Organoids: Future Possibilities in Regenerative Medicine

Stem cells can create organoids, mimicking human organs, enabling research on diseases and regenerative therapy.

### The Present and Future of Organoids: From Disease Research to Regenerative Therapy
* 🧫  Organoids can be created from induced pluripotent stem cells (iPSCs) and adult stem cells, allowing the **modeling of various organs in vitro**.
* 🩺  In colon cancer research, organoids derived from cancer patients' tissues are used to study **mutations, gene expression, and drug responses** at different stages of the disease.
* 🦠  Organoids provide a platform to study infectious diseases such as **Helicobacter pylori and coronaviruses** at the **molecular level**.
* 💊  The gut microbiota plays a **crucial role in human health**, influencing various diseases and maintaining **homeostasis**.
* 🔄  In regenerative therapy, organoids have the potential to **regenerate damaged tissues**, as demonstrated in mouse intestine wound models.
* 🧠  In a groundbreaking clinical study, brain organoids derived from patient-specific iPSCs were transplanted into a Parkinson's disease patient, leading to **significant improvements in symptoms**.
* 🏗️  Future advancements in organoid research may involve combining 3D printing technology with organoids to create **functional organs** and developing **multi-organoid systems** that **self-organize into complex structures**.

You can actually make a heart by putting in organoids. Like this shape, oh, really, you can make a heart. Now, this is made in the actual size of a rabbit's heart. So, while doing this, I shouted. We have plenty of time to greet you. This slow but cool rap meeting may waste your time, but nice to meet you, professors. Ethical issues that require agreement are put aside for now, and we cannot do other research. Now, a question arises. The picture I showed you initially is about creating stem cells. You can see more above, taking out cell clusters from the abdomen. Below, using the technology of Dr. Yamanka and Dr. Kui, we can make specialized stem cells. By using these induced pluripotent stem cells theoretically, we can create all organs.

So, instead of making embryos, it is now possible to make each organ separately. In fact, research on creating such cells is very active in life itself. These are cells I have created, heart cells. So, when we send a signal from stem cells to heart cells, they transform like this. Therefore, you can see them jumping in one direction on the culture dish. So, you can see the waves moving like this from the backline, just like waves occur. And when you zoom in, you can see the cells beating like this. Yes, I made this. You can make it from stem cells. Wow, it's amazing. And now, I can create cells with a real 3D structure, not just 2D cells, from stem cells.

If you look at the research of Dr. Yoshiki Sasai in Japan, who is specializing in Bishop cells, if you develop them well in three dimensions, now there is something called an optic cup that looks similar to the eye in the eye. If you watch the video on the left, you can see that they are making the shape of the cup with stem cells, gradually creating the shape of the eye. They are making the retina. That's right, it becomes the optic cup. In this way, if you make each organ like this, you can create organs. So, what characteristics should organs have to be able to make organs like this? Not all cells can make organs, so what specific characteristics should organs have to be able to make organs? This is what we need now. Stem cells are made from stem cells. The first thing is that they must be able to self-regenerate. Therefore, they must be able to continue to proliferate and produce.

First, self-organize. So, it's not just growing in an unstructured way; it should mimic the basic structure of organs in the human body. Right? Therefore, it should have a normal form. In three dimensions, it should not be a single-cell but a collection of functional cells and stem cells, forming a functional cell aggregate. We are now defining that we will create organoids. We call these cells collectively organoid organ replicas. As I mentioned, using induced pluripotent stem cells, we can create almost all organs with organoids. Actually, this was achieved in 2016 with organoids that were protected at the time. And now, we can create more organs. We can create the stomach, lungs, thyroid, liver, brain, eyes, and even teeth. So, I am a scientist studying intestines, making intestinal organoids.

I will now show you the law, and James Wells at the University of Cincinnati Medical Center in the United States created organoids. So, how did he make them? He simply mimicked the process of human embryo development on a dish. As a scientist myself, I always believe that nature holds the answers, so I think all the experimental hints are present in the normal processes that occur in nature. Therefore, by mimicking the normal process of embryo development on a dish, organoids can be created. By using adult stem cells as another source, when they become adults, adult stem cells can also be used to grow organoids in the same way. So, we can create organoids using adult stem cells for almost all organs.

