A New Era of Medicine with iPS Cells - Lecture by Professor Shinya Yamanaka - YouTube

I'd like to express my sincere thanks to Eva Stihl of Oslo, AstraZeneca and Nobel Media for having this great opportunity. So as you had in the introduction I started my career as a sergeant, a long time ago, almost 30 years ago, and I started my presentation with a picture of a person, of a man who I respect the most. Actually because of him I became a doctor, a sergeant. This is the person.

我想向奥斯陆的伊娃·斯蒂尔、阿斯利康和诺贝尔媒体表示真挚的感谢，感谢他们给予我这个非常好的机会。正如在介绍中提到的，我职业生涯的起点是一个警长，那是差不多30年前的事了，而我在演讲开始时用一张图片展示了我最尊敬的人，实际上，正是因为他，我成为了一名医生，一名警长。这就是那个人。

Do you know him? Have you seen him in textbooks? I don't think so because this is my father. So I think he is very handsome. I like his hair actually. I'm envious. So my father was not a doctor or a scientist. He was an engineer. He had a small factory and when I was a junior high school student he got a small injury while he was working on his own factory which resulted in blood transfusion. So his injury itself was okay but because of this blood transfusion after that he suffered from hepatitis. Other time he was diagnosed as non-A, non-B hepatitis.

你认识他吗？你在课本中见过他吗？我不认为你见过，因为他是我的父亲。所以我认为他很帅。事实上，我喜欢他的头发。我很羡慕。所以我的父亲并不是医生或科学家。他是一名工程师。他有一家小工厂，当我上初中时，他在自己的工厂工作时受了点小伤，结果需要输血。他的伤口本身没事，但是由于这次输血后，他患上了肝炎。后来被诊断为非A型、非B型肝炎。

So we didn't really not know the cause of his illness. Because we did not know the cause of his illness, of course there was no cure for his illness, non-B hepatitis. So he became worse and worse. He suffered from liver cirrhosis. Then he started saying me, you should become a doctor. You don't have to take over my own business but you should become a doctor. I don't know why he said so or because I was his own son.

所以我们实际上并不知道他生病的原因。因为我们不知道他生病的原因，当然就没有对他的非B型肝炎治疗方法。因此，他的病情越来越严重。他患有肝硬化。然后他开始告诉我，你应该成为一名医生。你不必接管我的生意，但你应该成为一名医生。我不知道他为什么这么说，也许是因为我是他的儿子。

So I was supposed to succeed his business but he told me not to do that instead he told me to be a doctor. So I listened to him and became a doctor. I in 1987. At that time he was very sick. He must have in pain but when I gave him some small medical procedure like some transfusion he seemed to be very happy. Even smiling by receiving medical procedure from his own son. So I thought he must be very proud of his own son becoming a doctor. Unfortunately however he passed away next year. So he passed away in 1988 when I was 26 years old. So I still needed him a lot.

所以我本来应该接手他的生意，但是他告诉我不要这么做，相反他告诉我要成为一名医生。所以我听从了他的话，成为了一名医生。那是1987年。那个时候他病得很重，他一定很痛苦，但是当我给他做一些小的医疗程序，比如输血时，他看起来非常高兴，甚至笑着接受儿子为他进行医疗程序。所以我觉得他一定为自己的儿子成为一名医生感到非常自豪。然而不幸的是，他在接下来的一年去世了。所以他在1988年去世的时候，我只有26岁，我还非常需要他。

So that his passing was very shocking to me. I felt very powerless, useless. I became a doctor but I couldn't help my own father. That was I believe one of the main reasons why I decided to change my career from a surgeon to your scientist. Because I believe it is a medical science who can help those patients like my father who are suffering from intractable diseases.

他的离世对我来说非常令人震惊。我感到非常无助，无用。我成为了一名医生，却无法帮助自己的父亲。这是我决定从外科医生转行成为一名科学家的主要原因之一，因为我相信医学科学可以帮助那些患有顽固性疾病的患者，就像我父亲一样受苦的患者。

So let me talk a little bit about my own my father's illness. One year after my father passed away this virus was identified in US. Hepatitis C virus. It was identified in 1988 1987. I'm sorry 1989 I believe. Still in Jatrak I'm sorry. Because now that this virus hepatitis C virus was identified many researchers jumped into researchers trying to find cures or hepatitis C. And thanks to those many researchers very recently we have a cure. We now have this sorry this is in Japanese but this is harmony.

让我稍微谈谈我父亲的疾病。在我父亲去世一年后，这种病毒在美国被鉴定为丙肝病毒。它在1987年1988年被鉴定出来，对不起，我觉得是1989年。对不起，我在打岔。因为现在丙肝病毒被鉴定出来了，许多研究人员投入研究，试图找到治疗丙肝的方法。多亏了这些研究人员，最近我们终于有了一种治愈方法。现在我们拥有了这个（对不起，这是日语，这是“和谐”）。

This is a very nice medicine for hepatitis C. Just one tablet each day can cure almost 100 100% patients suffering from hepatitis C virus. One tablet for three months that's all you need to do. So it's like a miracle. So this is what we medical scientists want to achieve. We want to overcome diseases by doing science. This is what we want to do and this hepatitis C the history of hepatitis C is a good example of a success of medical science because now we have overcome hepatitis C thanks to basic medical science. So this is very good.

这是一种非常好的治疗丙型肝炎的药物。每天只需一片药，就可以治愈几乎100% 的丙型肝炎病毒感染患者。只需连续三个月服用这种药物，就能达到治愈的效果。所以可以说简直像是一个奇迹。这正是我们医学科学家所希望实现的目标。我们希望通过科学手段战胜疾病。丙型肝炎的历史是医学科学成功的一个很好的例子，因为现在我们已经成功克服了丙型肝炎，这要归功于基础医学科学。所以这非常好。

At the same time the history of hepatitis C clearly shows two problems. Two hurdles we have. We medical scientists are facing two issues. The first one issue was that the virus was identified in 1989 and the cure was developed in 2014. So it took 25 years. It took too long. Well science did overcome but it just took too long. This is the first hurdle we are facing. We have another hurdle. We have another problem in medical science. How much do you think this one tablet cost? This is a small tablet. Very small. It costs 500 US dollars. I believe it's 3,800 grown up in this country. One tablet. So you need to multiply 90. So it's too expensive. So these are the two issues we are facing. It takes too long and it's too expensive. So overcoming these two programs is as important as overcoming diseases itself.

同时，丙型肝炎的历史清楚地显示了两个问题。我们所面临的两个障碍。作为医学科学家，我们面临两个问题。首先，这个病毒在1989年被鉴定出来，治愈方法在2014年才被开发出来。所以花了25年的时间。这太长了。尽管科学最终取得了突破，但这个过程实在太长了。这是我们所面临的第一个难题。我们还有另一个难题。在医学科学中还存在另一个问题。你认为这种小药片要多少钱？这是一片很小的药片。非常小。它的价格是500美元。我相信在这个国家要花3800美元。一片药片而已。所以你需要乘以90。这太贵了。所以这些都是我们所面临的两个问题。时间太长而且价格太高。因此，克服这两个问题和克服疾病本身一样重要。

Let me go back to my own science. I did I was not involved at all in hepatitis C research. I got my PhD in Japan and I did my postdoc in San Francisco where I met ESL's embryonic stem cells. Since then I have been working on embryonic stem cells but I realized a big skull issue about human embryonic stem cells. That is we need to use human embryos to generate human ESL's. So I tried we worked hard to overcome that skull issue about the usage of human embryos. Then in 2006 we were able to publish this paper.

让我回到我的研究领域吧。我从未参与过丙型肝炎的研究。我在日本获得了博士学位，并在旧金山做了博士后，那里我接触到了ESL的胚胎干细胞。从那时起，我一直在从事胚胎干细胞的研究，但我意识到了人类胚胎干细胞存在的一个重要问题，那就是我们需要使用人类胚胎来培养人类胚胎干细胞。所以，我们努力尝试克服这个问题。然后在2006年，我们成功地发表了这篇论文。

From mouse skin fiberglass we became able to convert skin fiberglass into stem cells that are nearly indistinguishable from embryonic stem cells. We designated this new type of stem cells IPS cells for induced pre-important stem cells. So the procedure was very simple. All we need is a combination of four transcription factors that listed here. Oaked 3-4, Sockstoo, K-L-Fol, C-MIC. We now know C-MIC is indispensable. So basically three factors can convert skin cells back into IPS cells stem cells.

