内容来源：https://www.quantamagazine.org/whats-the-future-of-gene-editing-20260611/

内容总结：

基因编辑技术未来展望：从革命性发现到临床突破

一项源自亿万年前细菌免疫系统的基因编辑技术——CRISPR，正在重塑生命科学领域。这项荣获2020年诺贝尔化学奖的突破性发现，已从实验室走向临床应用，为遗传疾病患者带来新生。

从细菌防御到基因编辑利器

CRISPR（成簇规律间隔短回文重复序列）本质上是细菌为抵御病毒入侵进化出的免疫系统。当细菌遭遇病毒攻击时，会截取病毒DNA片段存入自身基因组，形成"免疫记忆"。2012年，科学家成功将这一机制改造为可编程的基因编辑工具，通过引导RNA定位，配合Cas9蛋白这把"分子剪刀"，实现对任何物种基因组的精准切割与编辑。相比此前技术，CRISPR操作简便、适用范围广，迅速在全球实验室普及。

临床应用初现成效

2024年8月，一名患有罕见代谢疾病的男婴"KJ"成为CRISPR疗法的受益者。这名新生儿因基因突变无法正常消化蛋白质，生命垂危。研究团队利用已获批的CRISPR技术和新冠疫苗递送载体，在8个月内完成从诊断到治疗的全过程。经过三次治疗，患儿肝脏细胞得以修复，目前健康状况良好。这一案例证明，CRISPR疗法可实现"一次性"治疗，无需终身服药。

前沿探索：心血管疾病与农业应用

CRISPR正在心血管疾病防治领域展现潜力。研究发现，部分人群因特定肝脏酶基因变异而天然具备心血管保护作用。目前制药巨头礼来已收购相关初创公司，推进"一劳永逸"的降胆固醇基因疗法。此外，该技术还被用于培育抗旱作物、改造牛肠道微生物以减少甲烷排放，应对气候变化挑战。

伦理挑战与公共安全

2018年，中国科学家贺建奎擅自使用CRISPR编辑人类胚胎基因，引发全球伦理争议。对此，诺贝尔奖得主杜德纳强调，该行为存在三大问题：医学上不必要（已有成熟HIV阻断方案）、知情同意不充分、以及造成可遗传的基因修改。她指出，虽然国际社会对此予以坚决抵制，但仍有公司在探索生殖细胞编辑服务，这凸显持续开展公众科普与伦理讨论的必要性。

未来展望：递送难题待解

尽管前景广阔，CRISPR技术面临关键瓶颈——如何高效靶向不同组织器官。目前递送技术主要适用于肝脏，对肺部、肌肉、大脑等部位的修复仍有困难。杜德纳表示，这需要工程学创新与基础科研的协同突破。她领导的创新基因组学研究所正聚焦两大方向：一是分子机制的基础研究，二是跨学科合作攻克递送难题。随着人工智能加速科研进程，这项曾改写生命密码的技术，正在开启精准医疗的新纪元。

中文翻译：

基因编辑的未来是什么？

引言

CRISPR是近代科学史上最令人惊叹的发现之一。CRISPR是"成簇规律间隔短回文重复序列"的缩写，它是一种免疫系统形式，超过十亿年前在细菌中进化而来，用于抵御持续性的病毒威胁。受到攻击时，细菌可以剪下病毒DNA的一个小片段，将其储存在自身基因组的CRISPR区域中，然后利用它来识别并摧毁再次入侵的同一病毒。全称为CRISPR-Cas9的系统由一段负责识别DNA切割位置的小向导RNA和一个充当分子剪刀的蛋白质组成。

真正让这一系统具有革命性意义的是2012年的一个证明：它可以通过不同的向导RNA片段重新编程，以极高的精确度和便捷性编辑几乎任何物种的任何基因组，其水平远超现有的基因编辑工具。自那以后，CRISPR的编辑能力已应用于从开发疾病疗法、培育抗旱作物到复活灭绝物种基因等各个领域。其可能性扩展如此迅速，以至于研究人员、伦理学家和监管者都感到难以跟上步伐。

詹妮弗·杜德纳是深刻理解CRISPR力量的人之一，她是该技术的共同开发者。杜德纳因这项开创性工作与埃马纽埃尔·卡彭蒂耶共同获得了2020年诺贝尔化学奖，她不仅为其巨大潜力发声，也积极倡导其负责任和合乎伦理的使用。在本期《探索之乐》节目中，杜德纳告诉联合主持人詹娜·莱文，她早期"叛逆地"决定研究RNA是如何引领她偶然走上了通往生物学最具变革性发现之一的道路。她们还讨论了将定义CRISPR真正影响力的突破、障碍和前沿领域。

您可以在苹果播客、Spotify、TuneIn或您喜欢的任何播客应用上收听，也可以从Quanta网站直接流式播放。

文字记录

[音乐播放]

詹娜·莱文：好了，我们开始吧。我是詹娜·莱文。

史蒂夫·斯特罗加茨：我是史蒂夫·斯特罗加茨。

莱文：这里是《探索之乐》。

斯特罗加茨：一档来自《Quanta杂志》的播客，我们在此探讨当今数学和科学领域一些最大的未解之谜。

莱文：嗨，史蒂夫。我们又见面了。

斯特罗加茨：嗨，詹娜。新一季开始了。

莱文：是啊，真有趣。第五季了。我今天非常激动能和你聊聊CRISPR。我们以前聊过这个吗？

斯特罗加茨：没有，我们没聊过。

莱文：你还记得第一次了解CRISPR基因编辑机制是什么时候吗？

斯特罗加茨：嗯，我听说过CRISPR，但我几乎一无所知。我应该把它看作是某种分子剪刀，能够由细菌自己来切割细菌的DNA吗？

莱文：是的，天哪，你现在是要考我了，但没错。CRISPR，是一种既能切割DNA又能插入DNA的机制。所以它是剪切和粘贴的结合。

斯特罗加茨：啊哈！

莱文：我非常清楚地记得有人向我描述过，细菌中存在一种天然机制，表明它们可以编辑自己的基因组，例如拼接入侵病毒的DNA，并将其储存起来以备后用，这样如果同样的病毒再次攻击，它作为免疫系统会更有效。

斯特罗加茨：这本身就是一个非常酷的想法。我的意思是，撇开它可能有的任何应用不谈，我记得高中生物学上讲细菌没有任何免疫系统。

莱文：是啊。我是说，非常简单的生物体。我也在想这个，你只要想象一下它的分子按照既定程序运行，对吧？只是随机游走。当你从这个角度去听，听起来像是天才的杰作。然而，实际上并没有任何"思考者"在指挥。只是分子在做出反应。

斯特罗加茨：你知道吗，谢谢你这么说。因为当你听生物学家谈论这个或那个机制时，很容易忘记背后并没有一个"主宰"在思考。这，这仅仅是分子。

莱文：是的。只是一点点正电荷让它向这边移动一点。如此复杂精妙的东西，竟然能通过这样一步步迭代、仅仅基于基本电吸引的简单应用而涌现出来，并且对生物体的生存乃至生物体的定义本身都至关重要，这真是太不可思议了。绝对令人着迷。当然，这就是我们的历史。我们最终都源自非常简单的生物体，一路回溯，然而我们却没有CRISPR机制。

那么，让我来介绍一下我们的嘉宾。詹妮弗·杜德纳是生物化学、生物物理学和结构生物学教授。她因在CRISPR方面开创性的杰出工作而共享了2020年诺贝尔奖。顺便说一句，我相信这是首次两位女性共同获得诺贝尔奖。她在加州大学伯克利分校工作，并领导创新基因组学研究所，此外还做了很多其他事情。

多年来我一直想和她交谈，因为我觉得她的工作非常吸引人，而她也是一位极其多产且成果丰硕的科学家。真是个了不起的人。

现在，有请詹妮弗·杜德纳。

[音乐播放]

莱文：欢迎来到《探索之乐》，詹妮弗，非常高兴能邀请到你。

詹妮弗·杜德纳：我很高兴能来这里，詹娜。

莱文：感谢你加入我们。我说过我是你工作的超级粉丝。多年来我一直在尽可能关注你的研究。对你来说，你的职业生涯是如此难以置信地充满传奇色彩。你成就斐然，极其多产，无论在学术界还是产业界。你确实发现了一种重写生命密码的方法。这是一个影响深远的发现。我想每个人都想知道你成功的秘诀，或者至少是什么吸引你投身这个领域？你怎么知道你与这个领域是如此的天生契合？

杜德纳：嗯，詹娜，首先我要说，我当然不知道我与我的研究领域是天生的契合。我碰巧在夏威夷的一个乡村岛屿上长大。高中时我对化学着了迷。我有一位很棒的化学老师，我对岛上看到的生物多样性感到惊奇。我想我把这些都结合起来，对自己说："我想了解这一切的化学原理，想了解生命是如何进化的。"

在我读到詹姆斯·沃森的《双螺旋》之前，我其实并不真正从化学角度了解这一切。我想是那时我意识到，科学是一个发现的过程。它不是关于记忆一堆事实。而是关于弄明白事情。我记得很清楚，在高中时我就想，靠"弄明白事情"来获得报酬，这将是一个很有趣的职业，我想这就是我一直追求的东西。

莱文：《双螺旋》是一个引人入胜的发现故事。它确实是一本经典好书。他们如何从化学跨越到生命，这个过程太令人兴奋了。我在阅读你的工作时也常有这种感觉。它确实是对分子、化学键、酶和蛋白质折叠的描述。如何从那里到达"生命"，似乎仍然极其难以捉摸。这仍然是你巨大的好奇心来源吗？

杜德纳：这是一个好奇心的来源。我的工作领域是生物化学。我们一直与纯化的分子打交道，试图弄清楚它们的功能，它们在细胞内部做什么。但是，利用这样的知识，并试图将其编织成一个能够解释进化，或者只是解释我们自身身体和世界中体验到的生物学故事，这是一个巨大的跨越。所以，我们仍在为此努力。

莱文：是的，真迷人。你攻读博士学位是在80年代中期，你的研究工作大约在人类基因组计划开始成为真正可行的可能性、并吸引了很多人注意力的时期……所有这些关于DNA的工作。但你却选择了研究RNA的方向。你甚至自己描述这是一个有点大胆和冒险的举动。是什么促使你离开主流方向，转而研究RNA，即使你知道这有风险？

