The Rise and Fall of Stem Cell Research - YouTube

You know how great TV shows often take you on a journey with twists and turns leading to an ending you never saw coming? Sciences like that sometimes, too. Consider the case of IPSCs, a kind of stem cell researcher's thought was going to revolutionize cellular therapy. After years of clinical trials, that failed to happen. But as luck would have it, IPSCs ended up advancing completely different fields.

你知道那些精彩的电视节目通常会带领你经历曲折的旅程，最终以一个出乎意料的结局吗？科学有时也是如此。就拿诸如诱导型多能干细胞（IPSCs）这样的科学来说吧，研究人员最初认为它将彻底改变细胞疗法。经过多年的临床试验，这个目标未能实现。但出乎意料的是，IPSCs最终却推动了完全不同的领域的发展。

First, a little background. Each cell in your body is optimized to perform a highly specialized role. Your neurons have long thin structures called axons to carry electrical signals. Your red blood cells don't contain a nucleus, so they have more room to carry oxygen. Each cell also began as exactly the same thing, a humble stem cell with the potential to become anything. We used to think that once a stem cell had become specialized, a process called differentiation, and that was how it was stuck forever.

首先，简单介绍一下背景。你身体中的每个细胞都经过优化，以执行高度专门化的任务。你的神经元有被称为轴突的长而细的结构，用于传递电信号。你的红细胞不含细胞核，因此有更多空间携带氧气。每个细胞最初都是一种谦逊的干细胞，具有成为任何细胞的潜力。我们曾经认为一旦干细胞经历了特化的过程，即分化，它就被永久地固定在那个状态上。

But a surprising discovery in 2006, by Japanese biologist Dr. Shinya Yamanaka changed that. His team used modified viruses to deliver 24 genes into adult skin cells. When the viruses entered the cells, they hijacked the cellular machinery and inserted their DNA into the host DNA. When these cells were left to grow, they became something else entirely. They now looked and behaved just like the stem cells found in embryos.

然而，2006年日本生物学家山中伸弥博士的一个惊人发现改变了这一切。他的团队使用修改后的病毒将24个基因引入成年皮肤细胞。当病毒进入细胞时，它们劫持了细胞机器，并将它们的DNA插入宿主DNA。当这些细胞继续生长时，它们变成了完全不同的东西。它们现在看起来和表现得就像胚胎中发现的干细胞一样。

The team tested combinations of the 24 genes until they were left with just four that were necessary for the reversal of an adult cell back to a stem cell. Those four genes created a type of protein that controlled if and how much of other genes were expressed. They changed the genes expressed in an adult skin cell into something very similar to an embryonic stem cell. The researchers called these incredible new cells induced pluripotent stem cells, or IPSC. Sluripotency means the ability to turn into almost any other type of cell.

团队测试了24个基因的组合，直到最终确定只有其中的四个是将成体细胞逆转为干细胞所必需的。这四个基因产生了一种蛋白质，能够控制其他基因的表达情况及其程度。他们将成体皮肤细胞的基因转变为与胚胎干细胞非常相似的细胞。研究人员将这些令人难以置信的新细胞称为诱导多能干细胞，即IPSC。多能性意味着这些细胞有能力转变成几乎任何其他类型的细胞。

IPSCs were immediately seen as a major breakthrough in stem cell biology. And researchers believed they had incredible medical potential. Just imagine an unlimited supply of specific cell types to repair an organ or tissue that wouldn't be rejected by the patient's immune system because they came from the patient. And to top it all off, IPSCs could be made without the tricky ethical issues that come with using stem cells from embryos, which had been the basis for much stem cell research up to that point.

