第一期: 拥抱不可能

张旭朏/译

Peter [0:00]

您感觉如何,谢丽尔? 您觉得是什么呢?

Dr. Nickerson [0:04]

它可能是一种甜点,似乎里面有某种奶油,但总体上比较干燥。 我会说中等甜度,不是很甜,但有点甜味。

Peter [0:16]

如果非要让您用一个词来形容它放到您嘴里时的感觉呢。

Dr. Nickerson [0:23]

我想用一个连字符词汇:半-甜-干[…] 哦,这是个两连字符词汇。半-甜-干。

Peter [0:29]

现在您可以睁开眼睛了。

Dr. Nickerson [0:32]

是月饼! (看来猜的)还不算太离谱。

Peter [0:37]

太空,月亮,饼,我们试图将它们融合在一起。

Dr. Nickerson [0:38] 

很棒,很棒。 我没想到这一层。 太赞啦!

Peter [0:54] 

大家好,我是本期The Gastronauts 播客的主持人Peter。 在Gastronauts,我们将致力于理解人体的(内在)联系,尤其是肠道与大脑的对话方式。 在本期内容中,我们希望更深入地研究优秀科学家们及其工作背后的灵感和动机。让我们一起来到Gastronauts播客:探索科学家们的肠道情怀。

在首期播客中,我们非常高兴邀请到亚利桑那州立大学生物设计学院的Cheryl Nickerson博士。 Cheryl的研究重点在于太空、微重力和物理作用力对细菌和细菌病原体的影响。她曾与NASA(美国国家航空航天局)合作,在航天飞机执行任务时携带了细菌,并且研究了这些细菌在外太空条件下的改变。 Cheryl,欢迎您。

相信您从您的研究中获得了很多成果,我想问您的第一个问题是,什么吸引您进入太空领域的呢? 您如何决定将太空环境用于细菌研究?

Dr. Nickerson [2:24] 

这是个很好的问题,我以前也同样问过自己。 对了,顺便说一句,谢谢你们邀请我参加本期播客。 这是一个你永远不知道自己的生活会走向何方的故事。当时我在研究生院攻读微生物学博士学位,当我读到最后一年的时候,有个新学生加入这个项目,他那时已经获得了德克萨斯大学的工程学学位,而他却来攻读微生物学的博士。 我们很快成为了好朋友,我也立刻被他如何将微生物更多地看作是回路(这种思维方式)而着迷。 他总是像工程师那样进行分析(思考)。 而我对微生物却有完全不同的看法,因为我有传统的生命科学背景,并且(都是)信号转导机制。 这都非常复杂。 并没有100%的黑与白,而是一个灰色地带。而他非常注重数学。

直到今天,我们一直是很好的朋友。 我们一直在合作; 一直共同发表文章; 我们也一起拿到了项目资金。长话短说的话,在博士后期间,我开始在细菌病原学领域任职,主要研究食源性病原体沙门氏菌,研究它如何与人体肠道细胞相互作用以及它如何与肠道样动物模型小鼠相互作用,引发疾病。 而他去了美国宇航局约翰逊航天中心,开始在他们的微生物学小组工作。从而他参与了国际空间站航天飞机中空气和水系统中微生物的采样。 他是一位出色的微生物生理学家。

随着时间推移,他现在成为了约翰逊航天中心微生物学的负责人。而我在博士后阶段之后,掌握了细菌,尤其是肠道细菌病原菌的发病机理,并且知道如何培养肠道细胞、感染小鼠从而研究肠道与病原体的相互作用。在我启动了第一个实验室一个月后的一个晚上,也就是我在新奥尔良的杜兰大学医学院任职的第一个职位,而他在美国宇航局约翰逊航天中心(NASA JSC),他在电话中对我说:宇航员在太空中(开始)免疫力下降。由于我现在的专业专长是传染病,我说,稍等片刻,因为这只是感染后是否会患疾病的一半方程式。仅仅因为你被感染并不意味着你会罹患疾病,不是吗?它取决于病原体的毒力,病原体的剂量以及你(身体)的免疫反应。因此,你要知道太空飞行对该方程另一半的影响,即免疫反应。您知道些什么吗?(或者)是否有人知道航天微重力环境对病原体毒力能力的影响吗?

其实,没人知道这一点,所以这就是合作的开始。 我们进行了基于地面的实验,这些实验有力地表明了太空飞行(中的)培养可能会影响病原体的毒力、应激反应及其基因表达。从而(我们)进一步进行了多次太空飞行实验,这些实验进一步表明并证明了微重力环境太空飞行确实增强了病原体的毒力。这种病原体的确改变了它的基因表达,并且改变了它的应激反应。 我们将这些发现用于许多不同方式的机理研究中:我们发现,在航天中,其他细菌病原体可以使用与沙门氏菌类似的信号传导机制,我们也找到了在飞行中关闭毒力增强的方法。这也引导我们在相同种类的物理作用力下进行了三维细胞培养。

Peter [5:49] 

在我看来,这些(灵感)很多都是您与完全不同领域的科研工作者一起工作而产生的。曾经研究过工程学背景的人正在从更数学的角度思考系统的功能,而您的加入,带来了您在微生物学和毒力方面的专业知识。这似乎是一场完美的(头脑)风暴:他在NASA任职;他研究了宇航员的免疫反应,然后您对细菌有所了解,并且知道如何使免疫系统与细菌相互作用,这对于我们了解人类健康的未来发展至关重要。我想和太空开个玩笑。您是如何决定“啊哈”(关键)时刻的呢?就像,这就是我要走的路?您有什么顾虑吗?您是否因为微生物不在太空中频繁研究而对微生物发病机理方面有所顾虑呢?(例如)我没想到能将这些微小的微粒(微生物)送到太空呢?您是如何坚定这种信念,决定研究空间(生物学)的呢?

