利用干细胞治疗自闭症、癫痫与精神分裂症 | Sergiu Pașca博士专访

欢迎来到Huberman实验室播客，在这里我们探讨科学及基于科学的日常生活工具。我是Andrew Huberman，斯坦福医学院神经生物学和眼科学教授。今天的嘉宾是Sergio Posca博士。

Welcome to the Huberman Lab Podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor. Sergio Posca. Doctor.

Sergio Posca是精神病学与行为科学教授，兼斯坦福脑类器官生成项目主任。在本期节目中，我们将讨论自闭症、精神分裂症及人类大脑发育全过程——包括孕期大脑发育、童年期直至人生第三个十年的大脑发育。通过今天的对话，您将获取关于自闭症及其治疗的最新信息，了解自闭症发病率上升的原因、基因在自闭症中的作用，以及Posca博士正在研发的治疗重度自闭症（即最严重自闭症病例）的创新疗法。

Sergio Posca is a professor of psychiatry and behavioral sciences and the director of the Stanford Brain Organogenesis Program. During today's episode, we discuss autism, schizophrenia, and human brain development generally, both brain development during pregnancy, as well as during childhood and leading all the way up to our third decade of life. During today's discussion, you will get the most up to date information about autism and its treatments. You'll learn why the prevalence of autism is rising, the role that genes play in autism and the novel treatments that Doctor. Posca is developing to treat what is called profound autism, which are the most severe cases of autism.

Posca博士是少数率先发现并开发类器官和组装体的研究者之一。这些源自干细胞的体外培养人脑回路模型，虽听起来像是人工产物，但他将解释为何这些模型对精准解析重度自闭症、精神分裂症等精神疾病的病理机制及开发治愈方案具有重大价值。今天您将深入了解人类大脑发育与干细胞知识——这对关注脑神经连接机制、脑部疾病治疗的人群至关重要，对考虑干细胞疗法者亦极具参考意义。Sergio不仅是杰出科学家，更是卓越的教育者。

Doctor. Posca is one of a small handful of researchers that pioneered the discovery and development of what are called organoids and assembloids, which are essentially human brain circuits derived from stem cells that form in a dish so that one can study them directly. And while that might sound artificial, today he explains why those organoids and assembloids are immensely powerful for understanding exactly what is wrong in psychiatric illnesses like profound autism, schizophrenia, and other psychiatric challenges and for developing cures. So today you're going to learn a lot about human brain development and about stem cells, which is going to be important for anyone interested in how the brain wires up, how to treat various diseases of the brain, but also for anyone who is considering stem cell therapies. As you'll soon learn, Sergio is an extraordinary scientist, but also an extraordinary teacher.

节目结束时，您将掌握关于干细胞、类器官、自闭症及其治疗研究的最新进展。需要声明：本播客独立于我在斯坦福的教学研究工作，但符合我向公众免费传播科学知识的初衷。秉承此理念，本期节目含有赞助内容。现在有请Posca博士——

By the end of today's episode, you'll have the latest information on stem cells, organoids, autism, and what is being done to cure autism and other psychiatric conditions. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero cost to consumer information about science and science related tools to the general public. In keeping with that theme, today's episode does include sponsors. And now for my discussion with Doctor.

Sergio Posca博士，欢迎您。谢谢。

Sergio Posca. Doctor. Sergio Posca, welcome. Thank you.

很荣幸参与。我们是老朋友了。

It's great to be here. We're old friends.

嗯。多年前共用过实验室空间，这个稍后再聊。当前社会对自闭症存在大量关注与误解——每当提及自闭症，立刻有人质疑：为何要治愈这种特质？

Mhmm. Shared a laboratory space years ago. We'll get back to that a little later. In the meantime, these days, there's a ton of interest and I think misunderstanding about autism. As soon as the topic of autism comes up, immediately, some people will say, why are we trying to cure this thing?

我认识许多可爱的自闭症儿童和成人，他们过着功能性生活，或许与他人略有不同或大不相同。但为何要治愈自闭症？另一些人则会指出：有些自闭症患者需要终身监护，永远无法独立生活。请为我们解析自闭症谱系的本质，再谈谈您的实验室如何致力于治愈最严重的自闭症类型。

I know autistic children and adults that are delightful people that lead functional lives. They might be a little bit different or a lot different than other people, but why are we trying to cure autism? And then other people will say, well, there are people with autism who need constant care, who will never live independently. Tell us about autism, what this spectrum really is. And then we'll talk about what your laboratory is doing to try and literally find cures for the most debilitating forms of autism.

这是种复杂病症。如你所说，它是个谱系，某种程度上可称为自闭症谱系神经发育障碍。其诊断完全基于行为观察——事实上多数精神疾病都是如此——通过特定年龄段特定行为的存在与否来判定。近年来发病率攀升至总人口近3%，这引发了广泛讨论。

Well, is a complex condition. It's a spectrum, as you said. In a way you could say autism and neurodevelopmental disorders. It's behaviorally defined. There's no biomarker.

3%的比例确实不容忽视。

So in a way it's a condition that is defined exclusively by observing behavior, which is actually the case for most psychiatric disorders. But it's essentially diagnosed by the presence and absence of certain behaviors in a certain period of time or up to a certain age. And of course, what triggered, I think a lot of discussions in recent years is because the number or the prevalence of autism has increased. So now it's close to almost three percent of the general population, which of course, it's a big number. Three percent.

接近百分之三。这个比例甚至比我读医学院时还要高。实际上在我医学院时期，自闭症还被认为是一种罕见病。我当初研究自闭症的原因，正是因为它非常罕见且资源匮乏，我们以为研究罕见病会更容易。但现在我们对这种病症的了解已经深入许多。

Almost three percent. So that has increased even since I was in medical school. When I was in medical school actually, it was considered a rare disease. The reason why I actually studied autism, because it was a very rare disease and we had very few resources, so we thought studying a rare disease would be easier. But now we also know so much more about this condition.

比如我们现在知道它有很强的遗传因素——这在过去显然是不清楚的。事实上早期精神分析观点占主导地位，特别是在五六十年代。当时认为病因在于父母（尤其是母亲）情感冷漠。对，就是情感上的冷漠。

So we do know, for instance, that there is a strong genetic component to it, which for a while obviously we didn't. In fact, in early days the psychoanalytic perspective dominated, especially in the fifties and sixties. So it was thought that it was resulting from having very cold parents, in particular cold mother. Emotionally cold? Yeah, emotionally cold.

这就是所谓的自闭症'冰箱母亲理论'。到了七十年代，首批生物学研究（主要在双胞胎中开展）揭示了惊人发现：如果同卵双胞胎中一人患自闭症，另一人患病概率极高。

It was the so called refrigerator mother hypothesis of autism. And then in the 70s, some of the first biological studies were done, primarily in twins, that show something quite remarkable. That if you have twins that are identical, genetically identical, and one has autism, then the probability that the other one has autism is very, very high.

即使母亲不同也是如此吗？

Even with different mothers?

当然。但我们普遍认为自闭症有很强遗传性。这是七十年代末的认知。而近十到十五年，我们才真正发现与自闭症相关的基因——特别是某些特定类型的自闭症。现在我们将这些严重病例统称为'重度自闭症'，这些往往伴随智力障碍（低IQ）或癫痫等共病。

Sure, But generally we think that there is a strong heritable component to autism. So that was like in the late seventies. And really just in the last ten, fifteen years, we've learned actually that there are genes associated with autism and certainly with very specific forms of autism. So that's what we would call generally profound autism today. The conditions that are severe, that are causing an impairment, They're very often associated with other conditions such as intellectual disability, so low IQ, epilepsy.

由于自闭症是谱系障碍，自然会造成很多混淆。确实存在具有自闭特质但功能完全正常的个体，但现实中也存在需要终身照护的重症患儿。另一种理解方式是：自闭症不是单一疾病。任何研究自闭症的精神科医生或生物学家都不会认为这是单一病症。

So because it is a spectrum, of course, it creates a lot of confusion. And certainly there's no doubt that there are individuals that have autistic traits that are fully functional in the general population. But the reality is also that there are kids that have autism who are very impaired and will require actually lifelong care of sorts. Another way of thinking about autism is that autism is not one disease. And I think no psychiatrist or even biologist who's studying autism will ever consider that this is one single disease.

我常这样比喻：想象十九世纪医学中的'发热'诊断。就像电影里常演的——'他高烧不退会死的'。这发热可能是病毒感染、细菌感染，也可能是转移性癌症。

The way I look at it sometimes is, like think about the fever of the nineteenth century in medicine. So you see this very often in movies, right? They will say, Oh, he has a fever, high fever. He's going to die from high fever. Well, that fever could have been a viral infection, a bacterial infection, could have been cancer, metastatic cancer, right?

还可能是自身免疫疾病。这些病因的治疗方案截然不同，但当时我们只能观察到体温升高的表象。如今我们对这些病症会采用完全不同的治疗手段——有些甚至无需治疗只需观察。自闭症研究也是如此。

Could have been an autoimmune disease. The treatments are very different. But in that time, that's all we knew. It was we were observing that behavior, in which case raising of the temperature, but we didn't know the biology. Today, we will use very different treatments for those conditions.

许多精神疾病都是通过行为定义的，但这与生物学机制存在脱节。我们通常缺乏明确的生物标记物，这种脱节造成了大量困惑。

And some of them, of course, we don't even treat, right? We just observe. So I think in autism research, as it is the case for many psychiatric conditions, they are defined behaviorally, but there's a disconnect with the biology. Very often we don't have biological markers by definition. And so that disconnect, I think, creates a lot of confusion.

我有几个问题。首先，自闭症在男性中发病率更高吗？听说确实如此。如果总体发病率是3%，男女比例具体是多少？

I have a couple of questions. First of all, is the prevalence of autism higher in males? I've been told yes. If it's three percent overall, is it what what's the distribution for males versus cisterns?

这一比例也会根据严重程度而变化，但通常是一比四。所以男性患者多于女性。

The ratio varies also based on severity, but generally, it's been one to four. So more more males than females.

我们最近刚在播客中邀请了同事Nirau Shah，他基本上表示，生物学上男性和女性的差异归根结底在于这个SRY基因。甚至不一定在Y染色体上。嗯。如果婴儿有SRY基因，就会发育成功能完全的男性。是的。

And we just recently had our colleague, Nirau Shah, on the podcast who basically said, the difference between a biological male and female comes down to this SRY gene. Not even necessarily on the y chromosome. If Mhmm. If a baby has the SRY gene, you're gonna get a fully functional male. Yeah.

如果没有，本质上就是在处理女性发育。因此推测，SRY基因的某些特性可能导致了自闭症的易感性。我觉得这非常有趣。

If not, you're you're essentially dealing with a female. So presumably, something about the SRY gene is conferring a vulnerability to autism. I think it's fascinating.

当然，关于造成这种差异的原因有很多讨论。有些讨论仅涉及诊断方面，可能部分女孩没有被正确诊断，她们...我们确实知道其中有些人非常擅长所谓的症状掩饰。学习社交技能等，从而掩盖诊断。但可以确定的是，男性和女性大脑在承受损伤方面存在差异，尤其是在出生前后。以早产为例。

Well, there are a lot of discussions, of course, like what causes this difference. And some discussions are just in terms of diagnosis that perhaps some of the girls are not getting diagnosed properly, that they're We do know that some of them are very good at what we call masking the symptoms. Learning the skills, social skills, and so like covering for that diagnosis. But what we do know for sure is that there are differences in how the male and the female brain, especially around birth, can actually take up injury. So think for instance about premature birth.

对于早产儿预后最好的预测指标之一，实际上就是女性性别。总体而言，女早产儿无论出于何种原因都会表现更好。神经系统构建方式、恢复力方面，我们知道男女的成熟阶段也不同。想想女孩某些发育里程碑达成得更快。她们通常会更早几个月说话，更早几个月走路。

One of the best predictors for a premature baby in terms of outcomes, it's actually to be a female. Just in general, females, preemies will do much better for whatever reasons. The way the nervous system is built, the resilience, we know that the maturation stage is also different for the male and the female. Think about acquisition of certain milestones that happen much faster in girls. They generally tend to speak a few months earlier, to walk a few months earlier.

所以仅仅是神经系统的成熟速度不同，对损伤的反应也不同。这可能是原因之一，但与此同时，正如我们讨论的，由于自闭症不是单一疾病，很难指出背后某个特定因素。

So just the nervous system is maturing at a different pace and can take injury differently. So it could be that that is certainly the cause, but at the same time, and as we were talking, since autism is not one single disease, it is very hard to point out to one specific factor that is behind it.

我想稍作休息感谢我们的赞助商之一David。David生产的蛋白棒与众不同。每根含28克蛋白质，仅150卡路里且零糖分。没错，28克蛋白质且75%热量来自蛋白质。这比市面上其他蛋白棒高出50%。

I'd like to take a quick break and acknowledge one of our sponsors, David. David makes a protein bar unlike any other. It has 28 grams of protein, only 150 calories and zero grams of sugar. That's right, 28 grams of protein and 75% of calories come from protein. This is 50% higher than the next closest protein bar.

DAVID蛋白棒口感惊艳，连质地都很棒。我最喜欢巧克力曲奇面团口味，不过新出的巧克力花生酱和巧克力布朗尼口味也很喜欢。基本上所有口味都很棒，都超级美味。

DAVID protein bars also tastes amazing. Even the texture is amazing. My favorite bar is the chocolate chip cookie dough, but then again, I also like the new chocolate peanut butter flavor and the chocolate brownie flavor. Basically, like all the flavors a lot. They're all incredibly delicious.

实际上最大的挑战是决定每天吃哪种口味、吃几次。我限制自己每天两根，但真的非常喜欢。通过David，我能在零食级热量中获取28克蛋白质，轻松达成每日每磅体重1克蛋白质的目标，还不会摄入过多卡路里。我常在下午把它当零食吃。

In fact, the toughest challenge is knowing which ones to eat on which days and how many times per day. I limit myself to two per day, but I absolutely love them. With David, I'm able to get 28 grams of protein in the calories of a snack, which makes it easy to hit my protein goals of one gram of protein per pound of body weight per day. And it allows me to do so without ingesting too many calories. I'll eat a David protein bar most afternoons as a snack.

出门或旅行时总会随身带一根。它们极其美味，且28克蛋白质含量让150卡路里就能带来很强满足感。如果想尝试David，请访问davidprotein.com/huberman。再次提醒，网址是davidprotein.com/huberman。今天的节目也由Helix Sleep赞助播出。

And I always keep one with me when I'm out of the house or traveling. They're incredibly delicious, and given that they have 28 grams of protein, they're really satisfying for having just 150 calories. If you'd like to try David, you can go to davidprotein.com/huberman. Again, that's davidprotein.com/huberman. Today's episode is also brought to us by Helix Sleep.

Helix Sleep生产根据个人独特睡眠需求定制的床垫和枕头。我之前多次在播客中谈到，获得优质夜间睡眠是心理健康、身体健康和表现的基础。你所睡的床垫对每晚的睡眠质量影响巨大，其柔软度或硬度都关乎舒适度，需要量身定制。访问Helix官网完成两分钟简短测试，它会询问诸如你习惯仰卧、侧卧还是俯卧？夜间容易感到燥热还是寒冷等问题。

Helix Sleep makes mattresses and pillows that are customized to your unique sleep needs. Now I've spoken many times before on this and other podcasts about the fact that getting a great night's sleep is the foundation of mental health, physical health, and performance. Now the mattress you sleep on makes a huge difference in the quality of sleep that you get each night, how soft it is or how firm it is, all play into your comfort and need to be tailored to your unique sleep needs. If you go to the Helix website, you can take a brief two minute quiz and it will ask you questions such as, do you sleep on your back, your side, or your stomach? Do you tend to run hot or cold during the night?

诸如此类的问题。你可能知道答案，也可能不清楚。无论如何Helix都会为你匹配理想床垫。对我而言，最终匹配的是DUSK床垫。我使用DUSK床垫已有三年半，这是我迄今为止体验过的最佳睡眠。

Things of that sort. Maybe you know the answers to those questions, maybe you don't. Either way Helix will match you to the ideal mattress for you. For me, that turned out to be the DUSK mattress. I started sleeping on a DUSK mattress about three and a half years ago, and it's been far and away the best sleep that I've ever had.

若想尝试Helix Sleep，请访问helixsleep.com/huberman完成两分钟睡眠测试，Helix将为你定制专属床垫。现Helix所有床垫订单最高可享27%优惠。重申一次，访问helixsleep.com/huberman即可享受最高27%折扣。你提到自闭症通过行为测量或行为症状缺失（即我们所说的阳性和阴性症状）来诊断，这种表述容易让人困惑，因为人们会误以为阳性代表良好。其实不然。

If you'd like to try Helix Sleep, you can go to helixsleep.com/huberman, take that two minute sleep quiz, and Helix will match you to a mattress that's customized to you. Right now, Helix is giving up to 27 off all mattress orders. Again, that's helixsleep.com/huberman to get up to 27% off. You mentioned that autism is diagnosed by behavioral measures or the lack of behavioral symptomology, what we call positive and negative symptoms, which can be confusing language because people think positive means good. No.

阳性指症状存在，阴性指症状缺失。我许久未查阅相关文献，但上次了解时，婴幼儿无法将视线聚焦他人眼睛似乎是主要诊断标准之一。他们可能整体观察面部或只盯着鼻子，但缺乏真正眼神交流。这仍是诊断标准吗？

Positive is the presence, negative is the absence. I haven't looked at this literature in a while, but the last time I did, it seemed that babies or young children failing to focus their own gaze on the eyes of other people is one of the major diagnostic criteria. It seems they look at the face, they'll they'll more holistically or they'll zoom in just on the nose, but they're not really making as much eye contact. Is that still a diagnostic criteria?

这不属于诊断标准。但确实是被观察到的特征之一。当然，这也与共同注意力有关——这是早期发展的关键。比如当你对孩子说'看这里'时...

It's not part of the diagnostic criteria. Interesting. It's But it is one of the features that has been observed. Of course, it also has to do with just in general, joint attention is one of the earlier. So, you know, if you just tell a child like, Oh, look here.

