考里科四十载冷板凳终获诺奖 mRNA技术因克服免疫反应拯救数亿生命

考里科四十载冷板凳终获诺奖 mRNA技术因克服免疫反应拯救数亿生命 考里科通过化学修饰攻克了mRNA引发人体严重炎症反应的致命缺陷，让这项曾因缺乏经费且被同行边缘化的“疯女人技术”最终成为拯救数亿生命的商业与医疗基石。 本期节目详细回顾了女科学家考里科博士的传奇人生与科研历程。她从小在匈牙利物资匮乏的环境中长大，因对科学的执着而远赴美国，却在天普大学和宾夕法尼亚大学接连遭遇导师打压、科研经费断绝、降职甚至强制退休等重重逆境。在至暗时刻，她不仅在圣诞夜实现了人工合成mRNA产生特定蛋白质的历史性突破，更在复印机旁结识了魏斯曼博士，共同研发出修饰后的mRNA技术，彻底清除了免疫反应障碍。随着新冠疫情爆发，该技术成为商业巨头与疫苗的基石，考里科也最终荣获诺贝尔奖，并培养出了奥运冠军女儿。 考里科博士与魏斯曼博士因在mRNA技术上的奠基性贡献共同荣获2023年诺贝尔生理学或医学奖，但她获奖后依然渴望回归平静的科研生活，专注于未攻克的致命疾病。 (0:00) 考里科童年生活在物质匮乏的匈牙利小镇，父亲作为屠夫的精湛刀工和对质量的追求启蒙了她对生物体构造的好奇心，塑造了她坚韧的性格。 (0:00) 在匈牙利生物研究中心（BRC）进行博士后研究期间，考里科首次接触到RNA研究，当时的目标是人工合成25A分子以期制成抗病毒药物。 (0:00) 因为匈牙利研究资金撤走，考里科在1985年被迫前往美国天普大学苏哈多尼克博士的实验室工作，但随后遭遇了前老板长达数年的极端言语辱骂与科研打压。 (7:39) 面对毁灭性的打压，考里科践行汉斯·塞利著作中的“恶性压力转化法”，拒绝自怜与抱怨，将全部精力专注于寻找出路，开启了双城通勤的艰苦科研生活。 (24:19)

卡塔林·考里科（Katalin Karikó）博士在长达数十年的科研生涯中，历经资金断绝、学界打压与制度性边缘化，最终凭借对修饰mRNA的关键突破奠定了现代mRNA疫苗的基石，并于2023年荣获诺贝尔生理学或医学奖。 从物质匮乏到跨国求索的韧性成长 (0:00) 考里科在二战后匈牙利物质极其匮乏的小镇长大，父亲的屠夫手艺启蒙了她对生物结构的兴趣与动手能力，使她树立起教育与智慧不能画等号、需靠日复一日勤奋钻研的信念。1980年代在匈牙利生物研究中心（BRC）研究极短RNA分子“25A”期间，制药公司撤资使她失去经费支持，她与丈夫将变卖轿车换来的1200美元现金缝进女儿的泰迪熊玩偶中，赴美加入天普大学实验室。面对脾气暴躁的老板在言语辱骂、签证遣返威胁、撤回新工作及在排版阶段抹去其论文署名等多重极端打压，考里科践行汉斯·塞利的压力转化理论，拒绝自怜并专注于能掌控的事务，随后转入贝塞斯达开展博士后工作，靠每周高强度的双城奔波与在实验室睡睡袋维系科研。 宾大边缘化危机与mRNA路线的孤独坚守 (19:59) 加入宾夕法尼亚大学后，考里科与埃利奥特·巴纳森合作，在主流学界追逐DNA基因疗法的背景下，坚持选择被视作极不稳定、但安全性更高且不改变基因组的mRNA路线。1996年圣诞前夕，他们通过引入放射性分子，首次证实人工合成mRNA能在细胞内成功合成特定蛋白质，取得历史性突破。然而，随着巴纳森离职，缺乏外部科研经费的考里科被剥夺教授头衔、降职降薪为高级研究员，期间还经历患癌治疗及丈夫受困匈牙利半年的双重打击。在宾大医学院推行将实验室面积与经费绑定的考核机制下，她被同行贬低为“mRNA疯女人”，直到2013年其实验用品被清空弃置于过道，最终被迫强制退休。 复印机偶遇与修饰mRNA的破局 (39:59) 1997年，考里科在图书馆复印机旁结识了免疫学家德鲁·魏斯曼，两人随即开启跨学科合作。1999年宾大18岁受试者因基因治疗引发过度免疫反应死亡的悲剧，促使两人全力攻克mRNA诱发严重炎症反应的技术瓶颈。他们发现对照组的tRNA因存在丰富的化学修饰而能避开免疫系统攻击，以此为线索于2005年成功研制出修饰mRNA（modified mRNA），消除了该技术临床应用的核心障碍。尽管该突破被《Nature》以“渐进式贡献”拒稿并转投《Immunity》，且发表后并未立即引起学界重视，但该研究直接催生了Moderna的创办与BioNTech的早期布局，考里科也在2013年加入BioNTech，最终在2020年新冠疫情期间转化为挽救数亿人生命的疫苗成果。 超越学术荣衔的责任感与现实归宿 (49:59) 在斩获诺贝尔奖后，面对雪片般的国际巡回邀请，考里科仍渴望回归安静的阅读、思考与致命疾病攻坚。比起最高学术荣誉，她最珍视的是纽约Meadowbrook养老院全员接种后在疫情感染中实现零死亡、老人们为她举办感谢日的真实慰藉。她将mRNA技术的成功归功于60年来多代科学家的集体努力，并将自己持续研究的动力归因为绝症患者没有解药的现实紧迫感。在生活上，她培养了夺得两届奥运会赛艇金牌的女儿苏珊，并坦言即使没有新冠疫情导致其贡献终身不被认可也并不在乎，唯有行动与研究本身才具有决定性意义。 考里科的经历揭示了颠覆性科研在传统学术资助与评价体系中易被长期冷落的困境，同时也表明，在面对疾病救治的终极现实需求时，独立科学家的坚韧探索终将跨越制度偏见并释放出巨大的临床价值。

[0:00] 卡塔林·考里科: 那些患有绝症的患者正处于绝望之中，而我们还没有解决方案 [0:00] 卡塔林·考里科: 工作与娱乐互相渗透，直到失去界限 [0:00] 卡塔林·考里科: 智慧与教育并不能画等号 [14:59] 卡塔林·考里科: 不要去责怪，专注于你能控制的事情，将恶性压力转化为良好的行动力 [14:59] 卡塔林·考里科: 你不能花时间去自怜，或者去抱怨为什么有些比你差的同事能留下来，因为这会吸干你所有的精力。你必须立刻专注于下一步能做什么。 [14:59] 卡塔林·考里科: Just one more thing [34:59] 卡塔林·考里科: 他们救了我，因为他们，我才能在宾大工作24年 [39:59] 德鲁·魏斯曼: 准备好吧，你明天的手机会被打爆。 [44:59] 卡塔林·考里科: 连诺贝尔奖都无法带来 [44:59] 卡塔林·考里科: 集体的幸福 [49:59] 卡塔林·考里科: 大概只有在入土为安之后我才会休息 [49:59] 卡塔林·考里科: 当然有可能，但我不在乎

[0:00] Hello, Silicon Valley 101. I am Kate Corrico here from Philadelphia. She was called the MRNA-Fu-little person. She is Catalin Carrico. Dr. Catalin Carrico and her research partner were awarded the Nobel Prize in Medicine last month. On February 2, the Nobel Prize in Medicine was awarded to her research partner Drew Weissman to show her the success of the MRNA-Fu-little person in the past. And this is why the research of the mRNA was quickly used in the vaccine and was in the world's health and dangerous situation. And this is what she's proud of. It also her 10 years of patience and patience and even can be called as a to make the Katalin Curricule finally able to be able to Curricule在去年10月Catalin获得诺奖之后我们硅谷101向她发去了采访邀约而在半年的等待之后我们终于成为了首家专访她的中文频道那么这个视频我们就和Catalin以及通过她的自传Breaking Through My Life in Science这本书一起来走进这位拯救了数亿生命的女性科学家的人生来看一看MRNA这项重要的技术是怎么被研发出来的以及这位执着的女科学家在几十年的研发过程中经历着如何的人生Hi Kitty, first of all, I want to thank you for your timeYou mentioned to me you've been very busy and even under great pressure after receiving the Nobel Prize back in 2023. Can you tell us a bit about what you are working on right now? Somebody is receiving the Nobel Prize. Usually they can do the victory lap for the rest of their life because you get so many invitations that every day I could be three, four different corners of the world. I don want