“Isn't the California Institute of Regenerative Medicine (CIRM) out of business now that the Yamanaka and Thomson papers show human fibroblasts can be induced to pluripotency?” This was the most common question we heard from reporters after the publication last December of these two breakthrough papers. The questions implied that the availability of induced pluripotent stem (iPS) cells erases the need for CIRM-supported research on human embryonic stem (ES) cells. But, to paraphrase Mark Twain, reports of CIRM's death have been greatly exaggerated.

Alan Trounson and Richard Murphy.

The swiftly changing scientific landscape has seen the rise and fall of many favoured stem cell types and technologies. Some of what is de rigueur today will be dé classé tomorrow. Inducing pluripotency currently requires randomly inserting genes for transcription factors using engineered viruses1,2,3,4, whereas creating ES cells from primates using somatic cell nuclear transfer (SCNT) requires hundreds of mature oocytes5. These issues are but the tip of the iceberg; many complex problems remain unsolved. Numerous challenges and opportunities lie ahead in stem cell science, and the rapidly moving field requires continued funding by CIRM to meet them.

Challenges and opportunities in stem cell science

ES cells remain the best model for studying innate pluripotency, and they may yet turn out to be the cell of choice for therapeutic purposes, given the present liabilities of iPS cells.

In measuring cell potentiality, ES cells remain the gold standard. They were the source of data that identified the transcription factors necessary to reprogram somatic cells and enable those cells to re-differentiate into all the major germ lineages. ES cells remain the best model for studying innate pluripotency, and they may yet turn out to be the cell of choice for therapeutic purposes, given the present liabilities of iPS cells. Current iPS cell lines seem to require the induction (though not necessarily the insertion) of tumour-causing genes. They also require retrovirus insertion of multiple copies of the genes for each of the essential transcription factors, a process that is difficult to control. Further developments in research will no doubt solve these problems (and will be essential to obtain regulatory approval for the clinical use of iPS cells), but it is still too early to tell what other concerns might emerge.

SCNT should also be pursued to generate new embryonic stem cell lines, but interest in the technology may be on the wane. Obtaining very large numbers of human oocytes to produce disease-specific ES cells for research or to create histocompatible tissues for transplants poses significant ethical and practical dilemmas (though some of these problems would be ameliorated by more efficient methodology). Eventually, new in vitro fertilization techniques might allow the selection of just a very few eggs for reproduction. This would mean that more eggs would be collected than used; fertility patients could potentially donate the excess for research, but legal restraints and ethical concerns may make this approach impractical. Similarly, the possible use of animal ova as surrogate reprogramming cytoplasm for human nuclei is likely to be extremely inefficient6. Cell fusion also remains problematic, as the separation of donor and recipient nuclear DNA has not been adequately solved7.

The California Institute of Regenerative Medicine, headquarters pictured above, says recent stem cell breakthroughs are further reason to keep its doors open.

Even ES cells generated from fertilized eggs are not without problems that could be mitigated with further research. Cells need to be grown for long periods of time in order to reach numbers required for cell therapies. Selection methods in culture favour the rapidly dividing undifferentiated phenotype, resulting in the phenomenon of cell adaptation to the culture, which may include frequent aneuploidy and cell cultures that have properties of carcinoma cells8. The genetic stability of long-term stem cells of high passage number grown under 'bulk' culture conditions is an issue that needs to be closely examined. The absolute requirement for safety and efficacy in cell therapy is paramount, and regulatory authorities will need copious data to assess risk.

Another area for future research to explore is the potential of cell types that are readily available without being extensively expanded in culture, such as those found in the placenta9. For all sources of flexible cells, safety considerations will require close examination of the potentially unpredictable response of the organism to the delivery of stem cells. Mesenchymal stem cells, for example, seem to increase the mobility of metastatic cancer cells10.

There seems an obvious link between clinical trials of adult stem cells and the development of new cell types for therapeutic purposes. Interest is growing in clinical studies using bone marrow–derived cells, particularly mesenchymal stem cells, to treat a range of conditions including graft-versus-host disease, inflammatory lung disease, cardiac damage and autoimmune conditions such as multiple sclerosis. Stem cells that have been guided into the appropriate tissue stem cell and precursor populations show persuasive evidence of eventual therapeutic potential11.

