Perspectives
Ethics
Volume 196 - Issue 10

Tempering hope with realism: induced pluripotent stem cells in regenerative medicine

Authors:  Ronald K F Fung, Ian H Kerridge, Loane L C Skene and Megan J Munsie

Med J Aust 2012; 196 (10): 622-625. || doi: 10.5694/mja11.11039
Published online: 4 June 2012
The moral panic surrounding human embryo research has fuelled unrealistic public expectations for the imminent success of induced pluripotent stem cell therapyTraditionally, treatment for chronic degenerative conditions revolved around reducing symptoms and improving physiological functioning in the hope of gaining some (often limited) increase in life expectancy. However, in the past decade, the advent of ...
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The moral panic surrounding human embryo research has fuelled unrealistic public expectations for the imminent success of induced pluripotent stem cell therapy

Traditionally, treatment for chronic degenerative conditions revolved around reducing symptoms and improving physiological functioning in the hope of gaining some (often limited) increase in life expectancy. However, in the past decade, the advent of “regenerative medicine” has raised hope that normal structure and function may be restored in these intractable conditions, by harnessing pluripotent stem cells (cells that can be converted into all cell types of the human body) to produce specialised cells and replace diseased cells in vivo.

Until recently, pluripotent stem cells could only be derived from human embryos, which are destroyed when harvesting the embryonic stem cells. Although these embryos are left over from infertility treatment and would otherwise be destroyed, their use for research remains ethically contentious and is governed by tight statutory constraints.1

In 2007, it was discovered that somatic cells (eg, fibroblasts obtained from patient skin biopsies) could be reprogrammed into pluripotent stem cells (human induced pluripotent stem cells [iPS cells]) without using, or destroying, human embryos. Particular genes are inserted into somatic cells to cause them to revert to an embryonic stem cell-like state.2 As iPS cells are derived from a patient’s own cells, they are less likely to cause immune rejection. For these reasons, iPS cell therapy has been championed as a superior, “ethical” alternative to embryonic stem cell-based approaches.

While iPS cell research holds significant promise, its purported benefits may have been overstated by certain religious groups opposed to research involving human embryos, by stem cell scientists keen to embrace a technology free of the regulations governing human embryo research, and by a patient community willing to believe the rhetoric of scientific “advance”. For example, the group Australians for Ethical Stem Cell Research has labelled iPS cells as “functionally identical” to human embryonic stem cells but “ethically uncontentious” in that the technology “does not use women’s eggs and does not create and destroy human embryos”.3 Prominent scientists in iPS cell research have said that “the promise of regenerative medicine could soon be met”4 and that “we could be there in five years’ time for diseases that are well understood — like Parkinson’s”.5

The public has seemingly accepted this rhetoric. The majority (188 out of 264) of the public submissions to the 2010 Legislation Review Committee (chaired by the Honorable Peter Heerey, QC), which recently reviewed the federal legislation governing embryo research and human cloning, did not support the use of human embryos for research and supported the use of iPS cells instead.6 Increasingly, patients are asking clinicians about stem cell therapies, with a growing number of Australians attracted by overseas clinics offering unsubstantiated stem cell “therapies” (lacking evidence of efficacy or safety) for various chronic diseases. The practice of seeking stem cell treatment overseas has been termed “stem cell tourism”.7

However, the optimism surrounding cell replacement therapies (including treatment with iPS cells) disregards the inevitable delays in their effective translation into clinical practice.

Here, we consider Parkinson disease — one of the key candidate diseases for regenerative medicine. Therapy with iPS cells has been proposed as a potential “cure” for Parkinson disease. This would involve autologous transplantation of midbrain dopaminergic neurones, which could potentially integrate into the host brain and restore motor function (as demonstrated in animal studies) (Box).9 However, many barriers are yet to be overcome before this procedure can be adopted in the clinic. Some of these barriers, such as assessing the cognitive status of patients and obtaining consent, are particularly salient in Parkinson disease, but many are also relevant to other diseases targeted by iPS cell therapy.

Scientific and clinical challenges

While embryonic stem cells are harvested directly from human embryos, iPS cell technology requires reprogramming of somatic cells towards pluripotency. Initially, retroviral vectors were used to deliver the pluripotency-inducing transgenes into somatic cells.2 However, as retroviral vectors may randomly integrate into the host genome and trigger the expression of cancer-promoting genes, scientists have investigated alternative techniques, such as removing transgenes from genomic integration sites once reprogramming is complete, delivering the transgenes via non-integrating DNA microcircles, and exposing somatic cells to a cocktail of small molecules. These approaches have yielded varying reprogramming efficiencies.10

As iPS cell research advances, techniques for producing iPS cells will probably become safer and more efficient. However, this also means that reprogramming methods are at risk of rapidly becoming obsolete, and it may be difficult to generate the impetus to initiate clinical trials. Indeed, the field of reprogramming is moving so quickly that it may be possible to directly reprogram a patient’s somatic cells into replacement cells of the desired lineage without the pluripotent intermediary. To date, neurone- and hepatocyte-like cells have been successfully derived by this method, but their functional properties remain to be established.11,12

