David Anderson: Your brain is more than a bag of chemicals

Translator: Joseph Geni Reviewer: Morton Bast

譯者: William Choi 審譯者: Yuen-Lam Tsang

So raise your hand if you know someone

如果你的家人或者朋友

in your immediate family or circle of friends

曾經遭受到精神疾病的困擾，

who suffers from some form of mental illness.

請舉手。

Yeah. I thought so. Not surprised.

耶。我想應該如此的，不必驚訝。

And raise your hand if you think that

如果你認為

basic research on fruit flies has anything to do

利用果蠅進行基本研究

with understanding mental illness in humans.

與了解人類精神疾病 有關聯的話，請舉手。

Yeah. I thought so. I'm also not surprised.

耶。我想應該如此的，我也不會感到驚訝。

I can see I've got my work cut out for me here.

我知道在這裡 我的任務非常困難，

As we heard from Dr. Insel this morning,

正如Dr. Insel今早對我們說，

psychiatric disorders like autism, depression and schizophrenia

精神疾病，如：自閉症、 憂鬱症、精神分裂症等，

take a terrible toll on human suffering.

讓人類遭受無比的痛苦，

We know much less about their treatment

我們對精神疾病的治療

and the understanding of their basic mechanisms

和基本機制的了解

than we do about diseases of the body.

比身體疾病的認識知道得更少，

Think about it: In 2013,

試想想：在2013年，

the second decade of the millennium,

21世紀第二個十年，

if you're concerned about a cancer diagnosis

如果你想進行癌症診斷，

and you go to your doctor, you get bone scans,

你會找醫師安排去做骨骼掃瞄、

biopsies and blood tests.

切片檢查和血液檢查。

In 2013, if you're concerned about a depression diagnosis,

在2013年，如果你想進行憂鬱症診斷，

you go to your doctor, and what do you get?

你會找醫師，你會得到甚麼呢？

A questionnaire.

一份問卷調查。

Now, part of the reason for this is that we have

部分導致目前的情況的原因是由於

an oversimplified and increasingly outmoded view

我們對精神疾病的生物基礎，

of the biological basis of psychiatric disorders.

持有過份簡單和 越來越過時的觀點，

We tend to view them --

我們傾向於認為大眾媒體

and the popular press aids and abets this view --

對這觀點形成有所幫助和煽動 -

as chemical imbalances in the brain,

腦中的化學物質失衡了，

as if the brain were some kind of bag of chemical soup

腦部就像一盒含化學物質成分 的羹湯，

full of dopamine, serotonin and norepinephrine.

充滿了多巴胺、血清素和去甲腎上腺素，

This view is conditioned by the fact

這觀點取決於以下事實，

that many of the drugs that are prescribed to treat these disorders,

很多治療這類疾病的 處方藥物如百憂解(Prozac)，

like Prozac, act by globally changing brain chemistry,

全面地改變了大腦化學物質，

as if the brain were indeed a bag of chemical soup.

好像腦部確實是一盒含 化學物質成分的羹湯。

But that can't be the answer,

但這不是答案，

because these drugs actually don't work all that well.

因為這些藥物事實上不是那麼好，

A lot of people won't take them, or stop taking them,

很多病人不會服用 或者停止服用了，

because of their unpleasant side effects.

由於那些令人不快的副作用。

These drugs have so many side effects

這些藥物有那麼多副作用，

because using them to treat a complex psychiatric disorder

用以治療複雜精神疾病，

is a bit like trying to change your engine oil

有點像更換引擎機油時，

by opening a can and pouring it all over the engine block.

打開了罐，把機油傾倒 在引擎本體上，

Some of it will dribble into the right place,

部分流入了正確位置，

but a lot of it will do more harm than good.

但大部分弊大於利，

Now, an emerging view

現在，一項新興觀點，

that you also heard about from Dr. Insel this morning,

今早你也從Dr. Insel那裡聽說過，

is that psychiatric disorders are actually

說明精神疾病其實是

disturbances of neural circuits that mediate

神經中樞回路的擾亂，

emotion, mood and affect.

