Disabling One Gene Turns Human Pancreatic Cells Into Insulin Producers

Type 1 and type 2 diabetes are ultimately caused by a shortage of beta cells, which sit in the pancreas and produce insulin to control blood sugar. Researchers from Harvard Medical School have found they can transform a patient's own pancreatic duct cells into insulin-producing beta-like cells by disabling a single gene, according to findings published in Science Translational Medicine.

Using CRISPR gene-editing technology, the researchers screened more than 19,000 genes in engineered human pancreatic duct cells designed to glow green if they successfully turned into beta-like cells. They identified ALDH3B2, a gene that acts as a molecular brake keeping duct cells locked in their default identity. Under normal conditions, fewer than 1% of duct cells make the switch to beta cells; disabling ALDH3B2 raised that rate to about 8.5%.

When ALDH3B2 was silenced, the cells turned off genes that define duct cells and activated genes involved in producing and processing insulin, temporarily passing through an immature progenitor stage before maturing into beta-like cells. Transplanted into diabetic mice, the reprogrammed cells survived, released human insulin in response to blood sugar changes, and lowered the mice's blood glucose to near-normal levels for the six weeks of the study.

Because ALDH3B2 is an enzyme, the researchers note it could potentially be blocked with a drug rather than gene editing; a broad ALDH inhibitor called DEAB produced a similar conversion effect in human pancreatic duct cells in the lab, likely by blocking ALDH3B2 activity.