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她在自己研究的基因里,找到了女儿疾病的根源

更新时间:2018-4-24 20:13:34 来源:纽约时报中文网 作者:佚名

Infinitesimal Odds: A Scientist Finds Her Child’s Rare Illness Stems From the Gene She Studies
她在自己研究的基因里,找到了女儿疾病的根源

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.

俄勒冈州波特兰——在她母亲收到医生的电子邮件时,患有一种可怕的不明疾病的李允儿(Yuna Lee,音)已经两岁了。她不能说话、不能走路,也不能站立,深受身体痉挛和无法抑制的哭喊所困。

“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.

“为什么她受这么多苦?”她的母亲李洙京(Soo-Kyung Lee,音)痛苦地问道。大脑扫描、基因测试及神经检测都一无所获。但当一封邮件弹出来,暗示允儿可能带有一种名为“FOXG1”的基因变异时,李洙京僵住了。

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

“我就知道,”她说。“我知道那个基因。”

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.

世界上几乎没有其他人知道这个基因。但李洙京是大脑基因方面的专家,用美国国家神经疾病和中风研究所(National Institute of Neurological Disorders and Stroke)神经遗传学项目负责人罗伯特·里德尔(Robert Riddle)的话说,她是“一个明星”。多年来,在俄勒冈卫生科学大学(Oregon Health and Science University)研究发育生物学的李洙京曾从事过FOX基因族方面的研究。

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

“我知道FOXG1对大脑发育来说有多重要,”她说。

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变异是极为罕见的,通常是非遗传性的:这种基因会在孕期自行变异。全世界已知仅有约300人患有FOXG1综合征,这种情况在不久前才被列为一种单独的病。她自己的女儿患上这种症状的可能性微乎其微。

“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.”

“这是一个令人震惊的故事,”里德尔说。“一位基础研究人员从事一种可能会帮助人类的研究,结果却直接影响到她的孩子。”

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岁的李洙京与57岁的丈夫李载(Jae Lee,音)必须从冷静的科学家转变为迫切需要答案的病人父母。她的丈夫也是俄勒冈卫生科学大学的一名基因专家。

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.

他们身陷一个云翳诡谲的海洋,它由新发现的基因突变、新命名的诊断以及引发新问题的答案所构成。新发现的基因组测序能力正在引发一股基因淘金热,将神秘疾病与特定基因变异联系起来——它们常常是随机变异,并非遗传自父母。

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.

维康信托基金会桑格研究所(Wellcome Trust Sanger Institute)人类遗传学部门负责人马修·赫尔斯(Matthew Hurles)说,新研究表明,每年全世界大约有40万新生儿患有随机突变造成的神经疾病。医生称,随着测序费用降低,会有更多孩子得到FOXG1综合征这样的具体诊断。

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.

允儿现在八岁了,性情温和,在尿布的外面依然穿着学走路的孩子穿的连身衣。她的父亲李载说:“她的认知能力大约是18个月的水平。”

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.”

让允儿能够在尿布湿了的时候发出信号,或是让她靠在厨房的角落然后松手的那一瞬间能站稳,就是重大成就。“如果允儿不马上倒下,”李洙京说,“我们就认为成功了。”

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.

在允儿迎来第二个生日后不久,作为一个美国国家卫生研究院(National Institutes of Health)专家组成员的李洙京前往华盛顿,参与审查大脑发育研究人员提交的经费申请。在晚宴上,她发现自己坐在了大名鼎鼎的新生儿学家、神经学家戴维·罗威奇(David Rowitch)旁边,这是她第一次见到本尊。

“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.

“她开始和我说她女儿的情况,”罗威奇回忆说。罗威奇当时任职于加州大学旧金山分校(University of California, San Francisco),现在是剑桥大学(University of Cambridge)教授和儿科学系主任。他被难住了,但提出把允儿的脑扫描图发给神经放射学的“世界级专家”——加州大学旧金山分校的吉姆·巴尔科维奇(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.”

巴尔科维奇说,允儿的扫描图呈现出“一种非常少见的模式”,几十年来他评估过世界各地发送给他的脑部影像,从未见过这种情况。允儿的大脑皮层中有异常的白质,这意味着“可能有细胞正在死去”,他说,并且胼胝体“太薄”。人脑左右两个半球里的细胞正是通过胼胝体这条走廊交流的。

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.

他说,在搜索科学文献时,“我发现了一种似乎是在那个区域表达的基因,并且发现当它发生突变时,会产生一种非常相似的模式。”这种基因就是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.”

华盛顿大学(University of Washington)的儿科学和神经学教授威廉·多宾斯(William Dobyns)博士说,FOXG1是至关重要的,以至于最初被命名为“脑因子-1”(Brain Factor 1)。多宾斯在2011年发表了一篇论文,提出单列一个叫作“FOXG1综合征”的诊断。“这是大脑发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为一种帮助其他基因开启或关闭的蛋白质提供蓝图。它会对胎儿脑发育的三个重要阶段起到帮助作用:勾画上脑和下脑区域的轮廓、调节产生的神经细胞数量和“建立整个大脑皮层的结构,”多宾斯说。

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.”

早在允儿出生之前,李洙京就偶然接触过她觉得很有趣的研究。它们表明,两份FOXG1基因都不见了的小鼠没有形成脑。这可能也适用于人类。“没有人两份基因拷贝都丢失了,”国家神经疾病和中风研究所的里德尔说。“那是无法存活的。”

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

李洙京对李载说,她希望有一天能够研究FOXG1是如何促进大脑发育的。“然后,允儿就来了,”李载说。

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.

现在,在研究小鼠大脑的过程中,李洙京一家已经找到了与FOXG1相互作用的基因。这有助于解释为什么一份FOXG1拷贝受损会破坏胼胝体在两个大脑半球之间传输信号的能力。

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

“我们现在明白了这个基因是怎样起作用的,以及其中的原理,”李洙京说。

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.

许多奥秘依然没有揭开。个别FOXG1突变对基因功能的影响是不同的,因此FOXG1患者的症状可能因人而异。例如,波士顿儿童医院(Boston Children’s Hospital)和哈佛医学院(Harvard Medical School)的儿童发育与神经发育障碍专家查尔斯·A·尼尔逊三世(Charles A. Nelson III)评估了两名10岁的患者,他们突变的位置不同,损伤程度也明显不同。

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.

允儿这样的患者带有一组不健全的FOXG1基因和一组健全的FOXG1基因,只能生产身体所需的一半FOXG1蛋白质,李洙京想知道,基因治疗是否能够恢复某些蛋白质或增强正常基因中的蛋白质活性。

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.”

但是因为FOXG1在发育初期至关重要,所以洛维奇说:“我不认为你可以回到婴儿刚出生的时期,让她的大脑重新发育好。”

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?”

李洙京向来不愿意向科学家同行们提起女儿,但最近她开始在演讲中感谢允儿。“我每天都害怕第二天可能会失去她,”李洙京哽咽着说。“但是她做到了很多我们做梦都不敢想的奇妙事情。那么,人们怎么能说她永远无法做这个,她永远无法做到那个?”

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,他们把允儿抱到楼上那张巨大的婴儿床上,她的身体如弹簧一般拱起。推着车上上下下变得越来越困难,所以两夫妇打算离开他们买下的这座三层的崖边宅邸,搬到医院和他们的实验室附近。这座有壮美的圣海伦山景的房子属于乐观者,让人拥有可以越过地平线的视野。

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