Ultimately, clinical applications may combine several cell types, including adult bone marrow, placental, umbilical cord and iPS cells. In particular, diseases such as multiple sclerosis and perhaps juvenile diabetes may be treated more effectively by combining cell types that repair tissues and counter autoimmunity.

CIRM's plans

The diverse issues presented by ES cells, iPS cells and other cell types share one overarching theme: to move from interesting science to clinical utility, scientists will need to think laterally. With an eye to expanding the reach of more traditional funding bodies that focus on supporting research with well-defined preliminary data, CIRM has already committed $263 million to fund investigator-initiated research programs, training grants and programs for new investigators. For the future, CIRM is expanding funding programs and infrastructure to foster collaboration and cross-thinking.

To connect basic discoveries in regenerative medicine to their clinical applications, scientists need infrastructure and programs that foster collaboration. A number of new CIRM programs that address these needs have been initiated or are in the planning stages. For example, CIRM has recently issued a call for proposals to support the derivation and propagation of new pluripotent human stem cell lines and to devise new technologies for creating them. The goal of this program is to make available a wider array of cells for studying pluripotency and the influences that regulate differentiation. In addition, CIRM plans to fund research on patient-specific stem cells to study disease progression and drug toxicity and effectiveness.

CIRM has also requested applications to create teams of clinical and basic scientists who will work together to study specific diseases and facilitate the development of therapies or products that have a reasonable chance of being 'teed up' for market development within a five-year period. The program will be open to nonprofit and for-profit organizations, including biopharmaceutical companies. CIRM has the capacity, desire and determination to integrate the resources of the entire medical community — worldwide — in a collective effort to find treatments and cures. CIRM research dollars will, by law, be spent in California, but we will be seeking partnerships with scientists and organizations worldwide. Discussions with several government-sponsored organizations in Canada are ongoing.

CIRM is also in the midst of evaluating proposals for which it will provide up to $262 million in funds for the construction of research facilities in California in which human ES cell research can be carried out without the limitations imposed by US federal policies. In their proposals for CIRM funding, nonprofit institutions must pledge additional funds to these infrastructure projects. These funds could significantly exceed CIRM's contributions and will create one of the largest investments in medical research infrastructure in the state's history. This program lies at the core of our philosophy that a critical mass of basic and clinical stem cell researchers, working together under one roof with common goals and aspirations, will maximally accelerate scientific progress.

CIRM's ultimate goals are to help create the best research environment possible for California scientists and physicians and to expand the potential of innovative research by fostering links to the biopharmaceutical industries, whose ability to bring treatments into the clinic and ultimately to patients is clear. California has a long and successful history as an environment uniquely suited for this kind of work and has an extremely positive political awareness. The force of the state's intellectual energy was demonstrated by the passing of Proposition 71 despite the obstacles of US federal opposition, a state budget deficit, strongly articulated and negative conservative views, and interest groups with alternative agendas such as research limited to adult stem cells.

CIRM also has the distinct advantage of being governed by a broadly based Independent Citizens Oversight Committee whose members represent patient support and advocacy as well as academic, biotech and community groups. As a state agency, we are also subject to rigorous operational and conflict-of-interest regulations that ensure objectivity and transparency. Like any young, groundbreaking organization, CIRM has suffered and will suffer growing pains, but we consider our unique status and structure to be strengths rather than handicaps, because they ensure that all decisions are well vetted, strongly argued and made only after alternative strategies are assessed.

As a result of Proposition 71, some of the best stem cell scientists (including James Thomson, Shinya Yamanaka and Martin Pera) have been drawn either part time or permanently to leading research institutions in California. This is a natural process facilitated by the strong community support behind Proposition 71 and by the agreement of otherwise competing academic institutions to forge close alliances so as to achieve critical mass and raise additional funding. Both should be a model for other states and countries.

In conclusion, the creation of human iPS cells is indeed a major breakthrough in stem cell research, but it in no way signals the end of the need for CIRM. Many more breakthroughs are needed, and we are confident they will come. CIRM strives to meet the expectations of Californians who voted for Proposition 71: to use stem cell technology to treat incurable diseases and to repair injured tissues. When these goals are achieved, CIRM will happily close its doors.