IPSCs（诱导多能干细胞）被迅速认定为干细胞生物学的一个重大突破。研究人员相信它们具有令人难以置信的医学潜力。试想一下，我们可以无限制地获取特定类型的细胞，用于修复器官或组织，因为这些细胞来自患者自身，所以不会被患者的免疫系统排斥。更重要的是，IPSCs的制备过程不涉及棘手的伦理问题，而以胚胎干细胞为基础的研究在此之前一直存在。

The first clinical trial kicked off in 2013 with researchers making IPSCs from the skin cells of patients with macular degeneration. A condition where damage to the retina leads to loss of vision. The IPSCs were differentiated into retinal cells and transplanted into the eye of the first patient, whose vision improved. But the excitement that had been building over these cells was short-lived. The IPSCs generated from the second patient showed unexpected mutations. Due to safety concerns, the trial was immediately halted.

2013年，第一项临床试验开始了，研究人员从患有黄斑变性的患者的皮肤细胞中制造出iPSCs。黄斑变性是一种导致视力丧失的视网膜损伤状况。这些iPSCs被分化成视网膜细胞，并移植到第一位患者的眼睛中，其视力得到了改善。然而，对这些细胞的期望很快被打消了。从第二位患者产生的iPSCs出现了意外的突变。由于安全方面的顾虑，该试验立即停止了。

Now, that initial failure wasn't all that surprising. Something that it can take decades before scientific breakthrough results in something that people can actually use. But in the 16 years since IPSCs were discovered, there has been little progress on that front. Changing enough adult cells into IPSCs for cellular therapy turned out to be difficult. And genetic mutations have been a problem in subsequent trials. As of 2021, only 19 clinical trials have taken place that transplanted IPSCs into patients for therapeutic reasons. Of those, only one has advanced to the final phase of testing.

现在，最初的失败并不令人太惊讶。科学突破需要几十年才能真正被人们使用。但是自从发现诱导多能干细胞（IPSCs）以来的16年里，这一领域的进展很少。将足够数量的成体细胞转化为IPSCs以供细胞治疗一直很困难。而基因突变在随后的试验中也成为了一个问题。截至2021年，仅有19项临床试验将IPSCs移植到患者体内以进行治疗。其中，只有一项进入了最终的测试阶段。

But that's not the end of our story. Although research into the use of IPSCs for cell therapies stalled, they would soon lead to incredible advances in other areas. In those applications, the potential for genetic mutations or the technical difficulties of producing enough cells for use on humans weren't a problem. As we mentioned, IPSCs are very similar to embryonic stem cells.

但这并不是我们故事的结束。尽管对使用iPSCs进行细胞治疗的研究停滞不前，但它们很快在其他领域取得了令人难以置信的进展。在这些应用中，对基因突变的潜在风险或生产足够用于人类的细胞的技术难题并不是问题。正如我们提到的，iPSCs与胚胎干细胞非常相似。

This has allowed researchers to create embryo-like structures that mimic the early stages of human development about two weeks after an embryo has been implanted into the uterus. These structures are organized into the three layers of different cell types that give rise to tissues and organs. They can be used to study the incredibly complex biological processes of early development like organ formation and the development of the nervous system. Hopefully, this will help us understand why things go wrong during that stage of development like heart defects that are present from birth. Until IPSCs came along, we weren't able to study things like that due to an international policy that says embryos can't be used for research more than 14 days after fertilization.

这一技术允许研究人员在胚胎植入子宫后约两周的时间内，创建出类似胚胎的结构，模拟人类早期发育阶段。这些结构由不同细胞类型组成的三个层次组织，可以产生组织和器官。它们可以用来研究早期发育的极其复杂的生物过程，如器官形成和神经系统发育。希望这将有助于我们了解为什么在那个发育阶段会出现问题，比如从出生起就存在的心脏缺陷。在诱导多能干细胞技术出现之前，由于国际政策规定受精后超过14天的胚胎不能用于研究，我们无法研究这类事物。

And it doesn't stop there. IPSCs can also be used to study diseases in a dish. Take Parkinson's, for example. By the time it's diagnosed, most of the patients dopamine-releasing neurons in a critical area of the brain called the substantia nigra are already lost. Researchers have made IPSCs from the skin and blood cells of patients with Parkinson's using similar methods to those we described earlier. This has allowed them to grow an abundant supply of that kind of neuron, study why they're dying, and even test potential new drugs on those cells before moving into clinical trials.

