Ethics and reprogramming: ethical questions after the discovery of iPS cells

Reprogramming allows us to turn any cell of the body into a stem cell. This discovery surprised many scientists and changed the way they think about how cells develop. Does the new technology also change ethical discussions about stem cell research? What new questions does it raise?

Use of human embryonic stem cells (ESCs) for medical treatment and research is debated because of the moral implications of using human embryos. In 2006, a method was developed for artificially transforming skin cells (and other cell types) into ‘induced pluripotent stem cells’ (iPSCs), cells that have similar abilities as ESCs.

Do we still need ESCs? Should researchers switch to using iPSCs to avoid moral issues? What moral issues do iPSCs pose?

iPSC treatments will likely require donor’s cells to undergo genetic alterations. Will it be acceptable to people that their cells have been modified?

Many questions still remain about how cell reprogramming works and how closely/exactly iPSCs resemble ESCs.

Researchers believe that both iPSCs and ESCs are important in answering how stem cells grow, replicate and create specific types of cells.

Research on ESCs has led to the discovery of iPSCs and has greatly helped understand how iPSCs work. In turn, iPSCs offer new insights into how ESCs naturally control pluripotency and differentiation. Knowing more about both iPSCs and ESCs will greatly help researchers develop reliable methods to control the cells and use them in medical treatments.

One benefit to developing treatments with iPSCs is that transplanted iPSCs (made from a patient’s own cells) will not be rejected by the immune system of the patient.

A challenge to developing iPSCs treatments is that procedures to make iPSCs will require tailoring to each patient’s genetic background and needs, making iPSC treatments labour intensive and expensive.

The practicality of getting iPSC or ESC cell therapies to patients will be challenging. Specialists will need to be hired to deliver treatments and laboratories will need to be built to create and distribute large amounts of cells for treatments.

In 2006, Shinya Yamanaka showed that skin cells can be ’reprogrammed’ into stem cells. Like embryonic stem cells, these lab-grown ’induced pluripotent stem cells’ or iPS cells can make all the different cells found in the body. This discovery has led some people to argue that research on human embryonic stem cells is no longer necessary, and that human iPS cells solve the ethical dilemma posed by human embryonic stem research. But many questions remain about how reprogramming works. Most scientists think more research is needed to establish how similar or different iPS cells and embryonic stem cells really are.

Can we decide today whether iPS cells could or should replace embryonic stem cells? And would using only iPS cells resolve all ethical dilemmas about this research? To answer these questions, we need to consider both current scientific understanding and moral aspects of the issues: Are there any ethically relevant differences between iPS cells and embryonic stem cells?

Many scientific questions remain about both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). There is considerable disagreement among scientists about how these two types of cells may compare in terms of safety and likely effectiveness (‘efficacy’) in future cell therapies.

Immune response

As with organ transplants, cells transplanted into the body may be rejected by the patient’s immune system. Since hiPSCs can be made from the patient’s own cells, e.g. skin cells, it is hoped that reprogramming can provide a source of patient-specific specialized cells that would be recognized by the patient’s body and would not be rejected. However, producing tailor-made cells to treat individual patients would be a time-consuming, slow process and is likely to be costly. Many scientists believe it is more likely that large banks of cells with different immune properties will be created so that acceptable matches can be found for most patients. These cell banks could contain cells made from hESCs or hiPSCs.

Safety standards for cells used in patients

The first clinical trials using hESCs are just beginning, focussed on eye disorders. No iPS cells have yet been grown at ‘clinical grade’ – the quality standard required for use in patients.

The first clinical trials using hESCs are beginning, focussed on eye disorders. No iPS cells have yet been grown at ‘clinical grade’ – the quality standard required for use in patients.

