Click chemistry used to weave a custom web

Click chemistry turns bacteria-produced spider webs into a biomedical wonder, promising innovations in fiber optics, wound healing, and tissue regeneration.

For centuries, silk growers reigned supreme, their coveted threads harvested from silkworms, making them the envy of the ancient world. In modern times, spider webs have become an enviable material for their incredible physical properties—a remarkable combination of strength and flexibility.

Unfortunately, replicating large-scale spider silk production resembling historic silkworm farms is unlikely to happen anytime soon. “I don’t think mass production of spider webs is realistic,” explained Fei Sun, a researcher at the Hong Kong University of Science and Technology. “I think scalability is still a big issue.”

According to him, raising spiders on farms is unrealistic due to the aggressive and cannibalistic nature of spiders. Advances in synthetic biology, however, allow researchers like Sun to adapt spider silk for biomedical purposes that don’t require large-scale production.

In an article published in Advanced functional materials, Sun and colleagues describe a new method for producing spider web proteins in bacteria. Their process is not only efficient, but also allows them to equip the threads with a variety of different molecules that enhance the natural qualities of spider silk or even interact with living tissue.

A network of new techniques

To create a “customizable web,” the team combined two genetic and chemical technologies. The first is recombinant DNA, a synthetic biology technique that allows researchers to isolate and manipulate specific genes and even combine them with the genome of another species.

With this technique, Sun can insert silk web genes into bacteria, E. coliturning bacterial cells into spider web protein factories.

The team then used a relatively new method in the field of synthetic chemistry called genetically encoded click chemistry. In short, it’s a technique for efficiently linking (or ‘snap’ together) protein molecules like Lego building blocks.

The team used this method to genetically add a tag to the spider silk protein, which serves as an anchor point for other molecules of interest that are tagged with the corresponding capture molecule. This turns the normal spider web into a scaffold that can be coated with all kinds of beneficial molecules.

Functional threads

In two separate experiments, the team was able to demonstrate the power of this new technology. First, they coated spider silk threads with an enzyme called silicatein. This enzyme is used by marine sponges to transform silicic acid into silica, a glass-like structure that sponges use in their bodies.

The result was an organic-inorganic hybrid of spider silk proteins coated with vitreous silica. Not only did this prove that the team could modify silk proteins, but according to Sun, “we may be able to turn this into an optical fiber.”

To demonstrate the potential of silk proteins for biomedical purposes, the team then coated the spider silk proteins with molecules known as cell-binding ligands. As the name suggests, these molecules attach to cell surfaces and are used for various purposes in the body, such as wound healing and tissue growth.

Spider silk proteins coated with one of two different ligands were used as cell culture platforms, and after 10 days of growth, ligand-coated silks were covered with more cells than uncoated silks. Not only that, the cells on the ligand-coated silks grew in a more elongated fashion, mimicking how actual cells in tissues such as the vascular system grow and function, indicating that these silk scaffolds could be used to heal wounds or repair tissues.

Endless possibilities

According to Sun, this is a promising proof of concept. Spider silk proteins are already coveted for their strength, small size, and ability to resist degradation by the body’s enzymes and proteins. In addition, several reports claim that silk does not provoke the immune system.

Now with a way to efficiently manufacture silks and turn them into adaptable scaffolds, Sun believes the potential uses are limited only by the types of molecules they can attach to the silks. Fortunately, advanced AI is available for that, too, Sun said.

Powerful AI programs like AlphaFold, which predict how molecules and proteins will fold, function and attach, allow Sun to visualize how the desired protein will behave on the silk and how best to place it. Now, instead of making guesses and running experiments to see if it works, they can think about the desired outcome and then see which proteins might work for a given scenario.

Sun and his collaborators are now investigating specific uses of the functionalized silk proteins as a platform to regenerate neurons or grow organoids. For Sun, these achievements are driven by our ability to look to nature for inspiration and solutions.

“Researchers want to use biological systems to produce materials that can be comparable or even exceed what our ancestors have been doing for 1,000 years,” he said.

Reference: Angela Ruohao Wu, Fei Sun, etc. Engineered Multifunctional Silk Web Enabled by Genetically Encoded Click Chemistry Advanced Functional Materials (2023) DOI: 10.1002/adfm.202304143

Feature Image Credit: Nathan Dumlao at Unsplash

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