香港海洋公园门票:小小蛔虫揭开大脑的秘密

在一座可以俯瞰东河的八层实验室里，科妮莉亚·I·巴格曼正观察两位同事熟练操纵着显微镜下的蛔虫。 他们把它夹到透明玻璃片的小槽上，使它的鼻子正好陷进沟槽里。信息激素——其它蛔虫发出的化学信号，被输进沟槽中，如果蛔虫脑中的一个神经元产生反应，神经元研究人员就改变两个神经元的基因使它们发出亮绿色的光。

These ingenious techniques for exploring a tiny animal’s behavior are the fruit of many years’ work by Dr. Bargmann’s and other labs. Despite the roundworm’s lowliness on the scale of intellectual achievement, the study of its nervous system offers one of the most promising approaches for understanding the human brain, since it uses much the same working parts but is around a million times less complex. 

这些发掘小生物行为的独特技术是巴格曼实验室和其他实验室的成果。尽管蛔虫的智力等级低下，但是对其神经系统的研究提供了对人类大脑研究最理想的途径，因为它和构成人脑运作的部分大多相同，却要简单大约一万倍。

Caenorhabditis elegans, as the roundworm is properly known, is a tiny, transparent animal just a millimeter long. In nature, it feeds on the bacteria that thrive in rotting plants and animals. It is a favorite laboratory organism for several reasons, including the comparative simplicity of its brain, which has just 302 neurons and 8,000 synapses, or neuron-to-neuron connections. These connections are pretty much the same from one individual to another, meaning that in all worms the brain is wired up in essentially the same way. Such a system should be considerably easier to understand than the human brain, a structure with billions of neurons, 100,000 miles of biological wiring and 100 trillion synapses. 

秀丽隐杆线虫是蛔虫的学名，是一种只有1毫米长的透明小生物。自然界里，它靠食用腐烂动植物身上的细菌为生。它作为实验室首选的生物原因在于它的大脑构造相对简单，只有302个神经元和8000个（神经元的）突触，就是神经元之间的链接。这些链接个个都非常相似，也就是说所有的蛔虫脑内回路构造都是类似的。用这样的系统研究人脑的数十亿个神经元、十万英里的生物线和一百万亿的突触就相对容易了。

The biologist Sydney Brenner chose the roundworm as an experimental animal in 1974 with this goal in mind. He figured that once someone provided him with the wiring diagram of how 302 neurons were connected, he could then compute the worm’s behavior. 

1974年生物学家西德尼·布雷纳把蛔虫选作实验对象时就有这个目标。他认为某次别人给他302个神经元的连接图后，他能计算出蛔虫的行为。

The task of reconstructing the worm’s wiring system fell on John G. White, now at the University of Wisconsin. After more than a decade’s labor, which required examining 20,000 electron microscope cross sections of the worm’s anatomy, Dr. White worked out exactly how the 302 neurons were interconnected. 

重建蛔虫回路系统的重任目前落到了威斯康星大学的约翰·G·怀特身上。经过十多年的努力，研究了2万个电子显微镜下蛔虫的解剖结构横截面，怀特博士精准计算出了302个神经元是怎样连接起来的。

But the wiring diagram of even the worm’s brain proved too complex for Dr. Brenner’s computational approach to work. Dr. Bargmann was one of the first biologists to take Dr. White’s wiring diagram and see if it could be understood in other ways. 

但是，甚至是蛔虫闹内的接线图也足以复杂到让布雷纳博士的计算法难以运行。巴格曼博士是第一个接过怀特博士接线图并用其他方法去尝试研究的生物学家。

Cori Bargmann grew up in Athens, Ga., a small college town in the Deep South where her father taught statistics at the University of Georgia. Both her parents had been translators and met while Rolf Bargmann was working at the Nuremberg trials. Her mother, Ilse, would read to her in German the works of the Austrian animal behaviorists Konrad Lorenz and Karl von Frisch, planting the seeds of an interest in neuroscience. 