You can make organoids with stem cells. So, stem cells can make organoids. Thus, stem cells were created by Dr. Hans Clevers' team in the Netherlands. A scientist named Toshiro Sato, who was doing a post-doc training at that time, reported it in Nature in 2009. He called it '01.' He picked just one cell. If you treat this cell well day by day, at the end, you can create a large cell mass. Is that in a day? As the days go by, it grows to that size in 13 days. Yes, it grows very fast. Stem cells proliferate very quickly, so it becomes like that in just two weeks. So, when I grow organoids, after about two weeks, I separate them back to individual cell levels and distribute them again. Because they self-replicate. Then, those few cells grow again in two weeks.

I recreate something like me in just a few days, so I can create a lot. Wow, the organoid made in our lab is on the far left. So, if you look at it, all of these are organoids made from my stem cells. This part, called a window in the script, is where it grows very quickly in the video below. The second one is from the Hans Clevers group, an organoid made from adult stem cells. The shapes are quite similar, and like this, we can make intestinal organoids. How can we make intestines, and how can we make them functional? The third one is an electron microscope image. Since the intestines have a lot of villi to absorb nutrients, you can see that the surface area needs to be increased, so you can see that there are a lot of villi growing. But after raising the organoids, if you zoom in, you can see that those tiny villi have grown, increasing the surface area like that. Oh, villi.

Oh, I see. And the picture on the far right is the site you mentioned earlier where contact with the outside occurs, right? So, there is a defense mechanism because pathogens like viruses can penetrate, and that's the so-called phagocytic cell. This cell can encapsulate substances it can defend with in these small circular vesicles and shoot them out when they need defense. When should this defense be done? When immune cells trigger an immune response and say shoot now, that's when they shoot. By giving a cytokine called interferon-gamma, we can induce mimicry. So, if we give a certain concentration of interferon-gamma, we can see that the green unfolds slowly and seeps out into the cavity. Yes, this is the defense mechanism that is currently taking place. And the picture below shows that when a higher concentration is given, it demonstrates that the immune response intensifies, as the green color is rapidly secreted.

So, through this, we can see that the function that Oh Jang has is mimicking the organoid. Originally, it was a very good paper published in Nature Medicine, but another method of creating organoids has been developed. What it is, is that when a fetus is in the amniotic fluid, which is the fluid inside the amniotic membrane like this, there are actually bacteria from the intestines and cells that have fallen off from the fetus. So, by taking out a little amniotic fluid and collecting the cells there, we grew organoids, and the organoids grew. So, if you look at the cell picture on the right, it is actually an intestine organoid made using cells from the amniotic fluid. Therefore, it can be used as a tool to examine things like the development of genetic diseases that the fetus has without separating the fetus's tissues.

So, I showed that various types of oils can now be made from the oils that have been extracted. Next, as a researcher of intestinal flora, I would like to talk about what can be done with intestinal flora. First of all, we can conduct disease research. The most representative example is that a lot of cancer occurs in the human colon. Through intestinal flora, we can research colon cancer. For instance, by comparing the organoids derived from cancer tissues of colon cancer patients with those derived from normal tissues, we can see which genes have mutations, how gene expression differs, and we can also culture the organoids and test them with various drugs. By doing this, we can determine which drug the patient's cancer is most sensitive to.

Then, we just need to give that medication to the patient. Colon cancer has a very unique nature. The picture above is called the Vogelstein model, named after the scientist Bert Vogelstein. Colon cancer does not just randomly occur; it is now known to develop through certain stages. The first step is a mutation in the APC gene, then polyps form. When a mutation occurs in the intestinal tissue, the likelihood of a malignant transformation is high. So, it progresses to the stage of polyps, and if further mutations occur, the cancer tissue grows larger, forming a mass. It is still at an early stage and tissues like adenomas are formed, which can develop into benign tumors like polyps, fibroids, or adenomas. If additional genetic issues arise, it can turn into a malignancy.

