这事情听起来有点匪夷所思，但事实确实就是这样，是人类制造的原子弹帮助解决了一个长期争议的科学问题，那就是成年人的大脑神经细胞是否可以再生的问题。今天《科学》杂志上就有这个 Atomic Bombs Help SolveBrain Mystery 的文章，实际上是针对上 周《细胞》上的一篇文章的访谈。 上世纪五六十年代冷战时期大概有500个以上的原子弹核试验给地球和人类留下永久的记忆和纪录。例如地球表面环境中碳14同位素增加了一倍。50年后，科学家发现采用但是核爆炸引起的环境碳13同位素的变化规律，也就是但是那个年代增加，核爆炸减少后逐渐降低，这种变化会在一些细胞的核酸内留下标记（不增值的细胞DNA不再复制），而新生的细胞则因为年轻而碳13同位素减少。通过对人体大脑海马内细胞进行研究，结果发现，人的生中海马神经细胞持续不断更新。这可以说是非常重要的科学新闻，虽然关于成年神经干细胞，关于动物的神经元再生的证据已经有许多，但是对人类的脑神经细胞是否再生一直没有定论，现在的研究将给这一争论画上休止符。具体到人类脑细胞是否可以增值的研究可以追溯到1998年，但是一个瑞典研究小组给患者注射一种同位素药物，患者答应死后把脑组织捐献出来给该小组进行研究，研究结果发现，人类大脑海马组织内神经细胞会增值，后来发现这种药物有很大毒性，这一研究就没有再次开展。 1998 年后，人们用小鼠研究获得了同样的证据，但是由于没有其他实验室的佐证，科学家一直对这一说法表示异议。（也就是说，科学实验结果如果没有被其他实验室重复，一般不能被认可）。 这竟然是来自于人类核爆炸的恩赐，其实这本质上应该是监测手段敏感性的问题，核爆炸提供的是一种外标记的作用，如果掌握了非常灵敏的监测技术，即使不是核爆炸，自然界的同位素总是呈现规律性衰变，考古学早就用这类技术来研究化石的年代，不过那属于利用延长时间跨度来提高灵敏性而已。 大约10年前，瑞典卡罗林斯卡医学院的干细胞研究学者JonasFrisén采用无创伤碳14同位素示踪技术，这个技术是由她的学生Kirsty Spalding经过10多年的潜心攻关，终于实现的一个检测技术，攻克了一个科学难关。 虽然该技术过去曾经用于牙齿的研究，但用于DNA的研究没有先例，这真是具有巨大挑战性的工作。理论上，15个神经细胞上才可能有一个碳14的差异，所以必须有足够多的组织才能作出差异（听上去类似居里夫人的工作）。技术的关键就是必须提高检测的灵敏度。 开始的5年，他们的工作重点是如何把神经细胞从其他非神经细胞中分离出来，因为研究的目标是神经细胞，其他细胞早就证明可以再生，如果不分离，会产生巨大的干扰。他们采用萤光标记细胞分类方法（细胞分类识别并不难，但分离起来想想都吓人，所以用了5年），后面的5年重点是DNA的纯化和利用高能粒子加速器进行同位素检测。作者自己对这个过程的描述是We had many years without any results, Frisén says.It was fun, but frustrating. 经过多次失败，他们最终获得的数据，并证明 ，整个成年阶段，大约有三分之一以上的海马神经细胞经常性更新，海马内每天大约有1400个新的神经细胞产生。 . More than a third of hippocampal neurons were regularly replaced,with roughly 1400 new neurons added each day during adulthood , 这一精彩的研究真可谓“十年磨一剑” by Emily Underwood on 6 June 2013, 2:55 PM | 0 Comments Nuclear fallout. Radioactive carbon-14 atoms released by atomic bombs are helping scientistsdetermine the birthdays of new neurons in the hippocampus ( inset ). Credit: Spaldinget al., Cell (2013);(inset) Weissman, Livet, Sanes, and Lichtman/HarvardUniversity The mushroomclouds produced by more than 500 nuclear bomb tests during the Cold War mayhave had a silver lining, after all. More than 50 years later, scientists havefound a way to use radioactive carbon isotopes released into the atmosphere bynuclear testing to settle a long-standing debate in neuroscience: Does theadult human brain produce new neurons? After working to hone their techniquefor more than a decade, the researchers report that a small region of the humanbrain involved in memory makes new neurons throughout our lives—a continuousprocess of self-renewal that may aid learning. For a long time,scientific dogma held that our brains did not produce new neurons duringadulthood, says Pasko Rakic, a neuroscientist at Yale University who was notinvolved in the study. In 1998, however, a group of Swedish researchersreported the first evidence that neurons are continually born throughout thehuman lifespan. The researchers injected a compound normally used to labeltumor cell division into patients who had agreed to have their brains examinedafter death. When the scientists examined the postmortem brain tissue, theyfound that new neurons had indeed sprung forth during adulthood. The cells werelocated in a part of the hippocampus—a pair of seahorse-shaped structureslocated deep within the brain and involved in memory and learning. The compoundwas later found to be toxic, however, and the experiment was never repeated. Since 1998, anumber of studies have demonstrated that new neurons are generated in the samesmall region of the hippocampus in mice and appear to play an important role inmemory and learning, says Kirsty Spalding, a molecular biologist at theKarolinska Institute in Stockholm and lead author of the new study. Because the1998 work was never confirmed by independent research, however, scientists havefiercely argued over whether the neuron birth seen in mice also occurs inpeople. More than 10 yearsago, Spalding's adviser, Jonas Frisén, a stem cell researcher at the KarolinskaInstitute and study co-author, urged her to take on a project aimed at settling this debate by using an unconventional approach. The method, which has taken Spalding morethan a decade to develop, hinges on a massive pulse of radioactive carbon-14 isotopesreleased