一个研究脑部疾病的好方法?——在培养皿中配有的迷你大脑
One great way to study brain diseases? ‘Mini-brains’ grown in dishes
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2020-01-10 14:05
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火星译客

Neuroscience

神经科学

LA Biomed

生物群落

February 19, 2018 1 peer comment

2018年2月19日,同行评论

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The concept of scientists growing “mini-brains in dishes” might sound like the plot of a movie. However, this is exactly what scientists – like me – are doing. In the lab, these conceptual “mini-brains” are called organoids. They’re cultivated from stem cells in an artificial environment outside the body and self-organize to form 3D structures which, in part, resemble organs within the body. Lungs, pancreas, fallopian tubes, even taste buds - you name it, an organoid can be made to resemble it.

科学家在培养皿中培育迷你大脑的概念,听起来像是电影的情节。然而,这正是像我这样的科学家正在做的。在实验室里,这些概念上的“迷你大脑”被称为脑类。它们是在体外的人造环境中,从干细胞中培养出来的,自我组织形成3D结构,在某种程度上类似于人类的器官。肺、胰腺、输卵管甚至味蕾,只要你能想到的一类器官都可以被做成它的样子。

The fact that they’re easy to make and behave a lot like the organs they resemble make them an exciting tool in the scientific study of health and disease. And, while they are still in their infancy in terms of development, organoids have a lot of potential in investigating the cause of neurodevelopmental disorders that haven’t yet been cracked using more well-established methods, such as studying mice or two-dimensional cell cultures.

事实上,它们很容易制造和表现得很像他们的器官,这使它们成为健康和疾病科学研究中一个令人兴奋的工具。虽然这类器官再发育方面仍处于初级阶段,它们在研究神经发育障碍的原因方面有很大潜力,这些神经发育障碍尚未备用更成熟破解,比如研究小鼠或二维细胞培养。

You may not have a lot in common with a mouse (besides cheese) but we share a lot  genetically

你可能和老鼠没有多少共同点(除了奶酪),但我们在基因上有很多共同点

We have mice to thank for much of what we know about neurodevelopmental diseases. You may not think you have much in common with a mouse, besides a love of cheese, but we are quite similar at the genetic level. When common genes get messed up in mice, they end up with diseases that look similar to the way they do in people. However, this type of study doesn’t work as well when looking at diseases that are caused by more than one genetic mutation – diseases like schizophrenia or autism, which are caused by multiple genes, are almost impossible to fully model in mice.

我们对神经发育疾病的了解,多亏了老鼠。你可能觉得你和老鼠没什么共同点,除了喜欢奶酪之外,但我们在基因水平上很相似。当普通基因在老鼠身上混乱时,它们最终会得到和人类相似的疾病。然而,当研究多个基因突变引起的疾病时,这种类型的研究并不奏效。就像精神分裂症或自闭症这样的由多个基因引起的疾病,几乎不可能在老鼠身上建立完整的模型。

Enter organoids. Made out of stem cells, in their first incarnation (back in 2001) scientists figured out how to turn them into neural progenitor cells, self-renewing cells that can develop into the cells that make up the brain, like neurons and glia, but are not yet committed to one fate. These neural progenitor cells self-organized in 2D structures called rosettes that displayed features of the embryonic neural tube, the precursor to the nervous system. Ten years later, scientists found a way to go a step further: it became possible to create structures that look somewhat like the developed brain as a whole – or distinct regions of the developed brain, which could be fused together.

进入类脑。由干细胞构成,在他们的第一次化身(回到2001年),科学家们找到了如何把他们转变神经组细胞,自我更新的细胞,可以发展成为组成大脑的细胞,像神经元和神经胶质,但还没有承担一种命运。这些神经前体细胞组织称二维结构,成为花环,表现出胚胎神经管的特征,也就是神经系统的前身。十年后,科学家发现了一种更进一步的方法:可以创造出有点像发达大脑的整体结构,或者说是发达大脑的不同区域,这些区域可以融合在一起。

Making organoids

制造人类器官

To make these 3D structures, you basically have to recreate the same environment within which the brain develops. We don’t fully understand all the processes involved in neurodevelopment but, based on what we do know, it has been possible to recreate some important aspects of the process. For example, the protein SMAD, which is responsible for muscle and skin formation, can be inhibited, while the WNT signaling pathway,which involves numerous molecules responsible for regional patterning, can be carefully controlled, giving rise to different anatomical brain parts.