通过小鼠皮肤玻璃纤维，我们能够将皮肤玻璃纤维转化为与胚胎干细胞几乎无法区分的干细胞。我们将这种新型干细胞命名为诱导前重要干细胞（IPS）细胞。因此，该程序非常简单。我们只需使用以下四种转录因子的组合。Oaked 3-4，Sockstoo，K-L-Fol，C-MIC。我们现在知道C-MIC是不可或缺的。因此，基本上三种因子就可以将皮肤细胞转化回IPS细胞干细胞。

In the following year 2007 we were able to recapitulate same procedure in human adult skin cells. So by having the same combination we can convert human skin cells back into stem cells IPS cells. So that means we can make your own IPS cells from each of you. The procedure is actually surprisingly simple. We had a hard time to believe in the beginning. So but we repeated the same experiment again and again and to our surprise it was it is very reproducible. So in the beginning we used skin fiber brush to generate IPS cells. But now we can make IPS cells from many types of somatic cells. The most frequently used cells as an origin of IPS cells is this cell. Brat. More precisely Brat lymphocytes. So all you need is just one vial like 10 ml or 20 ml of Brat, peripheral Brat sample. From this by adding that combination of three or four factors we can convert lymphocytes into IPS cells.

在接下来的2007年，我们成功地在人体成年皮肤细胞中重复了同样的过程。通过使用相同的组合，我们可以将人体皮肤细胞转化回干细胞，即诱导多能干细胞（IPS细胞）。这意味着我们可以从每个人身上制造出自己的IPS细胞。而该过程实际上非常简单，一开始我们都难以相信。但通过反复重复同样的实验，我们惊讶地发现这个过程非常可靠。最初我们使用皮肤纤维刷来产生IPS细胞，但现在我们可以从多种体细胞中制造IPS细胞。最常用的来源细胞就是这一种，即Brat细胞，更准确地说是Brat淋巴细胞。所需的只是一小瓶Brat，大约是10毫升或20毫升的外周Brat样本。通过添加三种或四种因子的组合，我们就可以将淋巴细胞转化为IPS细胞。

As you know lymphocytes cannot proliferate to a large amount. We can expand a little bit but that's a rare limitation. And also of lymphocytes no matter how long we wait they are lymphocytes. They cannot become a heart cell or brain cell. But by adding those transcription factors we can convert Brat cells into IPS cells. So this is a colony of IPS cells. I believe we have approximately 500 IPS cells in this one tiny colony. Each IPS cell is like 10 micro meter. So one of the smallest cells. One of the smallest cells. But they are very small in size but the potential is enormous. Once again they have two very important properties. First of all we can expand IPS cells as much as we want. As you may know we capture IPS cells or other types of cells in this kind of plastic dish, petri dish, like 10 centimeter. From a very small amount of Brat cells we can have hundreds or even thousands of petri dishes containing IPS cells. Your own IPS cells.

正如你所知，淋巴细胞无法大量增殖。我们可以稍微扩张一点，但这是一个罕见的限制。而且，无论我们等待多长时间，淋巴细胞还是淋巴细胞。它们无法成为心脏细胞或大脑细胞。但通过添加这些转录因子，我们可以将Brat细胞转化为IPS细胞。所以这是一个IPS细胞的群体。我相信在这个微小的群体中大约有500个IPS细胞。每个IPS细胞大约有10微米大，属于最小的细胞之一。尽管它们非常小，但潜力巨大。再次强调，它们具有两个非常重要的特性。首先，我们可以根据需要扩大IPS细胞。你可能知道，我们可以将IPS细胞或其他类型的细胞捕捉在这种塑料培养皿中，比如10厘米的培养皿。从一小部分的Brat细胞，我们可以获得数百甚至成千上万个含有IPS细胞的培养皿。这些是你自己的IPS细胞。

And after expanding to a large amount by treating these IPS cells with some side kinds, growth hormones we can convert IPS cells into many types of cells. For example we can make this kind of beating hot cells in hundreds of petri dish from IPS cells. They are beating they synchronize. So we can see them beating even without microscope. Considering these cells used to be skin or Brat cells even now I feel a bit strange whenever I see them beating. They have stopped. So once again our vision is to overcome diseases by doing science. So by using IPS cells we can we want to overcome intractable diseases. There are two major ways to do that. One is regenerative medicine also known as cell therapy. The other application is drug development.

并且通过使用一些副作用种类的生长激素，我们可以将这些诱导多能干细胞扩展到大量数量，将其转化为多种类型的细胞。例如，我们可以从诱导多能干细胞中在数百个培养皿中制造出这种跳动的心脏细胞。它们可以同步跳动，所以即使不用显微镜，我们也可以看到它们跳动的情景。考虑到这些细胞过去曾是皮肤细胞或胚胎细胞，即使现在我看到它们跳动，仍然感到有些奇怪。它们已经停止了。所以我们的目标再次是通过科学方法来战胜疾病。因此，通过使用诱导多能干细胞，我们想要战胜难治性疾病。有两种主要的方法来实现这一目标。一个是再生医学，也被称为细胞疗法。另一个应用领域是药物开发。

So for example my father passed away from liver failure. We could help patients suffering from end stage liver failure by transplanting rivers. But in countries like Japan organ transplantation is next to impossible because in Japan brain death is not accepted. So like liver or heart transplantation is very very very limited in Japan. But by applying this technology we can make IPS cells from my father's blood cells. We can expand my father's IPS cells as much as we want. Then we can convert at least in theory my father's IPS cells into his liver cells. And then I instead of in state of liver organ we can transplant healthy liver cells back into my father back into patients. So that's how we do in regenerative medicine. Also by using this technology we can prepare a large amount of human liver cells. Otherwise it is very next to impossible to obtain a large amount of human liver cells. I believe that was one reason why it took 25 years for drug company to develop harmony.

例如，我父亲因肝衰竭而去世。我们可以通过移植肝脏来帮助患有晚期肝衰竭的患者。但在日本等国家，器官移植几乎不可能实现，因为日本不接受脑死亡的概念。所以在日本，肝脏或心脏移植非常非常受限。但通过应用这项技术，我们可以使用我父亲的血细胞生成诱导多能干细胞（IPS细胞）。我们可以无限扩展我父亲的IPS细胞。然后，理论上至少可以将我父亲的IPS细胞转化为他的肝细胞。然后，我们可以将健康的肝细胞移植回我父亲或其他患者的身体，取代受损的肝脏器官。这就是再生医学的做法。此外，通过使用这项技术，我们可以制备大量的人类肝细胞。否则，获取大量人类肝细胞几乎不可能。我相信这也是药物公司花费25年开发Harmony的一个原因。

With this technology now we can have researchers at pharmaceutical companies like AstraZeneca have a large amount of human liver cells heart cells or brain cells. So that should facilitate drug development. So with this technology I believe we could have certain that 25 years. I don't know how much it could be I don't know 20 years or maybe 15 years. But that's how IPS cells can contribute to drug development. So let me give you a few more examples about each of these two major medical applications.

现在有了这项技术，制药公司如阿斯利康可以拥有大量的人类肝细胞、心脏细胞或脑细胞，这将有助于药物研发。所以我相信，凭借这项技术，我们在25年内能够实现某种成果。我不知道具体需要多长时间，也许是20年或者15年。但这就是诱导多能干细胞在药物研发中的作用。接下来，我将给你举几个关于这两个主要医学应用的例子。

Let me begin with regenerative medicine. It's been 10 years since we reported the first generation of human IPS cells. Two my supplies, one researcher, one group in Japan has already studied a clinical trial using human IPS cells. That is Dr. Masayo Takahashi. She is an ophthalmologist and also very famous neuro scientist. So she has been working on age-related molecular degeneration in which a layer of retinal cells known as retinal pigmented or severe cells becomes degenerated because of aging. Because of that patients are losing vision.

