Industrialized Screening for Cancer and Neurodegeneration
by Melissa WithersWith most neurological diseases, patients experience a devastating disintegration of bodily function, frequently losing the ability to walk, talk, or control their movements.
Whitehead Fellow Brent Stockwell is using chemistry, genetics, and high-throughput automation to build a molecular roadmap of how neurological diseases progress, as well as identify new targets for drug therapy. In addition, Stockwell has applied a similar technique to study cancer.
Stockwell and his colleagues have turned their lab into a screening factory, wherein thousands of chemical compounds, also called small molecules, can be tested each day to see how they interact with a particular cell type. Specifically, Stockwell is searching for chemical compounds that induce, suppress, or reverse disease at the cellular level. Stockwell and his colleagues have developed the methodology and mechanical firepower to conduct more than 25,000 individual tests a day.
"We have put considerable time and effort into building the infrastructure we need to generate a large volume of high quality data," says Stockwell, referring to the arsenal of equipment and computing power that the lab has assembled. "We are now in the position to systematically march through these diseases and map out the molecular changes responsible for their onset and progression. In addition, we can use this same strategy to identify new drug candidates."
As part of their efforts, Stockwell and his colleagues have miniaturized their tests onto small, 384-well plates. Each well is large enough to hold a few thousand cells and a small amount of the chemical the lab wishes to study. With each test, they expose the cells to a chemical drawn from a library of well-studied molecules and measure how the cells react. Some chemicals may kill the cell or cause abnormalities, while others may have no effect at all. Stockwell hopes to find the rare molecules that can transform a diseased cell into a healthy cell.
Stockwell and his colleagues are also using this technique to study how particular cellular changes lead to disease. The lab can use small molecules to perturb a cell in a way that disables a gene and alters the function of the protein for which the gene encodes, mimicking the effect of a disease-causing genetic mutation. By observing changes in the cell, they can identify particular genes and proteins that play a role in disease progression. Because the lab uses well-studied molecules in these experiments, they can link new findings with existing information to better understand the specific cellular malfunctions responsible for disease, says Stockwell.
Stockwell and his colleagues are presently applying these techniques to the study of several severe neurological disorders, including Spinal Muscular Atrophy, Huntington's disease, Lou Gehrig's Disease and Alzheimer's disease.
Read another non-technical look at the Stockwell Lab:
Unlocking the Mysteries of Protein Function
