App-Controlled Designer Cells Treat Diabetes

Electronic monitoring and storing of health data is all of the rage right now. Many of us track the number of steps we take with our mobile phones or smart watches, log food consumption, and measure our heart rate. But would you trust a mobile health app to decide when you should receive a life saving, but in some cases, life threatening, drug? For diabetics, this possibility is approaching reality.

Diabetes is a condition in which the β-cells of the pancreas do not produce sufficient insulin to maintain blood glucose (BG) homeostasis.

BG levels that are too high or too low are both dangerous, but for different reasons. The brain needs glucose to function, so with too little glucose, the body starts shutting down and can slip into a coma. Too much glucose in the bloodstream damages nerves and organs—long-term elevated BG levels can lead to kidney damage, neuropathy, and blindness.

Glucose enters the bloodstream as the body breaks down food from a meal into simple sugars that cells can use for energy. Insulin stimulates muscle, liver, and fat tissue to take excess glucose out of the blood, and those cells can subsequently use that glucose for normal functioning.

Patients with type 1 diabetes (T1D) lack insulin because their β-cells, which produce insulin, have been attacked and killed by an autoimmune reaction. These patients usually develop diabetes early in life and need to inject insulin many times a day.

Type 2 diabetics experience high BG levels because their cells have become insulin resistant and no longer properly uptake glucose from the bloodstream, or their β-cells have become stressed out and no longer secrete proper levels of insulin. Type 2 diabetes (T2D) is associated with obesity and physical inactivity.

In some cases, T2D can be controlled by diet alone, oral medication, insulin, or by injections of glucagon-like peptide-1 (GLP1) receptor agonists. GLP1 agonists act by stimulating insulin secretion.

The management of diabetes has improved with the advent of the handheld glucometer, continuous glucose monitor, and insulin pump. Diabetics can manually test their BG easily from home with a fingerprick (handheld glucometer), continually monitor their BG using a receiver or cell phone (continuous glucose monitor), and avoid frequent injections of insulin by infusing insulin through a subcutaneous cannula.

Despite easing management, these technologies largely lack automation. The US Food & Drug Administration recently approved the use of the “artificial pancreas (AP),” a system that allows a continuous glucose monitor to talk to an insulin pump and give insulin infusions with little-to-no user interface. The AP has only been approved for a single company, however, and has not been widely adopted among patients yet.

Scientists have been exploring other biologic-based therapies to help treat or cure diabetes. The Hebrok and Sneddon labs at UCSF are trying to understand how to grow insulin-producing β-cells from stem cells in the lab that could be implanted back into patients and help control their BG.

Last week in Science Translational Medicine, researchers from East China Normal University sought to design a theranostic (both therapeutic and diagnostic) system that wirelessly controlled engineered cells to treat diabetes.

The paper outlines the stepwise process the team took to achieve a final system in which far-red light (FRL) activated the expression of insulin or a GLP-1 agonist in engineered cells that were implanted into mice and restored BG homeostasis.

The authors drew inspiration from the “Smart Home” concept and created a server box that would allow for the control of electronic devices by a mobile phone connected to the server via the internet. An app, “ECNU-TeleMed,” developed on the Android platform, allows users to send commands to the smart server box from anywhere in the world. It is important to note that the server box, dubbed “Smart Controller,” must be physically attached to the electronic device it is controlling.

Light sources can easily be turned on and off by electrical switches. But how can light exert a biological effect?

Over the past few years, scientists have discovered and developed several light-activated transcriptional pathways using a technique called optogenetics.

In optogenetics, cells are biologically engineered to express light-sensitive proteins. These proteins are often ion channels that reside in the cell membrane that when exposed to light, change ion concentrations in cells that lead to changes in gene expression. Changes in gene expression change the biologic function of the cell.

Cells were engineered that express BphS, a bacterial gene protein that when activated by FRL leads to increased amounts of a messenger inside a cell called c-di-GMP, which activates interferon signaling (IS) in human cells. Interferons are proteins that turn on other genes involved in the immune system.

To determine the activity of IS in the cells, the authors modified the cells to have a reporter construct that would lead to the production of a molecule called SEAP. If the FRL, turned on and off by the ECNU-TeleMed app, successfully activated BphS, levels of c-di-GMP would go up, turn on IS, the amount of SEAP should go up.

Version one of the engineered cells relied on IS, which can encounter crosstalk from other components of the human immune system. To minimize this crosstalk, the authors added BldD, a bacterial transcription factor that becomes active in the presence of c-di-GMP, and activates genes other than those involved in IS. A different reporter was added that would show increased SEAP with increased BldD activity.

Version two cells were encapsulated in gel and implanted in mice. SEAP production was successfully turned on with FRL from the app, but the cells did not receive uniform levels of FRL. Cells were then encapsulated into a hollow fiber tubes that were planted under the skin of mice, which received more uniform FRL.

Now that the authors proved their system was working using a reporter gene (SEAP), they modified their cells to produce insulin upon the application of FRL.

T1D mice were implanted with microtubes of cells engineered to express insulin; upon application of FRL the diabetic mice showed reduction of BG levels. Similarly, T2D mice were implanted with cells engineered to express a GLP-1 agonist, also showed rapid reduction of BG levels upon exposure to FRL.

These results were maintained when the FRL was controlled via smartphone instead of manually.

The authors realized that asking patients to sit under a red light to treat their diabetes is not a realistic therapeutic approach, so they designed HydrogeLED, a gel that contained their engineered cells and wireless FRL lights that turned on when they were inside an electromagnetic field.

Engineered cells in HydrogeLED were implanted into the peritoneum of mice that could move freely in an electromagnetic field that was controlled by SmartController via ECNU-TeleMed from a mobile phone.

A traditional glucometer, used by patients to monitor BG levels, was enabled to talk to the SmartController via Bluetooth. The microcomputing chip in the SmartController was programmed to change FRL values based on the manually sampled mouse BG levels it was receiving from the glucometer, yielding semi-automatic control of BG regulation in both T1D and T2D mice.

It is encouraging to see scientific innovation for the treatment of a disease that affects millions nationwide. However, while the author’s fascinatingly combined biology, software development, and engineering, this approach to treating diabetes is far from clinically useful.