她在自己研究的基因里，找到了女兒疾病的根源

PORTLAND, Ore. — By the time her mother received the doctor’s email, Yuna Lee was already 2 years old, a child with a frightening medical mystery. Plagued with body-rattling seizures and inconsolable crying, she could not speak, walk or stand.

俄勒岡州波特蘭——在她母親收到醫(yī)生的電子郵件時，患有一種可怕的不明疾病的李允兒(Yuna Lee，音)已經(jīng)兩歲了。她不能說話、不能走路，也不能站立，深受身體痙攣和無法抑制的哭喊所困。

“Why is she suffering so much?” her mother, Soo-Kyung Lee, anguished. Brain scans, genetic tests and neurological exams yielded no answers. But when an email popped up suggesting that Yuna might have a mutation on a gene called FOXG1, Soo-Kyung froze.

“為什么她受這么多苦?”她的母親李洙京(Soo-Kyung Lee，音)痛苦地問道。大腦掃描、基因測試及神經(jīng)檢測都一無所獲。但當(dāng)一封郵件彈出來，暗示允兒可能帶有一種名為“FOXG1”的基因變異時，李洙京僵住了。

“I knew,” she said, “what that gene was.”

“我就知道，”她說。“我知道那個基因。”

Almost no one else in the world would have had any idea. But Soo-Kyung is a specialist in the genetics of the brain — “a star,” said Robert Riddle, a program director in neurogenetics at the National Institute of Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental biologist at Oregon Health and Science University, had worked with the FOX family of genes.

世界上幾乎沒有其他人知道這個基因。但李洙京是大腦基因方面的專家，用美國國家神經(jīng)疾病和中風(fēng)研究所(National Institute of Neurological Disorders and Stroke)神經(jīng)遺傳學(xué)項目負(fù)責(zé)人羅伯特·里德爾(Robert Riddle)的話說，她是“一個明星”。多年來，在俄勒岡衛(wèi)生科學(xué)大學(xué)(Oregon Health and Science University)研究發(fā)育生物學(xué)的李洙京曾從事過FOX基因族方面的研究。

“I knew how critical FOXG1 is for brain development,” she said.

“我知道FOXG1對大腦發(fā)育來說有多重要，”她說。

She also knew harmful FOXG1 mutations are exceedingly rare and usually not inherited: The gene mutates spontaneously during pregnancy. Only about 300 people worldwide are known to have FOXG1 syndrome, a condition designated a separate disorder relatively recently. The odds her own daughter would have it were infinitesimal.

她也了解有害的FOXG1變異是極為罕見的，通常是非遺傳性的：這種基因會在孕期自行變異。全世界已知僅有約300人患有FOXG1綜合征，這種情況在不久前才被列為一種單獨的病。她自己的女兒患上這種癥狀的可能性微乎其微。

“It is an astounding story,” Riddle said. “A basic researcher working on something that might help humanity, and it turns out it directly affects her child.”

“這是一個令人震驚的故事，”里德爾說。“一位基礎(chǔ)研究人員從事一種可能會幫助人類的研究，結(jié)果卻直接影響到她的孩子。”

Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57, another genetics specialist at OHSU, had to transform from dispassionate scientists into parents of a patient, desperate for answers.

突然，42歲的李洙京與57歲的丈夫李載(Jae Lee，音)必須從冷靜的科學(xué)家轉(zhuǎn)變?yōu)槠惹行枰鸢傅牟∪烁改?。她的丈夫也是俄勒岡衛(wèi)生科學(xué)大學(xué)的一名基因?qū)＜摇?/p>

They were plunged into a fast-moving ocean of newly identified gene mutations, newly named diagnoses and answers that raise new questions. The newfound capacity to sequence genomes is spurring a genetic gold rush, linking mystifying diseases to specific mutations — often random mutations not passed down from parents.

他們身陷一個云翳詭譎的海洋，它由新發(fā)現(xiàn)的基因突變、新命名的診斷以及引發(fā)新問題的答案所構(gòu)成。新發(fā)現(xiàn)的基因組測序能力正在引發(fā)一股基因淘金熱，將神秘疾病與特定基因變異聯(lián)系起來——它們常常是隨機(jī)變異，并非遺傳自父母。

New research shows that each year, about 400,000 babies born worldwide have neurological disorders caused by random mutations, said Matthew Hurles, head of human genetics at Wellcome Trust Sanger Institute. As sequencing becomes cheaper, more children will receive specific diagnoses like FOXG1 syndrome, doctors say.

維康信托基金會桑格研究所(Wellcome Trust Sanger Institute)人類遺傳學(xué)部門負(fù)責(zé)人馬修·赫爾斯(Matthew Hurles)說，新研究表明，每年全世界大約有40萬新生兒患有隨機(jī)突變造成的神經(jīng)疾病。醫(yī)生稱，隨著測序費用降低，會有更多孩子得到FOXG1綜合征這樣的具體診斷。

Yuna is now a sweet-natured 8-year-old still wearing a toddler’s onesie over a diaper. “Cognitively she’s about 18 months,” Jae, her father, said.