格里·巴格曼在美国南部雅典城长大，她父亲在佐治亚大学教统计学。她双亲都当做翻译，当罗尔夫·巴格曼在纽伦堡大审工作时相遇了。她母亲伊尔泽会用德语读给她听奥地利动物行为学家洛伦兹和弗利希和著作，引发了她对神经系统学的兴趣。

“I went into science because I loved the labs,” Dr. Bargmann says. She liked the machines and instruments, the fun of building things with one’s own hands, of learning what no one else knew. An outstanding student, she chose for her Ph.D. degree to work in the M.I.T. lab of Robert A. Weinberg, a leading cancer biologist. The first mutated genes capable of causing cancer were being isolated. “It was an incredibly exciting time,” she says. 

“我踏入科学殿堂是因为我爱实验室。”巴格曼博士说。她喜欢机器和仪器，喜欢用自己的双手创造东西，探索别人不知道的一切。作为一名出色的学生，她在博士阶段选择了在马萨诸塞州理工学院罗伯特A·温伯格的实验室工作，他是一位杰出的癌症生物学家。第一次分离出能致癌的变异基因。她说：“实在是激动人心的一刻。”

Her task was to clone a rat gene called neu. When mutated, the gene causes a tumor, but one that the rat’s immune system can attack and destroy. Several years later, the human version of neu, called HER-2, was found to be amplified in breast cancer, and its receptor protein product is the target of the artificial antibody known as Herceptin, a leading breast cancer drug. 

她的任务是克隆出一个老鼠的神经鞘基因。基因突变时会引发肿瘤，但是是一个老鼠的免疫系统能攻击和摧毁的。几年后，神经鞘人用版本HER-2在乳腺癌内被放大，它的受体蛋白质会产生名为赫赛汀的人工抗体，对治疗乳腺癌非常有效。

For her postdoctoral work, Dr. Bargmann decided to work on animal behavior. The mouse is a standard organism for such studies, but she did not like hurting furry animals. “In Weinberg’s lab I would start to cry every time I had to do anything with a mouse,” she says. A nonfurry alternative was the fruit fly. She interviewed with a leading laboratory in California, but her husband at the time did not wish to move there. 

博士后时候巴格曼决定从事动物行为学的研究。老鼠很适用于这样的研究，但她不忍心伤害毛茸茸的小动物。她是：“我凡是在温伯格的实验室里对老鼠做了什么每次都会哭。”另一种不长毛的替代物是果蝇。她访问了加利福尼亚一流的实验室，但当时他丈夫不愿搬去那边。

That left the roundworm. There are now several hundred worm labs around the world, of which perhaps 30 or so, like Dr. Bargmann’s, focus on the worm’s nervous system. In 1987, “worms weren’t entirely respectable,” Dr. Bargmann says. But right there at M.I.T., H. Robert Horvitz had established one of the first serious worm labs in the United States. She joined his lab and read everything written on the worm, including all the back copies of the little field’s informal journal, The Worm Breeder’s Gazette. 

余下的就是蛔虫的研究。世界上目前有几百所蛔虫实验室，其中约30所像巴格曼的实验室一样主要研究蛔虫的神经系统。1987年时，“蛔虫一点也不受注重。”巴格曼说。但同时在马萨诸塞州理工学院，H·罗伯特·霍维茨已经建立起美国第一所重量级的蛔虫实验室。她加入了他的实验室，看取了每篇关于蛔虫的报告，以及该领域的期刊《蛔虫饲养员宪报》的所有备份。

She noticed that a particular behavior of C. elegans had been described but not well explored: it can taste waterborne chemicals and move toward those it finds attractive. Dr. White’s wiring diagram had been published the year before, in 1986. With this in hand, she told Dr. Horvitz she planned to identify which of the worm’s 302 neurons controlled its chemical-tracking behavior. 