Dr. Nickerson [6:48] 

首先,我要感谢美国宇航局为这些研究所提供的经费资金。 因为我一开始是向NIH(美国国立卫生院)提出了这些研究(项目),我想,当时这项目已经超出他们想要资助的范围。 所以我要谢谢他们,因为这促使(我们)进行了一系列卓有成效的实验,这些实验已转变为现实,不仅对飞行中的宇航员有益,减轻他们的传染病风险,也与地球上的(生命)健康直接相关。 一个完全符合逻辑的问题是:为什么-我和我的同事们都知道-为什么在世界上,谢丽尔(Cheryl),你会认为你将通过在微重力下进行微生物学来学习某些新知识,或促进传染病的某些方面呢? 我的意思是,(这种情况下)生命没有进化的吗? 对于地球恒定的一种力量就是重力。

这是使你思维受到限制的逻辑方法,而我的大脑则受到了不同的影响。 因此,我对自己说,当大大减弱自行星诞生以来一直存在于地球上的一种力量时,你为什么不去学习有关生物系统、微生物、人类细胞的新知识呢? 生命在单位引力的作用下进化,而我们对其他的一无所知。 为什么我们不思考一下,当大大减弱这种力量时,这些与健康或疾病相关的新兴表型特性是否可能会出现呢? 我们了解到,当我们研究极端环境下细胞和生物系统的反应时,我们会得到更多信息,也会得到更多有关细胞如何进化、适应和反应的机制。 对我来说,太空飞行只是下一个极端环境,其潜力才刚刚被挖掘出来。

Peter [8:33] 

这我十分感兴趣,尤其是作为一名正在发展的科学事业的年轻人:在不了解将要发生的事情的情况下开拓未知领域时,我想在进行研究时肯定会遇到很多困难。 当尝试纠正一切错误之后,你的结果对你来说还是变得毫无意义,这很容易使你陷入困境,并且有时会失去(前进的)动力。 我想知道,在这些困境中时,您是如何继续激励自己的呢?在这种情况下,您又是如何激励您的学生和学弟学妹们的呢?

Dr. Nickerson [9:08] 

首先,你必须要有一点点反抗(精神)。而且,当每个人都告诉你(停止)时,你必须要有反抗。每当你开拓创新,进行范式性变更研究,发现别人未曾见过的事物时,你都会听到很多人说“不可能”。没关系,(要学会)拥抱不可能。事实上,我是一个喜欢听“不” 的人,一开始并不喜欢听,你写的项目书“不行”,您发表文章的手稿不行。没关系。 如果你不能听“不”,也就无法在这个领域中解决“不”,那么这个领域就不适合你。“不”激励了我,因为我知道我们正在做的工作是极好的,因为我了解这些团队-我了解我的团队,我也了解我的实验室,我知道我们与之匹配的团队都是优秀的科学家。这并不意味着我们的每个假设都是正确的,这些假设可能是对也可能是错的。我们知道我们的科学(问题)是好的,并且我们相信自己所做的事情。我们相信我们的科学;我们相信彼此。而且我们知道我们(走)在正确的轨道上。

我保存了每份手稿、每份项目资助书中的每份拒绝意见,而从早期开始我就有两份。我不会告诉你他们来自什么资助机构。有人说,我们有单层,我们不需要3D组织模型。你对3D组织模型的细菌发病机理一无所知。好的,我们可以将其从清单中剔除,因为这只是激发您的动力,不是吗?所以在我们帮助诞生了这个领域的20年后,现在这成了一个非常热门的领域。这很棒!但是科学需要时间。这就是所发生的。我们提交的第一个项目经费申请书是研究:细菌在摇瓶中以350 RPM的速度生长和与在实验室静态生长(这是大多数人培养细菌的方式)的相对比时,生理流体剪切力如何将细菌完全重新编码的。我也收到了第一封拒绝信。它说这项(研究)是不合理的。没关系。现在,传染病的力学生物学已成为一项很酷的研究,这是一件令人兴奋的事情,而且这很好,[接受]拒绝信是关键。如果您保持专注、下定决心并坚持不懈,您最终将会成功。您必须有胆量去进行那场战斗与大火相抵抗的战斗。然后你付诸行动。

Peter [11:17]

真的受教了。 (要学会)接受“不可能”。

Dr. Nickerson [11:23] 

其实您不必一定要喜欢它,这只是来激励你。 最终益处的是,你可以让所有这些兴致勃勃的年轻科学家们产生新颖且有创意的想法。 我从我所敬仰的一位科学导师那里学到了非常重要的一课。我总是会告诉我的学生,她所说的一句话。 她说:“不要自大。 因为当你以为自己什么都知道而其实不然时,狂妄就杀死了你的好奇心。”我认为这是一个美丽的陈述。 每个科学学科都有很多东西要学习。 有许多新现象需要被发现。 一个实验室,一个课题组,一个团队不可能全部拥有它们。 每个人也都有自己的空间。 那么,要接受这点,不要认为你已经学到了一切。 因为这是不可能的。

Peter [12:31] 

到目前为止,您告诉我的所有内容都很有意义。 科学是在有趣的情况下完成的。 我认为,始终要根据前后因果来实现-我们想看看我们可以创建什么样的环境来给(所研究的)系统施压,然后看看会发生什么。但是我很想指出的一点是,当有人打电话给您并说太空可能很有趣以及它如何影响细菌时,您的第一反应是什么呢? [是刚好]恰逢时刻出现在您的脑海的呢?或者,(您想)这(刚好是)我可以融合在一起的东西的呢。