允兒現(xiàn)在八歲了，性情溫和，在尿布的外面依然穿著學(xué)走路的孩子穿的連身衣。她的父親李載說：“她的認(rèn)知能力大約是18個月的水平。”

A major achievement would be getting Yuna to indicate when her diaper is wet. Or to stand when they prop her against a kitchen corner and remove their hands for a split second. “If Yuna doesn’t fall down right away,” Soo-Kyung said, “we consider that a success.”

讓允兒能夠在尿布濕了的時候發(fā)出信號，或是讓她靠在廚房的角落然后松手的那一瞬間能站穩(wěn)，就是重大成就。“如果允兒不馬上倒下，”李洙京說，“我們就認(rèn)為成功了。”

Shortly after Yuna’s second birthday, Soo-Kyung traveled to Washington, D.C., to serve on a National Institutes of Health panel reviewing grant proposals from brain development researchers. At dinner, she found herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist she knew only by reputation.

在允兒迎來第二個生日后不久，作為一個美國國家衛(wèi)生研究院(National Institutes of Health)專家組成員的李洙京前往華盛頓，參與審查大腦發(fā)育研究人員提交的經(jīng)費申請。在晚宴上，她發(fā)現(xiàn)自己坐在了大名鼎鼎的新生兒學(xué)家、神經(jīng)學(xué)家戴維·羅威奇(David Rowitch)旁邊，這是她第一次見到本尊。

“She started to tell me what’s going on with her daughter,” recalled Rowitch, a professor and head of pediatrics at the University of Cambridge who was then at the University of California, San Francisco. He was stumped but offered to send Yuna’s brain scans to “the world’s expert” in neuroradiology: Dr. Jim Barkovich at UCSF.

“她開始和我說她女兒的情況，”羅威奇回憶說。羅威奇當(dāng)時任職于加州大學(xué)舊金山分校(University of California, San Francisco)，現(xiàn)在是劍橋大學(xué)(University of Cambridge)教授和兒科學(xué)系主任。他被難住了，但提出把允兒的腦掃描圖發(fā)給神經(jīng)放射學(xué)的“世界級專家”——加州大學(xué)舊金山分校的吉姆·巴爾科維奇(Jim Barkovich)博士。

Barkovich said Yuna’s scans revealed “a very unusual pattern,” one he had not seen in decades of evaluating brain images sent to him from around the world. Yuna’s cerebral cortex had abnormal white matter, meaning “there were probably cells dying,” he said, and the corpus callosum, the corridor across which cells in the left and right hemispheres communicate, was “way too thin.”

巴爾科維奇說，允兒的掃描圖呈現(xiàn)出“一種非常少見的模式”，幾十年來他評估過世界各地發(fā)送給他的腦部影像，從未見過這種情況。允兒的大腦皮層中有異常的白質(zhì)，這意味著“可能有細(xì)胞正在死去”，他說，并且胼胝體“太薄”。人腦左右兩個半球里的細(xì)胞正是通過胼胝體這條走廊交流的。

Searching scientific literature, he said, “I found a gene that seemed to be expressed in that area and found that when it was mutated it caused a very similar pattern.” That gene was FOXG1.

他說，在搜索科學(xué)文獻(xiàn)時，“我發(fā)現(xiàn)了一種似乎是在那個區(qū)域表達(dá)的基因，并且發(fā)現(xiàn)當(dāng)它發(fā)生突變時，會產(chǎn)生一種非常相似的模式。”這種基因就是FOXG1。

FOXG1 is so crucial that its original name was “Brain Factor 1,” said Dr. William Dobyns, a professor of pediatrics and neurology at University of Washington, who published a 2011 study recommending a separate diagnosis: FOXG1 syndrome. “It’s one of the most important genes in brain development.”

華盛頓大學(xué)(University of Washington)的兒科學(xué)和神經(jīng)學(xué)教授威廉·多賓斯(William Dobyns)博士說，F(xiàn)OXG1是至關(guān)重要的，以至于最初被命名為“腦因子-1”(Brain Factor 1)。多賓斯在2011年發(fā)表了一篇論文，提出單列一個叫作“FOXG1綜合征”的診斷。“這是大腦發(fā)育中最重要的基因之一。”

FOXG1 provides blueprints for a protein that helps other genes switch on or off. It helps with three vital fetal brain stages: delineating the top and bottom regions, adjusting the number of nerve cells produced, and “setting up the organization of the entire cortex,” Dobyns said.

