上善若水

grant writing

lxliuxi — Tue, 19 Oct 2010 19:22:10 +0000

A typical hypothesis driven grant in bio-med field.

Hypothesis:

Hypothesis in a grant is a big question whose answer can raise more interesting and meaningful question. The answer to a hypothesis should not be “yes” or “no”. A good hypothesis should be a key question in a field and worth of study for many years. A hypothesis should not be answered by a single grant.

Specific Aims

Usually specific aim is the most difficult part of a grant. A specific aim is a specific question, whose answer is important to the hypothesis. Or you can regard a specific aim as a solid step toward your hypothesis. Aim 1 to Aim 2 (to Aim 3) should have a logic flow. Aim 1 should contribute to Specific Aim 2, but Aim 2 should not depend on the completion of Aim 1.

Experimental design

Definitive experiment: each experiment must answer a specific question clearly.

Control group is more important than experimental group. Positive ctrl, negative ctrl, technical ctrl and other control should be considered.

Multiple approaches should be applied to answer a question. For example, if you want to show that protein A binds to protein B and induce downstream effect, genetic approach, biochemical approach, pharmacological approach and others should considered.

Rescue experiment: try to use rescue experiment for each question.

Alternative Approaches

Always consider what if a technique or experiment does not work, for technical or biological reasons.

I will put down more when they come up to my mind.

常识

lxliuxi — Thu, 07 Oct 2010 16:29:54 +0000

Scientific conclusions derive from an understanding of basiclaws supported by laboratory experiments, observations of nature,and mathematical and computer modeling. Like all human beings,scientists make mistakes, but the scientific process is designedto find and correct them. This process is inherently adversarial—scientistsbuild reputations and gain recognition not only for supportingconventional wisdom, but even more so for demonstrating thatthe scientific consensus is wrong and that there is a betterexplanation. That’s what Galileo, Pasteur, Darwin, and Einsteindid. But when some conclusions have been thoroughly and deeplytested, questioned, and examined, they gain the status of “well-establishedtheories” and are often spoken of as “facts.”

For instance, there is compelling scientific evidence that ourplanet is about 4.5 billion years old (the theory of the originof Earth), that our universe was born from a single event about14 billion years ago (the Big Bang theory), and that today’sorganisms evolved from ones living in the past (the theory ofevolution). Even as these are overwhelmingly accepted by thescientific community, fame still awaits anyone who could showthese theories to be wrong.

5月7日的Science发表了一篇很多科学家签名的呼吁, 说的是人类活动导致全球变暖的事实和停止政治对科学研究的干扰. 我的知识不足以对全球变暖做任何评论, 但是那个呼吁中间有两段话写得太好了, 适用于任何以事实为基础的领域, 深合我意啊. 我用中文写出来, 顺便把原文贴在下面. 如果有什么不通顺的地方, 敬请纠正.

“科学结论是由实验, 对自然的观察, 数学和计算机模型所支持的基本规律得出的. 科学家也是人, 也会得出错误的结论, 但科学的过程可以找出并且纠正这些错误. 这一科学的过程本质上是用来纠错的—-相对于验证已有知识来说, 发现旧理论的错误并且提供更好的解释为科学家赢得更大的声誉. 伽利略, 巴斯德, 达尔文和爱因斯坦都是如此. 当一些科学结论被广泛深入地检验, 质疑和验证过之后, 通常可以成为”被承认的理论”, 或者称为”事实”.

比如, 大量的事实表明地球的年龄大约45亿年(地球起源理论), 宇宙大约140亿年前由单一事件产生(大爆炸理论), 目前的物种都是由过去的物种演变/演化而来(进化论). 即使数不清的事实确认上述这些理论的正确性, 谁能证实它们是错的还是能获得巨大的声誉.“

以上是引用部分. 以后, 如果那些缺乏逻辑或者常识的人要来跟我辩论那些基本的科学常识, 我就引用这段话.