杜德纳：嗯，我觉得这有点叛逆，我想。老实说，这是部分原因。但我想，当你读研究生时，我那时还很年轻，二十岁出头，一无所知，我非常有幸能与一位杰出的导师——杰克·绍斯塔克一起工作，他是一位酵母遗传学家。

他研究染色体如何在酵母细胞中分裂。听起来有点深奥，但实际上，从这个系统中产生了许多基础性发现，最终与人类染色体如何出错并导致癌症等问题相关。所以这当然是一条有趣的研究路线。

然而，当我到达绍斯塔克的实验室时，他说："实际上，我正在改变我的研究领域，因为我对进化，特别是生命的起源产生了浓厚的兴趣。"

莱文：正是那个问题。

杜德纳：我想，哇，我想不出比这更大的问题了。不仅如此，他对如何发现这个问题有一条非常具体的实验路径。他很好奇RNA分子实际上可能如何通过DNA在地球上存在之前先于DNA存在，从而产生现代生命，也许RNA可能作为一种自我复制的遗传物质形式扮演了原始角色。

所以，你知道，我再次对那一切一无所知，但这听起来当然很神奇，这就是我最初进入这个领域的原因，实际上是受他的鼓励，以及我能够跳上一个看似有点叛逆的项目，而当时其他人基本上都没有在那个领域工作。

莱文：是的，当时RNA被严重低估了。我的意思是，他提出了这个听起来相当宏大的建议，但在当时，这并不是关于RNA的主流想法，对吧？我的意思是，RNA当时有点被低估了。

杜德纳：嗯，公平地说，有一些远见卓识者确实在思考这个问题。汤姆·切赫就是其中之一。

他与西德·奥特曼因发现催化性RNA（即可以像酶一样发挥功能的RNA）而共同获得了1989年诺贝尔奖。还有一群相当有趣的人，他们也对生命起源的问题非常感兴趣，并研究那些具有催化性质（可以像酶一样发挥作用）或在生物学中扮演其他非常重要角色的RNA分子的奇特例子。例如，作为病毒的遗传物质。对我来说，正是那些同事，实际上是我的前辈，是那一整代对当时并非主流的这些问题感兴趣的科学家，对我产生了巨大的影响。

特别是，我在1987年作为研究生二年级学生参加的一次科学会议，在那里我有机会看到许多人做讲座并第一次见到他们，这对我未来职业生涯的决定产生了巨大影响。

莱文：结果如何？RNA是否真的在生命进化过程中先于DNA出现？这是一个我们能回答的问题吗？

杜德纳：嗯，很难确切地回答，因为除非我们造出时间机器，否则我们无法真正回去验证，对吧？但我认为多年来令人着迷的是，越来越多的证据表明那个理论可能是正确的，或者至少它是地球进化故事的一个重要部分。

RNA最初从何而来仍然存在争议。你知道，它是在地球上产生的，还是来自宇宙的其他地方，像种子一样到达我们的星球？人们仍在争论这类事情。这是一个有趣的推测，但有很多证据表明，RNA可能是地球上第一种产生生命的自我复制生物分子。

莱文：嗯，我的意思是，胚种论的想法很迷人，但它也只是把问题往后推了。它总得在某个地方出现。但这确实是一个迷人的可能性。那么，你当时在这里，试图理解这些深奥的问题。这又是如何引导你走向CRISPR的故事的呢？

杜德纳：老实说，这是一条迂回曲折的道路，而这实际上也是我在科学工作中更普遍的体验：我认为你从一个方向开始，如果你对沿途出现的有趣想法和结果保持开放，道路就永远不会是笔直的。

就我而言，这个过程最初是我们研究催化性RNA，特别是了解它们的分子结构，试图找出它们如何能以酶的方式发挥作用，这是一个非常有趣的问题。坦率地说，现在依然如此。然后我们开始研究RNA分子如何控制基因表达的工作方式，这简单地来说就是控制在不同类型细胞中产生的蛋白质水平。

事实证明，这是所有生命都非常基本的东西。它不仅可能影响生物体的行为，当然也影响某些组织的形成方式、病毒的功能方式。基因调控的迷人之处，归根结底在于理解在任何给定时间产生的蛋白质水平。

大量证据表明，RNA分子以不同方式成为这个故事中非常重要的一部分。它们有助于控制基因的这些表达水平。因此，我们在病毒和不同类型的细胞中对此进行研究。那时我已经在耶鲁开始了我的职业生涯。2002年，我把实验室搬到了加州大学伯克利分校。我很着迷地结识了这里伯克利的吉尔·班菲尔德，她在计算层面发现了细菌中存在一个由RNA引导的适应性免疫系统的证据。对我来说，这是RNA分子控制基因表达的又一个迷人例子，我们想知道，它是如何工作的？

这实际上就是我进入CRISPR系统以及由此产生的所有CRISPR生物学的切入点。

莱文：哇。现在，CRISPR绝对是一个迷人的，我想我会说机制。你会如何最好地描述CRISPR？我的意思是，也许向门外汉解释一下这个缩写的含义会比较公平。

杜德纳：呃，让我试试看能不能想起来。成簇规律间隔短回文重复序列。哦！可别再让我说了！是的，有点拗口！

莱文：我有个小抄，如果我必须查的话。它是细菌基因组的一部分，对吗？

杜德纳：没错。它在细菌的基因组中，是基因组的一个非常特殊的部分，因为它实际上允许细菌创建一张"遗传疫苗接种卡"。

它们捕获来自病毒的小段DNA，并将其插入基因组中一个叫做CRISPR位点的特殊位置，该位点会随着时间的推移储存来自病毒的信息。它创造了一种惊人的，你知道，实时记录正在发生的感染。不仅如此，它不仅仅是"死"的信息，它实际上是一种会被重复利用的信息，以RNA分子的形式从DNA中的那些小模板中产生，这些RNA分子可以出去寻找DNA中匹配的序列。

当找到匹配时，它们会招募蛋白质过来剪断病毒DNA，从而保护细胞。

莱文：这简直难以置信，对吧？所以RNA扮演着非常积极的角色，出去消灭它可能以前感染过的病毒。但很难想象这一切仅仅是分子在电磁作用下相互作用。这，这确实是一个非常复杂的机制。我觉得一个有趣的问题是，为什么人类没有发展出这套惊人的免疫系统？

杜德纳：嗯，很难说为什么某种东西不存在，或者至少据我们所知不存在。但我想说的是，人类有其他防御病毒的方式，在某些方面更先进，它们是基于蛋白质的，能够对病毒本身也有巧妙方法试图避免免疫的情况进行非常复杂的防御。

我认为我们从CRISPR系统中看到的是，由于它们基于对病毒DNA序列的直接识别，这意味着病毒可以通过简单地突变其DNA序列来避免被检测到。这可能是我们在生物学中看到如此多种类CRISPR系统的原因之一。这些系统随着时间的推移一直在进行着活跃的进化。

莱文：它们必须保持领先。

杜德纳：它们必须保持领先。对吧？是的。所以我认为，当细胞快速生长时，比如细菌的繁殖速度与病毒的繁殖速度非常相似，这种机制是有效的。但是当病毒繁殖速度比它们感染的细胞快得多时，比如在我们体内，我怀疑如果是一个CRISPR系统，这种机制可能就跟不上了。因此，我们进化出了其他防御病毒的方法，以避开病毒中那些直接的逃逸机制。

莱文：现在，由于CRISPR机制也涉及切割宿主的DNA，它引入了可能损伤宿主自身的潜在风险。那么，修复机制是如何参与进来，以确保它不是一个破坏性超过保护性的系统呢？

杜德纳：嗯，在细菌中，这当然是重点，对吧？切割是免疫系统发挥作用的方式，它帮助细胞找到并切碎病毒DNA序列。但非常有趣的是，事实证明，在动物和植物细胞中，这些细胞对DNA切割的反应不同。它们检测到DNA中的切口，并倾向于修复它们，它们能够修复是因为有时间，这又是因为这些细胞的分裂速度远慢于细菌细胞。

因此，当DNA受到损伤时，例如由CRISPR引入的双链断裂，细胞可以找到断裂处并修复它。正如你刚才所说，当它们修复时，也就有了引入DNA序列改变的机会，而这正是CRISPR诱导基因编辑的基本原理。

莱文：现在，你在这里研究细菌中这种深奥的机制，可能对进化有关联。显然非常迷人。但随后有了一个巨大的进步，那就是考虑如何改变这种机制，使其能够编辑人类基因组。这是你特意寻求的目标，还是某种偶然意识到这是可能的？

杜德纳：嗯，这当然不是项目最初的目标。该项目旨在提出并回答一个关于细菌适应性免疫如何运作的问题。

然而，一旦我们理解了这种由RNA引导的、切割DNA的活性（涉及一种称为Cas9的蛋白质）的化学原理。你知道，这是一个极好的例子，说明当你做基础研究时，它会导向意想不到的方向。这种对RNA引导的DNA切割化学原理的理解，立即暗示了这种活性一个非常有趣的应用，即在像我们这样的细胞，或者像植物和动物细胞这样具有修复双链DNA断裂能力的细胞中，诱导精确编辑。

莱文：你提到了Cas蛋白。Cas蛋白具体有什么特别重要的地方？这些系统中蛋白质很多。那么，是什么让它如此重要？为什么它经常被并称为CRISPR-Cas9？

杜德纳：嗯，事实证明它是基因编辑的真正引擎，原因是它是执行DNA切割的酶。它使用来自CRISPR序列的RNA分子作为邮政编码。它是分子向导，告诉那个蛋白质去哪里以及在哪里切割DNA。

但Cas9是实际执行切割的机器。所以你真的需要两者结合，两者一起为在不同类型细胞中进行可编程的基因编辑提供了一个非常强大的工具。

莱文：一旦你开始编辑基因，你立刻意识到你有潜力从根本上改变地球上的生命，参与到进化过程中。但当时也有其他的基因编辑工具。这个基因编辑工具有什么特别之处，使它真正超越并普及，而其他基因编辑工具却没有真正发展起来？

杜德纳：嗯，你提出了一个重要的观点，因为你说得对，分子生物学家们长期以来一直在努力寻找精确操作基因的方法。

有一系列发现对实现这一能力起到了关键作用。一方面是对细胞中双链DNA断裂修复机制的理解，另一方面是弄清楚如何首先引入双链DNA断裂，尤其是在你可能希望诱导基因编辑事件的位置。