对吧？如果他们能产生这种注意力，这种互动特征确实与自闭症存在关联，但绝非诊断性特征，更非病征学表现。这并非疾病特异性指标。不过确实存在多种缺陷，其中部分后期可通过代偿机制改善。

Right? So if they have that attention, if they engage in that attention, it's one of the features that is associated with autism is not certainly diagnostic, not pathognomonic, so to speak. So it's not specific to the disease in any way. But there's certainly many deficits, and some of them can actually be compensated later.

有意思。我还听过一些说法，比如自闭症儿童发烧时症状会改善。

Interesting. There were some other things I've heard over the years, for instance, that when children with autism have a fever, that their symptoms improve.

现在仍是这样吗？是的。这些主要是高烧患者的轶事报告，比如原本非言语的自闭症患者——许多自闭症人士语言能力有限或无法交流——

Is that still the case? Yeah. So those are mostly anecdotal reports of patients who would have a very high fever, and then for instance, were nonverbal. So many patients with autism or individuals with autism will be nonverbal. They have very few words or if they're not able to communicate.

有家长报告称孩子突发高烧时会短暂说出完整句子或产生互动。实际上这种现象确实存在：儿童高烧时通常更健谈，这似乎激活了神经系统。对此有诸多假说——

And so there are a few reports of parents saying that when they had spiked a very high fever, they'll start talking in sentences, like very briefly or like engaged. And in fact, I mean, that is known. Kids in general, when they have a high fever, they tend to be more talkative. It activates somehow the nervous system. There've been a lot of hypothesis about this.

有人认为与去甲肾上腺素系统在发热时的激活有关；另一些假说指向发热时出现的细胞因子等免疫分子进入大脑激活神经系统；还有简单解释认为温度升高导致离子通道开放增加，从而改变神经回路功能。

Some of them having to do with how the noradrenergic system is activating during fever. Others saying that there are some of the cytokines, the immune molecules that are present during fever that are somehow getting into the brain, activating the nervous system. And others as simple as, oh, ion channels. Ion channels will open more when the temperature rises. Something about the circuits functioning differently during that.

但目前这主要还停留在轶事层面。而且它显然——再次强调——可能并非存在于所有自闭症患者身上。因为自闭症本身也不是单一疾病，所以我们不应期望这一现象在所有病例中都出现。

But it's mostly anodotic at this point. And it's certainly, again, probably not present in all individuals with autism. Also because autism is, again, not one single disease. So we would not expect it to be present in all.

几年前，学界曾对自闭症可能与微生物组缺陷相关甚至由其引发的观点兴奋不已。当时有实验将野生型健康小鼠的粪便移植到表现出类似自闭症症状的小鼠体内，并观察到症状改善，甚至后来还开展了人类粪便移植的临床试验。这些研究后来进展如何？

A few years ago, there was a lot of excitement about the idea that autism might somehow be related, perhaps even caused by deficits in the microbiome. There were some mouse experiments of doing fecal transplants from what we call wild type or healthy mice into mice that were, had some symptoms that resemble autism. And there were improvements observed to the point where I think there were some human clinical trials using fecal transplants. Whatever became of that?

事实上几乎所有因素都曾被关联或假设为致病原因，但确证极其困难。虽然改善微生物组可能提升部分患者的生活质量，但尚无明确证据表明其因果关系。举个类似例子——睡眠问题，约七八成重度患者存在严重睡眠障碍，整夜难眠的情况很常见。

Well, I think, again, almost everything has been associated or thought to be causal, but generally demonstrating this is very, very difficult. So, we cannot deny that perhaps improving the microbiome will improve the quality of life of some of these individuals, but whether it's really causal, there's no clear evidence for it. Think about it, just to give you another example, think about sleep. Many patients will report, especially the ones that are profoundly impaired, will have severe sleep disturbances. I mean seventy, eighty percent of them, they can have nights where they sleep very little, right?

持续一周如此。试想仅改善这些患者的睡眠质量就能创造奇迹。毕竟普通人三四天不睡也会社交能力下降。因此解决这类基础问题确实重要。

Then do that for like a week. So just imagine even just improving the quality of sleep for those patients can do miracle. I mean, all of us, right? If we don't sleep for three, four days, our social skills, we become socially impaired. So I think of course correcting a lot of these issues.

比如很多患者挑食，排斥特定食物质地（如蔬菜），早年我们曾认为这是核心饮食紊乱。但单纯纠正这些是否能改善或逆转症状，仍有待验证。

So for instance, many patients are picky eaters. They don't like certain textures. So they will never eat, for instance, veggies. So that creates, in the early days, for instance, we thought that there are dietary disturbances that really are at the core. Of course, it remains to be seen whether just simply correcting those is going to be just improving or certainly reversing some of these forms.

不过现有证据强烈指向遗传因素的主导作用。目前我们已发现数百个基因突变与特定自闭症亚型高度相关。

But again, most of the evidence points out towards a very strong genetic component behind it, and in fact we now have hundreds of genes that we know when they are mutated, that are strongly associated with specific forms of autism.

我好奇这些基因下游调控哪些蛋白质。哈佛大学的David Guinty做过精妙实验——他仅在周边系统（大脑之外）诱导突变...

I'm curious what sorts of proteins those genes are upstream of. And I ask because David Guinty at Harvard did these really beautiful experiments where he induced mutations just in the periphery. So outside the brain

是的。

Yeah.

...就在自闭症小鼠模型中观察到了相似症状谱。

Of these mouse models for autism and saw a lot of the same symptomology.

没错。

Yeah.

提出的问题是自闭症是否源于大脑，或者大脑中的缺陷是否是身体变化的副产品。是的，微生物组，但也许他们的皮肤、听力等更为敏感。也许这就是为什么你可以想象，如果你对环境极度敏感，你的大脑最终会根据感官环境中的情况以不同的方式连接，并某种程度上被其淹没。

Raising the question of whether or not autism originates in the brain or whether or not the deficits in the brain are the byproduct of changes in the body. Yes, microbiome, but perhaps their skin, their hearing, etcetera, are more sensitive. And maybe that's why they you you could imagine if you were ultra sensitive to an environment that your brain would eventually wire differently according to and kind of overwhelmed by what was happening in the sensory landscape.

是的，完全正确。他做的那些实验非常精妙。许多基因属于不同的类别。有些基因产生的蛋白质位于突触，这某种程度上是预料之中的。其中一些是离子通道。

Yeah, absolutely. And those are really elegant experiments that he's done. Many of the genes, they fit in different categories. You would have genes that would produce proteins that sit at synapses, which was sort of like to be expected. Some of them are ion channels.

这些蛋白质允许离子进出神经元。有许多这样的病症，所谓的通道病。还有一些与突触相关，即突触病。还有许多染色质基因，即负责细胞中DNA包装的蛋白质。这些是染色质病。

They're proteins that would let ions inside or outside of a neuron. There are many of these conditions, so called channelopathies. And there are the ones that are like synaptic related, so synaptopathies. There are a lot of chromatin genes, so like proteins that pack the DNA in cells. Those are chromatinopathies.

所以，这些基因确实分属许多不同的类别。另一个有趣的现象是，许多这些基因也在外周表达。我认为你提到的实验非常精妙，因为它们表明，即使仅影响外周，这些基因也能干扰神经系统的发育。当然，在患者体内，它们也存在于中枢神经系统中，因此总是难以区分。但仅仅错过或干扰这些发育的关键期，肯定会对后期产生毁灭性的影响。

So they're really, again, many, many categories of genes. And then what is also interesting is that many of these genes are also expressed in the periphery. So I think the experiments that you were mentioning are really elegant, because it showed that indeed that can perturb the development of the nervous system, even if they're affecting just the periphery. Of course now in patients, they are present also in the central nervous system, so it's always difficult to distinguish. But just missing some of these critical periods, or perturbing some of these critical periods of development can have certainly devastating effects later on.

那么，如果现在有家长带着被诊断为重度自闭症的孩子来诊所，治疗方式是什么？暂且不考虑癫痫的可能性（希望他们也会治疗）或其他可能的次要问题。但典型的治疗是什么？他们在做什么？假设资源无限，当然没有人有无限资源。

So if a parent comes into the clinic nowadays with a child that's diagnosed with profound autism, what is the treatment? Let's set aside the potential for epilepsy, which hopefully they would treat as well, or other things that might be secondary. But what is the typical treatment? Are they doing? And let's assume infinite resources, of course nobody has.

人们没有。但如果一个人有无限资源，会做什么？会是行为训练吗？会是控制大脑激活状态的东西吗？据我所知，目前没有单一的自闭症治疗方法。

People don't have. But if one had infinite resources, what would be done? Would it be behavioral training? Would it be something to control the activation state of the brain? I mean, as far as I know, there's no single treatment for autism.

不，没有单一的自闭症治疗方法。再次强调，这不是一种单一的疾病。今天我们可以说的是，如果一个家庭带着自闭症的诊断走进诊所，或者他们在诊所接受了诊断，仍有约20%的概率他们会带着基因诊断离开诊所。这意味着会有人向他们指出，这个基因在你的孩子身上发生了突变。有时可能是父母一方携带并遗传的突变，或者父母双方都携带，孩子以某种方式获得了两个被修改的副本。

No, there's no single treatment for autism. Again, in the context of this not being one single disease. What we can say today is that if, you know, family walks into the clinic with the diagnosis of autism, or perhaps like they receive it into the clinic, there's still like a twenty percent probability that they will leave the clinic with the genetic diagnosis. Meaning that it will be pointed out to them that this gene is mutated in your child. And it may be sometimes a mutation that was present in one of the parents and got transmitted, or maybe was present in both and somehow the child got two copies that were modified now.

或者许多基因实际上是新生突变，意味着突变在父母中都不存在，但在发育过程中出了问题，可能是在精子细胞、X细胞中，或是在发育的早期阶段，获得了新的突变。但这也是常见情况，我们所有人都会获得许多突变。我们有许多新突变，对吧？大约80个新突变，其中30个是蛋白质截断突变。因此，即使你看到一个基因发生了突变，确定这个基因是否真正导致疾病通常是一个挑战。

Or many of the genes were actually mutated de novo, meaning that the mutation was not present in either parents, but something went wrong during development, perhaps early in the sperm cell, in the X cell, or perhaps in early stages of development and a new mutation was acquired. But that is also the case, we acquire a lot of mutations, all of us. We have a lot of new mutations, right? About like eighty new mutations, thirty of them are protein truncating. So certainly the challenge very often is to, even when you see a gene that is mutated, to know whether that gene is truly causing the disease.

通常我们确认的方式是找到许多临床表现相似的患者。比如他们可能有并指症，即手指间有蹼，同时患有自闭症和癫痫，而且他们都在同一个通道（比如钙通道）上有突变。这就是蒂莫西综合征，一种遗传性自闭症，突变非常明确，实际上基因组中有一个字母的改变，导致所有这些患者表现出相对相似的临床表现。因此，约20%的患者会得到基因诊断。

So very often the way we know is that we find many patients that have a similar presentation clinically. Let's say maybe they'll have syndactyly. So they're webbing of the finger and they have autism and let's say epilepsy, and they all have a mutation in one single channel, let's say in a calcium channel. So that would be Timothy syndrome, a genetic form of autism, where the mutation is very clear, actually there is one single letter in the genome that is changed and causes a relatively similar presentation in all of these patients. So about twenty percent of the patients will get a genetic diagnosis.

遗憾的是，目前这并没有太大帮助，因为我们没有针对这些形式的特定疗法。我认为希望在于未来可能会有个体化治疗，无论是基因治疗还是其他方式。因此，成为这个群体的一部分通常是有益的。其余患者基本上属于更大的特发性类别，意味着我们并不确切知道具体原因。

Now sadly, that doesn't do that much today, because we don't really have specific therapies for those forms. I think the hope is that perhaps we will have individual treatments, whether they're going be genetic or otherwise. So being part of that community is generally useful. And then the rest of the patients will essentially fit into this larger category of idiopathic, meaning that we don't really know the precise cause.

我想谈谈蒂莫西综合征，同时也想讨论修复基因的遗传学方法，即所谓的基因治疗。在此之前，您是否愿意推测一下，为何自闭症发病率会出现如此显著的上升？人们常说可能是检测和诊断手段进步了。我很想听听您的见解。

I want to talk about Timothy syndrome, and I also want to talk about genetic approaches for fixing genes. So called gene therapy. Before we do that, would you be willing to just speculate on why you think there's this fairly dramatic increase in the incidence of autism? People will always say, well, maybe it's better detection, better diagnosis. So I'd like your thoughts on that.

如果有无法用上述理由解释的增长部分，也请分享您的看法。我们并非在进行正式的生物统计学讨论，只是基于您作为医学博士的经验——您长期关注自闭症，并致力于研发自闭症及其他神经系统疾病的潜在疗法。您如何看待这种患病率上升的现象？

And if there are increases that can't be explained with that, just would like your thoughts. Realize we're not talking formal biostatistics here. I just in your experience, you're an MD, you think about autism a lot. You're working on potential cures for autism and other neurologic conditions. How do you think about this increased prevalence issue?

确实，这种增长至今仍令人费解。一方面，诊断标准随时间推移发生了变化——我们不得不重新界定自闭症的本质定义，这在一定程度上改变了患病率统计。某种程度上也存在诊断迁移现象，比如三十年前可能被诊断为智力障碍的儿童，

Yeah. Well, certainly the increase is still puzzling, right? So I think on one hand, there's no doubt that the changes in diagnostic criteria, which has happened over time, I mean, we had to just refine what autism really is, that changed, to some extent the prevalence. We've also seen a diagnostic migration, so to speak. So some children, for instance, thirty years ago would have been diagnosed with intellectual disability.

如今却符合自闭症标准。约三分之一自闭症患者同时伴有智力障碍，因此这两种病症存在很大重叠。随着时间推移，诊断标签会发生转换。当然，关于服务可及性是否产生影响也存在诸多讨论。

And today they fit the criteria for autism. About a third of individuals with autism also have intellectual disability. So there is also a great overlap between the conditions. So there's been a move sometimes between the diagnosis over time. Of course, there are all kinds of discussions about availability of services and to what extent that is also contributing.

我们尚未完全理解这种增长背后的所有原因。根据遗传学研究，我们知道自闭症具有高度遗传性——其遗传率在精神疾病中名列前茅。但显然我们尚未掌握所有亚型的致病基因，其中某些可能非常罕见。

We truly understand all the reasons behind this increase. There's no doubt. We can explain, we know that it's highly heritable based on genetic studies. So we know the heritability is very high, one of the highest for psychiatric disorders that we know of. But of course we don't have the genes for every single form, It is likely that some of them are very rare.

可以这样理解：每种亚型单独看都很罕见，但集合起来却很常见。我们需要时间来完成全面基因图谱。此外，历史上某些环境因素确实会产生影响，比如早期接触沙利度胺等环境毒素会增加自闭症风险。这些因素都在起作用，

Essentially just think of it as like, they're individually rare form, but collectively common. It will take a while until we sort of map all of them. And then of course there are environmental factors that we do know historically can contribute to this. So there are various exposures to environmental factors like in early days, thalidomide for instance, was one of them that we know increases the risk for autism. So of course those are contributing,

但沙利度胺曾是用于预防孕妇流产的药物对吧？没错。现在已不再使用了。

but Thalidomide was a drug given to pregnant mothers to try and prevent miscarriage, right? Exactly. It's no longer prescribed.

确实已不再使用。

It's no longer prescribed.

它曾导致严重的出生缺陷。

It's caused major birth defects.

没错，正是如此。这个问题确实非常复杂——首先病症的定义本身就极具挑战性，这也是精神疾病研究的普遍难点。或许这正是我们在理解这类疾病方面进展缓慢的原因之一，毕竟现代医学的力量在于分子生物学。

Defects, yeah, exactly. Yeah. So there's certainly, you know, it's quite complex because first of all, the definition of the condition is quite difficult, right? And I think that is in general like the challenge with psychiatric disorders, right? And perhaps one of the reasons we've made such slow progress in understanding these conditions, because of course the power of modern medicine is in molecular biology.

我们运用这种非凡的理解力。为此，你需要两样东西。首先，必须对疾病在生物学上的定义有非常清晰的认识，对吧？比如心肌梗死，其定义就非常明确。你立刻就能通过生物标志物判断——患者一入院，抽血检测，二十分钟内就能根据生物标志物确诊是否心肌梗死。

We deploy this remarkable force at understanding. And in order to do that, you need two things. You need, first of all, to have a very clear definition of what that disease is generally biologically, right? Think about like myocardial infarction, very clearly defined in terms of what it actually means. You immediately have biomarkers, the patient walks in, you take blood, you can immediately tell, yes, in twenty minutes you can tell that they have a myocardial infarction based on a biomarker.

另一个关键点，也是我们所有工作的核心驱动力，就是人类大脑令人难以忍受的不可接近性。在大部分发育阶段，大脑都处于难以研究的状态。纵观医学各分支，你会发现器官可及性与现有疗法数量呈强相关性。以癌症为例——一个世纪前还被视作绝症。

And then the other one, which is certainly very important, which to a large extent is sort of like, is the source of all the work that we've done, is the unbearable inaccessibility of the human brain, so to speak. And to a large extent, the human brain is inaccessible for most of its development. And so if you look actually across branches of medicine, you can see that there's a very strong correlation between how accessible an organ is and how many cures or therapies we actually have. Think even just in cancer, right? Think about in cancers, which used to be, of course, an incurable disease, right, a century ago.

看看儿童白血病。上世纪五六十年代死亡率高达90%，如今可能只有10%。这是因为患者血液极易采集，我们得以在实验室研究病理机制，进而运用分子生物学开发疗法。

Think about leukemias in children. They are like ninety percent lethal in the 50s and the 60s. Today they are maybe ten percent lethal. And that is because blood from these patients, right, it's very easy to collect. We've been bringing it to the lab, studying it, what goes wrong, and then deploying molecular biology to develop therapeutics.

但大脑研究却无此捷径。我们一直在尝试突破这个瓶颈。我认为理解脑部疾病（无论是神经性还是精神性）的主要挑战，一方面是目标器官——大脑的不可接近性，另一方面是我们往往难以用生物标志物来界定某些...