Dr. Nickerson [13:00]

使用微重力平台来研究/鉴定新的生物学特性、现象、细胞反应、分子/遗传表型的整个概念对我来说似乎并没有不合理或惊讶-使用微重力平台来做研究似乎非常令人兴奋。但是你要知道,这可能是错的。 我们可能发现不了任何差异。 当我第一次获得用于资助这项研究的项目基金时,对我来说这并不是关键时刻的到来。 而当我们拿到结果并分析数据陷入僵局时,关键的时刻才真正到来,因为那才是真正令人激动的时刻。

我们能够模仿某些在微重力条件下发现的现象,并采用一些特殊的方式在类似于某些地面微重力的条件下培养细胞。他们虽无法模仿一切,但可以模仿我们在飞行中的一些关键发现。所以我们知道这不仅仅是一些现象-我们首先非常兴奋,因为我认为,哇,我们将帮助宇航员保持健康了,对吧?我们对此感到非常高兴,谁又不会呢?但是,当我意识到细菌随着引力变化而更新或进化并不合理时,这对我来说就没有意义了。我是说,这(种现象)对我来说并不合理,这种力的变化必须类似于他们在地球自然生命周期某个地方遇到的另一个物理环境。因为他们演变成这样是不合理的。事实证明,我们的证据表明它们并没有对重力减小做出直接反应,而是直接对减小流体剪切力做出反应,其程度与它们在组织中遇到的程度非常相似。当它们影响我们时,对我来说,就是一个关键时刻。然后,我们意识到,哦,天哪,我们在微重力平台上所发现的可以转换回此处,以帮助你我(的研究),也因此我们不必去太空(进行研究)了。然而我们基本上是在揭示病原体感染我们身体时可以做出的反应,我们并没有发现其他方式。因此,现在,我们已经开发出包含人体组织结构的三维肠道培养物。它们具有在肠上皮细胞中发现的多种细胞类型。他们有丰富的(肠)黏液。它们有顶部和底部。他们被很好的两极分化。当我们将免疫细胞放入其中时,它们可以显示出更多体内对感染所作出的反应。因此,我们的目标是使这些肠道模型越来越像体内的物质。我们既从研究细菌病原体如何响应生理流体剪切力的角度出发,又利用这些相同的力在体外开发出更多的有缺陷的患者人体组织模型,以研究宿主病原体的相互作用。这可能会致使但我并不保证一定致使研制出疫苗或其他新型疗法来帮助人们。

Peter [15:50] 

这是一个非常有趣的观点。 我想我将需要些时间来消化一下。 我想知道,您认为未来十年太空科学领域和微生物学领域的发展方向是什么呢? 从现在开始十年后您想看到实验室发展到什么程度呢?

Dr. Nickerson [16:06]

这又是个很好的问题。而我敢肯定,不同的人给你的回答是不同的。最终,我认为最重要的任务之一就是摆脱动物测试。我们必须在实验室中这样做,因为我们始终无法感染人类而且没办法(直接在)人体中测试一切。我们必须有更好的更具预测性的替代模型。而我认为我们可以实现这一点。顺便说一句,许多课题组正在取得长足的进步,做着我们未曾谈论过的事情,利用细胞来发展人体外部的人体组织和器官,这些细胞将具有功能性并100%预测你对病原体的反应方式。尚无人能100%预测,但是我们在实验室中做到了。其他正在做此研究的实验室也为人类提供了越来越多的预测模型。对我来说,这是我们必须解决的主要问题之一,这些领域也正在朝着这个方向发展。但是,这需要生命科学家、工程师和物理学家的跨学科团队合作,而这就是现代科学的运作方式,这很棒。我们的团队,您的团队正在执行此操作,因为没有人可以成为懂得一切的专家。当你采取这些多学科的方法来解决此类问题时,我们看到的是-我们看到了以新的方法来更好地解决或帮助理解病原体感染人类时的作用。他们在必须感染的整个微生物组的背景下做什么?他们是如何用物理作用力做到这一点的?他们又是如何在健康和疾病中做到这一点?我们又将如何建立更好的人体模型、人体外部组织和器官模型来概括我们体内的每个生物、化学和物理因素呢?

Peter [17:50] 

我从您刚才提到的内容中概括出的一件事是发现如此关联密切的事物,并将其与人类健康联系在一起是不可思议的。 我对您在讲话中表现出的热情,您在对话中的热情感到敬畏。那么,我想知道,这种热情真的会激励您吗? 您觉得它是自然而然的吗? 还是,您必须真正等到关键时刻才有呢?

Dr. Nickerson [18:12]

我一直说,(要)绝对自然。如果我不是绝对喜欢自己所做的事,我会心跳加速。我对自己对科学学科和领域的承诺充满激情。它驱动了我所做的几乎所有事情。我很高兴在实验室工作的团队成员的内心深处也是这样的。那么,是的,我们住在实验室外,但我们喜欢睡觉和呼吸,因为我们喜欢它。你的思维中必须有那股热情。当你找到对的事物时,它会激励你早晨起床,你迫不及待地要想出下一步的方法。这一直是一个难题,需要解决。激情就在那里;我们以它为食,我们互相激励;我们以发现为生,因为归根结底,离开这个世界要比你在这里时好一些。如果有我们的发现,我们的任何工作、任何研究,都意味着可以得出更好或新颖的方法来对抗、治疗和预防传染性疾病。这就是我们正在学习的方法。

Peter [19:22] 

谢丽尔,我们的谈话有了非常振奋人心的结尾。 非常感谢您成为Gastronauts 播客的第一位客人。

Dr. Nickerson [19:29] 

