STEM CELLS--science, ethics and politics at the forefront of biomedical innovation

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By Shane K. Green, PhD

In the early 1960s, two researchers at the Ontario Cancer Institute in Toronto performed a series of experiments that led to a remarkable discovery - and the 2005 Lasker Award for Basic Medical Research. Drs. James Till and Ernest McCullough, observed that bone marrow cells injected into irradiated mice grew as colonies of cells on the spleens of the mice. Each colony, Till and McCullough showed, grew from a single 'stem cell'. And so, the science of stem cell biology was born.

More than four decades later, on Nov. 25 2006, the front page of The Globe and Mail showed Dr. Till alongside Drs. John Dick (Princess Margaret Hospital), Peter Dirks (Hospital for Sick Children) and Robert Bruce (University of Toronto) and hailed the quartet as being in 'the vanguard of global stem-cell research'. Their most recent discoveries include stem cells responsible for the growth of cancerous tumours in the blood, brain and colon.

Few areas of biomedical research have captured the attention, imagination and passions of the public and scientific community more than stem cells. Stem cells are undifferentiated or partially differentiated cells with the capacity for self-renewal - they can make more stem cells - and for differentiating into the specialized cells that make up the tissues in our bodies (see Table 1). They are often compared to blank microchips, their ultimate fate and function dependent upon how they are programmed by cellular chemicals that serve as developmental signals.

Embryonic and Adult Stem Cells - A Primer

Not all stem cells are created alike. Embryonic stem cells (ESCs)are 'totipotent', meaning they can - and do - give rise to all the varied types of cells in the body. About five days after conception, a human embryo, or blastocyst, is a microscopic cluster of one type of cells within a hollow ball of another type of cells. The inner cluster of cells, appropriately named the inner cell mass (ICM), has the capacity to develop into a full human being. If the cells in the ICM are removed from the blastocyst and cultured in a laboratory, they retain their totipotency as ESCs and, in theory, can be shaped and coaxed, through controlled interventions, to become any type of cell.

Adult stem cells (ASCs) are present in many of our tissues and organs, such as bone marrow, skin and muscle, in which they produce new, healthy cells to replace those that have been damaged. Unlike the totipotent ESCs, however, multipotent ASCs do not appear to have limitless potential; they are more like chips with a few lines of programming, predestined to become only one or a few specific types of cells. Neural stem cells make neurons, blood stem cells make more blood cells, and so on.

Unfortunately, it seems that these cells may not be found in all vital organs. Some recent studies suggest, however, that ASCs may be able to form cells of other tissues, as well. Multipotent adult progenitor cells (MAPCs), for example, may form many types of cells that resemble bone, cartilage, liver and brain cells. Scientists are trying to find ways to coax ASCs into forming additional cell types that they normally would not.

While inherently interesting on a purely scientific level, much of the excitement around these master cells stems from their potential to provide a renewable source of healthy replacement cells and tissues to treat any number of diseases caused by defective, damaged or malfunctioning cells, including: insulin-producing pancreatic islet cells to treat diabetes; dopamine-producing brain cells to alleviate Parkinson's disease or functional motor neurons to restore movement in patients paralyzed through spinal cord injury. The list goes on.

Indeed, the immense promise of stem cells as therapeutic agents has given rise to at least 10 Canadian companies focused on the development of stem cell therapeutics, with an estimated 94 companies and counting worldwide similarly focused.

Few areas of biomedical research have captured the attention, imagination and passions of the public and scientific community more than stem cells.

However, between this tremendous potential and the large-scale realization of clinical utility lie years - perhaps a decade or more - of intense research to answer some fundamental questions: On a molecular level, what gives stem cells the capacity for self-renewal? What extra-, inter- and intracellular signals control their differentiation into specific cell types? How are these signals faithfully conveyed in the body or in the laboratory?

Setbacks, frequently characteristic of cutting-edge science, can seriously impede such promising research or even stop it in its tracks. Worldwide headlines celebrating a South Korean research team's breakthrough in creating ESCs from cloned human blastocysts in 2004 were followed by headlines expressing condemnation when the research was discredited as fraudulent and retracted in early 2006. Later, in October 2006, a US research team's exhilaration at having seemingly cured laboratory rats of Parkinson's-like disease by treating them with neurons created from human ESCs was sharply checked by their finding that those same cells caused brain tumours in the rats.

Ethical, legal and social implications of stem cell research

Further limiting our ability to answer these questions are still other important considerations - of ethics, of public approval, of preservation of human dignity and of protection against exploitation.

From a political standpoint, the most contentious of these issues marks a key point of divergence in discussions of the relative merits of ESCs vs. ASCs. Because embryos are destroyed when the ICM is extracted to create ESCs, a central question in the debate around ESC research is an age-old query - when does life begin? Does full human life and personhood, with all its attendant rights, begin at fertilization? Or do moral considerations, interests and personhood accrue gradually with embryonic or fetal development?

These are passionately disputed matters of conscience, of belief, but not questions that can be answered scientifically. Science can tell us that the primitive streak, which will go on to form the central nervous system - from which, it could be argued, personhood manifests - appears on day 14 of embryonic development. That observation, however, does not constitute incontestable proof of the beginning of life.

