Four to five insulin injections every day. This is the reality of 8.4 million patients world-wide affected with type 1 diabetes, a condition where the insulin-producing ‘beta’ cells of the pancreas are targeted and attacked by the body’s immune system, reducing or preventing insulin production. A common solution is to replenish insulin reserves via multiple daily insulin injections.
But, what if a tiny medical device containing specially designed insulin-producing cells could be implanted in a patient? What if these cells could pump out insulin in about 10 minutes, as needed, to help manage type 1 diabetes?
There is a new field of research in synthetic biology called ‘electrogenetics’ that promises to make this happen.
Cue electrogenetics
Electrogenetics uses electricity to control gene expression and produce a specific transcript or protein. Using electricity to treat diseases sounds like torturous shock therapies, but rest assured, it is not patients, but implanted ‘electrogenetic’ cells designed to respond to electrical or electrochemical signals that are shocked.
The exciting thing is that this method works for cells that do not normally respond to electricity. For example, human pancreatic beta cells can be modified by adding electro-sensitive receptors, and these cells can then be electrically triggered to produce and release insulin as and when needed for the management of type 1 diabetes.
It all comes down to a bacteria…
Like evolution, the birth of electrogenetics started with tiny bacteria, in this case, electrochemically active bacteria. These bacteria could naturally control their gene expression in response to electrical stimuli, something human and other mammalian cells cannot do. Three decades later, advances in scientific methods meant that researchers could modify mammalian cells (including mice and humans) to mimic the behaviour of electrochemically active bacteria. It became clear very quickly that this technology held potential in getting cells to produce what we wanted, when we wanted, and a new avenue in cell therapy or precision medicine was born.
The nuts and bolts of making it happen
To build a functional electrogenetic system, you need a source of electricity and a cell attuned to respond to electricity, where the response is to produce something: a transcript or a protein. Initial research in mammalian electrogenetics was focussed on controlling gene expression in electrogenetics cells (see our recent briefing [link] for more details). However, such start-to-stop production of a protein such as insulin can take as long as 24 hours. Not ideal if the goal is blood glucose control in diabetics where immediate action is usually needed to prevent adverse outcomes such as severe low blood glucose levels or hypoglycaemia.
Researchers are now exploring protein-based systems where proteins are synthesised and stored inside electrogenetic cells and released in response to an electrical signal. As electrical stimuli triggers protein release and not its synthesis, protein-based electrogenetic systems are faster than gene expression-based electrogenetic systems.
Protein-based electrogenetic cells
Currently, two main types of protein-based electrogenetic cells are being developed:
- vesicular secretion-based electrogenetic cells
- post-translational switch (POSH)-based electrogenetic cells
Vesicles are small sacs that can store and transport materials inside or outside of the cell. For example, in response to high blood glucose levels, beta cells in the pancreas release insulin stored in vesicles into the blood. Using the same principle, in method one, proteins are prepared and stored inside vesicles which release protein contents upon receiving an electrical stimulus. Such specially designed electrogenetic cells were found to release insulin in as little as 10 minutes.
In the second method called POSH, the protein of interest is synthesised with an additional tail of amino acid sequences that helps it latch onto other proteins in the endoplasmic reticulum, the part of the cell that helps produce and process proteins. When an electrical trigger is received, a protein-cleaving enzyme (known as a protease) is activated which specifically cuts the ‘amino acid sequence’ tail of the protein, releasing it from the endoplasmic reticulum, ready for secretion.
Protein-release in action
Recently, researchers added electro-sensitive receptors to human pancreatic beta cells which allowed these cells to release insulin from vesicles in response to an electrical stimulus. These cells were placed in a bioelectronic device and implanted under the skin of mice. Preliminary experiments showed that this vesicular secretion-based electrogenetic system could help control glucose levels of type 1 diabetic mice, with an effectiveness comparable to that of bioelectronic implants containing human pancreatic islets (clusters of pancreatic cells).
Reassuringly, the electrogenetic beta cells were able to tolerate the electrical stimuli i.e. cells did not die when an electrical stimulus was applied, and cells could be triggered multiple times to release insulin. Moreover, the bioelectronic implant was found to be safe for use in mice as it produced no apparent toxicity or immune system activation.
What does this mean for type 1 diabetes management?
The benefits are clear. Bioelectronic implants containing insulin-producing electrogenetic cells could replace the need for multiple insulin jabs and offer real-time control over insulin release. This could transform the lives of people with type 1 diabetes. Also, as these implants produce human insulin, they may not produce allergic reactions or other side effects such as hypoglycaemia in patients, which happens for current insulin jabs that use synthetic human insulin or insulin derived from pigs or cattle.
Despite these attractive clinical benefits, more needs to be done before these protein-based electrogenetic systems are ready for clinical use. Current vesicular secretion-based electrogenetic systems suffer from leakiness – the output is produced even when the threshold for electrostimulation has not been met. Such leakiness could be bad news for type 1 diabetics as continued insulin production can lead to hypoglycaemia. The good news is researchers have shown that they can create electrogenetic pancreatic alpha cells that release the hormone glucagon– which has the opposite effect of insulin in the body. Therefore, a combined electrogenetic system made of pancreatic alpha and beta cells, to maintain blood glucose levels and control leakiness, might be possible in the future. Additionally, the POSH system can help correct leakiness, as both electrostimulation and protease activation – which only happens at a certain threshold of electrostimulation, are needed to trigger protein release.
Furthermore, cells die and need to be renewed in bioelectronic implants. Researchers recently tested the possibility of refilling implants in mice with new batches of electrogenetic cells without having to remove and re-insert the implant. They found that replacing cells every week over a three-week period helped maintain insulin levels. However, methods to do such in situ refilling of electrogenetic cells in humans and the frequency of refilling remains to be determined. Should this challenge be overcome, the next consideration will be one of assessing clinical utility. This would require testing whether these electrogenetic cell implants work in humans, whether they are safe, and whether there is a benefit to using them in the health system, such as their cost-effectiveness compared to regular insulin jabs.
Although this technology is still in its infancy, it offers the potential to improve clinical care for diabetes, and other hormonal or protein-based diseases.
If you would like to read more on electrogenetics and its clinical potential, please also see Electrogenetics: a new avenue in precision medicine.