我很荣幸,谢谢你们的邀请。

Peter [19:43] 

Nickerson博士给我们提出了很多建议来(让我们慢慢)消化,这是第一期的结束方式。 但真正让我领悟到的是接受不确定性与接受挑战的重要性。 我们永远不知道最终将要到哪里,或者世界如何看待我们的科学。 因此,找到您感兴趣的东西并为之奋斗。 非常感谢您的收听,我们下期再见。 有关我们更多的内容,您可以关注我们的Twitter @gutbrains,或访问我们的网站thinkgastronauts.com。没有我们在这里的优秀团队,就没有Gastronauts 播客。 梅勒迪斯·施梅尔(Meredith Schmehl)是我们的制作人和音乐作曲家。 Laura Rupprecht博士是我们的社交媒体经理。 特别要感谢Gastronauts的创始人:Bohórquez实验室的Diego Bohórquez博士。

Episode 9: Beyond the Hypothesis (Transcript)

Peter  0:00 

What are your thoughts? What are you feeling right now?

Dr. Clevers  0:02 

I’m on a tropical island. Sweet, sweet fruits. Very relaxed. Enjoying the sun doing nothing.

Peter  0:12 

So what it was, was a gummy worm. The reason why I picked the gummy worm and I like your interpretation of it. The reason why I picked the gummy worm is because it kind of looks like an intestine with its ridges and I thought that was really interesting that they put the effort into making these ridges into gummy worms. Why not just make a smooth surface …

Dr. Clevers  0:30 

Can I have another one?

Peter  0:44 

Hi, and welcome back to The Gastronauts Podcast. My name is Peter and I’ll be your host. Here at Gastronauts we are committed to exploring communication throughout the body, with a particular focus on the crosstalk between gut and brain. We invite experts in this field to share both their research and their incredible journeys. So come join me as we explore the steps that go into shaping a scientist on the Gastronauts podcast.

Today, we have Dr. Hans Clevers, the director of research at the Princess Máxima Center for pediatric oncology and a professor of molecular genetics at Utrecht University. For those of you who study the gut or use organoids in your research, he needs no introduction. Dr. Clevers was the first to discover stem cells in the intestine and that the disruption of a downstream effector of the Wnt pathway, TCF4 abolishes stem cell crypts. He also showed that activating Wnt mutations underlie the development of colon cancer. He developed the first organoids through culturing living stem cells in the intestinal tract and has been awarded the Louis-Jeantet Prize for Medicine, the Breakthrough Prize in Life Sciences, the Heineken Prize from the Royal Netherlands Academy of the Arts and Sciences to name a few and has authored over 600 publications with over 100,000 citations. We really appreciate you taking the time to be on our podcast, Dr. Clevers.

I want to start by discussing your scientific journey. In hindsight, it is always easier to explain a career decision as planned; however, you have been very open about your initial thoughts on pursuing a career in both medicine and science. Can you take us through a few different big-decision moments in your career and what went through your head and what helped you make those decisions?

Dr. Clevers  2:48 

Yeah, so I’m actually 62 so I’m not the youngest anymore. When I was a young kid, I already knew that I was going to be a scientist. I was interested in biology. I read all the discovery stories of Africa and the bulls. And so when I was 18, in Holland, you go to university at 18. I picked up biology and was actually quite disappointed because it was still […] 19th century science, very descriptive, lots of Latin names, taxonomy, very little [instruments or] tools that you could do much with. Because this was [1975], this was just before molecular biology, DNA technology was just being developed and spread around the world. So I then also went to medical school. I completed two studies in the course of my master’s in biology. I spent some time at NIH; I spent a year in Nairobi, and that’s when I started learning about monoclonal antibodies that had just been developed, and about the first gene cloning experiments and I realized biology is probably going through a revolution now, but I also liked socially the medical environment, […] the clinical environment much more than the lab environment In labs, you’re locked up with a few people that you have selected. It’s much more social- you see the entire population of your city combined, all the young, poor, rich- you have nurses, you have the doctors, you have the students, you have the patients. In a lab, it’s 10 – 15 people, always the same. But so I then got a training position, pediatrics in Utrecht. They asked me, well, because of your double background, why don’t you start some research and you can do a PhD, which we don’t leave University with a PhD, we leave with a masters. So I started some research. And in that year, I realized although socially, it’s not always the simplest environment, really I’m a scientist. I’m not a doctor. And I then gave up that training position, wrote four papers on a project that I designed myself entirely, and didn’t end up in the biggest journals. Also, I was an immunologist. Essentially, I wrote two pairs of papers: on T cells and I repeated the exact same thing on B cells. And that already I think people started looking at me, “how can you be interested in T cells and be interested in B cells- you have to choose.” And that [is] something I I’ve learned that you don’t have to confine yourself to, to a discipline. But then I also realized I had to learn molecular biology from scratch. And I got a postdoc position in Boston in a lab of a Dutch PI, Terhorst. And I learned to clone TCL genes, and I was still a molecular biologist. And that is when I although was a tough time: 4 years. In the end, it worked out well and that’s when I realized this was the right decision for me. I’m a scientist. I find hospitals fantastic places, […] also the patients are better off if I’m in the lab and not with the patients.

Peter  5:47 

Yeah, so you mentioned- I know this is a while back at this point, but you mentioned that other people in the clinic and mentioned maybe you should go into research. Was there any hesitation or reservation thinking that, “oh, if I leave medicine now, I won’t ever come back to it at that time.” I think now you certainly have established yourself as a scientist, but at the time, did you have any concerns?

