Scientists in the 21st Century face a major challenge and opportunity to define the relationship between the DNA sequence and the biological result of that sequence on the development and physiology of an individual. This is particularly important in the human population as the genetic basis of the more common human diseases is being defined. Although ultimately we want to know these relationships in the human, much of the detail will be worked out in the mouse where genetic manipulations can be performed easily. The overlap in sequence similarity between human and mouse is greater than 99%. It is, therefore, believed that an understanding of the genetic basis of disease in the mouse will direct investigations in the human.
As one approach to define the relationship of genes in the mouse to their function in the organism, there is an internationally funded program to mutate all of the genes in the mouse (approximately 25,000), one gene at a time. This will result in 25,000 different mice for which the question will need to be asked, “How do these mice differ from a normal mouse which has all of its genes intact?”
This application will develop new technology based on imaging and automated computer analysis to visualize embryos and compare them to the non-mutated embryo. The three dimensional imaging will make use of magnetic resonance imaging (MRI) which has a major role in human diagnosis because of its capability of seeing soft tissues. An alternative imaging based on optical 3D imaging will also be investigated because it potentially has better resolution and unique tissue sensitivities. For both of these imaging modalities, sophisticated computer analysis will be developed to compare images of an embryo with a single mutation to the reference embryo, and as a consequence, point out the regions of difference. This is essential technology for making use of the 25,000 individual gene-modified animals. At the end of two years, we will have determined the best way to take images of embryos such that a computer can find most of the differences. This developed technology will then be available to Genome Centres in Canada and will be made available as a service to Genome facilities in other countries. Beyond the scope of this grant, it is our intension to establish a company in Ontario that will provide image-based phenotyping to the rest of the world.
This technology development project has placed Canada in a leading role in the use of imaging for phenotyping embryonic mice. This is important because the large international knockout consortium will complete its generation of 23,000 strains of mice within in the next couple of years. Initial funding has been provided by the NIH for the first round of phenotyping and more funding is expected from Europe. The Mouse Imaging Centre has been invited to be a subcontract on three of the U.S. grants which are currently under review for mouse phenotyping. The total value of these requests is $950,000. This leadership role would never have happened without this technology development competition.
In addition and within Canada, the development of thi technology project has been incorporated in a large-scale applied research project application entitled, “NORCOM 2 – In vivo Models for Human Disease and Drug Discovery” which is still pending review. The technology is also being used within the complex of The Centre for Modelling Human Disease for evaluating embryonic lethal mutants from the knock out repository. It is anticipated that the use of this technology will expand within Canada, into the United States and also in support of similar projects in Europe. As funding for these exercises develop, it is very likely that the Mouse Imaging Centre will spin off a service corporation to handle the large volume of this image-based phenotyping of embryos. The time line for this commercialization is estimated at approximately two years.
Beyond the advantages of the technology development, a number of trainees have obtained experience on three-dimensional imaging as a tool for genetics. This will provide a base of expertise in Canada for carrying on this kind of research.