cutting edge knowledge about molecular medicine from the human genome through to clinical and therapeutic strategies
What we provide: We analyse data on all types of stem cells, progenitor cells and reserve cells in normal and diseased tissues.
Our analyses. We examine cellular and clinical data on claims relating to the use of embryonic and adult stem cells for treating chronic and acute human conditions. This area is heavily congested, with daily laboratory "breakthroughs" for diabetes, spinal cord injury, heart failure, arthritis, brain disorders, renal failure, bone healing, incontinence, acute liver failure, muscular problems, immune and hematopoietic diseases. The potential use of stem cells in cosmetic surgery, in repairing aging deficits, and "turning back the clock" are also heavily promoted. In order to assist our clients, we conduct a thorough filtering process in which we carefully evaluate the molecular and clinical data that bear on the above areas.
Epigenetics, cell types, reprogramming and Attractor Basins. The characteristics of "stemness", the properties of cell types and the mechanisms by which they are altered, requires a deep epigenetic understanding of induction and determination in early embryogenesis and the manner in which cell types are altered during the lifetime of an individual. Maintaining the stability of normal tissues and organs requires a further understanding of the robustness of epigenetic Attractor Basins and the trajectories between them. The central questions revolve around the conversion of one cell type to another and the fidelity of that conversion in a population of cells. Which cell types, for example, first need to be reprogrammed to a stem cell-like ground state prior to adopting another fate? Which cell types can be reprogrammed more directly? The biological data on transdetermination reveal that if cell types are "close", then a direct reprogramming route may be possible. If however, they are more distant, then the trajectory from one cell type to another will involve transiting through an intermediate stable state.
In the above landscape, (which is for illustrative purposes only), it is relatively easy to transition from small depressions on a surface, (shown as the plateaus in white), but much more difficult to go from one deep valley to another, (shown in blue), or from one valley to a more distant valley via steep ridges. The recent reprogramming of adult pancreatic exocrine cells to pancreatic insulin-secreting beta-cells is very likely an example of two pancreatic cell types that share a close common developmental fate and hence are readily interconvertible. By contrast, the reprogramming of chandelier neurons to heart muscle would likely offer bigger challenges.
Without a proper foundation in this epigenetic area, commercial avenues involving cellular reprogramming are likely to end in costly cul de sacs, and in a worse case clinical scenario, partially reprogrammed cell populations reintroduced into a patient for therapeutic purposes, will lead to tumors and patient death.
Molecular and cell biological data. To circumvent the above problems, we evaluate the molecular drivers of cell phenotype in induced pluripotent stem cells, embryonic and adult stem cells, especially mesenchymal derivatives. We examine genome-scale methylation maps as well as chromatin maps involving histone methylation marks, proteomics of transcription factors, microRNAs, long non-coding RNAs and the cell biology and genetics of phenotypic conversions in contributing to pluripotency and differentiation. We also incorporate knowledge of acidic sugars expressed on the surfaces of cell types, particularly since human stem cells can not make N-glycolylneuraminic acid, (but can take it up from tissue culture supplements from non autologous serum). Cultured stem cells reintroduced to the body, will thus inevitably be subjected to circulating human antibodies, leading to an immune response and some degree of rejection; a therapeutically disastrous outcome.
Our biomedical analyses of microarray-based data, when applied to transcriptomic and proteomic data from stem cell populations, provide for solid biological and clinical interpretations. This is in contrast to many of the erroneous clinical and biological conclusions in this area, which upon analysis by independent experts, have been shown to be of far lesser clinical importance. Thus respected scientists (such as Professor Robert Tibshirani of the Statistics department, Stanford University, California, USA and Professor Eytan Domany of the department of Physics and Complex Systems at the Weizmann Institute of Science, Rehovot, Israel), have shown in Bioinformatics and The New England Journal of Medicine that unless very careful data analyses are performed, very little of clinical significance may emerge from some microarray data sets.
Our molecular knowledge of stem cells is complemented by input from Dr Phillip Baird (pictured) of Integrated Diagnostic Pathology and Professor David Tarin of the University of California, San Diego, USA. Their knowledge encompasses areas that are critical to understanding stem cells from a clinical perspective; namely the determinative and inductive processes of cell interactions; cell movements in human embryonic and adult material; the pathology of all human organ systems and most importantly, autopsy records.
The way forward. We evaluate cell type changes and their stability via epigenetics and Attractor Basins. We have advised clients in the DNA methylation area and we have provided significant input into patent applications in epigenomics. We also pay special attention to the immune responses of various transplanted stem cell populations.
2005, Ein-Dor, L. et al., Bioinformatics, 21, 171-178, Outcome signature genes in breast cancer: is there a unique set?
2005, Tibshirani, R. New England Journal of Medicine, 352, 14. Immune signatures in follicular lymphoma.
2004, Wuensche, A, Basins of Attraction in network dynamics: a conceptual framework for biomoleular networks, in; 2004, Modularity in Development and Evolution, pp 288, edited by G. Schlosser & G. P. Wagner.