These dilemmas beg some additional questions: Should ESC research be seen as too morally contentious for our society to allow it to proceed? In reflecting on the whole of our moral obligations, do they require us to limit our exploration of this field to the less contentious ASCs and preclude us from pursuing ESC research? Or do they, in fact, require us to forge ahead along both lines of research, lest we forego potential treatments to assuage human suffering? Rather than looking to give a green or red light to the ESC field, should society seek a middle ground, or amber light, where scientists can pursue ESC research through the least objectionable means possible?

Each year, thousands of embryos are created for the purposes of reproduction by in vitro fertilization (IVF). Often more embryos are created than are implanted, leaving a significant number of unused IVF embryos in fertility clinics, where the vast majority are destined for indefinite storage in liquid nitrogen and eventual destruction. These unused IVF embryos have been presented as among the most desirable and least ethically troublesome source - on a relative scale -for ESC derivation, since the embryos are not created solely for research.

The quest to find so-called 'ethical stem cells' has led to efforts to re-program ASCs to more closely mimic the full potential of ESCs. It also motivated a proof-of-principle study, published online in Nature in August 2006, which demonstrated that ESCs can be generated from single cells removed from an 8-cell IVF embryo without interfering with the embryo's developmental potential. The removal technique, known as a blastomere biopsy, has been used safely for years to enable pre-implantation genetic diagnosis of IVF embryos. Nonetheless, countless commentaries published after the study suggested that even this technique is not free of morally and scientifically contentious issues.

Canada's research and regulatory environment

In addition to being a highly supportive environment for top-notch scientific research, Canada's research environment is marked by laudable efforts toward social responsibility as part of the scientific endeavour. For example, genomics research funded by Genome Canada and its provincial partners through regional genome centres, including the Ontario Genomics Institute (OGI) - which has funded several large projects focused on understanding stem cells, their relation to human disease and underlying technologies for working with them - now includes integrated research into genomics-related ethical, economic, environmental, legal and social issues (GE3LS). Another organization, Canada's Stem Cell Network (SCN) is made up of 70 biological scientists, social scientists and other scholars from across Canada, including those whose work focuses on ethical, legal and social issues (ELSI).

As a result, the annual meetings of the SCN are remarkable for their integration of science and social science, where a talk on cardiac stem cells might be followed by a discussion of the ethical issues coming out of the scientific research.

The final piece of Canada's stem cell puzzle is the permissive regulatory environment in which our scientists operate.

There seems to be, however, a misconception that if one were to compare the regulatory environments for ESC research in the US, Canada and the UK, they would fall along a spectrum with the US being the least permissive and the UK being the most permissive. True, the UK is the most permissive of this trio, allowing ESC research including the creation of embryos via IVF or somatic cell nuclear transfer (SCNT) - better known as cloning - for research purposes; but claims that Canada is more permissive than the US warrant some clarification.

In Canada, while ESC research is permitted, and indeed supported by the majority of Canadians, the Assisted Human Reproduction Act (2004) prohibits the creation of embryos for research purposes and bans SCNT for any purpose, whether the intent is reproduction or generation of cloned embryos from which to derive patient-matched ESCs. Canadian scientists are permitted to derive new ESC lines but only from unused IVF embryos donated for research purposes. Indeed, the Canadian Institutes for Health Research (CIHR) Guidelines for Human Pluripotent Stem Cell Research (2006) hold that research to derive and study human ESC lines is permitted if and only if: embryos are created for reproductive purposes (i.e. unused IVF embryos); free and informed consent of the embryo donors has been obtained and no payment was provided in exchange for the gametes used to create the embryo.

In the US, by executive order of President George W. Bush, federal funds may be used only for ESC research on stem cell lines in existence prior to August 2001 and may not be used to support SCNT in any form. In July 2006, President Bush vetoed The Stem Cell Research Enhancement Act of 2005, which would have allowed federal funds to be used for the creation of new human ESC lines from unused IVF embryos, as in Canada. Yet, in spite of the veto, ESC research opportunities are plentiful, as the prohibition extends only to the use of federal funds.

As a result, a number of states including California, Connecticut, Illinois, Maryland, Massachusetts, New Jersey and Wisconsin, have created initiatives to preclude scientists' reliance on federal funds by providing state funding for ESC research. Also, unlike in Canada, SCNT has not been criminalized at the federal level in the US. A number of states have banned SCNT, but others have not, and still others have legislation that explicitly permits its use for research purposes. So, in effect, scientists in some US states enjoy a regulatory environment for ESC research closer to that found in the UK and certainly more permissive than that of Canada.

The road ahead

Reports of small-scale preclinical successes using ESCs and ASCs abound, yet the truth of the matter is that we do not yet know how the therapeutic utility of the two compare. Here, scientific research - and only scientific research - can provide answers. Without intense research in both areas, we will never know. Fortunately, cutting-edge research is ongoing on both fronts here in Canada, enabling our scientists to continue in their place at the vanguard of stem cell biology for many years to come.

Shane K. Green has a doctorate in medical biophysics from the University of Toronto (U of T) and studied bioethics at the U of T Joint Centre for Bioethics and the American Medical Association in Chicago, IL. He has served on the Research Ethics Boards of the Centre for Addiction and Mental Health and Sunnybrook Health Sciences Centre, in Toronto. Shane is currently Lead, Social Impact Programs at the Ontario Genomics Institute (OGI) in Toronto (www.OntarioGenomics.ca). OGI is supported by operating funds from Genome Canada and Ontario's Ministry of Research and Innovation.