FOXG1為一種幫助其他基因開啟或關(guān)閉的蛋白質(zhì)提供藍(lán)圖。它會對胎兒腦發(fā)育的三個重要階段起到幫助作用：勾畫上腦和下腦區(qū)域的輪廓、調(diào)節(jié)產(chǎn)生的神經(jīng)細(xì)胞數(shù)量和“建立整個大腦皮層的結(jié)構(gòu)，”多賓斯說。

Long before Yuna was born, Soo-Kyung stumbled upon research she found fascinating, showing that mice missing both FOXG1 genes did not form brains. That would apply to humans, too. “There’s nobody who is missing two copies of the gene,” said Riddle of the National Institute of Neurological Disorders and Stroke. “They don’t survive.”

早在允兒出生之前，李洙京就偶然接觸過她覺得很有趣的研究。它們表明，兩份FOXG1基因都不見了的小鼠沒有形成腦。這可能也適用于人類。“沒有人兩份基因拷貝都丟失了，”國家神經(jīng)疾病和中風(fēng)研究所的里德爾說。“那是無法存活的。”

Soo-Kyung told Jae she wanted to someday study how FOXG1 drives brain development. “Then Yuna arrived,” Jae said.

李洙京對李載說，她希望有一天能夠研究FOXG1是如何促進(jìn)大腦發(fā)育的。“然后，允兒就來了，”李載說。

Now, studying mouse brains, the Lees have identified genes that interact with FOXG1, helping explain why one crippled copy of FOXG1 damages the corpus callosum’s ability to transmit signals between hemispheres.

現(xiàn)在，在研究小鼠大腦的過程中，李洙京一家已經(jīng)找到了與FOXG1相互作用的基因。這有助于解釋為什么一份FOXG1拷貝受損會破壞胼胝體在兩個大腦半球之間傳輸信號的能力。

“We now understand how this gene works and why,” Soo-Kyung said.

“我們現(xiàn)在明白了這個基因是怎樣起作用的，以及其中的原理，”李洙京說。

Many mysteries remain. Individual FOXG1 mutations affect gene function differently, so one FOXG1 patient’s symptoms can vary from another’s. For example, Charles A. Nelson III, an expert in child development and neurodevelopmental disorders at Boston Children’s Hospital and Harvard Medical School, evaluated two 10-year-old patients with mutations in different locations and markedly distinct levels of impairment.

許多奧秘依然沒有揭開。個別FOXG1突變對基因功能的影響是不同的，因此FOXG1患者的癥狀可能因人而異。例如，波士頓兒童醫(yī)院(Boston Children’s Hospital)和哈佛醫(yī)學(xué)院(Harvard Medical School)的兒童發(fā)育與神經(jīng)發(fā)育障礙專家查爾斯·A·尼爾遜三世(Charles A. Nelson III)評估了兩名10歲的患者，他們突變的位置不同，損傷程度也明顯不同。

Since patients like Yuna, with one dysfunctional and one functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung wonders if gene therapy could restore some protein or boost protein activity in the good gene.

允兒這樣的患者帶有一組不健全的FOXG1基因和一組健全的FOXG1基因，只能生產(chǎn)身體所需的一半FOXG1蛋白質(zhì)，李洙京想知道，基因治療是否能夠恢復(fù)某些蛋白質(zhì)或增強正?；蛑械牡鞍踪|(zhì)活性。

But because FOXG1 is crucial so early in development, Rowitch said, “I don’t think you can just go back when the baby’s born and build the brain back up.”

但是因為FOXG1在發(fā)育初期至關(guān)重要，所以洛維奇說：“我不認(rèn)為你可以回到嬰兒剛出生的時期，讓她的大腦重新發(fā)育好。”

Soo-Kyung rarely used to mention her daughter to fellow scientists, but recently began thanking Yuna during presentations. “I was afraid every day that she might not be with me the next day,” Soo-Kyung said, voice breaking. “But she’s done amazing things that we wouldn’t dare to dream. So, how can anyone say she will never be able to do this, she will never be able to do that?”

李洙京向來不愿意向科學(xué)家同行們提起女兒，但最近她開始在演講中感謝允兒。“我每天都害怕第二天可能會失去她，”李洙京哽咽著說。“但是她做到了很多我們做夢都不敢想的奇妙事情。那么，人們怎么能說她永遠(yuǎn)無法做這個，她永遠(yuǎn)無法做到那個?”

At night they carry Yuna upstairs to her giant crib, her body arching elastically. Carting her up and down is getting harder, so the Lees expect to move from the three-level, cliffside house they bought to be closer, for Yuna’s sake, to the hospital and their labs. With breathtaking views of Mount St. Helens, it is an optimist’s house, where it is possible to see beyond the horizon.

晚上，他們把允兒抱到樓上那張巨大的嬰兒床上，她的身體如彈簧一般拱起。推著車上上下下變得越來越困難，所以兩夫婦打算離開他們買下的這座三層的崖邊宅邸，搬到醫(yī)院和他們的實驗室附近。這座有壯美的圣海倫山景的房子屬于樂觀者，讓人擁有可以越過地平線的視野。