It's a polyp. This can penetrate the blood vessels and spread. So, polyps are dangerous in the colon. Therefore, it's correct to say that polyps are removed during a colonoscopy. When polyps are found, they are all removed because they have a high probability of having cancer cells. So, after going through this process, we can create a normal organoid and then use gene editing technology to create each stage on a dish. We can modify the first gene, grow it, modify another gene, grow it, modify the third gene, the fourth gene, and so on, changing genes at each stage to see how cancer changes, behaves, which genes cause cancer at each stage, which treatments work well, etc. By modeling these things at the laboratory level, we can conduct experiments to find drugs.

You can do it, and next, now you can also research infectious diseases other than cancer because there are many diseases that are transmitted through the intestines, with Helicobacter pylori being a representative example. Helicobacter pylori infects the stomach, causing gastric cancer. By studying the organoids, we can understand how Helicobacter pylori causes danger and induces gastric cancer. So, we will create stomach organoids and inject Helicobacter pylori into them, and they will attach to the stomach organoid wall and live there. In fact, one of the doctors in our laboratory is conducting research on Helicobacter pylori using stomach organoids. Yes, so we can now analyze and study at the molecular level how the toxins in Helicobacter pylori cause damage to human cells and how they attack. And now, besides Helicobacter pylori, using organoids, we can also study how toxins in coronaviruses cause damage to human cells at the molecular level.

Dr. Yoon Ki-joon at KAIST, who actually used the Zika virus, wrote a very good paper and has now become a professor. Various viruses can be studied using organoids. Now, Dr. Hans Clevers' group has created intestinal organoids and infected them with the coronavirus. Within 24 hours, you can see the initial infection marked in white, and after 60 hours, you can see the virus spreading out. So, with organoids, virus infections can be studied. Also, in my paper here, after creating a model using organoids, we infected them with the coronavirus and with the help of that, we were able to detect the coronavirus infection in our organoids and confirm the growth, which we reported in the paper early on.

When you put gut microorganisms into the intestines of a germ-free mouse, what effect will it have on the host? You can conduct research on this. In fact, gut microorganisms are now being evaluated as a very important factor for humans. It is known that the total number of microorganisms in the gut is greater than the number of cells in the entire human body. Among the numerous microorganisms living there, the majority reside in the intestines. Therefore, it is known that the microorganisms in the intestines regulate aspects of the human body such as development and diseases. You can raise mice in a sterilized state, which is called germ-free, where you can completely sterilize the environment so there are no bacteria at all. When created, if there are no organisms in the intestines, as shown on the left side of the picture, the colon becomes extremely enlarged, and you can see that the intestines are somewhat swollen. On the right side, with normal microorganisms present, the actual normal intestines develop.

So, even if there are no microorganisms at all, it's a problem. Without microorganisms, organs or our bodies cannot develop normally. This is research conducted by a professor at Chonbuk National University in Korea. We can kill gut microorganisms by feeding them antibiotics. After killing them with antibiotics and analyzing them later, we can see that the gut is significantly reduced and damaged. Therefore, gut microorganisms do not just exist; they play a very important role in maintaining homeostasis in our bodies. We now know this. So, what will future organisms do? According to recent research, they are doing a lot of research. We are also conducting research in our laboratory by introducing gut microorganisms of organoids. We have also found and reported important probiotics for gut development in a paper. And not only development but also gastrointestinal diseases.

Liver diseases, obesity, diabetes, cardiovascular diseases, and cancer, and then what else? Inflammatory diseases are all influenced by gut microbiota, as reported recently. It's a lot, really a lot, that the intestines are very important. So, I also think that intestinal microbiota research is currently being conducted very actively. But then, is it possible for things like this? Just theoretically, if someone had cancer, for example, if they survived stage 3 or 4 and now have been cured, but let's say in the case of esophageal cancer, if it progresses beyond stage 3, they cut it off, lift the stomach, and in that case, is it possible to put the esophagus back in? Is that possible in such cases, is it in the realm of regenerative therapy? This is related to regenerative therapy. This is about Professor Watanabe in Japan.

Hans Clevers from the Netherlands, who first created organoids, is now inducing wounds in the intestines of mice through collaborative research. Then, after transplanting organoids to the wounded area, as shown in the left picture, you can see that the normal tissue, which originally did not express that fluorescent protein, now regenerates the intestine with the organoids that express fluorescence. The left side shows the transplanted appearance, and the right side shows the principle. Yes, that's right. So, the concept is that the organoids attach to the wounded area and rapidly regenerate the damaged part to alleviate the wound. This is what is included in my paper. By creating organoids and allowing stem cells to regenerate, we collect the stem cells and then induce wounds in the intestines and apply them.

