Cellular divisions

Saturday, October 17, 2009

Peter Andrews, Scientific Coordinator of the ESTOOLS programme, argues that a lack of knowledge about the ethics of stem cell research, its patenting and uses, could stifle potentially useful research

Many questions arrive on the website of ESTOOLS, the FP6 project that I co-ordinate on pluripotent stem cells, asking about the consequences of our research – for example, can we help to investigate or treat specific patient diagnoses? Much of this project's effort focuses on fundamental biology that will underpin eventual applications – understanding the nature of the stem cells, their self-renewal and differentiation – but we are also constructing models of some neurodegenerative diseases based on this biology, hence comments and questions like these also arrive on the website:
• "We know the gene (causing a neurodegenerative illness) that has to be treated. I am 46 and my daughter is 20; we both carry the infected gene. We are willing to partake in any trials or treatments";
• "Tell please, do you plan to begin clinical tests for children with a cerebral paralysis";
• "Damages in the spine, because due to an accident I had a lesion... possible to par­ticipate in future applications in humans?"

While therapies themselves do not feature in our project, the new knowledge from our work feeds into other parallel projects that focus on pathways to therapies. The short- and long-term goals that underpin the wide scope of activity in embryonic stem cell research range from a better understanding of abnormalities in embryonic development that cause birth defects, to the need for a wider perspective in human developmental biology that will underpin our understanding of a wide range of disease processes.

The structures and systems that meet society's norms for the wellbeing of its members require associated healthcare and disease prevention programmes that are expensive. The overall rationale for embryonic stem cell research is the challenge of solving medical problems that are intractable by other methods. Medical applications of this research are not restricted to cell therapies. For example, there is also potential to change and improve how drugs are evaluated and tested. The opportunities for industry are large.

Opinions matter
The exponential increase in biological discovery continues to create tensions in the relationship of science with society. As always, suspicion raised by new technologies is not always fully compensated by education and awareness.

Embryonic stem cell research is among the areas of science on which a wide range of perhaps incompatible opinions impinge. Generally, there is wide support in western societies for investigations with human embryonic stem cells (observed for example in the Eurobarometer survey 'Europeans and Biotechnology in 2005' or 'Results for America' surveys). This support is strongly linked with the potential of this research to lead to treatments for currently incurable diseases (eg. Alzheimer's, diabetes, Parkinson's, spinal cord injuries, etc.).

However, in most cases, the derivation of a human embryonic stem cell line necessitated destruction of an early human embryo at the stage of morula or blastocyst: four to seven days after conception. Destruction of an embryo at any stage of development arouses some to oppose embryonic stem cell research regardless of the potential benefits that may accrue, even though all other futures for the embryo in question would likely involve a similar fate. Others consider that embryos acquire human status at 14, or 40, or 120 days after conception, or even only at birth. In some countries, a legal consensus has been reached, considering the destruction of human embryo for research as an acceptable process if done no later than 14 days after conception. At this stage it can no longer divide to form twins or triplets and some cells start to be identifiable as committed to form the future nervous system.

These differing public opinions of different groups and lobbies have shaped national and international legislations in different ways over several years. Several countries prohibit or heavily restrict the use of human embryonic stem cells and derivatives (eg. Germany, Austria, Poland, or Ireland), while others have a more liberal approach (eg. United Kingdom, Sweden, Belgium). The recent scientific breakthrough by Shinya Yamanaka to reprogramme adult and fully specialised cells into embryonic-like cells – termed induced pluripotent cells – opened a new area. This work does not require the use of embryos, but does bring a new suite of ethical issues. These sit alongside a new range of scientific questions, and research with 'original' human embryonic stem cells seems far from rendered redundant.

Operational challenges
For many uses, we need to be able to grow large numbers of cells (for example, enough for transplantation, cell banking) that do not exhibit signs of adaptation to culture conditions. These cells must remain as much as is possible purely embryonic stem cells. Some genetic modifications that underlie culture adaptation are easy to monitor (loss or gain of a chromosome); others are traceable but less obvious (for instance, mutation in specific genes). Yet other types of modifications affect the epigenetic level of genome identity that acts as a shell rendering some sections of the genome unreachable while giving proprietary access to others. Epigenetic changes are extremely important for defining the identity of a cell – a muscle cell would exclusively give access to muscle-specific genes and would hide other part of its genome, while an embryonic stem cell would hide all differentiation-specific genes and leave 'open' the pluripotent cell specific genes. The context in which the cell evolves (ie. in vitro or in vivo) often influences its epigenetic modification, which is not straightforward to monitor. But with cell therapies in mind, it is of primary importance to know the exact cell identity of the stem cell cultures in our laboratories.

