Mouse models are awesome. No, I’m not referring to a new low in reality TV. I’m just pointing out that over the decades, the use of laboratory mice has been vital to understanding human biology and treating human diseases.

There are many reasons, both physiologic and practical, that make mice an ideal “model” of humans: their genomes share 95% similarity with our own, mutations that cause disease in human often cause similar diseases in mice, they’re small and easy to maintain in the lab and they have a short breeding cycle of about two months. Also, through genetic engineering, scientists can generate mice that mimic uniquely human diseases. One main drawback to the mouse model is that, well, mice are not humans. Many successful therapies have been developed in mice that eventually fail in humans.

That’s where the story begins with our latest video, “Spotlight on Muscular Dystrophy and Stem Cell Research”, which was presented by CIRM grantee and Stanford scientist Helen Blau during CIRM’s July governing board meeting. You can watch the video here.

Dr. Blau studies Duchenne muscular dystrophy (DMD), the most severe form of muscular dystrophy that affects 1 in 3500 boys and leads to progressive muscle degeneration and death by the second decade of life. It’s been nearly thirty years ago that dystrophin, the mutated gene that causes DMD, was identified. Without the large structural protein encoded by dystrophin, the muscle cell walls become stressed, leaky and eventually degenerate. A mouse model of DMD with a naturally occurring mutation in the dystrophin gene has been available nearly since 1989. But as Dr. Blau mentions in the video:

A lot of therapies have been tested in this model and then tried in humans and not worked. And the reason is the mouse doesn’t have the same disease 

Indeed, although the DMD mouse model leads to a futile cycle of muscle degeneration and regeneration seen in humans, these mice show none the hallmarks of DMD in humans: paralysis, curvature of the spine, cardiac dysfunction and shortened lifespan.

To solve the mystery of the DMD mouse model, Blau’s lab focused on the muscle stem cells that continually regenerate the dying muscle cells that lack normal dystrophin. In humans, this pool of stem cells eventually is depleted by the need to replace the stressed the muscle cells. But in the DMD mice the stem cell depletion doesn’t happen. Blau’s breakthough came with a hypothesis that telomeres were the culprit.

Telomeres are stretches of DNA at the end of chromosomes. Think of them as the clear plastic caps on the end of shoelaces. When those caps wither away, your shoelaces become frayed and eventually need to be replaced. Similarly, with each cell division, the telomeres get shorter and shorter until they disappear and the entire chromosome becomes unstable and eventually leads to cell death. It turns out that mouse telomeres are 5x longer than their human counterparts. So Blau hypothesized that even though both mouse and human muscle stem cells were continually called into action to regenerate muscle in the context of DMD, the mouse stem cells didn’t get depleted because their telomeres stayed intact longer.

So Blau’s lab generated DMD mice that also have slightly shortened telomeres. Lo and behold, these mice accurately mimic human DMD: they show paralysis, spine curvature, and most importantly the mice have cardiac dysfunction, which is the main cause of shorten lifespans in boys with DMD. With this new DMD mouse model, Blau and her colleagues are in a position to gain a better understanding of the disease and to develop novel therapies.

For a list of muscular dystrophy research projects funded by CIRM, visit our website.

Todd Dubnicoff