---- drug combination against recurrence of colorectal adenomas

 

Until now there have not been many examples of cancer chemoprevention.  The most famous chemoprevention might be the use of tamoxophin for breast cancer prevention.  Here I would like to discuss another newly published landmark of cancer chemoprevention: Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial, Cancer Prevention Research, 2008, 1:32-38. This work was published in the very first issue of this new AACR journal for a good start.  This study presents landmark advance beyond the chemoprevention community to the whole clinical and basic cancer research community.  The concepts conveyed by this study will set a stage for future cancer chemoprevention.

 

Let me briefly introduce the background of colorectal adenoma.  Colorectal cancer is the second most common cause of cancer death in America after lung cancer.  Adenoma is the precursor of colorectal cancer.  Currently early detection and diagnosis can find adenomas by sigmoidoscopy or colonoscopy.  If detected, adenomas can be surgically removed.  If the adenomas were not removed, it will develop to malignant colorectal cancer.  Patients with removal of adenomas are in high risk of recurrence since they are more likely to have adenomas than those who never had adenomas.  Generally, recurrence is one of the major targets of cancer chemoprevention.

 

This clinical trial recruited patients with a history of colorectal adenomas resected within last 5 years and were thus at high risk for recurrence.  These patients were randomized into treatment or placebo group for 3 years.  Overall, the incidence of adenoma recurrence were greatly reduces, from 41% in the placebo group to 12% in the treatment group.  Only one patient in the treated group was found to have multiple adenomas, compared with 17 patients in the placebo group.  The lack of significant toxic side effects of the combination is extremely important.  The authors deliberately selected the lowest possible effective dose of both drugs. 

 

With their global and nonreductionistic orientation, the authors focused on two processes that have long been known to involve in carcinogenesis: excessive polyamine synthesis and enhanced inflammation.  They did not seek to study these two processes in over-simplified, reductionistic terms, but tried to combine these two unfashionable but time tested drugs to control these processes.  The drug selection and dose selection are based on in depth investigation on clinic and animal studies.  Current anti-cancer drug discovery has tried to target those fashionable proteins, but the progress is still not satisfactory.  One reason is the reductionistic thought.  Cancer is not a single disease so target single protein or process may not be sufficient.  Also, even same cancer, such as pulmonary adenocarcinoma, is different in different patients.  This is why combination therapy and tailored therapy are necessary and everything should be able to translate into clinical improvement (translational research).

 

There are a few reasons that we think this is a landmark of chemoprevention trial. 

(1)     The drug combination did not have obvious toxicity.  Some previous chemoprevention trials failed because of the drug toxicity.  In this trial only very slight adverse effect was observed.  The low dose of both drugs may be the reason of low toxicity.  The low dose came from several in-depth animal studies. 

(2)     Neither Difluoromethylornithine (DFMO) nor Sulindac is effective anti-cancer reagent.  However, combination achieved clinical benefit in those high-risk patients, which provide a novel thought to cancer chemoprevention. 

(3)     Unlike those recently discovered or marketed anti-cancer drugs, neither DFMO nor Sulindac is specific targeted reagents, which means they don’t target a specific protein, while the clinical outcome are significant.

(4)     The animal study of both drugs drug provided a solid knowledge on dose selection, which tells us the important role of good animal study in cancer research.  Also, good animal models are critical the successful animal study.

 

As a member of chemoprevention community, I regard this successful trial as a landmark of cancer chemoprevention. However, it is still far from its widely clinical application. One reason is that pharmaceutical industrials are less likely to market these two drugs because the pattern expired long ago.

 

This exciting new study devoted to prevention of cancer provided a new perspective in this field and reached a milestone.  Now we have a new standard of excellence as our goal. The bar is higher.

 

 

Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial,  Cancer Prev Res 2008 1: 32-38

In the latest issue Angewandte Chemie, K.C. Nicolaou Lab published a communication titled “Synthesis of the sporolide Ring Framework through a Cascade Sequence Involving an Intramolecular [4+2] Cycloaddition Reaction of an o-Quinone.

The [4+2] cycloaddition in this paper is really a crazy idea if anyone proposed it, however, they made it. Usually an organic chemist would not think this reaction could work. So I guess this is the beauty of organic synthesis: a crazy idea can come true by your clever hand.

