A Powerful Marriage
Mary McElroy, PhD

A Powerful Marriage

Can synthetic biology revolutionize the field of stem cell therapy?

When it comes to 21st-century medicine, it doesn’t get any better than using cells to cure or repair what ails you.

Stem cell therapies hold great promise for the repair and regeneration of diseased tissues because of their ability to sense and integrate complex environmental signals, to migrate to diseased tissues and to execute complex responses. Stem cells have been used successfully in the lab to repair damaged heart muscle or restore movement to paralyzed limbs.

However, this complexity also presents significant safety concerns—such as tumor formation or inappropriate functionality—which have discouraged the widespread use of stem cells for the treatment of major diseases such as diabetes or Alzheimer’s.

One way to accelerate the safe development of cell therapies is by using synthetic biology to engineer external control of multiple complex cellular functions. Indeed, proof-of-principle studies have already demonstrated that synthetic biology techniques can control cell proliferation and cell death, redirect cell migration, and control the expression of selected proteins and direct intracellular communication.

Cellular Micromanagers
So what is Synthetic Biology? Synthetic Biology is the rational design of biological circuits using engineering principles and DNA building blocks.

The ultimate aim of synthetic biology is to mass produce biological levers and tools—otherwise referred A-Powerful-Marriage_2.jpgto as BioBricks —to control a given biological process in many different cell types. The term BioBrickTM was introduced about 10 years ago by Massachusetts Institute of Technology scientist Tom Knight to describe interchangeable biological components that could be used in engineered circuits. (For a good primer on this, check out Help: An Introduction to BioBricks.)

One of the major safety concerns of cell therapy products is the risk of tumor formation from uncontrolled cell proliferation. Using synthetic biology, you can actually design a number of engineered circuits to induce programmed cell death (or apoptosis). These engineered circuits trigger cell death following a given number of cell replications or in response to the administration of a harmless activator molecule such as a food component like biotin (part of the vitamin B complex). In doing so, these circuits  provide the means of removing cancer cells before a tumor is formed.

Progress in Mice
Other exciting developments include engineering cells to respond to optical signals or optogenetics.  Optogenetics are genetically-encoded molecular reagents that are controlled by light after being expressed in the targeted cells. Some think that optogenetic reagents will have application in the controlled release of hormones and peptides in diseases such as diabetes to enable the remote control of key cellular functions. Time will tell if this theory holds up, but if so it could eliminate the need for daily insulin injections for millions of diabetics.
In a recent proof-of-concept study Martin Fussenegger’s laboratory at the University of Basel, Switzerland engineered a cell containing a light-sensitive photoreceptor linked to a gene encoding glucagon-like-peptide 1 (GLP-1) under the control of an endogenous promoter (NFAT). The authors demonstrated that light-controlled expression of GLP-1was able to control glucose levels in type II diabetic mice.

Undoubtedly, applying synthetic biology techniques to cell therapies is revolutionary. But the practice is also not without additional safety risks associated with the mutation of engineered DNA and consequent loss or gain of function. However, potential applications for the development and manufacture of cell therapies products appears to be limitless—in short, a match made in heaven.

Though biologists and toxicologists will have to get used to using engineering terms such as genetic toggle switches and oscillators to keep up!

This blog is a result of a recent informal workshop organised by Edinburgh’s Centre for Synthetic and Systems Biology. Charles River Laboratories helped to stimulate thought and discussion around the real- world challenges posed by the need to improve the speed and accuracy of drug safety testing and minimizing the use of animals.