Unlocking the Mysteries of Protein Function
by Melissa WithersDeciphering the genetic code is only the first step toward understanding how genes function in the human body. Each gene carries the instructions for a single protein molecule. Using a technology called small molecule screening, Whitehead Fellow Dr. Brent Stockwell is deciphering the complex relationship between gene function and protein function.
Dr. Stockwell's approach is based on the knowledge that small glitches in the genetic code, known as genetic mutations, can produce proteins that function in abnormal or destructive ways. In the past, scientists have taken advantage of these mutations to glean new information about the activity of proteins in health and disease. However, studying natural mutations or mutations induced in laboratory animals is a time-consuming and laborious process.
With small molecule screening, Dr. Stockwell and his colleagues identify chemical compounds that bind to a protein molecule and mimic the effects of a genetic mutation. They are adapting this technique to trace the progression of protein malfunction in human disease.
According to Dr. Stockwell, small molecule screening is like hunting for a needle in a haystack. Researchers must screen hundreds of thousands of small molecules to identify a single organic molecule that alters protein function. "Let's say someone gives you a million diamond rings and all but one of them is made of cubic zirconia. If you inspected each ring individually, it would take so long that you might never find the diamond. But, if you could spread all the rings on a table and shine a light of a certain color on them so that only the diamond sparkled, you could quickly find the right ring," says Dr. Stockwell.
In this same spirit, Dr. Stockwell is working to develop high-throughput screens that can rapidly sift through millions of small molecules to find those that alter protein function in a useful way. Once identified, these molecules can be used to probe deeper into the mechanisms of disease progression and, possibly, lead to new candidates for drug development.
Dr. Stockwell is currently using small molecule screening to study amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Although the genetic mutations responsible for this onset of the disease have been identified, researchers know little about the mechanisms of ALS progression. Dr. Stockwell is working to find small molecules that suppress ALS at the cellular level in mice. The discovery of such molecules will lead to new insights into the mechanisms of ALS progression, and may ultimately be of therapeutic value to human patients. Furthermore, if this approach to studying ALS is successful, it could be extended to other neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease.
Small molecule screens developed in Dr. Stockwell's lab identify chemical compounds capable of altering protein function. Shown here are two identical mammalian cells treated with different small molecules. On the right, a protein (illustrated in green fluorescence) is outside the nucleus. On the left, a small molecule has caused the same protein to move into the nucleus. By identifying small molecules that manipulate protein function, Dr. Stockwell is adapting this technique to trace the progression of protein malfunction in human disease.
Read another non-technical look at the Stockwell Lab:
Industrialized Screening for Cancer