 

    As I wrote before, our department has a good tradition to have a “students invited speaker” each year. Usually graduate students nominate scientists and vote. Then the department will invite the winner if his/her schedule permits. This year I nominated Dr. Douglas R. Lowy, a great scientist and physician. Although my nomination did not win the vote (partly because my nomination competed with Nobel Prize winner) I still think it necessary to introduce this scientist and his team to you.

In April the 2007 Dorothy P. Landon-AACR Prize for Translational Cancer Research is awarded to the team of Douglas R. Lowy, M.D., and John T. Schiller, Ph.D., for translational research leading to the development of the human papillomavirus vaccine. The team identifyed the role of human papilloma virus (HPV) in carcinogenesis and helped the development of the HPV vaccine. Both Douglas R. Lowy and John T. Schiller uniquely involved with both the fundamental and the clinical aspects of this work.

I happened to attend AACR annual meeting this year in Los Angelos and I was lucky to listen to the presentation. This might be one of the reasons I nominated them. When people talk about biomedical science many people, especially graduate students, tend to focus only on basic science research, while the primary goal of biomedical research is to cure disease and improve human health. These two scientists make great contribution to both basic and clinical research, helping development of the PHV vaccine, which will lead to dramatic decrease of women cervical cancer. My personal opinion is that the cure or prevention of a human disease is as important, or even more sometimes, as a discovery in basic science, such as uncovering a mechanism.

I hope through my introduction, you can see how important translational research is and why we need it. You can also see my own opinion on evaluation of science.

 

The description of their contribution.

The study of papillomavirus virons was limited by the inability to efficiently propagate the viruses in cell culture. Drs. Lowy and Schiller demonstrated that the L1 major capsid protein of the papilloma virus could self-assemble into virus-like particles (VLP) that were capable of inducing high titer neutralizing antibodies, a finding which they felt suggested that L1 VLPs could be used as both a serological test and a vaccine against HPV infection. These initial observations were refined in HPV16 with the demonstration that the use of L1 from lesions which had not progressed to carcinoma was necessary for efficient VPL assembly. Drs. Lowy and Schiller used these observations to develop an ELISA using HPV16 VLPs which was capable of identifying women with current or past HPV infection, and could also be used to monitor the immune response to VLP vaccination.

Drs. Lowy and Schiller subsequently demonstrated in animal models that vaccination with VLPs provided protection against papillomavirus infection. These findings were translated to humans in a randomized dose-escalation trial to examine the safety and immunogenicity of an HPV16 L1 vaccine that demonstrated that the vaccine was both safe and highly immunogenic. Subsequent trials demonstrating the safety and efficacy of a multivalent L1 VLP vaccine have led to the clinical availability of an FDA-approved vaccine.

In addition to advancing the translational science of the HPV vaccine, Drs. Lowy and Schiller have engaged in the public health debate surrounding its application, which I will discuss later.

In the latest issue of JAMA, the Journal of the American Medical Association, an article reported a survey on 277 of 367 residents (75.5%) in 11 residency programs to evaluate their understanding of biostatistics and interpretation of research results. The conclusion is disappointing:” Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.”

When I read this article I was also disappointed because medicine residents are usually considered to have high quality of sciense background. Current physicians are required to practice evidence-based medicine (EBM), so they have to read evidence-based summaries or evidence-based practice guidelines, which contain the conclusion given in the form of biostatistics results. Their poor understanding of biostatistics represents a pressing need to enforce the biostatistics education in medical school as well as in residency program.

Here I quote some paragraphs if you want to know some detail.

 

Introduction: Physicians must keep current with clinical information to practice evidence-based medicine (EBM). In doing so, most prefer to seek evidence-based summaries, which give the clinical bottom line,1 or evidence-based practice guidelines.1-3 Resources that maintain these information summaries, however, currently include a limited number of common conditions.4 Thus, to answer many of their clinical questions, physicians need to access reports of original research. This requires the reader to critically appraise the design, conduct, and analysis of each study and subsequently interpret the results.

Context  Physicians depend on the medical literature to keep current with clinical information. Little is known about residents' ability to understand statistical methods or how to appropriately interpret research outcomes.

Objective:  To evaluate residents' understanding of biostatistics and interpretation of research results.