You can see the regenerated cells attached to the cells that do not express fluorescence, showing the expression of green fluorescence. This is our experimental result. In the next section, I will show you a very interesting video. This is the actual result of treating a patient by transplanting brain cells to a Parkinson's disease patient. The person who actually did this is a Korean professor at Harvard University, Professor Kim Kang-soo. So, I brought this video specially to show you. This person used to be healthy and active in the past, filmed in 2002. The person is Gregory Lopez, and around 2018, Parkinson's disease began to develop, and he started to have difficulties moving smoothly as before.

Unable to move, dribbling a bit, and now you can see the typical symptom of waving hands. When he goes swimming, he waves his hands, very slow, and you can see an uncomfortable appearance. So, the image taken in the death chamber five months ago, the person on the far right is Kim Kwang-soo. He reported to the New England Journal of Medicine, a global journal. Only one person, but he submitted a 2,500-page protocol to the FDA and actually transplanted urea made from stem cells from actual patients. Now, we are showing the scene of going for the transplant, it has been 18 months. He reported the results in an academic journal, and now he is reading a book normally, recovering his appearance. It's only one person, but a very meaningful result, and you will see him swimming.

It is possible to undergo treatments like swimming just like normal people. About five months ago, before the surgery, when skiing, this was how it looked. When you ski after 18 months, it will look like this, but it's very meaningful. This video shows the possibility that more things like this will be possible in the future. Finally, a few slides will show what might happen in the future with organoids. This will lead to questions about what will happen in the distant future and what we are trying to create in the near future. So, when engineering technology meets organoids, for example, by combining 3D printing and organoids, we can create a heart by 3D printing the mold and actually putting in the organoids.

It really works in shape. It's said that they took the heart out. Now, they've made it in the actual size of a rabbit's heart. So, they brought a video that has been protected, saying that they can create in that shape. It may not be functioning perfectly now, but they are hoping that in the near future, the functions will improve, and they will be able to create it in reality. The current organoids each mimic only one organ. In the next section, in the video I will show you, instead of one organ, various organs attached together as a part of the human body. Can we make multiple organoids, not just one organ? Yes. Therefore, a very young Japanese scientist, Takenori Takebe, who is now working at the Cincinnati Children's Hospital in the United States, is expecting that. So, by attaching two initial organoids, could they create a structure with a disorder in one part at the front?

One side makes the front, and the other side makes the back. In the middle, special cells are generated, which later form the bile duct, form the colon, and create complex organs. They grow gradually like that. Various organs were just attached separately, but they naturally form like that. Now, they are asked to self-organize, creating bile duct cells, colon cells, and shaping them. As time passes, real bile is produced in the bile duct, confirming its formation. There are many studies on how to connect blood vessels and veins. Currently, what is called the bile duct is the part where the bile flows.

So, in order for us to regenerate tissues, we need stem cell homes. To regenerate tissues, we need stem cell homes. That stem cell home is descending down the duct like this, as shown in the paper. Yes, that concept is now being developed, but if we can create stem cell homes like that, various organs made up of various cells, various tissues, we may be able to create organs in the future. It seems possible, right? So today, Dr. Kwon Ho-won explained about stem cells, what pluripotent stem cells are, what organoids are, how they are utilized, and how far we have come. Thank you for your hard work, Dr. Kwon Ho-won. Thank you. We have plenty of time to greet. It was a slow but cool lab meeting, not wasting your time. Thank you, professors. Thank you.