为了制作这些3D结构,你基本上必须重建大脑发育的相同环境。我们并不完全了解神经发育的所有过程,但是,根据我们所知道的,我们可以重现这个过程的一些重要方面。例如,负责肌肉和皮肤形成的蛋白质SMAD可以被抑制,而包含许多负责区域图案化的分子的WNT信号通路可以被小心地控制,从而产生不同的大脑解剖部位。

With that technological know-how, and the ability to turn a patient’s cells back into pluripotent stem cells, it’s possible to turn cells from patients who have complex diseases like schizophrenia into brain organoids, in a dish. We’ve been reprogramming and culturing patient-derived cells into pluripotent stem cells – with the kind of idiosyncratic genetic composition that is true to the nature of the genetic basis of schizophrenia – for years. But the ability to do this together with organoid technology is a step forward.

有了这种技术诀窍,以及将病人细胞转化为多能干细胞的能力,就有可能将环游复杂疾病,如精神分裂症的病人的细胞,在培养皿中转化为类脑器官。多年来,我们一直在重新编程,将病人来源的细胞培养成多能干细胞,这种特殊的基因组合,符合精神分裂症的遗传基础。但是与类器官技术一起做到这一点,是向前迈进了一步。

New models for psychiatric study

精神病血研究的新模型

This technology provides an incredible opportunity for us to better model diseases, as the more complex tissue structure offers new possibilities for cellular and molecular analysis. It hasn’t been extensively used to study neuropsychiatric disorders yet. But the few studies that have been done, like one in which organoids were generated from four patients with Austism Spectrum Disorder to reveal genetic abnormalities, are promising. Scientists speculate that self-patterning 3D brain organoids will allow for more accurate study of the cell-to-cell interactions that are involved in the formation of synapses, myelination (wrapping up nerve cells in a fatty white substance, which is crucial for proper signaling) and circuit maturation, all of which have been implicated in schizophrenia.

这项技术为我们更好地模拟疾病提供了难以置信的机会,因为更复杂的组织结构为细胞和分子分析了提供了新的可能性。它还没有被广泛用于神经精神疾病的研究。但是已经完成的一些研究,比如从四个患有奥斯丁铺系障碍的病人身上产生类脑组织,以揭示基因异常,是很有前途的。科学家们推测,自我模式化的3D脑器关将有助于更精准地研究细胞间的相互作用,这些相互作用,涉及神经突触的形成、髓鞘形成(将神经细胞包裹在一种脂肪白色物质中,这种物质对正确的信号传递至关重要)以及神经回路,所有这些都与精神分裂症有关。

It’s not just psychiatric diseases that could be better understood with the help of organoids. They are also being used to investigate the underpinnings of neurodevelopmental disorders. Because organoids resemble early stages of development, they have a lot of potential for studying developmental diseases that manifest in early embryonic fetal stages.

在类器官的帮助下,不只是精神疾病可以被更好地理解。它们也被用来研究神经发育障碍的基础。由于类脑类似于早期发育阶段,因此它们在研究胚胎早期发育方面具有很大的潜力。

Organoids exposed to Zika underwent growth reduction, consistent with microencephaly

暴露在塞卡病毒下的类脑器官发育减缓,与小脑畸形相符

In fact, organoids have been useful following the outbreak of Zika virus in 2016. Zika caused birth defects in babies born to infected pregnant mothers, including microencephaly, where babies are born with smaller-than-average heads and brain damage. Using organoids, it was possible to identify a causal relationship between Zika infection and the destruction of neural progenitor cells; one study showed that organoids exposed to Zika underwent growth reduction, consistent with the observation of microencephaly in affected infants. Another reported reductions in the number of neural progenitor cells and neurons as a result of cell death.