让我从再生医学开始。自我们报道了第一代人类诱导多能干细胞（IPS细胞）以来已经过去了10年。在日本，一位研究人员、一个研究小组已经开始研究使用人类IPS细胞进行临床试验。这位研究人员是高桥真绘博士。她是一名眼科医生，也是一位非常著名的神经科学家。所以她一直在研究与年龄相关的视网膜细胞分解，即视网膜色素上皮细胞层因为衰老而损失功能。因此，患者失去了视力。

Her team, Dr. Masayo Takahashi's team, generated IPS cells from patients on skin cells and then they converted IPS cells into a sheet of retinal pigmented or severe cells which is shown in this petri dish. And they transplanted this small piece of epsilon pigment, retinal pigmented or severe cells back. They transplanted this small sheet back into patients eye. They performed the first clinical trial, first surgery almost three years ago in 2014 and the patient is doing very well. Before the surgery her vision was getting worse and worse every month but after this surgery it stopped. So her vision is now very stable whereas the opposite side to which she did not get this surgery it is almost rinded by now. So I would say this first transplantation went very well, was very successful.

她的团队，高桥雅代博士的团队，利用患者的皮肤细胞生成了诱导多能干细胞（iPS细胞），然后将这些iPS细胞转化为一层显示在培养皿中的视网膜色素或严重细胞组织。随后，他们将这小块ε（伊普西龙）色素、视网膜色素或严重细胞组织移植回患者的眼睛中。他们在近三年前的2014年进行了第一次临床试验，第一次手术，患者状况非常良好。手术之前，她的视力每个月都在恶化，但是手术之后就停止了。因此，她的视力现在非常稳定，而没有进行手术的另一侧几乎已经完全失明了。所以我可以说这次第一次移植非常成功。

However she stopped after this first patient. There are two major reasons. One reason was legal reason. In 2015 our country Japan established a new law regarding regenerative medicine to ensure the safeness of regenerative medicine. Because of that new law or Dr. Masayo Takahashi had to start from the beginning all paper works. So that was one reason she had to postpone this clinical trial. But there's one more scientific reason. We helped this clinical trial or in many aspects and we found this kind of cell therapy using patients on IPS cells was too expensive. It took almost one million US data for just one patient. So we thought it was too expensive and it took almost a year to do all the processes required to generate IPS cells from the patients to do quality control of IPS cells to differentiate IPS cells into retinal cells and to do final quality checks of retinal pigmented figure cells prior to transplantation. In total it took almost a year. Within that year patients condition can change. For other patients like patients suffering from heart failure or a liver failure many of them cannot wait for one year. They may die. So once again the cost and also all time required for autorogous transplantation was the biggest part of we run from this first clinical trial.

然而，在这第一位患者之后，她停止了临床试验。有两个主要原因。一个原因是法律原因。2015年，我们国家日本制定了一项新的再生医学法律，以确保再生医学的安全性。由于这项新法律，高桥政代博士不得不从头开始所有的文件工作。这是她推迟这项临床试验的一个原因。但还有一个科学的原因。我们在许多方面帮助了这项临床试验，我们发现使用患者的iPS细胞进行细胞疗法太昂贵了。仅一个患者就需要将近100万美元的资金。我们认为这太昂贵了，并且需要将近一年的时间完成从患者获取iPS细胞、质量控制iPS细胞分化为视网膜细胞以及移植前对视网膜色素上皮细胞进行最后的质量检查所需的所有流程。总共需要将近一年的时间。在这一年中，患者的病情可能会发生变化。对于像心力衰竭或肝功能衰竭的患者，他们中的许多人无法等待一年。他们可能会死亡。所以，成本和自体移植所需的全部时间再次成为我们放弃这个第一个临床试验的最大原因。

In order to overcome those two practical hurdles we are now working on this project. IPS cell stock for regenerative medicine. So in this project instead of making IPS cells from patients on red or skin cells we are making IPS cells from healthy donors. So it's alografts. It's not autorogous transplantation. Since it's not autorogous transplantation we can save time and money of course but we need to overcome immune rejection because we don't use patients on IPS cells.

为了克服这两个实际障碍，我们现在正在进行这个项目，即再生医学中的IPS细胞储备。所以在这个项目中，我们不是从患者的红细胞或皮肤细胞中制造IPS细胞，而是从健康捐赠者中制造IPS细胞。因此，这是异体移植，而不是同体移植。由于不是同体移植，当然可以节省时间和金钱，但我们需要克服免疫排斥问题，因为我们不使用患者的IPS细胞。

In order to minimize immune rejection we need to match immunological type between donor and recipient. More precisely we need to match HLA haplotype. However HLA haplotype is very diverse. There are more than 10,000 haplotypes. So none of you in this audience has the identical or HLA haplotype unless we have identical twin in this room. So that means we need to prepare thousands of IPS cell stocks. It's not practical.

为了尽量减少免疫排斥反应，我们需要在捐献者和受体之间匹配免疫类型。更准确地说，我们需要匹配HLA单倍型。然而，HLA单倍型非常多样化。有超过10,000个单倍型。因此，除非在这个房间里有相同的双胞胎，否则在座的每个人都没有完全相同的HLA单倍型。这意味着我们需要准备成千上万个IPS细胞库存。这是不现实的。

Instead we are making IPS cells from so-called super donors. Super donors HLA homozygous donors. I won't go in detail but those super donors are super because when we transplant their cells like IPS cell derived retinal cells, IPS cell derived brain cells into recipients. We can minimize. We can expect very small amount of immune rejection. So that's why we call them super donors. So we are now making IPS cells from these super donors.

相反，我们正在从所谓的超级供体中制造诱导多能干细胞（IPS细胞）。超级供体的特点是HLA基因纯合体。我不详细解释，但这些超级供体之所以被称为超级，是因为当我们将他们的细胞（如IPS细胞派生的视网膜细胞、IPS细胞派生的脑细胞）移植到受体体内时，我们可以最大程度地减少免疫排斥的可能性。所以我们称他们为超级供体。因此，我们现在正在从这些超级供体中制造IPS细胞。

But super donors are very rare. It's usually one out of like 500 people. So we may have one or two super donors in this audience. But in order to identify those one or two super donors from this audience, we have to determine HLA haplotypes of all of you. It's a lot of work. But very likely we are now getting help from Japan Red Cross who has been working on programs like Phraytret transfusion or bone marrow transplantation and also called blood banks. So that means they have a huge database of Japanese HLA haplotypes already. Close to a million Japanese people. So now that we can access to their huge HLA database, we can easily identify these super donors.

但是超级捐赠者非常稀少。通常，500人中可能只有一个。所以在这个观众中可能有一两位超级捐赠者。但是为了从这个观众中找出那一两位超级捐赠者，我们必须确定你们所有人的HLA单体型。这需要很多工作。但很可能我们现在得到了日本红十字会的帮助，他们一直在进行Phraytret输血或骨髓移植等项目，也被称为血库。这意味着他们已经有了一个庞大的日本人HLA单体型数据库，接近100万人。现在我们可以访问他们的巨大HLA数据库，轻松地找出这些超级捐赠者。

So once we identify these super donors, we get informed consent from those potential donors. And once we get consent, we get blood samples. Then we transfer those blood samples in our CPC cell processing facility in our research institute in Kyoto, where we are making clinical grade, GMP grade IPS cells. We have enough time to perform rigorous quality check and we only ship high quality IPS cells stocks to other researchers in academia as well as industries. So far we have generated IPS cells, clinical grade IPS cells from two super donors. I would say they are super super donors. Because just two donors IPS cell lines from just two donors can cover up to 30% of all the Japanese population. So that means just two donors, they could help up to 30 million Japanese people. So they are really super super super. So once again, this is the process of autologous IPS cell transplantation. Once again, it took too long and it is too expensive. But by applying the IPS cell stock project, we can skip this initial portion. So that means we can lower the cost and we can save time tremendously.

一旦我们确定了这些超级捐赠者，我们会从他们那里获得知情同意。一旦获得同意，我们就会获得血样。然后我们将这些血样转移到我们在京都的研究机构中的CPC细胞加工设施，我们正在生产临床级、GMP级IPS细胞。我们有足够的时间进行严格的质量检查，只向学术界和工业界的其他研究人员提供高质量的IPS细胞库存。到目前为止，我们已经从两个超级捐赠者培养出了临床级IPS细胞。我可以说他们是超级超级捐赠者。因为仅两个捐赠者的IPS细胞株就可以覆盖日本人口的30％。这意味着仅仅两个捐赠者就可以帮助到3000万日本人。所以他们真的是超级超级超级的。所以再一次，这就是自体IPS细胞移植的过程。再一次，这个过程太长时间并且太昂贵。但通过应用IPS细胞库存项目，我们可以跳过这一初始阶段。这意味着我们可以降低成本并极大地节省时间。

Once again, we have already shipped IPS cells stocks from two super donors and to our deride, the same doctor, Dr. Masao Takahashi has already studied clinical trial using our IPS cells stocks. She performed operation this March, March 28th this year. So because this is allografts, this utilizes IPS of stocks. That means we can transplant cells to many patients simultaneously. In autologous transplantation, we can do only one by one. So it will take very long. But because this is autografts, we can transplant to multiple patients. We see studied this first patient in March, but she has performed many more patients already. It's she will publish it when it's ready, but I would say she's doing multiple patients by now.

