In the news

Creating mouse models of numerous human diseases – known as ‘knock-out’ mice – has been possible for many years, by disrupting the particular gene of interest (see previous news). However, due to numerous differences between murine and human biochemistry and physiology, in practice these models often perform poorly as models of the human disease process or as tests for novel drug action. Therefore developing models of diseases in human cells would offer considerable advantages.

 

Until now, this effort has been hampered by difficulties in isolating and culturing the relevant human cells from the many thousands of human diseases directly caused by known genetic alterations. However, a new technique for genetic manipulation using human embryonic stem cells (hESCs) may offer a solution to this problem [Song H et al. Cell Stem Cell (2010) 6:80-9]. Unlike normal cells, hESCs are able to undergo unlimited self-renewal whilst retaining the ability to differentiate into all cells types under the right conditions. By injecting standard hESCs with synthesized circles of human DNA, it is possible to substitute modified genes into the cells, thus effectively providing a method for creating ‘knock-out’ cells. Whilst only around 20% of the cells were modified using this technique, this is already a substantially higher efficiency than had previously been achieved through other methods.

 

Two genes were selected as test cases: p53, which encodes a tumour suppressor commonly mutated in cancer cells, and ATM, which encodes an enzyme mutated in the rare recessive condition Ataxia-telangiectasia. In both cases, homozygous mutant cells were generated that did not produce functional gene products. These cells could subsequently be differentiated into different cell types, in order to observe the effect of the mutation on the development and activity of diseased cells. Importantly, the technology can easily be adapted to allow different genes to be modified, thus providing a flexible system for generating hESC models of numerous human genetic diseases.