Survey Development: We developed an instrument to reflect the statistical methods and results most commonly represented in contemporary research studies (Appendix). Thus, we reviewed all 239 original articles published from January to March of 2005 in each issue of 6 general medical journals (American Journal of Medicine, Annals of Internal Medicine, BMJ, JAMA, Lancet, and New England Journal of Medicine) and summarized the frequency of statistical methods described (Table 1). From this review, we developed questions that focused on identifying and interpreting the results of the most frequently occurring simple statistical methods (eg, 2, t test, analysis of variance) and multivariate analyses (eg, Cox proportional hazards regression, multiple logistic regression).

Design, Setting, and Participants:  Multiprogram cross-sectional survey of internal medicine residents.

Main Outcome: Measure  Percentage of questions correct on a biostatistics/study design multiple-choice knowledge test.

Results:  The survey was completed by 277 of 367 residents (75.5%) in 11 residency programs. The overall mean percentage correct on statistical knowledge and interpretation of results was 41.4% (95% confidence interval [CI], 39.7%-43.3%) vs 71.5% (95% CI, 57.5%-85.5%) for fellows and general medicine faculty with research training (P < .001). Higher scores in residents were associated with additional advanced degrees (50.0% [95% CI, 44.5%-55.5%] vs 40.1% [95% CI, 38.3%-42.0%]; P < .001); prior biostatistics training (45.2% [95% CI, 42.7%-47.8%] vs 37.9% [95% CI, 35.4%-40.3%]; P = .001); enrollment in a university-based training program (43.0% [95% CI, 41.0%-45.1%] vs 36.3% [95% CI, 32.6%-40.0%]; P = .002); and male sex (44.0% [95% CI, 41.4%-46.7%] vs 38.8% [95% CI, 36.4%-41.1%]; P = .004). On individual knowledge questions, 81.6% correctly interpreted a relative risk. Residents were less likely to know how to interpret an adjusted odds ratio from a multivariate regression analysis (37.4%) or the results of a Kaplan-Meier analysis (10.5%). Seventy-five percent indicated they did not understand all of the statistics they encountered in journal articles, but 95% felt it was important to understand these concepts to be an intelligent reader of the literature.

Conclusions:  Most residents in this study lacked the knowledge in biostatistics needed to interpret many of the results in published clinical research. Residency programs should include more effective biostatistics training in their curricula to successfully prepare residents for this important lifelong learning skill.  

    Why is organic synthesis so fasinating that many talented people devote their life to it? One of the reasons is that organic synthesis, however it is developed as science, is still partly art. A great artist is usually gifted, so synthetic organic chemists always want to tell people they are gifted and actually some of them are.

    One of the key questions in organic reaction is selectivity: chemoselectivity, regioselectivity and stereoselectivity. For high chemoselectivity and regioselectivity, protecting groups are usually applied. However, gifted synthetic organic chemists are always able to achieve high selectivity without protecting group, which is the beauty of organic chemistry. Phil Baran, an associate professor in the Scripps Research Institutetitled “Total synthesis of marine natural products without using protecting groups” demonstrate the beauty of organic chemistry: you can always do better job.

    Total synthesis of marine natural products without using protecting groups, Phil S. Baran, Thomas J. Maimone & Jeremy M. Richter, Nature, 2007, Vol.446, 404-408,

A paper just published yesterday titled “Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity” is an example of good science can contribute and promote lung cancer therapy.

It is known that somatic mutant EGFR (activating mutation) and its amplification is a cause of non-small cell lung cancer (NSCLC). Currently there are two types of drugs targeting EGFR to treat NSCLC. One type is small molecular kinase domain inhibitors including Gefitinib (Iressa®), Erlotinib (Tarceva®), etc. and another type is humanized antibody binding to extracellular domain of EGFR, including Cetuximab (Erbitux®). Despite current therapy, lung cancer is still a deadly disease with high mortality rate. Obviously the above drugs are not perfect molecules targeting mutant EGFR.

Based on current condition there is a pressing need for development of novel EGFR targeting molecules. The paper I recommended here clearly showed the crystal structure of several mutant EGFR frequently found in clinical lung cancer. The authors also illustrated EGFR-drug co-crystal structure showing the binding situation of different drugs and proposed mechanism that is responsible for structure and activity relationship.

The contribution of this paper is not the neat crystal structure work, it also provided clear rationale for next novel drug development.

I always emphasize that basic should and can contribute to cure diseases, and this paper give us a good example.

Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity.   Cancer Cell, Vol 11, 2007, 217-227. Cai-Hong Yun, Titus J. Boggon, Yiqun Li, Michele S. Woo, Heidi Greulich, Matthew Meyerson, and Michael J. Eck

前一阵子跟老板聊天的时候, 我把做生物医学研究的课题组分成三类, 目标导向, 技术导向和两者混合.目标导向的研究, 即以某个疾病, 某个信号传导通路或者某个机理为目标的研究, 比如“role of EGFR in non-small cell lung cacer”或者“structure and function of G-protein coupled receptor and its role in cardiovascular disease”. 这一类的课题组以揭示机理或者发展疗法为最终目标, 并不致力于发展某个技术. 技术导向的研究一般以发展某种在生物医学里有用的技术为主, 通常并不局限在某个具体的生物医学对象. 比如“MRI in diagnosis of disease”或者“Developing new techniques for single-molecule detection and bio-sensing”. 还有就是两者混合的, 既致力于某个机理或者疾病的研究, 同时又发展某种技术.

大多数学术界的生物医学研究者属于目标导向的, 他们通常是生物出身, 看重对机理的阐明; 而很多非生物专业出身的研究者, 常常是技术导向的, 或者混合的, 因为技术正是他们所擅长的. 正如我在以前的评论里说的, 不同专业之间必然会产生偏见; 以我所见, 很多目标导向的研究者认为技术导向的研究不是主流. 当时庄晓薇在Cell上发表文章的时候, 我看了一些人的评论, 觉得研究某种技术没有那么大的贡献. 其实这是一种误解, 或者偏见. 从生命科学发展的历史来看, 生命科学还处于揭示事实的阶段, 不像物理学, 化学或者工程, 可以创造新的东西; 生命科学自身很难产生新的技术, 而生命科学的发展事实上是被不断的技术进步推动的, 这个推动力, 来自其它学科, 数学, 物理, 化学, 材料, 工程等等.

我可是算是化学出身的吧, 过去的化学训练使我对技术比较敏感(自认为的), 也喜欢看看技术的发展. 我觉得在生命科学研究里, 如果能发展并且精通某种技术, 同时选择一个生物医学的目标, 这样的课题组会比较有竞争力.

欢迎发表评论.

不知道各位是否听说过最近的台湾中兴大学在CELL上的论文作假并撤回的事. 这件事已经过去好几个月了, 我在本文后面放上了mitbbs上sanger总结的事件过程回放, 略有修改, 有兴趣的可以去看看. 在我看来这件事非常简单, 就是这篇CELL文章里面的电泳照片不是原始的, 而是用软件copy + paste的; 这种事实简单的造假文章居然引发这么多的争吵, 而争吵中反应出很严重的学术道德教育的缺陷.  

什么是作假

在这个事件的争论中, 有些台湾的学生坚持这样一种观点: 只要实验结果可以被重复, 即使发表的数据做了”过度美化”也是没关系的, 而且还有不少人这么认为. 常识是: 只要发表的文章里有假造的数据, 即使结论是正确的, 即使同样的实验可以被重复, 也是造假, 应该被追究.  

学术道德教育

我看了很多台湾学生的回帖争论, 虽然其中有很多感情上的原因, 但是我觉得学术道德教育还差很多(台湾和大陆), 在美国的学生好一些. 我不是说他们不知道什么是学术道德, 而是在具体问题上不清楚. 我在国内读研的时候, 根本没有系统性的学过学术道德的东西.

 

我以前的帖子里说过, 学术界需要对公众和政府证明这些钱被正确地使用, 所以要严厉对待诸如造假地人. 对于个人来说, 应该要明白, 在发表文章的时候玩些小把戏不是长远之计----出来混, 迟早要还的.