With the brain, sadly, you know, there's no way of doing it. And so largely to, you know, what we've been trying to do is like find a way of shortcutting that process. But I do believe that the major challenges that we're facing in understanding brain disorders, whether they're neurological or psychiatric, are on one hand, the inaccessibility of the organ of interest, the brain. And on the other hand, our challenges are very often defining some of

这些复杂病症。神经疾病研究中相关性的运用程度令人震惊。分享几个例子：我记得本科和研究生时期有个著名理论——孕妇在妊娠中期感染流感，其子女患精神分裂症概率显著增加。

these conditions with biological markers, because they're much more complex. The degree to which correlation has been leveraged to try and understand neurologic disease is kind of staggering. I'll just share a couple and I would love your reflections. I remember when I was an undergraduate and in graduate school, there was this prominent theory that a mother who contracted influenza, the flu, toward the end of her second trimester at a much higher probability of having a schizophrenic child.

嗯。

Mhmm.

当时这个理论甚嚣尘上，如今却鲜少提及。不过我觉得精神分裂症在冬季严寒的高纬度地区更普遍，赤道附近较少——但这个统计结论可能需要更严谨的验证。

And there was so much said of that. And then now we barely hear anything about it at all. Although I think schizophrenia is more prominent at the toward the polls where you have harsher winters as opposed to around the Equator. But someone needs to check me those on that because those statistics might have melted away with more careful analysis. I don't know.

另一个现象是现在人们越来越关注某些疾病的低发人群。比如当前疫苗争议中就有相关讨论——顺便声明，我个人认为疫苗导致自闭症的说法缺乏确凿证据。

The other thing is that you'll nowadays hear a growing interest in populations for which a given disease is very rare. So one of the things that's circulating out there now that's related to the vaccine debate Mhmm. And by the way, I'm just gonna I'll I'll myself go on record. I don't think there's any solid evidence that vaccines cause autism.

确实没有。流行病学上毫无依据。

And and there's not. Epidemiologically, there's no evidence.

确实。虽然存在疫苗是否引发炎症的开放性问题，而炎症可能引发后续反应。但截至目前，所有支持疫苗与自闭症关联的论文均已被撤稿。听说新政府正在重新调查这些论文，暂且不论。有人会举阿米什人群为例——他们的自闭症发病率明显更低。

There's not. I mean, there's this open question as to whether or not vaccines of all kinds can increase inflammation, and there might be things downstream of inflammation. But for the record, there right now, there are no published papers that have not been retracted that that support the vaccine autism link. I think those papers are being reinvestigated under the new administration, but let's leave that aside for now. People will say, well, you have groups like Amish populations where the incidence of autism is significantly lower.

事实证明它确实存在。我查看了这些数据，但数值明显偏低。然后人们会说，这是因为缺乏食品染料，或许是缺乏疫苗等等。但作为一种遗传疾病，你也可以说，阿米什社区的人倾向于与社区内其他人通婚。

Turns out it does exist. I looked at these data, but it's significantly lower. And then people say, well, it's the absence of food dyes. It's the absence of vaccines perhaps, etcetera. But then as a genetic disease, you could say, well, there's also there's a tendency for people in the Amish community to reproduce with other people in the Amish community.

所以这是一个更受限的基因库。是的。这也可能解释这一现象。我提出这点不是为了引发更多争论——人们之间已经有够多分歧了。

So it's a more restricted genetic pool. Yeah. And so that could explain it as well. And I I raised this not to create any additional arguments. There are enough out there between people.

但正因如此，我认为所有这些的关联性本质才是创造观察机会的关键，比如发烧时症状缓解。当然。但如你所说，没有严重自闭症的健康儿童发烧时也会说更多话。关于自闭症及其潜在诱因的各种说法已经太多了。

But just because I think the correlative nature of all this is what kind of raises the opportunity for anything that's observed, like a fever, they get better. Sure. But as you said, healthy kids without profound autism also talk more when they have a fever. And so there's there's been so much made of autism in the various conditions that could create it. Yeah.

我觉得这对公众来说非常困惑。即使作为科学家，我也深感困惑。感觉每半年或每年就会出现新的热门假说。但除了这些遗传数据，没有任何理论真正站得住脚。

And I think it's been very confusing for the general public. Even as a as a scientist, it's been very confusing for me. I feel like every six months or so, every year we have a new pet hypothesis. But nothing's really, except for these genetic data, nothing really is rock solid.

没错。当然另一个问题是这些病症属于人类大脑功能障碍。想想精神分裂症——那些幻觉或现象本身就极难研究。我们对此确实知之甚少。

Right. And then of course, other issue is also that these conditions are disorders of the human brain. So if you think about it, even talking about schizophrenia, right? Hallucinations or phenomena that are very difficult to study. And of course we don't know this.

我们知道精神分裂症在几乎所有已知人群中（包括孤立族群）都保持约1%的发病率。研究成年人相对容易些，儿童研究则困难得多。事实上，许多早期发现的自闭症基因正是在阿米什等群体中首次识别的——比如那个伴随严重癫痫和自闭症的经典基因案例。

We know that schizophrenia is present in almost every that we know of, even isolated population at one percent. And again, it's a little bit easier because it's done in adults. I think in children it's much more difficult. And in fact, many of the genes that were early on identified for autism were identified in this population, in the Amish populations for instance. There is a very classic example of a gene that is associated with severe epilepsy and autism that was identified there for the first time.

这种现象在其他地区也存在。问题的复杂性在于，我们不仅要建立关联，还需要逆向验证——比如通过改变变量观察症状是否消失。但在人脑研究中，我们无法随意开关机制来验证因果关系。更何况人脑发育需要极其漫长的时间。

It's present in other places as well. So yeah, I think of course the complexity of the problem is that you also want to make sure that you don't just associate something, you also want to reverse it in a way, right? So you would want to do the other experiment where you change it and then it goes away, but you can never do that in the human brain. We can't just turn things on and off to see whether they're truly causal. And then of course, human brain development also takes an incredibly long period of time.

可以说人类神经系统竭尽所能延缓了这个进程——髓鞘形成持续到三十岁，神经元在出生后早期仍持续生成并迁移。

If anything, it seems that the human nervous system has done everything possible to slow down that process. I mean, we myelinate all the way to the third decade. Neurons are born and migrating through the nervous system into early postnatal years.

等等，你是说我们的神经元髓鞘化（对不了解的听众解释：这是形成包裹层使电信号更高效传递的过程）会持续到30岁？

Wait, you're telling me that our neurons continue to get myelinated, which of course, for those that don't know, is the building of the sheathment that allows electrical signals to be passed down neurons more efficiently in until we're 30 years old.

是的。有证据表明大脑额叶区域的髓鞘形成过程确实会持续到第三个十年。

Yes. There's evidence that myelination, especially in the frontal areas of the brain, are are continuing up to the third decade.

我们那位不幸已故的前同事本·巴里斯，他过去常在实验室会议上对人吼叫。是的。当有人说了他不爱听的话，他就会说，你懂什么？你的髓鞘都还没长全呢。确实如此。

Our, unfortunately now, deceased former colleague, Ben Barris, he used to shout at people in lab meetings. Yeah. When they'd say something he didn't like, he'd say, what do you know? You're not even myelinated yet. Exactly.

所以他说得没错。

So he was right.

他完全正确。好吧。

He was absolutely right. Okay.

所以如果你和30岁以下的人有分歧，而你自己又超过30岁，你可以用这个论点占上风——你懂什么？你的髓鞘都还没长全呢。完全长全的那种。玩笑归玩笑，在我们深入探讨你正在做的那些惊人实验以及你攻克这些棘手疾病的方向之前，我必须先问两个问题。

So if you're in a disagreement with somebody younger than 30 and you happen to be older than 30, you can leverage the argument. What do you know? You're not even myelinated yet. Completely myelinated yet. All kidding aside, before we get into the incredible experiments that you're doing and the direction that you're taking to tackle these really hard diseases, I have to ask two questions.

首先，自闭症发病率在美国以外地区也在上升吗？还是说这是美国和北欧特有的现象？不知道为什么我们总把这两者相提并论。是的。我应该公平点说。美国与澳大利亚或其他地方。

First, is the incidence of autism also increasing outside of The United States, or is this something unique to The United States and Northern Europe? I don't know why we always pair those two. Yes. I should just be fair. To The United States and Australia or or whatever.

或者美国是否有什么特殊原因导致自闭症在这里增长得更快？

Or is there something going on in The United States in particular that autism is increasing faster here?

是的。不。这个，你知道，自闭症的患病率实际上早有报告显示在其他国家更高。多年前的一些早期报告就显示，比如在韩国患病率非常高。现在在斯堪的纳维亚国家的研究也表明，概率可能差不多，约三十分之一到四十分之一。

Yeah. No. This the, you know, the so, like, the prevalence for autism, you know, has been actually reported to be higher in other countries even before this. Some of the early reports many years ago showed that in Korea, for instance, prevalence was very high. Now that the studies are done, also like in Scandinavian countries, it shows that it's probably around the same kind like rate, one in thirty to one in forty.

所以大概介于这个范围。

So somewhere between.

好的。所以不能归咎于任何美国特有的条件。我是说，确实。因为你会听到这类论点。

Okay. So it can't be whatever is attached to whatever United States specific conditions. I mean Yeah. Very well. Because you hear these arguments.

哦，

Oh,

你知道，

you know,

是美国农作物中的草甘膦问题。虽然我不支持这种论点，但我确实认为我们需要对食品供应链中的成分保持警惕。

it's the glyphosates in the in the Yeah. The crops in The United States. And while I don't favor that argument, I I do think we need to be cautious about what's in the food supply.

但绝对如此。

But Absolutely.

这些人常会引用欧洲不使用这些物质的说法。但如果自闭症发病率同样在上升，这种论点的纯粹逻辑性就不攻自破了。

Those same people often will leverage the argument that, well, in Europe, they're not using these things. Well, if the incidence of autism is the same and rising, sort of does away with at least the clean logic of that.

或许另一个重要论点是，我们发现相同的基因突变。比如某个特定钙离子通道的突变，在丹麦患者身上能找到，在非洲或澳大利亚患者身上同样存在。这些基因突变具有跨地域的相似性。

And perhaps another argument, is very important to bring is that we find the same mutations. I mean, the same mutations, if we're talking, let's say mutation, a specific calcium channel, you'll find it in a patient in Denmark, right? As well as like one in Africa or in, let's say Australia. So I think some of these genetic mutations are sort of like the same.

是的。我们能简要谈谈基因治疗和CRISPR吗？在当前许多神经系统疾病缺乏完美治疗方案的情况下，基因治疗确实展现出希望。

Yeah. Could we briefly talk about gene therapy and CRISPR? Just briefly. Because I think in the context of a discussion about these neurologic diseases for which currently there aren't perfect cures or even cures in many cases, gene therapy does hold some promise.

当然。绝对值得探讨。

Yeah. Absolutely.

用我和普通人都能理解的方式，能否解释CRISPR能让医生实现什么？基因修复是否能在成年期进行？还是必须在胚胎阶段？请分享你对CRISPR和基因治疗的总体看法，因为多数人只是——

In simple terms that I and everyone else can understand, could you just explain what CRISPR allows physicians potentially to do? In other words, can genes be fixed in adulthood? Do they have to be fixed in the embryo? And just give your thoughts generally about about CRISPR and gene therapy, because I think most people have

听说过。对。

heard of it. Yeah.

但多数人对其运作原理缺乏直观理解。

But I think most people don't have an intuitive sense for how it works.

基因治疗实际上是一个相当宽泛的术语，它涵盖了许多可以纠正基因或我们认为具有因果关系的基因缺陷的方法。例如，在一个极端情况下，你可以设想一个基因发生了突变、损坏了。那么你想做的就是把它修复回去。这些是早期的一些尝试，你会把它放入病毒中，然后传递给患者。成年人。

So gene therapy is a rather actually broad term and it covers many ways in which you can correct generally a gene or a genetic defect that we think it's causal. So on one extreme, for instance, you can envision a gene is broken, has a mutation. So what you want to do is you want to put it back. So those were some of the early efforts where you would put it in a virus and deliver it to the patient. An adult.

成年人或儿童，取决于具体情况。其理念是基因不存在或数量不足，所以我只需要提供更多。这是一个极端。

In an adult or in a child, depending on the condition. With the idea is that the gene is not there or there's not enough of it, so I'm just going to deliver more. That's one extreme.

是注入血液中，还是必须进入缺乏该基因的特定细胞类型？

Does it inject into the blood or do you have to go into the specific cell type that's lacking the gene?

当然，许多研究是针对血液疾病进行的，因为这更容易，所以你会直接注射。当然，另一种可能性是，有时你不想放入基因，而是想直接放入已经制成的蛋白质。许多情况下，缺少的是一种酶，即一种能进行某些对细胞至关重要的有趣化学反应的蛋白质。所以有时你只需制造那种酶，然后传递它。虽然并不总是有效，但在某些情况下效果非常好。

Many of the studies were done for blood disorders, of course, because it was easier, so you would inject them. Of course, the other possibility is sometimes you don't want put the gene, you want to put the protein already made. And that is the case for many conditions where an enzyme, so a protein that does some interesting chemical reactions that are essential to a cell is missing. So sometimes you just make that enzyme and then you deliver that. It's not always working, but in some cases actually works really well.

现在，你可以做的另一件事是尝试直接纠正那个缺陷。这意味着你需要在DNA层面进行操作。因此，你需要以某种方式进入每一个受影响的细胞并进行纠正。这就是CRISPR发挥作用的地方，理论上你可以传递引导RNA——那些告诉你DNA上位置的微小核酸片段——以及一种进行切割和修复的酶，或者其他各种版本的纠正工具。当然，这也有挑战。

Now the other thing that you can do is you can try to correct that defect directly. That means you need to operate at the DNA level. So somehow you need to get into every single cell that is affected and correct that. And that's where CRISPR comes into play, where presumably you could at one point deliver the guides, so the tiny pieces of nucleic acid that tell you where to go on the DNA, and then an enzyme that will do the cutting and then the putting back, or various other versions of this that you would correct. Of course there are challenges with that.

是啊，你把它放在哪里？比如镰状细胞贫血症，我知道他们基本上已经用CRISPR技术逆转了镰状细胞贫血症。那是在血液中。对吧？

Yeah, where do you put it? I mean, so like for sickle cell anemia, I know they've essentially reversed sickle cell anemia using CRISPR technology. That's in the blood. Right?

是在血液中。

It's in the blood.

是血液的问题。

It's of the blood.

对。

Right.

但比如，假设我们知道一个基因缺陷——我们很快会详细讨论这个——比如一个突变的钙通道破坏了心脏和大脑功能。你带着CRISPR来了，你知道哪个基因发生了突变，你有潜在的健康基因可以放回去。你把它放在哪里？是注射进去吗？我是说，注射到心脏里是可能的。是的。

But if for instance, we know about a genetic defect of let's say a mutate we'll we'll talk more about this soon, but a mutate calcium channel that disrupts heart function and brain function, And you come in with CRISPR, you know what the what gene is mutated, you have the healthy gene that potentially you can put back. Where do you put it? Do you inject it? I mean, injecting into the heart is possible. Yeah.

那直接进入血液供应系统会更简单。对。虽然定向输送到骨髓比较困难，但输送到——

That's Into the blood supply, easier. Yeah. Getting it directed to the bone marrow, but to the

大脑就难多了。是的，不过理论上也可以直接脑部注射对吧？可以通过手术或椎管内注射（比如鞘内注射）实现。这确实是一种可行方式。但极具挑战性，因为大脑细胞类型复杂，而且通过病毒载体等方式递送时，神经系统能承受的病毒载量非常有限。

brain is hard. Yeah, well, presumably you could inject into the brain as well, right? There are ways in which you can inject through either surgery or through an injection in the spinal canal, like intrathecally. So that's certainly one way in which you can do it. It is very challenging though, because of course the brain has a lot of cell types and you very often, the way you deliver this, like through a virus or through other modalities, there's only so much of that virus that you can actually put inside the nervous system.

目前转染效率还不够高。所以另一种思路是退而求其次——让矫正基因先产生RNA，再由RNA生成蛋白质。或许我们不需要修复所有DNA错误，而是修正下游产物。这正是我们目前主要采用的策略，毕竟现阶段...也许十年内甚至更早，我们就能用CRISPR高效实现基因治疗了。

The efficiency is not yet like very high. So another way is to go like one level down. So that gene will produce an RNA that will produce a protein. Perhaps we don't have to correct the DNA everywhere, but perhaps we can correct something that happens downstream. And that's so like being the strategy that we've been using primarily, just mostly because at this point, and probably in the future it will be possible, who knows, like in ten years or maybe even earlier, we'll be able to deliver very effectively some of the genetic therapies using CRISPR.

在灵长类动物模型中，色盲等疾病确实已能通过病毒载体基因疗法治愈。提到病毒人们总会恐慌，但需要说明的是：腺病毒等感冒病毒经过改造后不会致病，却能携带目标基因进入神经系统或身体其他部位。所以基因治疗使用的病毒载体是善意的——这些腺病毒能在人体长期存留而不引发问题。

Because certainly in nonhuman primate models, things like color blindness Yeah. Have been rescued by introducing a gene through a when we talk about viruses, people often will think, oh goodness, why would I wanna get injected with a virus? But we should just mention there are things like adenoviruses, which cold viruses or adenoviruses that can be engineered so that they don't make you sick, but they can carry a cargo, like a gene you want to put into a nervous system or or body that lacks that gene. So when we say using viruses to deliver genes, it's of the benevolent or at least benevolent motivation. We think that those adenoviruses can live in our body for a long time without causing additional trouble.

这些病毒通常经过严格修饰确保安全性。但另一个限制是：若目标基因过大（比如钙离子通道基因），病毒载体根本装不下。

And they're very often modified to make sure that they don't cause disease. Of course, another limitation of that is that if the gene is really large, it simply won't fit in a virus. So for instance, that will be the case if you think about a calcium channel. Calcium channel is a gigantic gene. It will be very difficult to fit inside a virus.