她注意到秀丽线虫的某个特定行为没有被好好研究过：它能辨别并移动到吸引它的化学试剂旁。怀特博士的接线图在前一年发表了，也就是1986年。有了图在手，她告诉霍维茨博士她要找出蛔虫的302个神经元中哪个控制了它追踪化学试剂的行为。

He thought the project was too ambitious, but said she could spend six months on the attempt. Each neuron in the worm’s brain is known, and is assigned a three letter name. Specific neurons can be identified under a microscope and zapped with a laser beam, allowing the neuron’s role to be deduced from whatever function the worm may seem to have lost. 

他认为这个计划颇具野心，但说她能为此花费半年时间。每个蛔虫脑内的神经元都是已知的，都被编成三个字母的名称。显微镜下能辨认出被镭射杀灭的特定神经元，通过损失的神经元的用途来判断蛔虫可能会失去哪些行为。

Dr. Bargmann slogged her way through the task of killing each neuron one by one. Telling one neuron from another under the microscope is not easy. “It’s like knowing each grape in a bunch is different, but not quite being able to see it,” Dr. Horvitz said. “The first thing she had to do was learn the worm’s neuroanatomy, and she did so in a way only one other person has ever done.” (He was referring to John E. Sulston, who traced the lineage from the egg of all 959 cells in the adult worm’s body). 

巴格曼博士坚持不懈地完成任务，破坏了一个又一个神经元。在显微镜下区分神经元的不同之处是件难事。“就好比分辨一串葡萄上的每一个，细微之处很难看出。”霍维茨博士说。"T她先要学习蛔虫的神经解剖学，她做到了只有另一个人做过的事。“（这里提到的就是约翰·E·萨尔斯顿，他从成年蛔虫身体里的959个卵细胞开始追逐蛔虫的血统。）

She discovered, by accident, the neurons that control the worm’s switch into hibernation, a survival strategy for when food is scarce or neighbors too many. Finally, she found the neurons that control taste, showing that without them the worm could not track chemicals, and that it retained this ability even if she killed all the other neurons in the worm’s body. 

她偶然发现了神经会在食物短缺或是周围蛔虫太多时控制其进入冬眠。最后，她发现蛔虫失去控制味觉的神经将无法找到化学试剂，就算杀灭蛔虫体内其他神经，这个能力依然能够保留。

She also discovered that the worms have a sense of smell — the ability to detect airborne chemicals — as well as a sense of taste. Since worms eat bacteria that feed on decaying plants and carcasses, she figured they should be able to detect and home in on the aromas of putrefaction. The redolent draft from these experiments caused a certain degree of complaint in Dr. Horvitz’s lab. After she succeeded, she says, “Horvitz told me that my great strength as a scientist was that I could think like a worm.” 

她也发现蛔虫有味觉，同样也有嗅觉——它们能辨别化学气体。自打蛔虫靠腐烂动植物身上的细菌为生起，她认为它们能辨认和追踪腐烂的气味。实验发出的浓烈气味使霍维茨博士的实验室遭到了不少抱怨。她成功以后说道：“霍维茨告诉我，我作为科学家的钻劲是因为我能像蛔虫一样思考。”

“Cori is talented beyond thinking like a worm,” Dr. Horvitz now says. “She can think like very few other people in a rigorous and creative way, and so has repeatedly developed new kinds of approaches.” 

“葛利不仅爱思考，更是才华横溢。”霍维茨博士现在说：“很少有人像她一样有慎密和创造性的思维，正因如此她不断创造出各种成果。”

Dr. Bargmann moved in 1991 to the University of California, San Francisco, to start her own lab. She began by following up her finding that worms have a sense of smell. In 1991, Richard Axel and Linda Buck discovered the molecular basis for the sense of smell: there are about a thousand genes, at least in rats, that make odorant receptors, proteins that stud the olfactory nerves’ endings in the nose and respond to specific odors. 

