This page contains a Flash digital edition of a book.
Therapeutics


cells (product cells) to treat diabetes. More exam- ples are given in Table 3.


Reprogramming factors


SUBSTRATE CELLS


lAbundance l Proximity l Relevance


PRODUCT CELLS


l Damaged l Deficient l Depleted In diseases


Figure 1: The basic model of IVR technology. Using a combination of protein drugs (and/or small molecule drugs), we can convert one type of cells to another type of cells. Borrowing terms from enzymology, we named the starting cells we wish to reprogramme substrate cells and the reprogrammed cells ready for use product cells. Product cells are usually the damaged or depleted cells associated with certain diseases, and substrate cells are a cell type that is abundant, in proximity to or inside the affected organs, and close to product cells phylogenetically


Table 3: Selection of substrate and product cells in targeting some diseases DISEASE


SUBSTRATE CELL Diabetes Autoimmune diseases Obesity Stroke Myocardial infarction


Liver cells Pancreatic exocrine cells


T cells White fat cells Astrocytes Cardiac fibroblasts  cell Regulatory T cells (Tregs) Brown fat cells Neurons Cardiomyocytes


Reprogramming can be through any of the five mechanisms: 1) Differentiation, 2) Transdifferen- tiation, 3) Retrodifferentiation, 4) Transdeter- mination and 5) Dedifferentiation. These mecha- nisms are illustrated in Figure 2. Figure 2A is a view of cell differentiation using a simplified cell lineage tree. Figure 2B is adapted from the differentiation model proposed by Conrad Waddington 50 years ago6. The ball sitting atop a slope and poised to roll down into different branching ravines represents the totipotent zygote ready to differentiate into pluripotent and multi- potent stem cells and eventually somatic cells and to take different fates.


PRODUCT CELL


Reprogramming factors are mainly transcription factors and chromosome remodelling proteins, or agents that can induce, affect or express these pro- teins. Their modalities include proteins, small mol- ecules, RNAs (including siRNAs, miRNAs and mRNAs) or DNAs.


In applying the IVR technology, the key is select- ing the right combination of reprogramming fac- tors. How do we identify these factors after deter- mining the product cells and the substrate cells? The answer may come from systems biology and developmental biology.


The development process from a single cell to a complicated individual is hard-wired in the species’ genome – the pathways to different cell fates are encoded by the Gene Regulatory Network (GRN)7. The GRN is an extensive network that


AB


Pluripotent stem cells


Multipotent stem cells


Progenitor cells


Terminally differentiated cells


4. Transdetermination 2. Transdifferentiation


5. De-differentiation 3. Retrodifferentiation


Figure 2: Mechanisms of cell reprogramming. A Linage tree view. The conversion from the substrate cells to the product cells can be through any of the five mechanisms: 1) Differentiation, 2) Transdifferentiation, 3) Retrodifferentiation, 4) Transdetermination and 5) Dedifferentiation, which are illustrated here B Stochastic model view. The same mechanisms are illustrated using the Waddington model


84 Drug Discovery World Summer 2011


1. Differentiation


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92