26歲一年4篇Cell！他的經驗發表在IF36.13期刊上

「他創造了世界記錄：一年內作為第一作者發4篇Cell論文，迄今無人能夠打破。」

「他研究生期間共發表12篇第一作者的實驗論文，相當於一般好幾個研究生。」

「他的論文解決了一個重要問題，將研究推到新層次。」

首都醫科大學校長饒毅曾如此評價Ron Vale。因為Ron Vale在研究生時期和其導師 Mike Sheetz、Jim Spudich等在闡明生命分子運動機制方面的做出的奠定性貢獻，他們也因此一起成為諾貝爾獎的熱門候選人。2012年 ，三人共同獲得了拉斯克基礎醫學研究獎。獲獎後，在獲獎感言中，Ron Vale總結了他認為非常重要的博士研究生做科研的「TOP-Ten lessons 」發表在了Nature Medicine （IF=36）雜誌上，分享給大家。

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Ronald D Vale

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PhD，UCSF Professor，HHMI Investigator

Ronald D Vale教授 1959 年出生在美國加州好萊塢。21 歲畢業於加州大學聖塔芭芭拉分校，專業生物和化學。之後在史丹福大學念雙博士（哲學博士-醫學博士），在26 歲獲神經生物學哲學博士。因為他的研究生記錄太好，他就只要哲學博士，不要醫學博士。 27 歲成為助理教授，35 歲做正教授，42 歲當選美國科學院院士。美國藝術與科學學院院士以及美國國家科學院院士雙料院士。自 1995 年以來，一直擔任霍華德·休斯醫學研究所研究員。也是諾貝爾獎熱門人選。

1985 年，在Sheetz和Reese實驗室，年僅26 歲的Ron Vale，一年內發表了 5 篇 Cell ，其中 4 篇是第一作者，記錄保持至今，未被打破。

2006年，Ron Vale 教授創建了影響巨大的生物醫學學術視頻網站iBiology。2011年，iBiology合作網站-iBioChina開通，Ron Vale教授專門錄製了演講視頻表示祝賀。在視頻中，他特意選用了中國的平遙古城作為背景，表達了自己因事未能出席開通儀式的遺憾。

2012年 ，他和麥可·希茨和詹姆斯·斯普迪赫共同獲拉斯克基礎醫學研究獎。獲獎後，更是把他的獲獎感言：自己的求學經歷和總結的十條科研經驗（top-ten list ）發表在了Nature Medicine 雜誌上，題為：How lucky can one be? A perspective from a young scientist at the right place at the right time，以下為文中 Ten lessons 中文譯文及英文原文，分享給大家。

以下是我從之前的經歷中學到的最重要的10件事，其中大部分是事後才發現的。我沉醉在科學中，經常犯錯誤，也常常從錯誤中吸取教訓，但我幾乎不知道這會把我帶向何方，也不知道我最終會以什麼方式出現。我不知道科學將把我帶向何處，也沒想過最終能取得什麼成就。

Here is my top-ten list of what I learned from this experience, most which only became obvi-ous in retrospect. I was immersed in the sci-ence, making and sometimes learning from mistakes and having very little idea of where it would all lead and how or where I would emerge at the end.

——Ron Vale

TOP-Ten lessons

01

找到好導師，

學習他們然後發展出自己的風格

Find good mentors,

learn from them and then develop your own style.

三人行，必有我師。科學既是一個實驗過程，也是一個處理問題的哲學、個人研究風格和與他人合作本身就是一個實驗的過程。作為一名年輕的科學家，你要接觸不同的科研方法，從資深的前輩科學家那裡汲取思想和治學態度，加以消化吸收，最終沉澱出最適合自己的一種風格，這會讓你具有你所欽佩的人的氣質特徵。對他人不卑不亢，既不盲目崇拜也不輕蔑輕視。我很幸運，遇到了很多偉大的導師，其中包括Bruce Schnapp, Tom Reese, Mike Sheetz和Jim Spudich的核心團體。他們每個人都有獨特的個性和科研方法，這讓我受益匪淺。但他們有一個共同點：都非常友善，把我當做一個年輕的科學家來支持。我研究生時還遇到其他的貴人：首先是我的導師Eric Shooter。想想，有幾位論文導師能由著他的研究生游離在導師的課題之外，做一些與實驗室工作無關的事？而且任由其對學分一點都不上心？那個時候，我還沒有完全意識到，和其他許多科學家相比，Eric對他的實驗室「家庭」是多麼的無私。在MBL，我還遇到了Shinya Inoue和Andrew Szent-Gyorgyi等活躍的老科學家。他們在Woods Hole的冬季收留了我這個從西海岸來的孩子，他們的實驗室小而專一（不同於斯坦福的大型實驗室），他們熱愛生活，熱愛科研，實現生活和科研的完美統一，不偏廢其一。

