Scientists have successfully reprogrammed human skin cells to become embryonic stem cells capable of transforming into any other cell type in the body. It is believed that stem cell therapies hold the promise of replacing cells damaged through injury or illness.
While scientists have previously been able to make embryonic stem cells using this approach in monkeys and mice, until now they had not been able to this with human cells. This method could be used to study patient-specific causes of disease and for developing personalised therapies.
The research, led by researchers from Oregon State University, was published in the journal Cell, today.
Our colleagues at the Australian SMC collected the following expert commentary. Feel free to use these quotes in your reporting. If you would like to contact a New Zealand expert, please contact the SMC (04 499 5476; firstname.lastname@example.org).
Associate Professor Andrew Laslett, Research Group Leader, Stem Cells at CSIRO Materials Science & Engineering, comments:
“The production of human embryonic stem cell lines using somatic cell nuclear transfer (SCNT) or “therapeutic cloning” is big news for both the stem cell research community and the general public. Many groups worldwide, including some in Australia, have been attempting this for a long time. This technology breakthrough provides an alternative to induced pluripotent stem cells (iPS cells) for potential use in personalised medicine either via screening to identify the most effective drug combination for individual patients or for cell therapy. Both of these methods (iPS and SCNT) can produce genetically matched stem cells that can be turned into any cell type in the human body.
“However, previous non-human studies have shown that SCNT embryonic stem cells are closer to “normal” embryonic stem cells than are iPS cells. Moreover, the technology used to produce iPS cells can lead to unwanted gene mutations. Hence, SCNT embryonic stem cells may be a better option than iPS cells for some applications. That said, the use of donor human eggs, which are not easy to obtain, raises a number of ethical issues that should be carefully examined. Finally, the long term stability and safety of these SCNT embryonic stem cell lines is yet to be tested carefully.”
Associate Professor Ernst Wolvetang, Group Leader of the Stem Cell Engineering Group at the Australian Institute for Bioengineering and Nanotechnology, University of Queensland, comments:
“The most primitive and attractive stem cell known to man is the pluripotent stem cell because it is immortal and can make all the cell types of the human body. There are two ways to obtain such pluripotent stem cells; they can be isolated from five-day-old surplus IVF embryos or they can be artificially generated by reprogramming adult cells back to so-called induced pluripotent stem cell (a process for which Gurdon and Yamanaka were recently awarded the Nobel prize). Because of the use of fertilised embryos in their derivation the use of human embryonic stem cells has raised ethical concerns. Embryonic stem cells will also be subject to immune rejection upon transplantation because they come from donated embryos. While induced pluripotent stem cells do not have these issues, they appear to accumulate more DNA mutations than embryonic stem cells, raising potential concerns about their safety.
“In this study the scientists have now overcome the immune rejection hurdle associated with human embryonic stem cells by swapping the nucleus of a donated oocyte with that of a skin cell and then kick-starting the development of the oocyte in the dish to derive human embryonic stem cells. While the nucleus swapping part was previously successfully performed by other researchers, attempts to establish embryonic stem cells from such oocytes had always failed. The scientists in this paper showed that the trick was to use high quality oocytes and add caffeine. They claim that the efficiency of making patient specific/personalised human embryonic stem cells is now so high that regenerative medicine with such cells may become easier. However, the method will always rely on the willingness of women to undergo super-ovulation and donate oocytes for such purposes, a procedure that carries both inherent risks and its own socio-ethical concerns.”
Dr Bryce Vissel, Head of the Neurodegeneration Research Program, Garvan Institute of Medical Research, comments:
“All studies take a great deal of time to translate to the clinic, but the first step is the breakthrough. This study is a breakthrough development that overcomes a major scientific hurdle with significant implications for potentially treating a range of diseases. This study is an important advance that will not only influence scientific thought but in fact could change future therapies.
