Past, present and future of cell therapy
Stem cells
Sergey Kiselyov, "PostNauka"
The concept of a stem cell was introduced in order to explain why multicellular living organisms that possess various specialized tissues remain unchanged in time and space during vital activity. When an organism lives, it constantly loses certain cells. For example, a person loses a protective layer of cells – skin cells, lymphocytes are constantly dying, intestinal cells are dying. But at the same time we keep the same appearance, continue to live, fight infections, consume food. Cells in the adult body are restored and take their place again.
A stem cell is a cell that exists in the body at any stage of development, can divide and multiply, remaining unchanged. On the other hand, at the necessary moment, it can change its program during division and create other, new, specialized types of cells. The more specialized types of cells a stem cell can produce, the more its potencies and capabilities are considered. There are different types of stem cells: oligopotent, multipotent, pluripotent. Oligopotent cells can produce a very small variety of specialized cells. Multipotent stem cells can produce a fairly large variety of specialized cell types. For example, a blood stem cell is multipotent, as a result of division, about 20 different types of cells of the immune system can occur from it. If you transplant one blood stem cell into a mouse that does not have hematopoiesis mechanisms, then the animal will fully restore hematopoiesis. There are also pluripotent cells. For example, the cells of the embryo, from which more than two hundred different types of specialized human tissues then originate, are called pluripotent.
The first stem cell studies
For the first time the term "stem cell" was used by the German scientist Valentin Haaker at the end of the XIX century. He used this term in his writings, but did not give it further development. And the Russian scientist Alexander Maksimov, in his study published in 1909, has already developed this term. Using the example of blood cells, Maximov built a theory of a stem cell and explained that specialized descendants can be obtained from it. The first experimental evidence that stem cells really exist in nature was obtained by American scientists James Till and Ernest McCulloch in the 1960s. They irradiated mice with a lethal dose of radiation and saved them from death by transplanting just a single blood stem cell.
Till and McCulloch proved experimentally the previously developed theory of a hematopoietic cell located in the bone marrow. Then Russian scientists Alexander Friedenstein and Joseph Chertkov showed that the bone marrow contains not only a hematopoietic stem cell, but also a so-called stromal stem cell, which gives rise to bones, cartilage, fat. Joseph Chertkov found out that, despite the fact that all stem cells – hematopoietic and stromal – are nearby, they cannot exchange their functions. The hematopoietic stem cell will give only specialized blood cells, and the stromal stem cell will give only specialized bone and cartilage cells. These stem cells are specialized.
The next epoch-making event in the field of stem cells was the experimental proof of the existence of an embryonic stem cell. In 1981, scientists Martin Evans and Matthew Kaufman and, in parallel with them, Gail Martin, using the example of a mouse, proved the existence of embryonic stem cells that are pluripotent. They have completely unique properties: on the one hand, they can be maintained indefinitely outside the body without changing their properties, on the other – when they get into certain environmental conditions, for example, back into the body, they can give rise to various tissues or a whole living organism. Later, in 2007, the Nobel Prize was awarded for genetic manipulation of embryonic stem cells. The next and last major discovery in this field to date was the publication by Japanese scientist Shinya Yamanaka in 2006 of the technology for reprogramming somatic cells of an adult organism to the state of embryonic stem cells. These cells were called induced pluripotent stem cells. In 2012, Shinya Yamanaka received the Nobel Prize for his technology and prospects for its application. The first successful use of stem cells should be considered bone marrow transplantation, which Edward Donnell Thomas conducted in 1964. For this he received the Nobel Prize in 1990. Since then, blood stem cells have been effectively used in the treatment of oncohematological diseases.
Obtaining stem cells
The methods of obtaining stem cells are unique for each type. In the body, some cells live surrounded by other cells and cannot exist separately. They need special niches in which they can feel comfortable. Therefore, special conditions are needed for each specialized cell type. For example, hematopoietic stem cells are mainly isolated from the bone marrow by separating those cells that attach to surfaces and those cells that will float. Blood is a liquid tissue that is not attached to anything. Based on this property, it is possible to separate those cells, among which there will be blood stem cells. Further, in order to isolate a blood stem cell, it is necessary to carry out complex technical manipulations using so-called selective markers. And from the attached cells, stromal stem cells of the bone marrow can be obtained.
To isolate brain stem cells, you have to penetrate into certain areas of the brain. Only there can you find a small number of brain stem cells. It is problematic to do such procedures with a person. If aspiration, that is, taking bone marrow, is a relatively simple operation, then getting into a person's head and doing trepanation is a problem. Just get the hair stem cells. To do this, it is enough to pull out one hair and place the cells from the hair bulb in certain environmental conditions with growth factors. This is how hair stem cells are obtained.