事实上,在2016年塞卡病毒爆发后,类脑器官已经发挥了作用。塞卡病毒导致受感染孕妇所生婴儿出生缺陷,包括小脑畸形,婴儿出生时头部小于平均水平,脑补受损。使用类脑,可以确定塞卡感染和神经前提细胞破坏之间的因果关系;一项研究表明,暴露在塞卡中的类脑会发生生长减缓,这与观察病婴的小脑畸形是一致的。另一份报告称,由于细胞死亡,神经自爆和神经元的数量减少。

Organoids are also being used to explore the mechanisms behind human cortical expansion and surface folding, which give brains their funny convoluted, appearance and cannot be properly explored in mice, which have smooth, simple brains. Gyrification, the process of forming folds, can be partially achieved in human brain organoids.

有机物也被用于探索人类大脑皮层扩张和表面折叠的机制,这些机制使大脑具有趣的卷曲、外观,而在拥有光滑、简单大脑的老鼠身上无法得到正确的探索。获选作用,形成褶皱的过程,可以部分地在人脑器官中实现。

The biggest question facing researchers when it comes to organoids is how well they model human development. The answer, at present, is: not quite. But they are getting better.

研究人员面临的最大问题是,类脑如何模拟人类发展。目前的答案是:不完全是。但他们正在好转。

Limits of mini-brains

迷你大脑的极限

The brain continues to develop after birth. While organoid development resembles the prenatal period quite well, many aspects of brain development, including the maturation of cortical circuits, takes years to develop in growing humans, making it impractical to model these processes in organoids. There also remains much work to be done in terms of achieving more complex aspects of cortical organization, such as gyrification, establishing proper neural connections, and proper cortical layering.

大脑在出生后继续发育。虽然类器官的发育很像出生前的时期,但是大脑发育的许多方面,包括皮质回路的成熟,在成长中的人类身上需要数年的时间才能发育,这使得用类器官模拟这些过程变得不切实际。在实现更复杂的皮层组织方面,还有很多工作要做,比如回转化,建立适当的神经连接,以及适当的皮层分层。

On a more intricate level, genes are not expressed in exactly the same way in brain organoids as they are in human brains. The fact that the genetic identity of the different cell populations in brain organoids do not perfectly reflect the genetic identity of the different cell populations in the human brain needs to be addressed before organoids can be considered an airtight way to research human diseases. The difficulty is that during development, genes are turned on and off in an extremely controlled manner, both temporary and spatially, to create the brain as we know it, and these patterns are difficult to achieve artificially, because the complicated processes involved are not yet fully understood.

在更复杂的层面上,基因在类脑器官中的表达方式与人脑中的不完全一样。脑器官中不同细胞种群的遗传特性并不能完全反应人脑中不同细胞种群的穿特性,这一事实需要得到解决,然后才能被认为是研究人类疾病的无懈可击的方法。困难在于,在发育过程中,基因是以一种及其可控的方式开启和关闭的,不管是暂时的还是空间上的,来创造我们所知的大脑,而这些模式是很难人工实现的,因为涉及的复杂过程还没有被完全理解。

A complex system for studying countless brain disorders – in a dish

一个用来研究无数脑补疾病的复杂系统——在一个盘子里

Despite their current limitations, organoids represent the next generation in artificial cell-based models of the human brain. These “mini-brains”offer a complex system for studying the neurobiology of countless brain disorders – in a dish. Over the coming years, more and more scientists are likely to adopt these 3D mini-brains, expanding their application and in the process giving rise to improvements in current methods.

尽管它们目前的局限性,类器官代表了人脑人工细胞模型的下一代。这些“迷你大闹”为研究无数大脑疾病的神经生物学提供了一个复杂的系统。在未来的几年里,越来越多的科学家可能会采用这些3D迷你大脑,扩大它们的应用范围,并在此过程中改进现有的方法。

I cannot wait to see where the field goes. I work on a stem cell project which aims to cure a rare, genetic childhood neurobiological diseases called Sanfilippo syndrome Type B by supplying the brain, which lacks a particular protein, with neural stem cells that can provide a long-term supply of that protein. These neural stem cells have the potential to differentiate into different neuronal cell types. By injecting organoids into the brains of experimental models, it may be possible to provide the brain with a useful combination of already-differentiated cell types, increasing the therapeutic potential of our stem cell therapy. Not only are mini-brains helping scientists find answers to intractable genetic questions – they may also help to solve them.

