In a screen of more than 100,000 potential drugs, only one, harmine, drove human insulin-producing beta cells to multiply…
The Mount Sinai study found that harmine drove the sustained division and multiplication of adult human beta cells in culture. In addition, harmine treatment tripled the number of beta cells and led to better control of blood sugar in three groups of mice engineered to mimic human diabetes.
Senior study author Andrew Stewart, MD, Director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine, said that, “Our results provide a large body of evidence demonstrating that the harmine drug class can make human beta cells proliferate at levels that may be relevant for diabetes treatment.” “While we still have a lot of work to do in improving the specificity and potency of the harmine and related compounds, we believe these results represent a key step toward more effective future treatment of diabetes.”
As humans develop, each cell divides into two, leading to many more cells in subsequent generations as organs form. In the case of beta cells in the pancreas, most of this multiplication comes in a burst during the first year of life and then declines during childhood, leaving a limited supply to last a lifetime. During this burst, about two percent of a child’s beta cells are dividing at any one time. The current study found that harmine re-creates roughly the same amount of beta cell division, both in cell and animal tests.
While increasing the supply of beta cells seems an obvious approach, past attempts to do so have been met with limited success. Perhaps as a result of their unique genetic program, adult beta cells strongly resist attempts to nudge them into cell division.
Over several years, Dr. Stewart and colleagues unraveled genes and signaling pathways that drive multiplication (proliferation) of beta cells, and then confirmed proposed mechanisms with gene therapy. Based on the current study results, the team believes a particular enzyme, “dual specificity tyrosine-regulated kinase-1a (DYRK1A),” is the likely target of harmine. With this discovery, DYRK1A, known from past studies to drive cell division in other cell types, becomes a drug development target.
Peng Wang, PhD, Assistant Professor of Medicine, Endocrinology, Diabetes, and Bone Disease at the Icahn School of Medicine and first author of the paper stated that, “We found that harmine, likely by interacting with DYRK1A, increases levels of other known drivers of cell division.” “These drivers include the protein c-MYC, the gene for which was the basis of the screen we used to identify harmine as a potential treatment.”
Dr. Wang said the team designed a sensor to glow (thanks to a firefly gene) when any compound activated the promoter DNA snippet responsible for turning on the c-MYC gene. Of more than 100,000 compounds analyzed in a high-speed robotic screen, harmine was among 86 that caused the brightest glow, and was the only one of these that caused beta cell proliferation. The c-MYC pathway appeared to some researchers to be an unlikely therapeutic target for beta cell regeneration because past studies had found it to cause beta cell death when activated in high doses. However, the current study found that harmine causes only modest increases in c-MYC levels, and no beta cell death.
The research team will now focus on making changes to the harmine and its relatives (harmalogs) to find drug candidates that target only beta cells.
Harmine is derived from a flowering plant called Harmal (peganum Harmala) found in the Middle East, and from some South American vines.
- Developing drugs that can increase the numbers of healthy beta cells is a major priority in diabetes research.
- In a screen of more than 100,000 potential drugs, only one, harmine, drove human insulin-producing beta cells to multiply.
- The team believes a particular enzyme, “dual specificity tyrosine-regulated kinase-1a (DYRK1A),” is the likely target of harmine.
Mount Sinai Hospital Press Release. Published online March 10, 2015 in Nature Medicine.