在感情、情緒和感動之間 起中介作用。

When we think about cognition,

我們想起認知時，

we analogize the brain to a computer. That's no problem.

將腦部比喻為電腦， 是沒有問題的。

Well it turns out that the computer analogy

那麼證明了這比喻

is just as valid for emotion.

也可以應用到情緒上，

It's just that we don't tend to think about it that way.

只是我們不會有這樣子的想法。

But we know much less about the circuit basis

但是我們對精神疾病的

of psychiatric disorders

回路基礎知道得很少，

because of the overwhelming dominance

因為這個化學物質不平衡假設

of this chemical imbalance hypothesis.

勢不可擋兼具主導地位。

Now, it's not that chemicals are not important

化學物質在精神疾病中

in psychiatric disorders.

並不是不重要，

It's just that they don't bathe the brain like soup.

只是他們不會在腦部沉浸，像羹湯一樣，

Rather, they're released in very specific locations

而是將化學物質釋放在特定位置，

and they act on specific synapses

作用於特定的突觸，

to change the flow of information in the brain.

以改變腦部資訊的流向。

So if we ever really want to understand

如果我們真的想理解

the biological basis of psychiatric disorders,

精神疾病的生物基礎，

we need to pinpoint these locations in the brain

就需要找出化學物質

where these chemicals act.

在腦部作用的位置，

Otherwise, we're going to keep pouring oil all over our mental engines

否則我們不停把精神機器加滿油，

and suffering the consequences.

並遭受到痛苦的結果。

Now to begin to overcome our ignorance

現在開始戰勝我們的無知，

of the role of brain chemistry in brain circuitry,

尤其腦部化學物質在腦部回路中的角色，

it's helpful to work on what we biologists call

對於我們生物學家稱為

"model organisms,"

「模式生物」的研究還有幫助，

animals like fruit flies and laboratory mice,

一些動物如果蠅和實驗小鼠，

in which we can apply powerful genetic techniques

我們能以強勁的基因技術

to molecularly identify and pinpoint

在分子裡找出及確定

specific classes of neurons,

特定類型的神經元，

as you heard about in Allan Jones's talk this morning.

正如今早Allan Jones 所講。

Moreover, once we can do that,

此外，當我們確定哪類型後，

we can actually activate specific neurons

就能激活特定的神經元細胞，

or we can destroy or inhibit the activity of those neurons.

也能毀滅或抑制神經元的活動。

So if we inhibit a particular type of neuron,

如果我們抑制特定種類的神經元，

and we find that a behavior is blocked,

就會發現某些行為被阻止了。

we can conclude that those neurons

我們可以得出這樣的結論，

are necessary for that behavior.

某些行為確實需要那些神經元。

On the other hand, if we activate a group of neurons

此外，如果我們激活某組的神經元細胞，

and we find that that produces the behavior,

就會發現那組細胞產生這行為，

we can conclude that those neurons are sufficient for the behavior.

我們可以得出這樣的結論， 那些神經元足以應付行為。

So in this way, by doing this kind of test,

由此可見，我們憑這樣的測試，

we can draw cause and effect relationships

能為特定神經元之間的活動

between the activity of specific neurons

其因果關係作出結論，

in particular circuits and particular behaviors,

尤其是特定的回路和特定的行為，

something that is extremely difficult, if not impossible,

現在還未能在人類身上作同樣測試，

to do right now in humans.

測試是極之困難的。

But can an organism like a fruit fly, which is --

但是一個生物體例如果蠅 ─

it's a great model organism

牠是非常重要的模式生物，

because it's got a small brain,

因為它有一個細小的腦部，

it's capable of complex and sophisticated behaviors,

可以控制複雜的行為。

it breeds quickly, and it's cheap.

它們繁殖得很快，價錢便宜。

But can an organism like this

但是像這樣的生物體

teach us anything about emotion-like states?

能否教導我們有關情緒狀態的事情嗎？

Do these organisms even have emotion-like states,

究竟這些生物體有沒有情緒狀態

or are they just little digital robots?