我迫不及待地想看看场地的走向。我参与了一个干细胞项目,旨在通过向缺乏特定蛋白质的大脑,提供神经干细胞,来治愈罕见的遗传性儿童神经生物学疾病,这种疾病被称为B型sanfilippo综合症。神经干细胞可以长期提供这种蛋白质。这些神经干细胞有潜力分化成不同的神经元细胞类型。通过将有机物注射到试验模型的大脑中,可能为大脑提供已经分化的细胞类型的有效组合,提高我们干细胞疗法的治疗潜力。迷你大脑不仅可以帮助科学家找到棘手的基因问题的答案,还可以帮助解决这些问题。

Peer Commentary

同行评论

We ask other scientists from our Consortium to respond to articles with commentary from their expert perspective.

我们要求我们联盟的其他科学家从传家的角度对文章做出评论。

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杰克-巴顿

Cognitive Neuroscience

认识神经科学

University of Manchester

曼彻斯特大学

This research area is not something I was aware of as a psychologist, but the implications for this are interesting and exciting.

作为一个心理学家,我并不了解这个研究领域,但它的意义是有趣和令人兴奋的。

It seems a bit strange to think of a brain being grown in the lab but, as you mention, this allows certain questions to be asked about how cells in the brain communicate with one another. It is a shame that brain development over the longer term cannot quite be examined with this approach yet. As someone who studies risk factors for schizophrenia, organoids seem like a powerful tool to address this. An ability to understand early changes in the brain which are linked to psychiatric illnesses such as schizophrenia is much needed.

想到大脑在实验室里成长似乎有点奇怪,但是,正如你所提到的,这样就可以提出一些问题,关于大脑中的细胞是如何相互交流的。遗憾的是,大脑长期发育尚不能完全用这种方法来检测。作为研究精神分裂症风险因素的人,类脑似乎是解决这个问题的有力工具。我们非常需要一种能够理解大脑早期变化的能力,这种能力与精神疾病如精神分裂症有关。

Out of interest, has anyone expressed concern at scientists growing “mini-brains”? I worry that research like this would be hampered out of a lack of understanding of how brains work and how these admittedly complex cell cultures are not the same as a human brain.

出于兴趣,有人对科学家培育“迷你大脑'表示担忧吗?我担心这样的研究会因为缺乏对大脑工作原理的理解,以及这些公认的复杂的细胞培养物如何不同于人脑而受到阻碍。

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Yewande Pearse responds:

Yewande Pearse回复:

Schizophrenia is not actually an area of research I have personally worked in, but I also find it extremely fascinating, especially from a genetic point of view.

精神分裂症并不是我个人研究的领域,但我也觉得它非常有趣,特别是从遗传学的角度来看。

The concept of growing organoids in a dish is indeed a little hard to imagine. When my boss first encouraged me to have a go at growing brain organoids, I looked at her blankly for a second and said, “pardon?”

在培养皿中培养类器官的概念确实有点难以想象。当我的老板第一次鼓励我尝试培养大脑器官时,我茫然地看着她说:“什么?”

It’s great to hear the perspective of someone who actually studies schizophrenia – thank you for sharing it. Better models lead to better answers, although no one model can answer all questions. Organoids have a lot of potential for better addressing the consequences of real-life genetic implications on early development, as you say.

很高兴听到真正研究精神分裂症的人的观点——谢谢你的分享。更好的模型能带来更好的答案,虽然没有一个模型能回答所有的问题。正如你所说,类器官有很多潜力,可以更好地解决现实生活中基因对早期发育的影响。

Funnily enough, I’ve been asked before about what would happen if brain organoids were to model the human brain too well in terms of connectivity. The question of consciousness came up, which is something to contemplate. Hopefully though, as organoid research becomes more popular, people will gain a better understanding of what they actually are, dispelling any mystery!

有趣的是,以前有人问过我,如果类脑在连接性方面模拟人脑过于完美,会发生什么。意识的问题出现了,这是一个值得思考的问题。希望随着类器官研究变得越来越流行,人们能更好地理解它们的实际情况,解开所有谜团!

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