而且腺病毒或AAV载体往往只能单次注射——首次可能有效，但免疫系统会产生抗体阻碍二次递送。这些难题正在被全力攻克，我相信未来十年会出现突破性疗法。不过正如你提到的，最大挑战在于...

Of course, the other thing is like with this viruses very often, especially with adenoviruses or AAVs, is that you will have one shot, meaning that you have to inject once and hopefully it would work because next time you may have an immune reaction, right? You'll produce antibodies and so you won't be able to deliver again. So again, there are all kinds of challenges that people are working really hard to solve. And I have no doubt that in the next decade we'll see therapies or perhaps even cures for some of these conditions. Of course, and I think you were bringing this up, one of the challenges is like when we do this.

对于自闭症等脑部神经发育障碍，关键问题是干预时机——损伤是否已不可逆？能矫正到什么程度？这正是当前临床试验重点探索的方向。

Because especially for disorders of the brain, neurodevelopmental disorders, so autism and other neurodevelopmental disorders, The question is always how early it is too late. How much damage been has done and how much can I actually correct? And that's one of the things that we're only now starting to really explore as we're thinking about some of the first clinical trials in this space.

说出来可能吓到你——有些生物黑客（不是我）正在境外接受卵泡抑素基因治疗来增肌。美国禁止这种行为，但有人专程出国注射。我个人不会尝试（健身就够了），但这引出了干细胞的话题——全球范围内干细胞注射已很普遍。

This might shock you a bit, but folks in the quote unquote biohacking community, not me, are getting I know some that have gotten folestatin gene therapy as a body enhancement thing. So leaving the country because you can't do it in The United States and literally getting injection of a of a folestatin gene therapy to, I guess, have more muscle to improve I wouldn't do it personally. Also, like working out, so I don't need a follistatin gene therapy. But it's interesting to note that people are doing this, and I'm raising this as a segue into a discussion about stem cells. Because people around the world are getting injected with stem cells.

在美国，FDA仍未批准大多数干细胞疗法。基因治疗虽已起步，但医生不会轻易推荐——绝大多数应用仍处于实验阶段。

In The United States, it's still not allowed by FDA for most things. But I think gene therapy has started. It's certainly begun. It's not the sort of thing that your physician offers up early. It's still very experimental for most things.

回到基因治疗，正如你所说，有些改变是不可逆的。比如慢病毒载体整合进细胞基因组后，我们既无法取出也难以灭活它。因此必须格外谨慎，避免造成更大伤害。

And then for gene therapies, again, in the context of what you're mentioning is some of this, again, they're irreversible. So once you put the gene in and it goes into a cell, let's say through a lentivirus that will integrate, can't take it out anymore. That would be very difficult. It would get inactivated over time. So that's why we have to be extra careful with some of these therapies and make sure that we don't do more harm, right?

我想这始终是我们的追求。没错。我想稍作休息，感谢我们的赞助商AG1。AG1是一种维生素矿物质益生菌饮品，还含有益生元和适应原。如大家所知，我服用AG1已超过十三年。

Which I guess it's always what we try. Absolutely. I'd like to take a quick break and acknowledge our sponsor AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As many of you know, I've been taking AG1 for more than thirteen years now.

早在2012年我就发现了它，远在我拥有播客之前，从那时起我每天都饮用。过去十三年，AG1一直保持原味。他们更新了配方，但风味始终如一。现在AG1首次推出三种新口味：浆果、柑橘和热带风味。所有口味都含有最高品质的成分，精确配比，共同为肠道微生物群提供支持，增强免疫健康，提升能量水平等。

I discovered it way back in 2012, long before I ever had a podcast and I've been drinking it every day since. For the past thirteen years, AG1 has been the same original flavor. They've updated the formulation, but the flavor has always remained the same. And now for the first time, AG1 is available in three new flavors, berry, citrus, and tropical. All the flavors include the highest quality ingredients in exactly the right doses to together provide support for your gut microbiome, support for your immune health and support for better energy and more.

现在你可以选择最喜欢的AG1口味。我一直钟爱原味，尤其是加水兑一点柠檬或青柠汁的喝法——这基本上是我十三年的习惯。现在我特别喜爱新出的浆果味，口感很棒，无需再加柠檬汁。

So now you can find the flavor of AG1 that you like the most. Well, I've always loved the AG1 original flavor, especially when I mix it with water and a little bit of lemon or lime juice. That's how I've been doing it for basically thirteen years. Now I really enjoy the new berry flavor in particular. It tastes great and I don't have to add any lemon or lime juice.

我直接加水冲调。若想尝试AG1及其新口味，请访问drinkag1.com/huberman获取特别优惠。目前AG1正赠送迎新礼包，含五份免费旅行装和一瓶维生素D3K2。重申：访问drinkag1.com/huberman即可领取含五份旅行装和维生素D3K2的礼包。本期节目也由BetterHelp赞助播出。

I just mix it up with water. If you'd like to try AG1 and these new flavors, you can go to drinkag1.com/huberman to claim a special offer. Right now, AG1 is giving away an AG1 welcome kit that includes five free travel packs and a free bottle of vitamin D3K2. Again, go to drinkag1.com/huberman to claim the special welcome kit of five free travel packs and a free bottle of vitamin D3K2. Today's episode is also brought to us by BetterHelp.

BetterHelp提供持证治疗师的在线专业心理咨询。我个人接受心理治疗已超过三十五年，我认为这是整体健康的重要组成。事实上，我认为定期心理治疗与规律运动（包括有氧和抗阻训练，这些我每周也坚持）同等重要。优质治疗主要包含三个要素。

BetterHelp offers professional therapy with a licensed therapist carried out entirely online. I personally have been doing therapy for well over thirty five years. I find it to be an extremely important component to overall health. In fact, I consider doing regular therapy just as important as getting regular exercise, including cardiovascular exercise and resistance training, which of course I also do every week. There are essentially three things that make up great therapy.

首先，它能让你与真正信任的人建立良好关系，畅谈任何问题；其次，它能提供情感支持或定向指导，或两者兼具；第三，专业治疗应带来有益洞见，帮助改善工作、人际关系及自我认知。BetterHelp能轻松匹配与你契合的治疗师，提供这三大专业治疗优势。

First of all, it provides the opportunity to have a really good rapport with somebody that you can really trust and talk to about essentially any issue that you want. Second of all, it can provide support in the form of emotional support or directed guidance, or of course both. And third expert therapy should provide you useful insights. Insights that can help you improve in your work life, your relationships, and in your relationship with yourself. With BetterHelp, they make it very easy for you to find an expert therapist who you resonate with and that can provide those three benefits that come from expert therapy.

有趣的是，近期调查显示72%的BetterHelp用户报告负面症状减轻。若想尝试BetterHelp，访问betterhelp.com/huberman可享首月九折。再次提醒：betterhelp.com/huberman。现在我们来聊聊干细胞、类器官和组装体——稍后请你解释这些概念——但让我们按时间顺序展开。

Interestingly, in a recent survey, seventy two percent of BetterHelp members reported a reduction in negative symptoms as a result of their BetterHelp therapy sessions. If you'd like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. Let's talk about stem cells, organoids, and assembloids, and you'll explain what those are. But let's wade into this through the the way it happened chronologically.

当然。多数人听说过干细胞——能分化成其他细胞的细胞。我读博士后时，所有研究人类干细胞的实验室都使用人类胚胎干细胞，即从流产胎儿中采集的细胞，这些被捐赠用于医学研究。

Sure. Most people have heard of stem cells, cells that could become other things. When I was a postdoc, any laboratory that worked on human stem cells worked on human embryonic stem cells. Literally, cells that were collected from aborted fetuses. This was and given for medical study.

后来出现了革命性发现（稍后你会详述），这项发现不仅使该技术过时，还让科学家绕过了许多伦理考量。

There was an incredible discovery, which you'll tell us about, which basically made that technology obsolete and also allowed scientists to bypass a lot of the ethical considerations

嗯。

Mhmm.

无论你在这场辩论中持何种立场，这都是严肃的伦理考量。我的意思是，你正在使用人类胚胎的组织进行研究。可以说有些人会支持这种做法，有些人则不会。但随后一项新技术出现了

Serious ethical considerations regardless of where you sit on that debate. I mean, you're using the the the tissue from a human embryo to to study things. You could say some people will support that, some people won't. But then a new technology comes along

是的。

Yeah.

这项新技术基本上让原有技术变得过时，使你和他人能够在不从人类胚胎中提取细胞的情况下，开展干细胞和类器官组装等研究，这非常了不起。能否请你谈谈这项彻底改变游戏规则、消除了这场严肃伦理之争的干细胞技术发现？我们不妨直呼其名——当然。

And basically makes that technology obsolete, allowing you and others to do the work on stem cells and assembloids and so forth without having to take cells from human embryos, which is spectacular. So could you please tell us about that discovery of the stem cell technology that really changed the entire game and did away with this ethical serious ethical battle. Let's call it what it Sure.

让我们先从干细胞及其定义说起，我认为明确概念很重要。干细胞是具有两种特性的细胞：首先，它们原则上能分化成其他细胞。如果是最高效能的类型，它们会是全能性的，能生成所有组织；如果是多能性的，则能生成几乎所有组织。

Let's start first with stem cells and what they are, because I think it's also important to define them. So stem cells are cells that have two properties. First of all, they in principle can become other cells. And if they are of the most potent type, they will be totipotent, so they can make everything. If they're pluripotent, they can make almost everything.

当然细胞还有更低级别的效能。我们体内都携带干细胞，对吧？大脑中肯定较少或没有，但在肝脏等其他器官、肠道中都有——我们每隔几周就会更新肠道，这主要就是通过干细胞完成的。但这些干细胞功能受限，它们不能生成所有组织，主要只能生成它们被预设分化的特定细胞类型。

And then of course there are lower levels of potency for the cells. So we all carry stem cells in us, right? Not in the brain or fewer in the brain for sure, but in the liver and in other organs, in the gut, as we renew the gut every few weeks, that is done primarily through the stem cells, but those are restricted. They can make everything. They can make mostly that specialized cell type for which they have been so like primed.

最早期的干细胞，比如那些多能干细胞，它们存在于胚胎发育的早期阶段，这发生在受精之后。挑战在于你必须从受精卵中获取它们，而如果生命始于受孕，那么这显然构成了干预。我认为很多伦理争议正源于此。但早期即使这样做，你也无法保存这些细胞——事实证明它们极难维持。

Now the earliest, earliest of stem cells, like those pluripotent, they are very important, those are present at early stages of development of the embryo. And of course that happens post conception, so the challenge has been that you have to remove them from a fertilized egg, and if life starts at conception, then of course you're interfering. So I think a lot of the ethical debates have started because of that. But in early days, even if you were to do that, you wouldn't be able to keep those cells. It turns out that the cells are very difficult to maintain.

这就引出了干细胞的第二个特性：在理想条件下它们可以永久保存。如果提供适当环境，它们能无限分裂并保持原态。这两个特性意味着：你可以永久保存它们，冷冻在液氮中，随时复苏后它们会从停止处继续生长。然后在正确引导下，它们能分化成其他细胞类型。

And this brings us actually to the second property of the cells, which is that in principle they can be maintained forever. If you provide the right conditions, they will divide and stay the same forever. Those are the two properties. So, you you can keep them forever, you can freeze them down, put them in a liquid nitrogen, bring them out anytime, and they'll start exactly where they left. And then with the right guidance, they can become other cell types.

直到1998年左右，我们才真正能在培养皿中保存某些干细胞。当时有人发现特定的化学培养液配方能让这些细胞存活——此前这是不可能的。这自然引发了该领域的希望：现在我们可以获取这些细胞来培育各种器官，或许用于移植替代病变器官。

So only around 1998 was that when we could actually maintain some of the cells in a dish. So somebody figured out a soup of chemicals that you can add and these cells will survive. Because after that point it was not possible. So that triggered, of course, the promise of this field that now would be able to take those cells and derive various organs, right? Perhaps transplant them, replace organs.

当然实际远比这复杂，围绕这些细胞的来源和使用胚胎干细胞的伦理争议也持续不断。但早期我们通过这些细胞学到了很多关于其特性的知识。约二十年前，日本科学家山中伸弥（当时在UCSF）提出了绝妙设想——我们一直被教导生物发育是单行道：一旦开始分化就不可逆。

Of course that ended up being much more complicated, and of course there were all these ethical debates related to the source of those cells and what does it actually mean to use these embryonic stem cells. And yet we've learned a lot about those cells early days, what are the properties of those cells? And then almost twenty years ago, Shinya Yamanaka was a scientist in Japan at UCSF, came up with an absolutely brilliant idea. We were always taught that the development, the development of the human or of any it's a one way street. Once you go down development, you never come back.

比如从多能干细胞逐步分化为肝细胞后，永远不可能再变回多能干细胞。这通常被认为是有益机制，能防止癌症等异常——我们总不希望身体部位突然异变成其他组织吧？而他设想或许可以通过非自然的人工方式实现逆转，这将非常有用。于是他着手研究在多能干细胞中超高表达的基因。

So once you start making a stem cell that is more restricted, and then at the end you make, let's say, a liver cell, you can never go back and become that pluripotent stem cell again. And that generally is thought to be useful to protect us from like cancer or like any others where we don't have parts of our hands like differentiating into something else. And he thought that maybe you could do that, not in a natural way, in an artificial way. And that of course would be very useful. So what he did is he went and he looked at the genes that are expressed in pluripotent stem cells at very, very high levels.

确实是非常、非常高的水平。几乎就像基因疗法一样，因为我们之前讨论过基因疗法。他选取了其中最顶端的几十个基因，然后开始将它们添加到皮肤细胞内部。最初他使用小鼠的皮肤细胞，后来用人类的，逐步添加这些基因，一次一个、两个、三个、四个、五个、六个，观察这些细胞是否会因为拥有多能干细胞中表达的基因组合而混淆，误以为自己就是多能干细胞，从而时光倒流般地真正变回多能干细胞。他最终证明，四个基因的组合就足够了。

So very, very high levels. And almost as gene therapy, because we were talking about gene therapy. He took the top couple of dozens of these genes and then started adding them inside skin cells. So he took skin cells initially from mice and then from human, and then started adding them one by one, two by two, three by three, four by four, five by five, six by six, to see whether any of those cells, once they have this combination of genes that are expressed in pluripotent stem cells, would somehow get confused and think that they're actually a pluripotent stem cell, and then go back in time and actually become a pluripotent stem cells. And he showed indeed that a combination of four is enough.

当然，你也可以用六个。这最终成为了我们今天所称的山中因子。某种程度上这几乎像炼金术，对吧？将某种物质转化为另一种物质，比如把这种金属变成黄金。

Of course, you can have six. And that ended up being what we today call the Yamanaka factor. In a way it was almost like alchemy, right? Where you sort of transform something into something else, right? Make out of this metal, you make gold.

确实非常相似。这就像是炼金术的精髓。后来我们发现这一发现意义深远，因为突然间你可以从任何人身上取一个皮肤细胞，加入这些遗传因子，将其转变为多能干细胞——我们后来了解到它们几乎与胚胎干细胞完全相同——现在我们可以获取任何人的这些细胞，用于多种用途，比如未来制造血细胞，或者在体外模拟某些情况。那时我即将完成临床培训，还记得看到那篇论文时，天真的我以为，哇，就是它了。

It was pretty much like that. It was kind like the essence of alchemy. And it turns out that that discovery was so profound because suddenly you could take a skin cell from anybody and put those genetic factors in, turn those cells into pluripotent stem cells that we'd later on learn they're almost identical to those embryonic stem cells, and now have those cells from any of us and use them for various purposes, perhaps for, let's say, making blood cells in the future, or perhaps to model something outside of the body. And I was finishing my clinical training around that time, and I remember even seeing that paper. And of course in my naivete at that time, I thought, wow, this is it.

这将是我们研究人类神经科学的切入点。当时我正在做实验，研究大脑皮层，记录动物神经元的电活动，总在思考。我意识到临床观察（那些严重自闭症患者）与大脑记录研究之间存在鸿沟——我们永远无法直接在患者身上进行这类实验。既然连实时监听这些细胞活动都做不到，我们该如何理解这种复杂的大脑疾病？突然看到这个发现时，天真的我想，或许这就是我们能从任何患者身上制造神经元的途径。

This is going to be the entry point for studying human neuroscience. I was doing experiments at that time, studying actually the cortex and recording from animals electrical activity of those neurons, and always like thought. I thought this disconnect between what I was seeing in the clinic, which were these patients with severe profound autism, and then recordings from the brain and thinking, we're never going to be able to do that. How are we going to understand this complex disorder of the brain we cannot even listen to the activity of those cells live? And then suddenly, like seeing that discovery, again naive at that time, thought, well, that could be perhaps the way in which we could make neurons from any patient.

所以我很快来到斯坦福（我想我们就是那时认识的），怀着这样的想法：我们将能从患者身上制造神经元，或许能在体外重建部分脑细胞或神经回路，且无需任何伤害——因为我们不做脑部活检或任何侵入性操作，本质上只是在体外创建这些细胞的复制品，最终在培养皿中随意研究它们，进行各种增减实验，或许有朝一日还能开发疗法。自这一进程真正启动至今已十六年，虽然耗时漫长，但如今我们首次对某些病症（尤其是其中一种）有了深刻理解，甚至已能看到治疗曙光——我们正在筹备首个完全基于人类干细胞模型研究（未使用任何动物模型）的临床试验，直接在体外重现患者的细胞与神经回路。

And so very soon after I came to Stanford, which I guess where we met, with sort of like this idea in mind that we will be able to make neurons from this patient and rebuild maybe some of the cells or some of the circuits of the brain outside of the body without doing any harm, because we're not doing a biopsy of the brain or anything invasive, just essentially creating a replica of some of those cells outside of the body, and then finally study them at will in a dish, Do all kinds of experiments where you remove things and add things, and perhaps one day even develop therapeutics. Here we are sixteen years later since that process really started. It took a long time, but now for the first time we've gotten such a good understanding of some of these conditions, and one of them in particular, that actually a therapeutic is insight that we're preparing for the first clinical trial that is really arising exclusively through studies done with this human stem cell models, Without actually using any animal models, just essentially creating, recreating cells and circuits outside of the brain of those patients.

