Buzz your Insulin in: bioelectronics control of gene expression
A research group at ETH Basel developed a proof-of-concept cell therapy for Type I Diabetes, where electric impulses induce cells to produce insulin on demand.
My friend F. has Type I Diabetes. She found out when she was in her early twenties. In the first few months after her diagnosis, I remember once we were at a club. It was late night, and she checked her glucose levels:all over the place. She was terrified, as she had no insulin with her. I remember driving her back from the club in the narrow and winding roads on the coast of Northern Italy, hoping not to be pulled over, with her panicked voice repeating: “Omg omg I’m gonna die now!”
Of course she didn’t die, and now she manages her diabetes like a pro, with a career and two kids. That adventure, though, stuck with me. What if she didn’t have insulin at home?
Years later, another friend, also with Type I Diabetes, had his insulin doses lost with his luggage at the airport, while coming back to Boston from Brazil. That time, things went less smoothly and he got hospitalised. Again, he is fine now but had to pay a tall insurance bill and felt like crap for quite a while.
In both cases, these little dramas — along with the personal dramas of more than 8 million other patients of Type I Diabetes — could be avoided if their body were able to produce insulin on demand, through independent mechanisms.
That’s why I was super excited when, last summer, I saw this new article from the Fussenegger lab, at ETH Basel (@ETH-BSSE). They use electricity from common batteries to regulate the production of insulin in human cells.
For the past century, the most effective treatment for Diabetes has been administration of insulin via injections. Insulin had to be extracted from animals at high cost. With technological advances, new forms of synthetic and semi-synthetic insulin are now available and the cost of production of this important drug is still decreasing steadily.
Indeed, it is not difficult to engineer cells to produce insulin, since this hormone is just a small protein, and all the information you need to build it is encoded in one gene. What is hard is to regulate the expression of a gene within an organism with electric impulses.
Already three years ago, the Fussenegger lab published massive work in the journal Science, where they proposed the first prototype of a bio-electronic control of insulin.
They split the problem into two parts: biology and electronics. For the biology, they engineered a culture of pancreatic ꞵ-cells (those that are solely responsible for producing insulin) to regulate the expression of the gene for insulin in response to the opening of an ion channel.
Ion channels are structures on the membrane of cells that open up selective pores to enable specific communications between the inside and the outside of a cell. Specifically, they let ions (such as Ca2+, K+, Cl-) flow across the membrane from where there is a lot towards where they are less concentrated. This is called electrochemical potential. Some channels open when the cell membrane in which they are buried changes one of its properties (i.e. its electrochemical potential) after an electric impulse. Ion channels regulate large sets of genes. The Fussenegger group rewired some of the genes regulated by ion channels to also include insulin. The engineered ꞵ-cells were then encapsulated in a synthetic polymer able to conduct electricity and implanted in mice.
On the electronic side, they built a coin-sized chamber, containing a pellet of engineered cells and a switchboard that could be powered by a wireless field generator (like the one you use for wirelessly charging your phone) and installed it on the back of a mouse, with the cell pellet inserted under the skin of the animal, as a small implant. It was a good idea, but a bit cumbersome.
In their new article from last summer, they removed the need to implant complex electronics in the body, by rethinking the biology of the system.
The newly engineered cells pick up on electric stimuli by a completely different method. When you establish an electrochemical potential in a saline solution, you generate ions, such as protons (H+) or chlorine (Cl-). These ions induce the formation of reactive oxygen species (ROS) inside the cell. Low levels of ROS trigger the expression of several genes associated with stress in the cell, but high levels are extremely toxic. For this reason, cells tightly control the buildup of ROS and their promoters (the DNA regions that regulate the expression of a gene) are very sensitive to them.
The group at ETH rewired the ROS-sensitive gene circuits to also regulate the expression of the insulin gene. This method is way more sensitive than the previous one, uses lower voltages, and it is potentially compatible with commercial batteries. It could be powered by the same batteries as those used in pacemakers. Finally, to connect the batteries to the cell pellet, they used very thin acupuncture needles for subcutaneous stimulation, so that the whole battery pack and controls can be external and carried around, like a wearable. At this point, you just have to push a button, or flip a switch, and buzz the insulin in.
This is the latest example of more than a decade-long tradition in synthetic biology, trying to make biological systems and electronics interact, from bacteria to mammalian cells. In these two specific articles, all the genes used are entirely human, so the risk of immune reaction from the implant should be lower. A very important milestone on the way to real therapeutic applications.
Of course, there are other key points that need to be addressed before my friend F. could open an app on her phone and convince her body to produce some more insulin. First, cells encased in the capsule are not immortal. This is good and bad: it’s good because you don’t run the risk of introducing potentially cancerous cells; it’s bad because they will eventually die and will need relatively frequent replacements, since they are essentially separated from the body, and are not entirely supported by the organism. Second, the genetic circuits they developed, both in the first and in the second article, are very complex. Generally, these large synthetic gene networks need to be introduced with multiple operations and, even when they are entirely included, tend to stop working after a few cell replications. These two shortcomings, combined, would require a constant manufacturing of engineered cells with very complex behaviors, which right now is prohibitively expensive.
Despite these hurdles, this decade is definitely going to see an explosion of cell and gene therapies, where the new drugs are no longer small molecules or biologics, but entire engineered cells. This is already a reality for certain types of cancer (the NotBoring substack has a great summary of what’s happening in that field), but the Fussenegger group, along with others, showed that it is possible to generate implantable cell lines that could automatically or semi-automatically control the levels of Insulin in the body. The ultimate cure for insulin. And, if that holds, any other disease that could be fixed by “adding more” of something could in principle be controlled by similar genetic circuits.
Hopefully F.’s children will benefit from these new ultimate therapies.
[Thanks to Tara MacDonald (@tara_macdo) for scientific advice]