Soak up your surroundings. Science is as much about philosophies of approaching problems, personal styles of research and working with others as the process of experimentation itself. As a young scientist, you need to be exposed to different ways of doing science, absorbing the ideas and attitudes of more senior scientists.The net result is a maturation of a hybrid style that best suits you and is a composite of the characteristics that you admire in different individuals. Neither idolize nor ignore anyone. I was fortunate to have many great mentors, which included the core group of Bruce Schnapp, Tom Reese, Mike Sheetz and Jim Spudich. I gained tremendously from their unique personalities and scientific approaches. But they all shared one thing in common—they were incredibly kind and supportive of me as a young scientist. I had additional heroes in graduate school. First was my wonderful advisor, Eric Shooter. How many thesis advisors would let their graduate student wander off quite a distance to work on a project unrelated to his or her own lab’s work and without any thought of gaining credit for something that might emerge? I did not completely appreci-ate at the time how different Eric s unselfishattitude about his lab family is from that ofmany scientists. I also met lively older scien-tists at the MBL-Shinya Inoue and Andrew Szent-Gyorgyi who adopted this kid from the West Coast during the Woods Hole winter.They had small and focused labs (unlike the generally larger labs at Stanford) and merged alove of life and a love of science without com-promising either.

02

選擇一個重要的問題

Pick an important problem.

每個人都一樣，都喜歡去解決有趣的，令人著迷的問題，而不喜歡沉悶無聊的問題。但是，確定一個既重要又亟需解決的選題並非易事。況且，我們還必須在規定的時間節點內完成對應的結果，才能獲得學位、工作或者資助。這使得我們中的大部分人在大多數時間裡，精力並不是專注於生物學中的大問題上。但是，如果你想不一樣，在一些重要問題上，你必須實時跟進，時刻保持警惕，比別人多思考一點，哪怕超出了你的研究範圍或你的專長，從而找到一個重大問題的突破口。如果機會來了（見下一建議），千萬別錯過，抓住它。在大多數情況下，如果你一時候沒能提出一個重要的問題，你基本不可能做出重大成果。

Everyone would rather solve a fascinating problem than a boring one. However, it is not easy to identify a project that is both important and ripe forsolving. Furthermore, pragmatics dictate get-ting results in a defined time period in order to obtain a degree, job or grant. As a result, most of us are not always working on grand issues in biology all of the time, However, you should be vigilant and thoughtful, loking for a wedge or an opening to tackle an important problem, even if it is not in your area of research or expertise. If the opportunity comes along (see next point), seize it. In most cases, you cannot make an important discovery if you are not asking an important question from the start.

3

奮力領先，勇於冒險，敢於放手一搏

Get ahead but then take a chance: seek adventure

在Eric Shooter實驗室的頭兩三年裡，我發表了幾篇很紮實但並不出色的論文，但我知道，這些論文已足以讓我拿到博士學位。有了這個安全保障，我就有可以自由的去尋找並拿下一個重大但有風險的項目了。隨著對Sheetz/Spudich試驗不斷的接觸，我的機會來了。從我最後一刻決定去Woods Hole開始，軸突運輸項目對我來說整個就是一場冒險。當把科學當做一場偉大的冒險，整個事情就變得有趣了，無論是你的科學成果還是你的個人事業，會有很多意想不到的事情發生。

In my first two to three years in Eric Shooter s lab, I published a couple of papers that were solid but not outstanding, but I knew that they were sufficient to get a PhD.With that safety net, I had the freedom to lookfor and take on an important but risky project.That opportunity came along with the chance to build upon the Sheetz/Spudich experiment.The whole axonal transport project was an adventure, beginning with a relatively last minute decision to go to Woods Hole. Thinking of science as a grand adventure makes it fun and allows unexpected things to happen, interms of both scientific outcomes and your personal career,

4

讀文獻很重要，但不要讓它成為你的束縛

Read the literature but don’t be crippled by it

進入一個新領域，因為其悠久的歷史和大量的研究文獻，難免會讓人顯得底氣不足，畏手畏腳。這時你必須對先前的工作有一定的了解，但一定要避免陷於各種各樣先前試驗，掉入按照既有模型進行思考的陷阱。新鮮的視角，和一點很傻很天真的童心會很有用。我剛接觸這個領域時，當時軸突的快速運輸文獻已經很多，但其機理尚不清楚。然而，Allen，Brady和Lasek視頻顯微鏡研究成了關鍵的轉折點，因為它們提供了一種成像小運動囊泡的新方法。未來，通過生物化學來建立這種方法變得可行了，而在此之前，藥理學主導了整個工作。