这太神奇了，因为它让你能研究人类细胞，这有巨大优势。这些细胞本质上数量无限。是的。因为你只需要一个成纤维细胞，一个皮肤细胞或其他能接受山中因子的细胞，就能培育出其他细胞。稍后我们会讨论这些培育出的细胞能变成什么——不仅是细胞，还能形成神经回路。

It's amazing because it allows you to study human cells, which has immense benefit. They're essentially limitless in number Yes. Because all you need is one fibroblast, one one skin cell or or some cell that you can provide these Yamanaka factors to and essentially grow other cells. And we'll talk about what those cells that you create are capable of becoming, not just cells, but circuits

是的。

Yes.

很快会谈到。但我知道人们（当然包括我）心里会惦记一个问题：生孩子时应该保存脐带，因为脐带对。含有干细胞。通常脐带会被丢弃。

In a few moments. But I know it's going to be in the back of people's minds, certainly in the back of my mind. This idea that when one has a baby, that you should keep the umbilical cord because the umbilical cord Yeah. Contains stem cells. Usually, I think the umbilical cord is discarded.

嗯。

Mhmm.

可能有些人会保存。我不确定。目前对脐带干细胞的主流看法是什么？人们花大价钱冷冻它们，但大多数人家里并没有零下80度的冷冻柜嗯。

Maybe some people keep it. I don't know. What is the current thinking on stem cells that reside in the umbilical cord? People pay a lot of money to freeze those, and most people don't have a a minus 80 freezer Mhmm. Around.

所以他们付费做这件事。未来脐带血干细胞的潜力如何？这是不是父母——我不想说应该投资——但如果他们有可支配收入，这样做会是明智之举？

So they pay to do that. What what is the potential for umbilical stem cells in the future? Is it something that parents I don't wanna say should invest in, but if they have the disposable income, that they would be wise to do that?

从脐带收集的这些细胞确实是干细胞，但它们的分化能力已经相当受限。因此其应用主要局限于血液疾病领域。我认为重要的是要明白，它们并非未来涉及多能干细胞或干细胞疗法的万能解决方案。再次强调，虽然这些细胞在某些特定案例中确实有用——比如孩子后来患血液疾病时这些现成细胞发挥了作用——但它们绝不像某些广告宣传的那样具有普适性用途。

So those cells that are collected from the umbilical cord are stem cells, but they're already quite restricted in what they can make. So their applications are also restricted mostly to blood disorders. So I think it's important to keep in mind that they're not so like a universal solution to anything that would ever involve pluripotent stem cells in the future or stem cell therapies in the future. So again, I think it's important to know that while they have certain applications and there have been quite clear cases where the availability of those cells were useful in a blood disorder in that child later on, they're certainly not you know, they have these universal uses as maybe sometimes they're being advertised.

当我们听说人们专程离开美国去接受所谓的干细胞注射时，那些干细胞来源是什么？是来自患者自身吗？需要提到的是，佛罗里达州曾有诊所向黄斑变性患者提供眼部干细胞注射。后来该诊所被查封，据我所知美国境内所有干细胞注射都被叫停了，因为那些治疗不仅未能挽救视力，反而导致患者迅速失明。

When we hear about people typically leaving The US to get, quote unquote, stem cell injections, where are those stem cells coming from? Are they coming from those patients? And I should mention that there was a clinic down in Florida that was offering stem cell injections into the eye for people with macular degeneration. And that clinic was shut down, and all stem cell injections in The United States, to my knowledge, all were shut down because those patients not only did it fail to rescue their vision, it actually made them go blind very quickly. Right.

所以FDA叫停了商业干细胞注射。不过我知道有些地方还在通过某种变通方式操作。

So the FDA shut down commercial stem cell injections. I think there's still places where they do a kind of a workaround.

是的。

Yeah.

值得一提的是，富血小板血浆（PRP）是获得FDA批准的。尽管你可能读到过相关宣传，但它其实不含或含极少干细胞。你对人们专程去哥伦比亚——看起来他们确实常去哥伦比亚——或者墨西哥接受干细胞注射怎么看？假设操作环境是洁净的。

And it's worth mentioning that PRP, platelet rich plasma, is FDA approved. It does not contain many, if any, stem cells despite what you might read. But what what are your thoughts on, like, when people go down to Colombia, it seems like they go down to Colombia. Oh, yes. Or elsewhere to get or Mexico to get stem cell injections, assuming the conditions are are clean.

是的。我特别要提到这点，因为我至少知道一位患者因脊椎间盘干细胞注射导致瘫痪。

Yeah. And I'd I'd say that because I know of at least one patient who was paralyzed from an injection of stem cells into their spinal disc.

嗯。

Mhmm.

瘫痪，差点丧命。所幸现在情况好转，原因是注射部位感染引发了败血症。这其实只是...

Paralyzed, almost died. Yeah. Fortunately, is doing better now, and it was because it went septic the way it got infected. Well, that's one of

问题之一。很多时候我们甚至不知道被注射的到底是什么。这个认知盲区非常关键——有时是来自患者自身的细胞，有时是脐带血细胞，有时根本无从得知注射物的成分。

the problems. Very often, we don't even know what is being injected. I think that is a very important aspect. We don't know what is Sometimes are the cells from the patient that are being collected. Sometimes some of these umbilical cells, sometimes we don't even know what cells are being injected.

就像是来自别人的细胞。

Like it could be cells from somebody else.

是的，这些手术风险极高。当然，它们从未被真正观察过。几乎没有临床试验以系统化的方式真正解决这个问题。很多时候，这也是因为它们缺乏正当理由。在自闭症治疗领域，这种做法很常见，而且不仅在南美洲存在。

Yeah, they're incredibly risky procedures. Of course, they've never really been observed. There have been very few of any clinical trials trying to really address it in a very systematic way. And very often that's also the case, know, that's also because they're not really justified. So in the context of autism, this is very often like done, and it's done not just in South America.

有时在欧洲某些地方，你也能为自闭症注射一些干细胞。

Sometimes there are places in Europe where you can get an injection of some stem cells for autism.

等等，父母们带着孩子去这些诊所，让他们接受来自其他患者的干细胞注射？

Wait, parents are taking their kids to these clinics and getting them injected with stem cells, they come from some other patient.

这些收集的细胞是从患者身上提取的。具体取决于实施地点和方式。但再次强调，即使从生物学角度看——假设针对自闭症，这些干细胞理论上能做什么？我们并不认为大脑中缺少某种细胞类型，所以这些细胞不可能去填补。正如我之前提到的，大多数细胞的分化潜能本就有限。

Some cells that are collected, they did it from the patient. It depends a little bit on where it's done and how it's actually done. But again, even from a biological point of view, what are those stem cells presumably doing, let's say in autism? We don't think that there is a cell type that is missing in the brain, so it's not like those cells can go. And I think as I was mentioning before, most of the cells already restricted in their potential.

这些细胞已无法分化成任何细胞类型。所以那种认为只需将多能干细胞注射到膝盖里，就能神奇地长出软骨的想法，往往并不成立，因为这些细胞根本不具备生成软骨的能力。我认为很多时候，人们对这些疗法的本质存在误解。更可悲的是，人们往往也不清楚实际被注射的究竟是什么。就拿自闭症来说，这种情况发生的频率远超你的想象。

They can no longer make any cell types. So the idea that you take these pluripotent stem cells and you just inject them, let's say in the knee, and it will miraculously grow cartilage, it's very often not really the case because those cells are not even capable of making cartilage. So I think there's you know, very often, you know, a lack of understanding of what these therapies really are. And then of course, there's sadly a lack of understanding of what is actually being injected. So, you know, for autism, this is unfortunately happening much more often than you would think.

我经常遇到心力交瘁的家长或家庭成员绝望地问我：'我们已经无计可施了。尝试过行为疗法，试过各种治疗手段，但都无济于事。'

So I very often get parents or families that are asking me desperately, with exhausted old resource. We don't know what else to do. We've tried behavioral therapy. We've tried these therapies. Nothing works.

所有人都建议我们该去南美洲接受这种注射治疗。我们该去吗？当然，我的回答永远是否定的，因为这根本没有科学依据。有些家长事后会反馈说看到了改善，但据我们所知，这种改善通常是暂时的——毕竟从未有过系统性的研究验证。

And everybody's recommended that we should just go now to South America and do this injection. Should we do it or not? Right? Then of course my answer is always like, no, because again, there's no reason that that would work. Some parents come back and of course they report an improvement, which is generally temporary to the extent that we know, of course, it's never really been studied in a very systematic way.

部分原因在于强烈的安慰剂效应，尤其是家长通过孩子产生的间接效应。当孩子病情严重时，这种效应会异常强烈。家长极度渴望孩子好转，因此会注意到任何细微改善，何况这些孩子本身仍处于发育阶段，每周都可能达到新的成长里程碑。另一个可能因素是，这类治疗常会引发炎症反应。

Partly, it's of course there is a very strong placebo effect, which you can, especially in parents, like by proxy, when you have a child who's very sick, those placebo effects are very, very strong. These parents really want those kids to improve. And so they will see things that are improving, plus those are still developing kids. So week by week, they may acquire new milestones. And then the other thing, which of course could be part of this, is that there is an inflammatory effect very often.

这有点像发烧的原理，对吧？可能会提升某些细胞因子水平，引发发热反应——虽然具体机制尚不明确。但可以确定的是，这种缺乏科学依据的疗法首先存在理论缺陷，其次完全不受任何监管框架约束，必然伴随着风险。

So that's almost like the fever in a way, right? It would increase perhaps some of the cytokines, will create a fever, perhaps that is associated. We don't really know, but certainly there are dangers associated with procedures like this that lack the rationale, first of all. And then of course, then they lack any regulatory framework.

是的，我是说，我认为对干细胞注射到所有组织的担忧非常真实，但当涉及到眼睛或大脑时——当然眼睛也是大脑的一部分——这正是让我，你知道的，

Yeah, mean, I think the concern is very real for stem cell injections into all tissues, but when it comes to eyes or brain, and of course eyes are brain. Yes. That's where I just, you know,

深吸一口气

take a big

屏住呼吸，瞪大眼睛，像是‘天哪，不行’，因为我们不会获得新的神经元。神经元一旦失去就永远消失了。我是说，我们在嗅球、海马齿状回会生成少量，真的很少。但你知道，它们一旦消失就真的没了。对吧。

deep breath and hold it and like wide eye like, oh my goodness, no, because we don't get new neurons. You lose neurons, they're gone. I mean, we get a few in the olfactory bulb, in the dentate gyrus of the hippocampus, a few. But, you know, once they're gone, that's it. Right.

而往大脑里注射东西，肿瘤生长的概率极高。

And injecting something into the brain, probability of tumor growth is incredibly high.

完全正确。尤其在大脑这种空间有限的部位。对吧？我们知道任何在颅腔内生长的东西都会压迫重要中枢。所以这绝对存在风险。

Absolutely. And especially when it is in the brain where there's not enough space. Right? So we know that anything that grows in the cranial cavity will actually push down, right, vital center. So there are certainly risks associated with that.

那我们聊聊另一种方法，就是你正在探索的方向。我永远记得我们做博士后时——各位，我们当年在同一个房间做博后，D222室。没错。

So let's talk about the other approach, which is the one that you are you've been embarking on. I'll never forget when we were postdocs. Folks, we were postdocs in the same room. It was D 222. Yes.

我们对那个房间充满自豪。我们在房间两端摆了实验台，硬是把空房间占为己用。现在可能不允许这样了——看到空房间就说‘搬几台显微镜进去吧’。

We had a lot of pride in that room. We've had benches on opposite sides of the room, and we sort of took over that room as an empty room. This is you probably couldn't do this anymore. Was like, there's an empty room. Let's bring some microscopes in there.

我们直接在那儿开始做实验。我永远记得你开始构建类器官时的场景。你在培养皿里构建神经系统，那种兴奋劲儿。看着你一路走来真是了不起。我清楚地记得你当时就极其努力，如今已成为这个领域真正的领军人物之一。

We just started doing experiments there. I'll never forget when you started building organoids. You started building nervous systems in a dish, and how excited you were. And it's been remarkable to see your arc to from that. And it's not lost on me that you were working extremely hard then and continue to to become what really one of the luminaries of this field.

给我们讲讲什么是类器官。说说它们的用途，它们已经揭示了哪些大脑发育的奥秘，以及它们的治疗潜力。

Tell us what organoids are. Tell us why they're useful and what they're telling us already about how the brain develops and their therapeutic potential. Yeah.

那我们从源头说起。大约十五六年前，我们首次成功获得了现在被称为诱导多能干细胞的细胞。

So let's start from the beginning. So around like fifteen, sixteen years ago, we were able for the first time to get some of the cells that are now known as induced pluripotent stem cells.

这些就是山中伸弥的成果。

These are the Yamanaka.

是的，或者说iPS细胞。之所以称为诱导性，是因为它们是通过人工方式被诱导成为多能性的。但同样，它们会保持这种状态。因此之后你可以将它们与任何人共享。

Yes. Or iPS cells. So induced because they've been induced to become pluripotent in an artificial way. But again, they stay like that. So you can share them with anybody else afterwards.

所以我们早期就获得了一些这样的细胞。当时的问题是，我们如何制造神经元？你所做的实际上是利用发育生物学中已知的一切知识。我们已经知道某些分子对制造神经元非常重要。所以你只需将这些细胞放入培养皿中，然后就像烹饪一样，开始在上面添加各种分子，观察会发生什么。

So we got some of those first cells in those early days. And now the question was, how do we make neurons? And what you do is you really kind of leverage everything that is known in developmental biology. So we already know that there are certain molecules that are very important for making neurons. So all you do is you put those cells in a dish, in a plastic dish, in a petri dish, and then you start almost like when you cook, you start adding various molecules on top and you see what happens.

我们知道制造神经元实际上相当容易。这已经是已知的。在那之前的十年里，已经有很多实验表明，即使你只是移除一些维持这些细胞多能性的因子，这些多能干细胞也会开始分化，并且它们倾向于成为神经细胞。几乎是默认的。

And we knew that it's actually quite easy to make neurons. That was already known. There've been a lot of experiments done the decade before that showed that even if you just remove some of the factors that maintain those cells pluripotent, those pluripotent stem cells will start now to differentiate and they like to become neural cells. By default. Almost by default.

所以制造神经元其实并不那么困难。在早期，你会取出这些细胞，将它们妥善地培养在培养皿中，然后移除一些这些因子。几天之内，你就会看到它们形状的改变。几周后，其中一些会看起来非常像神经元。当你观察它们时，你甚至可以看到只有神经元才会有的蛋白质。

So it's actually not that difficult to make neurons. So in those early days, you would take those cells, play them nicely, those pluripotent stem cells in a dish, and then remove some of these factors. Then within a few days, you'll see that they'll change shape. And within a few weeks, some of them will really look like neurons. And when you look at them, you can even look at proteins that only neurons will have.

你甚至可以将电极插入细胞内，监听电活动。所以那非常令人兴奋，也许你还记得那些日子。我的意思是，这种迸发的好奇心就像是实验室生活的ATP，可以这么说。

You can actually get an electrode inside a cell and listen to the electrical activity. So it was very exciting as maybe you remember in those days. I mean, this bursting curiosity is always sort of like the ATP of the life in the lab, so to speak.

确实如此。

It is.

对吧？我的意思是，你几乎就是想要醒来，想去看看那些细胞发生了什么。当时很清楚我们能够制造这些细胞，但我们是否真的能在这些细胞中看到任何异常？我想这就是问题所在。你如何知道你从自闭症患者身上提取的细胞有什么不同？

Right? I mean, you just kind of like want to wake up and want to go see what happened to those cells. And it was clear in those days that we would be able to make those cells, but would we actually see any abnormalities in those cells? Think it was like the question. How would you know if you derive cells from a patient with autism?

你如何知道你发现了任何异常？我想这就是问题所在。我们甚至不知道大脑中什么会是异常的。所以那时我们决定专注于一些相对可预测的东西。那就是钙通道中的一个突变，这个突变在几年前被发现于极少数患者身上，他们的整个基因组中有一个字母在制造钙通道蛋白的基因中被改变了，这种蛋白存在于可兴奋细胞中，即心脏细胞和脑细胞。

How would you know that you found anything abnormal? I think that was like the question. We didn't even know what would be abnormal in the brain. And so that's when we decided actually to focus on something that would be relatively predictable. And that was this mutation in a calcium channel, which was discovered just a few years before in very few patients that had essentially one single letter in their entire genome changed in a gene that makes a protein known as a calcium channel, sits in excitable cells, meaning cardiac cells and brain cells.

每次细胞接收到电输入时，这种蛋白就会打开，让钙离子进入细胞内。这非常重要，因为它将网络的电活动与细胞内的化学活动耦合起来。关于那个突变，我们当时所知道的几乎就是这些早期信息，它可能让通道保持开放的时间稍微长一点，只是一点点。所以更多的钙离子会进入细胞内。当然，我们无法知道，因为你无法从这些患者身上获取神经元或心脏细胞来实际测试。

And every time a cell receives electrical input, this protein opens up and lets calcium go inside the cell. That's very important because it couples electrical activity of the network with chemical activity inside the cells. And what we knew about that mutation at that point, that is pretty much all we knew in those early days, is that it probably allows the channel to stay open slightly longer, just a little bit longer. So more calcium would go inside the cells. Of course, there will be no way to know because you can't get a neuron or a cardiac cell from those patients to actually test it.

我们所做的实质上是招募了部分这类患者，将他们送至斯坦福，获取微小的皮肤活检样本，培育出这些iPS细胞。这一过程耗时数月，大约需要四到五个月。随后我们将这些细胞置于培养皿中，开始诱导神经元分化，约五、六、七周后，将它们放在显微镜下观察钙离子活动。通过显微镜可以测量细胞内的钙离子浓度，直接观测其动态。

So what we did is essentially we recruited some of these patients, we flew them to Stanford, then we got a tiny skin biopsy, made these iPS cells. This takes months. This takes already like four, five months. And then we took those cells in a dish, started to deriving neurons, and after about five, six, seven weeks, then we put them under a microscope and we started looking at calcium. You can measure calcium inside cells through a microscope and just literally look at it.

