科學家將實驗室培養的人類腦組織移植到小鼠體內

威爾・丹翰報導By Will Dunham

華盛頓，9月16日（路透社）—— 科學家已將實驗室培養的人類腦組織移植到經生物工程改造的小鼠體內。他們稱，這是研究人類腦部發育的一項重要進展，可能加速探究重度自閉症、癲癇、腦性麻痺與思覺失調症等嚴重疾病成因與機制的研究。WASHINGTON, Sept 16 (Reuters) - Scientists have transplanted laboratory-grown human brain tissue into bioengineered mice in what they call an important advance for studying human brain development that may speed research into the causes and mechanisms of devastating disorders such as profound autism, epilepsy, cerebral palsy and schizophrenia.

研究人員表示，這些人類組織在被移植到小鼠體內後，重現了腦部發育的關鍵特徵，包括形成具功能的神經網路。這些小鼠經工程改造，缺少自身大部分的大腦皮質，也就是大腦最外層。研究人員說，這項成果具有重大意義，因為基於倫理理由，活體人類腦組織基本上無法用於研究目的。The researchers said the human tissue replicated key features of brain development including formation of functional neural networks after being transplanted into mice engineered to lack most of their own cerebral cortex, the brain's outermost layer. They said this is significant because living human brain tissue is essentially inaccessible for research purposes for ethical reasons.

史丹佛大學（Stanford University）神經科學家、週三發表於《自然》（Nature）期刊這項研究的資深作者塞爾久・帕斯卡（Sergiu Pasca）說：「這讓我們能從基因、個別細胞類型，到迴路與動物體內的功能性後果等多個層次，研究人類神經組織。我們可以開始探問，與疾病相關的人類基因變化如何改變神經發育與神經迴路，以及潛在治療能否預防或矯正這些變化。」"This gives us a way to study human neural tissue across several levels, from genes and individual cell types to circuits and functional consequences in an animal. We can begin to ask how disease-associated human genetic changes alter neural development and circuitry and whether potential treatments can prevent or correct those changes," said Stanford University neuroscientist Sergiu Pasca, senior author of the study published on Wednesday in the journal Nature.

研究人員在實驗室培養皿中製作出微型、三維的「類器官」，設計用來重現人類大腦皮質的關鍵細胞類型與發育特徵。大腦皮質掌管認知、語言、注意力與決策等高階功能。The researchers in laboratory dishes fashioned miniaturized, three-dimensional "organoids" designed to reproduce key cell types and developmental features of the human cerebral cortex. This part of the brain governs higher-level functioning such as cognition, language, attention and decision-making.

他們的做法是將皮膚或血液細胞重新編程，使其成為能轉變成體內幾乎任何細胞類型的幹細胞。They did so by reprogramming skin or blood cells to become stem cells capable of transforming into almost any cell type in the body.

在對小鼠進行生物工程改造時，科學家採用一種基因策略，阻斷大多數通常會發育成大腦皮質與海馬迴的細胞發育；海馬迴是對記憶形成至關重要的腦部結構。In bioengineering the mice, the scientists employed a genetic strategy that blocked development of most of the cells that normally give rise to the cerebral cortex and the hippocampus, a brain structure crucial for memory formation.

帕斯卡說：「通常由小鼠大腦皮質占據的空間，讓我們能在出生後不久移植人類皮質類器官，並給予人類組織廣泛生長的空間。在這些小鼠體內，人類移植物生成了多種大腦皮質細胞類型，並在整個小鼠神經系統中建立功能性連結。」"The space normally occupied by the mouse cortex allowed us to transplant human cortical organoids shortly after birth and gave the human tissue room to grow extensively," Pasca said. "In these mice, the human grafts generated a broad diversity of cortical cell types and established functional connections throughout the mouse nervous system."

生成的大腦皮質細胞種類包括一種罕見的細胞，稱為馮・艾可諾莫神經元（von Economo neurons），被認為在某些類型失智症中較容易受損。The kinds of cortical cells generated included a rare type, called von Economo neurons, considered vulnerable in some forms of dementia.

研究術語RESEARCH TERMINOLOGY

帕斯卡說：「我想強調的一點是術語。『人源化小鼠』、『具有人腦的小鼠』或『迷你腦』這類描述，並不能準確呈現我們所創造的東西。這些動物保有小鼠神經系統，但其中含有體積較大的人類大腦皮質組織，這些組織會發育、整合，並在其中形成連結。」"One point I would emphasize is the terminology," Pasca said. "Descriptions such as humanized mice, mice with human brains or mini-brains are not accurate representations of what we have created. These animals retain a mouse nervous system, but they contain a larger volume of human cortical tissue that develops, integrates and forms connections within it."