再次，我们已经从两个超级捐赠者那里寄出了iPS细胞库存，并令我们惊喜的是，同一位医生，髙桥真生博士，已经开始使用我们的iPS细胞库存进行临床试验了。她在今年3月28日进行了手术。因为这是异体移植，所以利用了iPS细胞库存。这意味着我们可以同时将细胞移植给多个患者。在自体移植中，我们只能逐个进行。所以这将花费很长时间。但是因为这是同种移植，我们可以向多个患者移植。我们在三月份研究了第一个患者，但她已经进行了更多的患者治疗。她会在准备好后发表相关研究结果，但我可以说目前她正在治疗多个患者。

In addition to retinal disease, many projects are going on. In Japan and also in many other countries using IPS of stocks. For example, Parkinson's disease, like corneal disease, heart failure, spinal cord injury, blood transfusion, cancer, and also arthritis. Blood transfusion. Now we can get enough blood from donuts, healthy, young donuts. But as you know, Japan is a growing society. Japan is probably the fastest fastest test in terms of aging. And also we are having less and less younger generation. So in countries like Japan, we are facing a huge problem. In five years, we will short on blood donuts. So millions of people will die because of the shortage of blood transfusion. It's a huge, huge problem. So this application, we are now making predicates as well as red blood cells from IPS cells. This should help that kind of shortage of blood donuts. And also we can make T lymphocytes attacking cancer cells from IPS cells. That would facilitate cancer immunotherapy, which is a very trendy therapy in cancer.

除了视网膜疾病外，还有许多项目正在进行中。在日本以及许多其他国家，使用股票的IPS进行研究。例如，帕金森病、角膜疾病、心脏衰竭、脊髓损伤、输血、癌症以及关节炎等。现在我们可以从健康、年轻的捐献者那里得到足够的血液。但正如你所知，日本是一个人口老龄化的社会，也是老龄化最快的一个国家。同时，年轻一代的人越来越少。所以在像日本这样的国家，我们面临着一个巨大的问题。五年内，我们会出现短缺血液的情况。因此，数百万人将因为血液短缺而丧命。这是一个巨大的问题。因此，我们正在利用IPS细胞制造血小板和红细胞，这应该可以缓解血液短缺的问题。同时，我们还可以利用IPS细胞制造攻击癌细胞的T淋巴细胞。这将有助于癌症免疫疗法的发展，这是癌症领域一种非常流行的疗法。

So let me move on to the second application of IPS cells. It's about drug development. So as I mentioned previously, we can prepare a large amount of human liver cells, heart cells, and brain cells. Those cells can be utilized in any types of drug development. For example, like Alzheimer's disease. But in today's presentation, I would like to focus on another type of diseases, which is known as rare diseases. One example is this, ALS, aneotropic lateral sclerosis. This is a form of motor neuron diseases. So this is a typical symptoms of patient. The patients progressively lose their muscle movement, beginning with their fingers. Then move to their speech. In the end, they cannot breathe without help of the sprayer. Because motor neurons progressively die, they cannot. So the brain message cannot be transmitted to peripheral muscle. So muscle itself is not sick. It's motor neuron disease. But because of that, they the muscle become very atrophy. In US, this disease is well known as luogeric disease. Luogeric was a very famous and popular baseball player, long time ago, 70 years ago. But in one season, he suddenly became unable to hit well. So everybody, including himself, thought he was in slump. But in reality, he suffered from this LS. And he had to retire because of LS. And he passed away just a few years later. So this became a very popular movie in US. So that's why this disease is well well known as luogeric disease in US. It's been more than 100 years since we got to know about LS. Many scientists have been fighting with LS in order to overcome this terrible disease.

让我继续谈谈干细胞的第二个应用领域，药物研发。正如我之前提到的，我们可以制备大量的人类肝细胞、心脏细胞和脑细胞。这些细胞可以在任何类型的药物研发中使用。例如，像阿尔茨海默病这样的疾病。但在今天的介绍中，我想专注于另一种疾病，即罕见病。一个例子是杰拉西病，一种运动神经元疾病。这是患者的典型症状。患者逐渐失去肌肉运动能力，从手指开始，然后是语言，最后，在没有喷雾器帮助下无法呼吸。由于运动神经元逐渐死亡，大脑的信息无法传递到周围肌肉。肌肉本身并不生病，而是运动神经元疾病。但由于这个原因，肌肉会萎缩。在美国，这种疾病被称为路加病。路加是一个非常有名且受欢迎的棒球运动员，很久以前的事了，大约70年前。但在一个赛季里，他突然无法打得好。每个人，包括他自己在内，都认为他是在低谷期。但实际上，他患有这种运动神经元疾病。而且他不得不因为这种疾病而退役。几年后，他就去世了。所以这在美国成为了一部非常受欢迎的电影。这就是为什么这种疾病在美国被称为路加病。我们知道杰拉西病已经有100多年了。许多科学家一直在与这种可怕的疾病作斗争，以克服它。

But this is. it has been unsuccessful. So this is kind of a symbol of a failure of medical science. We have a mouse model of LS. And many scientists and many companies have developed very effective drugs for mouse patients. But unfortunately, the same drug did not work at all on human patients. So in the case of LS, we need to work on human motor neurons, not mouse models.

但是，事实并非如此。这是一种失败的医学科学的象征。我们有一个LS的小鼠模型。许多科学家和公司已经开发了对小鼠患者非常有效的药物。但不幸的是，同样的药物在人类患者身上根本没有效果。所以在LS的情况下，我们需要研究人类运动神经元，而不是小鼠模型。

But as you can imagine, it is next impossible to obtain human motor neurons. Because if you get motor neurons from donors, the donor will lose his ability to move his muscle or her muscle. So we cannot do that. We may be able to obtain motor neurons after during autopsy. But motor neurons do not proliferate at all. They are terminally differentiated. So we cannot do a large experiment on such motor neurons. That's probably the major reason why it's been unsuccessful in fighting with LS.

但正如你可以想象的，要获得人类运动神经元几乎是不可能的。因为如果从捐献者处获得运动神经元，捐献者将失去他/她的肌肉运动能力。所以我们不能这样做。我们可能可以在尸检时获得运动神经元。但运动神经元根本无法增殖。它们是最终分化的。所以我们不能对这样的运动神经元进行大规模实验。这可能是为什么在与横纹肌萎缩症的斗争中一直未能成功的主要原因。

But now we can use IPSS. Many researchers in the world are now making IPSS from LS patients. And also they are successfully making motor neurons from patients' IPSS, including Haru Hisa Inoue, one of my colleagues. He is a neuro-herologist who have been working on LS patients. So even before, we reported our mouse IPSS generation. He saw many LS patients. Many of them died. But he took skin fiber breasts from those patients. Hoping in future, those skin fiber breasts would help. But at that time, there was no way to utilize those skin fiber breasts because they are not motor neurons. But as soon as we published our mouse paper, he came to me and we studied long-lasting collaboration. So as soon as we successfully generated human IPSS cells, he utilized his patients' skin fiber breasts in another protocol. So he was one of the first to generate LS patient IPSS cells.

现在我们可以使用IPSS了。世界上许多研究人员正在从LS患者中制造IPSS。他们还成功地从患者的IPSS中制造出运动神经元，包括我的同事Haru Hisa Inoue。他是一位一直在研究LS患者的神经学家。所以即使在此之前，我们报告了我们的小鼠IPSS的生成，他也看到了许多LS患者，其中许多人去世了。但他从这些患者那里获取了皮肤纤维组织，希望未来能有所帮助。但在那个时候，没有办法利用这些皮肤纤维组织，因为它们并不是运动神经元。但是在我们发表了我们的小鼠论文后，他来找我，我们进行了长期合作研究。所以在我们成功生成人类IPSS细胞后，他使用他的患者的皮肤纤维组织进行了另一项实验。所以他是最早生成LS患者IPSS细胞的人之一。

So in this disease, usually patients are fine until their 50s or 60s. So we thought probably it would take very long to recapture disease by using IPSS-derived motor neurons. If we culture them for 50 years in Petri dish, we may be able to recapture it. We may be able to shorten by giving motor neurons some kind of stress. But in reality, our prediction was wrong in a good way. As soon as they took the nowhere, generated motor neurons from patients' IPSS cells, they start dying automatically without any stimulation. Whereas motor neurons from healthy IPSS cells, motor neurons wouldn't die. So that means we can recapture it. Motor neuron disease in Petri dish, at least to some extent. And now that we can have patients' motor neurons in hundreds of Petri dishes, we can test different drugs in each of hundreds of Petri dishes.

