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To develop genuinely regenerative and reconstructive treatments, it is necessary to understand and exploit the self-healing capabilities and mechanisms of the human organism. Insights into regenerative processes and their underlying mechanisms will not only improve disease prevention, but also allow targeted interventions in the case of severe acute or chronic disease.
Intrinsic factors and milieu conditions control regeneration.
A molecular understanding of how endogenous mechanisms (intrinsic factors and milieu) control regeneration in health, disease and ageing will point to new therapeutic targets for regenerative medicine. Intrinsic mechanisms that are in our current research focus are developmental programmes of organogenesis, cell cycle regulation, cell migration, cell signalling, malignant transformation, telomere dynamics and senescence, as well as epigenetic (re-)programming.
However, genetic determinism does not reflect the whole complexity of regenerative processes. Epigenesis – in its original and wider sense – comprises all regulatory impulses originating from environmental conditions. In the context of development and disease, epigenetic factors play a major role in regulating gene expression at transcriptional and post-transcriptional levels. Regenerative processes often take place in stressed, microbiologically contaminated or ageing environments, generating distinct signalling contexts that may not be found during embryogenesis. Genes can thus be seen as modules whose specific expression and use will depend on the interaction with the micro- and macro-environment. This conception of genes and milieu as a totally interrelated, fully co-actional system is a major driving force of our programme.
Rationale and side effects of cell and tissue engineering.
Engineering cells or tissue may often be required to allow regenerating cells to escape the pathogenic mechanisms of underlying diseases (e. g. degeneration, immunity, infection, or similar) and can result in a more effective proliferation, migration or differentiation of the desired cell type than would be possible by merely stimulating the in vivo regeneration process. The therapeutic surrogates formed by engineering will thus need to replace the function of interest while avoiding destruction as the likely outcome of a pure replica. Cell engineering may thus introduce a conditional or default selective advantage, and engineered cells typically have to be expanded to huge numbers.
A hallmark of REBIRTH’s concept is that we introduce novel approaches to cell engineering and simultaneously aim to investigate their functional and genetic consequences in great detail, including potential side effects of forced cell expansion and reprogramming (“regenerative toxicology”). Anticipating side effects of regenerative products and preventing their occurrence will be of outstanding importance for the sustainable future of the field, thus preventing any overselling of its therapeutic potential in the public. With this “dialectic” approach in mind, we also understand certain areas of tumour biology such as identification of genes that enhance cellular self-renewal or mechanisms of genetic instability as relevant for regenerative medicine. Inasmuch as we address potential side effects of cell engineering, we believe in the future of this discipline, extending into the complex field of tissue engineering. De novo generation of three dimensional tissue structures and hybrid organs based on natural and nanostructured materials will enable reconstruction of lost or irreversibly damaged tissue. Tissue engineering thereby represents a logical extension of cell engineering.
Regenerative therapy versus enhancement.
From a practical standpoint, the first therapeutic goal is reconstitution to the minimal level required to re-establish systemic homeostasis. More ambitious projects aim for a complete restitutio ad integrum. Debatable though not necessarily out of reach are approaches to enhance general fitness to a “supranatural” level (enhancement). Our explicit aim to develop “reconstructive therapies” implies that our clinical targets exclude pure enhancement. We rather invest our efforts in the generation of novel therapies for severe inborn or acquired disorders, especially those of the heart, lung, liver and blood. These organ systems are chosen based on clinical needs and our previous achievements.
The search for regenerative remedies includes four complementary fields: novel endogenous regeneration, gene and cellular therapies, and biohybrid devices. Novelty may reside in the definition of novel entities or novel applications and combinations of known items. The comprehensive exploration of these four types of remedy requires an interdisciplinary network of biologists, engineers, chemists, physicists and physicians.