从古印度重建鼻子，到如今超净猪舍供肾：人类离“全身换新”还有多远？｜科学60秒

千年以来，医学界一直尝试用各种方式替换人体衰竭器官。但现代医学的产物仍然难以媲美人体的“出厂设置”。

古希腊有艘著名的船——忒修斯之船：每当一块船木腐朽，便被一块新木板替换。渐渐地，当船上所有部件都换了新，这还是原来那艘船吗？如果用拆下来的旧木板再造一条船，哪艘船又才是真正的忒修斯之船？

如今，这则悖论正在人类身上变成现实：从古印度的鼻重建术，到今天已经得到广泛应用的假肢技术，再到现在“超级清洁”猪圈中养殖的移植供体猪……在探索用新部件“取代”已经坏掉或有缺损的“原装零件”的过程中，科学家们屡屡意识到，人体这艘“活船”，远比想象中复杂：虽然能用义肢、再生组织或异种移植器官换掉身体的某一部件，但创造出与“原装设备”一样好用的东西仍然是一个巨大的挑战。

首先从名副其实的整形外科“鼻”祖——发源于古印度的鼻重建术说起。当时，割鼻是一项用于公开羞辱、惩罚犯人的手段。基于此，修复鼻子的需求应运而生。

公元前 6 世纪，印度医生苏施拉塔（Sushruta）在自己编纂的《苏施拉塔本集》（Sushruta Samhita）中详细描述了额头皮瓣鼻修复技术，具体操作包括：用酒精或草药麻醉，取额头皮肤，保留血管蒂，翻转覆盖鼻部缺损，保持血供，止血缝合以促进伤口愈合。据文献记载，当时的医生甚至会用竹片或芦苇作为支架固定鼻形，堪称最早的组织移植范例，感染率之高也可以想象。

如果把时间线拉回近现代，假肢或许是离我们更近的“人体替换”技术，有人甚至会因腿脚不便而选择接受截肢手术，再装上假肢，最终可以像健全的人一样跑步、徒步。

以骨科领域常见的髋关节置换术为例，从十九世纪末起，医生就尝试切除病变的髋关节；此后，为了保留关节功能，他们又试图用象牙、橡胶、玻璃等作为植入材料代替人骨，但手术成功与否全凭运气（和患者自身的愈合能力），常见松动、材料碎裂、感染等并发症。

直到 1938 年，英国外科医生菲利普·威尔斯（Philip Wiles）成功实施了首例全髋关节置换手术，使用不锈钢假体，以螺钉固定股骨和髋臼，至此，这一术式逐步走向成熟。此后又涌现出钴铬合金、骨水泥、聚乙烯、陶瓷等假体材料。在一百余年的漫长发展历程中，这一技术不断被迭代和改进，最终才变成今天的样子，造福无数被病痛折磨的患者。

尽管如此，假肢及关节假体植入等已是医学领域熟练掌握的“人体替换”技术。作为一架奇怪、奇妙又复杂无比的机器，人体其他器官或组织的更换则更为困难。

作为医学领域的前沿部分，再生医学正在蓬勃发展。与旨在利用人造装置（如机械或电子设备）替换或辅助实现肢体功能的假肢技术不同，前者的核心是利用生物学方法修复或再生人体组织和器官，主要涉及四个方面：干细胞疗法、组织工程、基因编辑和移植医学。

2012 年，再生医学领域迎来突破性进展。一篇发表于《科学》杂志（Science）的里程碑式论文为 CRISPR-Cas9 技术在人体中的应用拉开了序幕。该技术源于细菌的适应性免疫系统，后被改造为基因编辑工具。与前一代基因编辑工具（如锌指核酶）相比，CRISPR-Cas9 简化了基因编辑过程，同时还提高了基因编辑的精确度。这篇论文的两位通讯作者，詹妮弗·杜德纳（Jennifer Doudna）和埃马纽埃尔·卡彭蒂耶（Emmanuelle Charpentier）因此荣获 2020 年诺贝尔化学奖。

