Gene Editing and Diabetes
What gene-editing technology means for the future of diabetes
Think of genes as the body’s blueprint: Contained in each of your billions of cells is a plan for how they should work, encoded in long, twisted strands of DNA. Genes are sections of DNA that contain instructions for specific traits and cellular functions. Humans have about 20,000 known genes, each one controlling some aspect of how the body works or develops.
Many are specific: There are genes for blue eyes, color blindness, even dry earwax. Genetic influences on the development of disease are far more complex. In ways researchers have barely begun to comprehend, hundreds of genes working together can make it more or less likely that a person will develop diabetes, altering the way the body stores fat, transports glucose, or responds to insulin.
Treating undesirable genes like Legos—removable and replaceable—may sound like a scenario out of science fiction. But new techniques have brought it closer to reality in labs around the world. Over the past few years, a technology called gene editing has made a splash in the medical research world.
The most commonly used gene editing tool is a protein called CRISPR-Cas9, which has given scientists a new way to alter the genes of living cells. Think of it like a scissor for DNA. It’s based on a sophisticated self-defense mechanism developed by certain bacteria: enzymes that defeat invading viruses by slicing up and destroying their DNA.
In the lab, these bacterial blades are reprogrammed to make precise cuts in the DNA of living cells, removing specific spots on the long, tightly coiled strings of DNA that make up your genetic code but—hopefully—leaving the rest of the genome intact. “The beauty of CRISPR-Cas9 is you can target any piece of DNA you want,” says Senta Georgia, PhD, a molecular biologist and principal investigator at Children’s Hospital Los Angeles and the University of Southern California’s Keck School of Medicine.
Once the DNA is cut, a new bit of DNA can be slipped in, altering or reversing genetic defects or simply eliminating the gene. That’s why it’s sometimes referred to as a gene editor. “It’s a safe way to engineer the genome,” says Xiaoyang Wu, PhD, a biologist at the University of Chicago. “It allows researchers to modify the cell in a specific way.”
Rarely has a new technique been so rapidly adopted across so many fields. Relatively simple to learn, cheap to use, and incredibly effective, CRISPR is being used to find treatments for cancer and HIV, target malaria, kill weeds, and engineer oil-producing algae.
Laying the Foundation
Since it was first described in 2012 in a pair of pioneering papers in the journal Nature, the CRISPR technology has dramatically changed the way biologists work. The patents on the technology are worth billions of dollars and have been the subject of fierce court battles. Researchers, meanwhile, are using it to run experiments that would have been impossible a decade ago, delving into the causes of complex diseases.
Scientists are using the technique to learn more about how genes contribute to diabetes, too. Research ranges from finding ways to repair or replace genes that cause specific types of diabetes to untangling how hundreds of genes can work together to cause complex diseases such as type 2, which can have many different causes. And on the distant horizon, scientists say, is gene therapy: Using gene editing to change a patient’s own DNA, potentially offering a way around the autoimmune reaction that causes type 1 diabetes.
But for the foreseeable future, scientists caution, gene editing remains a tool, not a cure. “CRISPR-Cas9 has changed the game, depending on your approach,” Georgia says. “It is a tool that’s changing what we can do, but it’s not going to fix diabetes by itself.” What’s more likely in the next decade or two, researchers say, is that gene editing will help scientists understand how diabetes works and open up new targets for drug therapies.
Some of the fastest-moving gene editing research looks at individual genes that cause disease. Changes to genes, called mutations, are usually harmless. But some mutations are not. Cystic fibrosis, hemophilia, and sickle cell anemia, for instance, are all caused by changes to a single gene. And a rare form of diabetes called MODY, or maturity onset diabetes of the young, is caused by mutations in single genes. One mutation, for example, prevents the body from producing insulin.
Because it’s so specific, gene editing is a powerful tool to look at such single-gene diseases. Using skin cells donated by a man born with a type of MODY, Georgia isolated the mutated gene responsible for turning off insulin production. Then she fixed it—in the lab. “We use CRISPR to cut out the bad DNA and paste in good DNA, correcting the genetic mutation,” Georgia explains.
She then managed to turn the altered skin cells into insulin-producing cells. “Theoretically, if you could fix the mutation, cells should be able to be given back to the patient,” she says.
But Georgia and others are careful to say CRISPR is a long way from curing any of the types of MODY. She worries that breathless reports about gene editing will give people with diabetes the wrong impression. Even with the new tool, genetically altering the DNA of people with diabetes remains a science-fiction scenario. “We can manipulate DNA to understand how differences in genetics can manifest themselves in disease,” Georgia says. “It may allow us to correct disease, but that’s in the future.”