研究人員稱這些小鼠為「異種皮質」小鼠，指的是被移植進去的「外來」人類大腦皮質組織。The researchers called them "xenocortical" mice, referring to the "foreign" transplanted human cortical tissue.

帕斯卡說：「皮質類器官為我們研究人類腦部發育與疾病提供了一扇實驗窗口。它們不是微型大腦，也無法重現人腦的全部複雜性，但讓我們能研究人類神經細胞類型與發育過程；若非如此，這些研究將極難進行。」"Cortical organoids give us an experimental window into human brain development and disease. They are not miniature brains and do not reproduce the full complexity of the human brain, but they allow us to study human neural cell types and developmental processes that would otherwise be extremely difficult to access," Pasca said.

研究人員表示，這種方法可能特別有助於研究在腦部發育期間開始的疾病，例如自閉症、癲癇、思覺失調症與腦性麻痺，也可用於研究出生前後發生的缺氧等環境造成的損傷。This approach could be especially useful for studying disorders that begin during brain development such as autism, epilepsy, schizophrenia and cerebral palsy, as well as environmental injuries such as oxygen deprivation occurring around the time of birth, according to the researchers.

他們讓這些小鼠暴露於缺氧狀態，作為這項研究模型的首次應用。They exposed the mice to oxygen deprivation as a first application of this research model.

帕斯卡說，發育中的人腦可能對缺氧高度脆弱。若缺氧發生在懷孕期間或出生前後，可能造成重大神經系統後果，包括導致腦性麻痺，並提高癲癇或自閉症風險。不過，小鼠可以承受會傷害人類神經組織的缺氧程度。The developing human brain can be highly vulnerable to oxygen deprivation. When it occurs during pregnancy or around birth, it can have major neurological consequences including contributing to cerebral palsy and increasing the risk of epilepsy or autism, Pasca said. But mice can be resilient to levels of oxygen deprivation that injure human neural tissue.

帕斯卡說：「在異種皮質小鼠體內，一段低氧期間對人類大腦皮質細胞造成顯著傷害，並伴隨步態與動作協調異常。」相比之下，一般實驗室小鼠並未因低氧出現這類影響。"In the xenocortical mice, a period of low oxygen caused substantial injury to human cortical cells and was accompanied by abnormalities in gait and motor coordination," Pasca said, while ordinary lab mice experienced no such effects from low oxygen.

研究人員表示，這些實驗遵循倫理準則，尤其著重於兩項議題。The researchers said the experiments adhered to ethical guidelines focused on two issues in particular.

帕斯卡說：「第一是動物福利：科學問題必須足以合理化使用動物，必須盡量減少痛苦，而且只有在無法透過替代方法充分取得相關資訊時，才應進行實驗。」"The first is animal welfare: the scientific question has to justify the use of animals, suffering must be minimized and experiments should only be performed when the information cannot adequately be obtained with alternative approaches," Pasca said.

帕斯卡說：「第二是，將愈來愈複雜的人類神經組織導入動物神經系統，是否可能產生意料之外、湧現或新的特性，因而需要額外的倫理考量。」"The second is whether introducing increasingly complex human neural tissue into an animal nervous system could lead to unexpected, emergent or novel properties that would require additional ethical consideration," Pasca said.

這些經生物工程改造的小鼠在四處移動並探索環境時，看起來就像一般實驗室小鼠，但在精細動作協調上有缺陷，記憶能力也有所不同。The bioengineered mice looked like ordinary laboratory mice as they moved around and explored their environment, but had deficits in fine motor coordination and differences in memory abilities.

帕斯卡說：「我們也必須衡量不做這項研究的代價。」他指出，神經與精神疾病影響將近五分之一的人口，但科學界對這些疾病的理解仍然有限，許多疾病仍缺乏有效治療。"We also have to weigh the cost of not doing this work," Pasca said, noting that neurological and psychiatric disorders affect nearly one in five people even as scientific understanding remains limited and effective treatments remain lacking for many of these conditions.

（威爾・丹翰報導；丹尼爾・沃利斯編輯）(Reporting by Will Dunham; Editing by Daniel Wallis)