Think about your day for a second. You woke up, felt fresh air on your face as you walked out the door, encountered new colleagues and had great discussions and felt in awe when you found something new. But I bet there's something you didn't think about today, something so close to home, you probably don't think about it very often at all. And that's that all those sensations, feelings, decisions and actions are mediated by the computer in your head called your brain.
花一點時間想想你的一天 早上你醒來,走出家門口,感覺清新空氣輕拂過你的臉龐. 巧遇你的一些新同事並和他們相談甚歡、 也為新奇的事物目瞪口呆. 但我敢打賭,有一些東西你今天絕對沒想到- 有些東西是如此貼近您, 以至於很多時候你根本忽略它的存在. 那就是你所有的一切喜怒哀樂,一切感覺, 所有的決定和行動 都是被你腦袋裡的電腦所控制. 也就是你的大腦.
Now, the brain may not look like much from the outside -- a couple pounds of pinkish-gray flesh, amorphous. But the last 100 years of neuroscience have allowed us to zoom in on the brain and to see the intricacy of what lies within. And they've told us that this brain is an incredibly complicated circuit made out of hundreds of billions of cells called neurons. Now, unlike a human-designed computer, where there's a fairly small number of different parts, and we know how they work because we humans designed them, the brain is made out of thousands of different kinds of cells, maybe tens of thousands. They come in different shapes; they're made out of different molecules; they project and connect to different brain regions. They also change in different ways in different disease states.
大腦看起來和它的外表大不同-- 是幾英磅粉紅偏灰色的肉, 無特定形狀-- 但近百年來神經科學的研究 使我們能夠放大細究大腦, 看到大腦內的複雜構造. 過往的研究告訴我們, 大腦是由數千億的神經元細胞 組造成一個令人難以置信的複雜電路. 不同於人為設計的電腦, 只由相當少數的零件組成、 知道它們是如何運作,因為那是我們人類所設計的 而大腦是由數千種不同種類的細胞架構的, 或許有數萬種吧。 它們各有不同的形狀,是由不同的分子組成, 各自連結到大腦不同的區域。 會隨著不同疾病狀態而呈現不同的改變.
Let's make it concrete. There's a class of cells, a fairly small cell, an inhibitory cell, that quiets its neighbors. It's one of the cells that seems to be atrophied in disorders like schizophrenia. It's called the basket cell. And this cell is one of the thousands of kinds of cell that we're learning about. New ones are being discovered every day. As just a second example: these pyramidal cells, large cells, can span a significant fraction of the brain. They're excitatory. And these are some of the cells that might be overactive in disorders such as epilepsy. Every one of these cells is an incredible electrical device. They receive inputs from thousands of upstream partners and compute their own electrical outputs, which then, if they pass a certain threshold, will go to thousands of downstream partners. And this process, which takes just a millisecond or so, happens thousands of times a minute in every one of your 100 billion cells, as long as you live and think and feel.
讓我更進一步解釋. 有一類細胞,是一種相當小的、 具抑制作用的細胞,專門控制它的鄰居,使大家安靜下來守紀律. 在精神分裂症患者腦部被發現萎縮的細胞種類之一. 也就是所謂的籃狀細胞。 是我們正在學習瞭解中的 數千種細胞其中之一. 還有更多新種類的細胞每天不斷地被發掘。 這是第二個例子: 這些是錐體細胞,很大的細胞, 它們覆蓋大腦很大一部分. 它們具有興奮性. 當癲癇患者發病時, 這類細胞都可能有些過度活躍. 每一個腦神經細胞都像是 一種巧奪天工的電子器材。 它們接收上千個上游腦神經細胞傳來的訊息 規劃整理出自己的電子訊號, 然後等到訊號強過臨界點後, 就會把訊號傳送給成千上萬的下游細胞. 而這個過程,只需要一毫秒左右, 而且每分鐘發生幾千次, 同部在腦中1千億個腦細胞之間進行. 只要你還活著,
So how are we going to figure out what this circuit does?
有思想、有感覺都是如此.
Ideally, we could go through this circuit and turn these different kinds of cell on and off and see whether we could figure out which ones contribute to certain functions and which ones go wrong in certain pathologies. If we could activate cells, we could see what powers they can unleash, what they can initiate and sustain. If we could turn them off, then we could try and figure out what they're necessary for. And that's the story I'm going to tell you about today. And honestly, where we've gone through over the last 11 years, through an attempt to find ways of turning circuits and cells and parts and pathways of the brain on and off, both to understand the science and also to confront some of the issues that face us all as humans.