It can be daunting to enter a new field because of its considerable history and litera-ture. You have to be knowledgeable about prior work, but it is also good to avoid getting caught in the trap of doing variations of prior experi-ments and thinking along the lines of existing models. Fresh eyes and some naïveté can be a good thing. Fast axonal transport at the time had a long literature but relatively little clar-ity on the mechanism. The Allen, Brady and Lasek video microscopy studies, however, were a turning point because they provided a new way to image small moving vesicles . Going forward, it made sense to build upon that method by doing biochemistry and not stick-ing to pharmacology, which had dominated work in the past.

5

出好成果不一定要有頂級實驗室

You don’t need a fancy lab to do good science

我的實驗室在史丹福大學的一個相對較新的大樓中，它有些陳舊卻井然有序。而位於海洋生物實驗室中的Tom Reese的研究室則相對較亂，在Loeb大樓的地下室的一個小房間中，只有一臺化學試劑單放機和一些鋪滿設備間的小設備。我們在被海水燻的潮溼的地下室房間中解剖烏賊巨軸突。我們戲稱這個小房間為「海王星的洞穴」。但是這一切都沒有產生負面影響，相反，與那些在現代大樓中流行的井然有序卻單調的實驗室相比，這個實驗室讓人耳目一新。Tom的實驗室有符合目前水平滿足基本工作需要的設備-------視頻燈和電子顯微鏡。但是在對驅動蛋白提純的初始階段，我們樓裡沒有離心機，所以我們不得不到馬路對面的樓中去進行這一步，那時也沒有色譜分析設備。但是，一個人可以適應任何環境然後使其正常運轉。這也是科學探險一部分。

I came from a pristine, well-organized laboratory in a relatively new building at Stanford. Tom Reese’s lab at the Marine Biology Laboratory, in contrast, was a chaotic rabbit warren of small rooms in the basement of the Loeb building, with a monolayer of chemical reagents and small equipment covering most of the available bench space. We dissected squid giant axons in a wet and dank seawater room in the basement, which we called 『Neptune’s cave』. But none of this mattered, and it was a refreshing change from the well-organized rows of monotonous lab benches that popu-late most modern research buildings. Tom’s lab had state-of-the-art equipment that proved essential for the work—video light and electron microscopy. But at the start of the kinesin puri-fication, there was no centrifuge in the building(we had to go to a building across the street)and no chromatography equipment (we ini-tially used syringes with glass wool). One can adapt to any surroundings and make things work. This also adds to the scientific adventure.

6

玩命工作，盡情玩耍

Work hard, play hard and squeeze in time to do your laundry.

科學不是朝九晚五的工作。在Wood Hole時，我工作異常努力。1984年的整個冬季，我幾乎都在工作（Woods Hole的冬天本來也沒啥可幹，所以我也沒有多大損失）。攻堅時刻需要加倍的努力，我很高興，在關鍵時刻我花了儘可能多的時間在實驗室，見證了科學奇蹟的發生。但是，在接下來的春天，我需要離開一段時間來調整狀態，所以我騎車遊行了歐洲。在到UCSF工作前，我還在尼泊爾和日本玩了四個月。科研關鍵時刻的攻堅十分重要，就如同打仗時攻克關鍵要塞。但與此同時，你也必須花時間來平衡你的生活。

Science is not a9-to-5 job. I worked very hard on the projects at Woods Hole; during the winter of 1984, I pretty much only worked (there was not a lot to do during the winter at Woods Hole, so I was not missing much). Special times require special effort, and I was incredibly happy spending as much time as I could in the lab and seeing the science come together. But later in the fol-lowing spring, I needed time off and went on a long bike trip in Europe. I also spent four months in Nepal and Japan before starting my job at UCSF. It is crucial to push a project hard at some points, but you also must make time to balance your life.