因此，在这种疾病中，患者通常在50岁或60岁之前都表现正常。因此，我们认为使用由IPSS衍生的运动神经元可能需要很长时间才能重新捕获疾病。如果我们将它们在培养皿中培养50年，也许我们能够重新捕获它。我们可能可以通过给予运动神经元某种压力来缩短时间。但实际上，我们的预测在某种程度上是错误的。一旦他们从患者的IPSS细胞中生成运动神经元，它们就会自动开始死亡，而无需任何刺激。而健康的IPSS细胞中的运动神经元则不会死亡。所以这意味着我们可以在培养皿中重新捕获运动神经元疾病，至少在某种程度上。现在，我们可以在数百个培养皿中拥有患者的运动神经元，我们可以在每个培养皿中测试不同的药物。

That's exactly what Dr. Inuwet did, and he found one existing drug, both tinib, which is a clinically available drug for leukemia, is actually effective on preventing motor neuron deaths from area's patients. So this approach is now known as drug depurposing, or drug repotitioning. So this is very powerful because we can shorten the process and the money of drug development, because they are already being used with patients. So we are hoping we can utilize this finding with IPSS cells so that we can generate effective drugs for area's patients as quickly as possible. Bostinib itself is a cancer drug, so it has strong side effects. So at the moment, we are not sure whether we could or we should use this drug in area's patient. We have been talking to many people, like people from the government, we have to be very careful, but at least we can utilize this finding to search for new drugs.

这正是Inuwet医生所做的，他发现了一种已有药物，即tinib，这是一种用于治疗白血病的临床可用药物，实际上对预防该地区患者的运动神经元死亡非常有效。因此，这种方法现在被称为药物再利用，或者是药物重用。这非常有力，因为我们可以缩短药物开发的过程和资金，因为它们已经在患者身上使用。因此，我们希望能够利用这一发现与IPSS细胞结合，以尽快为该地区的患者生成有效的药物。Bostinib本身是一种用于治疗癌症的药物，因此具有强烈的副作用。目前，我们不确定是否能够或应该在该地区的患者中使用这种药物。我们已经与许多人进行了交流，比如政府的人员，我们必须非常谨慎，但至少我们可以利用这一发现来寻找新药物。

Let me give you one more example, which is a very rare disease. FOP, fibrodispressia, or syphacants, progressive FOP. We only have less than 100 patients in Japan. Worldwide, there should be less than 1,000 patients. I don't know how many patients in this country, but probably less than 50. So in this patient, their muscles, tendons, regimens become bonds, progressively. So in the beginning, when patients are very small, they are okay. But when they become like high school students, they have born everywhere. So they cannot move, and in the end, they cannot breathe. So it's a very also terrible disease for patients and also for family members.

让我给你举个例子，这是一种非常罕见的疾病，叫做纤维性骨化症（FOP），或称为骨化纤维组织囊性症（syphacants）或进行性骨化纤维组织囊性症（progressive FOP）。在日本，我们只有不到100名患者。全世界范围内，患者应该少于1,000人。我不知道这个国家有多少患者，但可能少于50人。所以在这种病患中，他们的肌肉、肌腱和骨骼会逐渐变得僵硬。所以在最开始时，当患者还很小的时候，他们还能正常活动。但当他们像高中生一样长大时，他们的骨头无处不生。所以他们动弹不得，最后甚至不能呼吸。所以对患者和家庭成员来说，这也是一种非常可怕的疾病。

It's a very rare disease, but we met one patient in Japan seven years ago. This is the patient. When I met him for the first time seven years ago, he was still in, he was very small, like 10 years old, and he was fine at the time. But seven years later, he suffered from multiple bone formation. He may look okay, but he's very skinny, actually, because he has many bones in his face, so he cannot open mouth. That means he cannot eat. So that's why he's very tiny.

这是一种非常罕见的疾病，但在七年前的日本，我们遇到了一名患者。这就是这位患者。当我在七年前第一次见到他时，他还很小，像十岁左右，那时他还很健康。但七年后，他开始出现多发性骨化。他可能看起来还好，但实际上他非常瘦弱，因为他脸上有很多骨骼，所以无法张开嘴巴。这意味着他无法进食。所以这就是他非常瘦小的原因。

He often comes to our Institute, and he, if I never, he's with us, he asked us to take pictures. And he asks us to do this posture. In the beginning, I had no idea what this means. What do you think this means? Do you think this means Dr. Imanaka, please be number one runner? Of course not. So this means he wants us to develop an effective drug as early as possible, even one day earlier. So it's a very strong will of him and also his mother. He precisely knows most likely we cannot make it for him. But he wants us to do it for patients after him.

他经常来我们研究所，而且，我从未见其它人，他和我们在一起，他要求我们给他拍照。他还要求我们摆出这个姿势。一开始，我不知道这意味着什么。你认为这是什么意思？你认为这意味着伊马那卡博士，请成为第一名的选手吗？当然不是。这意味着他希望我们尽早研发出一种有效的药物，甚至比原计划提前一天。这是他和他的母亲的坚定意志。他清楚地知道，我们很可能无法为他做到。但他希望我们能为他之后的病人做到。

So, but Professor Tokjira, a good friend of mine, he generated IP cells from this patient and also from many other patients, trying to understand why on us they generate ectopic bones in their muscles. Now they have crews. So they, to some extent, they were able to recapitulate ectopic bone excessive bone formation by using patients IP cells. So for example, from patients IP cells, from mesenchymal stem cells derived from IP cells, they can make cataracts. Patients mesenchymal stem cells tend to generate more cataracts than normal IP cells. Of course, cataracts is a one step earlier than ectopic bone formation. They also found that activity A is involved in this process.

因此，但我的好朋友Tokjira教授从这位病人身上以及其他许多病人身上生成了IP细胞，试图了解为什么它们会在我们身上在肌肉中生成异位骨。现在他们有了研究团队。所以，在某种程度上，他们能够利用病人的IP细胞重现过度骨生成形成异位骨。例如，从病人的IP细胞中，从由IP细胞分化而来的间充质干细胞，他们可以制造角膜混浊。病人的间充质干细胞倾向于比正常的IP细胞生成更多的角膜混浊。当然，角膜混浊仅仅是异位骨形成的一个早期阶段。他们还发现了A活性在这个过程中的参与。

By having this result in mind, they performed drug screening and they found that this existing drug, rapamycin, is very effective in preventing ectopic bone formation from patients IP cells. They confirmed this finding with IP cells in vivo using mouse model. So by transplanting FOP mesenchymal stem cells derived from patients IP cells into mouse muscle and by adding activity A, they observed this ectopic bone formation in mouse muscle. But by treating the same mouse with rapamycin, they did not see such ectopic bone formation. So rapamycin is being used for patients already, including small children. So that means we can translate this finding with IP cells into patients very quickly. As a matter of fact, he has, his application has been approved by the Japanese government. This is September 6th today. So as of tomorrow, September 7th, they will start clinical trial for patients suffering from FOP, including that patient. So that means we may be able to make it for that patient. At the moment, it's also successful in petrileis with IP cells and also just in mice. So we need to wait for the result of this clinical trial. But I believe it's very promising.