 

过程回放:
 
11.16 yuuli在MITBBS上首次发问怀疑中兴CELL造假, 尤其是Figure2C. 最初的发现者,据yuuli本人陈述,是其实验室的俄国同行.随后该文被大量转载,引发激烈讨论
11.17 MITBBS上anoia, SMTH上stray发文确认该文造假, 台湾ptt论坛上则是支持中兴的声音为主流
11.17 motif质疑该组在JBC上的文章(http://www.jbc.org/cgi/reprint/M605177200v1)  Figure1B也有问题
11.18 schiwann发文确定JBC图有假, 同时质疑Figure6也存在作假嫌疑
11.18 tataat对该组在J Gen Virol上的文章(87,1357-67,2006)的数据也表示怀疑
11.19 面对ptt, MITBBS上的反诘,anoia公布完整的质疑图档
11.21 CELL编辑部屏蔽该文大图,所有到本文的连接全部转去siencedirect
11.21 台湾大学guyspy用色阶调整确认质疑
11.21 anoia确认JBC中Figure1存在造假
11.21 ptt上lnalna刊出联系作者张邦彦的回信, 责难大陆的道德教育.造假讨论由此被推向极致.其后,大量大陆留学生给CELL编辑部写信打电话要求对该文进行调查
11.22 anoia公布保存所有可疑大图于capa.zoto.com
11.22 CELL第一作者dennishsien发文表示自己正在服兵役中,无法详细澄清造假传闻,但是对所有数据图片"问心无愧"
11.22 中兴JBC第一作者的回复被刊出, 认为灰度块来自文件压缩所致
11.23 anoia质疑JBC作者关于"文件压缩"说, 双方有私下接触. anoia其后宣布台湾中兴大学提供的所谓原图是经过严重contrast拉过的,仍然无法解释Figure 1中灰度块的问题.
12.03 中兴JBC作者Kuei-Min Chung承认他在图片转换过程中曾经进行过"美观化"修改
12.13 ScienceNow Daily News 宣布中兴方面决定收回他们发于CELL的论文,并转述中兴大学校长的话说:这是一件不幸的事(unfortunate case), 今后在全校的道德教 育中学校将以此作为一个严肃的教训 (the university will take this as a serious lesson for ethics education at all the colleges in the future.)
12.14 MITBBS和SMTH上对这个消息反映平淡,认为这是一场没有胜者的斗争("triumph without glory"),海峡两岸都受到了伤害. 另外大家对JBC调查结果的关注, 以及对anoia的感谢和祝贺也是大家回复的一个主轴
12.14 中兴方面在ptt上回复撤稿消息,并公布部分中兴与CELL编辑部的通信内容.他们坚持该文没有造假,是可以重复的(repeatable),撤稿是因为受质疑最多Figure2C"不幸"遗失的缘故,并再次质疑"大陆打压台湾"的动机

 

Role of the Sigma Factor in Transcription Initiation in the Absence of Core RNA Polymerase

Cell, Vol 127, 317-327, 20 October 2006

Hsin-Hsien Hsu, Kuei-Min Chung, Tsung-Ching Chen, and Ban-Yang Chang,

Institute of Biochemistry, National Chung-Hsing University, Taichung 40227, Taiwan, Republic of China

下面的图是其中一张, 可以看出copy and paste

It took me more than a year to generate 2 mouse lung cancer cell lines from the transgenic mouse lines lung tumor in our lab. It is really a technical challenge for me since no one in our lab has the experience of primary cell culture and making cell lines. Now I can proudly tell people that we obtained these cell lines.

Personally speaking, making these cell lines is not that hard, we just need to be patient and optimize the culture condition. Neither my boss and nor I am not easy to be discouraged. When one month ago there was a serious contamination destroyed almost half of the cells I thought this batch of cell might not survive, but finally I got the cell lines. I still feel I am lucky because I tried less than 15 tumors.

I was really proud to tell people of the newly made cell lines in my Research In Progress presentation.

Work hard and be patient.

近来聊起同性恋的话题, 觉得好像很多人对于”性别认同”和”性取向”不太分得清楚, 在此就说说.

 

自我性别认同: 指对自己的性别的认可, 比如认为自己是男性, 女性或者其它非传统观点的性别. 人对自我性别的认同很大程度上是在胚胎发育的某个阶段决定的, 在比较小的程度上可以被后天教育逆转(请注意我是说逆转而非影响), 这就是大多数变性人进行变性的出发点, 因为他们对自己性别的认同跟他们生理的性别不同.

性取向: 指性欲的对象是异性, 同性, 双性或者其它(比如事物). 性取向的决定因素很复杂, 有基因上的因素, 有胚胎发育的影响, 也有后天的影响. 令人惊奇的是, 动物的性行为是如此多种多样, 除了承担繁衍后代的人物, 动物的性行为也在很大程度上基于快感和性欲本身; 而动物基本上没有”道德”约束, 其同性和双性的性行为也没有受到约束, 基本上很常见; 甚至个体在性行为中同时扮演雌雄双性的情况也不罕见. 所以, 有的时候在界定”正常”和”异常”要很谨慎. 有兴趣的可以看看Discovery的节目.