那麼我們如何能確認這個電路各扮演什麼角色呢? 理想的情況下,我們可以通過電路, 開啟或關閉這些不同類型的細胞 看看我們能否找出 它們各自特殊的功能, 或是當它們表現不正常時,所產生的那些病癥. 如果我們可以啟動某些細胞,我們就知道它們可以發揮什麼能力、 什麼功能是它們可以啟動或維持的. 如果我們可以將它們關閉, 我們就可以試著弄清楚他們對我們的必要性是什麼。 這就是今天我要告訴你的故事. 真的,超過11年的研究經歷中, 我們企圖尋找方法 去開關腦中的電路、細胞、任何小部份 和它們傳導的途徑. 不僅是為了滿足對科學的好奇心 也為了正視、解決人類現在 所面臨的一些問題.
Now, before I tell you about the technology, the bad news is that a significant fraction of us in this room, if we live long enough, will encounter, perhaps, a brain disorder. Already, a billion people have had some kind of brain disorder that incapacitates them. The numbers don't do it justice, though. These disorders -- schizophrenia, Alzheimer's, depression, addiction -- they not only steal away our time to live, they change who we are. They take our identity and change our emotions and change who we are as people.
現在,在我開始告訴你有關的科技之前, 我要告訴您一個壞消息,在這房間裡的不少人 如果活的夠久 他們的大腦就會有機會紊亂,不聽指揮. 目前,約有十億人 已經得了大腦病變, 以至他們癱瘓殘障。 而數字無法真切代表出疾病的嚴重性. 這些疾病-精神分裂症,阿茲海默老年癡呆症、 憂鬱症,癮癖- 疾病不僅偷走我們的生命,還改變我們的人格 不僅剽竊走我們的自我認知,還改變我們的情緒-- 讓我們變成另一個人。
Now, in the 20th century, there was some hope that was generated through the development of pharmaceuticals for treating brain disorders. And while many drugs have been developed that can alleviate symptoms of brain disorders, practically none of them can be considered to be cured. In part, that's because, if you think about it, we're bathing the brain in a chemical -- this elaborate circuit, made of thousands of different kinds of cell -- is being bathed in a substance. That's also why most of the drugs, not all, on the market can present some kind of serious side effect too.
20世紀的今天, 由於治療腦部疾病的新藥品 不斷被研發出來,為我們帶來一絲希望。 縱使已有許多藥物能 緩解腦部疾病的的症狀, 幾乎沒有任何一種能被認為可以完全治癒腦部病變。 部分的原因是因為,服藥就好似把大腦浸泡在化學藥劑中 但是腦部內精心設計的電路是由 數千種不同的細胞組成 卻都被浸泡在同一種液體中. 這也是為什麼,市場上的許多藥物,並不是所有的, 都會引起一些嚴重的副作用
Now some people have gotten some solace from electrical stimulators that are implanted in the brain, for Parkinson's disease or cochlear implants. These have indeed been able to bring some kind of remedy to people with certain kinds of disorders. But electricity also will go in all directions -- the path of least resistance -- which is where that phrase, in part, comes from, and will also affect normal circuits, as well as the abnormal ones you want to fix. So again, we're sent back to the idea of ultraprecise control: Could we dial in information precisely where we want it to go?
現在有些人把電極植入大腦中 刺激腦細胞來改善某些疾病的症狀. 的確對於像帕金森氏症病患, 由耳蝸植入電極 確實能夠帶來 某種程度的緩解, 降低病人的身體殘礙的程度. 但是電流波會導向各個方向- 而且"專撿軟柿子捏",傳向阻礙力最小的通路 想來這也可能是這句名言的起源. 電流也有可能影響到正常的電路,不只在我們想修復的不正常處. 所以問題回到 極精密的控制上. 我們可不可能只把訊息傳送到標靶區呢?
So, when I started in neuroscience 11 years ago -- I had trained as an electrical engineer and a physicist -- the first thing I thought about was, if these neurons are electrical devices, all we need to do is to find some way of driving those electrical changes at a distance. If we could turn on the electricity in one cell but not its neighbors, that'd give us the tool to activate and shut down these different cells to figure out what they do and how they contribute to the networks in which they're embedded. It would also allow us to have the ultraprecise control we need to fix the circuit computations that have gone awry.
11年前,當我開始投入神經科學研究時, 我已受過電氣工程師和物理學家的訓練, 所以首先我想到是, 如果這些神經元都是電氣設備的話, 我們須要做的只是找到某種方式, 在一定距離中傳送電流的變化到目的地. 如果我們能使某一個細胞的電路被打開, 而不要干擾到它的鄰居們. 這將讓我們有能力去活化或催眠不同的各種細胞, 進而瞭解它們的功能和對 整體腦神經系統的貢獻. 同時也允許我們去執行極精密的控制, 以修改腦中出了錯的 電路運算.