巴格曼博士1991年转移到旧金山的加州大学开始创立自己的实验室。她继续蛔虫嗅觉的研究。1991年，理查德·阿克塞尔和琳达·巴克发现了分子性是嗅觉的基础：至少在老鼠身上大约有1000个基因，就是附在鼻子内嗅觉神经末梢上的蛋白质，接收气味信号并对特定的产生反应。

The C. elegans genome had just been decoded, and Dr. Bargmann was able to identify the worm’s odorant receptor genes. In fact, they have 2,000 of them, twice as many as the rat. 

秀丽线虫的基因组刚刚被破解，巴格曼博士证实了蛔虫接收气味的基因。实际上，它们有2000个这样的基因，是老鼠的两倍。

“This is what they do,” Dr. Bargmann says. The worm cannot see. Its world is one of smells, not sights. It needs to scent the soil bacteria that are its prey, while avoiding those that are poisonous to it. Ten percent of its genes are dedicated to making it a champion connoisseur of odors, mostly unpleasant. 

“它们就是这样接收气味的。”巴格曼博士说。蛔虫没有视力。它的世界由气味构成的，并非视觉。它需要在嗅出作为食物的土壤细菌的同时避开对它有毒有害的物质。它有百分之十的专用基因是鉴别气味的好手，特别是针对不愉快的气味。

With the odorant genes in hand, Dr. Bargmann could apply genetics to figuring out how the worm’s sense of smell worked. By working with mutant worms, she showed that a specific odor receptor recognizes a specific odor, a finding that was implied by the Axel-Buck discovery but that no one had managed to nail down. 

有气味基因在手，巴格曼博士就能把遗传学应用到蛔虫嗅觉是怎样运作的问题上。从事变异蛔虫的研究过程中，她表示蛔虫有辨识特殊气味的特殊接收器，这是从阿克塞尔·巴克那里得到的启示，但是还没有人下定论。

She found that worms with a mutation in a gene called odr-10 could not smell diacetyl, a chemical that gives butter its odor and is also produced by a bacterium that is a favorite worm food. The odr-10 gene, which makes the odor receptor protein that detects diacetyl, is active in neurons that guide the worm toward a scent. 

她发现含有变异基因ord-10的蛔虫闻不出联乙醯，联乙醯是一种细菌散发出的黄油味化学物质，是蛔虫最爱的食物之一。odr-10基因使接收气味的蛋白质能辨识联乙醯，是神经元中引导蛔虫追踪气味的活跃部分。

Dr. Bargmann switched things around so that odr-10 was expressed only in a neuron that detected scents repulsive to the worm. These worms backed away from the buttery odor, showing that it is not the odor receptors but the wiring of the nervous system itself that determines whether the worm deems an odor delicious or detestable. 

巴格曼博士调整了位置，传播给有odr-10的神经元蛔虫讨厌的味道。蛔虫们远离了黄油气味，这表示蛔虫判断气味好坏是靠神经系统回路本身决定的而不是气味接收器。

This was a surprising result because most people thought that sensory information was perceived as neutral, with the brain deciding later from the context whether it was good or bad. Some scientists said that only worms behave this way, but the same result was later obtained in mice. 

这是个令人惊讶的结果，因为多数人觉得感知信息是没有倾向性的，好坏是由大脑随环境而决定的。一些科学家说只有蛔虫表现出这种行为，但后来在老鼠身上也得出这样的结果。

Dr. Bargmann sees the arrangement in evolutionary terms. “The more reliable a piece of information is, the more it will be shifted into the genome,” she says. That way, an organism does not have to risk learning what is good or bad; the genes will dictate the right behavior by wiring it into the nervous system. Worms are wired up to know that diacetyl means good eating. 