近年来，学术界继续探索 CRISPR-Cas9 的更多可能性，如利用这项技术对诱导多能干细胞（iPSCs）进行基因校正。一旦实现，就能提高健康组织的生成效率，为遗传性疾病开发有效的再生疗法。

经过十余年的探索与研发，不少相关疗法已陆续从实验室走到临床。2023 年 12 月 8 日，美国食品和药品管理局（FDA）首次批准一款基于 CRISPR-Cas9 技术的基因编辑疗法 Casgevy，可用于治疗镰状细胞病（SCD）。次年 1 月，Casgevy 再次获得 FDA 批准，用于治疗 12 岁及以上患者的输血依赖性 β-地中海贫血（TDT）。未来，在多方努力下，这些疗法还有望纳入各种保险的承保范围，减轻患者负担。

不过，要想从“头”培育人体器官，只有 CRISPR-Cas9 还不够。一家名为 Stemson Therapeutics 的初创公司曾试图开发利用诱导多能干细胞培育毛囊的技术，解决现代人广泛遭遇的脱发问题。

诱导多能干细胞也是一项诺奖级发现。1962 年，约翰·伯特兰·格登（John B. Gurdon）通过著名的非洲爪蟾细胞核移植实验证明，成熟细胞核可被重编程回胚胎状态，这奠定了细胞的可塑性理论。在此基础上，2006 年，日本科学家山中伸弥进一步发现，为小鼠皮肤细胞引入四种转录因子（Oct3/4、Sox2、Klf4、c-Myc，被称为“山中因子”），即可将其重编程为多能性干细胞，分化能力与胚胎干细胞媲美。2012 年，约翰与山中伸弥共同获得了诺贝尔生理学或医学奖，“以表彰他们发现成熟细胞可以被重新编程为多能细胞”。

说回这家专注于“自体生发”的公司，Stemson Therapeutics 的基本构想是，利用诱导多能干细胞，“引导”其发育为毛囊的两种基本组织：毛囊基底细胞（真皮乳头细胞）和角质形成细胞，这些细胞会聚集在一起，形成一团处于混沌状态的原始毛囊。与真正的毛囊不同，它们可以产生类似于毛发的物质，却无法“破皮而出”，变成真正的头发。

为解决这个问题，公司的工程师设计出一些细小的导管，辅助毛发物质长出皮肤。但这些管子太脆弱，脆弱到无法承受植入毛囊时施加的力。Plan A 就这样失败了。很快，团队想到了 Plan B，他们像串珠一样把两种细胞串到一根线上，线头伸出皮肤，等毛囊中长出头发，就可以借助线的引导长出来，这时抽去原来的线，一根头发就成功长出来了。

这项技术听上去虽然复杂，但似乎可行，公司进展也很顺利，相信你一定开始摩挲头皮、暗自兴奋了吧……可惜，他们没有获得足够的资金，项目最终流产了。

现在，这家公司依然在探索多种多样的护发、生发技术。其中还包括提取患者体内的脂肪来源干细胞（ADSCs）或毛囊干细胞（HFSCs），对其进行处理后直接涂抹在头皮上，或注射进头皮皮肤中。他们宣称这种做法可以将干细胞、维生素和生长因子输送到皮肤，激活休眠的毛囊，改善头皮血液循环，最终促进毛发生长。按照疗程长度，总花费在 3000~30,000 美元（约合人民币 2.1 万~ 21 万元）不等。至于是否真的有效，就见仁见智了……

作为一项仍处于起步阶段的技术，截至目前，你大概只能从一些科幻片中看到利用人源干细胞培育出完整的单个器官。即便在实验室中，研究人员也只能借此创建出一些小的细胞簇和斑块。

好消息是，这些进展已经足够用于治疗一些顽疾了。例如，一种定制疗法可以将某位患者体内的成熟细胞“重编程”为多能干细胞，再将其转化为一种能产生多巴胺的神经细胞，治疗帕金森病；或者将其转化为能产生胰岛素的胰岛细胞，回输至患者体内，治疗糖尿病。即便是微小的突破，都可能成为患者治愈疾病的曙光。