Now, how are we going to do that? Well, there are many molecules that exist in nature which are able to convert light into electricity. You can think of them as little proteins that are like solar cells. If we install these molecules in neurons somehow, then these neurons would become electrically drivable with light, and their neighbors, which don't have this molecule, would not. There's one other magic trick you need to make this happen: the ability to get light into the brain. The brain doesn't feel pain. Taking advantage of all the effort that's gone into the internet, telecommunications, etc., you can put optical fibers connected to lasers to activate -- in animal models, for example, in preclinical studies -- these neurons and see what they do.
那我們該怎麼做呢? 自然界中存有很多小分子, 能夠將光能轉化成電能. 你可以把它們想像成類太陽能電池 的微小蛋白質。 如果我們將這些分子安裝在神經元內 那麼這些神經元將可以被光驅動 而相鄰的神經細胞因為不具有這些轉化分子不會被活化. 但是還需要一個神奇的技術配合一切才能成功. 那就是怎麼讓光進入腦中啊! 並且要做到這-把光導入大腦而不引起疼痛-- 我們運用腦中本有的 互聯網和其溝通能力等等功能- 將光纖連接到雷射光 使我們能夠精準的利用光束來啟動細胞 讓我們從臨床實驗前期的動物研究中 知道各神經元扮演的角色.
So how do we do this? Around 2004, in collaboration with Georg Nagel and Karl Deisseroth, this vision came to fruition. There's a certain alga that swims in the wild, and it needs to navigate towards light in order to photosynthesize optimally. And it senses light with a little eyespot, which works not unlike how our eye works. In its membrane, or its boundary, it contains little proteins that indeed can convert light into electricity. These molecules are called channelrhodopsins. And each of these proteins acts just like that solar cell that I told you about. When blue light hits it, it opens a little hole and allows charged particles to enter the eyespot; that allows this eyespot to have an electrical signal, just like a solar cell charging a battery.
那麼,如何才能做到這一點? 大約在2004年, 在與吉爾 納格(Gerhard Nagel),和卡爾 得許窪多(Karl Deisseroth) 的合作中 一切的構想終於開花結果 我們發現一種野生的藻類 它們會自動導航向光源游去, 好讓自身的光合作用發揮到最佳狀態。 它感光系統是一個光感眼點, 跟我們的眼睛運作方法不同. 在眼點的外膜,或者其周圍, 含有這些小蛋白質 可以將光能轉化成電能。 這些分子被稱為:視紫質管道(channelrhodospins). 這些蛋白質就像我之前說的跟太陽能電池的功能一樣。 當藍光照射到它,它會開一個小洞, 讓帶電粒子進入眼點。 然後眼點就能產生電子信號, 就像太陽能電池充電的道理一樣。
So what we need to do is take these molecules and somehow install them in neurons. And because it's a protein, it's encoded for in the DNA of this organism. So all we've got to do is take that DNA, put it into a gene therapy vector, like a virus, and put it into neurons. And this was a very productive time in gene therapy, and lots of viruses were coming along, so this turned out to be fairly simple. Early in the morning one day in the summer of 2004, we gave it a try, and it worked on the first try. You take this DNA and put it into the neuron. The neuron uses its natural protein-making machinery to fabricate these little light-sensitive proteins and install them all over the cell, like putting solar panels on a roof. And the next thing you know, you have a neuron which can be activated with light. So this is very powerful.
因此,我們需要做的就是把這些分子, 想辦法安裝在神經元中。 而且因為它是一種蛋白質, 而有關的DNA可以從藻類中被拆解出 所以我們要做的就是採取這段DNA, 利用基因治療的運輸工具,像是病毒, 攜帶進腦神經元中. 剛巧那幾年基因治療正蓬葧發展, 多種不同的病毒都可被利用. 我們發現原來這非常簡單容易 在2004年夏天的一個早上, 是我們第一次嘗試這個實驗,而且一舉成功。 我們把DNA送進神經元中, 神經元則利用它自己本有的蛋白質製造裝置 編造出許多小感光蛋白質, 很快的整個神經元細胞都佈滿了這種蛋白質, 就像在屋頂上安裝太陽能電池板一樣。 不用多久, 我們就有個能被光活化的神經元. 這是非常有價值的發現.
One of the tricks you have to do is figure out how to deliver these genes to the cells you want and not all the other neighbors. And you can do that; you can tweak the viruses so they hit some cells and not others. And there's other genetic tricks you can play in order to get light-activated cells. This field has now come to be known as "optogenetics." And just as one example of the kind of thing you can do, you can take a complex network, use one of these viruses to deliver the gene just to one kind of cell in this dense network. And then when you shine light on the entire network, just that cell type will be activated.