或只是一些微小的數碼機械人？

Charles Darwin believed that insects have emotion

查爾斯·達爾文相信昆蟲也有情緒，

and express them in their behaviors, as he wrote

並在行為中流露出來，

in his 1872 monograph on the expression of the emotions in man and animals.

1872年他把動物和人類的 情緒表達寫進了專著中，

And my eponymous colleague, Seymour Benzer, believed it as well.

與我齊名的同事Seymour Benzer 同樣相信。

Seymour is the man that introduced the use of drosophila

在六十年代，Seymour於 加州理工學院這裡，

here at CalTech in the '60s as a model organism

開始採用黑腹果蠅作為模式生物，

to study the connection between genes and behavior.

去研究基因與行為之間的關係，

Seymour recruited me to CalTech in the late 1980s.

在八十年代後期，Seymour招募我 加入加州理工學院，

He was my Jedi and my rabbi while he was here,

他是我的絕地武師、猶太教教士，

and Seymour taught me both to love flies

Seymour不僅教我愛上果蠅，

and also to play with science.

還教我玩科學。

So how do we ask this question?

因此，我們該如何提出這問題呢？

It's one thing to believe that flies have emotion-like states,

我們可以選擇相信 蒼蠅有情緒狀態這回事，

but how do we actually find out whether that's true or not?

但如何事實上分辨真假呢？

Now, in humans we often infer emotional states,

我們現在往往從人類面部表情 推測情緒狀態，

as you'll hear later today, from facial expressions.

今天晚些你會聽到的，

However, it's a little difficult to do that in fruit flies.

然而，有些難以在果蠅身上 做到這一點，

(Laughter)

(笑聲)

It's kind of like landing on Mars

這像登陸火星一樣，

and looking out the window of your spaceship

在太空船上，望向窗外，

at all the little green men who are surrounding it

被很多小綠人包圍，

and trying to figure out, "How do I find out

並試圖找出，

if they have emotions or not?"

「我怎樣找出他們有沒有情緒 ？」

What can we do? It's not so easy.

我們可以做些什麼呢？ 這不是那麼容易的。

Well, one of the ways that we can start

那麼我們可以嘗試其中一個方法，

is to try to come up with some general characteristics

就是盡量想出一些

or properties of emotion-like states

情緒狀態的特徵或屬性，

such as arousal, and see if we can identify

例如警醒程度，看看能否找出

any fly behaviors that might exhibit some of those properties.

一些果蠅行為，表現出那些屬性。

So three important ones that I can think of

因此，我能想到的三個重要屬性，

are persistence, gradations in intensity, and valence.

就是堅持、漸變強度、效價。

Persistence means long-lasting.

堅持即是要長期持久的，

We all know that the stimulus that triggers an emotion

我們都知道刺激會引發情緒，

causes that emotion to last long after the stimulus is gone.

就算刺激消失後， 情緒仍會持續一段很長時間。

Gradations of intensity means what it sounds like.

漸變強度即是它聽起來像什麼，

You can dial up the intensity or dial down the intensity of an emotion.

您可以把情緒強度增加或減少，

If you're a little bit unhappy, the corners of your mouth

如果你有點兒不高興，

turn down and you sniffle,

你的嘴角會向下， 你也會流鼻涕，

and if you're very unhappy, tears pour down your face

如果你真的不高興， 淚水傾瀉而下，

and you might sob.

那麼你可會抽泣。

Valence means good or bad, positive or negative.

效價是指「好」還是「壞」， 「正面」或「負面」，

So we decided to see if flies could be provoked into showing

因此，我們決定去看看 果蠅可否被激怒後，

the kind of behavior that you see

展示出那種行為，

by the proverbial wasp at the picnic table,

就像那些出現在野餐桌上 聞名遐爾的黃蜂，

you know, the one that keeps coming back to your hamburger

對吧，總是徘徊到你的漢堡包，

the more vigorously you try to swat it away,

你趕走得越起勁，

and it seems to keep getting irritated.