John Cleese’s Wine for the Confused

lxliuxi — Thu, 15 Apr 2010 02:15:52 +0000

向各位推荐这部电影John Cleese’s Wine for the Confused, 其实是一个很通俗的葡萄酒的介绍片, 挺有意思的. 主持人John Cleese是个演员/剧作家. 他在片子里面找来一帮朋友聚会喝葡萄酒, 让大家在不看到酒瓶标签的情况下给酒评分, 结果大家的评分跟酒的价钱毫无关联. 这是他要说的最重要的观点之一(我非常同意): 喝你喜欢喝的, 不要让别人告诉你该喝什么.

这部片子没有什么专业术语, 都是从一个普通人的角度来讲的, 包括葡萄酒的基本介绍, 怎么购买, 价钱并不意味好坏, 等等. 中间有一段主持人采访一个卖酒商店的老板, 老板介绍说, 有个牌子的酒一瓶$27, 但酒庄为了挣更多钱又不想降价(降低品牌价格), 就创造了第二个品牌, 同样的葡萄和酿造过程, 价格$15. 绝大部分人根本尝不出来. 主持人还故意搞错cheap和inexpensive这两个词, 然后纠正……

就好象大多数号称专业的发烧友不能准确区别mp3和CD (参考德国人的双盲测试)一样, 大部分人根本就不用理会那些酿酒业的昂贵的噱头. 几年前我和老婆拜访张天福老先生, 问他:”你觉得什么茶最好?”, 他泡了几种茶让我们喝,问我们喜欢哪个, 然后说, 你喝着最爽的就是最适合你的茶, 不要去理会那些几千块一斤的噱头. 这话他说大家都服; 如果我说, 估计就是无知者无畏.

Michael Sandel: Justice, what’s the right thing to do?

lxliuxi — Tue, 13 Apr 2010 05:34:28 +0000

最近在网上看了Michael Sandel给本科生上的一个公共课, 课名就叫Justice, what’s the right thing to do? 可以在各个视频网站上搜索一下, 或者查http://justiceharvard.org/这门课本质上讲的是政治哲学的原理, 但不是专业课, 从一些著名的案例/事例/道德困境开始讨论, 学生的辩论中有很多火花; 而Sandel总能把握住课程的主线. 从功利主义, 自由主义, 到现代的正义论等等, 讨论了很多重要的概念. 如果你爱思考, 就一定会有收获. 我常常听到Sandel提问, 在学生开始讨论前, 我先暂停, 自己想想, 然后看看学生们的看法.

我最大的收获是: 解决了一些我过去一直困惑的问题(不好意思, 我不是学这个的), 同时带来更多的困惑. 指望上一门课就真正理解政治哲学是不现实的(我还是不理解), 但重要的是让自己更深入思考, 更广泛的质疑. 很多人觉得哲学是高深的学问, 其实要看你怎么看待它. 大学毕业之后, 我觉得我似乎更会跟人打交道, 但思考的勇气少了很多, 思维变得比较平庸. 我很羡慕那些学生在课堂上可以从任何角度争论一个问题, 不必担心政治上正确与否.

在课程一开始和结束的时候, Michael Sandel说: When we first came together some 13 weeks ago, I spoke of the exhilaration of political philosophy, and also its dangers. But how philosophy works, and it has always worked, by estranging us from the familiar, by unsettling our settled sumptions. I tried to warn you that once the familiar turns strange, once we begin to reflect our circumstance, it is never quite the same again. I hope you have by now experienced at least a little of this unease, because this is the tension that animates the critical reflection and political improvement and maybe even the moral life as well. And so our arguments come to an end in a sense but in another sense goes on. Why we ask the outset, why do these argument keep going, even if they raise questions that are impossible ever finely to resolve? The reason is that we live answer to these questions all the time. And in our public lives and in our personal lives philosophy is inescapable even if sometimes it seems impossible. We began with the thought of Kant that skepticism is the resting place for human reason, where can reflect upon its dogmatic wanderings, but it is no dwelling place for permanent settlement. To allow ourselves to simply quiescence skepticism or to complacent, Kant wrote, can never suffice to overcome the restlessness of reason. The aim of this course has been to awaken the restlessness of reason and to see where I am lead. And if we have done at least that and if the restlessness continue to afflict you in the days and years to come then we together have achieved no small thing. (这一段是听的, 如果写错了, 请纠正)