其中一個關鍵的技巧是必須要準確地 將感光DNA傳送到某些特定腦神經元中的, 而不是它們的左鄰右舍們。 而我們可以這樣做:我們可以調整變換病毒 讓病毒只去襲擊某些特定的神經元。 當然也可以利用其他生物基因工程的技術 來獲得可被光活化細胞。 這個領域現在被稱為光電遺傳學(optogenetics)。 舉個例子來說,你可以這樣做, 你可以在一個複雜的網絡系統中, 使用一種病毒去輸送基因到特定的一類細胞內 即使是在高密度的細胞社區裡也能達成. 然後用光去照射整個細胞社區, 而只有那種具感光蛋白質的細胞會被活化.
For example, let's consider that basket cell I told you about earlier, the one that's atrophied in schizophrenia and the one that is inhibitory. If we can deliver that gene to these cells -- they won't be altered by the expression of the gene, of course -- then flash blue light over the entire brain network, just these cells are going to be driven. And when the light turns off, these cells go back to normal; there don't seem to be adverse events. Not only can you study what these cells do, what their power is in computing in the brain, you can also use this to try to figure out if we could jazz up the activity of these cells if indeed, they're atrophied.
好!讓我們用之前所提過的籃狀細胞為例子-- 就是那種具有抑制作用、精神分裂症者身上 萎縮的細胞。 如果我們能夠將感光基因送到籃狀細胞內-- 當然前提是它們不會因感光基因而突變-- -然後當我們用藍光照射所有腦細胞時, 只有籃狀細胞會被驅動活化. 把光線關閉後,籃狀細胞則會恢復正常, 不會產生不良的副作用。 我們不僅可利用這技術去研究這些細胞在做什麼, 它們在大腦內如何跟別種細胞協調互動, 而且也可以試著利用這技術去找到如何: 讓已經萎縮的細胞興奮起來、 手舞足蹈。
I want to tell you some short stories about how we're using this both at the scientific clinical and preclinical levels. One of the questions that we've confronted is: What signals in the brain mediate the sensation of reward? Because if you could find those, those would be some of the signals that could drive learning; the brain will do more of what got that reward. These are also signals that go awry in disorders such as addiction. So if we could figure out what cells they are, we could maybe find new targets for which drugs can be designed or screened against or maybe places where electrodes could be put in for people who have severe disability. To do that, we came up with a very simple paradigm in collaboration with the Fiorillo group, where, if the animal goes to one side of this little box, it gets a pulse of light. And we'll make different cells in the brain sensitive to light. If these cells can mediate reward, the animal should go there more and more. And that's what happens.
現在我想告訴你一兩個有關於我們如何利用 這項技術的故事, 都是應用在科學,臨床和臨床前的試驗. 我們所面臨的其中一個問題是: 在腦中的什麼信號會挑起被嘉獎的感覺? 因為如果我們知道就可以利用 這種信號去驅動細胞學習. 讓大腦會竭盡所能去得到獎勵。 正因為這些信號出差錯,才導致如癮癖性疾病,。 因此,如果我們能弄清楚這是哪些細胞, 我們也許能找到新的標靶細胞, 以設計出或篩選出適合的藥物,去對抗這類疾病, 或者也可以為有非常嚴重殘疾的病患 在標靶細胞植入電極。 要做到這一點,我們設計出一個非常簡單的模型, 並得到菲兒瑞拉(Fiorella)公司的贊助. 在這個小盒子的一邊, 如果動物跑到那兒,會被一道光照到, 用來刺激各種不同對光敏感的腦部細胞. 所以如果這些細胞可以產生被獎勵的感覺, 那動物會越做越樂意. 事情就是這樣.
The animal goes to the right-hand side and pokes his nose there and gets a flash of blue light every time he does it. He'll do that hundreds of times. These are the dopamine neurons, in some of the pleasure centers in the brain. We've shown that a brief activation of these is enough to drive learning. Now we can generalize the idea. Instead of one point in the brain, we can devise devices that span the brain, that can deliver light into three-dimensional patterns -- arrays of optical fibers, each coupled to its own independent miniature light source. Then we can try to do things in vivo that have only been done to date in a dish, like high-throughput screening throughout the entire brain for the signals that can cause certain things to happen or that could be good clinical targets for treating brain disorders.
