Bacteria across our planet contain nanometer-sized factories that do many different things. Some make nutrients, others isolate toxic materials that could harm the bacteria. We have barely scratched the surface of their functional diversity.

But all share a common exterior, a shell made of protein tiles, that Michigan State University researchers are learning how to manipulate in the lab. This will allow them to build factories of their own design, using the natural building blocks. Indeed, scientists see the structures as a source of new technologies. They are trying to repurpose them to do things they don’t in nature.

In a new study, the lab of Cheryl Kerfeld reports a new genetically engineered shell, based on natural structures and the principles of protein evolution. The new shell is simpler, made of only a single designed protein. It will be easier to work with and, perhaps, even evolve in the lab. The study is published in ACS Synthetic Biology.

Natural shells are made of up to three types of proteins. The most abundant is called BMC-H. Six BMC-H proteins come together to form a  hexagon shape to tile the wall.

At some time in evolutionary history, some pairs of BMC-H proteins became joined together, in tandem. Three of these mergers, called BMC-T, join to also form a hexagon shape.

“The two halves of a BMC-T protein can evolve separately while staying next to each other, because they are fused together,” said Bryan Ferlez, a postdoc in the Kerfeld lab. “This evolution allows for diversity in the structures and functions of BMC-T shell proteins, something that we want to recreate by design in the lab.”

To take his fledgling lab to new heights, Liangfang Zhang hatched a plan that he considered brilliant in its simplicity. It involved procedures that many of his peers found a little out there. But if he could make his idea work, it would clear a major hurdle to safely ferry therapies through the body on nanoparticles one-thousandth the width of a human hair.

Yet back in 2010, the young nanoengineer could not convince the National Institutes of Health, the main funder of U.S. biomedical research, to support the project. Zhang applied for funding four or five times over several years, to no avail.

“It felt quite lonely,” he says. “But I just felt this is very unique stuff. And it may become a big thing.”

Pulling funds from other projects and from the start-up package he received to set up his lab at the University of California, San Diego, Zhang did the experiments for his breakthrough paper, published in 2011 in the Proceedings of the National Academy of Sciences. He and coworkers created a new class of nanoparticles, made from carbon-containing polymers, that could slip through blood vessels in a mouse without triggering an immune reaction. While immune responses are important for killing disease-causing pathogens, the same reactions are a nuisance when they clear out molecules made to deliver lifesaving drugs.

Then, instead of just viewing their particles as a drug-delivery system, which most other researchers were focused on, Zhang and his team made a surprising pivot. They repurposed the particles to act as “nanosponges” that trap and remove toxins from the blood. In lab experiments, the nanosponges worked against toxins unleashed by E. coli and some of the harder-to-fight bacteria. Nanosponges also slowed harmful inflammation in mice with a form of rheumatoid arthritis and diverted HIV and Zika from the cells those viruses normally infect, the researchers reported last year.

Image Credit:  MSU


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