我永远忘不了进行那个实验的那天——我们通过显微镜刺激神经元时，可以清晰看到对照组细胞的钙离子如何进出细胞。而在蒂莫西综合征患者的神经元中，钙离子进入后会滞留更久，排出速度明显减慢。这是我们首次在非活检来源的患者神经元中观察到缺陷，这简直令人振奋！虽然当时观察的只是培养皿底部的少量神经元，结果相对简单。

And I'll never forget that day when we did that experiment, was looking down the microscope and we essentially stimulated the neurons and you could just see how control cells will go, calcium goes inside the cells and then it goes out. And then in patients that had Timothy syndrome, say in Timothy syndrome derived neurons, you could see how the calcium will go, and then it will stay longer. It takes longer to go out. So it's like the first defect that we saw in patient derived neurons that were actually not coming from a biopsy, they were not coming. So that was incredibly exciting as you can imagine, but it was still relatively simplistic, just a few neurons at the bottom of a dish.

最令我沮丧的是我们无法深入发育过程。以大脑皮层为例——这个被认为是赋予人类特性的外层脑组织——它拥有多层结构和丰富的神经元多样性。皮层细胞发育全程需要27周，这还不包括后续持续数年的胶质细胞发育。而我们在培养皿中的三项实验发现：这些细胞的发育时序竟能在体外完美重现。

And of course, for me, what was particularly frustrating was that we couldn't go very far in development. So think about the cerebral cortex, the outer layer of the brain that presumably makes us human, right? It has multiple layers, a large diversity of neurons. It takes twenty seven weeks to make all those cells in the cortex, twenty seven weeks to make all those neurons, and we're not even talking about glial cells, supporting cells that are coming much later for several years afterwards, But just making those cells takes about twenty seven weeks. And it turns out something that we discovered in three experiments done in a dish is that the timing of the development of those cells, it's actually recapitulated in a dish as well.

若将细胞持续培养，它们的发育速度与体内基本同步，不会显著加快。但让神经元在培养皿存活27周几乎不可能——每次传代时它们都会脱落，最终死亡。于是我们设想：何不让细胞始终悬浮？将它们聚集成球状细胞团如何？

So if you keep the cells in a dish, they'll actually essentially develop at the same pace, they're not like much faster. And it's very difficult to keep neurons in a dish for twenty seven weeks to get all the neurons. Essentially they peel off, you know, every time you start to move them to another plate, then at one point they just die. And so then we thought, how about like never letting them to sit down on a surface? How about just essentially aggregating them as balls of cells and then letting those float?

当时日本科学家笹井芳树正在进行突破性研究，他通过三维培养成功培育出视杯结构。这昭示着细胞培养正从二维平面转向三维自组织的革命。我们立即从德国订购了特殊培养板——其表面经过反直觉处理，细胞永远无法贴壁。

And in those early days, there was this amazing scientist from Japan, Yoshiki Sasai, who started doing really beautiful experiments where he was already moving some of these studies that he was doing of development in three d cultures. He showed you can make an optic cup, a part of the eye. And so it was clear, it was in the air, this revolution of actually moving cells from two d flat cultures to three d self organizing. And that actually unleashed amazing new properties of the cells. So essentially all we did in those days is I ordered from Germany this plate that were counter intuitively coated so the cells never stick.

通常细胞培养最困扰的就是贴壁问题，而这种培养板专门阻止细胞贴附。那些悬浮的细胞团起初被全实验室质疑：

I mean, every time we keep cells in a dish, you want them to stick, that's the major problem. So they were actually coated so the cells will never stick. And then there were like these balls of cells, they were floating there. Of course, I remember talking in the lab and everybody was like, Oh, they're not going to survive. It's going be a couple of weeks and they're going to Then a week passed and two weeks passed and then they kept growing and growing.

当然，每天最激动的事就是确认它们是否存活。后来我们发现这些三维培养物能持续存活数月，现在被称为类器官——这个命名或许不够准确，因为它们并非完整器官，但已成为三维自组织培养物的统称。我们开始长期维持这些培养体系。

Of course, the enthusiasm of every day to see, are they still alive? Right? And then we discovered that we can keep them for months. And these three-dimensional cultures are now known as organoids, which is perhaps not the most fortunate name because it suggests that it's organ like, And of course they're not an entire organ, so they're not a representation of the entire brain, but that's sort of like the term that we refer these days to anything that is sort like three-dimensional and organizing in some way. And so we started keeping these cultures.

最终我们实现了无限期培养。本实验室保持着最长培养记录——有些培养物在皿中存活了两三年。有次实验室经费紧张，我要求大家清理培养箱节省开支，结果发现有人养着500天、800天的培养物。这些细胞在恒温箱里持续生长，完全超出预期。

And then at one point actually we discovered that we can pretty much keep them indefinitely. My lab maintained the longest cultures that have ever been reported, like literally going for years, for two, three years in a dish. And at one point in those early days when actually I was running out of funds in the lab and I came one day in lab meeting, I'm really determined for us to actually cut costs. So I've told everybody, go into your incubators cause we're spending so much money in feeding the cells, and everybody throws out 20% of your cultures. Then people started saying, So should I throw the ones that are like 500 days old?

随后我们通过系列研究探索其发育极限：由多能干细胞分化的人神经元团在持续培养下，究竟能发育到什么阶段？它们的发育速度是快是慢？是否会停滞？结果令人惊叹——它们精确遵循发育时序，比如培养九个月（相当于出生期）时，会自然切换为出生后特征。

Somebody else was like, ones that are 800 days old? Then I said, What? You guys are keeping them for such a Yeah, they just keep growing, they're in the incubator. Then we actually did the first study, and then we had a series of three studies done over the years of trying to ask how far do they go in development? So if you have a clump of human neurons that you've made from pluripotent stem cells and you keep feeding them in a dish, how far do they go in development?

它们会加速发育吗？会延迟吗？还是停滞在某个阶段？事实证明它们完美遵循发育时序——例如当培养满九个月（相当于出生阶段）时，它们会精确转换为出生后的特征模式。

Do they move much faster? Do they move much slower? Are they stuck at one point in development? And it turns out that they actually keep track of development beautifully to such an extent that, for instance, we discover when they reach nine months of keeping them in a dish. So about the time of birth, they literally switch to a postnatal signature.

真的吗？它们自己就能在培养皿里完成？

Really? On their own. In a dish.

在培养皿里。这是神经生物学发展的经典案例。有一种蛋白质通常在出生前后发生变化，它是NMDA受体。可能有些人知道NMDA受体，它们与谷氨酸结合，非常重要。

In a dish. So, you know, there's this classic example development of neurobiology. There's this protein that usually changes around the time of birth. It's an NMDA receptor. So maybe some people know about NMDA receptors, binding glutamate, they're very important.

但在发育过程中它们变化很大。它们由不同亚基组成，这些亚基会替换。众所周知在早期发育阶段，即产前阶段，主要是2B亚基。出生后则主要变为2A亚基。如果观察大脑发育过程，你会看到2B先上升后下降，而2A逐渐上升。

But they change a lot during development. They're made out of different units and the units change. And it was very well known that during early development, so prenatal before birth, you primarily have 2B subunits. And then after birth, they're primarily 2A. So if you look in brain development, you just see how essentially 2B goes up and then it goes down and 2A goes up.

当观察时，发现这两种亚基在出生时交汇。所以人们常认为是分娩本身触发了这个转换。这被称为经典转换，因为我们都认为这是标准模式。然后你观察在培养皿中维持六百天的类器官——显然我们并没有诱导分娩过程。

And when you look, they meet around birth. So very often people thought that it's birth itself that triggers that switch. That canonical, it's called a canonical switch because we all thought that it was so classic. And then you take an organoid that you maintain in the dish for six hundred days. And of course we're not inducing birth.

我们没有更换培养基，也没有做任何特殊处理。

We're not changing media. We're not doing anything special.

也没有来自

And no hormones from

没有激素变化。我们保持完全相同的培养基——虽然只是非常简单的化学物质组合，但始终未更换。然后观察这两个亚基，发现2B下降2A上升，在培养皿中培养九个月后，它们几乎完美复现了交汇点。

the No hormones changes. We keep exactly the same media, which is certainly a very simplistic soup of chemicals, but we don't change it. And then you just look at this two subunits and you see how like 2B goes down and 2A goes up and they pretty much meet that nine months of keeping them in a dish.

太不可思议了。

It's amazing.

这说明存在某种内在计时机制。一旦启动发育程序，细胞就能精确测量发育时间。这并不意味着所有发育过程都能在培养皿中重现，但揭示了细胞——尤其是神经系统的惊人能力。毕竟这些神经元将伴随我们终生，不像肝细胞或肠细胞会更新。

So that tells us that there's some sort of intrinsic clock. Once you started development, the cells measure really, really well at the time of development. That does not mean that all aspects of development are going to now be recapitulated in a dish, but it tells us that there is this incredible ability of cells, especially in the nervous system, because of course those cells will keep for the rest of our lives. We're never going to renew neurons. It's going to be different for liver cells or gut cell.

特别是神经元，必须极其精确地记录时间。这是我们最初的重要发现，至今仍令人震撼。我们仍不清楚具体机制，正在全力研究细胞如何计时。因为如果破解这个分子机制——我们曾称之为生物钟，现在更倾向叫定时器——就能人为调控这个计时系统。

But for neurons, probably in particular, they'll need to keep track of time really, really well. So that was like the first discovery that we sort of like made, which is still stunning today, we still don't know the mechanism, we're still working really hard on figuring out exactly how the cells are keeping track of time. Because as you can imagine, if we understand what that molecular machinery is, we used to call it a clock, we now call it a timer. We think it's more of a timer than an actual clock. But understanding what the molecular biology of that is will allow us actually to play with that clock.

因此，如果你想从帕金森病患者身上培养出70岁神经元，我不必在培养皿中等上七十年。我能在几周内完成吗？或者能否通过调控那个计时器，让衰老的神经元重获青春。但需要明确的是，我们尚不清楚具体机制。我们有一些线索，但研究仍处于早期阶段。我认为这些培养技术最初带给我们的突破之一就在于此。

So if you want to make neurons that are 70 years old neuron from a patient with Parkinson's, I don't have to wait seventy years in a dish. Could I make it in like a few weeks? Or perhaps could I take an aging neuron and somehow rejuvenate it by playing with that timer. But just to make it clear, we still don't know that We have some clues about like what it may be, but I think it's still early days. And I think that was like one of the first things that these cultures allowed us to do.

只需观察培养皿中人类大脑在体外的发育过程，就能见证某些大脑发育的基本特征确实能在子宫和大脑之外重现。这是第一个发现。作为受过发育神经生物学训练的研究者，我早期做过大量神经环路研究。对于自闭症和精神分裂症这类复杂疾病，我的执念在于必须重现大脑的部分环路特性。现有证据表明，这两种疾病都不太可能是由于大脑真正缺失了某些细胞。

Just watch development, human brain development outside of the human body in a dish and actually witness that some fundamental aspects of brain development are actually recapitulated even outside of the uterus and of course of the brain. So that was the first. And then of course, I guess I'm a developmental neurobiologist by training and I've done a lot of circuit work in early days. Of course an obsession of mine was that especially for conditions as complex as autism and schizophrenia, we need to recapitulate some of the circuit properties of the brain. So we now know that probably both for schizophrenia and for autism, it is very unlikely based on the evidence that we have so far that there are cells really missing from the brain.

我们曾认为可能缺失某些细胞或某些细胞过量，但后来通过单细胞测序技术对已故患者大脑的研究表明，尤其是大脑皮层，其细胞组成极其相似。因此问题可能不在于细胞缺失，而在于细胞间的连接方式。最初我们培养的只是皮层细胞团，它们彼此孤立。后来产生了构建神经组装的念头，因为大脑多数细胞会与整个神经系统的细胞建立连接。更奇妙的是，神经系统中的细胞并不停留在其诞生位置。

We thought for a while that maybe some cells are missing, or maybe other cells are in excess, but now the studies that have been done, especially with single cell profiling of brains of patients that have already died, showed us that the composition of the brain, of the cortex in particular, it's very, very similar. So it's unlikely that the cells are missing, but likely the way they are connected with each other is that makes a difference. And of course, in the beginning, we were just making this clump of cells, they're all for the cortex, but they're like not connected to anything else. So then came the idea of assemblies, because most of the cells in the brain connect with cells across the nervous system. And in fact, even more interestingly, cells do not reside in the place in which they're born in the nervous system.

我们拥有所有器官中最丰富的细胞多样性——近2000种细胞类型。到妊娠首期末期，人脑已有约600种细胞类型。想想肝脏可能只有几十种，而大脑需要制造数百倍于此的细胞类型。

We have the largest cell diversity of any other organ, almost 2,000 cell types. By the end of the first trimester, there are about 600 cell types in the human brain. Think about the liver, right? Maybe a couple of dozens. The brain has to make hundreds of times more.

如何实现这一点？唯一方法是在大脑不同区域制造细胞类型，提供局部信号，待细胞特化后让它们迁移至最终位置。我们构建的第一个组装体就再现了神经系统中细胞最经典的迁移模式——与皮层相关。大脑外层皮层同时包含兴奋性和抑制性神经元，而多数抑制性神经元其实诞生于大脑深部。

So how do you do that? The only way is to actually make the cell types in different parts of the brain, provide local cues there, and then once the cells have been specified, let them move and find their final position. So the first assembly that we've actually made were of a very stereotypical canonical movement of cells in the nervous system, which has to do again with the cortex. So the cortex, again, the outer layer of the brain has both excitatory and inhibitory neurons. It turns out that most inhibitor neurons are not born in the cortex, but they're born deep in the brain.

我们实质上是构建了两个脑区：一个含兴奋性神经元，另一个含抑制性神经元。计划是将它们共培养，期待细胞能自主完成后续工作。这其实是我实验室最早的项目之一。我记得当时给一名学生布置了极具挑战的任务——研究如何融合这两种培养物。这些3毫米大小的组织肉眼可见，我原以为融合会非常困难。

So essentially, all we did is we made two brain regions, the ones that has excitatory neurons and the one that has inhibitor neurons, and the plan was to put them together, hoping that at one point the cells will know what to do. And in fact, that was one of the first projects in my lab, planning that. I remember gave to one of the students this very difficult task of figuring out how we're gonna fuse these two cultures. And they're about three millimeters in size, so you can see them by eye. And I thought it's gonna be very difficult to put them together.

那名学生花了数月尝试生物胶水，甚至用各种电极穿刺。直到有天另一个人提出简单方案：把它们放在最小的EP管底部过夜。次日它们就完全融合了——不仅是物理融合，几天后你会发现本该迁移的细胞开始向皮层方向伸出突触。它们能感知皮层释放的化学物质，并以特定方式向皮层迁移。

So the student worked for months trying to figure out like biological glues, kind of like using various electrodes and impaling them and everything else until somebody else came one day and said, like, it's very simple. You just put them at the bottom of a tiny Eppendorf tube, which is the tiniest like of tubes that you get. You put them there overnight and next day they're completely fused. But they're not just fused because now if you look inside, within a few days, the cells that are supposed to move start to actually point out towards the cortex. They literally smell the chemicals from the cortex and they start to move in this very stereotypical way towards the cortex.

这就是2015年我们构建的首个神经组装体。至今记得本·巴里斯当时的兴奋——他每天都要看那些细胞迁移的影像。

And so that was the first disassembled made around 2015. And I still remember it was Ben, actually. Ben was so excited. Ben Barris was so excited about seeing the cells. He wanted to look at these movies every day.

后来他说（我还保留着那封邮件），他执着地强调'这个新制备物不是类器官，不是类固醇，是别的什么东西。你们必须另起名字'。他特别痴迷命名。

And then he said, I still have this email from him where he was very preoccupied that he kept saying, This new preparation is not an organoid. It's not a steroid. It's something else. You have to find another name. He loved naming things.

他确实酷爱命名事物。

He loved naming things.

是的。他理解命名的重要性，不仅仅是为了职业原因，尽管他深谙如何

Yeah. And he understood the importance of naming things, not just for, like, career reasons, although he understood a lot about how to

建立 但是

build But a

因为命名，比如山中因子以山中伸弥命名是合理的。他因此获得了诺贝尔奖并以此名垂青史，就像干细胞那样永载史册。

because naming, like, Yamanaka factors made sense to name it after Yamanaka. He got a Nobel and is immortalized that way, like stem cells, immortalized.

没错。

Yes.

但我认为命名至关重要，否则事物可能会淹没在技术细节中。那么是谁提出了Soundorite这个名字？

But I think the naming is essential because otherwise, things can get lost in in the technical details. Yes. So who came up with the name of Soundorite?

他坚持要我来命名。于是我列了个长清单，至今还记在笔记本里。大约有20个候选名，我逐个发给本。你知道的，本几乎全天候在线。

So he kept insisting that I should find the name. So I made this long list. I still have like the in my notebook. Like I had a long list of about 20, And I would keep sending Ben one. And you know, Ben was always awake, twenty four hours.

是啊，他睡眠很少。几乎不睡。我记得来回发了好多邮件后，他总是回复：不行，难听，不喜欢。后来我突然想到'OID'这个后缀，加上'assemble'（组装）因为我们在组装电路。

Yeah, he didn't sleep much. He never slept. So I remember after sending many emails going back and forth, he was just like, No, bad name, bad name. I don't like it. And then at one point I thought, Well, OID because it's like, and then assemble because we're assembled the circuits.

于是我想出了'Assembloid'这个名字。发过去后他说：完美，我爱这个词。

So I thought, Assembloid. And I send this and says, Perfect. I love it.

所以是你命名了Assembloids？

So you named Assembloids?