這隻動物跑到盒子的右手邊,然後用他的鼻子戳那地方 每次它這樣做,藍光就會閃動照耀它一次. 他會一做再做,做上千百次. 這是多巴胺神經元, 在座的一些人可能已知道那是大腦的愉悅中樞之一. 您現在已看到我們這簡短的實驗 已可以鼓勵學習行為. 現在我們再進一步, 不是只影響大腦的一點, 我們可以設計一些儀器把這實驗應用到整個大腦, 由這一組組的光纖傳送 三度空間(立體)的光束 每個光纖都只連結到自己獨立的微型光源。 然後我們可以嘗試活體實驗, 試驗一些目前為止只能在培養皿中的實驗-- 像是對於整個大腦做全面高效率的篩選, 瞭解到這某些腦波信號會導致哪些事情發生。 或哪些可被應用到臨床治療上, 來治療腦部疾病。
One story I want to tell you about is: How can we find targets for treating post-traumatic stress disorder, a form of uncontrolled anxiety and fear? One of the things that we did was to adopt a very classical model of fear. This goes back to the Pavlovian days. It's called Pavlovian fear conditioning, where a tone ends with a brief shock. The shock isn't painful, but it's a little annoying. And over time -- in this case, a mouse, which is a good animal model, commonly used in such experiments -- the animal learns to fear the tone. It will react by freezing, sort of like a deer in the headlights. Now the question is: What targets in the brain can we find that allow us to overcome this fear? So we play that tone again, after it's been associated with fear. But we activate different targets in the brain, using that optical fiber array I showed on the previous slide, in order to try and figure out which targets can cause the brain to overcome that memory of fear.
另一個我想告訴你的故事是, 我們如何找到治療創傷症候群的標靶細胞 那一種無法控制的焦慮和恐懼的症候群。 首先我們採用一個被學術界接受的恐懼模式 ﹣經典的恐懼制約(Classical fear conditioning). 那就要回到俄國帕弗洛夫(Pavlovian )時代. 所以也被稱做:帕弗洛夫的恐懼制約(Pavlovian fear conditioning)- 在一陣聲響後,接著出現短暫電擊. 電擊並不會很疼痛但有點惱人。 然後一次又一次--在這個實驗中我們使用老鼠。 老鼠是一個很好的動物模型,常被用在此類實驗中。- 最後動物一聽到那種聲音就怕。 動物會作出呆僵的反應, 像鹿在夜晚被車頭燈照到一樣--呆僵在那兒. 那現在的問題是:在腦中的那部份 能夠讓動物克服這種恐懼? 我們於是放了這些跟恐懼有關的 聲音給聽了會害怕的動物聽, 然後我們活化大腦中的標靶位,每次都不同, 用我前面展示的幻燈片一樣的光纖儀器 去試圖找出哪些標靶細胞 希望能夠克服恐懼的記憶。
This brief video shows you one of these targets that we're working on now. This is an area in the prefrontal cortex, a region where we can use cognition to try to overcome aversive emotional states. The animal hears a tone. A flash of light occurs. There's no audio, but you see that the animal freezes -- the tone used to mean bad news. There's a little clock in the lower left-hand corner. You can see the animal is about two minutes into this. This next clip is just eight minutes later. And the same tone is going to play, and the light is going to flash again. OK, there it goes. Right ... now. And now you can see, just 10 minutes into the experiment, that we've equipped the brain, by photoactivating this area, to overcome the expression of this fear memory.
這個簡短的片段 展示了我們現在所試探過的其中一個標靶位, 這區是在額葉前部皮質, 這個區域讓我們可以用認知努力克服厭惡的情感。 動物將聽到聲音,然後看見閃光. 這閃光並沒有聲音,但你可以看到動物僵立凍結在那兒, 這聲音以前是用來警告老鼠壞消息的信號。 在左下方的角落有一個小時鐘, 所以我們可知動物大約僵立兩分鐘。 下一個片段是在 八分鐘後, 相同聲音和緊接的的閃光 好,開始了。現在。 看!才只有10分鐘後的實驗, 我們已經用光源活化這部份的腦細胞 幫助動物克服這種 恐懼的記憶。
Over the last couple years, we've gone back to the tree of life, because we wanted to find ways to turn circuits in the brain off. If we could do that, this could be extremely powerful. If you can delete cells for a few milliseconds or seconds, you can figure out what role they play in the circuits in which they're embedded. We surveyed organisms from all over the tree of life -- every kingdom of life but animals; we see slightly differently. We found molecules called halorhodopsins or archaerhodopsins, that respond to green and yellow light. And they do the opposite of the molecule I told you about before, with the blue light activator, channelrhodopsin.