to travel For three years I traveled so much And so I want to focus on things that better understanding certain diseases which I had previously had already ideas that what might cause And if we understand really that this is the cause, then we have a solution. And in the weekends and when I have time and I try to focus and then the focus means that on that day, I don't want to talk to anybody. I was just reading and thinking and coming to certain conclusions So, you know, the people are desperate who have, you know, deadly disease And then we don't have any solution So I'd rather just work on it And when I have something to say, then I will talk about it Kaiflin in receiving the award After all of the media interviews and meetings, the event was filled with the invitation But she had a lot of invitation to continue to return to her research life Like over the past few years as a research and research. Maybe after he received the experience of science and education, he will be able to do the work of science and education. But in the past few years, he has been able to study the research on MRNA. So, I was reading it on Catalan's book. This book is written very nicely So we go back to his story He in the early childhood of the year as a father father has various kinds of trees in the home凯特兰在1955年出生于匈牙利的小镇小新萨拉时他的童年在二战之后,父亲是一名屠夫,母亲是一位顾纪元她在一个没有自来水也没有冰箱也没有电视的小房子里面和姐姐一起长大在她的自传当中虽然从小家境并不浮育但是自理行间全是她对她父亲工作的自豪感就算是屠夫的工作父亲也专注专业试图给顾客提供最好的品质而Catlin从小而出木人她是父亲熟练的用刀工穿梭在猪牛等动物的器官之间让她对生物体的构造也是非常的着迷与好奇同时她和姐姐从小就方着家里面做各种的家务从用动物的脂肪来做肥皂到抓害虫来喂鸡到收集锤打钉子和夫妻一起加固仿佛正是在这样的大自然下长大让她的动手能力极强而对身边动植物生态的了解是让凯特伦不但在智力和兴趣上开始了对科学感兴趣也提升了她的基础技能为日后成为科学家 [4:59] 是打下了基础她在书中写道工作和娱乐可以互相渗透成为一体直到感觉他们的区别毫无意义Catalin对我说她的父亲是一位幽默又坚韧的人即使在战后的动荡时期也坚持着对家的责任以及给予妻女无尽的爱这样的乐观的性格很大可能对Catalin有着潜移默化的影响让她成为了一个同样快乐勤奋坚韧对自己的工作又无比骄傲的人而也许就是这样的性格特点才能够伴随他走过几十年中默默无闻不断被贬被打压的岁月他也在书中说从他父亲身上他学到了intelligence 智慧和education 教育并不花等号You seem so self-motivated all the timeYou do your hard workYou make sure you are the bestYou move forward and stay focusedI'm just wondering if self-motivation is something you are born withOr it's gained later from your surroundingsLike your parents我肯定是看到我的父母是助于我们的父母我们可以看到他们的父母我肯定是看到你的父母然后你肯定他们的父母然后你感到他们的父母然后你希望能够在一个新的高度因为我的父母是在学校的学校我的姻子是三年代 that what they gave you and then you want to put in a new level. And because my parents had just elementary school education and my sister, who's three years older, she got a PhD in economy. So, you know, we went to high school, university. I mean, that was so far, far away what our parents could. But because they had no chance to go to school, they work very hard. You know, it's important that in addition to your daily work, you set up some kind of goals and you work towards, You finish, you submit That's already victory Catalan's生长环境让周围一切可以成为她的科学启蒙她在采访中以及在书中都有写到她并不是天才型选手她有的只是从小比常人更多的努力日复一日的刻苦和有一丢丢的固执脾气还有性格那么在书中 Catalan说她见过太多有天赋的聪明人了他们有着过目不忘的记忆那么这种天赋 It will make you feel very easy. He is not just to practice as a good teacher, and then spend more time to practice, and then spend more time to practice, and then keep the rest of the time. Then he finds that this way, it is really useful to him. He is just like trying to keep the rest of his work. It is a habit that he has been working for a few years. And the hardworking kind of a few years is always working for a long time. It is alwaartworking这种多年如一日的执行力一直贯穿整本书也贯穿着她的人生Katalin从小对生物的着迷加上勤奋和努力在她14岁那年就拿下了匈牙利的全国生物竞赛的第三名之后初中高中就一直保持着这样的优移成绩考入了匈牙利塞格德大学在Katalin上大学的那段时间精英学开始在学界迅速的发展进展非常之快在他大学的最后一年有一天一名教授刚刚在跟同学们讲课说DNA和MRNA的关系如何如何结果短短一周之后科学家就推翻了这个观点和理论那么说明当时的精英学的进展之迅速而Catalin也很快就会投入他的整个人生到MRNA的研究当中1978年,Catalin Curricule在匈牙利塞格德大学获得了生物学士学位,然后又在4年后的1982年获得了生物化学博士学位,之后她进入匈牙利生物研究中心BRC生物化学研究所继续进行博士后研究,在那时她接触到了RNA的前沿研究,而当时BRC也是从一家匈牙利的制药公司Reno Pharmaceuticals拿到了资金他们当时非常的雄心正志的想将RNA制成药物这里我们先简单讲一讲DNARNA还有MRNA这几个词的区别DNA就像是一个生物体的一本书里面存储着所有关于这个生物是如何运作的信息它有着双螺旋结构携带着遗传的秘密那RNA呢是细胞内的另外一种分子类型的统称其中呢包括了mRNAtrRNA还有rRNA那么每一种RNA都有其独特的作用那相比DNA啊RNA的核糖磷酸骨架中多含一个氧原子并且它的四个碱基当中也有一个与DNA不一样那么这两种很重要的一个区别呢是DNA呢就是一个iogen有点社交恐惧在我们的细胞核内闭门不出主要活动就是保护它的编码的信息偶尔也会进行自我复制但是RNA是一个艺人社交大人不像DNA一样坐在细胞核里面负责这个管理信息RNA只要是在细胞核外展开工作产出蛋白质等等实际的产品 [9:59] 最后mRNA信使RNA是RNA的一种它的工作就像一个快递员它会根据DNA部分基因的密码籽复制得到对应的反密码籽随后这段mRNA就会被送到特定的细胞工厂那里那么在那儿mRNA会指导携带了氨基酸的TRNA生成正确的氨基酸序列进而制造出每一等蛋白质来进一步的构造细胞修复损伤还有抵抗疾病等等简单来说mRNA就是携带DNA信使用直到合成蛋白质的信实好 我们这三个区别搞清楚了那么先剧头一下在此后的很多年DNA疗法和RNA包括mRNA疗法这两派打架很多很多年其中很长一段时间都是DNA派占了上风导致主张mRNA的Katlin是坐冷板几十年那我们先来说一下Katlin在80年代的BRC想干啥70年代后期一名叫做Ean Kerr的伦敦研究员发现了一种特殊的分子简称25A当我们的细胞识别病毒的RNA入侵我们身体的时候会启动一个系统来产生极短的RNA分子那么这个RNA分子就是25A它可以和另外一种被称为RNA的酶结合来降解病毒的RNA来干扰病毒的作用所以在80年代Katlin所在的匈牙利生物研究中心BRC就想将25A这样的RNA在实验室中给生成出来能够直接做成药物进入人类细胞那么这将大大的增强人类抵抗病毒的能力那么从那个时候开始Katlin就迷上了RNA的研究并且负责组建了实验室一头是扎进去开始研究但是研究的道路并不顺利因为RNA太不稳定了它在体外环境中非常的容易降解更别说递送进细胞的复杂性还有人类的免疫系统等等等等难题了那么既然RNA研究如此困难为什么Katlin还愿意投身于此呢你必须明白我不是一个智慧的人我认为了解决定那是一个下班当然不是这就是唯一唯一我可以得到的工作我会领导人的一位一位一位一位一位一位他在访问他他在访问他我找到一个地方去做我的 PhD我问他那是如何是我不是一个人我只是你会想我会想我会想我会想我会想 that's how it is. I was not a visionary. I was just, whatever was, you know, came in front of me, then I tried to tackle and try to be good at. And then I started to work there. RNA already in 78, synthesized chemically, enzymatically, shorter RNA molecule that had antiviral effect. I had to set up an antiviral screening laboratory. I studied everything about viruses and did all of this work. in Kathleen Carrico in three years after 1985 Reno Pharmaceuticals came to RNA to be able to be able to make a successful希望 and then took the money Kathleen to be a part of the year so this time Kathleen's father just to be a kid her daughter Susan still young she needed a job so that she did not have to be a part of the research one in London one in the United States one in the United States but these researchers all gave her a request and she must have done it for her research. This is not possible for Catalan. There was a day, in the past, Catalan said, we need to talk about it. She said, we need to go to the United States. I think we must go to the United States. Catalan's research is the American Faijong Temple University of Robert Suhadonik博士那么当时Suhadonik博士的实验室正需要合成25A的虫草素而Catalan之前在25A分子上面的研究让它成为了合适的人选那么就这样Catalan是拖家带口是来到了美国费城而有意思的是匈牙利当年的外汇管制不允许公民带超过50美元的现金出国那Catalan把车卖了把大约1200美元的现金缝在他女儿的这个泰迪熊里面就这样啊让他女儿抱着全部的身价让这个泰迪熊脱家带口的到了费城然而苏哈东尼克博士的实验室啊却成为他很长一段时间的噩梦Robert苏哈东尼克博士的情绪非常的不稳定书里面啊是用了explosive这个词来描述他那他经常会朝实验室的同事吼叫会摔文他的暴脾气让整个实验室都沉浸在恐惧还有不安当中而当1988年的夏天Catalin准备接受来自John Hopkins大学的另外一个实验室的工作的时候Robert Sohardonic博士的愤怒爆发了除了当面大声的咒骂还有言语攻击之外Sohardonic教授采取了非常极端的一步Catalin是拿着工作签证来美国的作为现代的 [14:59] 雇主苏哈·多尼克教授就威胁到他有权利让移民局将Catlin遣返回凶压力而当Catlin浑身发抖了想要打电话给他先生的时候苏哈·多尼克教授拒绝让他用实验室的电话并且将他赶了出去而决绝了苏哈·多尼克教授是落实了他的威胁他给John Hopkins大学打了电话导致Catlin的新工作offer被取消他致电了美国移民局Catlin也是很快收到了美国移民局关于违反签证法的问询但甚至自掏腰包将Catlin的名字从已经通过文行评审和编辑修改的已经到了Gallery Stage的论文中抹去Catlin似乎被逼到了绝路那么在读这本自传的时候Catlin Carrico的性格从行文中表露的特别明显就是刚Catlin是一个很刚的人他也自嘲说自己很固执很倔强致死之中他受过很多的威胁但是以她的性格你越危险她就越不会妥协并且会继续找到剩下的可能性而且会全力以赴的去争取比如说书里面有提到她在高中申请大学的时候有一位男性的俄语老师因为Cathlin提前的干完了农活坐在地上休息她就命令Cathlin立刻的站起来继续干活而Cathlin认为不公平就拒绝了她的指令那么这位男老师赶到了自己的威严受损想要联合其他老师给Cathlin惩罚并且在过道上再次的拦住她威胁到说会给她申请的大学打招呼她将不会收到录取信但是Cathlin毫不理会扭头离开那多年之后Cathleen还记得给这位老师取的外号叫苦先生Mr.Bitter她在书中写道这种反抗的原因称之为年轻称之为过度自信称之为天真或者是固执亦或只是简单的愚蠢那么书读到这里的时候我真的是忍不住嘴角上扬我觉得这种反抗太迷人太有魅力了也许因为我也有着比较类似的性格所以非常能够共情但是每个人的人生中谁都会遇到这么几个Mr.Biller那么对于Cathleen来说高中的那位俄语老师是Temple大学的Rober·Sohadonik博士也是但是Cathleen的方法是他数次提到他在很小的时候就读过的一本书叫The Stress of Life我也买来看了里面教导他不要去责怪专注于你能够控制的事情将恶性的压力转化为良好的行动力所以他多他多年来每次遇到不同的Mr. Bitter的时候也都是这样做的。 Over the years, have you often thought of Mr. Bitter or those who had given you such a hard time? No, you know, I have to say also that I met him after I was accepted to the university. But that's what it is. You don't carry any grudge against anybody. It poisons you. so that when I was accepted to the university I didn't want to him when we went to five years reunion at the high school I didn't want to tell him oh you see I am in the university no you didn't stop me if you think about and that's what many awards ceremony I thank to the people who try to make my life miserable I thank them because they made me work harder if he says to me when I was 18 that I make sure