它似乎變得更惱火。

So we built a device, which we call a puff-o-mat,

因此，我們製造了一個裝置， 稱為噴風墊 ("puff-o-mat")，

in which we could deliver little brief air puffs to fruit flies

我們可以把短暫的空氣噴到果蠅，

in these plastic tubes in our laboratory bench

就在我們實驗室台上的塑膠管裡，

and blow them away.

吹走他們。

And what we found is that if we gave these flies

我們還發現如果給這些果蠅

in the puff-o-mat several puffs in a row,

在噴風墊上連續噴氣幾次，

they became somewhat hyperactive

他們變得有些過動，

and continued to run around for some time after the air puffs actually stopped

在停止噴空氣後， 還繼續到處跑了一段時間，

and took a while to calm down.

好一會才冷靜下來。

So we quantified this behavior

因此，我們使用自訂的

using custom locomotor tracking software

運動跟踪軟件去量化這種行為，

developed with my collaborator Pietro Perona,

這軟件由我的協作者 彼得羅佩羅娜(Pietro Perona)開發，

who's in the electrical engineering division here at CalTech.

他在加州理工學院這裡 的電氣工程系工作，

And what this quantification showed us is that,

這些量化數據顯示出

upon experiencing a train of these air puffs,

當果蠅遇到這些噴氣管時，

the flies appear to enter a kind of state of hyperactivity

就會進入過動狀態，

which is persistent, long-lasting,

而且是持久的，

and also appears to be graded.

然後我們會評分。

More puffs, or more intense puffs,

多噴些空氣、或噴出更強烈的空氣，

make the state last for a longer period of time.

使這狀態持續較長一段的時間。

So now we wanted to try to understand something

所以，現在我們嘗試去了解那些東西

about what controls the duration of this state.

可控制此狀態多久。

So we decided to use our puff-o-mat

我們決定使用噴風墊

and our automated tracking software

和自動運動跟踪軟件，

to screen through hundreds of lines of mutant fruit flies

通過對數百串突變果蠅進行篩選，

to see if we could find any that showed abnormal responses to the air puffs.

看看能否發現對噴氣 產生任何異常反應。

And this is one of the great things about fruit flies.

而這是關於果蠅最棒的地方之一，

There are repositories where you can just pick up the phone

你可以拿起電話筒接駁到儲存庫，

and order hundreds of vials of flies of different mutants

訂購幾百瓶不同突變型式的果蠅，

and screen them in your assay and then find out

在分析試驗中進行篩選，然後找出

what gene is affected in the mutation.

哪些基因受到突變的影響。

So doing the screen, we discovered one mutant

因此，做了篩選後，我們發現一個突變，

that took much longer than normal to calm down

使果蠅在噴氣後， 需要比正常更多一點的時間

after the air puffs,

才平靜下來，

and when we examined the gene that was affected in this mutation,

當我們研究這個基因 如何受到突變的影響時，

it turned out to encode a dopamine receptor.

整件事變成將一個多巴胺受體進行編碼。

That's right -- flies, like people, have dopamine,

這是正確的 - 果蠅也分泌多巴胺， 就像人一樣，

and it acts on their brains and on their synapses

而通過多巴胺受體，

through the same dopamine receptor molecules

它作用於大腦和突觸，

that you and I have.

而你和我也擁有相同的受體分子。

Dopamine plays a number of important functions in the brain,

在大腦中，多巴胺發揮了一些重要作用，

including in attention, arousal, reward,

包括注意力、警醒、報應，

and disorders of the dopamine system have been linked

而多巴胺系統的疾病與 很多精神疾病互相關聯的，

to a number of mental disorders including drug abuse,

例如：濫用藥物、

Parkinson's disease, and ADHD.

帕金森氏病、注意力不足過動症等。

Now, in genetics, it's a little counterintuitive.

現時，在遺傳學上， 這是有點違反直覺的。

We tend to infer the normal function of something

我們傾向於推斷， 當我們把某東西拿走時，

by what doesn't happen when we take it away,

那正常功能也會跟著消失，

by the opposite of what we see when we take it away.