7

堅持比才華更重要

Persistence is more important than brilliance

如果你不是天生聰慧（就像我），只要你能堅持，一樣可以在實驗科學中做的很好。反過來就很難說。舉個例子，在1984年夏天的大部分時間裡，因為一系列的實驗失誤，我未能在體外重建軸突運輸。眼看夏天就要結束，我馬上就要離開，開始我的見習醫生生涯。關鍵時刻，實驗卻毫無進展，或許這時，該去休息，去海邊的沙灘放鬆放鬆。但我並沒有這樣做，這也許是我在kinesin的故事中，唯一值得讚揚的地方。在我回到斯坦福之前，我近乎執拗的堅持完成這個實驗。接著，在度過了神奇的一周後，一個見證奇蹟的夜晚降臨，一切都是那麼的順理成章。於是，我取消了我的返程航班。

If you are not naturally brilliant (my case), you can still do well in experimental science if you are persistent. The converse is harder. As an example, for much of the summer of 1984, I failed to reconstitute axonal transport in vitro, mostly owing to a series of experimental mistakes. The summer was drawing to a close and I was soon off to start my medical clerkships. With no success up until that point,it might have been a juncture at which to relax and spend time at the beach. Perhaps the only point to my credit in the kinesin story is that I did not take this path. I was dogmatic about giving this experiment my best shot before returning to Stanford. Then, one magical night followed by one magical week, everything came together. I cancelled my return flight.

8

誰都會犯錯

No project or career is immune from mistakes

儘管1983 - 1985年期間取得了成功，但它在科學上並不像看上去的那麼完美。我們犯了一些概念上的錯誤和技術上的錯誤。幸運的是，這些錯誤並不致命，沒有讓我們偏離正確的軌道太遠以致脫軌。這或許對那些課題不是一帆風順的同學是一個安慰；時時的困惑，懷疑，對任何課題來說，都再正常不過了。同時，你也會錯過很多機會。那時，我們指出「溶液中的微管之間也相互作用，形成一個收縮的微管聚合門」8（現代術語：一個『aster』）這個論點，但是我們並沒有就此研究下去。運動蛋白對微管的自組織作用後來成為一個重要的研究領域。在美國國立研究院對我的第一次資助中，我還想以「存儲」逆行軸突運輸的純化（像是一種叫做HMW 1的atp酶），作為我獲得NIH資助的第一個項目，事實證明這並不是一個明智的決定。職業生涯的每一步都不可避免的混雜著不良決策和英明決策，你只要保持後者比前者多就行了。

As successful as the 1983–1985period was, it was not as scientifically perfect as it may appear. We took some conceptual wrong turns and made technical mistakes. We were fortunate that they did not derail us too far off the track. Perhaps this will be comforting to stu-dents whose projects may not be going forward in a straight line; moments of confusion and doubt are typical for any project. There were also plenty of missed opportunities. We noted that 「microtubules in solution also moved rela-tive to one another to form a contracted aggre-gate of microtubule」 8 (in modern terms, an『aster』) but did not pursue it. Self-organization of microtubules by motor proteins later became an important area of research. I also thought to 『save』 the purification of the retrograde axonal motor (most likely the ATPase called HMW 1 ) 8,9 for an aim in my first NIH grant,which turned out not to be a sensible decision,as I was scooped before I had the chance to do it. Every career is marked by poor and by good decisions; you just have to try to keep the score-card favoring the latter category.

9

莫對改變人生計劃感到惶恐

Don’t be afraid to change your life plans.

我二十歲和三十多歲早期時的人生是被規劃好的。MD-PhD項目後，最大可能是去醫院實習，然後跟大部分人一樣成為一名住院醫師，然後再回到科學領域。然而，Woods Hole的出現改變了我的人生規劃。回到醫學院？從我現在的觀點來看，答案當然是否定的。但是那時，其他人會怎麼說呢？我的導師鼓勵我繼續堅持自己的課題並延遲醫學實習；很顯然，我的心思一直在科學上，科學生涯將使我感到快樂。許多年後，單核馬達對醫學產生了影響使我感到極其滿意，同時，針對這種蛋白的藥物也正在研發中也是我倍感欣慰。

My twenties and early thirties could have been on autopilot—an MD-PhD program most likely followed by an internship and residency and a later return to science. However, the in vitro motility assays from Woods Hole threw a wrench into that plan. Return to medical school? Certainly not now from my point of view, but what would others say? My mentors encouraged me to stick with the project and defer my clerkships; Stanford Medical School was incredibly supportive, as well. I never returned to medicine; it became abundantly apparent that my heart was in science and that a scientific career would keep me happy. Many years later, it is gratifying to me that molecular motors are having an impact on medicine and that drugs are being developed that target these proteins.

10

科學發展太快：要堅持做時代的弄潮兒

Science is moving fast: hold on and enjoy the ride.