by nuclear explosions in the 1950s and '60s, which doubled the amountof carbon-14 in the atmosphere. This pulse stopped with the Limited Test BanTreaty of 1963, which banned aboveground tests of nuclear weapons, and theunstable carbon-14 isotopes have steadily decayed. Because cells incorporatecarbon from the atmosphere into their DNA as they divide, the proportion of carbon-14to the more stable carbon isotope carbon-12 acts as a time stamp for when acell was born. Spalding has beenusing this ratio to determine the age of teeth in forensic investigations andthe turnover rate of fat cells . But she had to improve the sensitivityof the technique so that it could detect the isotopic ratio in DNA from theroughly 6-gram sliver of neural tissue in the hippocampus thought to producenew neurons, the dentate gyrus. At best, the isotope is present in only one outof every 15 neurons, she says, making it difficult to detect in small amountsof tissue. For the first 5years, Spalding worked on finding an effective way of separating the roughly 20million neurons in the dentate gyrus from other types of hippocampal cells andthen extracting their DNA. Discovering that she could use afluorescence-activated cell sorting machine to distinguish non-neuronal cellsfrom neurons by making them glow in different colors was a highpoint, she says. The next 5 years were largely spent on finding ways topurify the DNA samples and extract and analyze the carbon atoms usinghigh-powered particle accelerators. We had many years without anyresults, Frisén says. It was fun, but frustrating. After finallygetting the technique down pat, Spalding decided that it was time to try it onsome real human brain tissue. She and her colleagues extracted hippocampi from 55 deceased people who had given informed consent tohave their brains studied. They then ground up the tissue samples, sorted thecells, and extracted the DNA. Next, she sent the purified genetic material tothe Lawrence Livermore National Laboratory in California, where it was reducedto pure carbon pellets and split into different carbon isotopes by weight in aparticle accelerator, allowing the researchers to calculate the ratio betweencarbon-12 and carbon-14. Spalding, Frisén,and colleagues then created a mathematical model estimating, based on thoseratios, the rate of cellular turnover within the hippocampal neurons. Morethan a third of hippocampal neurons were regularly replaced, with roughly 1400new neurons added each day during adulthood , they report onlinetoday in Cell . Some cells are dying, some are beingreplaced, Spaulding says. There is a constant flux of life anddeath. This is aspectacular independent confirmation of the 1998 study suggesting thatnew neurons are born during adulthood in the dentate gyrus, writes GerdKempermann, a neuroscientist at the German Center for NeurodegenerativeDiseases in Dresden, in an e-mail. It will likely settle the case. Kempermann saysthat his own and other's studies in mice indicate that fresh adult neurons havea specific function in the hippocampus—for example, in helping the braindistinguish between things that belong to the same category, or comparing newinformation to what it has already learned from experience. The ability todistinguish between the Beatles and Rolling Stones, yet still identify both asrock bands, is one example of this type of task in humans, Frisénsays. There is anotherpossibility, however: Our ability to replace hippocampal neurons could be anevolutionary vestige that is not all that important today, Rakic says. Heargues that human survival may have depended not so much on our ability toproduce new neurons, but on our ability to keep old ones in order to accumulatememories over the entire lifespan. Compared with fishes, frogs, reptiles, andbirds, some of which can regrow entire brain structures, he says, it isinteresting that neuronal turnover in humans is limited to a single populationof neurons in only one relatively small structure, and it is worthwhile toexamine why it persists.
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