顺便贴几个他一开始提的问题:

1. Do we have some fundamental rights?

2. Does a faire procedure justify any result?

3. What is moral work of consent?

康德说, 有两件事物越思考就越觉得震撼与敬畏，那便是我头上的星空和我心中的道德准则. 我想说, 那些伟大的哲学家总令我敬佩, 虽然我不理解他们的理论. 我们科学家总可以做实验来验证, 但哲学家不能做实验验证自己的理论, 只能靠讨论和思考.

什么是邪教

lxliuxi — Thu, 24 Dec 2009 03:39:23 +0000

我知道这个写出来肯定争议很大, 不过这个问题我想了很久, 还是决定贴出来.

要给邪教下个定义是很难的事, 但还是有一些准则的. 我比较倾向于从宗教本身的特点着手.

首先, 看现在不看过去. 要从现代的文明社会的环境来讨论, 而不能套用几百年前的社会环境; 同样,
评判某个宗教/教派应该看它现在的行为, 而不是看流传了千百年的教典,那些教典是千百年前写的, 现在基本上没人可以完全遵守, 因为当时的文化环境不同.

第二, 教徒违反法律与否其实不用考虑. 因为如果教徒违反法律, 自有法律制裁, 跟邪教不邪教没关系.

第三, 很多国家(很遗憾, 不是所有国家)的法律都规定宗教自由, 基本上可以认为个人有信教的自由, 也有不信教的自由; 有信这个教/教派的自由, 也有信那个教/教派的自由. 这是一个很好的参考.

第四, 言论自由的悖论. 言论自由没错, 但种族歧视的言论就不对; 同样, 因信教或不信教就歧视他人的言论也不对.

第五, 人与人相互尊重的原则. 悲天悯人是好的, 妄自尊大就很糟糕. 同样, 这个世界上有好多好多宗教并存, 这是事实.

第六, 这个世界不是非黑即白的, 所以有些宗教有邪教的特点, 但还没糟糕到那个地步, 各位自己判断吧.

总体来说, 我对邪教的判断是以文化为主. 打个比方, 如果有个宗教宣传杀光中国人(即使没有实行), 这个肯定是邪教, 这是基于它提倡的内容.

1. 活人自称神. 这个基本不用解释.

2. 唯我独尊. 这个有点不好解释, 基本上每个宗教都觉得自己的信仰是唯一正确的, 只要这个是关起门来说, 这个就不能算”唯我独尊”; 但是在现代社会, 如果某个宗教公开宣称其他宗教都是垃圾/错误/堕落等等, 这就是唯我独尊, 这就违反了基本的相互尊重. 我引用一句话”不得于教外称外教，不得于门外称外道”, 就是这个意思. 同样, 信教的人, 如果当面对不信这个教的人(包括信其他教的人)说”你是异教徒, 所以需要改变信仰才能得救,这就是邪教行为. 试想和尚碰到道士, 不该当面相互贬低,
就是这个道理.

3. 欺夺他人之信: 欺, 就是以欺骗的办法使人信某个教. 比如对教外之人说”不信我就完蛋了”,
这个就是欺骗, 因为人家还可以信别的教, 如果说信我就可以上天堂, 这个不算骗; 夺, 就是强迫他人信某个教, 比如说”不信我就把你家房子拆了”, 就是夺.

4. 提倡违反法律的行为. 这个无需解释.

最后, 我强烈反对任何向未成年人传教的行为.

Personalized Lung Cancer Targeted Therapy Obtained Support from Facts

lxliuxi — Mon, 12 Oct 2009 02:00:44 +0000

In Sep the New England Journal of Medicine published a clinical study IPASS (Iressa Pan-Asia Study). This study includes more than 1200 patients from mainland, Hong Kong, Taiwan of China, Japan, and Thailand. I would like to quote the conclusion here: Gefitinib is superior to carboplatin–paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib.