“The implication of this study is to suggest an important approach to ultimately generate a range of different cell types. The point is that we have a new way to ensure new cells being generated for treatment would be genetically
Professor Ed Stanley, Stem Cell Technology Laboratory, Murdoch Childrens Research Institute, comments:
“The paper is of academic interest but unlikely to have any bearing on the therapeutic use of stem cells. Essentially, the paper shows that human eggs can be used to reprogram tissue-derived cells (for example, skin cells or blood cells) so they become like embryonic stem cells. However, people can already do this using other methods that are much more accessible and simpler. Thus, although it is interesting to find out why this approach did not work in the past (people have been trying to do this for a long time), it is unlikely to impact on the course of experiments that researchers do in the future, nor on efforts to develop personalised stem cell based therapies.”
Dr Bernie Tuch, Director of the NSW Stem Cell Network and is a member of the Research Consortium at Fertility East, comments:
“This is an excellent manuscript, demonstrating for the very first time that it is possible to produce stem cells in humans by the process known as therapeutic cloning. The process has been achieved in many animal species previously, most recently in monkeys. Indeed, it was a group that achieved the monkey data who went on to apply this technical knowledge to make it work in humans.
“If the studies are confirmed by other groups, it will mean that tailor made human stem cells can be efficiently produced for regenerative purposes. Pluripotent stem cells derived by therapeutic cloning are technically superior to those obtained by other means.
“The only downside is that the technique requires availability of good quality human eggs, and paid egg donation for this purpose is currently not allowed in Australia. There is a program underway in Fertility East, Sydney – approved by the NHMRC Embryo Licensing Committee, and with the support of Monash University – to try and produce stem cells from human eggs that are donated without payment.”
Professor Martin Pera, Program Leader of Stem Cells Australia and Chair of Stem Cell Sciences at the University of Melbourne, comments:
“The study to be published in Cell represents a major breakthrough in stem cell research and regenerative medicine. Tachibana and colleagues report the first derivation of a human embryonic stem cell line, capable of turning into any cell type in the adult body, through the cloning technology known as somatic cell nuclear transfer. This is a feat that many scientists had concluded would be impossible. This discovery provides a new alternative source of cells for transplantation therapy to treat a wide range of devastating medical conditions. In particular the new method offers a unique approach to the prevention of inherited mitochondrial diseases, which cause debilitating degeneration in the brain and heart of affected individuals.
“Using detailed knowledge of human reproductive biology, the Oregon researchers refined the technique of somatic cell nuclear transfer to enable the development of new stem cell lines from only a few human eggs. Previous work had indicated that hundreds of eggs would be required. Somatic cell nuclear transfer will allow the production of stem cell lines that are closely matched to individual patients for use in transplantation. Although induced pluripotent stem cells made from adult tissues have been widely promoted as an alternative to cells from embryos, there are still questions over whether they are in fact equivalent to embryonic stem cells. This discovery opens up another exciting pathway for the development of new therapies in regenerative medicine. Australian stem cell scientists will be interested in applying this new technology in their research programs.”
From the UK SMC:
Christopher Shaw, Professor of Neurology and Neurogenetics at King’s College London and Director, Maurice Wohl Clinical Neuroscience Institute, said:
“This is an important advance because it is feasible – one embryonic stem cell line was generated from just two eggs. It also provides an alternative and more physiological method of reprogramming. Like many good experiments caffeine has made an invaluable contribution.“
Prof Mary Herbert, Professor of Reproductive Biology, Institute for Aging and Health at Newcastle University, said:
“This interesting report from the Oregon-based Mitalipov research group claims to have overcome a longstanding barrier to successful reprogramming of somatic cells by human oocytes. Provided that the experiments are reproducible in the hands of others, the findings offer the potential to accelerate progress towards the development of patient-specific embryonic stem cells to treat a range of degenerative diseases.”
Prof Alison Murdoch, Head of Newcastle Fertility Centre at Life, Newcastle University, said:
“The importance of the egg donor is again illustrated in this paper. Only high quality human eggs had the potential to reprogram somatic cells. It is remarkable that adding caffeine was the key that resulted in ES cell lines from all 3 donors.”
