This ‘CRISPR craze’ has descended on labs across the country. Find out more about this cutting edge lab technique and how Joslin is making use of it to fight diabetes.
Diabetes, both type 1 and type 2, is a complicated disease involving many genetic variations. Some genes, for example, allow immune cells to continue attacking the pancreas as though it were an infection. Others allow bad T cells to roam the body. Researchers at Joslin are using CRISPR to understand exactly how these genes work. (Learn more about CRISPR here.) In some experiments, they are modifying these mutated genes in the lab so that they become their healthy variations.
Stephan Kissler, Ph.D., Investigator in the Section on Immunobiology at Joslin Diabetes Center is excited about the promise of CRISPR moving experimental models forwards at a rapid pace. “It really opens new possibilities, things you thought weren’t directly feasible,” he says. “Modifying genes of human cells that you take out of people, it wasn’t possible, not with this efficiency that makes it feasible to do these experiments.” In his lab, Dr. Kissler has used CRISPR to create mouse models of type 1 diabetes that would have taken years to breed, allowing the progress of type 1 diabetes research to leap forward.
Amy Wagers, Ph.D., Investigator in the Section on Developmental and Stem Cell Biology is working with Dr. Kissler to create a gene editing core at Joslin. Dr. Wagers is using CRISPR to explore the potential for treatments for a different genetic disease, muscular dystrophy. One form of the disease, Duchenne’s, progresses rapidly. Patients are diagnosed as toddlers and have short life expectancies. Becker’s muscular dystrophy is less severe. Patients are diagnosed later and have significantly longer life expectancies. Both of these forms of the disease are caused by a mutation in the same gene. Using CRISPR, Dr. Wagers is changing the genetic code of cells pulled from Duchenne’s patients to resemble the DNA sequences of Becker’s patients. They have also tested this in a mouse model, and “the mice got stronger and they were more resistant to muscle damage. So it improved the pathology of the disease.”
The mutation causing muscular dystrophy is well known, and happens in a single gene, making the disease a good contender for early CRISPR success and prepping the researchers to handle the multiple genetic mutations of a disease like diabetes.
“It’s a proof of concept that you can do it,” says Dr. Wagers. “I think the next era, what our core at the Joslin is hoping to stimulate, is using this as a tool to discover genes in situations where it’s very difficult to discover those genes, as in the context of diabetes where there are many, many, many different genetic contributions to a particular characteristic of a diabetic.”
Other Joslin researchers are using CRISPR:
- Mary Elizabeth Patti, M.D., Director of the Joslin Diabetes Center Genomics Core and C. Ronald Kahn, M.D., Chief Academic Officer and Senior Investigator at Joslin Diabetes Center are bettering their understanding genetic insulin resistance by pinpointing the genes responsible and correcting that mutation and inducing that mutation in control cells.
- George King, M.D., Chief Scientific Officer at Joslin Diabetes Center, is correcting the mutations in certain connective tissues that are problematic in wound healing in people with diabetes.
- Peng Yi, Ph.D., Assistant Investigator in theSection of Islet Cell and Regenerative Biology at Joslin Diabetes Center, is finding ways to increase beta cell replication.
- Steven Shoelson, M.D., Ph.D., Head of the Section of Cellular and Molecular Physiology at Joslin Diabetes Center, is understanding genetic mutations that cause problems in metabolism.
More researchers at Joslin will soon have access to CRISPR as the new Joslin gene editing core comes online. The core will combine Joslin’s expertise in iPS cells with gene editing. “Human iPS cells are fantastic in terms of modeling disease in humans, but ultimately whatever you find there you really want to test in a whole organism context,” says Dr. Wagers. “Diabetes is a disease that affects not just cells in culture, it affects the whole organism. And mice are really still the best system for doing that. And so with CRISPR technology you can very rapidly make genomic modifications to mice, generate a mouse that contains a variant of a gene that you discovered in your human iPS experiments, then you can test that hypothesis in a whole organism in a mouse model.”
Dr. Kissler is happy Joslin is taking advantage of CRISPR technology to further diabetes research. “There’s a whole world of different applications of CRISPR that have been developed, not just to make one cut or delete a small portion of a gene. You can actually activate genes, inactivate genes, and do all kinds of stuff with this technique,” he says. “It’s a very powerful tool so everyone is very excited. There’s a lot of potential.”
This article was originally published on Aug. 25, 2016