到的。

But when we got around to doing the cell counts,

但，當我們去計算細胞數量時，

we found that only one out of 1,000 of our stem cells

我們發現，我們的幹細胞中 只有千分之一

were actually turning into heart muscle.

實際轉變為了心肌。

The rest was just a gemisch of brain and skin and cartilage

其他的都成了大腦、

皮膚、軟骨、腸子的混合物。

and intestine.

So how do you coax a cell that can become anything

所以，你要如何誘使 能變成任何東西的細胞

into becoming just a heart muscle cell?

只轉變成心肌細胞？

Well, for this we turned to the world of embryology.

為此，我們轉向胚胎學的世界。

For over a century, the embryologists had been pondering

一個多世紀以來， 胚胎學者一直在探索

the mysteries of heart development.

心臟發展的謎團。

And they had given us what was essentially a Google Map

他們給了我們像 Google 地圖一樣的資訊，

for how to go from a single fertilized egg

讓我們知道如何從單一受精卵

all the way over to a human cardiovascular system.

一路走到人類心血管系統。

So we shamelessly absconded all of this information

所以我們很不要臉地 帶走了這些訊息，

and tried to make human cardiovascular development happen in a dish.

嘗試把人類心血管發展的過程 在培養皿中重現。

It took us about five years, but nowadays,

我們花了大約五年，而如今，

we can get 90 percent of our stem cells to turn into cardiac muscle --

我們可以讓九成幹細胞 轉變成心肌——

a 900-fold improvement.

這是九百倍的改善。

So this was quite exciting.

所以，這很讓人興奮。

This slide shows you our current cellular product.

這張投影片上的是 我們目前的細胞產品。

We grow our heart muscle cells in little three-dimensional clumps

我們在小小的 3D 團塊中 培養我們的心肌細胞，

called cardiac organoids.

這一團塊叫做「類心臟器官」。

Each of them has 500 to 1,000 heart muscle cells in it.

每一塊當中都有五百 到一千個心肌細胞。

If you look closely, you can see these little organoids are actually twitching;

如果再靠近看，可以看到這些 小小的類器官其實正在抽動；

each one is beating independently.

每一個都獨自在跳動。

But they've got another trick up their sleeve.

但，它們還有另一項技能。

We took a gene from jellyfish that live in the Pacific Northwest,

我們從美國西北部太平洋岸 附近的水母身上取得基因，

and we used a technique called genome editing

我們採用了一種叫做 基因組編輯的技術，

to splice this gene into the stem cells.

把這個水母基因結合到幹細胞中。

And this makes our heart muscle cells flash green every time they beat.

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.

這樣，我們終於準備好 要做動物實驗了。

We took our cardiac muscle cells

我們把我們的心肌細胞

and we transplanted them into the hearts of rats

移植到老鼠的心臟中，

that had been given experimental heart attacks.

牠們先前已發作過實驗性心臟病。

A month later, I peered anxiously down through my microscope

一個月後，我很急切地 透過我的顯微鏡，

to see what we had grown,

想仔細看看我們培養出了什麼，

and I saw ...

而我看到……

nothing.

什麼都沒有。

Everything had died.

一切都死了。

But we persevered on this, and we came up with a biochemical cocktail

但我們堅持不懈，又做出了 一種生物化學雞尾酒，

that we called our "pro-survival cocktail,"

我們稱它是我們的「助生雞尾酒」，

and this was enough to allow our cells to survive

這足以讓我們的細胞

在很有壓力的移植過程中存活下來。

through the stressful process of transplantation.

And now when I looked through the microscope,

現在，當我透過顯微鏡觀察時，

I could see this fresh, young, human heart muscle

我能看到這些新鮮、年輕的人類心肌，

growing back in the injured wall of this rat's heart.

在這隻老鼠受傷的心室壁中長回來。

So this was getting quite exciting.