Dr Paul De Sousa, Reader, Centre for Regenerative Medicine, University of Edinburgh, and Chief Scientist, Roslin Cells Ltd., said:
“Fifteen years ago, the creation of Dolly the sheep by adult somatic cell nuclear transfer (SCNT) into an egg, and the derivation of human embryo stem cells, by the groups of Ian Wilmut and Jamie Thomson in the UK and US, respectively, inspired a vision for human “therapeutic cloning” whereby person specific embryo stem cells with a “pluri”-potency to make all of the cells of the human body could be created to model and treat human diseases. Realising this aspiration was challenged by the inefficiency of the SCNT process in animals and humans and the limited availability of human eggs for research. Almost a decade later scientific and public interest in SCNT was shifted by the ability to induce a state of pluripotency in adult cells by gene transfer, first reported by the laboratory of Shinya Yamanaka in Japan. This achievement also helped diffuse public concerns for the development of SCNT as a means for reproduction.
“This report from the group of Shoukhrat Mitalipov now provides a convincing demonstration that human SCNT can indeed be used efficiently to create pluripotent embryo stem cells. As such it will likely stir renewed interest in research and applications that had become discounted as impractical.
“The work buildson advances in SCNT validated by many researchers in diverse animal models since the original Dolly experiments, coupled with over a decade of committed effort of the group itself in primate and human SCNT and embryo stem cell derivation. The group’s success is attributed to optimisation of the component steps in the SCNT process beginning with egg quality and involving gentle forms of physical treatment and drugs to tightly control the onset of development during manipulation. Significantly, modest numbers of eggs recoverable from a single donor after hormonal stimulation were reproducibly sufficient to produce SCNT embryos and embryo stem cell lines with comparable efficiency and properties as can be obtained from fertilised embryos. Further research is required to assess how these cells will compare with those produced by gene transfer, although the comparative ease with which the latter are created means they are unlikely to be replaced any time soon.
“However, this achievement will undoubtedly renew interest not to mention concern for the use of eggs and SCNT for research and reproductive purposes. The remarkable and singular capacity of egg cells to “reprogram” developmental competence, provides valuable opportunities to identify the key factors which underpin this process. This knowledge alone would be valuable to both stem cell research and the treatment of infertility. This research can also underpin the development of new medical interventions to prevent the maternal transmission of mitochondrial diseases through embryo pronuclear transfer, which the group are also expert in. This application is distinct from the use of SCNT to produce children derived from an adult cell donor, although all such interventions demand comprehensive ethical and medical scrutiny to ensure that the risk of harm does not outweigh the intended benefit.”
Professor Robin Lovell-Badge, Head of Developmental Genetics, MRC National Institute for Medical Research, said:
“This interesting work at last brings the topic of therapeutic cloning in humans back into the realm of good science rather than controversy.
“This approach was proposed about 15 years ago as a way to derive patient-specific ES cell lines that can be used as a tool for research into the underlying causes and development of genetic diseases, and perhaps to derive treatments for these. However, although there have been proof-of-principle experiments using mice and monkeys, and several false claims and failed attempts, until now no one had been able to carry out the whole procedure with human somatic cells (such as skin cells) and human eggs to give ES cell lines (which have the ability to make any cell type in the body) that are genetically identical to the somatic cell donor.
“The scientists responsible for the latest work managed to overcome many of the technical problems experienced previously by others, making each step more efficient, and found that therapeutic cloning could work very successfully. This means that although early human embryo development is slightly different from that of other animals, including monkeys, we are not that unique.
“Patient-specific ES cell lines made in this way can now be compared with similar cells made by other more recent methods that don’t require eggs and cloning (so-called iPS, or induced pluripotent cells), but which may carry mutations and other abnormalities that could compromise their clinical application.
“With two methods available, it is exciting times for scientists trying to link underlying genetic causes to disease.“