巴格曼博士认为这是一种进化方式。“越是可靠的信息，越会被转换到基因组里。”她说。那样生物就不用冒着风险去学会分辨好坏。蛔虫通过回路知道联乙醯代表了美味。

Having studied the worm by mutating its genes, Dr. Bargmann then looked at natural variation in the genetic basis of worm behavior. Most worms in nature like to congregate in clumps, but the laboratory version of C. elegans has developed an unusual liking for being on its own. She linked this difference in behavior to the switch of a single amino acid unit in a protein called npr-1 (for neuropeptide Y receptor-1). 

通过改变其基因研究了蛔虫后，接着巴格曼博士专注于蛔虫基因为基础的行为中的自然变异。自然界大多数蛔虫喜欢簇拥成团，但实验室里的秀丽线虫却养成了独来独往的喜好。她把这种行为的不同与蛋白质内一个氨基酸单位中性蛋白酶-1的改变联系起来。（用于神经肽Y的接收器1号）。

It took several more years to learn how the system worked. It turns out that social behavior in the worm is controlled by a pair of neurons called RMG. The two RMG neurons receive input from various sensory neurons that detect the several environmental cues that make worms aggregate. RMG integrates this information and sends signals to the worm’s muscles. 

研究系统运作又花费了数年时间。结论得出蛔虫的社交习性是由一对叫做RMG的神经元控制的。两个RMG神经元收到来自感觉神经元的各种环境信号，使蛔虫们聚集起来。RMG集成信息并对蛔虫肌肉发出信号。

The usual role of the RMG neurons is to promote social behavior, but when the npr-1 gene is active, the RMG neurons cannot receive input from their sensory neurons, and the worms switch to solitary behavior. 

RMG神经元的特别用处在于它促进了社交习性，但当基因中性蛋白酶-1活跃时，RMG神经元无法收到来自感觉神经元的信号，蛔虫变得独来独往。

While working out the worm’s sense of smell, Dr. Bargmann fell in love with another olfactory researcher, Richard Axel. Dr. Axel works at Columbia University, and she was able to join him in New York by finding a place at Rockefeller University. Dr. Axel was helping her clear out her apartment in San Francisco when he heard he had won the Nobel Prize. 

了解蛔虫的嗅觉后，巴格曼博士与同样研究嗅觉的理查德·阿克塞尔坠入了爱河。阿克塞尔博士在哥伦比亚大学工作，她可以在洛克菲勒大学找到职位与他在纽约会合。阿克塞尔得知自己获得诺贝尔奖后帮助她清空了旧金山的公寓。

Right after that pleasant news, he had to drive to the local Goodwill store to drop off the stuff to be given away. “People think that if you’re married to a scientist you talk about science all the time,” Dr. Bargmann says. They read each other’s papers before publication, but they don’t plan experiments together. Dr. Axel works on how olfactory information is handled in the cortex, the highest level of human and mouse brains. 

刚得知喜讯后，他得把要分发掉的行李开车送去当地的慈善商店。巴格曼博士说：“人们觉得你和科学家结婚后就会无时不刻探讨科学。”他们在发表前互相阅读对方的论文，但他们不会一起准备实验计划。阿克塞尔博士致力于嗅觉信息在大脑皮层内的处理，这是人脑和鼠脑的最高等级研究。

“Probably once or twice a week we are sitting at dinner and Richard says, ‘The cortex is hopeless,’ and I say, ‘That’s why I work on the worm.’ ” Dr. Bargmann said. 

“有可能一周或两周一次我们吃饭时理查德会说：‘大脑皮层没希望了。’我会说：‘那正是我为何要研究蛔虫。’”巴格曼博士说。

After studying the little animal for 24 years, she believes she is closer to understanding how its nervous system works. 

研究这小动物24年后，她相信她对其神经系统运作的理解又加深了

Why is the wiring diagram produced by Dr. White so hard to interpret? She pulls down from her shelves a dog-eared copy of the journal in which the wiring was first described. The diagram shows the electrical connections that each of the 302 neurons makes to others in the system. These are the same kind of connections as those made by human neurons. But worms have another kind of connection. 

