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• 作者：收藏家 发布时间：2019-09-19 16:27:34

  但是你却慷慨大方的送给玛丽一台彩色电视机呀！

• 作者：FAKEWORM 发布时间：2023-03-07 17:34:35

  太可爱了

• 作者：皓天眩光 发布时间：2020-03-04 23:17:20

  文字配上彩图，上海的历史文脉一览无余，很美！

• 作者：春明门外客 发布时间：2021-12-11 19:38:14

  咪咪兄推荐的书。号称华北版白鹿原觉得有点言过其实了。仅是通过相爷回乡让所有人物出场，上册就基本上用了八成篇幅。人物众多，事情除了琐碎，实在没有什么精彩的地方。唯一看得人紧张的地方是二龙打完秋那一段，然后就是瘸国梁骂街，结果很多地方都写得虎头蛇尾。比如完秋被打之后，比如胎里坏给湾里下毒药，再比如相爷突然就没了，突然就转入了很多人的结局部分。倒是桂爷最后学会了安步当车，讲了一大段口的故事。通篇里骂人的零碎话已经是翻来覆去地重复又无趣，使粗俗都变得无聊。有个噱的地方就是相爷在屋里唱“三杯酒下咽喉把大事误了”那个桥段。可怜完秋也是个惨的结局，最后也没有说占义怎么样了。有点怀疑这本书是不是被删节了很多地方。总体有点失望，觉得很多人物都没有立起来。

• 作者：Ufakir 发布时间：2021-07-27 18:08:11

  第二本案例集，依旧是干货满满！

• 作者：加百 发布时间：2015-06-10 18:25:31

  其实也没读，只是好早就买了放在那，收藏吧

• 请大眼继续写杂文吧

  作者：秋叶 发布时间：2011-02-09 10:51:38

  大眼最大的特点是文字痛快，而不是经典。

  我最喜欢看李大眼写的博客视频，我知道他的博文很难一篇永流传，但绝对是酣畅淋漓。

  但如果把这些优点放进小说，那就是一场悲喜剧，有点闹。用喜剧的调门写悲剧，总觉得有点怪。

  我给这本小说的评价是还行，是针对这个题材，不是针对小说的水准。

  我买这本书不是相信李大眼写小说的水平，而是为了感谢他奉献了那么多痛快的杂文时评，我买你一本书，你赚三元稿费，我这样的人多了，将来大眼也可以在物质生活条件基本具备的情况下，心平气和地写让人不心平气和的文字。

  大眼写的不说小说，是段子，是微博，大眼写的不是故事，是生活，是现实，放在一起就是现实段子主义文学作品。

  让黑色的幽默，让灰色的和谐，让白色的无奈，让彩色的斑驳。

  有人会说大眼写这样的小说也是沽名钓誉，我不计较大眼的内心是个好人坏人，就算他是个坏蛋，我们也需要这个坏蛋。

  只有坏蛋才能对付坏蛋，这个世界不是能做好事的坏人太多了，而是不敢做好事的好人太多了。

  《李可乐抗拆记》不是一本对抗拆迁的指南，它只是告诉我们：

  这个世界不是坏人太狡猾，是好人没有坏人更有组织。

  对于大眼，我很矛盾，我喜欢你继续写杂文，但是如果不出小说，你有没有生活来源，一个肯写点有才的真话的人，我们有理由让你赚到钱活得好一点。

  这也是一种抗拆，抗玛勒戈壁的思维的拆。

• 《The Code Breaker》读书笔记

  作者：Di 发布时间：2022-05-22 10:38:36

  2022年的第17本书。

  Walter Isaacson的最新作品，新科诺贝尔生物奖得主的传记，比尔盖茨的年度荐书，这几个原因让我下了翻开这本大部头的决心。全书以Jennifer Doudna的个人经历为主线，讲述了CRISPR基因编辑技术的前世今生。然而坦白地说，这本书并未达到我预期的水平，前半部分写得勉强还算可以，但更多还是在描写人物的成长史，并没有将技术、产业的全貌梳理清楚，到了后半部分，注水太过严重，花了大量的笔墨在科学家之间的撕逼、技术伦理以及COVID19的抗疫工作上，实在是让人提不起兴致。相比之下，王立铭的《上帝的手术刀》写得要好得多，语言精练，逻辑清晰，将基因编辑技术的发展历程娓娓道来。这就是外行和内行的区别罢。

