Disabling a gene brake in pancreatic cells unlocks insulin-producing potential

Type 1 and 2 diabetes are ultimately caused by a shortage of beta (β) cells, which are present in the pancreas and produce insulin to control blood sugar. Researchers from Harvard Medical School found that they can tweak a gene and turn a patient’s own pancreatic cells into insulin-producing cells.

The researchers set out to explore whether there was a fast, reliable way to transform pancreatic duct cells into insulin-producing beta-like cells. Instead of trying to multiply existing beta cells, a process humans carry out very slowly, they looked for a way to harness and edit biological processes already present in the cells.

Using advanced CRISPR gene-editing technology, the researchers screened thousands of genes. They found ALDH3B2, a gene that acts as a molecular brake, keeping pancreatic duct cells locked in their default identity. Turning it off released the brake, allowing the cells to break out of that identity and transform into insulin-producing beta-like cells.

Under natural conditions, duct cells rarely transform into beta cells, with less than 1% making the switch. However, disabling the ALDH3B2 gene raised that rate to about 8.5% in human cells.

The findings are published in Science Translational Medicine.

In search of better diabetes care

The number of people living with diabetes rose from 200 million in 1990 to 830 million in 2022, and the prevalence is expected to rise. Current treatments, like daily insulin injections and blood sugar monitors, help control blood sugar. However, they cannot match what a healthy supply of functional β cells can do or prevent the long-term complications of diabetes.

At its core, diabetes is a disease of too few functioning pancreatic β cells. To restore those levels, scientists have developed ways to transplant insulin-producing beta cells into patients using cells from organ donors or cells grown from stem cells.

While transplanting is a viable option, donor shortages and the need for patients to take strong medications to prevent their immune systems from rejecting foreign cells make the process complex.

Immune rejection would no longer be a problem if patients could generate the beta cells they need from their own pancreatic cells. So the researchers investigated how to make that happen.

Looking for a transformation blocker

Their first step was to find a way to immediately identify when a pancreatic duct cell had successfully transformed into a beta cell. They used a line of immortalized human pancreatic duct cells that are easy to grow in large numbers in the lab and genetically engineered the cells to carry a custom-designed reporter package that would glow if a duct cell successfully reprogrammed into a beta-like cell.

The researchers started with millions of engineered reporter cells and used CRISPR to knock out one gene at a time. Across more than 19,000 genes, they looked for anything that prevented pancreatic duct cells from becoming beta cells. Their marker glowed green in cells with the ALDH3B2 gene knocked out.

Bringer of change

When ALDH3B2 was silenced, the duct cells began to change their identity. They turned off genes that define duct cells and activated genes that define beta cells, including genes involved in producing and processing insulin. It also left a lasting mark on how these cells organize their DNA. The insulin gene lost its chemical tags, known as DNA methylation, and stayed permanently open and readable to the cell.

The researchers then put these reprogrammed human cells into diabetic mice. The cells survived and responded to changes in blood sugar by releasing human insulin into the bloodstream. As a result, the mice’s blood glucose fell to near-normal levels and remained there for the six weeks of the study.

They also found that the transformation didn’t directly jump from duct cells to beta cells. Instead, they temporarily reverted to immature pancreatic progenitor cells before maturing into insulin-producing cells.

The researchers note that because ALDH3B2 is an enzyme, drugs can block its activity, not just gene editing. They already saw a similar effect with DEAB, a broad ALDH inhibitor, which pushed human pancreatic duct cells to convert into beta-like cells, likely by blocking ALDH3B2 activity.

Once future research can pin down the exact molecules that act specifically on ALDH3B2, it could pave the way for a targeted pill that helps diabetic patients regrow their own insulin-producing cells.

Who’s behind this story?

Sanjukta Mondal

Master’s in Chemistry. Freelance science journalist and communicator. Published in Chemistry World, BioSpace, and The Hindu.

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Sadie Harley

BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries.

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Robert Egan

Bachelor’s in mathematical biology, Master’s in creative writing. Well-traveled with unique perspectives on science and language.

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