在過去的幾年裡,我們一再檢驗大自然的生命樹, 因為我們想要找出把大腦中的電路關掉的方法。 如果我們能做到這一點,這作用可大了。 如果你能讓細胞停擺即使只要幾毫秒或幾秒, 你就可以找出他它們在大腦電路中 是承擔什麼必要的作用, 我們仔細調查生命樹上的物種-除了動物之外的 每一個生物,只要我們發現它們有一點任何差異。 我們發現多種不同的分子,所謂感光紫紅質蛋白質(halorhodopsins)或一種古細胞感光蛋白質(archaerhodopsins) 能對綠色和黃色光有反應。 它們跟我剛剛跟你提起的會感藍光的分子, 單胞藻感光紫紅質蛋白質(channelrhodopsin)的作用相反。
Let's give an example of where we think this is going to go. Consider, for example, a condition like epilepsy, where the brain is overactive. Now, if drugs fail in epileptic treatment, one of the strategies is to remove part of the brain, but that's irreversible, and there could be side effects. What if we could just turn off that brain for the brief amount of time until the seizure dies away, and cause the brain to be restored to its initial state, like a dynamical system that's being coaxed down into a stable state? This animation tries to explain this concept where we made these cells sensitive to being turned off with light, and we beam light in, and just for the time it takes to shut down a seizure, we're hoping to be able to turn it off. We don't have data to show you on this front, but we're very excited about this.
讓我舉一個例子來告訴你們,我們如何應用這技術。 比如說癲癇這個例子, 癲癇是因大腦某部份過度活躍。 如果癲癇藥物治療的策略失敗, 那其他治療選舉方案之一是:切除一部份的大腦。 但是這顯然不可逆的,而且有可能有副作用。 如果我們可以只關閉大腦不正常那部份一會兒,很短暫的時間, 直到癲癇症狀消失殆盡為止, 並讓大腦恢復到初始狀態- 有點像把一個將暴動的系統哄騙推回穩定的狀態一樣。 這個動畫只是試圖解釋 我們利用光源來關閉催眠腦細胞的概念。 當我們把光源射出, 時間僅僅是足夠終止癲癇發作。 我們希望實驗能夠成功。 現在我們還沒有這個方面數據可以展示給大眾, 但我們對此感到非常興奮。
I want to close on one story, which we think is another possibility, which is that maybe these molecules, if you can do ultraprecise control, can be used in the brain itself to make a new kind of prosthetic, an optical prosthetic. I already told you that electrical stimulators are not uncommon. Seventy-five thousand people have Parkinson's deep-brain stimulators implanted, maybe 100,000 people have cochlear implants, which allow them to hear. Another thing -- you've got to get these genes into cells. A new hope in gene therapy has been developed, because viruses like the adeno-associated virus -- which probably most of us around this room have; it doesn't have any symptoms -- have been used in hundreds of patients to deliver genes into the brain or the body. And so far, there have not been serious adverse events associated with the virus.
現在我要用一個故事來結束我的演講, 那就是我們認為這技術還有其他用途-- 如果能做到超精確的控制,這些感光蛋白質 可用於腦中使腦本身 形成的一種新型義肢,光學義肢。 就像我已經告訴過你們的,電極刺激器並不是很普遍。 只有75000個帕金森病患植入深腦刺激器, 也許有100,000人在耳蝸中植入刺激器 好讓他們能聽到聲音。 另一件事是,就是你得讓這些基因移植進細胞內。 而這基因治療的新希望已被開發出, 一些病毒像是腺病毒家族(adeno-associated virus), 在這個房間裡大多數人可能都感染過, 但沒有任何症狀, 這種病毒已被用來傳送基因 到數百個病人的大腦或身體內。 到目前為止,沒有發現任何有關該病毒 的嚴重不良反應。
There's one last elephant in the room: the proteins themselves, which come from algae, bacteria and funguses and all over the tree of life. Most of us don't have funguses or algae in our brains, so what will our brain do if we put that in? Will the cells tolerate it? Will the immune system react? It's early -- these haven't been done in humans yet -- but we're working on a variety of studies to examine this. So far, we haven't seen overt reactions of any severity to these molecules or to the illumination of the brain with light. So it's early days, to be upfront, but we're excited about it.