我命名了Assembloids，然后在某个凌晨三点正式确认了。第一个组装体用于细胞迁移实验。但问题是细胞需要相互识别并形成回路，所以几年后我们开始制作带有轴突的组装体。

I named Assembloids and then sort of like blessed it, like one night at like 3AM. And so that was the first assembly. And the first assembly was for cells migrating. But then the question was, cells have to find each other and form circuits. And so within a couple of years, started making assemblies that will have axons.

所以神经元通过长长的突起寻找其他伙伴。你知道，我忘了是谁说的，可能是Rodolpho Linas或其他人，他说大脑某种程度上是朝向运动的下一个进化步骤。有种理论认为，神经系统是作为移动方式进化而来的。

So the long projections of neurons finding other partners. You know how, I forgot who said this, must have been Rodolpho Linas or, you know, who said that the brain is sort of, the next evolutionary step towards movement. So the nervous system has been this theory that has evolved as a way of moving around.

那是Sherrington说的。Sherrington说最终共同通路是运动。他是生理学家。他的表述有点模糊，但我想应该是Sherrington。我也不怀疑Rodolfo也说过类似的话。

That was Sherrington. Sherrington said the final common path is movement. He was a physiologist. He was kind of vague in a statement, but I think that he was Sherrington. And I don't doubt that Rodolfo said something about it too.

我可不想抢Rodolfo的功劳。认识Rodolfo的人都知道，他可不是好惹的。

I'm not gonna try and take anything away from Rodolfo. Anyone that knows Rodolfo is he's not somebody you wanna piss off.

嗯，我们应该查证一下。到底是谁说的？

Well, we should check it. Like, who actually said it?

不，我承认是他。我喜欢Rodolfo。

No. I give him credit. I I like Rodolfo.

但对我们来说，这成了下一个目标。我们能否真正构建一个具有明确输出的回路？这样我们就能确认确实构建了这个回路。于是我们思考了最简单的运动回路——皮质脊髓束。这意味着皮层深层的神经元通过轴突一路延伸到脊髓，找到运动神经元建立连接，然后运动神经元离开脊髓到达肌肉。

But for us, that became the next objective. Can we actually build a circuit that will have a very clear output? We would know that we've actually built that circuit. So what we did is essentially, we thought about the simplest circuit for movement, which is the corticospinal tract. So that means that a neuron in deep layers of the cortex sends along axons all the way to the spinal cord, finds a motor neuron, makes a connection, then the motor neuron leaves the spinal cord, goes to the muscle.

本质上只有这两个神经元相互连接并与肌肉相连，两个连接点：一个在两者之间，一个与肌肉相连。这就是你能想到的最简单回路。

And essentially, you only have these two neurons, right, that are connecting with each other with the muscle, two connections, one between the two of them and one with the muscle. So the simplest of circuits that you can have.

现在让我动动大脚趾。对，就是这样。这段距离相当长，如果...

Now that's me move my big toe. Right. Exactly. It's pretty long distance, if

你想它非常简单。当然，在其他物种中会复杂些。比如小鼠那里多了一个神经元，进化过程中发生了一些变化。但对人类和灵长类来说就是这么简单。所以我们做了个类似皮层的类器官，包含这类神经元。

you think It's very simple. Of course, like in other species, it's a little bit more complicated. It turns out that in mice, there's an additional neuron there, so there are some changes that happened over evolution. But for us and in primates, it's as simple as this. So what we did was we essentially made an organoid that resembles the cortex and has some of those neurons.

然后我们做了个类似脊髓的类器官，内含运动神经元。还用人肌肉活检组织做了个人类肌肉球——你确实可以取肌肉活检获得成肌细胞，培养后就能得到完美的肌肉球。真正的挑战在于：我们不知道这些细胞如何相互识别。在发育过程中我们知道它们使用某些分子信号，但远未全面理解它们如何找到彼此。

And then we made an organoid that resembles the spinal cord and has some motor neurons in it. And then we made a ball of human muscle that you can make from a biopsy. You can literally biopsy a muscle, you get the myoblast, you grow them, and you get a nice ball of muscle. And then, of course, the challenge was that the reality is that we don't know how those cells find each other. Like in development, we know some of the molecular cues that they use, but we're far from having a comprehensive understanding of how they find each other.

我记得我们当时坐在实验室里思考，其实我一度抗拒在实验室首次进行这种组装，因为成功概率实在太低了。皮质类器官中那些细胞占比不足5%，运动神经元不到10%。要让它们精准找到彼此并以足够数量触发肌肉收缩，概率近乎为零。但当你真正将三个部分组合起来任其自组装时，几周后就能用电极或光刺激等任何方式激活皮质——然后肌肉就开始收缩了。事实上，重复次数越多，这个过程就越稳定可靠。

And I remember we were sitting down in the lab and kind like thinking I resisted actually doing this as the first assembly in the lab for a while, because the probability was against us. Those cells in the cortical organ are less than 5%, the motor neurons are less than 10%. So the probability that they find each other perfectly and in enough numbers to trigger muscle contraction was close to zero. And yet you do it, you put the three parts together, you let them assemble, and within a few weeks, you can actually now stimulate the cortex with whatever you want to use, with an electrode, with light, and then the muscle starts to contract. And in fact, the more you do it, the more reliable the process is.

随后我们自然进行了逆向工程验证，发现细胞确实以那种精确方式建立了连接。这让我们逐渐意识到：虽然干细胞生物学乃至整个生物学都建立在化学与物理因素基础上，但我们从未真正利用过生物学中这种更高阶的法则或力量——自组织能力。生物系统自我构建的能力。想想人类大脑的发育过程：虽有遗传指令，却不存在施工蓝图。大脑不会反复核对是否所有连接都正确建立，对吧？

And then of course we went on to reverse engineering in and figure out that indeed the cells have connected in that precise way. So I think what we started actually to realize was that, of course, a lot of stem cell biology was I think a lot of biology was based on chemical and physical factors that we were leveraging, but we've never truly leveraged this kind of like next level of law or power in biology, which is self organization. The ability of a biological system of build it itself. If you think about it, the human brain builds itself, There's, of course, are instructions, but there's no blueprint. There's no plan that the brain constantly looks to make sure that it actually made all the connections properly, right?

指令更像是分阶段逐步显现的，主要源自细胞间的相互寻找。我们从中领悟到：只需制造正确的部件，这些部件就会自带组装指令，让神经回路自主形成。这成为了我们研究真正的起点。

Instructions are sort of revealed at every step for kind of like the next step. And it mostly comes from the cells finding each other. So I think what we also started to learn from this was that all we need to do is make the parts. And if we make the parts right, then the parts will come with the instructions and then the circuits will assemble on their own. And so that has been really kind like the beginning of it.

当然构建回路变得越来越复杂。当你成功组装两个部件时就会想：能否做三个？三个成功后又会挑战四个。几个月前我们刚发表了首个四部件组装体，它完整重建了神经系统处理感觉信息的通路——要知道皮质不仅发出运动控制信号，还持续接收外界输入信息。

And of course it became progressively more difficult to build circuits. And so, of course, if you put two, you may think, Oh, let's make three. And if you make three, can you make four? So actually we just published a few months ago the first four part assembly that actually now reconstitutes the pathway that processes sensory information in the nervous system. So you think about the cortex, you know, sends out to control movement and has an output, but it receives information from the outside constantly.

这条通路始于靠近脊髓的神经元，其突触分布于皮肤感知触觉振动或疼痛刺激，信息经脊髓交叉上传至脑中部丘脑，最终抵达皮质。我们花了数年先制造这四部分，再将其组装。美妙之处在于：即便尚未完全掌握组装规则，只要按正确顺序（感觉神经元→脊髓→丘脑→皮质）排列，细胞就能自主连接。数百天后，你会突然观察到整个通路同步闪烁的自发电活动。

And that happens through neurons that sit close to the spinal cord, have projections in the skin where they sense tactile vibrations or pain stimuli, send that information to the spinal cord. From the spinal cord, they cross, they go up to the thalamus in the middle of the brain, and from the thalamus, they go to the cortex. So this is a four part pathway. So it took us years, first of all, to make the parts and then to put them together. And then, again, the beautiful thing about it is that while we still don't know all the rules of assembly, you can make this four part, we call it a sensory assembloid or somatosensory assembloid, because it turns out that the sensory neurons that we can make are mostly sensory neurons that sense pain stimuli.

我们称之为感觉组装体（或体感组装体），因为其中可制造的感觉神经元主要感知疼痛刺激。关键在于创造最小必要条件：制造正确的细胞类型并按特定顺序排列，余下的交给细胞自行完成。

And so you can actually put the four parts together, so the sensory, the spinal cord, the thalamus, and the cortex, and you have to put them in that order. If you change the order, the cells will not find each other. So you just have to create the minimal conditions for them, making the right cell types, putting them in the right order, and then they'll find each other. And within a few weeks, so it takes hundreds of days to build a circuit like this, but the beauty of it is that suddenly you look at it and you just see spontaneous activity that arises in the entire pathway, just starts to flicker all in sync.

能用这种组装体研究不同止痛药的效果吗？

Can you use this assembloid to study the effects of different pain medications?

可以，这是潜在应用之一。我们首个实际应用是研究遗传性疼痛疾病——这类基因突变就像理解疼痛机制的罗塞塔石碑。例如钠离子通道的某些有趣突变：当通道因突变过度活跃时会导致痛觉过敏；而当通道功能缺失时，患者会丧失痛觉。

Yes. So that is certainly one potential. The other thing that you can do, and the first application that we've had, was for genetic forms of pain conditions. So we very often think that genetic conditions, where you have a very clear cause, so like entry points, kind of like Rosetta stones for understanding anything. So there are these interesting mutations in a sodium channel, so another channel.

后者同样危险，许多患者最终会因完全无法感知疼痛而死亡。

But the sodium channel turns out that if the channel is overactive because of a mutation, you'll have excessive pain. So these patients are highly sensitive. But then if the channel is essentially unable to function, then these patients have loss of pain. And that's equally bad. Many of these patients actually will die because they can't sense pain at all.

没错。人们常忽视痛觉缺失突变者的困境——他们无法做出维持生命所需的姿势调整。比如可能长时间无意识地过度倚靠右腿，而正常人会自然调节。

Yeah. I think people don't realize that in mutations where people can't sense pain, people fail to make the postural adjustments Exactly. That allow you to stay alive. And or to because you they, unfortunately, they can be resting a little bit too much on their right leg. We we normally think, okay.

没什么大不了的。

No big deal.

但你在

But you're

不断进行这些姿势调整。如果不这样做，实际上可能会损伤右腿，因为你用力过猛。看似只是微不足道的重量，对吧？那是你自身的体重。

constantly making these postural adjustments. If you don't do that, you actually can damage Right. The legs that you're pushing down too hard on. It seems like a trivial amount of weight, right? It's your own body weight.

但我们未能意识到我们重新分配姿势的频率有多高。

But we fail to recognize just how often we're redistributing our position.

不不不，这绝对正确。一般来说，反馈非常重要，包括通过这种疼痛刺激，通过所有刺激。事实证明，如果你现在构建一个包含导致过度疼痛的突变的四部分组合体，感觉神经元就会过度活跃。所以它们会持续爆发活动。

No, no, no. And it's absolutely true. Like feedback in general is very important, including through like this painful stimuli, through all stimuli in general. And it turns out that if you now make essentially a four part assembly that carries the mutation that causes excessive pain, now the sensory neurons are excessively active. So they keep bursting with activity throughout.

然后我们以为要把它移除。当然，在这些患者中它们可以放电。但事实证明并非如此，由于某些原因它们可以放电，可能是其他通道在帮助它们补偿，但它们未能以同步方式激活通路的其余部分。这就是为什么我们需要四部分组合。我认为这就是为什么组合体通常非常有用，因为细胞间的相互作用会产生涌现特性，大脑中的远距离连接可能涉及许多疾病，当然我们距离理解自闭症等复杂疾病还很遥远。

And then we thought we're going to take it out. And of course in these patients they can fire. It turns out that's not true, that they can fire for some reason, there are probably other channels that are helping them compensate, but they fail to engage the rest of the pathway in a synchronized way. So that's why we need the four parts. I think that's why assemblies generally are gonna be very useful because there are emergent properties that are arising from the interactions of the cells, distance in the brain and likely many disorders, and of course are very far from understanding complex disorders such as autism.

但可以肯定的是，这些远距离回路中的故障性相互作用可能是理解这些疾病生物学机制的关键，并有望在某个时刻逆转它们。

But certainly, these interactions, fault interactions at a distance in the circuits are probably going to be key to understanding the biology of these conditions, and hopefully at one point, kind of reversing them.

我想稍作休息，感谢我们的赞助商Function。去年，在寻找最全面的实验室检测方案后，我成为了Function会员。Function提供100多项高级实验室检测，为你提供全身健康的关键快照。这份快照能让你了解心脏健康、激素健康、免疫功能、营养水平等诸多方面。他们最近还新增了对BPA等有害塑料毒素暴露的检测，以及PFAS（永久性化学物质）的检测。

I'd like to take a quick break and acknowledge one of our sponsors Function. Last year, I became a Function member after searching for the most comprehensive approach to lab testing. Function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health. This snapshot offers you with insights on your heart health, hormone health, immune functioning, nutrient levels, and much more. They've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFAS or forever chemicals.

Function不仅提供超过100种与身心健康相关的生物标志物检测，还分析这些结果并提供相关领域顶尖医生的见解。例如，在我第一次使用Function检测时，发现血液中汞含量偏高。Function不仅帮我发现了这一点，还提供了降低汞水平的最佳建议，包括限制金枪鱼摄入。我当时吃了很多金枪鱼，同时努力多吃绿叶蔬菜并补充NAC和乙酰半胱氨酸，这两者都有助于谷胱甘肽生成和解毒。通过第二次Function检测，我可以说这个方法确实有效。

Function not only provides testing of over a 100 biomarkers key to your physical and mental health, but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas. For example, in one of my first tests with function, I learned that I had elevated levels of mercury in my blood. Function not only helped me detect that, but offered insights into how best to reduce my mercury levels, which included limiting my tuna consumption. I'd been eating a lot of tuna while also making an effort to eat more leafy greens and supplementing with NAC and acetylcysteine, both of which can support glutathione production and detoxification. And I should say by taking a second function test, that approach worked.

全面的血液检测至关重要。许多与身心健康相关的问题只能通过血液检测发现。问题是血液检测一直非常昂贵且复杂。相比之下，Function的简洁性和成本水平让我印象深刻，非常实惠。因此，我决定加入他们的科学顾问委员会，也很高兴他们赞助这个播客。

Comprehensive blood testing is vitally important. There's so many things related to your mental and physical health that can only be detected in a blood test. The problem is blood testing has always been very expensive and complicated. In contrast, I've been super impressed by function simplicity and at the level of cost, it is very affordable. As a consequence, I decided to join their scientific advisory board and I'm thrilled that they're sponsoring the podcast.

如果你想尝试Function产品，可以访问functionhealth.com/huberman。Function目前有超过25万人的等候名单，但他们为Huberman播客听众提供早期访问权限。重申一次，通过functionhealth.com/huberman即可获得Function的优先体验。现在我想讨论一个伦理考量/担忧。但在开始之前，我需要先退一步，请你进行反思。

If you'd like to try Function, you can go to functionhealth.comhuberman. Function currently has a wait list of over 250,000 people, but they're offering early access to Huberman podcast listeners. Again, that's functionhealth.com/huberman to get early access to Function. So I wanna discuss an ethical consideration slash concern. But before we do that, I I want to take a step back and just have you reflect.

我永远不会忘记第一次学习神经发育时的情景——精子与卵子结合后，细胞开始分裂增殖，接着胚胎会分化出肌肉组织和神经系统。能理解这个过程的哪怕一小部分，都令人深感谦卑。确实，直到上世纪初期，人类对这些基础组织和相互作用的认知仍非常有限，这曾是一门相当年轻的科学。

I mean, I I will never forget the first time I learned neural development, like sperm meets egg, and then you get cell duplications, and then the embryo figures out what's gonna become muscle, what's going to become nervous system. And it's really a, it's a humbling thing to be able to realize that we understand even a small bit of that. Yeah. And very little was known until, you know, sort of early parts of the last century, really, is where some of the defining tissues and interactions were first discovered. It was a relatively young science.

如今我对此更加敬畏。因为只要看看九个月前还不存在的孩子...虽然大多数人都明白婴儿是如何形成的，但这个过程依然令人震撼。我认为最不可思议的——这确实是个奇迹——在于其自我组织的特性。

Nowadays, I'm even more humbled by it. Mhmm. Because one only has to see a child that were, know, nine months ago didn't exist, and you and you really start I mean, most people understand how babies are made. And yet, it just it's staggering. And I think what's so staggering about it, what's so miraculous, and it really is it's a miracle, is the self organizing aspect of it.

是的。现在我又听说这种细胞自我组织的智慧——细胞关于何时该做什么的内在知识——被保留了下来。我必须再次强调并赞赏这个事实：无论人们对胚胎干细胞的争议持何种立场，你所描述的这些组合体是通过提取成纤维细胞（皮肤细胞）...

Yes. And now I'm hearing that these self organization knowledge of the cells own knowledge about what they should do and when is maintained. And I also have to just both highlight again and applaud the fact that regardless of where one stood on the embryonic stem cell debate, you're describing assemblies that were made from essentially taking a fibroblast, a skin cell

完全正确。

Exactly.

来自患者或健康人群（至少不携带该突变基因），将其放入培养皿，通过山中因子使其逆转为干细胞状态，再给予特定诱导使其分化为神经元或其他细胞类型，最后进行组合。整个过程完全不涉及流产组织。那么请允许我问：如果现在你能将成纤维细胞转化为少量神经元进行储存...

From a patient or from a non patient, a healthy person that does at least doesn't have that mutation, putting them in dish, reverting them to stemness through the Yamanaka factors, then giving them certain things to drive them towards neuronal fates and then other fates, putting them together. And none of this involves the use of aborted tissues. No. May I ask you this? If today you could bank your fibroblasts turned into a few neurons.

你会这么做吗？要知道这些细胞未来可能用于培育任何组织。比如——Sergio我祝你长命百岁——但假设你百岁时心脏出现问题。人类已经可以进行心脏移植手术...

