Controlling the brain with light earns a physiology Nobel
Controlling the brain with light earns a physiology Nobel
用光控制大脑的研究荣获诺贝尔生理学或医学奖
Over decades of research, scientists have built up a partial picture of what specialized cells within the brain and spinal cord do. By studying how the brain develops, they could identify genes that were active in different populations of neurons and where in the brain those neurons resided. In some cases, these genes could then be used to genetically delete the neurons, allowing us to get some indication of what they might be doing, building on the information we’ve obtained from studies of brains with damaged regions. 经过数十年的研究，科学家们已经初步勾勒出大脑和脊髓中特化细胞的功能图谱。通过研究大脑的发育过程，他们能够识别出在不同神经元群体中活跃的基因，以及这些神经元在大脑中的位置。在某些情况下，这些基因可被用于从基因层面剔除特定的神经元，从而让我们通过研究受损大脑区域所获得的信息，进一步推断这些神经元的功能。
But this approach has its limits. The brain is flexible enough to potentially adapt to the loss of some cells, and their loss early in development may alter the development of any neurons they would have normally formed connections with. It would be far more informative to activate and shut down the neurons in an otherwise intact brain. Today’s Nobel Prize in Physiology or Medicine rewards three people—Karl Deisseroth, Peter Hegemann and Georg Nagel—who developed our ability to do precisely that. Starting from studies of single-celled algae that are attracted to light, these and many other researchers built an entire field of study that we now call optogenetics: using light to alter the behavior of nerve cells marked by the activity of individual genes. 但这种方法存在局限性。大脑具有很强的适应性，可能会对部分细胞的缺失进行代偿；而如果在发育早期缺失这些细胞，可能会改变它们原本应建立连接的神经元的发育过程。如果能在完整的大脑中激活或关闭神经元，获取的信息将更有价值。今年的诺贝尔生理学或医学奖授予了三位科学家——卡尔·戴瑟罗斯（Karl Deisseroth）、彼得·黑格曼（Peter Hegemann）和格奥尔格·内格尔（Georg Nagel），正是他们开发出了实现这一目标的技术。从对趋光性单细胞藻类的研究开始，他们与其他许多研究人员共同开创了一个全新的研究领域，即我们现在所称的“光遗传学”：利用光来改变由特定基因活动所标记的神经元的行为。
From algae to human cells: Nerve impulses are generated by proteins called ion channels, which sit in the membrane and allow charged atoms to cross it. The nervous system uses a population of ion channels that are only active under specific circumstances, like when they sense a neurotransmitter or experience voltage changes. It’s this fine level of control that allows specialized nerve cells to send impulses only under specific circumstances, keeping the brain from descending into a haze of electrical noise. So if we want to find out what any of the multitudes of specialized nerve cells might be doing, the easiest way is to hijack this system: force the cell to send ion-based impulses when we tell it to, and see how the animal’s behavior changes. 从藻类到人类细胞：神经冲动是由一种被称为“离子通道”的蛋白质产生的，它们位于细胞膜上，允许带电原子穿过。神经系统使用的一类离子通道仅在特定情况下才会活跃，例如当它们感知到神经递质或经历电压变化时。正是这种精细的控制水平，使得特化的神经元只在特定情况下发送冲动，从而防止大脑陷入电信号的混乱噪声中。因此，如果我们想弄清楚海量特化神经元中任何一个的功能，最简单的方法就是“劫持”这个系统：在我们指定的时刻强制细胞发送基于离子的冲动，并观察动物的行为如何改变。
The Nobel Committee notes that this idea was obvious enough that people tried several methods of doing so before developing optogenetics. But it turns out “the easiest way” did not mean “easy,” and most of these methods didn’t end up widely used because they involved some combination of needing to insert multiple genes, supplying the nerve cells with some very specific chemicals, or using lasers at an intensity that physically damaged the cells. The ultimate solution, it turned out, was lurking in a single-celled algae called Chlamydomonas. 诺贝尔委员会指出，这个想法显而易见，以至于在光遗传学发展之前，人们已经尝试过多种实现方法。但事实证明，“最简单的方法”并不意味着“容易”。大多数方法最终未能得到广泛应用，因为它们往往需要结合多种手段，例如插入多个基因、向神经元提供特定的化学物质，或者使用强度足以造成物理损伤的激光。最终的解决方案，竟然隐藏在一种名为“衣藻”（Chlamydomonas）的单细胞藻类中。
