Meeting Rita Levi-Montalcini

The NGF meeting, and indeed the neurotrophin field, could be attributed to one person: Rita Levi-Montalcini, an Italian neurobiologist who discovered nerve growth factor (NGF) in the 1950^th during her visit to Victor Hamburger’s lab at Washington University in St. Louis. She received Nobel Prize in 1986. I was a graduate student in Ira Black’s lab in New York at the time, and I was thrilled about the news, thinking that I was fortunate to be in such an important field. When I called Yi Rao to share the exciting feelings, he said, “it is too bad that you are working in a field that the Nobel Prize has already been given”. It is true that Nobel Prize has rarely been given to the same subject twice. There was another subtext in Yi’s comment: all the important discoveries have been made in the field. History has proven otherwise: there was an explosion of the field in the following years. Moses Chao led the wave by cloning of the first neurotrophin receptor p75. With the help of PCR technology, the groups led by Hans Pearson, Yves Barde, George Yancapoulos competed fiercely in the discoveries the entire family of neurotrophins (NGF, BDNF, NT-3 and NT-4/5). In the mean time, David Kaplan, Luis Parada, Mariano Barbacid were raising frantically in identifying the trk family of tyrosine kinases (TrkA, TrkB, TrkC) as the high affinity receptors for their respective neurotrophins. The field has never been short of dramas ever since. The gene knockout in mouse helped elucidates the functions of different neurotrophins and their respective receptors. Subsequent breakthroughs include the apoptotic function of p75; the receptor signaling mechanisms; the synaptic functions of BDNF; the biological function of pro-neurotrophins and their cleavage; the human polymorphism in BDNF that affects cognitive function and emotional behaviors; etc, etc. As years gone by, both Yi and I appreciated more and more that we are not working for the sake of winning prizes or recognitions, but for the “pleasure of finding things out” and the journey of pursuing truth.

My first encounter with Rita Levi-Montalcini was in 2002 at the NGF meeting in Modena, Italy. At 93, she looked fragile but still elegant. As the only living Italian Nobelist and the oldest in the Nobel history, Rita was a national treasure in Italy. She was surrounded by secretaries, assistants, and reporters anywhere she went. At the Gala dinner in a medieval castle in Bologna, I grabbed an opportunity to take a photo with this legendary person, thinking that this would be the last chance I would see her alive. She surprised everyone year after year. She was in the Leon meeting in 2006, and here again in Israel. It is a miracle that a 99-year old lady could walk around without help, attend a scientific meeting, and even give an opening remark that makes some sense: she showed a powerpoint slide!

My astonishments continued. Through chatting with her secretary, I learned that Rita was appointed as “Senator for Life” in the Italian Parliament in 2001. She attends sessions regularly. In bills related to science that were difficult to pass, her votes often tipped the balance in favor of science. I also learned that she still runs a research lab, with two current graduate students. This year is unseasonably hot in Israel, but one morning I saw that Rita was sitting in the grass surrounded by 5 female students. An Italian TV crew was filming a documentary on her life. I was speechless when Moses Chao pointed out the word “proNGF” in the title of a poster by her lab. She could even catch up the latest research!

On Tuesday I finally got an opportunity to speak to her. She asked me to sit next to her on a couch in the hotel lobby, and speak loudly to her (her hearing and vision are not very good anymore). “Do you know Moses Chao?” she asked. “Yes. Moses was on my Ph.D. thesis committee, and we knew each other very well for years”, I spoke to her ears. “He is a very nice man and an excellent scientist. He has made important discoveries. I am trying to nominate him for something, but don’t tell him about that”, she gave me a wink. She even has a sense of humor! “Where are you from?” she obviously did not remember me. “I am originally from China but now working at NIH”, I showed her my badge. “China is a great country. It is now rising and it will be good for science”. “Have you been to China?” I asked. “Yes, a long time ago. Now it is all different. Magnificent! Olympics!”. Now I know she is truly functional. “What are you working on?” she asked. “The role of BDNF in cognitive function and psychiatric diseases”, I said. “What?” “BDNF, memory and depression” I raised my voice. “That is very important field. Very important! I invite you to come to my Institute in Rome and give a lecture to our students”. I was truly flattered. How could I refuse such an honor? “Yes, I will come and visit you and your Institute next year”.

“We are all here because you created this field. We hope that you continue to live in a healthy and happy life”, I said. “I don’t care when I die”, she obvious knew what I was talking about, and took the point to elaborate. “It is the message that is important”, she said, with her finger pointing to the air. I know she meant “the legacy”. Indeed, she has left a great legacy: an entire field of science, an active group of scientists, and an interesting life that inspire generations of woman scientists. Her words resonated in my mind for a long time. I wonder how it feels like when one lives long enough to see his/her own legacy. When would one arrive to a state that he/she feels no fear to death anymore?