为什么怀特博士制造的线路图如此难破译？她从书架上取下一本折角的杂志，上面第一次描述了回路。图表显示系统中302个神经元每个都和其他的形成电连接。这和人脑神经元的连接类似。但蛔虫有另外一种连接方式。

Besides the synapses that mediate electrical signals, there are also so-called gap junctions that allow direct chemical communication between neurons. The wiring diagram for the gap junctions is quite different from that of the synapses. 

除了形成电子信号的突触以外，还有使得神经元之间产生直接化学通信的缝隙连接。缝隙连接的接线图和突触的接线图非常不同。

Not only does the worm’s connectome, as Dr. Bargmann calls it, have two separate wiring diagrams superimposed on each other, but there is a third system that keeps rewiring the wiring diagrams. This is based on neuropeptides, hormonelike chemicals that are released by neurons to affect other neurons. 

不光巴格曼博士口中的蛔虫连接体有两个分别重叠于各自的接线图，还有第三个重新连接接线图的系统。这是基于神经肽，神经元影响其他神经元后散发出的类似激素的化学物质。

The neuropeptides probably help control the brain’s general status, or mood. A strong hint of how they work comes from the npr-1 gene, which makes a protein that responds to neuropeptides. When the npr-1 gene is active, its neuron becomes unavailable to its local circuit. 

神经肽很可能帮助控制了大脑的一般状态，或是情绪。中性蛋白酶-1基因发出的强烈工作暗示使得蛋白质对神经肽产生反应。中性蛋白酶-1活跃时，神经元无法控制其局部回路。

That may be a reason why the worm’s behavior cannot be computed from the wiring diagram: the pattern of connections is changing all the time under the influence of the worm’s 250 neuropeptides. 

这就是蛔虫的行为为何无法通过接线图计算得出：在蛔虫250个神经肽的影响下，连接的形式时刻在变化着

The connectome shows the electrical connections, and hence the quickest paths for information to move through the worm’s brain. “But if only a subset of neurons are available at any time, the connectome is ambiguous,” she says. 

连接体显示出电子连接，也因此是信息传输到蛔虫脑内的最快途径。她说：“但如果只有一个子集的神经元是时刻有效的，连接体就会发生分歧。”

The human brain, too, has neuropeptides that set mood and modify behavior. Neuropeptides are probably at work when the pain pathways are cut off in acute crises, allowing people to function despite serious wounds. 

人脑同样有调节心情和调整行为的神经肽。神经肽任凭在重伤时痛觉通路被切断的紧急情况下也可以调节人体。

The human brain, though vastly more complex than the worm’s, uses many of the same components, from neuropeptides to transmitters. So everything that can be learned about the worm’s nervous system is likely to help with the human system. 

尽管人脑比蛔虫大脑复杂多了，但是从神经肽到发射器的成分都相似。所以从研究蛔虫大脑得出的知识都对研究人体系统有帮助。

Though the worm’s nervous system is routinely described as simple, that is true only in comparison with the human brain. The worm has 22,000 genes, almost as many as a person, and its brain is a highly complex piece of biological machinery. The work of Dr. Bargmann’s and other labs has deconstructed many of its operational mechanisms. 

尽管蛔虫的神经系统通常被描述得很简单，但那只是和人脑比较的情况下。蛔虫有2万2千个基因，几乎和一个成人一样多，蛔虫大脑是生物体系中非常复杂的部分。巴格曼博士和其他实验室的研究解构出了很多它的运行机制。

What would be required to say that the worm’s nervous system was fully understood? “You would want to understand a behavior all the way through, and then how the behavior can change,” Dr. Bargmann says. 

怎样才能说明蛔虫的神经系统已经完全研究清楚了呢？巴格曼博士说：“你会通过所有方式了解一种行为，然后看这项行为会怎样改变。”

“That goal is not unattainable,” she adds.

“这一目标并非高不可攀。”她补充道。