 

需要澄清的是, 自我性别认同和性取向是相对独立的, 或者说, 人对自身性别的认同跟其性取向是两件事. 一个男性, 可以因为自己认为自己是女性而去变性, 但他/她的性取向却不一定会随之改变. 如果要从一个更广泛的角度来看, 福柯(Michel Foucault)的<性史>(Histoire de la sexualité)是不错的参考书.

 

我发现很多人对上述这些都很模糊, 而且喜欢在模糊的情况下做判断(judgement), 所以有必要罗嗦两句. 这于美国一直争论的同性恋婚姻是否合法化的问题, 实在是很难在这么短的篇幅说清楚, 以后再说吧.

很长时间以来, 我一直听到这样的观点: 癌症的基础研究和临床研究脱节, 化疗和放疗的毒性还是如此之大. 其实我承认癌症的基础和临床研究确实有点脱节, 但是并不是想象的那么严重. 很重要的一个因素是药物研发的周期很长, 现在临床上可以使用的药, 可能是基于十多年前的基础研究的成果.

 

就化疗来看, 十年前的药物对肿瘤细胞和正常细胞的选择性很差, 这是有其机理决定的, 因为它们大都是基于肿瘤细胞代谢和分裂很快这个事实的. 但是现在应用的很多抗癌药, 比如erlotinib (tarceva), 基于更合理的作用机理. 其实这十多年来抗癌药的发展已经进步了很多, 乳腺癌的死亡率已经降低了很多.

 

我在”丁香园”的肿瘤版看了很多帖子, 里面发帖的大都是国内医学院的学生, 我感觉他们对临床比较熟, 但是对怎么做好的科学研究还很欠缺, 对基础科学的理解也很欠缺, 这个欠缺是因为他们没有好的指导(他们的老板就不知道怎么做真正的研究), 而不是没有足够的经费(当然经费也是一个问题). 另一方面, 我看到一些美国的研究生, 他们也在做癌症的研究, 很多人比较偏基础, 对癌症的临床缺乏认识, 这是很遗憾的事情, 因为癌症研究的最终目标是治愈疾病, 而不是发现某个蛋白或者基因; 如果对这个最终目标缺乏认识, 那么选择正确的研究方向可能会有点问题, 最终会使整个基础研究的方向有点偏差.

 

所以我觉得translational research还是比较合适的, 就是说, 要避免研究方向脱节.

一点想法, 随便说说.

I was really busy on my research project and qualify exam (writing a NIH grant). Here are what I learned form my boss.

1.       Design definitive experiments that can answer important questions

2.       Design experiments to disprove your hypothesis instead of prove it. If you tried different means to disprove your hypothesis and failed, you are proving it.

3.       Less experiments but more control. Control is usually important than experiment itself.

4.       Rescue experiments

5.       Think more rigorously.

…you young scientists should stick to your data instead of authority; 400 years ago people (Bruno) were executed only because he insisted that the earth moved around the sun.

----几个月前系里的一位老教授以此作为那节课的结束语.

 

前一阵子, 有人说, 假如大爆炸理论是正确的, 你真的能接受我们存在的宇宙是由一次大爆炸产生的吗? 难道你不认为由神创造这个宇宙更有人情味更容易接受吗? 或者说, 你真的能接受我们存在的宇宙是由那些最简单的粒子经过漫长的时间形成的吗?

 

很高兴有人问这个问题, 因为问题的答案比问题本身更更有意义. 关键的问题在于, 我们不能根据我们的好恶去描述一个真实存在的世界.