Embryonic stem cells are of paramount interest because they can produce any cell lineage. Within the framework of the questions 'how to initiate differentiation processes' and 'how to control these processes', we need to take further the characterisation of the checkpoints and related signals leading to specific differentiating cells. We need also to isolate pure populations of the differentiating cells. To transplant even one embryonic stem cell to a patient would create risks of tumour development. For some diseases, especially neurodegenerative diseases, the transplanted cells will need to integrate in the tissue in such a way that it is viable, it does not affect other functions of the organ or tissue and obviously that it cures the pathology.

The risk of rejection is still important but a solution may be at hand with Yamanaka's discovery of the induced pluripotent stem cell, and its possibility to generate embryonic stem cells from a patient's differentiated cells.

Science spillovers
Until Yamanaka's breakthrough, the cell lineage model was a unidirectional path from the totipotent zygote cell evolving in stages towards embryonic pluripotent stem cell, tissue-specific multipotent stem/progenitor cells and finally fully differentiated functional cell. Scientists have started to investigate the sets and patterns of signals needed in order to obtain every differentiated cell type of the body. This is a gigantic task requiring the help of systems biology. But many cellular contexts of these pathways are beyond accurate modelling in bioinformatics.

The recent development of induced pluripotent stem cells could open new opportunities by breaking up those complex systems into individual bi-directional models that, in turn, could be assembled. We could for example study how embryonic stem cells become neural stem cells and how to revert the neural stem cell to the embryonic stem cell state. From the neural stem cell all the branches reaching to brain-based differentiated cells could be individually studied. Put together we could obtain the full picture of all neural lineages including signals involved at each checkpoint.

Currently there is a map of the full developmental tree of cell lineages for just one animal, the microscopic worm Caenorhabditis elegans. For this work a Nobel Prize was awarded in 2002. From the induced pluripotent stem cell field and with the help of systems biology, lineage development at cellular level of more complex organisms (including humans) could be within our grasp.

Discussion of applications to emerge from embryonic stem cell research often focuses on cell replacement therapies. But stem cells can also be used to create tissue models that can be used for in vitro screens of new drugs, and this may have a larger, earlier impact. With induced pluripotent stem cells, in vitro models can be produced from a patient's cells to provide the exact genetic environment of particular human diseases. As today diseases are often studied in animal models that only mimic human symptoms, this may reduce the need for some animal testing – obviously an advantage for those who care for animal health and welfare, in parallel with greatly improving the quality of the research model.

Patent laws and consequences
It is sometimes said that patents on products derived from embryonic stem cells, and consequent personal or corporate incomes beyond some well-deserved norm, are inappropriate for publicly-funded work. Yet this is standard in other fields: national grants to young writers lead to books whose commercialisation does not reimburse the grant provider. The public receives financial returns through corporate and personal taxation on those who profit; patentability is necessary for this outcome. To restrict patent­ability might be justified morally or ethically, but there are moral or ethical reasons supporting the opposite position. In our global economy, European publicly-funded discoveries are translated into patents overseas; the European public then pays again to benefit.

Strong voices, but whose?
How does the lay onlooker form an opinion? Many issues in science can be difficult to grasp fully. Laboratory scientists and patient groups have sometimes been absent from decision processes that are often limited to discussion between lawyers, ethicists, religious leaders and business. Do research funding agencies need better decision tools? In European democracies, who should decide where the acceptable boundaries lie? The European Commission, through its financial support for the ESTOOLS consortium, is supporting a meeting of the general public, ethicists and stem cell scientists, including Shinya Yamanaka, in Lisbon in May 2010, to consider the latest progress, issues and possibilities in the science and ethics of embryonic stem research. This meeting will engage with the ethical problems raised by iPSCs, and the wishful thinking that all ethical problems will disappear if all work on human embryonic stem cells is stopped. Some ethical problems will disappear, but new ones will emerge. We simply do not know enough now, nor in the near future will we, to be able to take any responsible decision to limit research to any one cell type.

ESTOOLS will hold its final International Public Symposium and Ethics Workshop 'Stem Cells in Basic Biology and Disease' in Lisbon 26-28th May 2010.

Authorship of this article was led by Sébastien Duprat (ESTOOLS Training and Outreach Manager) with input from Andrew Smith (ESTOOLS Project Manager), Göran Hermerén (ESTOOLS Director for Ethics) and Peter Andrews (ESTOOLS Coordinator)