  无论如何，总算还是把这本书翻了一遍。读完的感想如下：

  首先，

  改变世界需要不同的角色，需要像Elon Musk这样的工程师，像Steve Jobs这样的产品经理，也需要Jennifer Doudna这样的科学家。在这个时代，后者尤其可贵，她们往往解决的是从0到1的问题，是开拓性的。

  如果说每10年会出现一批伟大的企业，那么恐怕每50年才会出现1、2个ground breaking的科学发现。在生物学领域，上一个伟大的发现恐怕还是六七十年前对DNA结构的破译。然而，尽管科学上的拓荒更加困难，但成功的科学家却并未享受到更为丰厚的激励 - 无论是财富上还是舆论上。相比于企业家，公众对于科学家是极其陌生的。这也是为什么应该鼓励更多类似书籍的出版。

  其次，科学的第一推动力是好奇心。Doudna的成长是一个对大自然不断追问、不断探究的过程，她的童年和青少年时期都是在夏威夷度过的，和某生物学教授为邻、整天泡在野生环境里做实验的经历铸就了她坚定的为生物学奋斗终身的信仰。她很小的时候就读了父亲书柜里的描写DNA发现史的《The Double Helix》，并且是当做推理小说而不是科普书来读的。她的宿敌张锋也有类似的经历 - 从小对科学着迷，中学时就跟着大学教授做细胞实验，早早就确认了自己的志向。科学是漫长而崎岖的道路，只有以强大的好奇心作为底层的使命，才有可能撑过那些艰难而迷茫的时刻。书中提到，

  I want to convey the importance of basic science, meaning quests that are curiosity-driven rather than application-oriented. Curiosity-driven research into the wonders of nature plants the seeds, sometimes in unpredictable ways, for later innovations. Research about surface-state physics eventually led to the transistor and microchip. Likewise, studies of an astonishing method that bacteria use to fight off viruses eventually led to a gene-editing tool and techniques that humans can use in their own struggle against viruses...In a larger sense, her career would also be shaped by the realization that she was right when she first saw The Double Helix on her bed and thought that it was one of those detective mysteries that she loved. “I have always loved mystery stories,” she noted years later. “Maybe that explains my fascination with science, which is humanity’s attempt to understand the longest-running mystery we know: the origin and function of the natural world and our place in it.”

  The scientist does not study nature because it is useful.He studies it because he takes pleasure in it,and he takes pleasure in it because it is beautiful.

  - Henri Poincaré, Science and Method, 1908

  当然，仅有好奇心是远远不够的，科研方向的选择尤其重要。Doudna之所以能够取得诺奖的成就，关键是她一路上都“踩对了点儿”，尤其是她早年选择专注于RNA结构的研究，而不是当时大热的DNA领域。

  这是源于她的导师Szostak（也是诺奖得主）的观念：要敢于去问更大、更基础的问题，敢于去解决那些非常困难、然而一旦解决可能带来更深答案的挑战，比如破解RNA的结构可能会帮助人类理解生命是如何诞生的。这是对高风险和高收益的追求。

  书中提到：

  “For both Szostak, who was well established, and Doudna, who wasn’t, switching to a focus on RNA was risky. “Instead of following the herd doing DNA,” Szostak recalled, “we felt we were pioneering something new, exploring a frontier that was a little bit neglected but we all thought was exciting.” This was long before RNA was being considered as a technology to interfere with gene expression or deliver edits to human genes. Szostak and Doudna pursued the subject out of pure curiosity about how nature works.Szostak had a guiding principle: Never do something that a thousand other people are doing. That appealed to Doudna. “It was like when I was on the soccer field and wanted to play a position that the other kids didn’t,” she says. “I learned from Jack that there was more of a risk but also more of a reward if you ventured into a new area.”Sz

  ostak’s excitement about discovering how life began taught Doudna a second big lesson, in addition to taking risks by moving into new fields: Ask big questions. Even though Szostak liked diving into the details of experiments, he was a grand thinker, someone who was constantly pursuing truly profound inquiries. “Why else would you do science?” he asked Doudna. It was an injunction that became one of her own guiding principles.The

