Many big advances, like the discovery of human embryonic and tissue stem cells, have been made only during the past 25 years.
Thanks to stem cell research, today we understand the earliest stages of human development quite well and can therefore differentiate stem cells into different specialized cells and mini-tissues in the laboratory. In addition, many causes of previously poorly understood disease have been discovered due to stem cell research. In some cases, research has already led to new treatment options.
Stem cell research originates from more than hundred years of research on developmental biology. In 1885, Hans Driesch showed that both cells of a two-cell sea urchin embryo are able to develop into a complete sea urchin, demonstrating the totipotency of these cells. Pluripotency of vertebrates (salamanders) was demonstrated by Hans Spemann in similar experiments in the early 20th century.
It took half a century, until 1962, before John B. Gurdon showed that the identity of specialized cells could be changed. Gurdon replaced the nucleus of a frog egg with the nucleus, containing its DNA, from an intestinal cell. The result was a normally developed tadpole. This proved, for the first time, that a nucleus can return to a pluripotent state – in a sense back in development. Gurdon got the Nobel prize in physiology and medicine together with Shinya Yamanaka in 2012.
In 1981 Martin Evans, Matthew Kaufman and Gail Martin isolated pluripotent embryonic stem cells from a mouse embryo and managed to grow them in the laboratory. Human embryonic stem cells were discovered by James Thomson and Jeffrey Jones as late as 1998. This launched a new important line of research, which led to better understanding of the first steps of human embryonic development.
The world’s first cloned mammal, the sheep Dolly, was born in 1997 as a result of research by Keith Campbell and Ian Wilmut. Dolly originated form a mammary cell nucleus, that replaced the nucleus of an egg cell.
Research led by Shinya Yamanaka showed in 2006 that specialized mouse cells can be reprogrammed back to a pluripotent state, to induced pluripotent stem cells or iPS cells.
Since the turn of the millennium, researchers have been able to differentiate, first mouse and later also human, embryonic stem cells into cells that resemble functional tissue cells. Today it’s possible to make beating cardiac muscle cells, insulin producing pancreatic cells or mini-brains, which resemble the structure of the human cortex. Cells originating form pluripotent cells have already successfully been transplanted into mice where the cells gain functionality. The usage of such cells in treatments of human disease is however only under development.
Already in the early 20th century, Alexander Maximov presented a hypothesis according to which all the cells of the blood would originate from a common stem cell. Half a century later, in the early 1960’s, James Till and Ernest McCulloch demonstrated the existence of blood stem cells in experiments where they transplanted bone marrow to mice, whose own bone marrow had been destroyed by irradiation. This was the first proof of the existence of tissue stem cells in adult mammals. Bone marrow transplants have been used successfully in treatments of humans since the 1960’s.
In the 1970’s Howard Green unknowingly managed to grow tissue stem cells in the laboratory for the first time and at the same time laid the ground for skin transplants. Skin stem cells were discovered over 30 years later.
In the early 1990’s James Rheinwald managed to get biopsies of corneas to grow in the laboratory thanks to the stem cells that were present in the samples. A few years later a research group led by Michele De Luca already performed the first corneal transplantations on humans.
Due to the development of research methods since the early 21st century, it has been possible to demonstrate the existence of stem cells in nearly all organs. The development has led to the discovery of for example intestinal, lung, stomach and liver stem cells. The so-called linage tracing method, where stem cells express a tracing substance, has been vital to these discoveries. By following the inheritance of the tracing substance from cell to cell, it’s possible to determine which tissue cells the stem cells give rise to. In this way, it has been shown which cells are in charge of renewing a particular tissue by producing other cells.
Today, scientists think that nearly all tissues contain stem cells or progenitor cells that renew the tissue. Cells with stem cell properties exist even in the brain, but their possible role in renewing nerve cells is still not clear. The renewal capacity of the human brain is in any case very limited.
Another important method in tissue stem cell research is the usage of organoid cultures. Organoids are 3D cell cultures which resemble tissues. Stem cells and their neighbour cells can usually be maintained over long periods of time in organoids. A good way to demonstrate that a cell is a stem cell is to show that it can make an organoid. If the organoid contains all cells of the tissue in their right proportions, the cell that produced the organoid is able to renew the tissue by balancing cell division and differentiation. Although organoid cultures have been around only for little over ten years, they are already used a lot for example in precision medicine and in tissue renewal research.
Stem cell research includes both basic research, which aims to understand biological phenomena, and applied research, which builds upon basic research and attempts to develop new treatments. Thanks to stem cell research, we nowadays understand the early phases of human development quite well and can therefore in the laboratory differentiate stem cells into specialized cells and mini-tissues. In addition, many causes of previously poorly understood diseases have been discovered using stem cell research and we are thus one step closer to developing new treatments.
