Cell identity theft
In an essay in this month’s Nature Chemical Biology, the Broad’s Bridget Wagner describes her view of one of the greatest challenges in chemical biology today – identifying chemical compounds that coax cells to take on new properties. With these compounds in hand, you could transform cells from what they were to what you want them to be.
This month’s issue includes a special feature: Chemical Biology: Past, Present, Future. As part of this effort, young researchers who had been in the field ten years or less were asked to contribute essays describing the grand issues remaining to be met within the next decade. Of the ten essays selected, two were written by Broad researchers.
Bridget, a group leader in pancreatic biology and metabolic disease in the Broad’s Chemical Biology Program, wrote about challenges related to chemical transdifferentiation—a process by which chemical compounds called small molecules induce cells to change from one state to another—and regenerative medicine. Her group's research focuses on the cell biology of diabetes. The mission is to find small molecules that will increase the number and function of pancreatic beta cells, those cells responsible for producing insulin. In diabetes, the body’s beta cells either stop working well or die completely leaving the body unable to control sugar levels.
To do this, Bridget’s group focuses on a few approaches: coaxing beta cells back into cell division, making more beta cells, or inducing other cells in the pancreas, including alpha cells and ductal cells, to take on the job of insulin production, a process called beta cell transdifferentiation. It has been shown in mice that three genes can cause non-beta cells to take on beta cell-like characteristics. They make and secrete insulin. From this finding, Bridget’s group is on the hunt for chemical compounds that can do the same thing. In August, the group published a paper reporting that they had found a small molecule capable of pushing pancreatic alpha cells to make insulin. This was an important first step, but not yet a medical breakthrough, a point Bridget emphasizes in her current essay on the long road ahead for transforming this work into medical treatments.
Only in the last few decades have researchers been able to cause cells to take on the properties of other cell types. A popular example today are inducible pluripotent stem (iPS cells), which are created from adult cells that have been driven backwards in development by four genes (over a course of three weeks) to an embryonic-like state from which they are capable of becoming most different cell types. Now, many research groups are trying to find chemical replacements that do the same thing as those four genes.
Bridget’s essay highlights that while researchers have had early success in transforming alpha cells in the laboratory the challenges are extensive to reach the efficiency needed for creating a life-changing therapy. A lot of work has been done over the past ten years to find excellent small compounds that do have some cell effects, such as those that kill cancer cells. But we are only now poised to find chemical compounds that will do more complicated tasks, like changing a cell’s identity. Bridget explained that we are asking small molecules to change a cell’s natural development state. That’s a lot to ask. She suggests that success will come incrementally from perhaps combining small molecules and replacement genes, like those now used to make iPS cells.