that I arrange that you will be accepted to the university? Probably in the summer I will sit back. I am in, you know. But he said he will make sure that I don't get, so I had to be the best. And so it inspired me to work harder. So thanks to him. You have to practice this. You know, it's not coming easy when you are fired from your position and to be happy that, oh, that's great. I have a new opportunity to find another job. No, you don't. You get the thinking of what happened, but do not spend time to feel sorry for yourself and thinking about that you have some more colleagues there who are, in your opinion, is worse than why you, why not them. And it's because it can take out all of your energy. You have to immediately, OK, it is done. And then you focus on what can I do? You know, I mean, I don't I was not happy that I was terminated in Hungary. I was not happy that, you know, they took my stuff out of my lap here, you know, but without it, probably you won't get the BioNTech Pfizer vaccine. Maybe, you know, so so, you know, that it is to go to Germany. And what next? When I am 58 years old and I am terminated, I could see at home and see the grass growing. But I said, OK, I still can do things and then go there. And that's always your decision. So somebody else deciding that you are not good enough, but you believe in yourself and then you find a new job. And that's your decision. [19:59] 所以Cathlin是遵循着她的方法冷静地寻找一不需要前老板的推荐性二了解Suhadonik的为人并且理解为什么Cathlin跟她的关系破裂第三需要Cathlin的研究技术的实验室她开始打电话介绍自己解释终于原来她找到了一份博士后的工作但是唯一的缺陷是Cathlin的家在费城而新工作呢在200多公里外的Bethesda市每周一早Kathleen凌晨三点起床带着一包食物这个袋子里面装着够她吃五天的西兰花和香肠一袋面包还有半家伦的牛奶每周如此七点到达办公室把食物放在办公室的冰箱然后投入工作她随身带着睡袋有时候睡同事的客厅有时候直接睡在实验室里她没有任何的娱乐活动工作一结束就去图书馆看书看报纸看论文然后呢在周五下午迎着堵车的高峰回到费城的家而期盼已久的丈夫还有女儿一起度过周末在无数次来回往返的途中Cathlin最喜欢听的一首歌是一首匈牙利歌手Zoran唱的歌歌名叫钻石和黄金 Kátelen nem停止过, szükszerebb Katerlund到冰大后,首先在Eliad Bernafin博士的课题组实验室工作Eliad博士当时对一种被称为尿基酶的千溶酶原激活剂非常感兴趣,他非常期待如果能识别并且分离尿基酶受体的基因训练,人们就可以在手术之后将这些受体递送到手术部位的阻止尿基酶具有促进血液中纤维蛋白溶解的功能而纤维蛋白是血液凝固的关键成分所以尿基酶通过分解这种蛋白帮助溶解血栓以恢复正常的血流并且减少组织损伤但是Elliot Bernadette教授并没有分子生物学的经验所以他需要Catalin最开始Elliot计划用DNA技术来实现但是Catalin这个时候提议说为什么不试试mRNA呢在这个时候mRNA技术已经得到了显著的发展到了1989年的时候mRNA运送载体比如说BipothectinGGG体转染剂这种能够把遗传物质高效的送入细胞内的实验室工具已经有了科学家们可以制造编码任何想要的生物活性蛋白质的mRNA同时1989年被科学杂志评为年度分子的type DNA聚合酶使得科学家们拥有了被称为PCR聚合酶烈氏反应的新技术可以无限复制遗传物质那么简单来说呢这些技术的更新已经到位Katlin认为是时候呢搞点事情了但是说实话啊当时在业界mRNA非常的臭名昭著我们在前面提到过啊包括mRNA在内的RNA分子呢是非常不稳定的所以呢很多科学家是对其近而远之但是在Katlin看来mRNA技术的实现可以被类比为载人横天这其中面临着无数的挑战每一个环节都很难但是每一个挑战都有一个单独的解决方案而mRNA的挑战也是如此的这些挑战可能会令人畏惧但是它们并不是永远无法实现的Katlin就说我们可以去识别每一个挑战然后开始去寻找解决的方案一次解决一个总有一天会有突破那很有意思的是他在书中将这种思维模式称为Just one more thing我知道很多人肯定会想到乔布斯在开发布会的时候说的那句Just one more thing但是Catherine这句话来说对于科学家们是有不同意义的因为做实验是一件很枯燥的事情但是在每一天的重复当中你一定会变得更好再提出一个问题再做一次实验再去阅读寻找新的灵感再去一遍一遍地重复Just one more thingYou mentioned in your book that you would always keep your window open especially when you are tired to let the cold wind come into the house to keep you awakeIs your window open right now?No, I didn't openactually, but you can see [24:59] What I can see here. But during the night, even if it is snowing outside, I keep open during the night. I don't really sleep much. Science is, you know, is an endurance sport. You have to get long distance for and this is not a sprint. And so it is we have just limited time in a day. And then we have to absorb so many different fields, so many experiments which were done. And we don't have to do it. But it takes time to read and understand and come up with the best solution. And, you know, as I describe in the book, every time we made experiments, you know, try to answer one question, we get more questions and not the answer. And that's we have to be researcher because we are searching and researching. That's why we are researcher, not just searcher. But when Catalan started to study the MRA, the problem was to find the money. When Catalan entered the hospital the hospital was in a small group of doctors The new doctor called Bill Kelly He came here after the hospital he started to develop a lot of resources to