怀着这个结果的想法，他们进行了药物筛查，并发现这种现有的药物雷帕霉素在防止病人的诱变性骨形成中非常有效。他们使用小鼠模型，在体内用来自病人诱变性骨发生细胞（IP细胞）的FOP间充质干细胞移植到小鼠的肌肉中，并添加活动A，观察到这种诱变性骨在小鼠的肌肉中形成。但是通过用雷帕霉素治疗同一只小鼠，他们并没有观察到诱变性骨形成。所以雷帕霉素已经在包括小孩在内的病人中使用。这意味着我们可以将这个关于IP细胞的发现迅速转化到病人中。事实上，他的申请已经得到日本政府的批准。今天是9月6日。所以从明天9月7日开始，他们将对患有FOP的病人进行临床试验，包括那位病人。这意味着我们可能能够为那位病人提供帮助。目前，使用IP细胞的治疗在实验室动物和小鼠中也取得了成功。所以我们需要等待这个临床试验的结果。但我相信它非常有前途。

So let me finish my talk by introducing this very unique collaboration with pharmaceutical company Takeda is the largest pharmaceutical company in Japan. Of course, I know it's smaller than AstraZeneca, but it's largest in Japan. So we have studied this collaboration one and a half year ago. This is very unique. You know, collaboration between academia and pharmaceutical companies are very common. I believe you have many, many collaborations. But this is very unique because the direction is opposite from conventional collaborations. In conventional collaborations, researchers of pharmaceutical companies, they come to universities to make some collaboration, to make some experiments together in academia. But in this collaboration, we go to Takeda's huge research facility in Tokyo area in Shonen. It takes us, it takes us like two hours from Kyoto to Shonen. But it's worth doing. Seven professors from our institute, they spend like 20% of their efforts every week in Takeda's research institute. They make a team with Takeda's employees. So because we go to Takeda inside pharmaceutical company, everything is available. Not only the chemical libraries, huge libraries, we can access to everything they have, including their experiences in drug development, many other experts in many different areas. So we found this very, very useful. So I found by, I hope, by doing this kind of new type of progression between academia and pharmaceutical company, we can promote translation of academia-driven researches like IPS cells into patients.

让我通过介绍与日本最大的制药公司武田制药公司进行的这个非常独特的合作来结束我的讲话。当然，我知道它比阿斯利康小，但它在日本是最大的。所以我们一年半前研究了这个合作。这非常独特。你知道，学术界和制药公司之间的合作非常常见。我相信你们有很多合作。但是这个合作非常独特，因为方向与传统合作相反。在传统的合作中，制药公司的研究人员会来到大学进行一些合作，在学术界一起进行一些实验。但在这个合作中，我们去了武田位于东京周边的巨大研究设施-少年研究所。从京都到少年需要大约两小时的车程。但这是值得的。我们研究所的七位教授每周要花费20%的时间在武田的研究所工作。他们与武田的员工组成一个团队。因为我们进入了武田内部，所以我们可以使用他们所有的资源，不仅仅是化学库，还包括他们在药物开发方面的经验以及其他许多领域的专家。我们发现这非常有用。所以我认为通过这种新型的学术界和制药公司之间的合作，我们可以促进学术界驱动的研究（如iPS细胞）向患者转化。

So I have been dealing this so-called Takeda side project. My counterpart of Takeda is this scientist, Dr. Sego Ismo. So 30 years ago, I was looking for postdoc position in the States. And number one position, I mean, lab, to me, was in Harvard University. That lab was run by Dr. Ismo. So same person. 30 years ago, he didn't take me. I was so sad. But 30 years later, we met again, and we worked together. So we are very happy. Well, who knows? So, thank you so much again.

所以我一直在处理这个所谓的武田副项目。我的合作伙伴是武田的科学家，塞戈·伊斯莫博士。所以30年前，我在美国寻找博士后职位。对我来说，第一选择的实验室是哈佛大学的一个实验室，由伊斯莫博士管理。所以就是同一个人。30年前，他没有录取我，我很伤心。但是30年后，我们再次相遇，并且一起工作。所以我们非常开心。谁知道呢？再次感谢你们。

We have more than 600 people in Kyoto. We have more than 100 people in this Takeda joint program. And I also have a small group in San Francisco. I will be in San Francisco next week. So all of them are very important colleagues of mine. We have a common vision. We want to overcome diseases by doing science. And I believe it's same to you. And finally, I would like to express my sincere thanks to Dr. Zhang. So thank you very much again. Thank you for your attention. Thank you. Thank you very much. Thank you so much for sharing that story with us. I think it's very fascinating.

我们在京都有超过600人。我们在这个Takeda合作项目中有超过100人。而且我还在旧金山有一个小团队。下周我将在旧金山。所以他们都是我非常重要的同事。我们有一个共同的愿景。我们希望通过科学来战胜疾病。我相信你也是一样的。最后，我想向张医生表示最真诚的感谢。再次非常感谢你。谢谢你的关注。谢谢。非常感谢你与我们分享这个故事。我认为非常有趣。

This basic discoveries at the beginning of this century is already having such tremendous impact in medicine. So, for Siamen Akka, I have agreed to take a few questions. There should be two microphones, one on either side. So if you have a question, raise your hand and wait until you have the microphone before you ask the question. You only speak into the microphone because this is also being recorded. So, we can take questions.

这个世纪初的基础发现已经在医学领域产生了如此巨大的影响。所以，对于西门·阿卡，我同意回答一些问题。应该有两个麦克风，一个在每一侧。所以，如果你有问题，请举手等待拿到麦克风再提问。你只需要对着麦克风说，因为这也会被录制下来。所以，我们可以开始提问了。

Thank you, Dr. Zhang Manaka. It was a really inspirational talk. I want to ask you how you see this going in the future. You see, for example, combining IPS technology with genome editing, for example, to fine-tune the properties of your IPS cells. Yes, that's very important. Combination with this technology and genome editing technology is very promising and that's exactly what we have been working on. That's one reason why I go to San Francisco every month because the area is one of the hottest areas for genome editing.

谢谢张玛娜博士。你的演讲真的很有启发性。我想问你对未来的发展有何看法。例如将诱导多能干细胞（IPS）技术与基因编辑技术结合，来优化IPS细胞的特性。是的，这非常重要。将这两种技术结合起来非常有前景，正是我们一直在努力研究的方向。这也是我每个月会去旧金山的一个原因，因为那里是基因编辑领域最为热门的地区之一。

There was another one in the front here. Thank you. Arun Suros, I'm working in epigenetics and how much is known about epigenetics, especially about the reprogramming process? Is it known? How it happens? Sorry, is it very much known? That's also extremely important. So, each cell fate has unique epigenomic status and we and others have found that they are in IPS generation. Most epigenomic epigenomic status is diverted or, I'm sure, erased back into the embryonic state. But it's not 100% concrete. So, we do see some abdominal, abnormal or like DNA maturation. So, we are now studying the impact of such epigenetic abnormalities in IPS cells. So far, we believe it doesn't affect too much but we still need to do a lot more research. So, it's extremely important.

在前面还有一个。谢谢。我是Arun Suros，在表观遗传学领域工作。关于表观遗传学，特别是重编程过程，已经了解了多少？已经知道了吗？它是如何发生的？对不起，它被了解得非常多吗？这也是非常重要的。所以，每个细胞命运都有独特的表观组状态，我们和其他人发现它们在诱导多能干细胞产生过程中，大部分表观组状态被转变或者，我确信，被归零回到胚胎状态。但这并不是百分之百确定的。因此，我们确实观察到了一些异常的DNA成熟情况。所以，我们现在正在研究这些表观遗传异常对多能干细胞的影响。到目前为止，我们认为它不会造成太大影响，但我们仍然需要进行更多的研究。所以，这非常重要。

There's one. Is any structure analysis for that it's done to show the differences between what makes stem cells different than normal cells? Yes. So, for example, stem cells, especially for important stem cells, can flow refract for almost infinity in finitary. So, we and others have shown that in a sense, ES cells and also IPS cells are similar to cancer cells in that they have very high telomere activity. But as soon as they are timeily differentiated, they use their telomere activity. So, and many signaling pathways that function in cancer cells are also activated in pre-important stem cells. So, compared to normal somatic cells, ES and IPS cells are kind of in between normal cells and cancer cells. But it's reversible. Cancer cells are not reversible because they are formed by DNA mutation. Whereas ES and IPS cells do not have such mutations. So, it's impossible. So, that's what we know at this moment. Well, I'll be waiting for that.