  re are some truly grand questions that our mortal minds may never be able to answer: How did the universe begin? Why is there something rather than nothing? What is consciousness? Others may be wrestled into submission by the end of this century: Is the universe deterministic? Do we have free will? Of the really big ones, the closest to being solved is how life began.The central dogma of biology requires the presence of DNA, RNA, and proteins. Because it’s unlikely that all three of these sprang forth at the exact same time from the primordial stew, a hypothesis arose in the early 1960s—formulated independently by the ubiquitous Francis Crick and others—that there was a simpler precursor system. Crick’s hypothesis was that, early on in the history of earth, RNA was able to replicate itself. That leaves the question of where the first RNA came from. Some speculate it came from outer space. But the simpler answer may be that the early earth contained the chemical building blocks of RNA, and it didn’t require anything other than natural random mixing to jostle them together. The year that Doudna joined Szostak’s lab, biochemist Walter Gilbert dubbed this hypothesis “the RNA world.”An essential quality of living things is that they have a method for creating more organisms akin to themselves: they can reproduce. Therefore, if you want to make the argument that RNA might be the precursor molecule leading to the origin of life, it would help to show how it can replicate itself. This was the project that Szostak and Doudna embarked upon.”

  第三，科学界越来越不是个人英雄主义，而是团队合作，是传承。像牛顿、爱因斯坦那样坐在摇椅里思考一下就能得到答案的时代早已一去不复返了。在生物学领域，达尔文在发现进化论的过程中，极大地受到了马尔萨斯人口理论的影响，尤其是自然资源限制导致适者生存的理念。在发现DNA双螺旋结构的过程中，如果没有富兰克林和威尔金斯（因病去世未获得诺奖）在X射线晶体衍射图像上的帮助，沃森和克里克是无法成功的。至于基因编辑技术的演进，更是一场巨大的接力赛，书中提到的相关选手包括：

  1987年，日本学者Yoshizumi Ishino最先发现了大肠杆菌基因序列中的“重复”和“间隔”现象，但他没有做进一步的研究；

  1993-2005，西班牙微生物学家Francisco Mojica最先认识到了CRISPR的重要性，他在不同的细菌中都发现了CRISPR现象，并且提出了CRISPR是细菌免疫系统的假说。CRISPR这个词语（Clustered Regularly Interspaced Short Palindromic Repeats，成簇的有规律间隔的短回文重复）也是他创造的；

  2005.8，法国微生物学家Horvath和Danisco食品公司的研究主管Barrangouz通过酸奶嗜热链球菌实验证明了CRISPR的工作原理：它确实是一种适应性免疫系统，将新的噬菌体DNA整合到CRISPR阵列中，这使它们能够对抗下一波噬菌体的攻击。此外他们表明Cas9可能是干扰所需的唯一蛋白质，但CRISPR系统灭活入侵噬菌体的过程的细节尚不清楚；

  2006年，Berkeley的微生物学教授Jillian Banfield将CRISPR系统介绍给了Jennifer Doudna，让她进入了该领域的研究；

  2008.10，Luciano Martini和Erik Sontheimer发现CRISPR系统的靶向分子是DNA而不是RNA，并提出将该系统转移到非细菌系统，可能造出强大的基因编辑工具；

  2012.06，Jennifer Doudna和Emmanuelle Charpentier团队证明除crRNA外，还存在第二种tracrRNA，tracrRNA与crRNA形成双链体将Cas9蛋白引导至其靶标。此外，她们将crRNA和tracrRNA可以融合在一起，形成一个单一的合成导向RNA（sgRNA），简化了系统；

  2013.01，张锋团队首先成功地将CRISPR-Cas9用于人体真核细胞的基因组编辑。

  这个名单并不完整，还有不少科学家个人和团队都是这张拼图的组成部分。这是一场漫长的发现之旅。旅程的前半部分（2008年之前）是一条少有人走的路，Mojica的论文先后多次被一流期刊拒绝，在很久的延迟之后才得以发表在并不令人瞩目的位置。他们当时并不知道自己这项研究的重要性，以及成功的可能性。而旅程的后半部分则突然变得人满为患，当确定性变大的时候，赛道一下子拥挤起来，各路人马纷纷涌入，竞争变得白热化，也暴露除了科学界丑陋的一面。书中花了大量的篇幅来介绍Doudna团队和张锋团队的撕逼过程，其争执的核心在于，将在细菌中已经被证实的CRISPR-Cas9基因编辑方法用在人类的细胞上，是不是一项“显而易见”、“顺理成章”的工作：