develop the DNA technology to introduce DNA treatment Kelly并不重视Catlin所坚持的MRNA的路线Catlin呢说他自己更加倾向MRNA的原因是他承认DNA的稳定性使他比MRNA更容易使用但是DNA基因疗法涉及到改变一个人的基因组而这种变化是更加持久的当被操纵的细胞分裂的时候用于治疗而加入的基因组呢也会随之被复制并且传递到新的细胞周而复始其实在康复之后细胞依然会不断产生用于治疗的蛋白质而相较之下mRNA疗法呢却不会对细胞产生持久的改变他意识到mRNA呢是一种非常有效率的疗法由于mRNA会被身体快速的分解所以mRNA疗法呢可以产生显著的效果但也是暂时的理论上人们可以将正确的蛋白质通过mRNA传递到正确的位置而根本不需要将DNA移入细胞核Catalin试图让宾大对DNA和mRNA疗法都保持开放的态度但是可惜宾大医学院的新院长Bill Kelly Wilson Kelly包括Ed Holmes作为医学主任Ed Holmes又找来自己的老婆Judy Swan作为下面的科主任而Judy恰好就管Catlin和Catlin合作的Allian博士的科技组总之呢Judy让Catlin的研究工作变得十分的困难但是Catlin的职业生涯又取决于Judy当Catlin进入冰大的时候她是研究助理教授她需要在五年内的时间证明自己的价值才能够被晋升到研究副教授继续的留在冰大如果不晋升那就只能走人那这是这两个位置的惯例此前从无例外Catlin说她从来没有放弃过证明自己的价值也没有放弃过去争取研究经费他写道说每天晚上都在写经费申请写申请写申请因为他的英文不是母语所以需要花更久的时间去写作但是年年申请年年悲剧所以到了Cathlin到冰大的第五年其他的地方可以去她只能留在了冰大接受了降职降薪新的职位Title是高级研究员连教授这两个字都被抹去了这还不是最坏的消息那么就在同一时间呢Cathlin被检查出了癌症自己的丈夫呢却因为签证的原因啊被困在了匈牙利长达半年之久他呢又只能一边接受治疗一边照顾孩子甚至呢还带着女儿开车去白宫面前抗议让丈夫呢能够尽快地返回美国可以说呢这是他人生的治安时刻但好在他停过来了而在漫长的被打压的境地之下也有让他开心和骄傲的事情这就是科研上的突破1996年12月在实验室已经亮起圣诞灯的时候Catalin,Ali教授以及另外一位实验室技术人员Alice在实验室里进行一个重要的实验通过传递编码mRNA来诱导细胞产生尿基酶受体简单来说他们想把mRNA注射到细胞里面让细胞产生特定的受体蛋白如果这个实验成功了那么这就证明 [29:59] 细胞能够结合一些原本结合不了的分子说明Catlin他们注射进细胞的mRNA真的能够让细胞合成所想要的蛋白让人紧张的时刻开始了这将关乎整个团队过去七年的努力他们三人把本身不产生尿基酶受体蛋白的细胞分为两组 试验组和对照组在试验组的细胞里面递送往mRNA那么由于尿基酶受体无法用显微镜看到所以它们在细胞中加入了放射性分子实验的结果将会很直接如果细胞产生了尿基酶受体它们就会将这些放射性分子固定在适当的位置说明mRNA发挥了作用如果没有产生那么就不会观测到放射性分子那么mRNA失败而观测放射性分子需要通过连接在打印机上的γ计数器来测量当时三个人围着一台打印机紧张的看着打印机吞吐出来的一行一行的点就在圣诞树灯的闪烁下数据开始在打印纸上形成试验组有大量的放射性物质而对照组没有任何这说明试验成功了而这意味着人类科学家首次成功的使用mRNA在细胞内制造出了特定的蛋白质而且这个技术是简单并且便宜的这意味着巨大的临床潜力Katelman在书中直言没有什么比成为第一个知道其他人从未理解过的事情更好的感觉了那么这就是科学上突破的时刻在科学界很多人会有一个习惯在冰箱里面冻一瓶香槟在出现科技突破的时候这一天拿出来庆祝甚至在冰大还有裸奔庆祝的学校传统但是Katlin回忆说他当时既没有喝香槟也没有裸奔而是立即做了一件他一直在做的事情这就是重返工作岗位在那个时候他满脑子都是如何进一步的去调整实验如何用不同的细胞系使用不同量的mRNA来尝试优化实验他回忆到冰大所在的费城在那个圣诞季是非常温暖的在他来到了这所大学的七年之后终于有一年的冬天一股反常的暖流让他感觉到异常的温暖充满了力量as a scientista failure perhaps is somethingyou have to deal with all the timewhile breakthroughs take so many yearshow do you keep yoyour passion in the lab? You don't have to so seriously take failure. You know, if you are a scientist, you constantly fail, you know, because you said, oh, experiment did not work. But I had a Leonardo da Vinci quote there that experiment never fails, only your expectation, because you didn't do the experiment you expected the result for. So, you know, but we constantly experimenting things that we expected something and we didn't happen in an experimental setting. And we know that, OK, this happens and just you stand up and move on and do the next experiment and try to figure out why you didn't get the result you expected. And so that's it. And the good spirit. So if you are not happy, you know, understand for the graduation, Steve Jobs said that if a couple of days, one day after the other, you think about that it would be the last day of my life. This is what I would want to do. And a couple of days you're saying, no, no, I don't want. Then you have to leave that thing. You know, you have to be enjoying whatever you are doing, and it could be the weirdest thing. I mean, many people thought I am unsuccessful, but I was very well.可以享受你做的事可能是最奇怪的事很多人觉得我成功不成功但是我在研究中很幸运我知道我没有钱但是我完全控制我可以做每个试图我身体的做了自己因为我没有试图但是它是玩笑的它必须是玩笑的科学突破的感觉如此之美好只是这份美好并没有坚持多久Catalin很快又将面临再一次的挫败就当Catalin和Elliot教授的合作开始出现突破之际呢命运又给Catalin开了一个玩笑几个月之后Elliot教授呢决定离开冰大加入了一家生物科技公司Cyndacore当Elliot教授离开之后呢Catalin陷入了更加不利的境地那么此前呢Catalin挂靠的是Elliot教授的实验室项目而当Elliot离开之后呢摆在Catalin面前呢只有两条路要么找到一个实验室逛考要么自己申请到科研经费凯特林已经尝试数年申请经费均以失败告终他无法自己承担MRNA的研究课题那么这个时候与他在之前Elliot教授那里曾经共事过的一名同事David Langer博士短暂地递出了救命稻草他向冰大的神经脉科系的主人推荐了 [34:59] Cathlin为她暂时的谋得了一席之地那么就此呢Cathlin再次的转组来到了宾大医学院的神经外科系但是很快呢Cathlin转到神经外科系的短短两年之后呢David Langer博士呢也离开了准备去纽约接受一份新的工作那么此前呢Elliot教授和老朋友David博士的课题组呢就像Cathlin的一把保护伞但是现在保护伞没有了Cathlin再次陷入了孤立无援的境地他需要独自承受更多的质疑压力还有挑战时间来到了1999年宾大医学院当时陷入了财政危机在医学院院长Bill Kelly的执掌下宾大医学院的人类基因治疗研究所耗费了巨大的资金同时收购了三所医院聘请了上百名的时间医师新建或者重修了100万平方英尺的新临床空间基本上每个学院都是换了新的负责人然而这么大手笔的投资和豪赌并没有迅速的得到回报反而让整个医学院陷入了财政危机当中那么这样的压力也是影响着每一位医学院的研究人员Katalan所在的神经外科系系主任Sean Grady是引入了了一个概念叫做Dollar Per Net Square Footage