There are several major hurdles researchers must clear before gene editing can be used in people with diabetes. Although the technology has come a long way, turning skin or other cells into cells that can produce insulin is still laborious and tricky, even with the help of gene editing. Georgia says that in the lab the complex process takes almost a month. “Once we’ve corrected a gene, we still have to show we can make enough cells that make enough insulin to help a patient,” she says.
There are also safety concerns. Some worry that CRISPR “scissors” could accidentally cut the wrong thing, damaging DNA and causing unintentional—and possibly dangerous—mutations. Called “off-target effects,” researchers are just beginning to figure out how to identify this possible collateral damage, a key step in showing CRISPR is safe and ready for use in human patients. (Researchers have already tested it in animals.)
The possibilities are tremendous—and tricky. In 2018, a Chinese scientist used CRISPR to edit the genes of human twins in utero, in an attempt to protect them from HIV. The announcement caused an uproar among ethicists and researchers worried that without clear ethical guidelines, CRISPR could be used to make “designer babies,” going beyond curing diseases to engineer babies with specific traits. Others worry that unrestricted gene editing could have unpredictable—and possibly dangerous—consequences, because many genes have more than one function.
While a tiny fraction of diabetes cases is caused by single mutations, most cases of type 1 and type 2 involve more than one gene. When it comes to type 2 diabetes in particular, the role of genetics is still poorly understood. Though scientists once talked hopefully of a “diabetes gene” or “obesity gene,” researchers have realized that type 2 usually involves lots of different genes. “Type 2 diabetes is the result of hundreds of subtle interactions that make the body more likely to develop diabetes,” says Mete Civelek, PhD, a bioengineer at the University of Virginia who is using an American Diabetes Association (ADA) grant to unravel the genetics of fat storage. “A disease like type 2 is not the result of one gene being on or off.”
CRISPR, Civelek says, can still help identify which genes are key and which ones are bit players. Genetic testing of hundreds or thousands of people with diabetes shows that some genes are more influential than others. He compares such genes to people with a lot of Facebook friends: A post by someone with 5,000 Facebook friends is going to have a bigger impact on the network than something shared with just 100 connections.
If Civelek could use CRISPR to identify the most influential genes involved in fat storage—a contributor to type 2 diabetes—it would be a first step toward developing drugs that target those genes. The same goes for other complex processes, such as the transportation of glucose to the cells.
When Jingshi Shen, PhD, started his lab at the University of Colorado Boulder a decade ago, for example, he wanted to understand how glucose enters the cells and why the process doesn’t work as well in people with diabetes. He knew he’d have to play an elimination game: First, he would knock out or alter each of the 20,000 genes humans have, one at a time. Then, after each tweak, he would have to grow the altered cells in the lab and then see if there were any changes to the way they transported glucose.
Eventually, he hoped, it would be possible to narrow down a list of genes that played a role. Only then could he start looking for the reasons some cells had more trouble than others. Pre-CRISPR, the very idea was daunting. The methods commonly available even five years ago were inefficient and mostly inaccurate. For every 10 attempts to knock out or alter a gene, Shen says, one succeeded.
The new CRISPR technique dramatically sped up Shen’s research. “Now we can do projects we couldn’t have dreamed about five years ago,” he says. “We’re really only limited by imagination.”
He was recently given an ADA grant to map the genetics of glucose transport, a task he hopes to wrap up in the next three years. Helping identify the genes that make some people better at moving glucose than others is a starting point for developing therapies to improve glucose transport in people with diabetes. “It’s curiosity-driven basic research, but it’s going to open up a lot of possibilities,” Shen says. “CRISPR genome editing changed everything.”
Tricky Type 1
Type 1 diabetes is the result of the body’s immune system mistakenly attacking and destroying the insulin-producing beta cells. Introducing beta cells back into the body would just prompt another attack.
One company, ViaCyte, has developed a way to grow insulin-producing cells in a lab—in quantities large enough to supply a patient’s insulin needs. They’ve already experimented with ways to place them in the bodies of people with type 1, either using special encapsulation devices to keep the beta cells safe or giving people drugs to suppress their immune systems.
In a partnership announced last year, ViaCyte teamed up with CRISPR Therapeutics, a large company specializing in using CRISPR for medical applications. The two companies recently announced that they had used CRISPR to develop “stealthy” insulin-producing cells, designed to look different enough to evade the body’s immune response and avoid the need for immunosuppressant drugs. “There are a lot of genes you want to manipulate, and prior to the advent of CRISPR, the technology available just wasn’t efficient enough,” says Kevin D’Amour, PhD, a ViaCyte researcher. They hope to begin testing the cells in humans soon.