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Far-Red-Light-Activated Optogenetically Engineered Cells Produce Insulin

Researchers at East China Normal University have optogenetically engineered cells in diabetic mice to produce insulin when illuminated by far-red light. The insulin dosing is controlled via smartphone. 

“The cells we used in this study are HEK-293 cells— human embryonic kidney cells,” says Haifeng Ye, PhD, professor of synthetic biology and biomedical engineering at the Shanghai Key Laboratory of Regulatory Biology in the Institute of Biomedical Sciences and School of Life Sciences, East China Normal University. In the future, he adds, these cells will be replaced by stem cells from a patient.

In their experiments with mice, the researchers integrated the HEK-293 cells into a soft, bio-compatible sheath along with wirelessly powered red LED lights to create so-called HydrogeLEDs that could be turned on and off by an external electromagnetic field. Implanting these HydrogeLEDs into the skin of diabetic mice then allowed the scientists to remotely control the delivery of insulin via a smartphone application.

How the light controls insulin production 

“Far-red light activates the engineered bacterial photoreceptor BphS, which converts GTP into c-di-GMP,” explains Ye. “Increased cytosolic c-di-GMP production triggers the transactivator (p65-Vp64-BldD) dimerization and binds it to its specific operator sites, and then initiates insulin gene expression. The implants containing the optogenetically engineered cells could be activated by far-red light to initiate insulin or shGLP-1 gene expression to control glucose homeostasis.”

Gene expression triggered by far-red light controlled by smartphone app

The new far-red-light-controlled transgene expression circuit developed by Ye and his colleagues shows high induction folds. What is more, the study represents the first time anyone is using a smartphone to control gene expression to treat diabetes in mice. Indeed, Ye reports, “We have developed a closed loop system for diabetes therapy.”

Benefits of far-red-light-controlled insulin production

This is not the first closed loop system for diabetes therapy. In the US, the FDA has approved the so-called “artificial pancreas” last year. And Ye confirms, “You can say, our system is some kind of artificial pancreas as well.”

Benefits

He says the advantages of his team’s system include that it could be ultra-remote controlled by a smartphone. Furthermore, the optogenetic designer cells are engineered to produce either insulin for patients with the auto-immune disease type 1 diabetes (insulin dependent) or to produce GLP-1 for people with type 2 diabetes. Adds Ye: “These designer cells are very easy to handle and could be frozen and thawed.” For patients with type 1 diabetes, who need a continuous dose of background insulin, the cells can produce basal insulin 24/7. “We can make engineered cells with less or a little bit more of basal insulin,” Ye affirms. “This is very flexible.”

Confirming that the insulin is indeed essentially “human insulin” (or, for now, mouse insulin), rather than more like slower-acting synthetic insulin, Ye says, “Yes, we have tested both human and mouse insulin. They have almost the same biological activities.”

Hope for millions of patients with diabetes

“I really hope this new diabetes therapeutic strategy can benefit millions of diabetic patients,” the professor responds to the question about the most exciting aspect of this research breakthrough. “With this technology, the quality of life can be substantially improved.”

Challenges

Speaking about his team’s biggest challenges during the research project, Ye says one of the most difficult things is how to design and create a far-red-light-controlled transgene expression circuit. “At the very beginning, the optogenetic device did not work at all,” he reports. “And then, we tried hundreds of optimization tests ,and finally we created a very nice and robust optogenetic device.”

The professor further reports that the software engineering and the electronic engineering efforts in this study were difficult as well: “We did not know how to write a smartphone app or how to create a circuit board,” he says. They later brought on an electronic engineer to help solve the issues at hand.

Path and timeline to application in the real world

Ye notes it will take time to push this technology to being available to patients at clinics. 

Before that can happen, however, Ye and his colleagues are currently working on:

  • A fully automatic blood glucose monitor and diabetes therapy system that could continuously monitor the glycaemia dynamics 24 hours and share the data via smartphones. Meanwhile producing corresponding doses of insulin or GLP-1 in a hyperglycemia-dependent manner will provide a great convenience for diabetic patients.
  • A cell macroencapsulation system based on a high-capacity immunoisolation device with artificial extracellular scaffold, allowing for the long-term survival of encapsulated designer cells is preferred.

Ye is now looking for venture capitalists to joint the research. “We hope we can translate this technique to clinics as soon as possible,” he says.

The research is detailed in the article “Smartphone-controlled optogenetically engineered cells enable semiautomatic glucose homeostasis in diabetic mice,” published in the journal Science Translational Medicine.

Written by Sandra Henderson, Research Editor, Novus Light Technologies Today

Labels: Artificial pancreas,East China Normal University,closed-loop insulin delivery system,optogenetically engineered cells,Professor Haifeng Ye,HydrogeLEDs

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