沒錯!這技術有一個不能忽視的大隱憂,有關蛋白質本身, 感光蛋白質是從藻類、細菌、真菌 或生命樹上其他不同的物種上取出的, 大多數人沒有真菌或藻類(的DNA)在我們的大腦中, 如果移植蛋白質進入大腦中,那究竟大腦會有什麼反應? 腦細胞會容忍它們嗎?免疫系統會有什麼反應呢? 在這渾沌的初始階段--還未有人體實驗過-- 但是,我們正努力做各種研究, 試圖評估這可能的副作用。 目前為止,我們還沒有明顯看到因為這些分子 所引起的任何嚴重不良反應 而對腦照光也一樣沒有任何嚴重的的不良反應。 當然這只是初期的研究,但即使是如此,我們還是很興奮。
I wanted to close with one story, which we think could potentially be a clinical application. Now, there are many forms of blindness where the photoreceptors -- light sensors in the back of our eye -- are gone. And the retina is a complex structure. Let's zoom in on it so we can see it in more detail. The photoreceptor cells are shown here at the top. The signals that are detected by the photoreceptors are transformed via various computations until finally, the layer of cells at the bottom, the ganglion cells, relay the information to the brain, where we see that as perception. In many forms of blindness, like retinitis pigmentosa or macular degeneration, the photoreceptor cells have atrophied or been destroyed. Now, how could you repair this? It's not even clear that a drug could cause this to be restored, since there's nothing for the drug to bind to. On the other hand, light can still get into the eye. The eye is still transparent and you can get light in. So what if we could take these channelrhodopsins and other molecules and install them on some of these other spared cells and convert them into little cameras? And because there are so many of these cells in the eye, potentially, they could be very high-resolution cameras.
我想用一個故事來結束演講, 我們認為這技術具有 臨床應用的價值。 我們知道失明有很多種原因. 像是眼內的感光細胞消失, 也就是在我們的眼球後面的光接受器不見了。 我們的視網膜當然是一個複雜的結構。 讓我們放大它的結構圖,仔細研究一下。 照片中感光細胞在頂部, 感光細胞接收到光線,然後一層一層 轉變成各種不同信號直到 到達視網膜的最後一層底部的細胞:神經節細胞, 然後將信息轉遞給大腦, 轉換成視覺認知。 有很多原因導致失明,如視網膜色素變性, 或黃斑變性, 感光細胞萎縮或者根本破壞殆盡。 那我們怎麼才能改善修復呢? 沒有明確證據指出藥物可以治療修復這些症狀, 因為藥物很難停留在那兒(沒特效藥)。 但是,光線仍然可以射入眼睛。 光線仍然經由眼睛透入接觸視網膜。 所以如果我們能將單胞藻感光紫紅質蛋白質 或其他感光分子安裝在其他健康的細胞上, 把它們轉換成一台台小相機。 而且因為眼部有很多的這種細胞存在, 理論上,它們可以成為高清晰度攝像機。
This is some work that we're doing, led by one of our collaborators, Alan Horsager at USC, and being sought to be commercialized by a start-up company, Eos Neuroscience, which is funded by the NIH. What you see here is a mouse trying to solve a six-arm maze. There's a bit of water to motivate the mouse to move or he'll just sit there. The goal of this maze is to get out of the water and go to a little platform that's under the lit top port. Mice are smart, so this one solves the maze eventually, but he does a brute-force search. He's swimming down every avenue until he finally gets to the platform. He's not using vision to do it. These different mice are different mutations that recapitulate different kinds of blindness that affect humans. So we're being careful in trying to look at these different models so we come up with a generalized approach.
這就是我們正在進行的工作之一。 我們的合夥人之一,艾倫 (Alan Horsager) 在南加州大學正領導這個計劃, 也正在一家由美國國立衛生研究院提供經費的 創投公司(Eos Neuroscience)的協助下將其技術產業化 現在你可以看見這隻老鼠試圖在迷宮裡找出口。 在這六臂迷宮裡被倒入一些流動的水 來激勵老鼠移動,否則牠就停在某處不動。 這迷宮設計的目的 是讓水會從出口處流出到一個 安裝光源的平臺. 老鼠是很聰明的,這隻老鼠最終找到出口了, 但牠可是努力搜索才達成的. 他試過每一條途徑最後才到達有點燈的平臺。 由此可知,它不是用視力來游出迷宮。 這些不同的老鼠經由不同的突變而失明, 每隻老鼠各代表人類失明的不同種原因. 所以我們小心試圖尋找在這些不同的失明模型中 一個通用的方法去解決失明問題。
So how can we solve this? We'll do exactly what we outlined in the previous slide. We'll take these blue light photo sensors and install them onto a layer of cells in the middle of the retina in the back of the eye and convert them into a camera -- just like installing solar cells all over those neurons to make them light-sensitive. Light is converted to electricity on them. So this mouse was blind a couple weeks before this experiment and received one dose of this photosensitive molecule on a virus. And now you can see, the animal can indeed avoid walls and go to this little platform and make cognitive use of its eyes again. And to point out the power of this: these animals can get to that platform just as fast as animals that have seen their entire lives. So this preclinical study, I think, bodes hope for the kinds of things we're hoping to do in the future.