與之相反，當我們拿走它時， 看到了什麼。

So when we take away the dopamine receptor

所以當我們拿掉多巴胺受體時，

and the flies take longer to calm down,

果蠅需要較長時間冷靜下來，

from that we infer that the normal function of this receptor and dopamine

由此推斷，這些受體 和多巴胺的正常功能，

is to cause the flies to calm down faster after the puff.

就是導致果蠅在噴氣後 較快冷靜下來的原因。

And that's a bit reminiscent of ADHD,

也有點讓人聯想到 注意力不足過動症，

which has been linked to disorders of the dopamine system in humans.

已被證實與人類 多巴胺系統疾病有關。

Indeed, if we increase the levels of dopamine in normal flies

事實上，如果我們用可卡因 餵養正常果蠅，

by feeding them cocaine

以增加多巴胺的水平，

after getting the appropriate DEA license

在取得美國緝毒局許可證的情況下，

— oh my God -- (Laughter) —

噢！我的天呀！ - (笑聲) -

we find indeed that these cocaine-fed flies

事實上，我們發現這些體內 含可卡因的蒼蠅，

calm down faster than normal flies do,

比正常果蠅較快冷靜下來，

and that's also reminiscent of ADHD,

也讓人聯想到注意力不足過動症，

which is often treated with drugs like Ritalin

醫師常處方藥物如利他能，

that act similarly to cocaine.

與可卡因的作用相近。

So slowly I began to realize that what started out

因此，我慢慢地開始了解到，

as a rather playful attempt to try to annoy fruit flies

試圖惹惱果蠅， 這個頗為有趣的玩笑，

might actually have some relevance to a human psychiatric disorder.

實際上可能與人類精神疾病相關。

Now, how far does this analogy go?

現在，這個比喻有多貼題？

As many of you know, individuals afflicted with ADHD

正如你們許多人知道， 注意力不足過動症患者

also have learning disabilities.

也有學習障礙。

Is that true of our dopamine receptor mutant flies?

多巴胺受體發生突變的果蠅 也是如此嗎？

Remarkably, the answer is yes.

令人意想不到的是，答案是肯定的。

As Seymour showed back in the 1970s,

Seymour於七十年代己指出，

flies, like songbirds, as you just heard,

果蠅像燕雀一樣，正如你剛聽到的，

are capable of learning.

也有學習的能力。

You can train a fly to avoid an odor, shown here in blue,

你可以訓練果蠅迴避一股氣味， 此處顯示為藍色，

if you pair that odor with a shock.

如果你將那種氣味 與震驚來進行配對，

Then when you give those trained flies the chance to choose

然後，讓那些受過訓練的果蠅有機會

between a tube with the shock-paired odor and another odor,

在與震驚配對的氣味和另一氣味 的塑膠管之間進行選擇，

it avoids the tube containing the blue odor that was paired with shock.

果蠅迴避了含有與震驚搭配 含藍色氣味的塑膠管，

Well, if you do this test on dopamine receptor mutant flies,

好的，如果你在多巴胺受體突變 的果蠅身上進行這項測試，

they don't learn. Their learning score is zero.

他們不會學習，他們的學習分數為零，

They flunk out of CalTech.

在加州理工學院考試不及格而退學。

So that means that these flies have two abnormalities,

實驗結果顯示這些果蠅有兩種異常，

or phenotypes, as we geneticists call them,

或顯型，如我們遺傳學家稱他們為，

that one finds in ADHD: hyperactivity and learning disability.

過動和學習障礙， 注意力不足過動症中找到的，

Now what's the causal relationship, if anything, between these phenotypes?

在兩個顯型之間，如有的話， 是什麼樣的因果關係呢？

In ADHD, it's often assumed that the hyperactivity

在注意力不足過動症中，往往假設

causes the learning disability.

過動造成了學習障礙。

The kids can't sit still long enough to focus, so they don't learn.

小孩坐也坐不住，無法集中注意力， 所以不能學習。

But it could equally be the case that it's the learning disabilities

也可會是同樣的情況，學習障礙

that cause the hyperactivity.