正因为这些知识已经存在，我认为它为CRISPR铺好了一条很好的道路，因为CRISPR提供了一种产生双链断裂的简便方法。不仅如此，回到Cas9蛋白的作用，关于CRISPR技术真正有趣且有点疯狂的是，我们可以使用完全相同的蛋白质来操作小麦、水稻、人类肝细胞、大脑等任何你想到的基因，对吧？它是同一种酶。之所以有效，是因为我们只需改变告诉它去哪里的向导RNA，就可以将其活性重定向到任何细胞类型中的某个目标基因。

正因为如此，它成了一种非常容易部署的技术，这正是我们在该领域看到的。2012年夏天，我和合作者埃马纽埃尔·卡彭蒂耶那篇原始文章一经发表，立即就有许多实验室开始使用它，并在不同系统中测试其基因编辑能力。这引发了一场巨大的竞赛，当然随后也开启了众多实验室将该技术用于各种应用的轨迹。

莱文：我的意思是，这是一生难得一次的发现。真的。你在回应与埃马纽埃尔·卡彭蒂耶共同获得诺贝尔奖时曾描述，那是一段充满喜悦的发现时光，仿佛是独特的，非常突出。我想知道，你会将其描述为一个恍然大悟的时刻，还是更多是发现的过程？

杜德纳：嗯，不是瞬间发生的，但实际上相当快。因为，你知道，这多少是我多年来在科学中的体验：当你发现某种真正重要的东西时，在某种意义上你会立刻知道。

对于CRISPR，我们当然无法预见该技术后来带来的一切。但我们真的几乎立刻就能看到这可以成为一个多么强大的工具，因为它部署起来非常容易，改变这个RNA分子并把Cas9送到基因组中不同位置是多么简单。以及这类技术的所有潜在用途。思考和想象可能实现的事情，真是令人兴奋。

莱文：那么，技术有没有发生重大变化？你认为自其发现以来，最具影响力的技术进步是什么？

杜德纳：嗯，自从CRISPR发现以来，它已经变成了一个完整的工具箱。发生这种情况的方式是，我们能够再次利用CRISPR系统作为RNA引导的识别和切割DNA机制的基本化学原理。

我们已经能够将其转变为一种以不同方式识别和改变DNA的机制。这真的使它成为一项极其通用的技术，现在可以用于各种不同类型的基因操作。坦率地说，我对所有这些都感到兴奋，因为我认为它为科学家提供了非常丰富的一整套技术，可以根据需要在不同场景中部署，而且这种势头只会持续下去。我的意思是，每次我去参加关于CRISPR的会议，我都会对工具箱的扩展感到震惊。所以我认为它只会变得越来越好，越来越好。

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斯特罗加茨：哇，听这个让我努力回忆我的一些生物学课程，比如"双链断裂"这个说法。我不确定自己是否完全理解这里发生了什么。让我们回想一下，如果我弄错了，你可能会纠正我。

DNA是双螺旋结构，我们都学过。它有两条链，你可以切断一条链而让另一条链保持完整。有些酶能造成单链断裂，从DNA分子或基因的完整性角度来看，这并不非常危险，因为你仍然有一条完整的链。在整个双螺旋结构中，碱基配对仍然存在。你在一条链上切了一个口子，但你没有把分子的"脊梁"打断。双链断裂则是字面意义上的将分子——DNA——切成两半。这是非常剧烈的操作。

莱文：对。原则上，这应该对细胞造成很大损害。

斯特罗加茨：是的，所以能够拥有不仅能造成这些双链断裂，而且能以可控方式进行操作的遗传机制，这一点让我很感兴趣。它有点像一种万能剪刀。可以在任何生物体中工作。

莱文：是的。

斯特罗加茨：而且你可以把它引导到任何地方。

莱文：是的，这太疯狂了。

斯特罗加茨：对吧？在过去，有些酶擅长切割一条链，但只有在序列是某某特定序列的时候才行，你知道，像是限制性更强的剪刀。这真是一个了不起的万能工具。

莱文：我认为她说得很好："它部署起来太容易了。"你立刻看到它马上在其他实验室得到使用。它的应用几乎没有障碍。我认为关于双链断裂这一点，单链断裂据我理解更容易修复。是的。原则上你可以修复，但不会改变DNA。但如果你造成双链断裂，你现在可以插入新的碱基对。

斯特罗加茨：好的。

莱文：而这正是CRISPR所做的。例如，从入侵病毒中获取DNA。它切割自己的DNA，并把病毒DNA放入自己的链中。它插入碱基对，你需要双链断裂来实现这一点。这之所以有趣，是因为你基本上制造了一张免疫卡，一个你自己能够针对该入侵者进行免疫的记录。至少在细菌中是如此。

现在我们可以从细菌的工具包中调整这个，并在人类中实施，从根本上改变遗传物质。

斯特罗加茨：真不可思议。

莱文：真不可思议。

斯特罗加茨：这与我学过的生物学完全不同，我想真正的专家也同样感到震惊，对吧？这真是一个里程碑式的发现。

莱文：我得说，这种对CRISPR的兴奋之情，我认为是我听说过的最迷人的科学发现之一，它有潜力从根本上改变人类的蓝图。

斯特罗加茨：现在可能实现的事情真是惊人。但这听起来像是在实验室里发现并测试的。它是否正走向病床边、走向临床？它是否在帮助真实的人？

莱文：是的，没错。詹妮弗讨论了几个案例，真实病人，活生生的人，他们之所以活着正是因为CRISPR疗法。所以，我们休息一下之后就来聊这个。

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莱文：欢迎回到《探索之乐》。今天我们请到了生物化学家詹妮弗·杜德纳，与我们讨论CRISPR和基因编辑的未来。

差不多不到20年，但我们正生活在这些真正具有影响力的技术进步的时代。你参与了KJ宝宝的工作。我们为什么不聊聊KJ宝宝呢？也许你可以告诉我们，这是一个非常具体的例子，说明了目前在治疗方面实际取得的成果。

杜德纳：嗯，KJ宝宝出生于2024年8月，他患有一种罕见的代谢疾病，出生后立即被诊断出来。他无法正常消化蛋白质，这意味着他病得非常重。他不能正常饮食。他体重不增。他住在新生儿重症监护室。你可以想象他的父母当时是多么悲痛欲绝，你知道，他们不顾一切地想要帮助他们的孩子。

幸运的是，他在费城儿童医院的临床团队意识到他可能患有罕见的遗传疾病，并能够迅速获取样本并对其DNA进行测序。他们发现这个男孩的两个编码一种消化蛋白质所必需的关键酶的基因拷贝都存在突变。

不仅如此，他们意识到这是一种原则上可以使用具有这种能力的CRISPR版本进行修复的突变类型。于是他们联系了许多团体，包括加利福尼亚州的创新基因组学研究所，请求帮助他们制造一种能够治疗这个男孩的CRISPR版本。难以置信，真的难以置信，我到现在还不敢相信，但这确实在八个月内发生了。

莱文：这太不可思议了。

杜德纳：这个婴儿接受了治疗，今天他看起来恢复得很好，这绝对太棒了。所以，你知道，这是一个关于团队合作的非凡故事。这是一个关于使用现成技术的非凡故事。不需要进行新的研究。我们可以使用现有的CRISPR版本以及最初为新冠疫苗开发的一种递送工具。通过将其用于患者，有可能创造出一种疗法——我不知道是否有人曾如此迅速地创造、测试并将一种疗法交付给患者。但现在我们知道这是可能的，这真的令人兴奋。

莱文：真迷人。我有好多问题，但当你提供这种疗法时，由于它是一种基因编辑疗法，是一次性给药吗？基因组就被编辑了？还是一种需要随时间重新给药的疗法？

杜德纳：嗯，在这种情况下，两者兼而有之，患者接受了三次治疗，但之后就没有了。我认为希望是对患者肝脏细胞的充分编辑——这些细胞本质上会随着时间的推移重新填充他的肝脏，已经得到了编辑，以至于他现在拥有一个功能正常的肝脏，能够产生他健康所需的消化酶。当然，这需要随着时间的推移进行监测。而且由于这是一个单一患者的情况，我们实际上无法测试他的肝脏中是否发生了编辑以及编辑了多少。我们只能通过观察他现在的生理特性，并试图评估他的健康状况。

但令人印象深刻的是，只需要这样一次非常简洁的递送。它不需要每天或每月治疗患者。他接受了三次这种疗法的治疗，我们希望这足以让他拥有正常的寿命和正常的前景。

莱文：太不可思议了。我的意思是，在人类健康治疗的其他领域，你也会看到这种可能性，比如心血管疾病，或者，我不知道，改变微生物组。你认为基因疗法最富有成效的方向在哪里？

杜德纳：嗯，你刚才提到了我们经常考虑的两大方向。所以我认为，心血管的角度很迷人。对于听到这个的人来说，可能并不明显，你知道，为什么CRISPR对治疗心脏病有用？但它确实有用。原因是许多研究表明，肝脏中具有某种特定形式的酶（能以不同于他人的方式处理胆固醇）的人，对心血管疾病有保护作用，因为他们往往不会随着时间的推移在动脉中积聚斑块。那么，如果能用CRISPR给每个人都赋予这种形式的基因，岂不是很好？这就是以这种方式使用CRISPR的原理。

事实上，有一家名为Verve的公司就是为了做这个而创立的，该公司已经展示了这种方法有足够的潜力，以至于去年它们实际上被礼来公司收购了。所以，你知道，甚至连大型制药公司都对追求一种策略非常感兴趣，这种策略可以为人们提供一个选项，无需每天服药、频繁注射或彻底改变饮食，而是通过一次性疗法，从基因上解决高胆固醇问题。

莱文：这就是好的一面，成功的故事。但大规模开发这些疗法也存在障碍。障碍是什么？它们都只是财务障碍或获得FDA批准的问题，还是存在实际的技术规模扩大障碍？

杜德纳：嗯，财务和监管障碍当然存在。KJ宝宝的案例特别令人兴奋的一点是，这些障碍被克服了，这说明了可能性。另一方面，我们知道这种策略并非对每个人都适用。很难大规模复制。例如，我们如何为患有其他罕见病的患者复制这条特定的路径？