A challenge that applies to both iPS cell- and embryonic stem cell-based therapies is deriving clinical-grade dopaminergic neurones. Exposing pluripotent stem cells to specific growth factors successfully induces differentiation into dopaminergic neurones, but leaves behind contaminating non-dopaminergic cell types in the culture.13 Also, to generate the correct type of dopaminergic neurone (ie, of midbrain phenotype, as implicated in Parkinson disease), it may be necessary to include an additional cellular feeder layer or to overexpress certain genes important for early midbrain development.14 But it is unclear whether these strategies, which were tested on embryonic stem cells, work with iPS cells. Subtle differences between iPS cells and embryonic stem cells have been reported at the molecular level, as iPS cells may be imprinted with information tracing them back to their cell of origin.15 Even after continuous passaging in vitro to attenuate these epigenetic anomalies,16 iPS cells may still have less stability, homogeneity and ability to differentiate into all cell types than embryonic stem cells (which possess a more fully “naive” ground state of pluripotency).15 As grafts containing a low proportion of dopaminergic neurones may cause side effects such as dyskinesia (sudden switches between mobility and immobility),17 attaining high-purity yields of midbrain dopaminergic neurones is clearly an important prerequisite to conducting first-in-human trials.

Another limitation of iPS cell therapy is that deriving immunologically matched grafts for each patient would require generating, expanding and testing multiple iPS cell clones before obtaining one suitable for transplantation — a time-consuming and costly process.18 Contrary to the assumption that autologous iPS cell therapy eliminates the risk of immune rejection, a recent study showed that abnormal surface antigen expression in iPS cell-derived grafts induces a T cell-mediated immune response and tissue damage when transplanted into genetically identical recipients.19 Therefore, as with embryonic stem cell-based therapies, scientists would need to assess the stability and immunogenicity of each iPS cell clone (for which reliable and efficient assays are currently lacking) before transplantation.18 Because of these practical limitations, any future application of iPS cell therapy, except for the select few who can afford personalised treatment, may involve public stem cell banks with limited iPS cell lines that represent sufficient genetic diversity to be compatible with most of the population. This raises important ethical concerns about resource allocation, donor consent and equity of biological access.20

The absence of reliable animal models of Parkinson disease poses an additional barrier to translational research on iPS cell therapy. Although a translational gap exists whenever moving from preclinical to clinical testing of any medical intervention, in Parkinson disease research the animal models are notoriously unreliable in predicting the patient response. Many of these models rely on exposing animals to a toxin that acutely and selectively depletes nigrostriatal dopaminergic neurones, and thus fail to reflect the progressive deterioration or the broader phenotype associated with the disease.21 For example, a novel class of drugs (monoamine uptake inhibitors) that had yielded promising results in toxin-based primate models produced limited functional improvement and many side effects when tested in patients with Parkinson disease.22 Thus, animal models may have limited value in predicting the safety and efficacy of iPS cell therapy for humans.

Assuming iPS cell research is translated into clinical practice, patients receiving therapy will require long-term monitoring because of the potential risk of serious, irreversible harm. As with embryonic stem cell-based therapies, grafts contaminated with undifferentiated cells may cause tumour formation. This was tragically illustrated when a patient with ataxia telangiectasia developed a multifocal brain tumour after travelling overseas to receive neural stem cell “therapy” from an unlicensed clinic.23 In response to the real risk of tumour formation, scientists have developed molecular imaging technologies to monitor grafts after transplantation, but these currently lack the spatial resolution and sensitivity to be adopted clinically.24 Another strategy is inserting “suicide genes” to render cell lines susceptible to specific drugs that can be administered if the graft undergoes malignant transformation. However, this approach is untested in humans, and the administered drugs may have non-specific toxicity.25

Even if iPS cell therapy is shown to be safe, it cannot be assumed that it will be beneficial. First, as Parkinson disease is a multisystem disorder, symptoms such as dementia and autonomic dysfunction, which are caused by pathology in non-dopaminergic systems (and may be as disabling as the motor symptoms), may not be reduced by dopaminergic grafts alone.26 (The caveat is that a proposed treatment may not need to resolve all disease pathology to provide substantial benefit, and thus its use may have merit.) Second, virtually all previous animal studies have targeted the striatum as the primary site of graft placement, but this one-size-fits-all approach may be unsuitable for humans, as the extent of dopaminergic depletion varies between individuals and may involve extrastriatal regions.26 Third, grafted neurones may not fully integrate into the host’s neuronal circuitry, resulting in minimal functional improvement.27 Finally, the transplanted neurones may be susceptible to degeneration within the toxic environment of the diseased host brain.28 Although co-transplanting neurones with neuroprotective molecules may hinder disease progression in the host brain and hence improve survival of the grafted cells, this approach remains unproven.29

Ethical and regulatory challenges

The clinical testing of iPS cell therapy also raises important ethical concerns given the substantial risks involved. First is the degree to which iPS cells must be shown to be safe in animal models before first-in-human studies are justified. Even when it is decided that human trials can begin, serious questions remain about subject recruitment, safety monitoring and consent. The high prevalence of dementia and dependency among patients with Parkinson disease may limit their ability to make voluntary informed decisions about trial participation.30 The challenge of obtaining informed consent is compounded by the limited scope and predictive value of the various clinical tests that have been developed for assessing individual decision-making capacity.31 Alternative mechanisms will be required to increase participation of patients with Parkinson disease in iPS cell therapy trials, including research advance directives and the identification of appropriate surrogate decisionmakers.32 The types of research to which surrogate decisionmakers may consent and the degree of risk to which they may subject the patient will also require clarification.