造成了過動。

Because the kids can't learn, they look for other things to distract their attention.

由於孩子無法學習，他們得 尋找其他事來分散注意力。

And a final possibility is that there's no relationship at all

最後的可能是

between learning disabilities and hyperactivity,

學習障礙和過動之間 根本沒有關係。

but that they are caused by a common underlying mechanism in ADHD.

但是他們由一個過動症的 共同內在機制所造成的。

Now people have been wondering about this for a long time

長久以來人們一直想知道人體上的機制，

in humans, but in flies we can actually test this.

但是我們可以在果蠅身上實際測試，

And the way that we do this is to delve deeply into the mind

而我們這樣做的方式是 深入鑽研果蠅的頭腦，

of the fly and begin to untangle its circuitry using genetics.

開始採用遺傳基因以解開其回路，

We take our dopamine receptor mutant flies

我們拿掉突變果蠅的多巴胺受體，

and we genetically restore, or cure, the dopamine receptor

然後以遺傳學方法， 修復或治療多巴胺受體，

by putting a good copy of the dopamine receptor gene

把多巴胺受體基因的好拷貝

back into the fly brain.

放回果蠅腦中，

But in each fly, we put it back only into certain neurons

但是在每隻果蠅身上， 我們只放回某些神經元，

and not in others, and then we test each of these flies

不是其他神經元， 然後我們測試每隻果蠅的

for their ability to learn and for hyperactivity.

學習和過動的能力。

Remarkably, we find we can completely dissociate these two abnormalities.

我們出奇地發現，兩種異常可完全分離。

If we put a good copy of the dopamine receptor back

如果我們把多巴胺受體的好拷貝

in this elliptical structure called the central complex,

放回這個橢圓形的中央複合體，

the flies are no longer hyperactive, but they still can't learn.

果蠅就不再過動，但仍不能學習，

On the other hand, if we put the receptor back in a different structure

另一方面，我們把受體放到別的組織，

called the mushroom body,

名為蕈狀體，

the learning deficit is rescued, the flies learn well,

學習缺陷從而得以倖免，果蠅便好好學習，

but they're still hyperactive.

但他們仍然過動。

What that tells us is that dopamine

這事告訴我們，多巴胺

is not bathing the brain of these flies like soup.

沒有在這些果蠅大腦中像羹湯一樣沐浴，

Rather, it's acting to control two different functions

相反，它對兩個不同回路上的

on two different circuits,

兩個不同功能，擔任控制角色，

so the reason there are two things wrong with our dopamine receptor flies

所以有兩件關於果蠅多巴胺受體 的事情是錯誤了，

is that the same receptor is controlling two different functions

是同一個受體控制腦部

in two different regions of the brain.

兩個不同區域的兩個不同功能。

Whether the same thing is true in ADHD in humans

我們不知道同樣的事情在 人類的注意力不足過動症上

we don't know, but these kinds of results

是否相同，但是這些結果

should at least cause us to consider that possibility.

至少導致我們考慮那個可能性，

So these results make me and my colleagues more convinced than ever

所以這些結果使我和我的同事 更加深信，

that the brain is not a bag of chemical soup,

腦部不是一盒含化學物質的羹湯，

and it's a mistake to try to treat complex psychiatric disorders

把治療複雜的精神疾病看成

just by changing the flavor of the soup.

改變羹湯味道是錯誤的。

What we need to do is to use our ingenuity and our scientific knowledge

我們需要運用聰明才智和科學知識，

to try to design a new generation of treatments

去嘗試設計新一代的治療方法，

that are targeted to specific neurons and specific regions of the brain

針對特定的神經元和特定的腦部區域，

that are affected in particular psychiatric disorders.

受特定精神疾病所影響的，

If we can do that, we may be able to cure these disorders

如果我們能夠做到這點， 或者可治癒這些疾病，

without the unpleasant side effects,

而沒有令人不快的副作用，

putting the oil back in our mental engines,

把汽油加回我們的精神引擎，

just where it's needed. Thank you very much.

這就是那裡所需要的。謝謝。