这里有一点。对此进行了任何结构分析吗？用于展示干细胞与正常细胞的区别？是的。所以，例如，干细胞，尤其是重要的干细胞，可以在有限的时间内不断地自我复制。所以，我们和其他人已经表明，从某种程度上讲，胚胎干细胞和诱导多能干细胞在很多方面与癌细胞相似，它们有着非常高的端粒活性。但是一旦它们开始分化成其他细胞，它们的端粒活性就会减弱。此外，许多在癌细胞中起作用的信号通路也会在早期重要的干细胞中被激活。所以，与正常体细胞相比，胚胎干细胞和诱导多能干细胞介于正常细胞和癌细胞之间。但是这是可逆的。癌细胞是不可逆的，因为它们由DNA突变形成。而胚胎干细胞和诱导多能干细胞没有这样的突变。所以，这是不可能的。这就是我们目前所知道的。好的，我会等待那个。

I'd like to ask another question because you sort of in transplantation immunosuppression is often needed. Maybe not in the eye but in other sites. And so, the great thing about using the patient's own cells is you don't need immunosuppression. But now you have sort of switched from that idea to use sort of donors for that. Do you think that this field will move to that sometime in the future that will be using the patient's own cells? Was that going to be more cheap and faster or is that something that you're also working on? Yes, that's very good point. That's exactly what we want in the future. At the moment, using this kind of IPS cells stuck, I believe is the way to go because of its price and time required. But we are doing best to promote the method to generate IPS cells. So, that's something you also want. Once they become much more quicker and cheaper, I think autologous transplantation is the way should be the way to go. There was one in the middle there.

我想再问一个问题，因为在移植免疫抑制中通常需要使用。也许在眼部可能不需要，但在其他部位可能需要。所以，使用患者自己的细胞的好处是不需要免疫抑制剂。但现在你已经从那个想法转向使用供体细胞。你认为这个领域将在将来移向使用患者自己的细胞吗？这样会更便宜更快吗？这是你们也在研究的内容吗？是的，这是一个非常好的观点。这正是我们未来的目标。目前，使用这种诱导多能干细胞的方法还有一些困难，因为价格和时间的需求。但我们正在努力推广诱导多能干细胞的方法。因此，这也是您们所期望的。一旦它们变得更快更便宜，我认为自体移植应该是未来发展的方向。在中间还有一个问题。

Question is, what's related to the same thing? So, for the cell therapies, are there certain conditions or diseases where you think it's absolutely necessary to use the patient's own cells even today or can you use the stock cells for everything? So, because of the development in immunosuppressants, I think we can go with alografts for most, if not all, diseases, patients. But it would be much better if we could use autologous transplantation because we can avoid any immunosuppressants. Plant cells are much more easy to read program and can a much more pluripotent than animal cells. Do you have a viewpoint on the reason behind this, the mechanism behind that? And could one learn something in the medical science from the plant science possibly? Well, that's a fundamental question. So, many scientists have been trying to understand what's going on during IPSL generation. I would say largely it's still like a black box. For example, we now know that at least in human, during IPSL generation reprogramming, endogenous retroviruses play a major role. So, as you know, we have more than like 3,000 endogenous retroviruses in our genome. Until very recently, we thought those are just junk. But to your surprise, we found many of them activated during IPSL generation and we found it is not just coincidence. We found the activation of endogenous retroviruses essential for IPSL generation. But we don't know why they are essential. So, and also endogenous retroviruses are not conserved between human and mouse. But even without endogenous retroviruses, we can generate mouse IPS cells. But in human endogenous retroviruses are essential. So, we still don't know the answer. That's what I have been working on in my San Francisco lab for the last five years. Basic aspect, basic question. Why endogenous retroviruses are important in human? So, if you can wait for five more years.

问题是，和同一事物相关的是什么？因此，对于细胞疗法，您认为是否有某些病症或疾病是绝对需要使用患者自身细胞，即使在今天，还是可以使用库存细胞进行一切治疗？由于免疫抑制剂的发展，我认为对于大多数（如果不是全部）疾病患者，我们可以采用同种移植。但是，如果我们能够使用自体移植，那将会更好，因为我们可以避免使用任何免疫抑制剂。植物细胞更容易编程，并且比动物细胞更具多能性。您对此有何见解？植物科学的机制可能能从医学科学中获得一些启示吗？这是一个基本问题。因此，许多科学家一直在努力了解iPSL生成过程中发生了什么。我认为主要还是个谜团。例如，我们现在知道，在人体内，内源性逆转录病毒在iPSL生成重编程过程中起着重要作用。正如您所知，我们的基因组中有3000多个内源性逆转录病毒。直到最近，我们认为这些只是垃圾。但令人惊讶的是，我们发现在iPSL生成过程中激活了许多内源性逆转录病毒，而这不仅仅是巧合。我们发现激活内源性逆转录病毒对于iPSL生成是必不可少的。但我们不知道它们为什么是必不可少的。此外，内源性逆转录病毒在人类和小鼠之间是不保守的。但即使没有内源性逆转录病毒，我们也可以生成小鼠iPS细胞。但在人类中，内源性逆转录病毒是必不可少的。所以，我们仍然不知道答案。这是我在旧金山实验室里研究的内容，已经有五年了。这是一个基本方面的问题，为什么内源性逆转录病毒在人类中是重要的？所以，如果您能再等五年。

Second right here. Thank you, Professor, for coming to us and sharing a story with us. My question would be longevity research. So, Japan is having a huge amount of population who are actually aged. So, since you are in the forefront of this research, do you think that you would be allowed to conduct clinical trial on helping people to live longer or healthier? So, our purpose is to overcome diseases. Right. So, we have a lot of heart failure or Parkinson disease or Latino or molecular degeneration. And happier. So, we don't have any intention to make our longevity itself longer. But as a result of overcoming diseases, I think our ability to longevity should become longer. I did a very interesting paper earlier this year about hematopoietic stem cells. So, all of our red blood cells, lymphocytes are derived from hematopoietic stem cells. And in young people like you, we believe we have approximately 10,000 hematopoietic stem cells. But that paper studied how many hematopoietic stem cells are there in one very elderly woman who is actually 115 years old. And how many did you think they found? They found only two. So, without those two, they cannot survive. So, I think that's the limitation of how long we can. You have 10,000. After 100 years, you have only two. And this we perform bone model transplantation. You cannot survive. That was the question on that side there.

拜托教授，谢谢您能来与我们分享故事。我的问题是关于长寿研究的。日本有很多老龄人口。因此，作为这项研究的先驱，您认为能否获准进行有助于人们更长寿或更健康的临床试验呢？我们的目的是克服疾病。没错。我们有很多心衰、帕金森病、白内障或分子退行性疾病。而且更幸福。所以，我们并不打算单纯追求长寿本身，但通过克服疾病，我认为我们的长寿能力也应该更长。我今年早些时候做了一篇非常有趣的论文，关于造血干细胞。我们所有的红细胞、淋巴细胞都来源于造血干细胞。像你这样年轻的人，我们估计你有大约1万个造血干细胞。但那篇论文研究了一位实际上已经115岁的非常老的妇女，看她身体里有多少造血干细胞。你猜他们发现了多少？他们只找到了两个。所以，没有这两个干细胞，她无法存活。我认为这就是我们能活多久的限制。你有1万个，100年后只有两个。而且我们进行骨髓移植，你也无法存活。那边坐的就是问这个问题的人。

Thank you very much for the excellent talk. My field is in the organ transplant. And I'm very curious what you think of using the IPS to building organs. Do you think we should do the maturation of the cells in vitro or should that be done in vivo to kind of get the cells to be become what you want to be? And also what you think about encapsulation of the cells to control the immunity?

非常感谢你的精彩演讲。我的研究领域是器官移植，我很好奇你对使用诱导多能干细胞（IPS）来构建器官的看法。你认为我们应该在体外培养细胞成熟，还是应该在体内让细胞自然发育成我们所期望的类型？此外，你对利用细胞包埋来控制免疫反应有什么看法？感谢！

So your question is how to make organs from IPS or other stem cells. Actually, three types of research is going on. I myself are not working on that. But many other scientists are working very hard on three different strategies.

所以你的问题是如何利用IPS或其他干细胞制造器官。实际上，有三种类型的研究正在进行中。我自己并没有在从事这方面的工作。但是许多其他科学家正在为三种不同的策略努力工作。

One approach is to make human like peak chimera. Injecting human IPS cells in peak process. Those peak genetically engineered so that those peak themselves cannot make like pancreas or kidneys. So that means they cannot survive. But by putting human IPS cells into the embryos, those human IPS cells can make kidneys or pancreas in peak. And of course, because they are from human IPS cells, they are human pancreas or human kidneys. It's been partially successful. So that kind of research has been conducted in the US and also in Japan. There have been escal controversy about how much we can do that. But the research is ongoing.