那麼我們該如何去執行呢? 我們要照著前一張幻燈片所展示的藍圖一樣去做。 我們要將這些對藍光感光的蛋白質 安裝在眼球最後面的視網膜 的其中一層細胞上面, 並將其轉換成一台照相機。 就像將太陽能電池佈滿在這些神經元上, 使它們對光敏感。 讓這些細胞將光能轉換為電能。 所以即使這隻老鼠在此實驗前幾個星期就瞎了, 只接受過一次病毒攜帶的感光分子的治療。 現在你可以看到,老鼠能避過牆 找到有亮光的小平臺, 再一次的使用牠的視覺訊息。 為了顯現出這實驗的功力: 這些動物游出迷宮的速度還跟 沒瞎的動物一樣快。 雖然這是臨床前研究, 但我相信這是個好預兆 我們希望未來能成功應用到人體上。
We're also exploring new business models for this new field of neurotechnology. We're developing tools and sharing them freely with hundreds of groups all over the world for them to study and try to treat different disorders. Our hope is that by figuring out brain circuits at a level of abstraction that lets us repair them and engineer them, we can take some of these intractable disorders I mentioned earlier, practically none of which are cured, and in the 21st century, make them history.
最後,我要指出的是我們正發展的一種 新的商業模式,雖然這神經科學的技術 是我們研發的, 但我們願意讓世界各地的不同組織自由分享這技術, 這樣更多人可以深入研究並有機會造福治療各種不同疾病。 我們的希望是:經由瞭解大腦的電路系統,再借助 精簡化來修復和建構神經網絡, 讓那些我先前提到的一些棘手的疑難雜症, 這些在21世紀幾乎無法治愈的疾病, 從此被存封在歷史印記中。
Thank you.
謝謝。
(Applause)
(鼓掌)
Juan Enriquez: So some of this stuff is a little dense.
Juan Enriquez:您的演講有些部份有一點深奧。
(Laughter)
(眾笑)
But the implications of being able to control seizures or epilepsy with light instead of drugs and being able to target those specifically is a first step. The second thing that I think I heard you say is you can now control the brain in two colors, like an on-off switch.
但重點是 能夠利用光來控制痙癵或癲癇發作, 而不是用傳統的藥物控制, 並且能夠精確找到標靶位(對症下光) 是第一步 第二件事是我想我聽到您說 您現在已經可以用兩種顏色的光來控制大腦 像電燈開關一樣。 Ed Boyden:沒錯!
Ed Boyden: That's right.
JE:也就是刺激大腦的訊號已進階至二進制代碼。
JE: Which makes every impulse going through the brain a binary code.
EB:對,沒錯。
EB: Right. With blue light, we can drive information, and it's in the form of a one. And by turning things off, it's more or less a zero. Our hope is to eventually build brain coprocessors that work with the brain so we can augment functions in people with disabilities.
當藍光亮時,我們可以驅動神經元傳播信號,所以可被認為是"1"。 如果燈光黯淡時,大致可把它歸類為"0"。 我們最終的希望是想建立大腦輔助處理器 來幫大腦工作, 所以我們可以增加其功能來幫助殘疾人士。
JE: And in theory, that means that, as a mouse feels, smells, hears, touches, you can model it out as a string of ones and zeros.
JE:這意味著在理論上, 不管是任何有關老鼠的的感覺,嗅覺, 聽覺,觸覺, 你可以模擬出來一連串的"1"和 "0"。
EB: Yeah. We're hoping to use this as a way of testing what neural codes can drive certain behaviors and certain thoughts and certain feelings and use that to understand more about the brain.
EB:當然,是的。我們希望借此方式, 去測試瞭解是什麼神經代碼可以驅動某些行為, 某些想法和某些感受, 並利用它進一步來瞭解大腦。
JE: Does that mean that someday you could download memories and maybe upload them?
JE:這是否意味著有一天,你可以下載回憶, 也許也可再上傳回去大腦嗎?
EB: That's something we're starting to work on very hard. We're now working on trying to tile the brain with recording elements, too, so we can record information and then drive information back in -- sort of computing what the brain needs in order to augment its information processing.
EB:這件事情我們已經開始了, 目前正朝幾個方面努力中, 我們也正在嘗試在大腦每個角落安置記錄器。 因此,我們可以收錄大腦信息,然後驅動信息返回大腦- 來計算什麼是大腦所須要的, 以便來增強其信息處理。
JE: Well, that might change a couple things. Thank you.
JE:嗯,這可能會對我們的世界有所改變或影響。謝謝。 (EB:謝謝。)
EB: Thank you.
(鼓掌)
(Applause)