This study had two important messages: (1) targeted therapy (gefitinib) is better than traditional chemotherapy (carboplatin–paclitaxel); (2) somatic mutation of EGFR predict clinical outcome.

During recent years, target cancer therapy has been criticized due to its toxicity and efficacy. However, more and more
clinical data showed that targeted therapy had better clinical outcome than traditional chemotherapy. This study used Tyrosine Kinase Inhibitor—Gefitinib, while we should understand TKI is the earliest type of targeted anticancer drug. There are more types currently in clinical trial, including Hedgehog inhibitor, CDK inhibitor.

The more fascinating information from this study is that personalized medicine is not only good but necessary. The hypothesis is quite straightforward: gefitinib target EGFR, so the lung cancer patients should have EGFR overexpression or activating mutation. This study confirmed the hypothesis, which means (as most cancer scientists agree) lung cancer therapy should base on the genotype or genetic profiles or biomarker profile of a patient.

This study also support the other clinical trial BATTLE (Biomarker integrated Approaches of Targeted Therapy of Lung Cancer Elimination) and BATTLE 2. I discussed this in my previous comments: http://htscorpio.spaces.live.com/blog/cns!3D9493EB6FD3999F!1529.entry

Direct RNA sequencing

lxliuxi — Mon, 12 Oct 2009 01:34:44 +0000

In
the latest issue of Nature, a paper titled “Direct RNA sequencing” caught my
attention. Although the technique looks
simple it greatly reduces errors in the step of RNA to cDNA. I would not say too much of it because I think
the title speaks itself.

Direct
RNA sequencing, Nature, 2009, V461, p814-818

红酒, 划船, 钓鱼

lxliuxi — Sat, 27 Jun 2009 02:27:27 +0000

美国有什么特别让我喜欢的吗?
答曰: 红酒, 划船, 钓鱼.
红酒保证是葡萄酿的; 没喝过贵的, 超过15块一瓶的不买; 最爱Pinot Noir, Cabernet Sauvignon和Shiraz/Syrah, 不喜欢Merlot;
划船很方便很便宜; kayak, canoe; 湖里, 河里, 海里; 以后搬到海边城市去, 可以常在浪里划船;
钓鱼很爽, 钓不到还常常去钓才是真的爱钓鱼.

Permanent head Damaged了, 我的研究思路

lxliuxi — Sun, 24 May 2009 18:16:34 +0000

终于成了Permanent head Damaged了. 感慨一下.

其实我好像并没有觉得特别激动或者如释重负, 没啥变化.

总结一下, 4年半之前转学(加上转学之前的一年半, 一共6年), 根本没有想到今后几年会做什么研究. 来了这个学校, 加入了一个很不错的实验室(不错是指老板人很好, 实验室气氛很好, 经费不错, 还有临床的支持, supportive, nice, productive…), 按时毕业, 运气不错.

发了一篇小文章, 还有一篇大文章被审稿人要求补实验(正在努力中), 希望能被接受; 不算很出色, 还凑合吧.

回顾我从金属有机化学到ligand-targeted anti-cancer therapy到现在的lung cancer translational research (mouse models, miRNA, lung cancer stem cell), 跳跃很大. 那么我到底算是什么专业的呢?

我现在的研究领域算是生物医学, 但我好像从来不觉得我是学生物的. 就算现在, 我还是觉得我的生物基础很差; 有时候别人说起一些生物的基础实验, 我居然根本就没有听过; 说起一些基础生物学的大人物, 我也没有听说过; 我对奇妙的生物世界似乎也缺乏足够的兴趣. 我也不是学医的, 尽管我在药理系(药理是医学的分支), 跟医学院的学生一起上了一年的药理学, 但我对临床知之甚少. 更不用说有机合成了, 也许现在只能勉强看懂文献, 或者做最简单的有机反应.

我常说:”Once a chemist, always a chemist” 我觉得化学的训练对我的思维方式影响很大. 在我看来, 有机化学是一个应用的学科, 绝大部分有机化学家在合成新的化合物, 或者发展新的合成方法, 只有少数专注于反应机理的研究. 而有机化学领域对也是以合成出新的化合物或者发展新的反应方法作为评价标准(那些人名反应就足够说明问题了).