Ratio顾名思义呢就是科研经费除以实验室面积的比率将每一个科研人员啊所占用的实验室面积呢和他所能够拉来的科研经费强制的绑定在一起呢作为了研究人员的绩效考核那之后的十多年时间中网Katalin被无数次的叫去谈话提醒她说按照Dollar per Nesco footage ratio的标准她的表现非常非常的差劲Cathlin在戏里面也非常的被边缘化她能够从同事和其他人看她的眼神中感觉到鄙视她被称为MRNA疯女人如此固执如此平庸如此碌碌不为直到2013年Shangreedy和冰大医学员的彻底对Cathlin失去了耐心在没有通知她的情况下将实验室强制的收回他的实验用品和私人物品被扔在过道上就像他们是垃圾一般史上对Kathlin说你可以在医学院养实验动物的animal house 旁边给他用一个小隔间但是显然这对RNA的研究来说根本无法达到实验室条件终于Kathlin在2013年被冰大医学院强制退休你提到PEN有这个$ per Nesca的ned that PEN has this dollar per net square footage policy for the department to make sure staff and researchers can bring funding. And maybe it's not a PEN thing. It's like all across the U.S. or the world. But it doesn't sound very fair to scientists, including yourself. I was terminated in my position 10 years ago, so I don't have a laboratory here anymore. I was forced to retire and then I don't get any laboratory, any team I don't have here at University of Pennsylvania. How could I stay with the system? You know, I didn't get support. But for seven years, Elliot Barnet and my colleague who hired me at Cardiology, he paid my salary. It was supposed that as a faculty, I supposed to get the grant. But even I didn't get the grant for seven years. He paid my salary. And when it was there that now he has to leave, there were, you know, another person, this was David Langer, the neurosurgeon, who was just a resident, but he couldn't convince the chairman of neurosurgery that they need a molecular biologist. And they gave me laboratory and a small salary. So that it is people who can, who are working together with colleagues and they can see that the person is doing good. So maybe there should be some extra fund to help those scientists, because they both recognize that what I am doing is interesting. They have, we did together. And of course, they were there in Stockholm when I get the Nobel Prize. Both of them were there. I invited them because they saved me, you know, because of them I could work 24 years at FEN. That can be heard, Kathleen has been a very proud of 24 years of time. It is still a感激 for me. Maybe it is because in his last 10 years of time, although he was in the series, he was attacked in the series. But he also met a special friend of his fellow MRNA技术, as he was the same as a scientist, Drew Wiseman. We can't imagine over 20 years later. We are being able to take away the future. We have arrived in the end of the day, because we are still alive. We are all the most aware of the things that we have been living with. But this battle is not easy to come, let's take a look back to our next future. In the future, we would like to share our experiences with you. [39:59] 本的时候啊Kathleen的保护子阿利安教授还有她的老朋友David博士呢刚刚前后离开了冰大医学院那Kathleen呢因为没有研究经费她连杂志都无法订阅为了看到最新的论文啊她不得不去图书馆复印那么在1997年的一天Kathleen在复印机边上是劫持了刚到冰大不久的免疫学家Ju WeissmanJu Weissman博士到冰大之前啊在安多尼福奇博士的实验室工作大家现在都知道了安德尼福奇在新冠期间是美国抗疫政策重要的制定人可能他当时大力推动mRNA技术的重要原因之一就是很早就对朱和Kathleen的研究非常信任和了解了不过这都是后话了那么朱Weissman是免疫学家和微生物学家在遇到Kathleen之际他正好在寻找传染病的新疫苗的方案此前Kathleen聚焦的mRNA方向是偏治疗的他一直认为在疾病治疗上MRNA有很大的潜力但是Jewiseman博士的研究方向让他开始感兴趣查特勒描述说他眼睛微微睁大脸部的肌肉也有轻微的闪烁那么这可能就是两个合拍的搭档最好的化学反应Jewiseman博士正需要有合成RNA技术的研究员去帮助他而就在这部复印机前他找到了今后并肩作战并且走向了熔虑之巅的mRNA的搭档凯特伦就回忆说有时候即使是科学也需要依赖运气那么之后两个人就开始合作凯特伦在诸的帮助下如愿以偿的是拿到了一笔研究的经费凯特伦当时还隶属于神经外科所以他当时和朱的合作相当于是跨系合作神经外科系的老板和同事们都非常不理解他估计Katlin也不在乎就在两人一起开始合作研发MRNA疫苗之际1999年9月9号宾大医学院出了件大事当时18岁的美国男孩Jesse Gelsinger因为患有遗传病来到宾大医学院由James Wilson教授的实验室预导下的实验性基因治疗之后出现死亡原因是基因疗法让Jesse的免疫系统过度运转进而导致器官衰竭和急性的呼吸窘迫那么这场悲剧不仅使的James Wilson教授的事业中断更加让整个基因治疗行业的发展几乎停止了10年那么最终冰大医学员不得不支付了大俄的罚款并且关闭了这个人类基因治疗研究所那么这件事情也给Cathlin和Ju敲响了警钟因为他们发现mRNA也会引发人体的炎症免疫反应Cathlin心理医疗如果无法弄清楚如何阻止mRNA激活免疫系统那么她多年的工作和坚持将毫无用处但是Cathlin和Ju并没有放弃接下来的时间他们将研究的重心放在了安全问题上之后的几年两人发现mRNA带来的严正免疫反应是因为mRNA会形成局部的双链结构那Katlin和Ju就意识到在过去的实验当中他们曾经在对照组里面使用了一种叫做转运RNATransfer RNA又被称为TRNA的分子那么这种RNA也会形成复杂的结构却在实验中不会引发免疫系统的误伤那么Catalin得出结论因为TRNA上面有很多化学修饰那么从结构上来看这些化学修饰就像伪装一样能够躲开免疫系统的攻击所以如果能够制造出修饰mRNAmodifiedmRNA那么就将有可能能够避免炎症免疫反应那么终于经过无数实验和努力之后在2005年Catlin和Ju呢终于制造出了修饰MRA并且发现修饰后的MRA不会再引起额外的免疫反应那么这意味着MRA技术定用最大的障碍被清除了几十年的坚持啊Catlin等到了实验室制造MRA等到了将MRA运送脂细胞等到了MRA解决免疫反应这些细小的技术突破就像一块块的拼图一样几十年的研究之后终于能够拼凑在了一起科学突破终于到来了然而就当Catalon和朱激动的向Nature杂志投稿的时候却很快等来了同行编辑的评论Incremential