而且这还不止于此。可编程诱导多能干细胞（IPSCs）还可以用于“病变盘中研究”。以帕金森病为例，当它被诊断出来时，患者大脑中一种被称为黑质致密部位的多巴胺释放神经元大多已经丧失。研究人员使用我们前面提到的类似方法，从帕金森病患者的皮肤和血细胞中制备出IPSCs。这使得他们能够大量培育出这种神经元，并研究它们为何会死亡，甚至在进入临床试验之前在这些细胞上测试潜在的新药物。

In the future, this might lead to more personalized medicine where your IPSCs are used to test what treatment works best for you. IPSCs are even on their way to tackling organ donor shortages. Cells generated from mice have been inserted into rat embryos, which were genetically edited so the rat could no longer grow a pancreas. The mouse IPSCs filled the empty niche growing into a pancreas. In theory, we can use the same technique to grow human organs in animals like pigs. But we're not quite there yet. Human IPSCs have been successfully incorporated into pig embryos before, but in small numbers. So there are a few more kinks to iron out before we can grow a full custom organ.

在未来，这可能会导致更个性化的医学，其中您的诱导多能干细胞（IPSCs）将被用于测试哪种治疗对您最有效。IPSCs甚至正在解决器官捐献短缺的问题。通过将从小鼠中生成的细胞插入经过基因编辑的大鼠胚胎中，使大鼠无法生长胰腺，小鼠的IPSCs填补了空缺，生长成了胰腺。理论上，我们可以使用相同的技术在像猪一样的动物体内培育人类器官。但我们还没有到达那个程度。人类IPSCs曾成功地并入猪胚胎，但数量有限。因此，在我们能够培育出完整的定制器官之前，还有一些问题需要解决。

In 2012, Shenya Yamanaka won the Nobel Prize in Physiology or Medicine for his discovery of IPSCs. At the time, IPSCs were promised as the future of cell therapies, but their true value was unexpected. They've changed how scientists approach many other aspects of biological research forever. Like that TV show with a wicked twist, IPSCs have delivered a satisfying ending no one could have predicted. I can't wait for season 2.

2012年，山中伸弥因为他发现诱导性多能干细胞（IPSCs）而获得诺贝尔生理学或医学奖。当时，IPSCs被誉为细胞治疗的未来，但其真正的价值是出乎意料的。它们彻底改变了科学家对生物研究的许多其他方面的方法。就像一部有意料不到结局的电视剧，IPSCs带来了无法预料的令人满意的结局。我迫不及待地期待第二季。

I also can't wait for this month's SciShow Space Pin. And you shouldn't wait because it's going away at the end of the month and will never come back. The November Pin features Near Shoemaker, a NASA mission designed to meet up with an asteroid near Earth. And when this pin is no longer available at the end of the month, there will be another one for you, specially made for December. And what do you do with these pins you ask? Put them on your fancy new pinboard. You can find the pin and pinboard at dftba.com slash SciShow and the link in the description down below. They come separately or bundled. Thanks for taking a look.

我也迫不及待地想要这个月的《科学秀空间团队徽章》。而且你也不应该再等待了，因为这个徽章将在本月底消失，再也不会再回来了。11月份的徽章以“近亲鞋匠”（Near Shoemaker）为特色，这是一项NASA任务，旨在靠近地球附近的一颗小行星。当这个徽章在本月底不再可用时，将会有一个专门为你制作的12月份徽章。那么你可能会问，你可以拿这些徽章做什么呢？把它们放在你那时髦的新针板上。你可以在dftba.com/SciShow（或链接在下面的描述中）找到这个徽章和针板。它们可以分开购买，也可以捆绑购买。感谢你的关注。