所以，我认为该领域值得思考的是，哪些方法可以大幅降低成本，并使其他患者更容易获得这种类型的治疗。因此，我认为这不仅需要在工程和这些分子的制造方式上进行创新，这方面已经在进行以降低成本。但这也要回到科学和技术本身。例如，你知道，KJ宝宝很幸运，他的疾病影响的是肝脏，所以可以使用现成的递送技术将CRISPR分子引入他的肝脏细胞。但这对于那些患有肺病、肌肉疾病或脑部疾病的人来说是没用的。

因此，该领域目前真正的前沿之一，就是弄清楚如何解决所有其他组织类型的递送问题。我认为这是可以解决的。你知道，我非常看好这一点。但这需要真正的努力。我的意思是，你知道，它不会凭空发生。我认为我们必须真正专注于它。

幸运的是，许多人认识到这是一个重要的挑战。因此，我们看到了越来越多的这方面努力。我们加州创新基因组学研究所的许多年轻学生对此当然非常有动力。他们对此感到兴奋。这是一个难题。他们想努力攻克它。他们想弄明白。所以，我认为正是这种能量和创新将解决像递送这样的难题。

莱文：如果你有一个患有严重遗传病、预期寿命不长的新生婴儿，你可以想象不惜一切风险来治疗这个孩子。但对于那些有替代疗法的人，人们对进行像编辑自己基因组这样激进的事情有多害怕？是否有负面后果？在编辑的内容、编辑的方式或免疫反应方面，出现错误的可能性存在吗？

杜德纳：是的。嗯，你知道，任何技术当然都有风险，对吧？特别是基因编辑，你可以想象，对吧，你不想得到不准确的结果，或者编辑了非预期的甚至是有害的位点。你当然不想陷入编辑后果导致不良结果的情况。

我认为一个很好的例子实际上是镰状细胞病的情况，因为这种疾病中，镰状细胞突变在人类群体中的存在，可能部分原因是它能提供一些抵抗疟疾感染的保护。所以，那些拥有一个拷贝的所谓镰状细胞基因的人，表型上是正常的，但他们有一定程度的抗疟疾感染保护。所以你可以说，在疟疾流行的世界部分地区，拥有这个突变对他们来说是一种优势。

这只是一个很好的提醒，我们的遗传学很复杂，基因，你知道，不一定非好即坏。它们可能根据情况好坏参半。所以我认为，基因编辑，我们必须谨慎使用，因为它确实需要大量了解一个遗传改变在一个人的一生中会产生什么影响。

莱文：是的，你提出了一个迷人的可能性：一个我们认为纯粹有害的基因，实际上有保护作用。我们经常谈论，你知道，也许近视的人也在某些能力上有关联，或者你修复了一件事，却可能损害另一件。我认为这对于人类来说通常是正确的。

这也引发了一些伦理问题，我知道你对伦理问题有很多思考。我觉得我们必须谈谈那个有点令人震惊的案例：2018年，一位中国科学家使用CRISPR对人类胚胎进行基因改造，这似乎真的越过了底线，导致了一对双胞胎女婴的出生。据我所知，他试图让婴儿对HIV具有抵抗力。现在，当你听到这个消息时，你感到震惊吗，还是你觉得有人会逾越这条不成文的伦理底线是不可避免的？

杜德纳：这很令人震惊。不，这绝对是令人震惊的。不过这之前我已经想过，你知道，这当然是可能的。这个特定的人当时一直在参加关于基因编辑的会议，所以他对基因组编辑界来说并不陌生。

但尽管如此，发现这不仅仅是闲聊，而是他确实采取的实际行动，当然还是令人震惊。一旦细节被披露，很明显，出于多种原因，这是一件极其不道德的事情。

你知道，如果这个故事有什么好的方面，那就是我认为国际上的人们立刻认识到这是错误的，并对此表明了立场。事实上，那位科学家被捕了，他的实验室被关闭，他被监禁了几年。所以，让我们看看未来会发生什么，但我很高兴，我想，国际社会对他的行为做出了非常强烈和一致的回应。

莱文：最大的问题是它是针对胚胎的，是编辑生殖细胞系。换句话说，它可能被遗传下去。与另一种疗法相比，这是越过的最大底线吗？

杜德纳：嗯，对我来说，甚至比这更重要的是，首先它的使用方式在医学上是不必要的，因为已经有其他经过验证的方法可以保护那些婴儿在发育和出生过程中免受HIV的传播。

其次，从我看到的证据来看，我认为父母并不特别清楚他们实际同意了什么，这也是非常令人震惊的。然后，正如你提到的，第三点是这是一项永久性的技术。不仅如此，当你在胚胎中操作时，你所做的改变是可遗传的。所以这些改变现在将传递给后代，我们真的不知道这会产生什么影响。

莱文：你认为是否还有其他不道德的人在偷偷进行这类实验？如你所说，这是一项极其灵活、可编程、快速且不太昂贵的技术，这也让它有点可怕。

杜德纳：你知道，这是可能的。我认为我的评估是，最初的那个肇事者，我想你可以这么说，对于CRISPR生殖系应用，坦白说，我认为他的很多动机是为了博取名声。所以我认为现在的一种威慑因素是，今天如果有人再这样做，得到的舆论将会非常负面。

然而，你知道，我们确实知道有些公司，例如，我听说过全国有少数几家公司在再次探索生殖系编辑的可能性，并将其作为一种服务提供给人们。所以，这并非已经不在考虑范围之内，或者没有人再想这件事了。我认为它仍然存在于环境中，我们必须看看未来会发生什么。但这对我来说，只是强调了公众参与的重要性，以及科学家参与到关于CRISPR及其应该如何使用的对话中的重要性。

莱文：使用这项技术对气候、植物生命也有影响。我的意思是甚至可能涉及食物，以解决粮食短缺问题，或者像疟疾这样的疾病，你可以在昆虫层面阻止它，而不是在人体层面。你认为这些进展会如何推进？这是目前非常活跃的领域吗？

杜德纳：是的，相当活跃，我认为现在我们正看到CRISPR在这类事情上的应用出现真正的上升趋势。尤其是在应对气候变化带来的挑战方面，无论是在粮食安全方面，我们如何确保拥有抗旱、抗虫、营养价值提高的健壮植物。所有这些都是使用CRISPR的有趣应用。

另一个是直接考虑碳排放，以及涉及改变牛体内微生物组以避免甲烷排放的应用。牛是全球每年甲烷排放的主要来源之一，而CRISPR原则上可以通过改变那些微生物的基因来减少甲烷排放，可能是永久性的。所以，我认为这是让我非常兴奋的事情，也是创新基因组学研究所这里的一个活跃项目。

莱文：你认为在未来十年你的研究中，主要关注点是什么？你会更专注于产业和应用，还是回到实验室的探索？

杜德纳：嗯，两者都有。我认为，你知道，在我自己的研究实验室里，我继续有同事在做基础发现，坦白说，现在这项努力中涌现出许多令人兴奋的工作。同时，我们也认识到解决递送挑战的价值。我认为这是一个巨大的挑战。

我们在实验室里不是工程师。我们喜欢工程师，但我当然不是工程师。但有机会从根本上理解细胞如何吸收新分子，这些分子如何进入特定类型的细胞，这其中的许多机制基础，正是像我的实验室这样的地方喜欢深入挖掘的东西。所以这两方面肯定是我们将要关注的两个领域。

除此之外，我真的很想继续担任导师。我很高兴看到，在我们研究所这里，我们已经能够招聘一批年轻教师，他们正在启动自己令人兴奋的研究项目，这些项目与研究所的整体目标和使命相一致。这些人在很大程度上是因为他们热爱处理重大而困难的问题而来到这里。他们喜欢合作。他们喜欢在湾区这里工作，因为我们能接触到各种类型的不可思议的资源。

我们喜欢正对着海湾，与硅谷隔海相望。你知道，随着人工智能不断进步并加速我们的工作步伐，我们越来越多地将其整合到我们所做的事情中。所以这真的很有趣，我想做更多这方面的工作。

所以我要说，这是一个非常激动人心的时刻。

莱文：当你最初从事这项工作时，在早期，当你从研究RNA转向研究CRISPR，并意识到它在重写生命密码方面的惊人力量时，可以说是这样。当你回顾那段时期，你是否会怀念那一切开始之前、成功和关注到来之前，以及看到它正在对这么多其他研究人员和这么多其他工作产生影响之前的那段时光？

杜德纳：嗯，是的，呃，我的生活在2012年左右确实发生了巨大变化。我经常开玩笑……我丈夫也是加州大学伯克利分校的教授……我经常，呃，跟他开玩笑说，我的生活分BC时期——CRISPR之前——然后一切都变了。

你知道，我怀念吗？嗯，是的，有些部分我确实怀念。你知道，每天走进实验室，和我的学生们待在一起，这是一种快乐。我尽可能地多这样做，但是，你知道，我也在做像现在这样的事，这没问题，你知道，但感觉不一样了。

而且，是的，我非常热爱科学。我热爱发现的过程。我热爱与那些刚刚开始职业生涯的科学家一起工作，你知道，他们富有创造力。他们无所畏惧。他们想弄明白事情。而且，你知道，科学总是充满挣扎，对吧？总是很难。所以我确实很享受和他们一起经历那种挣扎，但我现在做得不如从前多了。我确实很怀念。

莱文：所有伟大的故事都必须有挣扎。

杜德纳：当然。

莱文：没有挣扎来推动情节，就写不出伟大的书。

非常感谢你，詹妮弗。这真是一个令人脑洞大开的话题。看到它向前发展，看到它正在发生，而且实际上发生得很快，真是太令人兴奋了。我们将活着看到这一切的影响。非常感谢你加入我们。

杜德纳：谢谢你邀请我，詹娜。很高兴来到这里。

[音乐播放]

斯特罗加茨：哇，听这个让我感触良多。首先是，我记得有一次旁听进化生物学家兼作家斯蒂芬·杰伊·古尔德的讲座时，他说过这样的话：那是细菌的时代，现在是细菌的时代，而且永远都将是细菌的时代。

你知道，我们看不到它们。我们不太会去想它们。但它们如此重要，你可以像詹妮弗·杜德纳和她的合作者们那样，通过关注细菌，了解到关于生命的如此多的东西。

莱文：是的。但与一个对技术、疗法、改善人类状况的潜力有如此直接影响的人交谈也很有趣，但这并不是她当初开始的原因，这是人们常常忘记的一点。这真的是好奇心驱动的科学，是她一生都保持的那种孩童般的热忱。我们如何说服人们，我们需要鼓励这种精神，才能对人类产生这样的影响？

