Fifteen years ago, chemical genetics was a young discipline. Before the discovery of RNA interference transformed nature’s gene silencer into a routine lab tool, scientists seeking to explore cellular mechanisms at the molecular level relied on other methods: they amassed cells in arrays, exposed them to interesting chemical compounds, and waited to see what happened.
Randall King ’97, the Harry C. McKenzie Professor of Cell Biology at HMS, knows well what it means to invest time in discovery. He studies the cell cycle: how it works and what goes wrong in disease. In 1999, in one of the first assays undertaken at the Institute of Chemistry and Cell Biology–Longwood Screening Facility, King’s team turned up some promising chemical leads. Pursuing those leads has kept them busy for more than a decade.
That assay found several chemicals that inhibited the cell cycle, the process by which a cell duplicates and then divides to form daughter cells. When working properly, cell division ensures healthy growth. When running out of control, defects in the process can result in cancer. In 2004, the group reported in Science that one chemical, ubistatin, blocked cell division by inhibiting the cell’s protein elimination system.
Learning how cancerous growth might be stemmed is central to King’s research, so two other chemicals that also influenced cell division piqued his interest. In 2010 King and his colleagues published a paper in Cancer Cell that detailed how one of those inhibitors, tosyl-l-arginine methyl ester, delays the cell cycle briefly. In a 2014 Nature paper, his team described how another compound, apcin, briefly delays mitosis, the phase of the cell cycle in which chromosomes are duplicated and distributed to daughter cells. When working together, however, the two inhibitors slow mitosis to a crawl. The cell in fact dies without completing the mitotic process.
“Having these chemical tools, we can screen cancer cells and ask if there are different cell lines that are particularly sensitive to this type of intervention,” King says.
While the chemical compounds that proved interesting in that 1999 screen might one day be developed into drugs, those findings of 15 years ago are prized primarily because they answered fundamental questions about the inner workings of cells, insights that will be crucial to the success of any future therapeutic. Patience, insight, focus: the stuff of discovery-based research.
Image: John Soares