2021 Seed Grant
Xiaojing Gao, Ph.D.
Dementia Society of America Seed Grant
Cells are the building blocks of our bodies. We get sick when the cells “misbehave”. The way modern gene therapies work is to introduce genes, fragments of DNA molecules that can direct the creation of specific proteins, into cells, and to fix what’s wrong about the cells or to make the cells behave in new ways that might combat diseases. However, there is no current method to control how much gene each individual cell gets, the consequence of which is highlighted in the two following examples of brain-related diseases. First, some diseases are very sensitive to the amount of specific genes. To take the Smith–Magenis syndrome (SMS) as an example, patients with this syndrome have only one copy of a gene named Rai1 in their cells, whereas healthy people have two. However, people with three copies of Rai1 develop another set of symptoms. We can’t simply put Rai1 back into SMS patients, because the lack of control means that we can easily overshoot from the one copy situation to the three copy situation. Second, some other applications require specific ratios between genes. For example, we might want to make up for pathological loss of neurons, such as that in Alzheimer’s disease, by adding genes into the other cell types in a patient’s brain, and to convert these cells into neurons. However, current methods can only convert an extremely small fraction of cells, too inefficient for any practical use. One of the reasons is that, to change the identity of a cell, it takes multiple genes delivered at specific ratios, but the ratios achieved by current delivery methods vary wildly from cell to cell. Motivated by fundamental challenges such as those mentioned above, our project aims to demonstrate that it is possible to control in each individual cell the level of gene delivery and the ratio of two delivered genes. We will do so by building control “circuits” using biomolecules. The logic isn’t that different from the consumer electronic circuits that enable fine control of our cars and computers, but our circuits will be made of DNAs, RNAs, and proteins that can send signals to each other and therefore likely to function inside our cells.