斯特罗加茨：嗯。如果我们能以一种对人们真正有吸引力的方式来讲述科学史，那可能会有所帮助。你知道？我的意思是，在整个科学史上，我们听到这些关于偶然发现的故事，有人发现了如此重要的东西，而且常常被描述为偶然。

但我在某处读到过，你不应该认为它完全是偶然。以她为例，她当时确实在非常专注地寻找某些东西，思考细菌中的RNA。但她最终发现了她并没有在寻找的东西，并且以某种方式让你的思维进入那种好奇和警觉的状态——我的意思是，就是那句老话：机会只眷顾有准备的头脑。

莱文：嗯嗯。哦，你肯定能在她的故事中体会到这一点。"然后我遇到了某某，然后我们讨论了这个问题。"所以这并非她只是坐下来，剩下的只是时间问题。其中确有偶然性。有做决定，选择对某人保持开放态度，选择就你正在研究的课题稍微偏离中心的东西进行对话，并愿意用你所拥有的一切去追求它。

斯特罗加茨：这也是我作为科学家或数学家在我们更广泛的集体事业中所思考的——闪电会降临到我个人头上吗？你知道，我们的工作中有自我意识。我有时不得不提醒自己，只要发生在某人身上，是否发生在我身上并不重要。

莱文：是的，绝对如此。好了，史蒂夫，我们下次再聊。让我们都回去工作吧。

斯特罗加茨：好的。去工作吧，詹娜。下次见。拜拜。[笑声]

莱文：再见。

[音乐播放]

斯特罗加茨：如果你喜欢《探索之乐》并且还没有订阅，请在你收听的地方点击订阅或关注按钮。你也可以为节目留下评论。这有助于人们找到这个播客。在Quanta Magazine [DOT] org上可以找到文章、新闻通讯、视频等等。

莱文：《探索之乐》是《Quanta杂志》的一档播客，是一份由西蒙斯基金会支持的编辑独立出版物。西蒙斯基金会的资助决定对本播客或《Quanta杂志》的主题选择、嘉宾或其他编辑决策没有影响。

