One chemist’s solution for re-using industrial polymers: the cell-like microgel

Polymer chemist Julian Thiele of the Leibniz Institute of Polymer Research Dresden extracts the protein-making skills from living cells and places them inside polymer microgels. His ambition: to teach the cell’s enzymes to accept synthetic substrates that can make new compounds, for example from inert industrial chemicals. “We are now applying polymer materials in new ways using biology.”

Dr. Julian Thiele: “At my lab, we look at the relationship between cell structures and cell functions in order to mimic a cell’s properties using microgels. For instance, we extract the lysates from E. coli cells, which is the biological machinery for protein synthesis, and load these lysates into a polymer hydrogel, which can then perform protein synthesis. The gel provides a cell-like environment. It acts as a synthetic cell or container, pre-modified to carry a cell’s DNA.”

Dr. Julian Thiele (on the right) in discussion with his coworker MJ Männel behind one the high-resolution 3D printers of his lab at Leibniz IPF Dresden

What are the advantages of working “cell-free” with microgels instead of living cells?

By using microgels I can mimic many properties of living cells, such as size, shape, density, and porosity. I can also explore experimental conditions that don’t exist in nature – they might cost a cell too much energy for example – and that can make the gel function better than a cell can. Cells use a great part of their metabolism to survive, but a microgel can spend all its energy on protein function. Moreover, microgels can produce proteins faster and at a higher yield than conventional cell-free approaches in solution.

In circumstances where the products forming inside a cell are toxic, it makes sense to work with microgels as a synthetic alternative, or in cases where a biosynthesis path of interest is too complex to handle or manipulate in a living cell – for instance when producing a drug. Microgels are cheaper than cells, recyclable, and more robust against degradation. So, getting your product out becomes easier: since microgels can’t be killed, we can just use centrifugation to separate them from the valuable product, then take out the microgels and use them again.

Are there difficulties with using microgels?

One of the challenges of using microgels is how to control material transport so that things produced inside the gel stay inside and don’t just randomly leave. Gels don’t have a boundary like the cell membrane or other artificial platforms like vesicles (e.g., liposomes, polymersomes). Things can go in and out of the gel without hindrance if its pores are sufficiently large. We have found solutions for this: we can tailor microgel porosity to make it as small as tens of nanometers. We can reversibly collapse the hydrogel matrix on demand, e.g., by temperature, pH or light. We can also immobilize DNA in the gel to act as a target, making sure the products formed in protein synthesis stay within the DNA’s vicinity.

When immobilizing DNA in a microgel, the protein that is produced will stick to the microgel and stay inside

What are your ambitions with your research?

My lab’s ambition for the next few years is to get microgels to work together with a living cell’s biological machinery. As a polymer chemist, it is much more challenging to work with living cells than to use an artificial platform, as we are doing now. I want to teach the cell’s enzymes to accept not only the substrate they always use but also artificial substrates, for instance, a synthetic polymer. This makes it possible for these synthetic enzymes to create new compounds, or we can bring the cells into new applications – for example in medicine or in reducing chemical waste by re-purposing the materials.

The vision of my lab is to make a bioreactor with microgels instead of cells, which can produce synthetic materials. We want to bring the key architectural things that make cells so unique and so efficient into an artificial environment, such as out-of-equilibrium reaction conditions and nano- and micron-scale compartmentalization of the reaction volume. The goal is that these measures will allow us to outperform conventional cell-free as well as a cell-based biotechnology regarding yield and purity, for instance. To get there, the material of the microgel needs to be able to interact with the biological functions of a cell and actively adapt to it.

What applications do you envision with adaptive microgels in the next few years?

The materials we use in our daily lives are implemented on an enormous ton scale. They produce a lot of waste everywhere. By using adaptive microgels that can act as robust and tailored reaction platforms to host engineered enzymes, we hope to be able to convert and process high-molecular-weight substrates like polymer materials that are chemically inert – and can even be considered trash – and provide them with new functions. This new functionality will be the key to overcoming the industry’s challenge to reduce waste. The adaptive microgels could support the recycling of polymer materials, or improve the degradation of them into non-toxic remains.

We are now applying materials in new ways using biology, like the widely known PEG. Polyethylene glycol is used for drug enhancement, for instance, to increase the half-life circulation time of a drug in the body. Together with our partners at TU Dresden working in the area of molecular biotechnology, we are trying to use enzymes to functionalize such polymers in a way that is not possible chemically; provide them with new functional groups, and thus expand their applicability.

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