一种方法是制造类似于人类的峰期嵌合体。将人类诱导多能干细胞注入峰期过程中。这些峰期经过基因工程，使它们自身无法制造类似胰脏或肾脏的器官。这意味着它们无法存活。但是通过将人类诱导多能干细胞注入胚胎中，这些细胞可以在峰期内生成肾脏或胰脏。当然了，由于它们来自人类诱导多能干细胞，所以它们是人类的胰脏或肾脏。这一研究在美国和日本进行了部分成功的尝试。关于我们能够这样做的可行性一直存在争议，但这项研究仍在进行中。

The second approach is to use 3D printer using various cells from IPS cells or ESLs as ink of making 3D organs. And 10 years ago, I thought it would be like science fiction. But now there are many multiple venture companies working on that. So it's also making a significant progress.

第二种方法是使用3D打印机，将人类诱导多能干细胞（IPS细胞）或人类成体干细胞（ESLs）等各种细胞作为墨水，制造3D器官。10年前，我觉得这听起来像是科幻小说，但现在有很多创业公司正在致力于这个领域。所以它也取得了显著的进展。

The third approach is to utilize cells' automatic ability to form 3D structure. So stem cells can make many brains or many gut. It's super small. But I think it's fascinating actually. They form 3D structure by themselves. I don't know how they are being programmed that way. So it's amazing. But it seems working. So one of those approaches may work in the future.

第三种方法是利用细胞自身形成3D结构的自动能力。因此，干细胞可以形成许多大脑或肠道。这是非常微小的，但我觉得实际上非常迷人。它们能够自主地形成3D结构，我不知道它们是如何被程序化的。所以这是令人惊奇的。但它似乎是有效的。因此，这些方法之一在未来可能会起作用。

Moving towards the end, but we have three more questions. I think we have one there in the middle. Thank you again for the elegantly updated lecture. I would like to ask you how would you compare IPS derived cells from the same patient when the same cell is available? For example, extracted from your talk, mesenchymal stem cells. So how would you compare IPS derived cells to the same cell derived from the same patient? For example, mesenchymal stem cells.

接近尾声，但是我们还有三个问题。我想我们中间有一个问题。再次感谢您精彩更新的讲座。我想问一下，当同一个细胞可用时，您如何比较来自同一患者的诱导多能干细胞（IPS）与相同细胞（例如您演讲中提到的间充质干细胞）的区别？

Oh, I see. It's very important. At least in cell, we can make many types of cells from IPS or ES cells. But in reality, it's still very difficult. For example, we can make beating heart cells or like dopaminergic neurons from IPS cells. But how similar they are with normal cells that exist in a body depends on each cell type. For example, retinopigmental inferior cells, they are very similar to what we have in our body. Whereas beating, also dopaminergic neuron, they are very similar to what we have in our brain. But like heart cells or liver cells, they are still very immature. They are more like fetal heart cells or liver cells. What we can now make from IPS or ES cells.

哦，我明白了。这非常重要。至少在细胞中，我们可以从iPS或者ES细胞制作出许多类型的细胞。但实际上，这仍然非常困难。例如，我们可以从iPS细胞制作出心脏细胞或者多巴胺能神经元。但它们与身体中存在的正常细胞有多相似取决于每种细胞类型。例如，视网膜色素下细胞，它们和我们身体中的细胞非常相似。而心脏细胞或者肝细胞，它们仍然非常不成熟。它们更像是胎儿的心脏细胞或者肝细胞。这是我们现在可以从iPS或者ES细胞制造出来的东西。

What about stem cells? Mesenchymal stem cells? Hematopigtic stem cells. It's a hot topic. The problem about hematopigtic stem cells is that we cannot take out hematopigtic stem cells from patients, like one model transplantation. But nobody has successfully keep them in culture. Nobody can expand normal hematopigtic stem cells in petri-dish. We don't know how to culture them. Without that knowledge, it is next impossible to generate hematopigtic stem cells from ES or IPS cells. The research is still ongoing. It's a very hot topic. Competition is very hot. Don't touch.

干细胞呢？间充质干细胞呢？造血干细胞呢？这是一个热门话题。关于造血干细胞的问题是，我们无法从患者身上取出造血干细胞，就像一个模型移植一样。但是没有人成功地将它们保存在培养皿中。没有人可以在培养皿中扩展正常的造血干细胞。我们不知道如何培养它们。没有这个知识，就几乎不可能从胚胎干细胞或诱导多能干细胞生成造血干细胞。研究仍在进行中。这是一个非常热门的话题。竞争非常激烈。请不要触摸。

We have one question on the aisle here. Yes. My name is Eustain. I made a children's fact book about stem cells. You are in it. Sorry for not asking. I didn't have your number, but you can have one afterwards. But I'm going in a big tour now to speak to kids all over the country. I'm wondering if there's. This is like a general of everything going on in stem cells that I could figure out for 10-year-olds. But do you have anything I should tell children now about stem cell research so they'll be super up to date when they grow up? Oh, it's probably the most difficult question. Well, all I can say is what you're doing is very important to educate. So just keep going. Okay.

我们这里有一个问题。是的。我叫Eustain。我制作了一本关于干细胞的儿童事实书。你在里面。很抱歉没有事先咨询。我没有你的电话号码，但你之后可以获得一本。但现在我要进行一次大型巡回演讲，向全国各地的孩子们讲述。我想知道是否有一本关于干细胞的综合内容，方便我给10岁的孩子们解释。但你现在是否有任何我应该告诉孩子们的干细胞研究最新进展的信息，以便他们长大后能够掌握？哦，这可能是最困难的问题。嗯，我只能说你所做的教育工作非常重要，所以继续努力吧。好的。

This is the last question I think was. I think. Thanks for the lecture. When you were talking about the ALS, you said that you were kind of surprised in a good way when you see that the differentiated IPS cells, when you differentiated them into motor neurons, they still suffer from the disease. It's known how this happens, how can the cell remember after differentiating that disease? Thanks. That is also a fundamental question. So any disease is caused by genetic factors and also environmental factors. So probably the second one will affect epigenetic status. And as I answered in the previous question, epigenetic status is erased upon IPS cell research. So only genetic information is maintained after IPS cell generation.

这是我认为的最后一个问题。我认为吧。谢谢你的讲座。在你谈到ALS时，你说当你将分化的iPS细胞分化成运动神经元时，你感到有些惊讶，因为它们仍然患有这种疾病。你知道这是怎么发生的吗？细胞在分化后如何记住这种疾病？这也是一个基本问题。所以任何疾病都是由遗传因素和环境因素引起的。所以可能第二个因素会影响表观遗传状态。并且正如我在前一个问题中回答的那样，表观遗传状态会在iPS细胞研究中被抹去。因此，只有遗传信息在iPS细胞生成后得以保留。

So the fact that we can recapitulate at least to some extent disease phenotype in ARS-derived IPS cells, that means those patients should have some genetic background. Like 10% of ARS patients is caused by just one mutation of just one gene. So they are called familial areas. But it's only 10%. But even from the other 90% of ARS patients, we can recapitulate disease. So that means although they are not familiar, they should have some genetic background. Probably it's a combination of multiple genetic alterations, which we don't know yet. But to our, from our result, it is clear that they should have some kind of genetic background. So if we can understand what's going on in the genome, we may be able to identify better strategy to overcome.

所以，我们能够在ARS衍生的IPS细胞中至少部分地重现疾病表型的事实，这意味着这些患者应该有一些遗传背景。像10%的ARS患者仅由一个基因的单个突变引起。所以他们被称为家族地区。但这仅占10%。即使来自其他90%的ARS患者，我们也能够重现该疾病。所以这意味着虽然他们不是家族的，但他们应该有一些遗传背景。可能是多个遗传改变的组合，我们目前还不清楚。但根据我们的结果，很明显他们应该有某种遗传背景。所以如果我们能够了解基因组中发生了什么，我们可能能够找到更好的克服策略。

Once again, thank you very much for the lecture. It's certainly engaged the audience. Thank you for answering all the questions. And there will be a debate in just half an hour in the science library for those that are interested in that. Thank you.

再次非常感谢您的讲座。它确实吸引了观众的兴趣。感谢您回答了所有的问题。对于对此感兴趣的人来说，半个小时后将在科学图书馆进行一场辩论。谢谢。

So two-cent yet we talk. Are you? Thank you.

所以我们只是说说而已。你呢？谢谢。