Washington University scientists are finding new treatments for human diseases. Research for these cures involves learning how the body functions and how diseases affect the body. Animals are used for some of these studies where human patients, computer models, or experiments in cultured cells cannot provide the needed information. Techniques have been developed to make mice especially useful models for human disease. These techniques are difficult to perform, and the Washington University Mouse Genetics Core helps scientists with these techniques. While mice and humans look very different, important physiological and molecular functions are similar between the two. Results can be obtained from experiments performed in mice that directly apply to human disease, allowing experiments to be performed that would not be ethical or practical in humans. Experiments with mice are frequently more feasible than in humans because of the small size and short generation time of the mouse.
Techniques for making the mouse a particularly useful model of human disease involve manipulating the mouse genome, which controls formation and function of the mammalian body. The genome is made up of DNA strands, which are long molecules created from four different bases (abbreviated A, T, G, and C). The sequence of the bases contains the information necessary for creating a mouse (or person) from a fertilized egg. There are over 3,000,000,000 bases in the mouse genome, and the exact sequence for the mouse, human, and other species has been determined. The genomic sequence in every individual is different, except in identical twins. Some individuals are more likely to develop a disease such as diabetes or cancer due to differences in their DNA sequences. Errors can also occur when DNA is copied into a new person, resulting in birth defects such as Down syndrome. One useful aspect of the mouse as an experimental model is the existence of inbred strains. As the name implies, inbred strains are created by inbreeding until all the animals in the strain are genetically identical. In other words, all the mice in an inbred strain are identical twins to each other, and have the exact same DNA sequence. The ability to obtain large numbers of genetically identical mice allows experiments to be performed without the complication of individual differences. Moreover, each inbred strain has unique characteristics, just as any two individual humans would. The differences in physiology or response to disease between inbred strains of mice can be linked to differences in the DNA sequence.
It is now possible for scientists to make changes in the mouse genome, and this technique makes the mouse a powerful tool to investigate human disease. Mutations that cause birth defects in humans can be created in mice to study possible cures. DNA sequences that lead to disease or that control the development and function of the body can be identified and their function tested. Creating alterations in the murine genome is slow and difficult, but the studies done in these animals provide important information that is available in no other way. The Mouse Genetics Core assists scientists in the manipulation of the mouse genome, and in breeding of the mutant animals.
There are two main ways in which scientists manipulate the mouse genomic sequence. One way is to add extra genes to the mouse genome to make “transgenic” mice. Genes are DNA sequences that produce the proteins which make up the body and control its functions. Scientists can create synthetic genes in the laboratory, and the Mouse Genetics Core injects these genes into mouse eggs, where they are incorporated into the mouse genome. The injected eggs are put back into a female mouse, and later they are born as baby mice carrying the transgene. These transgenic mice can then be mated to produce additional transgenic mice which are all genetically identical to one another and that can be used for studies. Transgenic mice are frequently used to study how genes function or how a protein made by the gene functions.
The second way scientists manipulate the mouse genome is to alter the sequence of the naturally occurring mouse genome. This can be done through the use of mouse embryonic stem cells (ES cells). The mouse (or human) is made up of millions of cells, each with a complete copy of the entire genomic DNA sequence. Each cell performs different functions that are appropriate in the animal (for example, skin cells are different from bone cells). Cells can be taken from the mouse and grown in a dish in the laboratory, where they may be manipulated and studied. ES cells are taken from a very early mouse embryo, and if they are placed back into an early mouse embryo they will make up some of every tissue of the mouse that is born from that embryo. The adult mouse from a mixture of ES cells and a mouse embryo is called a “chimeric” mouse. This mouse can be mated and some offspring will have the DNA of the ES cells while others will have the DNA of the embryo into which they were added. While ES cells are growing in a dish, it is possible to make any desired change in their genomic DNA sequence. Chimeric mice can then be produced from the ES cells, and some of their offspring will contain the altered DNA sequences from the ES cells. The Mouse Genetics Core can implant the ES cells into mouse embryos, and put the embryos into a female mouse so that they can develop into mice.