最近一段时间，有关异体移植的新闻屡屡出现，猪器官在人体内运转的时间纪录正在被不断刷新。

在中国四川，有一家专门培育无指定病原体环境饲养（DPE）医用供体猪的超净无菌猪舍，这些猪经过专门的基因编辑，敲除了引发人体排斥反应的三种猪抗原基因，同时转入人补体调节蛋白和凝血调节蛋白基因，可以说是专为器官异种移植而生。

为保障猪舍的“超清洁”环境，所有和猪接触的工人都需要在工棚里隔离三个月。一旦进入猪舍，就不能离开。这里的猪需要在无菌环境下通过剖腹产接生，接受一系列包含 40 种不同细菌、病毒和真菌的检测；猪舍每三天进行全面彻底的清洁；人和猪吃的食物也需要经过高温高压、辐照处理，彻底杀菌。除了无法训练猪用厕所…… [查看全文]

Thanks so much for coming on to chat today.

Mary Roach:Oh, thank you, Rachel, for having me on.

Feltman:So your books have explored everything from the human gut to the hunt for ghosts, scientifically speaking. What is your latest about?

Roach: Replaceable You is a look at efforts to swap out, build, replace bits and pieces of the human body. Some of the book is historical and much of it is set in the present, so it’s just about the amazing challenges, and also the progress, but the—just how complicated it is to try to create something that functions as well as what we start out with.

Feltman: And what got you interested in that topic?

Roach: I got an email from a woman who said, “I think your next book should be about pro football referees,” and I’m like, “That’s a really odd choice for me, and I don’t watch football.” But we started corresponding a bit, and she mentioned that she’s an amputee, specifically an elective amputee, meaning she had an underperforming foot, and she had multiple surgeries and still wasn’t able to really walk on it in a way that she felt she wanted to be able to do, and she used to see people walking around with prosthetics, running, hiking, and she’s like, “I want that. Why won’t somebody cut off my foot [laughs]? Somebody please cut off my foot.”

That got me thinking about replacement parts, and so that was the spark. Then I meandered down the road through another few possible chapters I might cover, and I thought, “Okay, this is the human body—that’s kind of my turf.” I like to explore our bodies, the strange and wonderful, complicated machines that they are.

Feltman: I would say that’s a pretty good inspiration story [laughs]. But ...

Roach: Odd, though. She’s still after me to write a book about [laughs]—she’s like, “Okay, now you can start on that book about professional football referees [laughs].”

Feltman: [Laughs.] Maybe later.

Roach: Yeah, maybe next time, heh.

Feltman: What did you learn about this field? How has it changed in recent years, and what kinds of things are possible right now?

Roach: Oh, gosh. Well, that’s a 200-page question [laughs]. I guess I would say that the whole field is both moving very quickly and, at the same time, amazingly slow. You know you look at something like a hip replacement: the first one was done in 1938, and there’s been this progression of changes and advancements and improvements, and it’s become something effective and safe and commonly done, but it was a long road.

And, you know, and you look at stuff that’s going on now in regenerative medicine and CRISPR, what was that—like 2012? I mean, already we’re seeing treatments coming out of that. And so things are happening at a breakneck speed, but still, you know, it’s—you have the discovery. You work things out. You go to clinical trials. That’s 10 years, probably, before something is ready to be released, and then you have to convince the insurance companies. Anyway, so it’s a strange mix of things happening at a really amazing pace, but also, it’s just a long haul, always.

Feltman: And could you give our listeners some examples of the kinds of parts we’re talking about replacing? Just a couple of your favorites, since, like you said, that is a 200-page question [laughs].

Roach: [Laughs.] Yeah, yeah. I started out with, with noses ’cause I—you know, the nose was the first thing that was widely replaced, partly because nasal mutilation was a, going back hundreds of years, a punishment. So it was both a punishment and a deterrent to hack someone’s nose off because everybody can see it. So there was this need for rebuilding noses. Even going back to 1,000 B.C. there were people who had the idea that you could take a little piece of the forehead or the cheek and you could cut it out, kind of flop it over onto the nose, leave it attached and rebuild a nose that way, which is astounding.