我本科的时候学过生物的基础课, 像分子生物学, 细胞生物学, 生物化学, 动物生理学, 但我还是觉得缺乏系统的生物学知识. 以我的理解, 生物学的目的是研究各种生物的结构, 功能, 发生发展的规律; 很多实验室致力于弄清一些信号通路的组成, 机理和相互作用—-这些知识很重要, 但我的兴趣不在这里. 我的一个好朋友(跟我做室友三年半), 是遗传学的博士, 生物知识的广度和深度简直骇人听闻, 从来没有他不知道的; 我经常跟他讨论生物医学研究的问题, 他最喜欢问的是某个成果的生物学意义和机理, 而我关心的是对疾病治疗有什么潜在的帮助.

我的导师是学医出身(MD—residency—postdoc—faculty), 虽然以基础研究为主, 但临床也是他工作的一部分(白血病和肺癌), 同时也做临床试验(proof of principle clinical trial). 我从他身上学到的最重要的东西, 是从临床的角度来看问题. 比如很多基础研究号称是面向癌症的, 但是那些研究甚至连潜在的对临床的帮助都没有. 比如新发现某个蛋白在肿瘤里高表达, 我们就问, 有没有可能成为therapeutic target(潜在的治疗), 如果没有, 那么有没有可能成为diagnostic marker(潜在的诊断). 当然, 我从他身上学到很多别的, 就不在这里罗嗦了. 虽然我的论文里没有什么临床的内容, 但其实有时候思路比具体的实验更重要.

这些研究经历影响了我的研究思路: 我更注重通过基础研究解决临床的问题, 比如提供跟好的药物测试的模型, 发现新的pharmacologic target, 不同病人对药物的不同反应的机理是什么, 等等. 我把化学, 生物学看作是解决问题的工具. 现在提的很多的translational research, 指的是临床和基础相互反馈和受益; 我觉得这里的基础, 不仅仅是生物医学手段, 包括化学, 物理, 工程等等都包括在内. 其实Translational这个词也暗含不同学科之间难以理解的困难: 化学家, 生命科学家和医生之间其实很不容易沟通, 他们说不同的”语言”, 所以需要翻译. 我就想做这样的翻译.

Paper Recommended

lxliuxi — Fri, 23 Jan 2009 02:13:19 +0000

This time I would like to recommend two articles. One of them is stem cell in mouse model, the other is about tissue engineering in curing patient.

1. Generation of a prostate from a single adult stem cell. Kevin G. Leong, Bu-Er Wang, Leisa Johnson and Wei-Qiang Gao. Nature, 2008, Vol 456, page 804.

2. Clinical transplantation of a tissue-engineered airway. Paolo Macchiarini, Philipp Jungebluth, Tetsuhiko Go, M Adelaide Asnaghi, et al. Lancet, 2008, Vol 372, page 2023.

The reason I put these two articles is that I strongly believe high quality basic research in biomedicine will eventually benefit clinic.

The first paper is from Genentech, which is a company, which is a little bit surprising because people still don’t believe that industrial can conduct high quality basic research. Simply by reading the title we can have an idea of the article. The authors isolate prostate stem cells (lin^-Sca-1⁺CD133⁺CD44⁺CD117⁺) from mouse prostate and transplant a single prostate stem cell into the other mouse and a generate functional, secretion-producing prostates developed. This article showed the powerfulness of stem cell, not even embryonic stem cell, but just prostate stem cell.

The second article is the fantastic application of tissue engineering in clinical: removal of cells and MHC from a human donor trachea, growth of the recipient’s epithelial cells and mesenchymal stem-cell-derived chondrocytes on this trachea and finally replace the recipient’s failed trachea with this graft. It seemed easy but it is technically challenging. This is a example that technology saved patient’s life, again.

The figure shows volume-rendering CT (A and C), and virtual bronchoscopic (B and D) reconstructions before (A and B) and 1 month after (C and D) engraftment of tissue-engineered trachea to replace left main bronchus.