這十分讓人興奮。

The next question was:

下一個問題是：

Will this new muscle beat in synchrony with the rest of the heart?

新的肌肉會和心臟的 其他部分同步跳動嗎？

So to answer that,

為了找出答案，

we returned to the cells that had that jellyfish gene in them.

我們返回有水母基因的那些細胞。

We used these cells essentially like a space probe

基本上，我們是把這些細胞 當作「太空探測器」來用，

that we could launch into a foreign environment

我們可以把它們 發射到陌生的環境中，

and then have that flashing report back to us

接著，透過閃光得到反饋，

about their biological activity.

來了解它們的生理活動。

What you're seeing here is a zoomed-in view,

各位現在看到的是放大的影像，

a black-and-white image of a guinea pig's heart

這張黑白影像上的是白鼠的心臟，

that was injured and then received three grafts of our human cardiac muscle.

這顆心臟受過傷，接著接受了 三塊嫁接的人類心肌。

So you see those sort of diagonally running white lines.

你們可以看到有一些 白色的對角線。

Each of those is a needle track

每一條極細的軌道

that contains a couple of million human cardiac muscle cells in it.

都含有數百萬個人類心肌細胞。

And when I start the video, you can see what we saw

我開始播放影片時，各位就能看到

when we looked through the microscope.

我們當時透過顯微鏡所看到的。

Our cells are flashing,

我們的細胞在閃爍，

and they're flashing in synchrony,

且它們是同步在閃爍，

back through the walls of the injured heart.

透過受傷的心室壁將閃光傳回來。

What does this mean?

這意味著什麼？

It means the cells are alive,

意味著這些細胞是活的，

they're well, they're beating,

它們很健康，它們在跳動，

and they've managed to connect with one another

而且它們找到方式和彼此連結，

so that they're beating in synchrony.

因此它們能夠同步跳動。

But it gets even more interesting than this.

但這還不是最有趣的。

If you look at that tracing that's along the bottom,

請看看最底部的描繪線，

that's the electrocardiogram from the guinea pig's own heart.

那是白老鼠自己心臟的心電圖。

And if you line up the flashing with the heartbeat

如果和呈現在底部的閃爍心跳

that's shown on the bottom,

互相對照著看，

what you can see is there's a perfect one-to-one correspondence.

你會發現它們完美地一對一呼應。

In other words, the guinea pig's natural pacemaker is calling the shots,

換言之，白老鼠的 天然心臟節律器在主導，

and the human heart muscle cells are following in lockstep

而人類心肌細胞則是 亦步亦趨跟隨著，

like good soldiers.

就像優秀的士兵。

(Applause)

（掌聲）

Our current studies have moved into what I think is going to be

我們目前的研究已即將開始 用在我個人認為

the best possible predictor of a human patient,

最能模擬人類病人的動物身上，

and that's into macaque monkeys.

也就是獼猴。

This next slide shows you a microscopic image

下一張投影片是顯微鏡的影像，

from the heart of a macaque that was given an experimental heart attack

影像中的是獼猴的心臟， 我們讓牠發生過實驗性心臟病，

and then treated with a saline injection.

接著用沙林注射液來治療牠。

This is essentially like a placebo treatment

基本上，這就像是安慰劑治療，

to show the natural history of the disease.

用來呈現疾病的自然歷史。

The macaque heart muscle is shown in red,

紅色部分是彌猴的心肌，

and in blue, you see the scar tissue that results from the heart attack.

藍色部分是心臟病 所造成的疤痕組織。

So as you look as this, you can see how there's a big deficiency in the muscle

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。

in part of the wall of the heart.

And it's not hard to imagine how this heart would have a tough time

不難想像，這顆心臟實在是

generating much force.

使不上力。

Now in contrast, this is one of the stem-cell-treated hearts.