  Thus the battle lines were drawn. Doudna and her colleagues had identified the essential components of CRISPR-Cas9 and engineered a technique to make it work using components from bacterial cells. Their contention was that it was then “obvious” how it would work in a human cell. Zhang and the Broad Institute countered that it was not obvious that the system would work in humans. It required another inventive step to make it work, and Zhang had beaten Doudna to it. In order to resolve this issue, the patent examiners in December 2015 launched an “interference proceeding” to be decided by a panel of three patent judges.When Doudna’s lawyers asserted it was “obvious” that a system that worked in bacteria would also work in humans, they were using a term of art. In patent law, the term “obvious” refers to a specific legal concept. Courts have declared that the “criterion for determination of obviousness is whether the prior art would have suggested to a person of ordinary skill in the art that this process would have a reasonable likelihood of success.” In other words, you don’t deserve a new patent if you merely modified a prior invention in a way that was so obvious that a person with ordinary skill in the field could have done the same with a reasonable likelihood of success. Unfortunately, phrases such as “person of ordinary skill” and “reasonable likelihood of success” are fuzzy when applied to biology, where experiments are less predictable than in other forms of engineering. Unexpected things happen when you start fiddling with the innards of living cells.

  撕逼的结果就是，两边都是赢家，也都是输家。Doudna和Charpentier赢了诺奖和成就感，而张锋赢了专利和商业利益。我个人看来，这个结果还算是公平的，但过程实在是非常令人遗憾。撕逼和对簿公堂的大量精力如果用在合作上，相信一定可以更快地推动人类的进步。但没办法，在利益面前，人非圣贤，每个人在主观上都会放大自己的价值，而淡化他人的贡献。这是人性。事实上，即便是共同合作良久并且赢了诺奖，Doudna和Charpentier之间也是心存芥蒂，貌合神离，并且到最后都分别成立了各自的公司。

  科学家也是普通人，我们并不能要求他/她们比其他人更高尚、更有胸怀，但我依旧向往那种学术界里乌托邦式的、传承的美好。正如书中写到的，诺奖结果公布之后的时刻，The nicest toast came from Jack Szostak, the Harvard professor who had turned her on to the wondersof RNA back when she was a graduate student. Szostak, who had won a Nobel in medicine in 2009 (jointly with two women), raised a glass of champagne while sitting in the backyard of his stately brick Boston townhouse. “The only thing better than winning a Nobel Prize,” he said, “is having one of your students win one.”

  第四，关于创新的范式。

  在书中的某些片段里，作者探讨了美国创新的范式。美国科研模式的创始人是MIT的Vannevar Bush。二战后，他给杜鲁门总统写了一份很长的报告，名为《科学：无尽的前沿》（Science The EndlessFrontier），建议将科学研究确定为美国永久的国策，建立研究性大学和国立实验室。这里的关键是让国家投入经费，但研究内容由科学家自主驱动。这一点是美国和其他国家不同的地方。美国只有很少的政府科研机构，大部分还是二战时为了战争的需要建立的，比如洛斯阿拉莫斯实验室、劳伦斯实验室等，此后几乎没有建立新的实验室。它甚至把一些国家实验室交给大学管理。即便是在实施阿波罗登月期间，NASA（美国航空航天局）也只是领头的机构，大量的工作交给了大学和公司的研究机构。这奠定了美国科技强国的基础。

  作者在文中将这种范式称为“linear model of innovation”，并且认为这种模式已经有些过时：There is some truth to the linear model. Basic research in quantum theory and surface-state physics of semiconducting materials led to the development of the transistor. But it wasn’t quite that simple or linear. The transistor was developed at Bell Labs, the research organization of the American Telephone and Telegraph Company. It employed many basic science theorists, such as William Shockley and John Bardeen. Even Albert Einstein dropped by. But it also threw them together with practical engineers and pole-climbers who knew how to amplify a phone signal. Added to the mix were business development executives who pushed ways to enable long-distance calls across the continent. All of these players informed and prodded each other.The story of CRISPR at first seems to accord with the linear model. Basic researchers such as Francisco Mojica pursued an oddity of nature out of pure curiosity, and that seeded the ground for applied technologies such as gene editing and tools to fight coronaviruses. However, as with the transistor, it was not simply a one-way linear progression. Instead, there was an iterative dance among basic scientists, practical inventors, and business leaders.Science can be the parent of invention. But as Matt Ridley points out in his book How Innovation Works, sometimes it’s a two-way street. “It is just as often the case that invention is the parent of science: techniques and processes are developed that work, but the understanding of them comes later,” he writes. “Steam engines led to the understanding of thermodynamics, not the other way round. Powered flight preceded almost all aerodynamics.”As Doudna and her team began working on CRISPR, two young food scientists on different continents were studying CRISPR with the goal of improving ways to make yogurt and cheese. Rodolphe Barrangou in North Carolina and Philippe Horvath in France worked for Danisco, a Danish food ingredient company that makes starter cultures, which initiate and control the fermentation of dairy products.Starter cultures for yogurt and cheese are made from bacteria, and the greatest threats to the $40 billion global market are viruses that can destroy bacteria. So Danisco was willing to spend a lot of money for research into how bacteria defend themselves against these viruses. It had a valuable asset: a historical record of the DNA sequences of bacteria it had used over the years. And that is how Barrangou and Horvath, who first heard of Mojica’s research into CRISPR at a conference, became part of the relationship between basic science and business.

