Health, innovation and iPS stem cells: Why co-operation matters
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There are several thousand intractable diseases in the world for which no therapy has yet been developed. Stem cell technology known as iPS cells could provide a solution, but international co-operation will be needed to secure the future of this important innovation.
Stem cells known as iPS cells are produced by taking skin, blood, or other somatic cells from humans or animals, inserting specific genes or other factors, and culturing them for a few weeks. Developed as a world’s first by our research group in 2006, iPS, or induced pluripotent stem cells, are not to be confused with embryonic stem cells, which are another type of artificially created pluripotent stem cell first developed in 1981. Both iPS cells and ES cells have the ability to continue almost unlimited proliferation, while their pluripotency means they are able to differentiate into nerve cells, myocardial cells, blood cells or any other of the body’s various cell types. However, ES cells are created by culturing cells extracted from the fertilised egg (blastocyst). As this necessitates the destruction of the fertilised egg, which can be seen as a burgeoning life form, there is strong opposition to their use.
The objective of iPS cell development was to create cells that were like ES cells but without destroying fertilised eggs. Indeed, being from somatic cells, there is no need to use fertilised eggs at all. Moreover, as iPS cells utilise gene insertion technologies already in general use in life sciences, they can be produced relatively easily after a certain amount of training. The procedure for creation of iPS cells has a high degree of reproducibility, while the procedures for their culture and differentiation into the target cell type have a degree of interchangeability that allows us to apply the knowledge gained in ES cell research.
These factors help to explain why iPS cell technology achieved rapid and widespread dissemination. Another major difference between iPS and ES cells is that iPS cells can be prepared from the patient’s own cells, allowing reproduction of pathological processes, which gives potential for application in the elucidation of pathological states and drug discovery.
Many researchers worldwide have engaged in iPS cell research over the eight years since our discovery, and science is steadily progressing toward the realisation of iPS cell based medical applications. In 2013 iPS cell-based clinical research was approved by Japan’s Ministry of Health, Labour and Welfare and cell transplantation therapy is forecast to begin before the end of 2014. Drug development using iPS cells is also becoming a reality.
New drug potential At present, there are said to be several thousand intractable diseases in the world for which no therapy has yet been developed. iPS cell technology has great potential to contribute to elucidating the causes of disease and realising new drug development.
For instance, using iPS cells means that, even with the cells of disease sites from which it is difficult to collect cells by biopsy, it is possible to obtain cells for research at the time needed and in the quantity needed. Using patient derived cells also makes it possible to elucidate the causes of disease and the mechanism of progression. This opens up the prospect of screening to identify substances effective as pharmaceuticals from among an enormous number of candidate substances.
Researchers around the world have, in fact, started work on research on this. At Kyoto University’s Centre for iPS Cell Research and Application, where I serve as director, the research group of Professor Haruhisa Inoue took iPS cells derived from patients with amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease and induced them to differentiate into nerve cells, thus successfully creating a pathological model of the disease. These iPS cells are now being used in ongoing research aimed at elucidating disease mechanisms and establishing new therapies.
Using patient-derived iPS cells can also allow more precise classification of diseases, as conditions which had hitherto been classed together because of their symptoms can be categorised more accurately according to the cause of the disease in the individual patient. This means that iPS cell technology can also contribute to personalised medicine, in which patients are given the drugs most suited to their individual condition.
Regenerative medicine Research is also making progress in the field of regenerative medicine for cell transplantation therapy. In July 2013, the research group of project leader Masayo Takahashi of the Riken Centre for Developmental Biology, working with the Institute of Biomedical Research and Innovation Hospital, received approval from the Ministry of Health, Labour and Welfare to undertake iPS cell-based clinical research into the eye disease known as age-related macular degeneration. In this clinical research, iPS cell-derived retinal pigment epithelial cells generated from patient somatic cells will be transplanted back into the same patient in an attempt to restore visual strength. The world’s first transplantation using iPS cell-derived cells is envisaged before the end of 2014.
At our research centre, Professor Jun Takahashi’s research group plans to file an application in 2015 for approval of clinical research in Parkinson’s disease patients, while Professor Koji Eto’s research group, having developed a method of producing platelets in large volumes from iPS cells, is looking to commence clinical research in chronic thrombocytopenia patients in 2016. At Keio University, the research team of Professor Hideyuki Okano is working toward clinical research into spinal cord injury using iPS cell derived neural progenitor cells, while at Osaka University the research team of Professor Yoshiki Sawa is targeting clinical research into myocardial regeneration therapy for severe heart failure using iPS cell-derived myocardial cell sheets.