相對的，這是用幹細胞治療的心臟。

Again, you can see the monkey's heart muscle in red,

同樣，紅色部分是猴子的心肌，

but it's very hard to even see the blue scar tissue,

但幾乎看不見多少藍色的疤痕組織，

and that's because we've been able to repopulate it

那是因為我們讓人類心肌

重新入住到這顆心臟裡，

with the human heart muscle,

and so we've got this nice, plump wall.

才會有這種撲通跳的優良心室壁。

OK, let's just take a second and recap.

好，咱們花點時間來做重點回顧。

I've showed you that we can take our stem cells

我已經讓各位看到， 我們能取用人類幹細胞

and differentiate them into cardiac muscle.

將它們特化，轉變成心肌。

We've learned how to keep them alive after transplantation,

我們也學會了如何 在移植時不讓它們死亡，

we've showed that they beat in synchrony with the rest of the heart,

各位也看到，它們能 和心臟的其他部分同步跳動。

and we've shown that we can scale them up

我們還能更進一步，

into an animal that is the best possible predictor of a human's response.

把它們放到最能預測 人類反應的動物體內。

You'd think that we hit all the roadblocks that lay in our path, right?

你們可能會認為，我們該碰到的 障礙都碰過了，是吧？

Turns out, not.

然而，並不是這樣。

These macaque studies also taught us

這些彌猴研究讓我們認識到，

that our human heart muscle cells created a period of electrical instability.

人類心肌細胞會造成 一段時間内的電流不穩定。

They caused ventricular arrhythmias, or irregular heartbeats,

這些細胞會造成心室心律不整， 或心臟節律不整，

for several weeks after we transplanted them.

在移植後數週都會有這種現象。

This was quite unexpected, because we hadn't seen this in smaller animals.

這是我們沒有預料到的， 因為在小動物身上並沒有發生。

We've studied it extensively,

我們對這個狀況進行了廣泛研究，

and it turns out that it results from the fact that our cellular graphs

結果發現，發生的原因 是因為我們的細胞圖

are quite immature,

還不太成熟，

and immature heart muscle cells all act like pacemakers.

而不成熟的心肌細胞 都像是有自己的心臟節律器一般。

So what happens is, we put them into the heart,

情況是，我們一旦把 這些細胞放進心臟，

and there starts to be a competition with the heart's natural pacemaker

它們就開始和心臟的 天然節律器競爭，

over who gets to call the shots.

搶著要主導權。

It would be sort of like

這就有點像是

if you brought a whole gaggle of teenagers into your orderly household all at once,

你把一群吵鬧的青少年 通通放到很有秩序的家庭裡，

and they don't want to follow the rules and the rhythms of the way you run things,

而他們不想遵守規則 和你做事的節奏。

and it takes a while to rein everybody in

要花一點時間才能控制住每個人，

and get people working in a coordinated fashion.

讓大家用很和諧的方式合作。

So our plans at the moment

所以，我們此時的計畫

are to make the cells go through this troubled adolescence period

是要讓細胞還在培養皿中的時候，

while they're still in the dish,

就先度過這段麻煩的青春期，

and then we'll transplant them in in the post-adolescent phase,

接著，我們再把青春期後的 細胞拿來做移植。

where they should be much more orderly

這時候的細胞便會更有秩序，

and be ready to listen to their marching orders.

且準備好聽命令來行軍了。

In the meantime, it turns out we can actually do quite well

同時，我們也發現 使用抗心律不整的藥物

by treating with anti-arrhythmia drugs as well.

進行治療的效果也相當好。

So one big question still remains,

但是，有個大問題仍然沒解決，

and that is, of course, the whole purpose that we set out to do this:

當然，那個問題也就是 我們動手做這一切的目的：

Can we actually restore function to the injured heart?

我們真的能夠幫 受傷的心臟恢復功能嗎？

To answer this question,

為了找到答案，

we went to something that's called "left ventricular ejection fraction."

我們轉向所謂的 「左心室射出分率」，

Ejection fraction is simply the amount of blood

射出分率就是每一次心跳時，

that is squeezed out of the chamber of the heart

從心室擠出的血液量。

with each beat.