So that was, that was where it began, and now we’re talking about trying to grow things from scratch. I thought, “Because I don’t have a background in this, let’s start with something simple.” And there was a company, Stemson Therapeutics, that was attempting to grow follicles using induced pluripotent stem cells. And it was both like, “Wow, look what they’re doing,” and also, “That’s all you got?” [Laughs.]

So they would take, like, off-the-shelf induced pluripotent stem cells; they’d figured out a way to teach them to become the two kind of building blocks of a follicle. And they had these two types of cells, dermal papillae cells and keratinocytes, and the cells would kind of come together and create a primitive follicle—like, more than a blob, less than a follicle. It was producing hair, right? It was producing hairlike—hair material, but it was underneath the skin; it wasn’t coming up.

So they’re like—they called it “disorganized hair.” And they’re looking—they’re like, “We’ve gotta get it to come out of the skin. It’s gotta—” Wherever they put it, it would heal over, like skin does, and then they’re like, “We need a little tube.” And so they got these amazing engineers to create little, tiny tubes for the hair material to grow up and out of the skin, but the tubes, it turned out, they were too delicate to implant, and how are they gonna get to implant a follicle? It requires a little force to get it in there. And so that wasn’t gonna work.

And then they were threading the two types of cells on a piece of kind of thread and letting them come together, and then at some point they’d pull the thread out. And it was incredibly complicated, and it was working and exciting—and then they didn’t get enough funding, and they went out of business [laughs]. So that’s kind of the story.

Nobody’s growing organs from stem cells, whole organs; that’s still science fiction. But creating just, like, little clusters and patches and—of cells that are, maybe, you have folks looking at treatments for diabetes and, potentially, for Parkinson’s where you could, you could, in a bespoke way, take somebody’s cells, regress them to pluripotency and then turn them into the kind of neuronal cells that produce dopamine or turn them into islet cells that produce insulin. So you have this “primitive,” in quotes, but pretty exciting stuff.

Feltman: Yeah. What excites you the most about the future of some of the research you covered in the book?

Roach: I’m gonna—I mean, I don’t get into how AI is used in all of these things, but my sense is that’s gonna really speed up this work. That’s gonna make it quicker to find molecules that work, quicker—just everything may be speeded up. And, and that makes me sad that—the kind of cuts that are going on to basic research, that’s been really sad. The book was about to go to production when [the U.S. DOGE Service] kicked in, so, you know, I had to call all the labs and kind of say, “Are you still okay? What’s going on?”

But that’s not what you—you asked me what’s exciting, not what’s depressing [laughs]. Oh, it’s all, “We’re just in this period of massive potential.” And then you dive in, and you look at the challenges—it’s just very, very difficult to do something as well as the body does it. But things are moving fast.

Feltman: Your books always take you to such interesting locations. Were there any labs or other places in particular that really stuck out to you?

Roach: I spent time in a designated pathogen-free pigsty in China where pigs are being raised for xenotransplantation of organs. Just the idea of a highly clean [laughs]—“superclean” is the technical term—a superclean pigsty was kind of appealing, so I visited. I wasn’t allowed in. I went all the way to China, and I’m like, “Oh, over the hill there, that’s where they, that’s where they are. So how are we getting there? We’re gonna—” and they’re like, “Oh, we’re not going in.” They’re like, “You’re a massive pile of bact—

Feltman: “You’re too dirty” [laughs].

Roach: “You’re a filthy human. You don’t come anywhere near our pigs.”

That was fascinating. I got to see them in the control center; they have videos on all of the pigs. And so I got to, I got to see them but not say hello in person. But it’s kind of an amazing—I mean, they had a bunkhouse where the workers stay for three months; they’re quarantined. And then they stay there—they can’t leave. It’s just them and the pigs. The pigs are tested for 40 different bacteria and viruses and fungi. Everything is disinfected every three days. The food gets irradiated. I mean, it’s an amazing operation. And then you look on the screen, and, like, there’s a pig taking a crap, and I’m like, “Okay, it’s just a pigsty.” It’s a—I mean, you can’t train a pig to use a toilet, so...[full transcript]

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