Conclusions and Outlook

Taken together, the current state of research into stem cell models for the replacement ofanimal tests in toxicology and efficacy studies justifies far-reaching hopes. The validated mESC-assay for testing embryotoxicity appears to represent only a first example en route to further, and eventually humanized, in-vitro models [76-78]. The development of these novel models must be embedded in and accompanied by cutting-edge analytical technologies, exploiting their advantages to the fullest extent. The realization of the huge potential to address mechanistic questions (protein surrogate biomarkers, differential pharmacology and silencing technologies, and various tissue-specific but genetically homogeneous cell types) would also require the incorporation of novel concepts concerning in-vitro pharmacokinetics and bioavailability into related projects [79-81]. Given the biological complexity in developmental toxicity or neuroprotection, and also taking into account upcoming regulatory requirements, it will likely be a battery of related in-vitro tests necessary for the timely, safe, and cost-efficient generation of related information [82]. Remaining problems, such as systemic barriers, endocrine disruptors and metabolism, will certainly be addressed in the foreseeable future by in-vivo models, but even there, some of the expected tools from in-vitro ESC research could be extremely valuable in the sense of the 'three Rs' (refinement, replacement and reduction [83]). The post-translational protein information emerging from ESC models, for instance, could serve as the content for chip-based HTS methods in assessing in-vivo effects.

Technologies and infrastructural support for the maintenance, characterization and control of hESC lines are rapidly improving [84-87], and have the potential to provide a worldwide set of standardized tools for validated alternative methods in toxicity and efficacy testing [5, 41, 69, 78, 88].

The final consideration belongs to ethical questions concerning the generation of hESC, which includes issues ranging from the donation of oocytes, in-vitro fertilization, and the need for the continuous sacrifice of human embryos to medical therapies at very early stages and with new scientific challenges of risk assessment [89-94]. This controversy in the therapeutic field [95] is fuelled by immense hopes, promises and commercial interest, and related efforts have suffered a number of recent high-profile set-backs. Yet, all of these topics are essentially absent in the case of hESC-based in-vitro screening systems for the replacement of animal tests.

In contrast, the purely diagnostic use of hESC - with its immense experimental advantages (as discussed above), and in particular with the major benefit of being "human" - has a tendency rather to establish a few selected cell lines and validated protocols as worldwide standards, thus avoiding the ethical implications surrounding the generation of new cell lines and therapeutic risks. Today, this is acknowledged even in European countries, where there is very restrictive legislation with regard to hESC (e.g., Germany and Italy). Nevertheless, in these countries substantial public funding has been approved by central ethics committees for related research projects involving regulatory agencies, academic institutions, major pharmaceutical companies, and small biotechnology units. More recently, the media coverage on these projects has been relatively low profile - but essentially positive - and the projects are well under way [5].

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