Would you do it? Knowing that those cells could eventually be used to create any tissue, like, I hope you live a very, very long life, Sergio. But let's say when you're 100, your heart has an issue. We humans can do heart transplants Yeah. From another human.

虽然存在免疫排斥问题。猪心脏也曾移植给人类。但理论上...你可以用自身细胞培育出心脏，完全避免排斥反应。有什么理由不储存自己的细胞呢？

There are immune rejection issues there. Pig hearts have been transferred into humans. But we could potentially you could potentially build a heart that is of your cells. No immune rejection. Why wouldn't you bank your cells?

我认为原则上随时都可以采集这些细胞

I think you you can collect them at any time in principle

只要在你90岁生日时获取就行。

as long as you get them on your 90 birthday.

我认为你仍然可以获取它们。好吧。确实，这可能引发一场争论，各位。没错。可以提出一个论点，即所有细胞都会老化，因此这些细胞内部会发生一些变化。是的，也许有人可以就此提出一些论点。

I think you can still get them. Okay. For sure, it could be an argument time, folks. Right. So it could be an argument made that all the cells are going to be aging, so there are going to be some changes happening in those cells that Yeah, maybe they have that some could be an argument made about it.

另一方面，我们现在更广泛地看到一些正在开发的细胞疗法，它们不一定需要个性化。也就是说，它们不必由你自己的细胞制成，因为你可以使用免疫抑制。这是实现这一目标的一种方式。因此，你可以移植他人的细胞。当然，如果你考虑大脑，替换大脑的大部分区域，这无疑会带来更多挑战，你知道，这还远未实现。

On the other hand, what we're also seeing with some of the cell therapies that are just being developed now more broadly, is that they don't have to be necessarily personalized. So they don't have to be made from your own cells because you can use immunosuppression. That's one way in which you can do it. So you can transplant the cells from somebody else. Of course, that poses more challenges if you think about the brain, replacing large parts of the brain, which certainly is you know, far

进入一个谨慎的，谁的大脑

into one the careful whose brain

是的，谈论。但总的来说，你可以看到未来我们可能会有现成的细胞，这些细胞来自一个通用的个体，通过免疫抑制进行移植，或者经过基因改造的细胞，使其不会被免疫系统排斥。因此，它们与我们所有人都兼容。我认为这更有可能成为一种广泛使用的疗法。这就是为什么我现在并不太担心采集自己的细胞。

you're Yeah, talking But in general, like, you know, you can see how in the future we may have like off the shelf, right, cells that have been made from a generic individual that you transplant with immunosuppression, or cells that have been genetically modified so that they're not rejected by the immune system. So they're compatible with all of us. It's much more likely to become a therapy that is broadly used, I think. So that's why I'm not that worried about harvesting my own cells right now.

你对这个观点持什么态度？在不久的将来，我们是否能够实现体内整个器官的永生，也许不是我们自己。但我们的同事，斯坦福大学遗传学系主任迈克尔·斯奈德告诉我，他认为至少在我的有生之年，我比他年轻一些。我快50岁了。忘了迈克多大了。快70岁了。

Where do you sit on this idea that at some point in the not too distant future, we will be able to immortalize entire organs within our body, perhaps not ourselves. But our colleague, Michael Snyder, chair of genetics at Stanford, told me that he thinks that at least in my lifetime, I'm a little bit younger than he is. I'm almost 50. Forget how old Mike is. Almost 70.

但他说，至少在我的有生之年，人体组织的永生将成为可能。他认为这不是幻想。

But he said at least in my lifetime that immortalization of tissues, human tissues will be possible. He doesn't think that's a fantasy.

是的。不同的人对“永生”有不同的理解。一般来说，在体外研究或培养皿研究中，当你使某物永生时，意味着细胞被永久保存，但这通常涉及使用类似癌症的因素，赋予它们癌症特性。我是说，永生的细胞，如果你仔细想想，要么是我们之前提到的干细胞，要么是癌细胞。因此，我们必须谨慎对待“永生”细胞的实际含义。

Yeah. Think different people mean different things by immortalizing something. Generally think like for in vitro studies or for an a dish study, when you immortalize something, it means that the cell is maintained forever, but it generally involves using a cancer like factor, giving them cancer properties. I mean, the cells that are immortalized, if you think about it, are either the stem cells that we talked about or the cancer cells. So we always have to be careful about what it means to actually immortalize a cell.

rejuvenate细胞，这是一个有趣的概念。我们是否能够真正 rejuvenate自己，即使它们已经老化？最近有很多讨论，关于是否可以使用山中因子，不是完全重编程细胞，而是稍微使用它们，使细胞 rejuvenate但不完全。但你可以想象，这些是复杂的实验，对吧？它们需要精细调控。

Rejuvenate cells, that's kind of like an interesting concept. Will we be able to actually rejuvenate ourselves even if they're aged? So a lot of discussions have been happening lately, whether you can actually use the Yamanaka factors, not to the extent that you completely reprogram a cell, but that you just use them, you know, just a little bit so that you rejuvenate the cells not fully. But as you can imagine, those are complicated experiments, right? They're gonna have to be tuned.

你需要非常小心地控制这个“剂量”。微剂量山中效应。没错。因为你实际上可能会冒险进入另一种状态。但你知道，这可能在某一天成为现实。

You need to control very carefully the dial there. Microdosing Yamanaka effect. Right. Because you would actually you you risk moving into another state. But, you know you know, that may be possible at one point.

是的。我曾认为，使用山中因子和整个治疗技术的一个担忧是，你可能会将细胞的年龄逆转回干细胞状态。是的。但然后你如何让它们停在那里？还有，你如何引导它们？毕竟，你想要的并不是干细胞。

Yeah. I thought that at one point, one of the concerns of using Yamanaka factors and this whole technology therapeutically was that you could set the reversal in age of cells back to stemness, back to stem cells. Yeah. But then how do you stop them there? And also how do you send them I mean, ultimately, it's not a stem cell that you want.

你想要一个完全分化的心脏细胞或神经元，并且希望就此止步。

You want a fully differentiated heart cell or neuron and you want to stop there.

没错。

Right.

我的意思是，对于那些试图逆转年龄的人来说，你愿意回溯到多远？

I mean, the idea being for anyone trying to reverse their age, I mean, how far back are you willing to go?

对，对。确实如此。当你使用山中因子或它们的组合时——因为后来我们发现，不仅仅是那些因子能做到这一点，其他因子的组合也能达到同样效果。所以有多种组合方式。

Right, right. And it's true. When you use the Yamanaka factors or a combination of them, because, you know, we've discovered afterwards that it's not just those factors that can do that. There are combinations of other factors that can do the same. So there are various combinations.

这个通路中存在大量冗余。如果你在细胞中适时击中正确的组合，就能将其推回时间原点。当然，现在的挑战在于，重编程是彻底的——如果操作得当，所有甲基化标记（那些随着年龄积累附着在DNA上的甲基基团）都将被清除。所有衰老特征本质上都会被抹去。

There is a lot of redundancy in that pathway. And if you hit the right combinations in a cell at the right time, you can push it back in time. Now, of course, the challenge is that, you know, that reprogramming is full in the sense that everything is gonna be erased. If the reprogramming is done properly, directly all the methylation, so all this metal groups that you put across DNA that, you know, accumulate with age are gonna be removed. Signatures All are essentially removed.

细胞会像初始状态那样真正 rejuvenated（ rejuvenated）。就像你提到的，可能你并不想完全这样做。能否实现所谓的部分重编程？虽然这方面仍处于早期阶段，但这确实是一种可能性。

The cells truly rejuvenated as like in the beginning. And as you mentioned, you know, perhaps you don't wanna do that, right, fully. Can you do it in a way that is a partial reprogramming, as some people refer to? But certainly, these are still like early days for that. Certainly, it's a possibility.

我想对大多数人来说，如果我说：科学家正在开发工程眼球来替代失明者的眼睛——单眼或双眼——人们会说太棒了。

I think for most people, if I said, look, scientists are developing engineering eyes that can replace eyes with Mhmm. People that are blind. Maybe one eye, maybe both. They'd say, great. Right.

这实质上是在治愈失明。确实有人在做这方面的尝试，比如Neuralink，还有斯坦福的EJ Chisholmowski和Tan Palankar。

You're curing blindness effectively. And people are trying to do this. Neuralink is doing this. EJ Chisholmowski and Tan Palankar at Stanford are trying to do this. Yeah.

如果我说有科学家和公司正研发芯片让瘫痪者重新行走，或让闭锁综合征患者通过某种方式重新发声，人们会表示支持。但如果说科学家正在培养皿中构建类器官组装体，让你可能拥有三个海马体而非两个，获得超级记忆力——多数人恐怕会说：哇，慢着...

If I said, you know, there are scientists and companies trying to develop chips so that paralyzed people can walk again, or that people who have locked in syndrome can speak again through one modality or another, they'd say great. But if I said, there are scientists who are building assembloids in a dish so that maybe you don't have, like, two hippocampi, you have three. You have a super memory. Yeah. I think most people will be like, woah, slow down.

这简直是在扮演上帝。不可接受。就像我们之前讨论过的CRISPR基因疗法这个平行案例。

You're playing God. That's not okay. And as a parallel example, CRISPR gene therapy, which we talked about earlier

是的。

Yeah.

据我所知，是被一位中国科学家雇佣，目的是——我想是——让HIV受体发生突变。

Was employed by a Chinese scientist to I think it was to mutate the HIV receptor.

进行基因修改，对，针对两个个体。嗯。两个婴儿。

To modify, yeah, two individuals. Mhmm. Two babies.

没错。目前我们知道的至少有两个婴儿，可能全球范围内还有更多，但数量不会太多——这些案例中CRISPR技术被用于基因改造。这些婴儿都足月出生，且改造目的并非治疗特定疾病，而是赋予他们额外的特性。

Yeah. So there are at least two babies that we're aware of, and probably more around the world, but not terribly many who have for whom CRISPR was used to make a genetic modification. Those babies were carried to term, and it wasn't to fix any particular disease. It was to confer them with something additional.

是的。在这个案例中是为了预防...嗯...预防HIV的母婴传播。嗯。但这种情况下的操作未必合理，所以...

Yeah. To to prevent in this case, to prevent Mhmm. Presumed transmission of HIV from the mother. Mhmm. Is not necessarily justified in that case, so.

明白。那位母亲本身携带HIV吗？

Right. Did the mother have HIV?

我认为初衷是——是的——为了避免母体将病毒传给胎儿，但本可以通过其他方式实现。所以选择这个疾病作为改造对象可能并非最佳方案。确实。这也正是科学界对此强烈愤慨的原因——无论是实验动机还是操作方式，都明显违背了科研规范。

I think the idea was that, yeah, to avoid maternal transmission to the fetus, you would not have that. But there are other ways in which that can actually be avoided. So in this case it was not perhaps the best choice of a disease to make. Correct. And I think that's why the scientific community has been quite outraged by both, gets the rationale and the way the experiment was done, which was not following certainly.

对。正如你所说，科学界对此非常不满。这就引出了伦理问题。是的。

Yeah. Yeah. The the scientific community, as you as you said, was very upset about that. Which brings us to the question of ethics. Yes.

考虑到你对这项技术的深入了解，相信你思考过许多我可能想不到的伦理问题，或者从公众、医生及精神科医生那里听说过相关讨论。当考虑如何将类器官最终发展为疾病治疗方案时，你认为哪些是关键的伦理问题？

So I'm sure being really familiar with this technology that you've thought about a number of ethical issues that aren't going to occur to me, or perhaps you've heard about things from the general public or from physicians and psychiatrists. What are some of the key ethical issues that come to mind when thinking about how a symbolize are going to be implemented as eventually treatments for disease?

我们团队在斯坦福经常探讨伦理问题——我的研究中心有法律教授兼伦理学家Ken Greeley等人参与，实际上我们还联合了众多伦理学家、宗教社会学家。今年11月我们将在Asilomar召开首次关于神经类器官、组装体及其移植伦理的会议。伦理问题可以从多个维度分类：我个人认为，一方面涉及细胞本身的伦理——我们获取人类细胞时，必须确保获得使用这些细胞的正当授权。

So we think a lot about like the ethical issues and we think this as a group at Stanford, as part of like my center, we have like Ken Greeley, who's a professor of law and an ethicist, but actually we've engaged many ethicists, sociologists of religions. We're actually gonna have the first meeting at Asilomar this November on the ethics of neuro organoids, assembloids, and their transplantation. And there are various ways of classifying the ethical issues. The way I sort of think about it is that on one hand, there are ethical issues that are related to the cells. We are taking cells from a human, and so you expect that you have received proper consent for the use of those cells, whatever that is.

另一方面，如果将它们植入动物体内，就会涉及与该动物相关的伦理问题。你是否造成了伤害？我们如何管理这只被移植动物的疼痛？此外还存在介于两者之间的议题。比如，这些培养物或动物体内是否会在某个阶段出现任何涌现特性？

On the other hand, if for instance you put them into an animal, then there are ethical issues related to that animal. Are you doing any harm? How do we manage pain in that animal that has been transplanted? And then there are issues that are at the interface between the two. So for instance, are there any emergent properties that are arising at one point, whether they're like in a dish or maybe perhaps in an animal?

这类神经回路能复杂到什么程度？是否存在某种形式的学习或计算能力？当然有人提出可能存在感知、意识或觉知的问题——它们会感到疼痛吗？比如这已成为对我们近期某项工作的主要质疑点。

How complex can a circuit like this become? Is there any form of learning, of computation? Of course, some people have raised the issue that perhaps there is sentience or awareness, consciousness. Are they feeling pain? So for instance, that has been like one critique for one of the recent work that we've done.

当然，我们知道疼痛的情感成分由不同脑区处理。培养皿中并不存在这些脑区，因此可以确定它们并非真正感受疼痛，虽然具备疼痛传导通路。这也提醒我们必须谨慎对待这类研究的传播方式——即便是看似无害的术语也可能引发巨大误解。

Of course, in that case, we know the emotional component of pain is processed in different brain regions. We don't have those in a dish. So we know that they're not really feeling pain, we have the pathway of pain. But also speaks to the fact that we need to be very careful about how we communicate this type of research. Even just using terms that are trivializing can actually create a lot of confusion.

我们领域最典型的例子就是将类器官或组装体称为'迷你大脑'。这看似是个无伤大雅的玩笑，但当公众首次听说'科学家在培养皿培育出迷你大脑'时，他们会直观联想到完整人脑的微型版本——被孤立保存在器皿中。

And the classic example in our field has been to call these preparations, these organoids or assembloids, to call them mini brains. Then it may seem like as a trivial joke that it can do anything, any harm, but you hear that for the first time, scientists have made mini brains in a dish, right? And what do you think? You think, Oh, it must be a miniature human brain that they're keeping in a dish, right? Isolated.

这显然与事实不符。我们尚未构建完整神经系统，只能制造部分神经组织并进行不同组合。实际上，据我所知没有科学家以精确复制完整大脑为研究目标。

And of course that's not true. We have not made the entire nervous system. We can make parts of the nervous system. We can put them in various combinations, but we've never made an entire brain. Actually, I don't know of any scientist who has as a goal to try to build the entire nervous system as an exact replica of the brain.

因此术语使用至关重要。几年前我们召集领域内多数科学家，通过大量会议讨论最终在《自然》发表了领域命名规范。这份共识文件明确了分类标准和使用禁忌——例如禁止将复杂概念简单投射到类器官研究上。

So I think the words matter a lot. And in fact, that has been, you know, one of the things that we've done over the years. A few years ago, I thought it would be really important to get most of the scientists in the field together and start thinking about these terms really carefully. And so we got together, created sort of like an ad hoc consortium and through many, many calls, one on one in various groups, we came up with one paper, which was published in Nature a couple of years ago, which really comes as a nomenclature for the field. We as scientists decided this is also like the way we classify them, these are the terms that we all agreed should be used, and not use, not for instance, you know, project, let's say, complex terms onto this.

我们绝不会因存在视网膜就称某类器官具有视觉，也不会认为皮层类器官拥有智能——因为这是完整神经系统的属性。这种规范对公众科普尤为重要。那个临时联盟成效显著，最近我们又在《科学》发表论文，进一步确立了领域研究框架。

We'll never say that an organoid like C's just because there's a retina, right? We'll never say that a cortical organoid has intelligence because that's a property of an entire nervous system. So we think that this is actually quite important, especially in communicating with the public. And that that consortium turned out to be an actually great exercise of getting everybody together and now thinking what are some of the common practices that we should all use when we report this experiment? So we just had a few months ago another paper that came also as a perspective in science, nature, where we also lay it out, so like the framework for the field.

这标志着科学界正在进入新时代——虽然各实验室存在竞争关系，但我们仍能召集25个团队达成共识。随着生物学复杂度提升，未来需要更多此类协作，因为没有任何单一方法能解决所有问题。

I think this also speaks to the fact that we're entering sort of like a new year in science, where I think, you you would say all these labs are working separately. They're competing with each other. And yet we all got together, you know, 25 or so labs, discussed some of these issues, reached some consensus, you know, and I think that moves the field forward. And I think in general, in science, we will need more and more of this collaborative effort because the science is getting more complex, biology is getting really, really complex, and there's no one single app that can solve all of that.

完全赞同。多年前协作就已从偶然行为转变为常态。我一直认为实验室应该以项目而非个人命名——不过这是另一个话题了。

Yeah, I completely agree. I think some years back collaboration became the norm as opposed to the occasional thing. And I always thought that laboratories should be named after projects, missions, as opposed to individuals. But that's a Yeah. That's another story.

你们对这些议题的审慎思考及召集同行制定术语的做法值得赞赏。命名问题确实至关重要，这在公共卫生领域尤为明显——如今人们谈论功能获得研究时，很少提及其对认知事物的重要价值，并非所有研究都涉及病毒突变。

Well, kudos to you for thinking about these issues so carefully and for gathering people around them in order to come up with nomenclature. Going back to this issue of naming what things are called is so critical. It's so critical, and we see this in the public health sphere. You know, when people talk about gain of function research now, it's rarely mentioned that gain of function studies are critical for understanding things. It's not always the case you're mutating a virus.