【聯合報╱By JAMES GORMAN╱陳世欽譯】
Scientists Light Up Workings Of Brain
SAN DIEGO, California — Optogenetics is a technique that allows scientists to turn brain cells on and off with a combination of genetic manipulation and pulses of light and allows them to go beyond observation.
The tools of optogenetics are allowing scientists to find and control neurons that, for example, control a kind of aggression in fruit flies. The hope is that this tool will uncover deep mechanisms of brain function that hold true for the human brain.
A year ago, President Obama announced an initiative to invest in new research to map brain activity, allocating $100 million for the first year. The money is small compared with the $4.5 billion the National Institutes of Health spends annually on neuroscience, but it is intended to push the investigation of the brain and map its pathways, starting with the small creatures like flies.
“Optogenetics is the most revolutionary thing that has happened in neuroscience in the past couple of decades,” said Cori Bargmann of Rockefeller University in New York . At the heart of all optogenetics are proteins called opsins. They are found in human eyes, in microbes and other organisms.
When light shines on an opsin, it absorbs a photon and changes.
In 2005, Dr. Karl Deisseroth, a psychiatrist and a neuroscientist, and Edward Boyden and Feng Zhang, his colleagues at Stanford University in California; Ernst Bamberg of the Max Planck Institute of Biophysics; and Georg Nagel at the University of Würzburg published a paper showing an opsin called channelrhodopsin- 2 could be used to turn on mammalian neurons with blue light.
This was the breakthrough research, but it had antecedents. In 2002 Gero Miesenböck, now at Oxford, and Boris Zemelman, now at the University of Texas, proved that optogenetics could work. They reported their success using opsins from the fruit fly to turn on mouse neurons that had been cultured in the lab.
Ehud Isacoff of the University of California, Berkeley, reviewed the development of optogenetics recently after the awarding of the 2013 European Brain Prize to six people, including Dr. Deisseroth and Dr. Boyden, for work on optogenetics.
Dr. Deisseroth’s group, said Dr. Isacoff, turned to microbial opsins, building on the work of Dr. Bamberg, Dr. Nagel and Peter Hegemann at Humboldt University in Berlin. They figured out how to get one of these opsins safely into mammalian neurons so that the neurons would respond strongly to light.
Shortly thereafter the lab of Stefan Herlitze of Ruhr University Bochum in Germany reported a similar finding. Dr. Deisseroth pointed out, however, that that research involved only cells in culture. Many questions remained.
“How are you going to get the light deep into the brain?” he said. “How are you going to target these genes? Will it control behavior? Will you be able to turn on or off behaviors?”
Researchers are now developing techniques, which, Dr. Isacoff wrote, “have been used to study brain waves, sleep, memory, hunger, addiction, aggression, courtship, sensory modalities, and motor behavior.”
In 2013, while continuing the work on developing optogenetic techniques, the Deisseroth lab produced another technique that Dr. Deisseroth has high hopes for. He and Kwanghun Chung turned whole mouse brains transparent, with a method called Clarity.
They infused mouse brain tissue with a hydrogel, a substance well known to chemists but not one previously used in neuroscience. The method leaves the brain tissue not only transparent, but also still available for biochemical tests. The lab is now working on making a whole preserved human brain transparent .
Dr. Deisseroth ’s goal continues to be to find a way to help people with severe mental illness or brain diseases, and he has recently proposed ways that optogenetics, Clarity and other techniques may be turned to this aim.
Optogenetics is a crucial tool in understanding function. Clarity, on the other hand, is an aid to the basic mapping of structure, which, he says, is as important to understand as activity.
“I’ve administered electroconvulsive therapy — I know we can administer this therapy and cause a general seizure,” he says, in which the activity of the whole brain is disrupted.
“Within a few minutes, the whole person comes back. Where does it come back from? From the structure,” he said.
中譯
光遺傳學技術使科學家得以結合對基因的操縱與光脈衝，開閉大腦細胞，讓科學家超越觀察的限制。
光遺傳學的工具使科學家得以找出並控制特定神經元，例如控制果蠅侵略行為的神經元。他們希望利用這種工具破解同樣適用於人腦的腦部功能深層機制。
一年前，美國總統歐巴馬宣布一項繪製大腦活動圖的研究投資計畫，第一年編列一億美元預算。如與美國國立衛生研究院每年用於神經科學研究的45億美元相比，這筆經費小巫見大巫。然而它旨在推進大腦研究，同時繪製它的路徑，而且從果蠅之類的小動物著手。
紐約洛克菲勒大學的科莉‧巴格曼說：「光遺傳學是數十年來神經科學領域最具革命性的突破。」
光遺傳學的核心是一種名為視蛋白的蛋白質。人類的眼睛、微生物與其他有機體裡都有。如果以光照射視蛋白，它會吸收光子，然後改變。
2005年幾位科家聯名發表研究報告指出，稱為光敏感通道蛋白-2的視蛋白可在藍光配合下，開啟哺乳動物的神經元。這些科學家是加州史丹福大學的精神病學家兼神經科學家迪塞洛斯及其同仁波伊登、張鋒，德國馬克斯普朗克生物物理研究所的班柏格，以及德國維爾茨堡大學的納吉爾
這是突破性研究，但有前例。2002年，目前任職於牛津大學的麥森波克與德州大學的席梅爾曼證明，光遺傳可以發揮作用。他們利用取自果蠅的視蛋白啟動在實驗室中培養的老鼠神經元。
包括迪塞洛斯與波伊登在內的六名學者因為在光遺傳學領域締造的成就而共同獲得2013年歐洲大腦獎之後，柏克萊加州大學的伊薩科夫最近詳細檢視該學術領域的研究進展。
伊薩科夫說，迪塞洛斯團隊以班柏格、納吉爾與柏林洪堡大學赫吉曼等人的研究成果為基礎，專注研究微生物視蛋白。他們找到把其中一個視蛋白安全植入哺乳類神經元，使神經元對光產生強烈反應的方法。
此後不久，德國波鴻魯爾大學的赫里茨實驗室提出類似的發現。不過迪塞洛斯指出，這項研究僅涉及培養皿中的細胞，仍有許多問題待解。他說：「如何讓光深入大腦？如何鎖定這些基因？它能否控制行為？我們能否啟動或關閉行為？」
伊薩科夫說，科學家研發中的技術「曾經用於研究腦波、睡眠、記憶、飢餓、成癮、侵略、求偶、知覺形式與動作行為」。
2013年，持續研究光遺傳技術時，迪塞洛斯實驗室發明的另一項技術讓迪塞洛斯寄以厚望。他與史丹福大學博士後研究生鍾光弘（譯音）以一種名為「澄澈」的技術使老鼠的整個大腦變成透明。
他們把一種水凝膠注入老鼠的大腦組織。化學家對這種物質很熟悉，，然而它此前從未用於神經科學的研究。這種方法使大腦組織不但變得透明，而且仍可用於生化實驗。實驗室目前正致力使完整保留的人類大腦變成透明。
迪塞洛斯的目標仍然是找到能幫助嚴重精神疾病或腦部疾病患者的方法。他最近提出了把光遺傳、「澄澈」與相關技術用於這方面的方法。
光遺傳學是瞭解功能的關鍵性工具。另一方面，「澄澈」有助於結構的基礎測繪。他說，瞭解結構與瞭解活動一樣重要。
他說：「我曾經施作電痙攣療法。我知道我們可以實施這種療法，然後導致全部發作。」在這種情況下，整個大腦的活動會受到干擾。
他說：「幾分鐘內，整個人回神。它從哪兒回來？從結構。」
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