Date: 5th November 2019
Light-switchable cells have been designed to combat diabetes by producing increased insulin levels.
Diabetes is one of the top ten causes of death worldwide. There are many approaches to diabetes management currently being employed. From medication, insulin injections or pumps, to islet cell transplants or the more exploratory development of artificial pancreata.
However, synthetic biology tactics are also starting to be employed towards treatment progression. From a manufacturing perspective we recently reported the generation of nanomachines; engineered enzymes created in order to yield a cleaner and quicker method of producing anti-diabetic drugs.
Now scientists from Tufts University have employed a synthetic biology approach to engineer pancreatic cells to produce increased levels of insulin in response to high glucose levels in mice.
Insulin is a hormone produced by β-cells in the pancreas and regulates how the body uses and stores glucose and fat. Crucial for regulating blood sugar levels, β-cells recognise extracellular glucose concentrations and secrete insulin via a process called glucose‐stimulated insulin secretion (GSIS). In diabetic patients the cells of the body can either become inefficient at responding to insulin or there is a lack of insulin to elicit an appropriate response.
The most accessible treatments currently available, therefore, either stimulate the production of insulin or replace it. However, this involves careful and frequent, manual monitoring of blood glucose and often is associated with peaks and troughs of glucose levels which can cause long term damage.
In an attempt to restore an optimal and more consistent regulation of blood sugar levels, Emmanuel Tzanakakis and Fan Zhang engineered β-cells with a stable photoactivatable adenylyl cyclase (PAC) gene. PACs are naturally occurring proteins that combine the capacity of a photoreceptor with that of an adenylyl cyclase, they can be genetically manipulated for use in a range of organisms. In this case when exposed to blue light, the molecule cAMP is produced, which in turns potentiates GSIS within the β-cells.
In engineered β -cells exposed to blue light, a greater than 2-fold level of GSIS was observed in the presence of high levels of glucose whilst, in the absence of glucose, insulin production remained at a low steady state.
The light-activated β-cells were then transplanted under the skin of diabetic-induced mice. On stimulation with blue light, the mice showed improved tolerance and regulation of glucose, with reduced hyperglycemia (high glucose) and higher levels of insulin detectable in the plasma compared to controls.
Current diabetic treatments often lead to hypoglycaemia (low blood sugar), mainly due to overcompensation when insulin is added to the system. Manually achieving steady-state levels of glucose is difficult as temporal, exogenous factors come into play.
By embedding optogenetic networks (the use of light to control cells in living tissue) in β-cells, the researchers have managed to control GSIS in a physiologically relevant manner.
The response on exposure to blue light is immediate and the method has been compared to a ‘boost’ system, whereby, insulin is produced at higher levels for a transient period of time until glucose levels return to ‘normal’ state.
One important advantage of this optogenetic method is that the oxygen consumption of the engineered cells is not increased when the ‘boost’ has been activated, which can be a common problem in transplanted pancreatic cells and often leads to loss of islet function.
Whilst it is recognised there are many steps before this may become a viable treatment for diabetes, this offers an exciting development towards disease management and the ability to control insulin administration in a much more physiological manner.
Future developments could see a closed-loop circuit involving embedding a tiny, remote light source, coupled to a glucose biosensor creating in effect a bioartificial pancreatic device.
For more information please read the press release
Zhang, F. and E. S. Tzanakakis (2019). “Amelioration of Diabetes in a Murine Model upon Transplantation of Pancreatic β-Cells with Optogenetic Control of Cyclic Adenosine Monophosphate.” ACS Synthetic Biology 8(10): 2248-2255.
https://doi.org/10.1021/acssynbio.9b00262