《探索之乐》由PRX Productions制作；制作团队包括凯特琳·

英文来源：

What’s the Future of Gene Editing?
Introduction
One of the most surprising and remarkable discoveries in recent scientific history has been CRISPR. Short for Clustered Regularly Interspaced Short Palindromic Repeats, CRISPR is a form of immune system that evolved in bacteria more than a billion years ago to defend against persistent viral threats. Under attack, bacteria can snip a small fragment of a virus’s DNA, store it in the CRISPR region of their genome, and then use it to recognize and destroy the same virus if it returns. The CRISPR-Cas9 system, to give it its longer name, consists of a short strand of guide RNA that identifies where to cut the DNA and a protein that acts as the molecular scissors.
What made this system truly revolutionary was the demonstration in 2012 that it could be reprogrammed with different pieces of guide RNA to edit virtually any genome in any species, and at a level of precision and ease that far surpassed existing gene-editing tools. Since then, the editing capability of CRISPR has been tested on everything from developing disease treatments to engineering drought-resistant crops to resurrecting genes of extinct species. The possibilities have expanded so rapidly that researchers, ethicists, and regulators have found themselves struggling to keep up.
One person acutely aware of the power of CRISPR is Jennifer Doudna, co-developer of the technology. Doudna, who received the Nobel Prize in Chemistry in 2020 with Emmanuelle Charpentier for this pioneering work, has been a prominent voice not only for its vast potential but also for its responsible and ethical use. In this episode of The Joy of Why, Doudna tells co-host Janna Levin how her early, “rebellious,” decision to study RNA led her on a serendipitous path to one of biology’s most transformative discoveries. They also discuss the breakthroughs, barriers, and frontiers that will define CRISPR’s true impact.
Listen on Apple Podcasts, Spotify, TuneIn or your favorite podcasting app, or you can stream it from Quanta.
Transcript
[Music plays]
JANNA LEVIN: Okay, here we go. I’m Janna Levin.
STEVE STROGATZ: And I’m Steve Strogatz.
LEVIN: And this is The Joy of Why.
STROGATZ: A podcast from Quanta Magazine, where we discuss some of the biggest unanswered questions in math and science today.
LEVIN: Hi, Steve. Here we are.
STROGATZ: Hi, Janna. It’s a new season.
LEVIN: I know, this is fun. Season Five. I’m pretty excited to talk to you about CRISPR today. Have we ever had this conversation?
STROGATZ: No, we have not.
LEVIN: Do you remember first learning about the CRISPR mechanism for gene editing?
STROGATZ: Well, I, I have heard of CRISPR, but I barely know anything about it. Should I think of it as some kind of molecular scissors that can do chopping of bacterial DNA by the bacterium itself?
LEVIN: Yeah, gosh, now you’re going to be challenging me, but yes. CRISPR, it’s a mechanism that can chop the DNA and then insert it. So it’s a combination of a cut and a paste.
STROGATZ: Aha!
LEVIN: And, I so distinctly remember hearing someone describe to me that there was a naturally occurring mechanism in bacteria which indicated they could edit their own genome and splice in the DNA of an invading virus, for instance, and store it for later so that it was more effective as an immune system if that same virus attacks.
STROGATZ: It’s a really cool idea in itself. I mean, aside from any applications it might have, I think I remember from high school biology that bacteria don’t have any immune system.
LEVIN: Yeah. I mean, pretty simple organism. I think about this also, if you just imagine its molecules acting as prescribed, right? Just moving around. When you hear it from this perspective, it sounds like a stroke of genius. Yet, there’s really nobody doing the thinking. It’s just molecules responding.
STROGATZ: You know, thank you for saying that. Because it’s so easy when you hear biologists talk about this or that mechanism. It’s good to remember there’s nobody home. This is, this is molecules.
LEVIN: Yeah. It’s just a little bit of positive charge making it move a little bit towards this. It is incredible that through this kind of iterative steps of just very simple application of basically electrical attraction that something this sophisticated could emerge, and is essential to the survival of an organism, and even the definition of an organism. Absolutely fascinating. Of course, this is our history. We come from very simple organisms ultimately all the way back down, and yet we don’t have a CRISPR mechanism.
So, let me tell you about our guest. Jennifer Doudna is a professor of biochemistry, biophysics, and structural biology. She shared the 2020 Nobel Prize for her incredible pioneering work on CRISPR. First time two women have won the Nobel Prize together, I believe, by the way. She’s at UC Berkeley, and she leads the Innovative Genomics Institute and does so much beyond that.
And I’ve been wanting to speak to her for many years because I find the work so fascinating, and she’s an incredibly productive and prolific scientist. Really incredible person.
If you will, here is Jennifer Doudna.
[Music plays]
LEVIN: Welcome to The Joy of Why, Jennifer, it’s such a pleasure to have you.
JENNIFER DOUDNA: I’m delighted to be here, Janna.
LEVIN: Thanks for joining us. I was saying I’m a big fan of your work. I’ve been following it for years as much as I can. For you, you have had such an unbelievably storied career. You’re so accomplished, incredibly productive, both in academia and outside in industry. You literally discovered a means to rewrite the code of life. It’s a discovery of almost unfathomable ramifications. I think everyone wants to know the secret of your success, or at least what drew you to your subject? How did you know you were such a natural match for this subject?
DOUDNA: Well, Janna, I’ll start by saying I certainly did not know that I was a natural match for my subject area. I happened to be growing up on a rural island in Hawaii. I got fascinated by chemistry in high school. I had a great chemistry teacher and I was amazed at the variety of life I saw on the island there. And I guess I put all of that together and said, “I wanna understand the chemistry of all of that, of how life evolves.”
And I didn’t really know about that from a chemical perspective until I read The Double Helix by James Watson. And I think it was the realization that science is a process of discovery. It’s not about memorizing a bunch of facts. It’s about figuring things out. I remember thinking clearly when I was in high school that it would be a really fun career to be paid to figure things out, and I think that’s what I’ve always pursued.
LEVIN: Now The Double Helix is a fascinating story of discovery. It really is a great classic book. How they go from chemistry to life is so exciting. I feel that a lot when I read about your work. It’s really descriptions of molecules and bonds and enzymes and protein folding. How you get from there to life just seems to still be tremendously elusive. And is that still a huge source of curiosity for you?
DOUDNA: It is a source of curiosity. My line of work is biochemistry. We’ve always worked with purified molecules and tried to figure out how they function, what they’re doing inside of cells. But taking knowledge like that and trying to weave it into a story that explains evolution or even just explains biology as we experience it in our own bodies and in our world. That’s a big stretch. So, we’re still working on that one.
LEVIN: Yeah, fascinating. When you were doing your PhD work, it was in the mid-’80s, and your work went on around the time the Human Genome Project started to become a really viable possibility and was grabbing a lot of people’s attention… all of this work on DNA. But you took the direction to study RNA. And you’ve even described that yourself as a kind of bold and risky move. Why was it that you were motivated to move away from where the crowd was going and to look at RNA instead, even knowing that it was risky?
DOUDNA: Well, it felt just a little bit rebellious, I guess. If I’m honest, that’s part of the reason. But I guess I feel that when you go to graduate school and I was, you know, very young, I was in my early 20s, I didn’t know anything and I had the really good fortune to work with an amazing mentor, Jack Szostak, who was a yeast geneticist.
So he studied how chromosomes divide in yeast cells. Sounds kind of esoteric, but actually a lot of fundamental discoveries were made from that system that ended up relating to things like how human chromosomes go awry and give rise to cancer. So that’s been an interesting line of work for sure.
However, when I arrived in Szostak’s lab, he said, “Actually, I’m changing my field of research because I’ve gotten very interested in evolution and specifically in the origin of life.”
LEVIN: Exactly the question.
DOUDNA: And I thought, wow, I can’t think of a bigger question than that. And not only that, but he had a very specific experimental path to discovery there. He was curious about how RNA molecules might have, in fact, given rise to modern life by preexisting DNA being around on our planet before there was DNA, and that perhaps RNA could have played an original role as a self-replicating form of genetic material.
So, you know, I didn’t know, again, anything about that, but it certainly sounded amazing, and that’s how I got into the field in the first place, was really through his encouragement and my ability to jump onto a seemingly kind of rebellious project at a time when nobody else, for the most part, was working in that space.
LEVIN: Yeah, RNA was highly underrated at the time. I mean, here he proposed this suggestion that seems quite grand, but that wasn’t really a popular thought about RNA at the time, was it? I mean, RNA was kind of underrated.
DOUDNA: Well, to be fair, there were a few visionaries who were absolutely thinking about that. Tom Cech is one of them.
He, with Sid Altman, won the Nobel Prize in 1989 for their discovery of catalytic RNA, RNA that could function like an enzyme. And then there were quite an interesting collection of people who were also very interested in questions about the origin of life and were investigating curious examples of RNA molecules that have either catalytic properties, they can function like enzymes, or seem to play other very interesting roles in biology. For example, serving as the genetic material of viruses. For me, it was really those colleagues, my superiors really, but it was that whole generation of scientists who were interested in these questions that were not really in the mainstream at the time, who had a huge influence on me.
And in particular, a scientific conference that I went to when I was a second-year graduate student in 1987, where I had the chance to see a number of those folks giving lectures and meeting them for the first time, hugely influential on my decisions for the future of my career.
LEVIN: And how did it play out? Does RNA have that role of possibly preceding DNA in the emergence of life in evolution? Is that a question we can answer?
DOUDNA: Well, it’s hard to answer it definitively because unless we build a time machine, we can’t really go back and check, you know? But I think what’s fascinating is that over the years, I think there’s only been increasing evidence that that theory is probably correct, or at least that’s an important piece of the story of evolution on the planet.
Where RNA came from in the beginning is still debated. You know, did it arise here on the planet, or did it come from somewhere else in the universe and arrive on our planet as a seed? People still debate that kind of thing. It’s an interesting speculation, but there’s a lot of evidence that RNA was probably the first kind of self-replicating biological molecule that gave rise to life on the planet.
LEVIN: Hmm, I mean, the idea of a panspermia is fascinating, but it also just sort of kicks the question down the road. It emerged somewhere. But it is a fascinating possibility. So here you are, you’re trying to understand these deep questions. How does that lead you to the CRISPR story?
DOUDNA: It was a circuitous route, if I’m honest, and this has really been my experience more generally in science, is that I think you start off in one direction, and if you are open to interesting ideas and results that come up along the way, the path is never straight.
In my case, that was through a process where initially we investigated catalytic RNAs and, in particular, understanding their molecular structures to try to find out how they could actually function in an enzymatic way, which was a very interesting question. Still is, frankly. And then we started to look into how RNA molecules control the way that gene expression works, and that simply means control the levels of proteins that are made in different kinds of cells.
It turns out that that’s something that is very fundamental to all of life. It probably influences not only organismal behaviors, but also the way that certain tissues form, the way that viruses function, of course. Fascinating aspects of gene regulation that really boil down to understanding the levels of proteins that are made at any given time.
There’s a lot of evidence that RNA molecules in different ways are a very important part of that story. They help control those expression levels of genes. And so we were investigating this in viruses and in different types of cells. And at that point I had started my career at Yale. I moved my lab to UC Berkeley in 2002. And I was fascinated to make the acquaintance of Jill Banfield here at Berkeley, who had discovered evidence at a computational level of an adaptive RNA-guided immune system in bacteria. So this was, for me, yet another fascinating example of RNA molecules controlling the expression of genes, and we wondered, how does that work?
And that was really my entrée into the CRISPR system and all of the CRISPR biology that came from that.
LEVIN: Wow. Now CRISPR is an absolutely fascinating, I guess I would say mechanism. How would you, how would you best describe CRISPR? I mean, maybe it would be fair to the uninitiated to tell us what the acronym stands for.
DOUDNA: Uh, let’s see if I can pull it out. Clusters of Regularly Interspaced Short Palindromic Repeats. Ooh! Don’t ask me to do that again! Yeah, it’s a bit of a mouthful!
LEVIN: I had a little cheat sheet somewhere if I had to look it up. It’s part of the genome of bacteria, is that right?
DOUDNA: That’s right. It’s in the genome of bacteria, and it’s a very special part of the genome because it actually allows bacteria to create a genetic vaccination card.
They capture little pieces of DNA from viruses and insert them into this special place in the genome called the CRISPR locus that stores that information from viruses over time. It, it makes an amazing, you know, recording really in real time of infections that are happening. And not only that, it’s not sort of dead information, it’s actually information that gets reused in the form of RNA molecules that are produced from those little templates in the DNA to make molecules of RNA that can go out and search for matching sequences in DNA.
When those matches are found, they recruit proteins that can come in and snip the viral DNA and protect the cell.
LEVIN: That’s just unbelievable actually, right? So the RNA is playing a really active role going out and then annihilating the virus that it might previously have contracted. But it’s hard to imagine that all of this is just molecules interacting electromagnetically. It’s, it really is such a sophisticated mechanism. I think one of the interesting questions is, why did humans not develop this amazing vaccination system?
DOUDNA: Well, it’s hard to say, you know, why something doesn’t exist, or at least as far as we know. But I guess what I would say is that humans have other ways of defending against viruses that are in some ways more advanced, in the sense that they are protein-based and they allow very sophisticated defenses against viruses that themselves have clever ways of trying to avoid immunity.
And I think what we see with CRISPR systems is that because they’re based on direct recognition of a viral DNA sequence, it means that viruses can avoid being detected by simply mutating their DNA sequences. And this is probably one of the reasons why we see so many different types of CRISPR systems in biology. There’s a lot of active evolution of those systems going on over time.