The organism’s single cell is remarkably complicated, having two flagella that help it move around, and an eye spot that detects the light it moves toward. People had been studying the organism for quite some time as a model for basic biological processes. This is where Hegemann, then working at Berlin’s Humboldt University, entered the picture. He and his coworkers managed to hook an electrode up to a Chlamydomonas and showed that exposing it to a flash of light resulted in a very rapid influx of ions, suggesting the light was triggering an ion channel to open. 这种生物的单细胞结构非常复杂，拥有两条帮助其移动的鞭毛，以及一个用于探测光线方向的眼点。人们长期以来一直将这种生物作为基础生物过程的研究模型。这时，当时在柏林洪堡大学工作的黑格曼（Hegemann）介入了研究。他和同事们成功地将电极连接到衣藻上，并证明了当它受到闪光照射时，会产生非常迅速的离子内流，这表明光线触发了离子通道的开启。
As other scientists started scanning the messenger RNAs made by Chlamydomonas, Hegemann spotted a couple of genes that were similar to a light-activated ion pump found in an archaeal species. Suspecting these might be responsible for the ion fluxes in Chlamydomonas, Hegemann used RNA interference to block their activity. This did limit the flow of ions in response to light, clearly implicating these genes in the organism’s light sensing. At that point, Hegemann started an extended collaboration with Nagel, then at the University of Würzburg, an expert in ion fluxes. 当其他科学家开始扫描衣藻产生的信使RNA时，黑格曼发现了几种与古菌中发现的光激活离子泵相似的基因。黑格曼怀疑这些基因可能就是衣藻离子通量的来源，于是利用RNA干扰技术阻断了它们的活性。这确实限制了衣藻对光的离子反应，明确了这些基因与该生物光感应之间的联系。随后，黑格曼与当时在维尔茨堡大学工作的离子通量专家内格尔（Nagel）开始了长期的合作。
They showed that one of the two genes was selective for only letting protons (which you can think of as a hydrogen ion) into the cell, while the other would allow a broad range of positively charged ions through. They were also sensitive to somewhat different wavelengths of light. The proteins also used a chemical relative of Vitamin A to sense light, just as the receptors in our eyes do. Collectively, this class of proteins is now termed “channelrhodopsins.” Nagel was instrumental in broadening the use of channelrhodopsins, showing that the genes that encode these proteins could work everywhere from developing frog embryos to cultured human cells. He went on to show that, when active in the neurons of a small worm called C. elegans, exposing the worms to light could cause them to alter their behavior. 他们证明，这两个基因中的一个具有选择性，只允许质子（可以看作氢离子）进入细胞，而另一个则允许多种带正电的离子通过。它们对不同波长的光也表现出不同的敏感度。这些蛋白质还利用维生素A的化学衍生物来感知光线，就像我们眼睛里的受体一样。这类蛋白质统称为“通道视紫红质”（channelrhodopsins）。内格尔在推广通道视紫红质的应用方面发挥了关键作用，他证明了编码这些蛋白质的基因在从发育中的青蛙胚胎到培养的人类细胞中均能发挥作用。他进一步证明，当这些基因在一种名为秀丽隐杆线虫（C. elegans）的小虫神经元中活跃时，用光照射这些线虫可以改变它们的行为。
Deisseroth and his coworkers at Stanford then played key roles in developing this into a broadly useful technology. They showed that the channelrhodopsins work in neurons, and the ion fluxes they trigger are transmitted as nerve impulses. They also found more members of the channelrhodopsin family, some of which are sensitive to different wavelengths of light. A version that allows negatively charged chlorine ions into the cell was also discovered, allowing researchers to selectively shut down nerve cells. At the same time, Deisseroth and his team worked on the engineering side of the problem, developing compact light sources and small, flexible fiber optics that allowed the system to act in the brains of animals that were free to move about and behave relatively normally. 随后，戴瑟罗斯（Deisseroth）和他在斯坦福大学的同事们在将此技术转化为广泛适用的工具方面发挥了核心作用。他们证明了通道视紫红质在神经元中有效，且其触发的离子通量可以作为神经冲动进行传递。他们还发现了更多通道视紫红质家族的成员，其中一些对不同波长的光敏感。研究人员还发现了一种允许带负电的氯离子进入细胞的版本，从而能够选择性地关闭神经元。与此同时，戴瑟罗斯团队致力于工程方面的攻关，开发了紧凑型光源和小型柔性光纤，使得该系统能够在自由活动且行为相对正常的动物大脑中发挥作用。
The result has been nothing short of a revolution in our ability to understand what different populations of nerve cells are doing. If we know a gene is active in a small population of nerve cells, then we can use the mouse version of that gene to activate channelrhodopsin there and start testing how light changes the behavior of the resulting mice. We’ve described work that relies on optogenetics a dozen times or more. And the Nobel Committee cites its use in everything from understanding how memor… 这一成果彻底改变了我们理解不同神经元群体功能的能力。如果我们知道某个基因在小群神经元中活跃，就可以利用该基因的小鼠版本在那里激活通道视紫红质，并开始测试光线如何改变这些小鼠的行为。我们已经多次介绍过依赖光遗传学的研究工作。诺贝尔委员会也提到了它在各个领域的应用，从理解记忆的形成……