 

很早以前, 大家都觉得地是平面的, 一直延伸到远方; 也有认为地面是圆的, 比如毕达哥拉斯和亚里斯多得. 后来随着航海的发展, 人们逐渐发现我们居住在一个”球”上, 尤其是1519年麦哲伦（Megellan）首次环球旅行直接告诉世界地球是圆的. 从最初人们认为地面是平面到现在普遍接受的地球, 大概有好几千年吧. 另一方面, 古代的人都认为太阳, 月亮和其它星星都是绕着地球转的, 人类居住在宇宙的中心. 与麦哲伦同时期的哥白尼（Nicolaus Copernic）提出了日心说, 将人类从太阳系中心搬到边缘. 可是哥白尼一直不能出版他的著作, 在1543年去世. 布鲁诺发展了哥白尼的日心说, 认为太阳也不是宇宙的中心, 被宗教裁判所烧死. 后来伽利略又推广日心说, 以至教皇保罗五世下达了著名的“1616年禁令”，禁止他以口头的或文字的形式保持、传授或捍卫日心说. 1633年因此入狱. 直到1757教廷宣布解除对哥白尼《天体运行论》的禁令；1882年承认了日心学说----其实我个人觉得他们承认不承认无所谓, 人们对世界人探索永远不会停止.

 

看来人们接受地球是圆的没有那么多阻碍, 而接受地球不是宇宙中心却困难重重: 哥白尼的学说被禁止传播, 布鲁诺被烧死, 康帕内拉被长期打入死牢, 伽利略入狱. 现在看来, 教廷不断被迫承认事实, 比如承认地球不是宇宙中心, 教皇保罗二世承认进化是事实(我实在不明白为什么还有那么多人根据圣经说进化不是事实), 等等.

 

回到一开始的问题, 你能接受现在的宇宙是最初大爆炸的产物(如果是真的)吗? 或者说, 难道这个世界确实由那些最基本的粒子慢慢演化而来的吗? 我觉得问题的根本是: 你能不能接受真实的世界, 能不能接受非人类中心的思想. 过去之所以有地心说和神创论, 除了缺乏科学探索以外, 人类中心的思想是重要原因. 后来的宇宙观和进化论在很大程度上把人来从中心搬开了. 每个人都可以接受或者拒绝任何理论或者思想(在心里), 但是他/她总得面对事实.

Laboratory-based investigations into the nature of cancer cells and clinical efforts to control cancer often seemed to inhabit separate worlds. ---- Harold Varmus, Science, 312, 1162 (2006).

 

It is true that during the past 50 years basic scientific research (bench work) contribute much less to clinical cancer therapy (bed side) than other diseases. The reason partly lies on gap between physicians and scientists. Physicians and scientists say different languages, so we need to translate between them, which is Translational Research: bidirectional research between basic science and clinical therapy. Both basic science and clinical therapy provide basis and give future directions to each other.

 

As my research going on I realize the importance of translational research, not because we are doing that, but it is the way we should do to cure cancer.

We are sicientists, we should fight back!----上次来做报告的大牛说的.

I am a scientist, I work for science and human health.

 

本来不该写这种科普的东西, 可是近来跟不少人讨论科学和宗教的问题, 也看到很多人攻击科学和科学研究, 心下不平. 令我惊诧的是, 好多人(包括很多理工科的学生)都对科学有很大的误解. 我觉得有必要写点东西(我自己的理解), 把这些问题说清楚(虽然前人说过无数次). 如果你功力深厚, 不必浪费时间读, 或者欢迎指正补充; 如果我写的东西能消除你的误解, 那我的努力就没有白费.

 

 

科学精神和科学研究

 

在我看来, 质疑是科学精神的核心, 证伪是科学研究的核心.

 

质疑就是对任何东西都不盲从, 不迷信. 哥白尼和布鲁诺的伟大, 不仅仅在于他们提出的宇宙观, 而在于他们敢于质疑被认为是神圣的东西. 看看科学史上的重大发现, 大都是推翻了前人的东西, 或者实现了通常认为不可能实现的.

 

为什么我不说科学研究的核心是实验, 因为实验是证伪的方法. 基本上科学研究的方法是提出假设—证伪—提出新假设—证伪的循环. 从逻辑上说, 绝大部分科学的假设/定理都不可能通过实验完全证实, 因为你不可能穷尽世上所有的东西来测试这个假设/理论, 只能试图从各个方面去证伪. 如果没有办法被证伪, 那么这个假设/定理暂时是被认为是对的. 这才是科学研究的基本方法: 不要试图去证实你的假设, 而要设计实验从各种方面试图去推翻你的假设, 如果你的假设无法被推翻, 那么它应该比较可信.