Furthermore, as with gene therapy trials, subject selection for clinical trials of iPS cell therapy is invariably problematic. Recruiting patients with mild Parkinson disease may be preferable, as they are more likely to benefit from the procedure and have the capacity to provide informed consent. However, subjecting relatively “healthy” patients to the uncertain risks of stem cell therapy is controversial, as their condition is stable and manageable by other available treatment options. From an ethical standpoint, it may be preferable to recruit patients with late-stage Parkinson disease who lack alternative treatment options. Yet these patients may be susceptible to unrealistic expectations of efficacy, be unable to provide informed consent (although surrogates perhaps could) and be least likely to benefit from iPS cell therapy because of the advanced and potentially irreversible state of their disease.

Conclusion

iPS cell technology clearly has the potential to transform the field of regenerative medicine and may one day be able to deliver personalised therapeutics for a broad spectrum of chronic degenerative conditions, not merely limited to Parkinson disease. Preliminary results from animal studies have been promising and there are compelling reasons for public optimism and support for continued research. Initially, the benefit of iPS cell technology for medicine may be realised in disease modelling and screening of promising new drugs.33 However, we must recognise that the scientific, clinical and ethical issues facing iPS cell therapy are as complex as those presented by embryonic stem cell-based approaches and are likely to delay its translation from bench to bedside. iPS cell therapy may indeed prove beneficial in the future, but we must be careful that the rush to embrace its potential is tempered with realism and is not just a manifestation of “moral panic” over human embryonic stem cell research.

Glossary of key terminology

Stem cell

A cell with the ability to divide indefinitely in culture and to give rise to specialised cells. Examples include adult somatic stem cells, embryonic stem cells and induced pluripotent stem cells (iPS cells).

Embryonic stem cell

A type of pluripotent stem cell derived in the laboratory from the inner cell mass of a preimplantation in-vitro fertilisation embryo (blastocyst).

Induced pluripotent stem cell (iPS cell)

A type of pluripotent stem cell created in the laboratory from a non-pluripotent cell, typically an adult somatic cell, by reactivating the expression of specific genes associated with pluripotency.

Potency

The capacity of a stem cell to differentiate into different cell types. Embryonic stem cells and iPS cells are pluripotent and can differentiate into cells from all lineages of the body.

Transgene

A segment of genetic material (DNA) that is transferred from one organism to another organism.

Autologous transplantation

The transplantation of cells, tissues or organs that have been derived from a particular person back into the same person, with perfect immunological compatibility between donor and recipient.

Stem cell tourism

The practice of patients seeking unproven stem cell-based treatments outside the accepted clinical trial framework. Many companies offering such “treatments” use aggressive online advertising strategies to recruit patients and charge considerable sums of money, despite little or no evidence of efficacy or safety of the treatments.

Differentiation of patient-matched induced pluripotent stem cells (iPS cells) into dopaminergic neurones for transplantation into patients with Parkinson disease*

* Reproduced with permission (in abridged form) from Kiskinis and Eggan.8

Authors

  • Ronald K F Fung BSc(Adv)1
  • Ian H Kerridge MPhil, FRACP, FRCPA1,2
  • Loane L C Skene LLB(Hons), LLM, LLD3
  • Megan J Munsie BAppSc, MRepSc, PhD4
  • 1. Centre for Values, Ethics and the Law in Medicine, Sydney Medical School, University of Sydney, Sydney, NSW.
  • 2. Haematology Department, Royal North Shore Hospital, Sydney, NSW.
  • 3. Melbourne Law School, University of Melbourne, Melbourne, VIC.
  • 4. Education, Ethics, Law and Community Awareness Unit, Stem Cells Australia, University of Melbourne, Melbourne, VIC.

Correspondence: rfun6468@uni.sydney.edu.au

Competing interests

Ian Kerridge is a board member of the New South Wales Stem Cell Network and was a member of the 2006 Lockhart Committee, which reviewed the federal legislation on embryo research and human cloning. Loane Skene was Deputy Chair of the Lockhart Committee and a member of the Heerey Committee, which reviewed the same legislation in 2011. Megan Munsie was formerly Senior Manager (Research and Government) at the Australian Stem Cell Centre and is currently Director of the Education, Ethics, Law and Community Awareness Unit at Stem Cells Australia.

References

Provenance: Not commissioned; externally peer reviewed.

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