As for human embryonic stem cells, they are obtained from the internal cell mass of blastocysts, which are intended for destruction. This group of cells develops on the fifth day after the in vitro fertilization (IVF) procedure. Usually, about a dozen blastocysts are obtained during IVF. A couple of the best of them go for implantation and develop into an embryo. The remaining blastocysts can be stored for a fee or simply discarded. Science provides an opportunity to use this group of underdeveloped cells to study the development processes and save other people. Today, about 20-25 thousand blastocysts obtained for in vitro fertilization are thrown out weekly in the world. Because of their unique properties, the conditions for the cultivation of these cells outside the body are the most difficult.
Induced pluripotent stem cells can be obtained from any adult cells, such as skin or blood. Cells are transferred to laboratory conditions, and then technological manipulations are carried out: reprogramming using certain genes, that is, changing the genetic program, returning cells to an embryonic, young state. The development of this technology today makes it possible to do without the use of genes, but nevertheless there is a change in the work of the genetic program. Each cell type is unique and requires its own, unique way of isolation and maintenance.
Using stem cells
Today, blood stem cells are successfully used in the treatment of oncohematological diseases. People have been treated for blood cancer with stem cells since 1964. Actually, cells are not treated, but restored after treatment. If there is a malignant transformation of blood cells, then drugs kill all blood cells, and then transplant healthy blood stem cells, for example, from a donor. On average, the effectiveness of the use of hematopoietic cells in the treatment of certain forms of cancer reaches 70-80%.
But this is where the widespread use of stem cells for the treatment of diseases ends. All other technologies are at different stages of clinical trials. For example, clinical trials for the treatment of diabetes are currently underway. Human embryonic stem cells are used for this purpose. Specialized beta cells are obtained from them and transplanted into people. In addition, the second phase of clinical trials of the use of human embryonic stem cells to restore vision is underway. This therapy shows good effectiveness, and most importantly, it allows people with hereditary forms of diseases to acquire vision. They also began testing reprogrammed induced pluripotent stem cells to obtain pigment epithelium and restore vision with age–related changes occurring in the macula - the central part of the eye. Of course, everything is not limited to this, there are clinical trials on the use of cells derived from bone marrow and adipose tissue. It turned out that adipose tissue is very attractive in terms of obtaining stem cells. In total, there are about 4 thousand clinical trials using stem cells in the world, but there are practically no approved technologies yet.
Development of technologies in the field of stem cells
Over the past few decades, the pace of introduction of medicines developed using technologies of the XX century has significantly decreased. Advances in genomics and cell biology provide new opportunities to eliminate not only the symptoms of diseases, but also the root causes. In order to accelerate the introduction of modern technologies into practice, appropriate programs are being adopted in many countries. In the United States, a California initiative was adopted to finance the research of human embryonic stem cells in the amount of $ 3 billion for 10 years and to accelerate the translation of scientific achievements into practice. Within the framework of this and other programs, research is actively developing on the treatment of diabetes, cancer, vision restoration, treatment of neurodegenerative diseases, in particular Parkinson's disease and spinal cord injuries. Scientists are transplanting neurons obtained in the laboratory to restore the affected areas of nervous tissue destroyed by the disease.
In Europe, there are also clinical trials of age-related macular degeneration therapy using pigment epithelial cells derived from human embryonic stem cells. Scientists are investigating the possibility of treating Parkinson's disease with cells derived from fetal material. In the planned clinical trials, neurons obtained from reprogrammed cells will already be used. Undoubtedly, other studies are also being conducted, when cells, for example, blood or fat are used to treat neurodegenerative diseases. The reasons for this are not very clear, but if it will help, then why not use it? Clinical trials using induced pluripotent human stem cells are being actively conducted in Japan.
A number of pathologies, such as age-related macular degeneration, diabetes, parkinsonism, heart disease, are the target of ongoing clinical studies. In order to accelerate the entry of new therapeutic products into the market, changes were even made to the federal law on medicines. These changes facilitate and accelerate the entry into the market of innovative products, it is expected that changes in legislation will reduce the withdrawal time of a medical drug from 15 to 5-7 years.
At the moment, many studies have come to the conclusion that the technology should be worked out not on mice, but on humans. It will still be necessary to conduct experimental studies on humans in order to make the technology safe and effective. If you competently and responsibly approach the research and promotion of relevant drugs, they can have a 100% guarantee of entering the market.
Open questions
If you look at yourself in the mirror, you can see that every cell is in its place. And this happened due to the natural process of individual development. In laboratories, we are already able to obtain many different cells that are similar to the cells of the body. Now humanity wants to develop such technologies with which it is possible to replace the desired cell anywhere in the body. The main problem that exists and will continue to exist for a long time is to ensure that the right cell gets to the right time and place. Doctors will solve this problem in the next decade.
About the author: Sergey Kiselyov – Doctor of Biological Sciences, Professor, Head of the Epigenetics Laboratory of the N.I.Vavilov Institute of General Genetics of the Russian Academy of Sciences.
Portal "Eternal youth" http://vechnayamolodost.ru
09.09.2016