Year 3

An important class of neurological diseases predominantly affects spinal motor neurons, the neurons that control muscle movement. The most well known of these motor neuronopathies is Amyotrophic Lateral Sclerosis (ALS), commonly referred to as Lou Gehrig’s disease for the famous Yankee first baseman who died of the disease. The first symptoms of ALS are usually increasing difficulty walking or speaking clearly. People with ALS progressively lose their ability to initate and control movements, and may become totally paralyzed during the late stages of the disease. There are no cures or effective treatments for these diseases. Riluzole (Rilutek), the only FDA approved medication for ALS, only modestly slows disease progression. Consequently, ALS is usually fatal within one to five years from onset, with half dying within eighteen months.

Although genetic studies have identified many mutations that cause these diseases, it is not understood why these mutations kill motor neurons. This lack of understanding about the root causes of motor neuron diseases currently hinders the development of effective treatments. We seek to study motor neurons carrying these mutations in cell culture dishes to understand how these diseases sicken and kill these cells.

To generate these motor neurons, we are using embryonic stem cells. Embryonic stem cells can become any cell in our body, including motor neurons. We have developed a new technology that allows us to quickly replace healthy genes with mutant genes in mouse embryonic stem cells. We are using this technology to insert both normal and disease-associated versions of genes into embryonic stem cells. Study of the healthy and mutant mutant motor neurons derived from these embryonic stem cells will shed light on the ways in which the mutations cause harm.

We have been using the mutant embryonic stem cells to assay leading hypotheses about how diseases like ALS begin. In addition, we are using the embryonic stem cells to create new animal models of ALS. Finally, we are adapting our technology to be able to create more faithful models of disease using embryonic stem cells in order to expedite understanding into the origins of these diseases.