Fishing with a screen

Robots and the fleet of professional scientists who make sure the machines do their job in high-throughput screening may seem far afield from a fishing expedition. But that may be the best metaphor to explain how researchers at the Broad and elsewhere trawl for chemical compounds that might lead them to a new understanding of human biology.

Scientists use such advanced screening technologies to search for small molecules they call probes, which serve as tool compounds to learn what might be happening in diseases such as cancer, diabetes, or schizophrenia. Nicola Tolliday, manager of screening outreach in the Broad’s Chemical Biology Platform, has organized a free, one-day conference to explore past successes and future innovations in the field. The Second East Coast Academic Screening Symposium, 2011, will be held on September 28 at the Broad. For more details and to register, click here.

A screen is a large-scale test in which cells are exposed to a variety of molecules and their responses are observed. Testing hundreds of thousands of random compounds within the Broad’s libraries or even more through a national network called the Molecular Libraries Probe Production Centers Network (MLPCN) can lead to surprises.

“Biology is full of unexpected discoveries,” Nicky says. “Serendipity has played a key role, but you also need to have the open-mindedness to be able to embrace and explore unexpected findings.”

A recent discovery by a team of scientists from the Broad and Massachusetts General Hospital proves her point. Nicky is a co-author on a Nature paper about a novel compound that selectively kills cancer cells by interfering with a cellular process cancer cells depend on. The work is described here.

Associate members and senior co-authors Sam Lee and Anna Mandinova were looking for proteins that might improve the function of the tumor suppressor gene p53 in fighting cancer. They designed a phenotypic assay – a test based on cancer cells – seeking chemicals that would thwart cancer activity. Early results showed that a compound derived from a pepper plant that grows in Asia seemed to affect the cancer cells. Additional tests, including experiments in the Proteomics Platform designed to get at how the compound was working, revealed that the compound, called Piperlongumine, wasn’t acting on the tumor suppressor gene at all. Instead, it blocked a process that cancer cells use to cope with their hyperactive metabolism.

In this case, the chemical tool illuminated an aspect of cancer biology. The probe may also become the first step on the long road toward developing a drug.

The September screening symposium will feature other success stories while also highlighting newer technology development and projects that got off the ground more recently. Speakers and their topics, including psychiatric disease, learning and memory, infectious disease, stem cells, neurodegeneration, and cancer, can be found here.