If Japan leads the world in the field of regenerative medicine using iPS cells, it is because structures were put in place to realise early-stage research and development and medical applications using the new technology immediately after the successful creation of human iPS cells had been announced in 2007. There was also strong backing from the Japanese government. Generous budget allocations were made for iPS cell research, with research funding of more than ¥50 billion provided in the six years from fiscal 2008. From fiscal 2014, the Japanese government is committed to continuing intensive budget allocation to the regenerative medicine field including iPS cell research, with plans to provide funding of more than ¥100 billion (US$1 billion) over nine years.
iPS cell stocks needed The generation of iPS cells requires time, and if we follow a procedure whereby iPS cells are prepared from patients, the treatment could be too late for many diseases. Moreover, operating an exclusive process of iPS cell generation and target cell differentiation for a specific disease with just one patient would be impractical from a logistical point of view. It would also incur huge medical costs.
An iPS cell bank like a blood bank could help overcome these limitations. Our centre prepares clinical-grade iPS cells in advance from the cells of healthy subjects and distributes them to research or medical institutes that carry out advance preparation of iPS cell-derived cells for transplantation. We refer to this as iPS cell stock operations. With the support of the Japanese government, we are progressing with a range of related preparations to enable supply of iPS cells for use in regenerative medicine.
Building an iPS cell stock would make it attractive to use iPS cell-derived tissue from a subject other than the actual patient––in terms of time and medical costs. This so-called allogeneic transplantation would also be an effective method of promoting widespread clinical application of iPS cells. Of course, in iPS cell supply through such operations, due consideration must be given to safety, efficacy and ethics, which are not an issue in autologous transplantation, where the transplanted cells are derived from the patient’s own tissue.
International co-operation matters iPS cell research is flourishing at universities and research institutions, not only in Japan but also in OECD member countries and in the rest of the world. International cooperation is important to realising the medical application of this technology. In the UK and the US, there are plans for iPS cells banks, where iPS cells, whose safety has been confirmed in advance, will be produced and then stored. Building up an international network of such iPS cell banks is also important in promoting regenerative medicine at global level. However, different countries have different regulatory systems in the field of medical treatment, while the quality control standards applying to iPS cell production and storage also differ. We therefore need to overcome formidable barriers if we are to realise a level of international co-operation whereby the iPS cells stored in different banks can be supplied multilaterally across national borders.
Obtaining important iPS cell-related patents is also an important strategy towards the realisation of medical applications for iPS cells. So far, Kyoto University has been granted fundamental patents in 29 countries and one region worldwide, including the US and Europe. By establishing important fundamental patents and granting non-exclusive licenses, a public institution like ours can enable many business enterprises to utilise technologies at an appropriate price, which should speed the realisation of medical applications. Moreover, to prevent certain enterprises from gaining exclusive use of important patents, we are investing energies in acquiring and maintaining patents that also cover peripheral technologies.
Ethical issues While iPS cells avoid the destruction of the fertilised egg, which is an issue with ES cells, they are not completely free of ethical questions. For instance, iPS cells contain the genetic information of the somatic cell donor, and this point needs to be adequately explained to the cell donor, with checks to ensure that the genetic information is appropriately protected and managed. There are also questions as to how far permission should be given for research that makes use of germ cells derived from iPS cells, or research into the use of iPS cells to grow human organs inside animal bodies. These and related matters need to be widely debated in society, with consideration given to the possible outlines of international ethical regulation.
The advent of iPS cells offers exciting prospects and hope for millions of people by making it possible to select the pharmaceuticals most suited to the individual and to cure disease using the potential contained within the cell. In other words, tailor-made medicine may become a reality. However, before drug discovery and regenerative medicine based on iPS cells can find widespread application in medical practice, a range of other issues must be addressed, including development of technology for inducing differentiation, transplantation methods, regulatory enhancement, and resolution of ethical issues.
Time must be allowed for discussion and debate. iPS cell technology is not only revolutionising medical science and medical treatment, but stands to bring major changes in society too.
*Shinya Yamanaka and John Gurdon were awarded the Nobel Prize for Physiology or Medicine in 2012
Reference Centre for iPS Cell Research and Application, Kyoto University Visit www.cira.kyoto-u.ac.jp/e/index.html
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Shinya Yamanaka, Director, Center for iPS Cell Research and Application, Kyoto University*
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