Now, in healthy macaques, like in healthy people,

健康的彌猴就跟健康的人一樣，

ejection fractions are about 65 percent.

射出分率大約是 65%。

After a heart attack, ejection fraction drops down to about 40 percent,

在心臟病發之後， 射出分率會下降到約 40%，

so these animals are well on their way to heart failure.

所以這些動物正在走向心臟衰竭。

In the animals that receive a placebo injection,

針對接受安慰劑注射的動物，

when we scan them a month later,

我們在一個月後掃瞄牠們時，

we see that ejection fraction is unchanged,

發現射出分率並沒有改變，

because the heart, of course, doesn't spontaneously recover.

因為，當然啦， 心臟並不會自己復原。

But in every one of the animals that received a graft

但，在所有接受

人類心肌細胞嫁接的動物身上，

of human cardiac muscle cells,

we see a substantial improvement in cardiac function.

我們都發現心臟功能 有了大幅的改善，

This averaged eight points, so from 40 to 48 percent.

從 40% 增加到 48%， 平均有 8% 的提升。

What I can tell you is that eight points is better

我能告訴各位的是， 8% 的成果已經勝過

than anything that's on the market right now

目前市面上用來治療

for treating patients with heart attacks.

心臟病病人的任何東西。

It's better than everything we have put together.

比我們所有的療法加起來都還要好。

So if we could do eight points in the clinic,

所以，若我們 在臨床上能達成 8%，

I think this would be a big deal that would make a large impact

我認為，這會是件大事，

對於人類健康會有巨大的影響。

on human health.

But it gets more exciting.

但，更讓人興奮的還在後頭。

That was just four weeks after transplantation.

剛才談的只是移植後四週的狀況。

If we extend these studies out to three months,

如果我們把這些研究 延伸到三個月，

we get a full 22-point gain in ejection fraction.

射出分率能增加足足 22%。

(Applause)

（掌聲）

Function in these treated hearts is so good

這些接受治療的心臟， 功能變得非常好，

that if we didn't know up front that these animals had had a heart attack,

好到如果我們沒有事先知道 這些動物曾經心臟病發過，

we would never be able to tell from their functional studies.

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,

至於未來，我們的計畫 是要展開第一階段，

first in human trials here at the University of Washington in 2020 --

2020 年先在華盛頓大學 這裡做人體實驗——

two short years from now.

也就是短短的兩年後。

Presuming these studies are safe and effective,

假設這些研究是安全且有效的，

which I think they're going to be,

我認為應該會是如此，

our plan is to scale this up and ship these cells all around the world

那麼我們的計畫就是把規模擴大， 把這些細胞運往全世界，

for the treatment of patients with heart disease.

去治療心臟病病人。

Given the global burden of this illness,

這種疾病在全球都是很大的負擔，

I could easily imagine this treating a million or more patients a year.

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,

我的遠景是，將來， 也許十年之後，

where a patient like my mother will have actual treatments

像我母親這樣的病人 能接受可以根治的治療，

that can address the root cause and not just manage her symptoms.

而不只是在處理她的症狀。

This all comes from the fact that stem cells give us the ability

所有這些，都是因為 幹細胞讓我們有能力

to repair the human body

可以從人類身體的 各組成部分來修復人類身體。

from its component parts.

In the not-too-distant future,

在不久的將來，

repairing humans is going to go

修復人類將不再是

from something that is far-fetched science fiction

牽強附會的科幻小說，

into common medical practice.

而會變成是常見的醫療做法。

And when this happens,

當這一天到來時，

it's going to have a transformational effect

將會帶來轉化性的效應，

that rivals the development of vaccinations and antibiotics.

不輸給疫苗和抗生素 被開發出來的壯舉。

非常謝謝各位聆聽。

Thank you for your attention.

(Applause)

（掌聲）