The discovery of mammalian embryonic stem cells at the end of the previous millennium made it possible to study the earliest stages of development. Many valuable so-called cell-lines were also made from these cells. The cell-lines can be frozen and thawed, which has diminished the need to use new embryos. Thanks to embryonic stem cells, we for example know the genetic mechanisms that control embryonic development in great detail. Research that relies on embryonic stem cells has also been very valuable for example for the development of infertility treatments.
Soon after the discovery of embryonic stem cells scientists learned to differentiate the cells in the laboratory into for example cardiac muscle cells or nerve cells. Previously, human cells used in research were mostly derived from tumours. Numerous important discoveries have been made using tumour cells, but only the development of methods for differentiating stem cells has made it possible to study many human diseases, such as neurological diseases, using relevant cell models. Besides cells derived from embryonic stem cells, cells derived from iPS cells are used more and more for disease modelling.
The attractiveness of iPS cells in research is partly due to their accessibility but their biggest value comes from the possibility to make them from patient cells. Thanks to iPS technology, it’s today for example possible to study disease mechanisms of the nervous system using nerve cells that originate from the patient’s own skin or blood cells and thus also genetically match the patient. By using the patient’s own cells it’s possible to resolve the causes of the disease on an individual level.
Since it’s not easy to get hold of human tissue stem cells, scientists rely heavily on model organisms, such as mice or fruit flies, for studying tissue stem cells. By studying model organisms, it possible to resolve how whole organs, such as the intestine, the skin or the blood is renewed and how diseases, such as aging related tissue degeneration or cancer, develop. The use of model organisms also enables studying how tissue structure and systemic factors, such as the blood circulation or metabolism, influence tissue renewal.
Nowadays, mini-organs, or 3D-organoids, which originate from animal or human stem cells, are also often used for stem cell research. The structure of the tissue is partly maintained in the organoid cultures. The method has made it possible to perform detailed studies of tissue renewal and has thus taken stem cell research one step forward towards future treatments.
Centre of Excellence in Stem Cell Metabolism, MetaStem
The Centre of Excellence in Stem Cell Metabolism focuses on investigating what role the distinctive metabolism of stem cells may play in stem cell biology. The CoE also addresses how stem cell function can be modified by regulating their metabolism, and aims to develop approaches utilizing metabolic control in stem-cell-based therapies. Link to web pagesCentre of Excellence in Body-on-Chip Research
The Centre of Excellence will produce comprehensive knowledge, for example, on understanding tissue interactions, constructing complex in vitro tissue co-cultures and controlling their functionalities. The resulting expertise and technologies will improve, for instance, the development of new personalized treatments and drugs. Link to web pages
Stem Cells and Metabolism Research program, Faculty of Medicine
For example Timo Otonkoski, Anu Suomalainen-Wartiovaara, Henna Tyynismaa, Sara Wickström, Kirmo Wartiovaara, Taneli Raivio, Satu Kuure and Juha Kere. Link to webpagesHelsinki Institute of Life Science, HiLIFEInstitute of Biotechnology, for example Pekka Katajisto, Marja Mikkola, Ville Hietakangas, Anamaria Balic, Jette Lengefeld, Fredric Michon, Osamu Shimmi and Jukka Jernvall. Link to webpagesNeuroscience Center, for example Jari Koistinaho, Takashi Namba and Olli Pietiläinen. Link to webpagesFIMM, for example Helena Kilpinen. Link to webpagesOthers at The University of Helsinki
For example Maija Castrén, Kari Alitalo, Tomi Mäkelä, Jaakko Mattila, Sanna Vuoristo and Kirsi Sainio
Tampere University, Faculty of Medicine and Health Technology
For example Katriina Aalto-Setälä, Heli Skottman, Keijo Viiri, Minna Kellomäki, Susanna Miettinen and Susanna Narkilahti. Link to webpages
University of OuluFaculty of biochemistry and molecular medicine
For example Seppo Vainio and Aki Manninen. Link to webpagesFaculty of Medicine
For example Reetta Hinttala and Petri Lehenkari. Link to webpages
University of Eastern Finland
For example Riikka Martikainen, Johanna Kuusisto, Annakaisa Haapasalo, Tarja Malm and Sarka Lehtonen. Link to webpages
University of Turku
For example Riitta Lahesmaa, Riikka Lund, Terhi Heino and Johanna Ivaska. Link to webpages
Blood service Link to webpages