Dr. Clevers  6:06 

It was a real decision point for many reasons, but one thing is that the medical profession is a hard profession; it’s not easy. You have to be able to work hard. You have to be social. You have to be smart. But what I could see is that most doctors that would bring this with them, have a nice life, they have a good career. They work hard, but everybody understands what they do. There’s not this hierarchy, you have a few top doctors and then all sorts of other levels of doctors. There’s not this constant competition that you have in science. On the other hand, I knew that I am a scientist that says. Im not really sure I’m going to be a successful scientist, but that’s where my passion is. So I actually sat with my father for quite some time and asked him for advice. He said, it’s your decision. That’s if you if that’s where your heart is, go there. But it’s extremely risky because a career in science is very unpredictable […] As a doctor, you know, by the end of your day, you know, whether you have the skills to be a good doctor. As a scientist, even after a PhD or a postdoc, you don’t know whether you have the skills and the luck and persistence to be a PI and everything with it for many, many years because it’s just very hard work.

Peter  7:17

So when do you know that you have the stuff to be a scientist?

Dr. Clevers  7:20

Well when we first started discovering things [that were really just] small but were important. I was probably eight years into being a PI when I realized that we’re now doing things that […] people find interesting. And it was luck. So we’ve apparently made a few choices of where to go with the with the science, but it might also have not happened. And there’s also if you’re too long without a significant new insight, that is the end of your career, even if you’re as good as somebody else who did get an insight and got this boost to the career.

Peter  7:57 

But you mentioned earlier that people were telling you can either be a T cell scientist or a B cell scientist and you saw this not true- you can always pivot your research in the direction that you want it to go. Could you elaborate or unpack a little bit more about that?

Dr. Clevers  8:08 

Yeah, I can maybe describe the trajectory of my lab, which is very abstract. It’s because almost everything we did failed, and I forgot about it, but my [early] people actually know all this, because they went through that. So we started as a lab that wanted to find transcription factors in T cells. And knowing that these genes, although the genome was known in the late 80s, at all was still a decade away. But we knew that transcription factors are very important for cell decisions. And so we cloned a few amongst them, [and one] was a gene called TCF1. And then it took about five to six years until we realized that this was a crucial transcription factor, but not so much for T cells, but for early development in any kind of animal. It’s part of the Wnt pathway. So then I basically changed my lab from a molecular immunology lab. We had fruit flies, we had frogs, all these in collaborations. We have zebrafish, we did lots of mouse genetics. And then we finally hit on this link with the gut. And then I again converted my lab from a developmental model organism lab to a gut lab and we had to get to know somebody who knew histology and paraffin sectioning.

Peter  9:19 

Do you have any hesitation with making that switch?

Dr. Clevers  9:21 

No, it’s part of the personality of me, but also you sense that the lab around you starts to, I don’t know how that works, but has the same personality as yourself. I don’t know whether the lab programs me or I program the lab, so as long as the technologies around it doesn’t really matter if you need DNA sequencing. It doesn’t matter if it’s a zebrafish, or yeast or human cancer, sequencing is sequencing. So we’ve always been going in areas where we at least knew that we have mastered the technology and then the biological questions in the end [everything that] we’ve discovered is always simple. So there’s a few things if I can, if I look back, because I’ve been doing this now for 30 years, that have been very well for us. One is no fear [and] an enormous amount of trust. And that’s what I learned from my PhD advisor. So you can trust other scientists, you can share unpublished information you can, and you always get more bang [for your buck], because if people trust you, they are easy collaborators, they will help you when you need them. And it’s more fun. So there’s a lot of paranoia in science, which I think is sort of self-fulfilling. Because if you’re paranoid about your neighbor, bad things will happen. And if you’re open to your neighbor, that’s one thing. So trust, and courage so you can make a difference in somebody else’s discipline. If you bring in the right technologies and a good way of thinking, you can actually make a discovery. You have to have good collaborators to protect you from stupid mistakes, but also introduce you into that community. We’ve done that a lot. So we’ve written on fruit fly genetics on zebrafish genetics on the highest level journals, but always with a collaborator in that field that had helped us. And then one thing that I’ve often said is, I strongly discouraged my lab to formulate hypotheses. Now this is not how science is supposed to work. So my strong sense is if you enter a field where little there’s known and where you don’t really know the questions, you can ask. So don’t ask strong questions that are looking for strong answers where you already know the answer, because that’s your hypothesis. Just be open-minded, go into experiments, build a robust experimental system, and just watch. Watch and watch and watch. And then the human brain always immediately comes up with solutions, which other hypotheses, but you can sit down with a number of smart people and come up with 1000 solutions to your problems that could all be true. And evolution has picked one randomly. So why would your brain- I think it’s very arrogant to sit down and formulate a hypothesis in a field where you know nothing. And the human brain also works in that way that once you have your hypothesis, you will publish the hypothesis. You’ll find the evidence that it’s true. And that’s I think, where many non-fraudulent but papers are produced that turned out to be wrong, because in that process, you lose your open-mindedness. That’s not how our brains are comfortable to work with. So that’s something that I see a lot in my lab and somebody says, experiment fails, I say, “why? Did you drop it on the ground?” No, no, no, because you know, this is the result I got, and I should have gotten this. This is because you have your hypothesis. Get rid of your hypothesis and look at the results with an open mind […] So I think for discovery science, this is really the way to go. You cannot write grants, you cannot write papers [in which] you refuse to work with hypotheses, but it’s for me at least has been the most productive way of doing this. I guess a more applied science like in clinical science where you have to have a strong question and you have to have a hypothesis and there’s only a few answers: a drug will or will not work. So there it works. But for this open end where, you have no clue what you’re looking at and what the processes are, the hypotheses will blind you rather than help you.