LEVIN: They have to keep ahead.
DOUDNA: They have to keep ahead. Right? Yeah. And so I think when you have rapidly growing cells, like bacteria that are reproducing on a scale that is very similar to the rate at which viruses are reproducing, that kind of works. But when you have viruses that reproduce much faster than the cells they’re infecting, like in us, I suspect that kind of a mechanism just can’t keep up if it’s a CRISPR system. And so we evolved other ways of being able to defend against viruses that avoid those immediate escape mechanisms in viruses.
LEVIN: Now, because the CRISPR mechanism also involves cutting the DNA of the host, it introduces the potential to damage the host as well. And so how does a repair mechanism get involved to make sure that it’s not a more damaging system than it is protective?
DOUDNA: Well, in bacteria, of course, that’s kind of the point, right? The cutting is the way that the immune system functions, so it helps the cell to find and then cut up viral DNA sequences. But what’s very interesting is that it turns out that in animal and plant cells, these cells respond to DNA cutting differently. They detect cuts in DNA, and they tend to try to fix them, and they can fix them because they have time, and that’s, again, because the cells are dividing much slower than if the cell is a bacterial cell.
And as a result, when there’s an insult to the DNA, like, say, a double-stranded break that gets introduced, for example, by CRISPR, cells can find the break and fix it. And when they fix it, as you just said, that’s an opportunity to also introduce a change to the DNA sequence, and that’s fundamentally how CRISPR works to induce gene editing.
LEVIN: Now, here you’re studying this esoteric mechanism in bacteria, might be relevant for evolution. Clearly really fascinating. But then there’s a big step forward, which is to contemplate how you might alter this mechanism to allow editing for, for the human genome. Was that something you intentionally sought out, or was it kind of an accidental realization that this was possible?
DOUDNA: Well, it certainly wasn’t something that was the motivation for the project in the beginning. The project was designed to ask and answer a question about how bacterial adaptive immunity was operating.
However, as soon as we understood the chemistry of that RNA-guided DNA-cutting activity of a protein known as Cas9. It was, you know, an amazing example of how when you do fundamental research, it leads in unexpected directions. That understanding of the chemistry of RNA-guided DNA cutting immediately suggested a very interesting application of that activity, namely to induce precision editing in cells like ours, or like plants and animal cells, that have this capacity to repair double-stranded DNA breaks.
LEVIN: You mentioned the Cas protein. What was so important about the Cas protein specifically. Proteins abound in these systems. So what was so important? Why is it often paired, CRISPR-Cas9?
DOUDNA: Well, it turns out to be the real engine of gene editing, and the reason is that it’s the enzyme that does the DNA cutting. It uses the RNA molecule that comes from the CRISPR sequence as the zip code. It’s the molecular guide that tells that protein where to go and where to cut DNA.
But Cas9 is the actual machine that does the cutting. And so you really need both together and the two together provide a very powerful tool for programmable gene editing in different kinds of cells.
LEVIN: Once you’re editing genes, you immediately realize that you have the potential to radically alter life on Earth, to participate in the process of evolution. But there were other gene-editing tools also at the time. What was so special about this gene-editing tool that really made it transcendent and ubiquitous in a way that the other gene-editing tools didn’t really take on?
DOUDNA: Well, you bring up an important point because you’re right, that there had been a fairly long-standing effort among molecular biologists to figure out how to manipulate genes in a precise way.
There were a whole series of discoveries that were made that were instrumental to that capability. Partly it was the understanding of how double-stranded DNA-break repair works in cells, and the other was figuring out how to introduce a double-stranded DNA break in the first place, especially at a place that you might want to induce a gene-editing event.
And so because that knowledge was preexisting, I think it created a very nice path for CRISPR because what CRISPR offers is an easy way to generate double-stranded breaks. And not only that, back to the role of this Cas9 protein, what’s really interesting and kind of crazy about the CRISPR technology is that we can use exactly the same protein to manipulate genes in wheat, rice, human liver cells, the brain, you name it, right? It’s the same enzyme. And the reason that works is because we can simply change the guide RNA that tells it where to go, and we can redirect its activity to a gene of interest in any cell type.
Because of that, it just makes it a very easy technology to deploy, and that’s really what we saw in the field. As soon as that original article with my collaborator Emmanuelle Charpentier was published in the summer of 2012, immediately there were many labs that started using it and testing it for gene editing in different systems. And that set off an enormous race, and then of course a trajectory of many labs adopting the technology for all kinds of applications.
LEVIN: I mean, this is the discovery of a lifetime. I mean, it really is. You described, in response to receiving the Nobel Prize with Emmanuelle Charpentier, that this was a joyous time of discovery, as though it was singular, as it stood out. And I guess I’m wondering, would you describe it as a moment of a realization or was it more the process of the discovery?
DOUDNA: Well, it wasn’t instantaneous, but it was pretty fast actually. Because, you know, and that, that’s sort of been my experience in science over the years is that, you know, when you discover something that is of real import you kind of know it right away in a sense.
With CRISPR it’s not as though we could foresee everything that was to come, of course, from the technology. But we could really pretty immediately see how this could be a very powerful tool because of the ease of deployment, how easy it was to alter this RNA molecule and send Cas9 to different places in a genome. And all of the potential uses of that kind of technology. It was just very exciting to think about and contemplate and imagine what could be possible.
LEVIN: So, has the technology changed significantly? And what do you think the most impactful technological advances have been since its discovery?
DOUDNA: Well, since the discovery of CRISPR, what’s happened is that it’s become a whole toolbox, and the way that’s happened is that it’s been possible to take advantage of, again, the fundamental chemistry of the way the CRISPR system functions as an RNA-guided mechanism of recognizing and cutting DNA.
It’s been possible to change that into a mechanism of recognizing and changing DNA in different ways. And so that’s really made it an incredibly versatile technology that can now be used for all kinds of different types of genetic manipulations. And I think that I’m just excited about all of those, to be honest, because I think that it gives scientists a very rich set of technologies that can be deployed as they’re needed in different settings, and it’s only gonna continue. I mean, every time I go to a meeting about CRISPR, I’m continually blown away by you know, by that expansion of the toolbox. And so I just think it continues to get better and better and better.
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STROGATZ: Wow, this is making me try to remember some of my biology classes because, for instance, the phrase double-stranded break. I’m not sure I fully appreciate what’s going on here. So let’s just remember, maybe you can correct me if I’m getting this wrong.
DNA is a double helix, we all learned that. It has these two strands, and you can break one strand and leave the other strand intact. There are enzymes that do single-stranded breaks, and that’s not super dangerous from the point of view of the integrity of the DNA molecule or the gene because you’ve still got one intact strand. There’s still all the base pairing along the whole double-stranded structure. You put a snip in one strand, but you haven’t broken the back of the molecule. A double-stranded break is literally chopping the molecule, DNA in half. Really very dramatic move.
LEVIN: Right. In principle, it should be very damaging to the cell.
STROGATZ: Yeah, and so to be able to have access to genetic machinery that can not only do these double-stranded breaks, but do it in a manageable way, and this is the part that got me, it’s like it’s a sort of universal scissors. It can work in any organism.
LEVIN: Yeah.
STROGATZ: And you can just guide it to any place.
LEVIN: Yeah, it’s insane
STROGATZ: Right? Like, in the old days, there were enzymes that they’re good at snipping one strand, but only if the sequence was such and such, you know, like much more restricted kinds of scissors. This is like a really magnificent all-purpose gadget.
LEVIN: I think she really says it well when she says, “It was just so easy to deploy.” And you saw it right away in use in other labs immediately. There was very little barrier to its application. I think this point about the double-strand breaking is a single-strand breaking, as I understand, is more easily repaired. Yeah. And you can, but you don’t, in principle, change the DNA. But if you double break, you can now insert new base pairs.
STROGATZ: Okay.
LEVIN: And that’s really what CRISPR is doing. It’s, for instance, taking the DNA from an invading virus. It’s cutting its own DNA and putting the viral DNA in its own strands. It’s inserting the base pairs, and you need the double break to do that. And the reason why that’s interesting is you’ve essentially made an immunization card, a record of your own ability to immunize against that invader. At least that’s the case for bacteria.
So here now we can adapt this from the bacterial toolkit and implement it in human beings, and fundamentally change the genetic material.
STROGATZ: It’s incredible.
LEVIN: It’s pretty incredible.
STROGATZ: It’s, it’s not the biology I ever learned, and I guess the real experts are just as shocked, right? It was a really monumental discovery.
LEVIN: I’ve got to say, this sort of excitement over CRISPR, I think, is among the most fascinating scientific discoveries that I’ve ever heard of, and it has the potential to change fundamentally the human blueprint.
STROGATZ: It’s just astonishing now what’s possible. But it sounds like it’s been discovered in the laboratory, tested in the laboratory. Is it making its way to the bedside, to the clinic? Is it helping real people?
LEVIN: Yeah, exactly. Jennifer discussed cases, real patients, living human beings who are alive precisely because of CRISPR therapies. So, we’re gonna get right into that after the break.
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LEVIN: Welcome back to The Joy of Why. We’ve got biochemist Jennifer Doudna with us here today to discuss CRISPR and the future of gene editing.
It’s not quite 20 years, but we are living in the time where there’s these really impactful technological advances. You have this work with Baby KJ. Why don’t we talk about Baby KJ? Maybe you could tell us, it’s a very concrete example of what’s actually being done therapeutically.
DOUDNA: Well, Baby KJ was born in August of 2024 and he had a rare metabolic disease that was diagnosed right away after he was born. He couldn’t digest protein properly, meaning that he was extremely sick. He couldn’t eat a normal diet. He wasn’t gaining weight. He was in the neonatal intensive care unit. You can imagine that his parents were distraught and, you know, desperate to do something to help their boy.
Fortunately, his clinical team at the Children’s Hospital of Philadelphia realized that he probably had a rare genetic disorder and were able to quickly get a sample and sequence the DNA. They figured out that this boy had mutations in both copies of a gene encoding an essential enzyme required for protein digestion.
And not only that, they realized that this was a type of mutation that could in principle be fixed using a version of CRISPR that would have that capability. And so they reached out to a number of groups, including the Innovative Genomics Institute out here in California, about helping them to create a version of CRISPR that could treat this boy. And incredibly, incredibly, I still can’t really believe it, but it did happen in an eight-month time period.
LEVIN: That’s incredible.
DOUDNA: And the baby was treated and today he seems to be thriving, which is absolutely wonderful. So, you know, it’s just an extraordinary story of teamwork. It’s an extraordinary story of using off-the-shelf technology. No new research had to be done. We could use existing versions of CRISPR and a delivery tool that had been developed originally for the COVID vaccine, actually. And using that in the patient, it was possible to create a therapy I don’t know if anyone’s ever created a therapy that quickly tested it and delivered it to a patient. But now we know it can happen, which is really exciting.
LEVIN: It’s fascinating. I have so many questions, but when you deliver this kind of a therapy, since it’s a gene editing therapy, is it a one time you deliver it? The genome is edited? Or is it a therapy that has to be re-administer over time?
DOUDNA: Well, in this case it was a little of both in the sense that it was three times into the patient, but not since then. And I think the hope is that sufficient editing of that patient’s cells in his liver, that are essentially repopulating his liver over time, have been edited such that he now has a normal functioning liver that’s producing the kind of digestive enzymes that are needed for his health. That will just have to be monitored, of course, over time. And because it’s a one patient situation, we don’t have any way of actually testing whether and how much editing occurred in his liver. It’s just, looking at his physiological properties now and trying to assess what his health is.
But it is quite impressive that it took just this, you know, kind-of very succinct delivery. It doesn’t require treating the patient every day or every month. He had three treatments with this therapy, and we hope that that’s sufficient to give him a normal lifespan with a normal outlook.
LEVIN: It’s incredible. I mean, there are other areas in terms of human health therapeutics where you would see this kind of possibility, cardiovascular disease or, I dunno, altering the microbiome. Where do you see the most sort-of productive direction for thinking about gene therapies?
DOUDNA: Well, you just mentioned two big ones that we think about a lot. So I think, you know, the cardiovascular angle is fascinating. It might not be obvious to someone listening to this, you know, why would CRISPR be useful for treating heart disease? And yet it is. And the reason is that many studies have shown that people that have a particular form of an enzyme in the liver that processes cholesterol differently than others have protection against cardiovascular disease because they don’t tend to accumulate plaques in their arteries over time. So, wouldn’t it be great if you could actually use CRISPR to give everybody that form of the gene? And that’s what the principle is for using CRISPR in that fashion.
And in fact, there was a company that was founded to do this, a company called Verve that has demonstrated enough potential for this approach that they were actually purchased by Eli Lilly last year. And so, you know, there’s a lot of interest on the part of even big pharmaceutical companies in pursuing a strategy that could give people an option that doesn’t involve taking a daily pill or getting, you know, frequent injections or something, or having to radically change their diet, but instead having a one-and-done therapy that just gives them a genetic fix to the problem of high cholesterol.