Contribution意思呢就是一小点贡献被剧搞了那接着他俩又去继续尝试更加垂类的期刊Immunity在免疫上发表了他们的研究那终于Immunity是接受并且刊登了他们的论文那非常有意思的一个细节是在杂志出版的前一天Drew就对Cathlin说Catty准备好吧你明天的手机会被打爆然而事实是Cathlin的手机在第二天安静如常甚至在之后的几年时间当中Cathlin就只收到过两个演讲的邀请那么现在我们回头来看是不是觉得非常的讽刺即便是如此有突破性的 [44:59] 想发现跟发布的时候根本没有人关注之后发生的就像我们在前一章当中所说的那样直到Katlin在2013年被赶出实验室被强制退休的时候她也没有懂到MRA技术被世界认可的那一天但是她当时不知道的是正是她和Drew的这篇论文让两家重要的公司诞生了2005年正在斯坦福大学做博士后的年轻学者Derek Rosy看到了Catalan和Ju的论文意识到修饰MRNA是如此具有突破性的科学进步Derek Rosy使用论文中提到的MRNA技术成功在细胞里表达出四个关键因子将人类细胞重编成为多能干细胞Russy和他的同事看到了背后蕴藏的巨大商机随后他们在2010年创立了一家公司它的名字代表修饰的RNA这就是Moderna2013年起Moderna开始使用mRNA技术开发一系列的疫苗而更早一些的2008年在德国另外一个团队也看到了这项技术的巨大潜力组建了名为BioNTech的新公司那么这就是之后与辉瑞合作研发出辉瑞新冠疫苗的公司在新冠疫情之前公司聚焦在MRA的癌症疫苗上而Cathlin也在被宾大医学院强制退休之后来到德国加入了BioNTech技术它在MRA上的研究直到新冠疫情的爆发那么这两家公司的技术公认都是基于Cathlin和Ju Weissman的研究成果之后的故事我们都知道了Catalin和June因为他们多年的坚持是推动了mRNA技术的突破和成熟共同获得了2023年的诺贝尔生理学或医学奖Messenger RNA, mRNA, mRNA therapiesThis is a very exciting technologyIt saved millions of livesThe 2023 Nobel Prize in Physiology or MedicineTo Catalin Carrico and Drew Weissman你找到哪一天你赢了我试图我的孩子但她躲起了全部的电话她有一年年和三年年那些人不需要设定的 alarm clock因为他们有两个小时孩子会醒醒然后她说我叫我姨当我学习她说 Those children would wake up. And then she told then I called my sister when I learned, you know, and she could turn on the TV and watch it. And what my daughter was just later on, she said that her son woke her up. And so she she went to prepare something because he was hungry. And then she turned on the telephone and all of these messages there and congratulating her. And she started to cry. And the little boy was, Mommy, it's OK. He didn't know why she was crying. How does it feel like to save billions of lives? Yes, I have to say that there is an elderly home, Meadowbrook elderly home, which in New York, they received a resident, they received a vaccine. And one week later, first person get infected and then more infected. And they knew prior to that, it was in 2021, January. Prior to that, they knew that if in an elderly home, infection is there, one third of the people die and nobody died. And they just get one vaccine. And this was already sufficient, you know, one dose to protect them. And then, you know, they figured out that they have to say thank you to me. And so in 21 September, they had a Catalina Carrico Appreciation Day and all of the elderly were sitting in the sun and they were celebrating. They had a T-shirt with my picture on it and Catalina Carrico Appreciation Day. And they were just, you know, and the staff sent me the pictures that how happy the residents were. And then, you know, there is not even a Nobel Prize can generate that kind of feeling. You know, when you see these elderly people happy and they send me pictures when the first time, you know, whether it was Mother's Day and, you know, the children could visit their elderly mother there and they took pictures. And so that was, you know, feeling that how important I, you know, I don't take it that I discovered I did so many people this we did together because all of those people, I mean, RNA, messenger RNA was discovered 60 years ago. And during those 60 years, so many people worked and advancing, advancing. And I feel that not just my colleague at BioNTech or Pfizer or Moderna, we did. [49:59] all together, but even those who not with us anymore, so all contributed to it. So I just feel collective happiness that it worked. Now, the rest of the, whether it's in the vaccine or in the medicine, all have BioNTech and Moderna and other other public companies to enter mRNA. The following video, we mentioned in the 5-year transformer. One of the one of Jacob Wooskowitz, he created the Inceptive, using AI platform to find new mRNAs, and will be used in the vaccine. So if you are interested, please check out our硅谷101. We can also visit the硅谷 and Boschstown and the area of the world and the world. Let's see how MRNA's development. I'll show you my experience of Kathleen's life. I was thinking about her before, I'd like to read this book. I already done this