Peter  13:21 

Yeah, one thing that you just said that really resonated with me was the fact that our context really biases our hypotheses. Where we are situated in a particular lab, or where we are in the world biases or informs our decision on how we approach science. And this is why it’s important to have collaborations with people who have different viewpoints than your own. In an era where communication internationally is just a few clicks on your computer away, what do you see the value in, in these large […] scientific organizations or societies that bring people together for an international conference? And if you were in charge of one of these conferences, how would you run it so that you would have effective communication?

Dr. Clevers  13:58 

That is a very good question. So for me, personally, these meetings [where] I’m a speaker, I have good access to the other speakers. So that’s where I get my information from. That’s where I build my, my networks, my collaborators. And that’s where I hear about the newest technologies about who to trust, who not to trust, what works, what doesn’t work. I rarely read papers. So I don’t read- I read Nature and Science but not the second or only the first part about the political things. So because we review a lot of papers so there’s a source of information so […] I would advise anybody you know, [when] you get asked to review, review. Because it gives you connections with journals; you learn a lot you learned before it’s appears half a year later in print. And so that’s for me, and I guess for many people, the face to face is still very important and Skype works well once you know people and you collaborate, so it’s a very good way of collaborating long distance. I guess for young people, it’s these larger meetings really, for me when I was young, you get a very good sense of who’s who in the field, you know what’s happening? What’s the general thinking, you know, what is the argumentation in this field? Or do people like or don’t like? Where are the open questions? On whose toes will I step if I say this? […] so I’m not really sure what I would do if we would organize meetings- I spend lots of time in meetings. I would organize them very differently. I would have more young people into podium. Shorter talks to basically get them exposed to, to communicate to audiences. Yeah, I think they get-togethers like large poster sessions with free beer work fantastically well. But the face to face at least for me, I’m not from the millennial generation, is very important. And many of the papers that that that we’ve written often result from talking to someone, get a good idea together, work it out together and you create a lot of friendships along the way as well.

Peter  16:15 

You talked about […] not stepping on other people’s toes, but the value of a lot of these conferences is to know who’s in the field. I saw recently that you tweeted some classic images from Lieberkühn’s thesis regarding the structure of the gut, and then some of Joseph Paneth’s pictures of the Paneth cells. I was wondering what drew you to these pictures in particular and what about these scientists encourage you to tweet about them?

Dr. Clevers  16:36 

Yeah. Well, so of course, these two have written extensively about guts and Lieberkuhn, who lived in the 1700s was German but worked in Holland did a PhD, which my students were very happy to read that it was only 32 pages. But then I could point out this actually written in Latin, so… well as a as a medical student, I had a very good memory, which isn’t so good anymore. But there’s many structures and diseases and phenomena that have a person’s name attached to it […] and nobody ever knows, you know, [for example], who was Merkel? And so I’ve made it a bit of a hobby to try to figure out, you know, who was this person? Why, and often they’re not the first discoverers, but for some reason they were the most visible person. Actually between Europe and the US, there are differences; like Kahler for us is multiple myeloma. Now I don’t think the US uses Kahler’s disease for this, but it was discovered by a German called Kahler. So I’d like to dig up these […]  just a hobby, and to find something that’s 300 years old, and it would be sitting in a museum and nobody knew what it was. So I found this thesis and then I realized this is really good.

Peter  17:50 

Do you encourage your graduate students to go through and the history of science as well?

Dr. Clevers  17:54 

Not really. So what I do a lot with my graduate students is discuss the process of science, and all the different decisions you take and what information is true, everything published, and doubt what was published. And so that I do a lot. I try to create a culture of interrogation and also try to explain that when you argue with somebody or you criticize or you have remarks about the work of somebody, you’re not criticizing the person, you’re criticizing something that the person says because it feels very personal. When you the paper gets reviewed, you see the review report, it hurts when it’s negative. But the process intended not to hurt you, but actually  say something about the same bit of work that you have. So that’s something is that I do a lot with my students.

Peter  18:45 

If you could travel back in time and have a conversation with any scientist, who would it be in what would you talk about?

Dr. Clevers  18:51 

Yeah, there’s a guy, Leblond, who is my personal hero, who is I think, originally French [and] migrated, because his wife is Jewish, migrated to Montreal in Canada, French Canada, and was still an active scientist at a very high age when he was 94-95, actively engaged, and many of his original discoveries [were] when he worked in the Curie University in Paris where radioactivity was discovered. So he learned how to use radio labels and he started applying them in biological systems. He saw the first label DNA, the first to label protein, the first to label sugars. Essentially, I think, he discovered stem cell hierarchies by showing how labels travel through the skin. For instance, he was the first to show that all cells make protein- quite a quite a spectacular finding because people believed that the liver makes all protein and the rest just take it up from serum. He was the first to show the ER Golgi secretory pathway. So he could have earned three, four Nobel prizes. Those papers are published in journals and were repeated later and several people got Nobel Prizes [for this work]. He’s always a bit a bit neglected. I don’t know why. But also everything we published about the gut stem cells. After the fact I found out that he had published sort of theoretical papers that predicted everything. So this is like a string of maybe 10 Nature, Cell, Science papers, we can now safely say after they have published that they were not original, because actually Leblond, CP Leblond had already published the hypotheses.

Peter  20:27

What would you like to ask him?

Dr. Clevers  20:28

What would have liked to ask him? I think, how his findings relate to disease, the various diseases of the gut. He doesn’t say much about [his views] in his papers. But it’s clear that he was a pathologist. He must have been looking at all of these structures from a pathological point of view.