  我个人认为这种评价是比较片面的。美国的科研创新和商业创新从来都是结合在一起的，在过去的很多年里，在各个领域，都证明了美国的科技成果转化是多么有效率。今天很多人感叹为什么SpaceX（美国太空探索技术公司）作为一家私营企业的航天技术如此先进，其实SpaceX拿的也是NASA的钱，只是美国的科研运作方式和世界上很多国家不同而已。事实上，美国研究最新飞机、导弹、潜艇技术的，都是拿了政府合同的私营企业和大学。这恰恰说明了Vannevar Bush模式的成功。

  真正值

  得讨论的，是科研创新范式的进化。之前听陆奇老师讲过，科学的发展经历了几个阶段，

  第一

  范式，实验科学，于12世纪起在西欧一些大学兴起，最早的倡导者是英国的R．培根，对实验科学产生巨大影响的是17世纪英国的F．培根；第二范式，理论科学，指偏重理论总结和理性概括，不局限于描述经验事实，例如牛顿、爱因斯坦等；第三范式，计算模拟/仿真，在20 世纪50、60 年代兴起，起初应用于洲际导弹的研制、阿波罗登月计划、核电站运行等方面。第四范

  式，是由图灵奖得主、关系数据库的鼻祖吉姆·格雷生前的最后一次演讲中提出。他认为科学的第四范式是“数据密集型的科学发现”，是数据驱动的创新。

  的确

  ，

  在数字化进程已经十分深入、计算能力不断增强的今天，站在下一波科学进化最前沿的究竟是谁？按照陆奇老师的说法，“人工智能前沿到底是谁真正在驱动？答案是有一些大公司，也有一些大学和科研机构，但其中跑得最快的却是DeepMind、OpenAI、SpaceX这样的研究型创业公司。DeepMind可能大家最近都知道，AlphaFold对蛋白质折叠有巨大的突破，OpenAI的GPT3对创新也带来了巨大的影响，SpaceX对航天发展的贡献，这些都是新一代的emergent的体系在形成。这些都是小公司开启的革命，但是它们有长期的、宏大的使命，有数据和研究的能力，它们走得比大公司还快。数字化技术和交叉学科正在大大加速科学和技术的发展，比如信息科学、生命科学和材料科学等。我们活在一个非常振奋人心的时代，如果观察每个科学领域，它们几乎都在高速发展。”

  10

  年后，20年后，市值最高的公司还是Facebook、微软、Amazon和苹果吗？还是说，会有第四范式驱动的新物种跑出来？这让人十分兴奋，也十分期待。

  最后，关于大自然的美丽，关于造物主的神奇。在阅读的过程中，让我印象最深刻的，始终还是CRISPR这种机制的巧妙之处 - 这是细菌的免疫机制，在CRISPR那些“成簇的有规律间隔的短回文重复”当中，我们看到的是亿万年以来细菌幸存者的记忆，是进化论的遗产。到目前为止，人类在生物学领域取得的绝大部分进展，都不是“原创”的，而是“大自然的搬运工”。费曼说过，What I cannot create, I do not understand。我们对于宇宙的理解还如此浅薄，以致于我们还只能做粗鄙的抄袭和简陋的模仿，离从零开始创造一个生命，还有遥远的距离。然而，哪怕仅仅是抄袭和模仿，在那些“顿悟”的时刻，在那些窥见答案的瞬间，依旧让人无比幸福。

  书中提到了Doudna的顿悟时刻：They paused for a moment and looked at each other, then Doudna said, “Wow.” As she recalls, “It was one of those moments in science that just comes to you. I had this chill and these little hairs on my neck standing up. In that moment, the two of us realized that this curiosity-driven, fun project had this powerful implication that could change the direction of the project profoundly.” It’s a fitting scene to imagine: the behavior of a little molecule being able to get the little hairs on Doudna’s neck to stand up.

  以上。