It is the year 2053. A mere century after James Watson and Francis Crick resolved the structure of DNA, scientists at the forefront of medical research have just announced the first successful regeneration of a human heart. After re-routing the blood of Jón Sigurdsson, a terminal heart-failure patient, to an advanced cardiac assist device and removing most of the damaged organ, doctors thawed a frozen tube of Jón’s personalized stem cells—established in 2013 from embryonic stem cells created through somatic nuclear transfer—and injected them into his chest. Thanks to a sophisticated cocktail of growth factors, the new stem cells target the damaged area and rapidly get to work, perfectly rebuilding a youthful heart. Several weeks later, Jón is discharged in excellent health. Regenerative medicine provided him with a new kidney ten years ago, and subsequent double knee regeneration gave him renewed mobility. Now his new heart will soon have him running a six-minute mile again. Jón Sigurdsson is 100 years old.
This scenario might sound like pure science fiction, but it could become reality a few decades from now. Stem cells have attracted huge scientific and public interest, not only because they bear the promise of miracle cures for age-related heart diseases, but also because their medical use is so appealing: stem-cell therapy could augment the human body’s own regenerative capacity, which declines as we grow older. The appropriate source of cells for these therapeutic applications is hotly debated, but the technical feasibility of generating replacement tissues and organs is well within realistic projections. Nevertheless, although the prospect of rejuvenation has captured the public imagination, the field is plagued with controversy: some of the most dramatic studies have been subsequently refuted, and heated ethical debates threaten to distort the scientific work that must be done before stem-cell therapy can become a medical reality.
The recent explosion of information on stem cells highlights their capacity for self-renewal and their contribution in creating multiple tissue types, but has still not brought us a clear understanding of the underlying molecular biology in any system. A classic distinction has been drawn between the plasticity of stem cells in the early embryo—whose fate encompasses all cells of the organism—and the more limited potential of stem cells found in adult tissues. In addition, embryonic stem (ES) cells that are derived from humans also differ significantly from ES cells derived from mice, the main animal model for stem-cell researchers. For instance, mouse ES cells proliferate more rapidly than their human counterparts, which are difficult and slow to grow ( Pera & Trounson, 2004 ). Furthermore, whereas many of the molecular mechanisms that underlie mouse ES-cell growth are well characterized, it is not clear if these are shared by human ES cells ( Rao, 2004 ). Experimentally, mouse ES cells have distinct advantages because they can be genetically manipulated and can be used in assays that cannot be performed on humans for ethical and sociopolitical reasons. However, basic scientific questions about human stem cells must be answered before we can start exploring their regenerative potential and ensure their safe use in the clinic.
Human ES cells are harvested when a fertilized egg has divided for five days to form the blastocyst—a small hollow ball of cells. As with mouse ES cells, they survive and proliferate indefinitely in tissue culture when removed from the embryo. Most human ES cells recover after freezing and thawing, and can differentiate into a variety of cell types in vitro . However, it is now becoming clear that not all human ES-cell lines are the same, but rather reflect the genetic diversity of the embryos from which they were derived ( Rao, 2004 ). Recent studies have described the potential of human ES cells to differentiate into multiple lineages, giving rise to a mixture of nerves, blood, heart muscle and other cell types, and researchers are now testing the differentiation potential of a human ES-cell line using molecular markers that were originally characterized in mice. Such functional assays are needed to determine the behaviour of specific stem-cell lines in the context of ageing or diseased tissues.