Peter  20:47 

I think that’s fascinating. And personally, I like to get to know the scientists behind the science and I know a lot of times for people who are key figures in the field, they publish books, and we really like to know what their frame of mind is or what their reference and viewpoints are, but oftentimes when we’re judging the science currently in when we’re reviewing […] some article during a journal club, we […] dissociate the scientists from the science and I was wondering, at what point do you think we should look at the context that the scientist is working in when we’re evaluating their work?

Dr. Clevers  21:20 

I think always. So my thought when I started science was this is this is an extremely rational activity that you know, you sit, you’re smart, you design, you test, that’s how you define hypothesis, you design experiments that would contradict what you’re thinking and you would re-formulate your hypotheses. Over the years, I’ve learned that in experimental biological sciences that’s not how it works. I think 80-90% of what happens leading up to a discovery is random events between people. It’s characters of individuals, and eventually when that turns into a potential discovery, then we go into this mode that people think scientists always do. You become very rational you do your experiments you do your controls and this and that and then you write your paper as if you would always be looking for that particular phenomenon which you basically stumbled across it and you interpreted it well. So I think that first 80% that’s the biggest difference between people who constantly make discoveries and people who are extremely smart and know everything but don’t make discoveries that […] actually in this process of searching, stepping into dark [and] changing opinions, talking to people, hooking up with people, that that is where the discoveries really arise and then once use you see the light then you switch to this mode and that is the second part is you can learn. For a doctor there’s much more of the second part; so if you’re a clinician a lot of what you do once you know, it is this disease then you do this and these are the tests I do this how I follow up. For us is much less so, in basic exploratory science. So the context of a person that contacts you know why this person all of a sudden switch from this model system or that model system? What happened in his life that he meets somebody? Did he do that? That is that is crucial if you want to really, it would be good if you could make the discovery process more efficient, because we waste most experiments, as everybody knows, end up on the floor. And if you could make that process more efficient, that would be fantastic. So I’ve been talking a lot to colleagues knows more senior scientists who have made discoveries and they also don’t know exactly how this works. And it would be great […] but a lot of it is in the social interactions in the unexpected ideas that pop up because somebody says something, you make a link with something you’re thinking and all of a sudden there is an answer.

Peter  23:49 

I think that’s a nice way to paint it because a lot of people who aren’t in the scientific field think it’s a very isolated process. You’re working on a project you’re kind of hitting your head against the wall, kind of racking your brains but you need to reach out to other people and communicate with them to see if they have some other framework for you to think about.

Dr. Clevers. 24:04

Exactly.

Peter  24:06 

I also noticed on the other aspect of your Twitter, you posted a couple of animations or videos. Could you tell me a little bit about what got you into using videos or animations to explain science?

Dr. Clevers  24:18 

Yeah, so I’ve always I used to draw a lot as a kid. I collect art paintings. And so I’ve always been drawn by the visual. So stepping back I learned how to write papers over the years and what I used to do for a long time, so I spend endless amounts of time on the title and the summary. And if the title and the summary don’t draw attention, build up some tension and resolve. The storyline of a scientific paper is extremely important. And if you cannot write up your story in 125 words, which some of these journals [require], then there’s something wrong with the stories. There’s two stories or there’s only three quarters of a story or the order is wrong. If you cannot produce a 100 character title that has the message and draws attention has all the keywords, there’s something wrong with what you’re trying to communicate. So that I knew that for a long time. Then I got into contact with this guy who was, I think a physics PhD student, and he never graduated. He had this extreme talent- I think he uses the Pixar software. And the way we started working together is whenever I thought, we have a really nice discovery, I will do my title, my summary and we then try to write a script, they have a one minute audio, video animation video. And he would look at it, we talk he said, Well, this doesn’t work, and then he would turn it into so he gave a lot of images. Now what does this look like ? And he asked how many cells are there? How fast the move? So really, a lot of this is really correct modeling in these as many 40 or 50 animations now. Then he makes a cartoon of how we think the animation should go. And then we’ll go back and forth. And then I’ll say, well, that’s not what I said. Then read your text. This is what you say. I said, well, I meant something else. Yeah, so text is very ambiguous. And it’s clear that to listen to people talk or to read, particularly to two people talk, you get tired and lecture can last 45 minutes, but then it’s done. So and part of it, I think, because it takes a lot of brainpower to interpret what the person is trying to communicate. So once we figured out, okay, this is what I mean and okay, now I understand it, then he would make this movie and then it will be back and forth. And then when the movie is there, all of a sudden, everybody who watches the movie is effortless. They just look at when I give talks- I have many but often what I used to do is I would first show the experiments and summarize in the video, but I didn’t realize what works much better is if I first showed a video, people know the story and you see it and it’s the moment that it moves, people sit up, and they watch and it’s effortless to enjoy. And it’s artistically well done. And then I just showed the slides that show the evidence for what I just said. So you can say show, much more in 45 minutes you could ever do if you’re just talking and showing static slides. I also see when it’s playing- I speak a lot for lay audience like politicians or an artist [or] journalists, and the moment it moves, everybody pays attention. So the more I have movement on the screen, the easier people find it to just stay with me and I can communicate much, much more information through these visuals and they could ever do. Probably the people who are in in animations probably know this, I just discovered this. And the way they are made […] originally, they were made for scientific audiences. But it turns out that it works [for] any lay person with some education, know what the stomach looks like. You zoom in, they know what they’re looking at. They know more or less what a cell looks like […] so they understand immediately. The enjoy the aesthetics, they would not enjoy the aesthetics of a table. So in papers, I have very few tables or blocks […] You want different kinds of variables in the paper, and definitely colorful ones. You don’t want just numbers or lines.

Peter  28:20 

Do you feel like working on these animations has influenced how you write your papers? And is there kind of now a different type of structure or some principles that you follow when you’re writing?