 

有人说: 物理学的一些定理无法证明, 凭什么就要信它? 那些物理学家相信这些定理也不是理性的. 这个问题需要认真对待, 否则确实有些人不明白. 比如热力学第二定律无法被证明, 为什么我们要用它作为热力学的基础? 因为在目前的尺度上, 热力学第二定律是符合事实的, 没有被事实推翻过, 我们就认为它暂时正确, 作为热力学的基础; 当然, 你可以不同意并试图通过实验推翻它, 如果你做到了, 那么它就被推翻了(估计至少是诺贝尔奖).

 

什么是不可证伪的? 讲个故事: 三个秀才进京赶考, 出发前找一个算命先生问能否考取. 算命先生对他们三个伸出一根手指头, 什么话也不说----这就是不可证伪的, 因为这根手指头可以对付所有的考试结果.

 

科学是鼓励质疑和证伪的(这是科学和宗教或者迷信的本质区别, 所以我非常反对有人用宗教信仰来干涉科学的事实). 如果你能合理地质疑前人的东西, 成功地证伪前人的理论并用自己的理论代替, 那你就成名了----没有任何一个科学的定理是神圣的. 所以当伽利略只需一个实验就可以推翻亚里士多得的理论; 而量子力学要经过漫长的争论和实验才能被科学家广泛接受, 绝不是某个人说了算的(即使爱因斯坦反对).

 

经常有人说, 科学也不能解释所有的现象----当然不能! 但是, 在能够解释这些现象以前, 用超自然的或者神创的观点来解释是非常有害的, 因为我们应该努力去接近和发现真理, 而不是麻醉和欺骗自己.

 

 

科学和数学

 

严格说来, 数学不属于科学的范畴.

 

以几何为例. 几何起源于生产生活, 然后由一些数学家以几个公理为基础构建的一个空间规则(最早是欧式几何), 并且衍生出很多定理. 从本质上说, 几何不必跟现实相符合, 而是现实比较接近(欧式几何的空间规则), 就用了. 比如像黎曼几何的空间规则就跟欧式几何不一样, 它有另外的用处. 基本上绝大部分的数学理论都是如此.

 

有人说: 你凭什么说存在绝对平行的平面? 凭什么几何的那些公理就该相信? 相信那些公理不就像信仰一样吗? 其实几何的公理是设定的, 是这种几何的空间规则的基础, 没有必要一定要在现实中存在----只不过人们觉得这种几何的空间规则可以用来解决这些问题, 就用了. 所以用数学公理不能被证明来攻击科学是没有意义的.

 

 

进化论

 

进化是事实, 而试图对进化现象的解释就是进化的理论(有很多种). 对进化论的攻击之一就是: 有这样那样的事实无法用进化论解释, 所以进化论是错的----这种说法多么荒谬: 这世上哪有完美的科学理论, 但是我们都在努力向真理靠近. 进化不是由某个人说的, 也不是由某一个化石确定的, 而是无数的事实积累得出的结论. 生物学家从环境, 物种自身, 分子生物学等等方面来研究进化的过程是怎样的, 遵循什么样的规律, 因此有了种种不完善的学说. 如果因为这些学说不完善就否定进化, 那就相当于因为不能造出完美的房子就因此不造房子一样愚蠢. 还有一些人, 凭着对生物学和化学的一知半解, 就跳出来说进化是不可能的----too simple, sometimes naïve啊. 科学家们, 你们应该站出来反击啊. 还有人说, 进化是存在的, 但完全是有神安排的, 而人无法理解神----这种理论无法被证伪, 既不能证明它错, 也不能证明它对, 基本上跟废话没什么区别, 可以存在信仰中, 但是不应该用来干涉科学.

 

 

科学和信仰

 

科学就是科学, 信仰就是信仰, 不要互相干涉. 任何人要信仰任何宗教都是自由的, 我尊重每个人的宗教信仰; 但我反对任何人要用自己的信仰来干涉科学. 科学的任务是发现事实和事实背后的规律, 不管这些事实和规律是人们喜欢的还是痛恨的. 有不少教会保守人士认为科学发现的事实冒犯了他们的信仰, 于是就要反击. 我觉得任何理性的怀疑/质疑/反思都是好的, 但有多少人是理性的呢. 1600年布鲁诺被教会烧死, 仅仅因为他说太阳不是绕着地球转; 现在的科学家没有那么危险了(连前任教皇都承认进化是事实), 但科学家们永远都不能大意, 人们总是非理性的.

 

 

“让上帝的归上帝, 恺撒的归恺撒”