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Broad Institute Lands $3M JDRF Grant to Hunt Molecules That Stimulate Beta Cells

The Broad Institute announced this week that it has received a two-year, $3 million grant from the Juvenile Diabetes Research Foundation to support research aimed at identifying small molecules that could stimulate the production of beta cells in vivo as a treatment for type 1 diabetes.
A Broad Institute official told CBA News that the bulk of the money will be spent on developing high-throughput screens in human pancreatic beta islet cells and mouse cell lines called insulinoma cell lines. The insulinoma cell lines are derived from beta cell tumors in mice that produce insulin and therefore behave very similarly to beta cells.  
Many of the screens will use imaging technology such as high-content imaging microscopy. Bridget Wagner, a group leader in pancreatic cell biology and metabolic disease at the Broad Institute, said that the scientists will primarily use a Molecular Devices ImageXpress Micro and will also perform high-throughput real-time PCR experiments to measure gene expression levels.
“In our case, we are looking for key transcription factors that are important for maintaining beta cell survival and activity,” said Wagner. The gene expression is more of a 384-well PCR reaction, she said.
“We are developing a number of high-throughput screens in mouse cell lines as well as primary human islet samples that we obtained from affiliated hospitals,” said Wagner, adding that the institute has access to an islet cell network that allows organ donors to donate tissue samples to research.
The Broad Institute has also assembled a 10-person team that is working on different aspects of the project. “We have some people working on proliferation of the beta cells themselves, and some are working on the transdifferentiation of other cell types [into insulin-producing cells],” said Wagner.
“We are not biased at all in terms of how we stimulate that increase in beta cells: stimulate beta cell proliferation or stimulate other cells in the pancreas to reprogram and become more beta cell-like. As long as they produce insulin in a glucose-dependent manner, we are happy with that,” she added

“We are not biased at all in terms of how we stimulate that increase in beta cells.”

The Broad Institute has in-house a large chemistry facility where Stuart Schreiber, the principal investigator on the grant and the director of the chemical biology program at the Broad Institute, has used a technique known as diversity-oriented synthesis to develop a structurally diverse set of small molecules. Wagner said “we think that [these molecules] are maximally poised for high activity in phenotypic assays.”
According to the Broad Institute’s website, its DOS platform exploits split-and-pool synthesis to build large collections of both natural product-like molecules and small molecules that exhibit skeletal, stereochemical, and appendage diversity.
Once the investigators identify small molecules that are hits, those compounds can be optimized and considered lead candidates.
“We would like to get three high-throughput screens completed in the first year, meaning run against all of the compounds that we have at our disposal,” said Wagner. Although the number of compounds keeps changing, it is in the range of 100,000 compounds or so.
Broad to Fruition
The Broad Institute has been working with the JDRF for a year doing proof-of-concept work for this project, Schreiber told CBA News this week. The project is centered on the idea that scientists could use human primary cells and tissues, which is not usually done because it is difficult to maintain these cells in culture while preserving their physiological properties.
“One of the major advantages of the past year is that we have learned how to do that, and have combined this ability with the Broad’s set of compounds,” Schreiber said. “The proof of concept is that not only can we do that, but we can identify very promising compounds with, we believe, therapeutic potential.”
The Broad scientists have performed a series of screens and experiments that have yielded candidate compounds. These compounds need “to be explored further [before] we truly understand how they are functioning,” said Schreiber.
However, they certainly have exhibited “highly unusual and promising” activity in human pancreatic islets. “We have found compounds that cause human pancreatic islet cells to increase their insulin production and become more sensitive to glucose,” Schreiber said.      
That was the basis for this new grant, which basically says that, “If you can accomplish this level of discovery in the first year, let’s now really push the ball over the goal line, and discover small molecules that work in humans to increase beta cell performance or numbers as a way to treat type 1 diabetes.”
The goal for the next two years will be to develop new approaches to the treatment of diabetes.

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