3D 프린터로 오가노이드도 만들어낸다? 파킨슨 병의 치료가능성을 보다! 오가노이드의 현재과 미래! (한국생명공학연구원 권오만 박사 2부)

과학의 대중화를 위해 박사급 아재들이 직접 만든, 
될 과학 “안될 과학” 다 만드는 본격 과학 채널

안될과학과 함께 세상을 바꿀 과학자 및 과학기술 분야 전문가+덕후분들을 항상 기다립니다.
과학의 경이로움을 보여주실 수 있는 본인의 연구분야나 전문적인 지식이 있다면,
아래 메일주소로 내용을 보내주세요! 협업 절차에 대해 안내해드리겠습니다. (원고료 지급)

*안될과학 콘텐츠 카테고리
[1] 랩미팅 : 매주 화요일, 목요일 밤 10시 라이브로 진행되는 역수직 과학 토크쇼 (카페 공지 일정 참고) 
[2] 긴급과학 : 하나의 주제에 대하여 방대한 자료와 함께 빠르게, 깊이있게
[3] 초긴급과학 : 긴급과학보다 시의성이 있는 최신 주제를 더 긴급하게
[4] 언박싱사이언스 : 초최신 과학 논문을 언박싱하여 쉽게 설명
[5] 과학자열전 : 과학자의 잘 알려지지 않은 삶과 그들의 업적
[6] 안될과학TMI : 일상의 궁금증을 과학적으로 풀어내는 콘텐츠
[7] 떠날과학 : 직접 현장으로 떠나 전하는 과학 이야기 
[8] 랩무비 : 영화 안의 과학을 다룹니다. 단, 억과주의! 
[9] 게임속과학 : 게임인가요? 과학인가요? 게임속과학
[10] 과학적리뷰 : 무엇이든 과학적으로 리뷰합니다!
[11] 긴급홍보 : 과학관련 주제를 굉장히 빠르게 홍보
[12] 카테고리 없어도 결국 과학과학, 과학은 사랑입니다♡

- 쉬는 중 -
[-] 브이로그 : 일상 콘텐츠. 아재들에 맞지 않는 것 같아 한편 만들고 잠시 중단 
[-] 안될실험 : 과학적인 설명이 가미된 과학 실험 꽁트 콘텐츠. 잘 만들진 않음 

※ 협업 및 비즈니스 문의 : MoreScience2018@gmail.com


안될과학 Unrealscience

Creating Organoids: A Breakthrough in Organ Replication

Scientists can now create organ replicas using induced pluripotent stem cells, allowing for the production of a wide variety of organs such as the stomach, lungs, brain, and even teeth.

The process involves self-regeneration, self-organization, and the formation of functional cell aggregates, mimicking the basic structure of human organs.

This groundbreaking research opens up possibilities for studying and potentially treating various medical conditions.

Creating Organoids from Stem Cells: A Mimic of Nature

James Wells at the University of Cincinnati Medical Center created organoids by mimicking the process of human embryo development.

Organoids can also be made from adult stem cells, proliferating rapidly and self-replicating.

The organoids can mimic the functions of intestines, including the growth of villi to increase surface area and the defense mechanism against pathogens.

Using Intestinal Organoids from Amniotic Fluid for Disease Research

A new method of creating organoids from amniotic fluid cells has been developed, providing a tool for studying genetic diseases without separating fetal tissues.

These organoids can be used for researching colon cancer, allowing for the comparison of gene mutations and expression, as well as testing different drugs for sensitivity.

The organoids can also be used to model the development of colon cancer at different stages, providing a platform for experimenting with gene editing and identifying effective treatments.

Studying Infectious Diseases and Microorganisms Using Organoids

Researchers are using stomach and intestinal organoids to study the effects of Helicobacter pylori and coronaviruses on human cells at a molecular level.

Germ-free mouse studies have shown the crucial role of gut microorganisms in normal organ development, with antibiotics causing significant damage to the gut.

The research on organoids is also contributing to the understanding of gut microorganisms' impact on human body regulation and the development of potential probiotics.

The Impact of Gut Microbiota on Health and the Potential for Regenerative Therapy

Gut microbiota has been linked to a wide range of diseases, including liver diseases, obesity, diabetes, cardiovascular diseases, and cancer.

Research on intestinal microbiota and regenerative therapy, led by experts like Professor Watanabe in Japan and Hans Clevers in the Netherlands, shows promising results in regenerating damaged intestines.

Additionally, a Korean professor at Harvard University, Professor Kim Kang-soo, has successfully transplanted brain cells to a Parkinson's disease patient, leading to significant improvement in symptoms.

Organoids are being used to create a functioning heart, with the hope of improving its function in the near future.

Japanese scientist Takenori Takebe is working on combining multiple organoids to create complex organs.

The development of stem cell homes is a key concept in the potential future creation of various organs and tissues.