LEVIN: Now, this is the upside, the success stories. But there are also barriers to developing these treatments at scale. What are the barriers? Are they all just financial barriers or getting FDA approval, or are there actual barriers to scaling up these kinds of treatments?
DOUDNA: Well, certainly the financial and barriers are there. What’s exciting about the case of Baby KJ in particular is that those barriers were overcome and that sort-of speaks to what’s possible. On the flip side, we know that that strategy isn’t going to work for everybody. It’s very hard to scale that. For example, how would we replicate that particular path for other patients that have rare diseases?
So, I think it’s worth really for the field to think about what are the approaches that could just radically reduce the cost and make it a lot easier for other patients to get access to this type of a therapeutic. And so I think it’ll take not only getting creative with engineering and the way that these molecules are manufactured, and that’s already underway to try to reduce costs there. But it also goes back to the science and the technology. For example, you know, Baby KJ was lucky that his disease affected his liver, so it was possible to use an off-the-shelf delivery technology to introduce the CRISPR molecules to cells in his liver. But that’s not going to be helpful for people that have a lung disorder or a muscle disease or a brain disorder.
And so, one of the real forefronts in the field right now is figuring out how to solve the delivery problem for all these other tissue types. I think it’s gonna be solvable. You know, I’m very bullish on this. But it’s gonna take real work. I mean, you know, it’s not going to just happen. I think we have to really focus on it.
And fortunately, many people recognize that this is an important challenge. And so we’re seeing more and more efforts in this regard. A lot of our young students that come in to the Innovative Genomics Institute here in California certainly are very motivated by this. They’re excited about it. It’s a hard problem. They wanna grapple with it. They wanna figure it out. So, that’s the kind of energy and innovation that I think will solve a hard problem like delivery.
LEVIN: If you have a newborn baby with a terrible genetic disease, who is not going to have a long life prognosis, you can imagine risking anything to treat this child. But for somebody who has alternative therapies, how scared are people of doing something as radical as editing their genome? And are there negative consequences? Are there possibilities of having mistakes in what’s edited, or how it’s edited, or immune response?
DOUDNA: Yeah. Well, you know, with any technology of course there’s always risk, right? And with gene editing in particular, you could imagine, right, you don’t wanna have something that’s not accurate, or editing sites that are unintended or even that are harmful. You certainly don’t want to be in a situation where you have consequences of editing that lead to undesired outcomes.
I think a good case in point is actually the situation with sickle cell disease, because that’s a disease where the presence of the sickle cell mutation in the human population is probably in part because it gives some protection against malaria infection. So, people that have one copy of the so-called sickle cell gene, phenotypically they’re normal, but they have some protection against malaria infection. So you could argue that for them a bit of an advantage to have that in parts of the world where malaria is endemic.
And so that’s just kind of a good reminder that our genetics are complex and genes, you know, aren’t necessarily good or bad. They could be a little of both depending on the situation. So I think, gene editing just, we have to employ it cautiously because it does require a lot of knowledge about what effect a genetic change is going to have on a person over the course of their life.
LEVIN: Yeah, you raised this fascinating possibility that a gene we think is simply harmful, actually has a protective purpose. And we talk a lot about, you know, maybe myopic people also have some correlation with abilities, or you can’t fix one thing without possibly damaging another. I think that’s just generally true about human beings.
It also leads to some ethical questions, and I know you’ve thought a lot about the ethical questions. I feel like we have to talk about the somewhat shocking case of the Chinese scientist in 2018 who used CRISPR to genetically alter human embryos, which seemed like it was really crossing a line, resulting in the birth of two twin girls. It’s my understanding that he was trying to make the babies resistant to HIV. Now, when you heard about that were you shocked, or did you feel it was inevitable that somebody would transgress across this unspoken ethical line?
DOUDNA: It was shocking. No, it was definitely shocking. It had already been on my mind though that, you know, this was certainly a possibility. And this particular individual had been going around and attending meetings on gene editing, so he wasn’t unknown to the genome editing community.
But that all being said it was certainly shocking to find out that this wasn’t just chat, it was actual action that he had taken. And once the details were revealed, it was pretty clear it was an extraordinarily unethical thing to have done for multiple reasons.
You know, if there’s a silver lining to that story, it’s that I think internationally people recognized right away that this was wrong and they took a stand against it. And in fact, that scientist was arrested and his lab was closed and he was jailed for a few years. So, we’ll see what happens going forward, but I was pleased, I guess, that there was a very strong and concerted response by the international community about his action.
LEVIN: And the big issue being that it was in embryos, it was editing the germline. So in other words, it could be passed down. Was that the big line that was crossed versus another therapy?
DOUDNA: Well, for me, even more than that was that it was first of all used in a way that was medically unnecessary because there were other proven ways to protect those babies from transmission of HIV during their development and birth.
Secondly, I don’t think from the evidence that I saw that the parents were aware particularly of what they were actually agreeing to, which is also very shocking. And then as you mentioned, the third piece is that this is a permanent technology. And not only that, when you perform it in embryos, you are making changes that are heritable. So those changes will now be passed to future generations, and we really don’t know what the impact of that will be.
LEVIN: Do you think that there are others that are unscrupulously performing these kinds of experiments? As you said, it’s an incredibly flexible, programmable, swift, and not terribly expensive technology, which also makes it kind of scary.
DOUDNA: You know, it’s possible. I think that my assessment is that the original perpetrator, I guess you could say of that germline application of CRISPR, a lot of his motivation I think was frankly for publicity. And so I think that part of the deterrent now is the idea that publicity would be pretty negative for somebody forging ahead with something like that today.
And yet, you know, we do know of companies, for example, I’ve heard of a few around the country that are exploring again the possibility of germline editing and offering that as a service to people. So, it’s not as though this is off the table or no one’s thinking about it anymore. I think it’s still very much in the milieu and we’ll have to see what happens in the future. But it, to me, just underscores the continued importance of public engagement, of scientists being involved in the conversation around CRISPR and how it should be used.
LEVIN: There are implications for using this technology for climate, for plant life. I mean possibly even food, to address food scarcity, or diseases like malaria, where you stop it at the level of the insect, not at the human-body level. How do you see those advances progressing? Is that an area that’s very active at the moment?
DOUDNA: Yeah, it’s pretty active and I think there’s a real upswing in the applications of CRISPR for those kinds of things that we’re seeing right now. Especially for addressing challenges that are coming with the changing climate, both in terms of food security, how we ensure that we have plants that are robust with respect to drought, with respect to pests, that have improved nutritional value. All of those things are interesting applications using CRISPR.
And then the other is thinking directly about carbon release and applications that involve changing the microbiome in cattle to avoid the emission of methane. Cattle are one of the major sources of methane emissions around the world every year, and CRISPR in principle can dial that back by changing the genes in those bugs to reduce methane emissions potentially permanently. So that’s, I think, something that I’m very excited about, and is an active program here at the Innovative Genomics Institute.
LEVIN: What do you see as a primary focus in your research in the coming decade? Do you see it as being more focused on industry and application, or back to exploration in the lab?
DOUDNA: Well, it’s a little of both. I think that, you know, in my own research lab, I continue to have folks that are doing fundamental discoveries, and there’s a lot of exciting work, frankly, coming out of that effort right now. And then we also appreciate the value of figuring out this delivery challenge. I think it’s a big challenge.
We’re not engineers in the lab. We love engineers, but I’m certainly not an engineer. But the opportunity to understand fundamentally how cells take up new molecules, how these molecules can access specific kinds of cells. There’s a mechanistic basis for a lot of that, that is something that we do love to dig into in a lab like mine. So those are gonna be two areas that we’re gonna focus in, for sure.
Beyond that, I really want to continue to serve as a mentor. I’m enjoying the fact that at the Institute here, we’ve been able to hire in a number of younger faculty who are kicking off exciting research programs of their own that align with the kind of overall goals and mission of the Institute. These are folks that are here in large part because they love working on big, hard problems. They love doing that collaboratively. They love doing it here in the Bay Area, where we have access to incredible resources of all types.
We love being literally right across the bay from Silicon Valley. You know, as AI continues to advance and accelerate the pace of our work, we’re increasingly integrating that into what we’re doing. So that’s been really fun and I wanna do more of that.
So it’s a really exciting time, I would say.
LEVIN: When you were working on this originally, in the early days when you were making the transition from studying RNA to studying CRISPR to realizing its incredible power in terms of rewriting the code of life, so to speak. When you look back at that time, is there a time that you miss of, you know, before all of this, before the success, the attention, and also seeing the impact it’s having on so many other researchers and so much other work?
DOUDNA: Well, yes, um, my life certainly changed dramatically right around 2012. And, I often joke… my husband’s also a professor here at UC Berkeley… and I often, uh, joke to him that there was my life BC — before CRISPR — and then everything changed.
And you know, do I miss it? Well, yeah, some parts of it I definitely do. I, you know, there’s a joy in just coming into the lab every day and spending time with my students. I try to do as much as that as I can, but, you know, I’m doing things like, this, which is fine, you know, but it’s different.
And yeah, I love science so much. I love the process of discovery. I love working with scientists who are just starting out in their careers, you know, and they’re creative. They’re fearless. They want to figure things out. And it’s, you know, science is always a struggle, right? It’s always hard. And so I do enjoy going through that struggle with them, and I don’t do that as much as I used to. And I do miss it.
LEVIN: All great stories have to have a struggle.
DOUDNA: For sure.
LEVIN: No great book was written without a struggle to drive the plot.
Thank you so much, Jennifer. It really is such a mind-blowing topic. It’s so exciting to see it moving and that it’s happening and it’s actually happening fast. We’re gonna live to see the implications of this. Thank you so much for joining us.
DOUDNA: Thanks for having me, Janna. Great to be here.
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STROGATZ: Wow, I’m hit by so many things as I listen to that. The first is something that I think I heard Stephen Jay Gould, the old evolutionary biologist and writer, say when I was sitting in on a lecture of his one time, which was that it was the age of bacteria, it is the age of bacteria, and it will always be the age of bacteria.
You know, we don’t, see them. We don’t think about them much. But they’re so important, and you can learn so much about life as Jennifer Doudna and her collaborators have done by focusing on bacteria.
LEVIN: Yeah. But it’s also fascinating to talk to someone who’s had such a direct impact on technology, therapies, the potential for improving the human condition, but that’s not really why she got started, and this is something people keep forgetting. It really was just curiosity-driven science, childlike enthusiasm that she maintained her whole life. And how do we convince people that we need to encourage that to have the impact on humanity?
STROGATZ: Hmm. Well, it might help if we could convey the history of science in a way that was as engaging to people as it really is. You know? I mean, throughout the history of science, we hear about these stories of serendipity, where someone discovers something so important, and it’s often described as being by accident.
But it was pointed out in some place that I read that you shouldn’t think of it as exactly by accident. Like in her case, she was really looking for something very focused and thinking about RNA in bacteria. But then she ended up finding something she wasn’t looking for and somehow putting your mind in that state where you’re curious and alert — I mean, it’s that old line about chance favoring only the prepared mind.
LEVIN: Mmm-hmm. Oh, and you definitely get that in her story. “And then I met so and so, and then we talked about this.” So it’s not as though she simply sat down and it was just a matter of time. There is that serendipity. There is that making decisions, choosing to be open to somebody, choosing to have a dialogue on something a little left of center of what you’re working on, and being open to pursuing that with everything that you brought to the table.
STROGATZ: It’s something, too, that I think about as a scientist or a mathematician in the broader collective of our enterprise that will lightning strike for me personally? You know, there’s ego in what we do. And I sometimes have to remind myself that it doesn’t matter if it happens to me as long as it happens to somebody.
LEVIN: Yeah, absolutely. Well, Steve, to be continued. Let’s both get back to our work.
STROGATZ: All right. Get to work, Janna. I’ll see you next time. Bye-bye. [laughs]
LEVIN: Bye.
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LEVIN: The Joy of Why is a podcast from Quanta Magazine, an editorially independent publication supported by the Simons Foundation. Funding decisions by the Simons Foundation have no influence on the selection of topics, guests or other editorial decisions in this podcast or in Quanta Magazine.
The Joy of Why is produced by PRX Productions; the production team is Caitlin Faulds, Jade Abdul-Malik, Genevieve Sponsler, and Merritt Jacob. The Executive Producer of PRX Productions is Jocelyn Gonzales. Edwin Ochoa is our project manager.
From Quanta Magazine, Simon Frantz and Samir Patel provided editorial guidance, with support from Samuel Velasco, Simone Barr, and Michael Kanyongolo. Samir Patel is Quanta’s Editor-in-Chief.
The episode art is by Chanelle Nibbelink and our logo is by Jaki King and Kristina Armitage. Special thanks to Garth Avery at the Cornell Broadcast Studio.
I’m your host, Janna Levin. If you have any questions or comments, please email us at [email protected]. Thanks for listening!