book before But when I first started reading this book I found that this book is such a great and interesting这中间的每个故事我都看得非常的尽尽有味细节非常让我注迷那么看到凌晨三点然后在第二天早上跟他在线上做个访谈那么Catlin在书中分享了很多她和她家人的有趣的故事包括她和她丈夫约会的时候发现对方比她小很多还是一个高中生当时Cathlin是22岁然后她的老公是17岁和她在一起第一次约会的时候是狂流鼻血还有她对Mr.Bitter这样不公众待遇的反击还有叛逆还有大胆地去披露之前看低她打压她恐吓她的人物和故事甚至在跟我的采访当中聊嗨的时候她会放声地大笑个性非常的鲜明非常的乐观那么采访之前因为Cathlin提前告诉我她基本上不接受媒体的采访因为她很珍惜自己每一分钟的时间所以当时我还挺紧张的但是没有想到和她的采访比我预想中这个氛围要好太多那么还有一个Cathlin和中国的小缘分她的女儿叫做Susan没错就是那个抱着朋友所有身家 The little girl in the middle of the world was the winner of the two championship championship The first time she won the championship was in 2008 Kathleen didn't have a growth in her daughter. Susan became the only woman with her and with her thinking and feeling. We didn't have money here. We came in this country. I never had a housekeeper. Nobody ever wanted our clean our home. We never had a babysitter. So in the school, we put Susan there and the elementary school, they had this after school program. And that's why she started to do all of the sports, because that was the after school program. And then, you know, she she friended with all of those other kids. And that's just good. And we were there in the Shunyi, this is a rowing venue. and we stay nearby in a very Chinese hotel, very ancient. And so it was, my sister was there, my husband was there. We went to the opening ceremony. I mean, it was unbelievable, fantastic. It all of those drummers and it was so hot The weather was very warm and it is unbelievable performance we could see there Anyway but you know when they were in the final and and they get the gold medal and everything, you know, people telling me, oh my God, if my daughter would get the gold medal, oh, what I would do. But for me, it was just a relief that finally over Because you have to understand that for four years, every day, every morning, every day, they are practicing, practicing. And then after, she always called me, you know, when I was working in the lab and told me that, oh, today it didn't went well. And then I had to always prepare in my mind what I will tell her to, you know, keep her spirit up. And that four years, you know, it was like a second or five minutes that they have, you know, to go, madam. But yeah, it was like four years every day getting the phone call. And of course, we were very proud of her. And we went, we were, you know, in the big nest. Also, we have seen different athletics. We also went to look at swimming, basketball, different kind of activities. [54:59] competition we went there in Beijing and it was just so perfectly arranged beautiful正是Catalin从小父母给予她的爱和支持还有丈夫给她的包容和温暖以及女儿带给她的快乐让她就算在几十年被打压默默无闻的科研时光当中是依然保持着自己对于科学的热爱以及呢依然是那个有趣的Catalin她告诉我快乐是一切动力的源泉 Even today, people say, oh, you can stop now, Cati, you did enough. But when I have the feeling that I might be able to help somebody, because I understand. I feel I understand the disease, and nobody understands. And I understand, and I even have a solution. This is like a blessing and a curse to be a scientist. because, you know, the curse is that it won't let you to sit down because those people are suffering and you might have the solution. And then it is just urging you that you have to read more. You have to figure out how you can help directly sooner than later than. And they are waiting. The patients are there and they are waiting and they are suffering. And somehow it is just cannot lay. I cannot lay back. You can name it curse. You know, what the scientists just cannot stop. As long as they move they try to find solution for problems Yeah probably never rest six feet under probably I will rest but我尽量我的最好我尽量我在采访中问Catlin如果没有新冠是不是有可能她这一生都不会看到自己的研究成果被世界认可她很坦然地说当然有可能但是她不在乎我用Catlin自转里面的序言我很喜欢的一句话来结尾吧他说他不知道这些突破最终由他本人实现而是由别人来完成他也不确定自己是否能够亲眼见证突破的出现但是这些问题并不重要重要的是工作本身是行动本身说实话这本书给了我很多的温暖鼓励还有养分我们向这群前沿科技和科学的研究者们致敬而将他们的故事讲出来也是我们硅谷101觉得非常有价值的事情好了这就是本期视频的全部内容我们准备在这期视频的评论区下方收集一些我们的中文观众对于Castleon想说的话之后呢我们会翻译给他作为一个小礼物所以呢如果你们有任何想要对他说的话欢迎留言给我们同时呢你们的点赞转发还有评论呢都是鼓励我们硅谷101持续做好深度内容的最佳动力那我们就下期视频再见啦Bye