 长寿与影响，女科学家Rita Levi-Montalcini的传奇

今年六月，我去了赫尔辛基，参加两年一度的神经生长因子年会。这让我想起两年前在以色列召开的年会上遇见该领域鼻祖Rita Levi-Montalcini的往事。

神经营养因子研究领域，甚至整个神经科学，都不得不提到Rita Levi-Montalcini。19世纪50年代，这位来自意大利的神经生物学家在华盛顿大学圣路易斯分校做访问学者期间，发现神经生长因子(NGF)，由此开拓了一个新的研究领域。1986年，Rita Levi-Montalcini因为这一重要发现荣获诺贝尔奖。当时的我还是Ira Black实验室的一名研究生。消息传来，我非常振奋，深感自己幸运地选择了一个如此重要的研究领域。可是当我将内心的喜悦与饶毅（当时在华盛顿大学圣路易斯分校读研究生）分享时，他却回答道：“很不幸，你进入的领域，再没有诺贝尔奖可得。”  的确，诺贝尔奖很少两次授予同一个研究方向。同时，我也明白饶毅的弦外之音：神经科学领域的这一重要研究命题也许很难得到突破。 然而，我相信历史将会证明故事远未结束，下一轮如火如荼的研究即将拉开序幕。 果然，康奈尔大学医学院的Moses Chao于1988年因成功克隆第一个神经营养因子受体而引领这一研究热潮，紧随其后，借助于PCR技术的兴起，Hans Pearson, Yves Barde, George Yancapoulos等研究小组在整个神经营养因子基因家族 (NGF, BDNF, NT-3 and NT-4/5) 的鉴定上展开了激烈的竞争。几乎同时，David Kaplan, Luis Parada, Mariano Barbacid等研究小组在神经营养因子高亲和力受体--trk 酪氨酸激酶基因家族 (TrkA, TrkB, TrkC)的鉴定上也展开了疯狂的竞争。自此，这一研究舞台高潮迭起，一幕接一幕，让人眼花缭乱。 基因敲除小鼠帮助阐明不同神经因子功能及其特异性受体。随后一系列突破包括p75的细胞凋亡功能；受体信号转导机制；BDNF的突触功能；神经营养因子前体生物学功能及其剪切机制；影响人认知功能和情绪行为的BDNF基因多态性等等。 随着时间推移，饶毅和我也越来越意识到，我们的工作并不为赢得奖励与认可，而是为了探究真理的快乐。

我第一次见到Rita Levi-Montalcini是在2002年，当年的神经生长因子年会在意大利摩德纳举行。93岁高龄的她看起来身体虚弱但举止依然优雅，作为诺贝尔奖历史上最高龄的获奖者，同时也是唯一一名在世的意大利籍获奖者，Rita被意大利尊为国宝。无论她走到何处，身边都围绕着秘书、助理和记者。在博洛尼亚一座中世纪的城堡里举行的晚宴上，我抓住机会与这位传奇人物合了一张影，心想这也许是与她在世时的最后一次见面了。 但一年年过去，她的生命力让每个人为之惊讶。 2006年她参加于里昂举行的年会。而这次在以色列举行的年会上也同样看到她的身影。对于一位99岁高龄的老妇人，能无需搀扶行走自如，并且参加学术会议用ppt做开场讲话，真是一个奇迹。2008年的夏天，Rita再一次参加于以色列举行的神经生长因子年会。

让我惊讶的事情远不止这些。通过与Rita的秘书交谈，我得知自2001年意大利议会任命她为“终身议员”以来，Rita一直定期与会，在一些关于科学的较难通过的议案上，她的一票能决定性地引导投票结果向利于科学的方向倾斜。同时我还了解到，Rita的一个实验室现在还在运行，并有两名在读研究生。2008年的夏天，以色列异常炎热，但一天清晨我却看到Rita与5名女学生围坐在草坪上。意大利的一家电视台正在拍摄Rita的生活纪录片。当今该领域最前沿的课题之一是“神经生长因子前体”。 当Moses Chao向我指出Rita实验室海报标题中出现的“proNGF”( 神经生长因子前体的一种）时，我不禁目瞪口呆，现在的她甚至还能跟踪最新的研究进展。

周二那天，在饭店的前厅我终于有机会和她交谈了。她让我坐在她的身旁，跟她交谈时声音大一点（因为她的听力和视力不太好了）。她问我：“你认识Moses Chao吗？”我答道：“认识，Moses是我邀请的博士论文答辩委员会的委员，我们已经相识很多年了。”  “他人非常好，也是一个非常出色的科学家，他做出了很多重要的发现。我正在设法给他某项大奖提名，但是千万别告诉他。” 她给了我一个眼色。她还拥有幽默感！她问我：“你是哪里人？”显然她已经不记得我了。“我来自中国，现在在美国国立卫生研究院工作。”  我给她看我的姓名牌。“中国是一个伟大的国家，现在正在崛起，这对世界科学的发展将非常有益。”，她说。 我问她：“你去过中国吗？”  “去过，不过那是很久以前的事了。 现在一切都发生了翻天覆地的变化，到处都恢宏壮丽，奥林匹克运动会也在中国举行。”  她接着问我：“你的研究方向是什么？”我告诉她：“我的研究方向是脑衍化神经营养因子（BDNF）在认知功能和精神病中的作用。”  “什么？”她没有听清楚。 “脑衍化神经营养因子（BDNF），记忆力，抑郁症。”我提高了声音。“这是一个非常重要的领域，非常非常重要。我想邀请你去罗马，给我们研究所的学生和科学家们做一个讲座。”  我真是受宠若惊。我怎能拒绝这样的荣誉？ “好的，我明年就来拜访你和你们研究所”。

 “正因你开创了这一研究领域，我们才能来到这里就研究进展进行交流切磋。我们衷心希望你能一直健康快乐地生活，”我对Rita说。“我不在乎自己究竟还能活多久”，显然，她明白了我的意思，并且想就这一话题继续深入。 “能为世界留下什么才是最重要的”，她一边说着，将手指指向天空。 的确，她已留下了一笔丰厚的宝藏——整个神经生长因子研究领域、一群活跃的科学家、以及她那激励着无数女科学家和年轻人的传奇人生。很长一段时间里，她的话一直萦绕在我的脑海中。我想象，当一个足够长寿的人见证自己留下的东西对后世的影响，那将是一种怎样的感觉？一个人又在什么时候才能达到不畏生死的境界？（谢文兵/译）