Dr. Clevers  28:29 

Yeah, so this is writing this script, but it’s a bit like writing a summary but at the same time, you have to it’s not only the summary where you have you know, 10 sentences or so of a paper but you also have all the support that you would have that you use the entire paper for. So animation essentially captures everything that’s in the paper in one minute. And so I must say that I now find myself thinking, is this story ready to be submitted? Is a complete? Is it exciting? Will people like this? What is the real message here? When I think through the eyes of the animator, I get a much better sense of you know, what we need [is] a single message, we don’t need three message. We don’t need […] to prove five times what we know is true. We just show it once. And then we have all the backup evidence if needed. So to make a sort of an abstracted, clean, aesthetically pleasant representation of the work that I think in these animations works best.

Peter  29:27 

Really neat. How do you feel like how you frame a picture has influenced how you think about questions in science, when you’re doing this animation, you need to have this kind of viewpoint or this needs to be zoomed in here. Does that affect how you think about when you’re conversing with other people about their science? Like, oh, should we focus more on this part of the scientific process?

Dr. Clevers  29:47 

Yeah, sort of? Well, there are what you’re asking. There are several questions that have arisen in the process of making these animations because, like where cells come from where do they go and why? Why does this go there. So when you visualize the process you’re looking at you actually, you note the holes in your knowledge? Well, we’re not looking at this at all, but it’s a big issue because we don’t know where the cell will go next, or why it dies here and not there. So I guess it’s formalizes, in a way, a process of asking questions or seeing where the openings still are, or where the research can go, because literally you can see in these animations, we know this, we know this, but we don’t know this. So we just keep it out of the current animation [and it’s where] we should really be moving the [of] in the lab.

Peter  30:41 

I want to ask one quick question about your lab work. I know you have pioneered the field of organoids. And people are using organoids. And they’re using kind of spheroids, tumoroids. They’re developing a lot of different in vitro systems to model […] high throughput personalized screening of therapeutics. Where do you see the field going? And what do you think the current limitations of organoids are.

Dr. Clevers  31:03 

There are two types of organoids. The type that we developed is based on the stem cells or stem cell activities that are present in adults, in born bodies. And so every organ will have its own stem cell function. And then there’s the embryonic stem cell-based organoids that [built] brain that we cannot do or built our kidney or heart. So we basically use stem cells that maintain or repair tissues, [which is a] very different, very different approach. So for our approach, and I won’t speak for the other field, but for our approach, it is, like the best lab models, extremely reductionist, so it is an abstraction of reality. The original mini guts grown from one stem cell was aesthetically very nice because you start from one cell, it builds a gut. It’s very surprising that’s possible at all, and we still don’t understand much of that process. But is a complete gut, it has no immune cells, it has no muscle. It has no nerves, no blood vessels. So I think the big challenge is now is to, and this looks extremely promising, add additional layers. My approach would always be start as reductionist, as simple as you can. Add one variable, figure out how it works, add another variable and slowly build up the system. There’s a strong tendency with many scientists to say well there’s not a real life this is not how it works; it’s much more complex. And then they add everything together, and reviewers will tell us, you have to add this and that, but then I no longer know what I’m looking at. It’s too noisy. But that’s the style of research. So I thought I see now people are adding the microbiome by injecting and scientists many guts people adding organs, nerve cells, muscle cells, co-culturing […] You can you can have a piece of gut and a piece of brain and see how they communicate so that I think the developments that are currently happening in any place is just adding more complexity and getting closer to what a real organ looks like. Having said that, I must say there have been a large number of discoveries made by many labs in these extremely simplified systems that could then be checked in mice or in humans and patients, and confirmed to be true. So I think the power of modern science has been reductionism to a large extent and these organoids are an ideal model for that approach.

Peter  33:25 

Well, thank you so much for your time, Dr. Clevers.

Dr. Clevers  33:27 

Okay, thank you.

Peter  33:39 

Dr. Clevers shared a few of the things that went through his mind over his extensive research career. And one of the things that really stood out to me was the importance in trying to interpret your results without any preconceived notions. Natural processes are incredible, and it is important for scientists to really appreciate all the facets of the process. When you think you have a handle of these biological phenomena try and portray it as a movie. Use your imagination to piece together your observations and direct your future scientific questions by filling in the missing parts. I want to thank you all so much for listening, and we’ll see you on the next episode. For more of our content, you can follow us on Twitter @gutbrains or visit our website at thinkgastronauts.com. The Gastronauts Podcast would be impossible without the incredible team that we have here. Meredith Schmehl is our producer and theme music composer. And special thanks to the founders of Gastronauts, Dr. Diego Bohórquez, and the Bohórquez laboratory.

Mar 2020 – Julia Kaltschmidt

Dr. Kaltschmidt is a Wu Tsai Neurosciences Institute Faculty Scholar and an Associate Professor in the Department of Neurosurgery at Stanford Medical School. Originally from Germany, she received her undergraduate degree in Molecular Biology and Biochemistry from the University of Madison, Wisconsin. She then completed her PhD at the University of Cambridge in the UK, where she trained as a developmental biologist and studied the cellular mechanisms underlying early Drosophila nervous system development. During her postdoc at Columbia University, she began working with mouse as a model system, and became interested in mechanisms that underlie sensory-motor circuit connectivity in the spinal cord. She continued to explore the development and molecular regulation of spinal circuity as an Assistant Professor at the Sloan Kettering Institute in New York City. During this time, the focus of her laboratory further expanded to include neuronal circuits that underlie sexual function and gut motility.

Her lab’s goal is to understand the molecular basis of neuronal circuit formation. They are particularly interested in circuits that underlie locomotion, sexual function and gut motility.

See more of her work here.