Both hESCs and hiPSCs can self-renew (copy themselves) indefinitely and this property must be turned off to prevent tumours from forming. In addition, the reprogramming techniques involve manipulating the genes inside the cells and hiPSCs may also be affected by the age of the cells they are made from. These issues pose challenges for scientists attempting to grow cells with controlled characteristics for use in patients. Some solutions have been proposed for such problems but further research is needed to assess all the effects of the reprogramming process and produce hiPSCs suitable for clinical use. Since the cells are patient specific, standardization will be a challenge. This means it is likely to be some time before reprogrammed cells will be approved for use in patients by regulatory bodies such as the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) in the USA.

The safety and efficacy of hESC- or hiPSC-based therapies are complex issues, and it is not yet possible to draw any conclusions about whether one of these cell types is safer or more valuable for therapeutic use than the other. In both cases, more work is needed to fully understand how the cells behave and how they can be controlled to produce the particular specialized types of cells needed for treating certain diseases.

An important ethical consideration is accessibility of any new stem-cell-based therapy. Who should these therapies be available to and when? Will they be available only to rich patients in developed countries, or will they also be accessible to those in developing countries who may not be in a position to pay for the treatment? It seems difficult to identify any clear differences between hESC- or hiPSC-based therapies in this respect. Some points to consider are:

  • Either hESC- or hiPSC-based therapies would need a well-developed healthcare system with the necessary infrastructure for producing and distributing the cells, and highly trained specialists to manage and deliver treatments.
  • hESC-based therapies may not be made available to patients in the countries where use of cells from early embryos is viewed as morally unacceptable. However, it is not yet clear whether such moral objections will in reality prevent patients from obtaining life-saving therapies when they become available.

If it becomes possible to produce therapeutically useful hiPSCs from umbilical cord blood or other easily accessible sources of cells, this may make hiPSC-based therapies more readily accessible in the future.

Scientists have shown that iPSCs made from a mouse can be inserted into a mouse embryo, where they can contribute to the mouse as it grows. hiPSCs could also in theory be turned into sperm and egg cells and used to make a new embryo. Although this has not been done using human cells, some people argue that it is unacceptable to use any cells in research that have the potential to develop into a new life. If hESCs have a special moral status because they can contribute to a human embryo under appropriate conditions, then hiPSCs should have the same special moral status if they, too, can contribute to a human embryo. Some also think hiPSCs do not resolve the discussions about use of embryonic cells in research because iPS technology was developed based on knowledge obtained by studying hESCs - though the force of this argument is debated.

But if we assign hiPSCs a special moral status, then should we also give that moral status to the skin cells from which they were derived? Some argue that there is a difference between what a cell can be converted into using human technology, and what its ‘active potency’ or ability is under natural conditions. They argue it is the cell’s active potency that determines what the cell is. For example, simply because a house can be converted into a pile of rubbish by the action of a tornado does not eliminate the important differences between a house and a pile of rubbish.

Other, less debated differences between hESCs and hiPSCs concern their use as tools for drug testing and in disease studies, their possible application in reproductive medicine and the impact of hESC and hiPSC research on women. These areas do not constitute ethical dilemmas to the same extent as the issues above, although there is some scientific debate regarding which type of cells is more suitable as tools for drug testing and disease research.

There are still many scientific questions that need to be answered before any final judgement can be made about whether hiPSCs could or should eventually replace hESCs in research and future therapies. Most scientists agree that further research is needed on both types of cells in parallel.

The most contested differences between hESC- and hiPSC-based therapies concern patient safety, effectiveness for use in treatments, the possibilities of standardization, accessibility to large numbers of patients and ethical controversy about the moral status of the cells. All these issues are ethically relevant and none can yet be answered definitively. Research on both hESCs and hiPSCs is in rapid development and as the scientific picture develops, the moral implications of both scientific and ethical differences between these cells must be re-assessed.

Text and material in this factsheet created by Kristina Hug.

The web version of the text was drafted by Zara Mahmoud

Revised in 2012 by Emma Kemp and reviewed by Kristina Hug and Göran Hermerén.

Reviewed and updated in 2018 by Göran Hermerén.

Lead image © Fibroblast image by Tilo Kunath. iPS colony image by Daniela Evers from the Institute of Reconstructive Neurobiology, University of Bonn