作為研究發現的親歷者是非常棒的感覺。但更大的樂趣是，你正在科學的大舞臺上，親眼目睹著科學作為一個整體所取得的驚人進步。科學家是非常幸運的，因為我們能站在世界的前沿，是巨大進步的見證者。科學冒險有許多形式，在實驗室的任何一天都有可能「擁抱」微小卻美妙的發現。在未來的某一天，某個巨大的驚喜最終到來。永遠相信美好的事情即將發生。

It is nice to make your own discovery. But there is also great pleasure in having a seat in the big scientific arena and watching the amazing progress that is taking place overall. As an illustration, I was capti-vated by watching kinesin move vesicles or plastic beads, but it seemed hard to imagine in1984 how one would be able to understand the detailed inner workings of a motor so small. At that time, I could not envision the many new tools that would come along (single-molecule techniques, better structural methods, genomic studies of a multitude of kinesins) and the ideas contributed by the many people who would enter the field. In the subsequent two decades,we know of many kinesins and the many roles they play and have reasonable ideas of how they produce motion. This incredible progress is being played out in all areas of the life sci-ences, and we scientists are fortunate to have a front-row seat and witness the tremendous advances that are taking place.

附：

1985年他在Sheetz和Reese實驗室發表的五篇《Cell》，其中 4 篇他是第一作者：

[1] Vale, R.D., Schnapp, B.J., Sheetz, M.P. and Reese, T.S. (1985) Movement of organelles along filaments dissociated from the axoplasm of the squid giant axon. Cell 40: 449-454.

[2] Schnapp, B.J., Vale, R.D., Sheetz, M.P. and Reese, T.S. (1985) Single microtubules from squid axoplasm support bidirectional movement of organelles. Cell 40: 455-462.

[3] Vale, R.D., Schnapp, B.J., Reese, T.S. and Sheetz, M.P. (1985) Organelle, bead and microtubule translocations promoted by soluble factors form the squid giant axon. Cell 40: 559-569.

[4] Vale, R.D., Reese, T.S. and Sheetz, M.P. (1985) Identification of a novel force generating protein, kinesin, involved in microtubule-based motility. Cell 42: 39-50.

[5] Vale, R.D., Schnapp, B.J., Mitchison, T., Steuer, E., Reese, T.S. and Sheetz, M.P. (1985) Different axoplasmic proteins generate movement in opposite directions along microtubules in vitro. Cell 43: 623-632.

研究生期間，在史丹福大學 Eric Shooter 實驗室的另外 8 篇第一作者研究論文：

[1] Vale, R.D., DeLean, A., Lefkowitz, R.J. and Stadel, J.M. (1982) Regulation of insulin receptors in frog erythrocytes by insulin and concanavalin A: evidence for discrete classes of insulin binding sites. Mol. Pharm. 22: 6 19-629.

[2] Vale, R.D. and Shooter, E.M. (1983) Conversion of nerve growth factor receptor complexes to a slowly dissociating, Triton X-100 insoluble state by anti-nerve growth factor antibodies. Biochem. 22: 5022-5028.

[3] Vale, R.D. and Shooter, E.M. (1983) Epidermal growth factor receptors on PC12 cells: alteration of binding properties by lectins. J. Cell. Biochem. 22: 99-109.

[4] Vale, R.D., Peterson, S.W., Matiuck, N.V. and Fox, C.F. (1984) Purified plasma membranes inhibit polypeptide-induced DNA synthesis in subconfluent 3T3 cells. J. Cell Biol.

[5] Vale, R.D., Szent-Györygi, A. and Sheetz, M.P. (1984) Movement of scallop myosin on Nitella actin filaments: regulation by calcium. Proc. Natl. Acad. Sci. USA

[6] Vale, R.D., Hosang, M. and Shooter, E.M. (1985). Sialic acid residues on NGF receptors on PC12 cells. Dev. Neurosci.

[7] Vale, R.D., Ignatius, M.J. and Shooter, E.M. (1985) Association of nerve growth factor receptors with the Triton X-100 cytoskeleton of PC12 cells. J. Neurosci. 5: 2762-2770.

1996年，他與 Fletterick 合作，首次解析了 kinesin 的結構：

Kull, F.J., Sablin, P., Lau, R., Fletterick, R.J. and Vale, R.D. (1996) Crystal structure of the kinesin motor domain reveals a structural similarity to myosin. Nature 380: 550-555.

1996年，已經是正教授的他，自己做實驗首先直接看到 kinesin 單分子運動：

Vale, R.D., Funatsu, T., Pierce, D.W., Romberg, L., Harada, Y. and Yanagida, T. (1996) Direct observation of single kinesin molecules moving along microtubules by fluorescence microscopy. Nature 380: 451-453.

參考文獻：https://www.nature.com/articles/nm.2925。來源：科研大匠、Nature Medicine 、科普中國、,生物谷等