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Thursday, January 22, 2009

A Virus that Rebuilds Damaged Nerves

Viral scaffolding: This fiber is made of billions of viruses and is being studied as a tissue-engineering scaffold. The fiber helps progenitor cells grow into neurons.
Credit: Nano Letters

Viruses that mimic supportive nerve tissue may someday help regenerate injured spinal cords. While other tissue-engineering materials must be synthesized and shaped in the lab, genetically engineered viruses have the advantage of being self-replicating and self-assembling. They can be designed to express cell-friendly proteins on their surfaces and, with a little coaxing, be made into complex tissuelike structures. Preliminary studies show that scaffolds made using a type of virus called a bacteriophage (or phage) that infects bacteria but cannot invade animal cells can support the growth and organization of nerve cells.

Researchers working on tissue engineering hope to eventually be able to use a patient's own cells to grow replacement tissue for damaged hearts, livers, and nerves. But mimicking the structure and function of the body's tissue has proved difficult. Matrices of supportive, fibrous proteins sustain the cells of the heart, lungs, and other tissues in the body. These scaffolds provide both structural support and chemical signals that enable an organ or nerve tissue to function properly.

Some biological engineers are using scaffolds made of polymers to try to mimic the supportive matrix of real tissue. Seung-Wuk Lee, a bioengineer at the University of California, Berkeley, has turned to viruses instead. "Viruses are smart materials," he says. "Once you construct the genome, you can make billions of phages, and they're self-replicating materials." The phage that Lee is working with, called M13, is long and thin like the protein fibers that make up the cellular matrices inside the body.

First, Lee and his colleague Anna Merzlyak genetically engineered M13 to display nerve-friendly proteins on their outer coats. These proteins are known to help nerve cells proliferate, adhere, and extend into long fiberlike shapes. Next, the researchers grew large numbers of the viruses in bacterial-cell hosts and dropped them into a solution containing neural-progenitor cells. These cells are more fully developed than stem cells but are still young and need coaxing to form new tissues. In the solution, the viruses align themselves like a liquid crystal, says Lee. He and Merzlyak used pipettes to inject the solution into agar, a Jell-O-like cell-culture medium, creating long, nerve-like fibers of the virus interspersed with cells. The progenitor cells then multiplied and grew the long branches characteristic of neurons. Lee says that the phage are well suited to making long, fiberlike structures such as nerve tissue but can also be made into more complex structures by varying their concentration or manipulating their position with a magnetic field.

Lee is not the first to use a virus as an engineering material. Other researchers have used the same virus to build battery electrodes. Using the virus in this way was pioneered by Angela Belcher, now a professor of materials science and engineering and of biological engineering at MIT, and was the basis of Lee's graduate work while he was in her lab. Genetically engineered phages have already been approved as an antibacterial food preservative by the U.S. Food and Drug Administration, for use in lunch meats like bologna, for example. Phages are also under study as a potential treatment for chronic bacterial infections.

MIT Institute Professor Robert Langer says that Lee's work is interesting from a materials perspective, but he cautions that its practicality must be established through in vivo studies.

Lee says that his group plans to establish the safety of phage scaffolds in live animals next. M13 has a good safety record and is not capable of infecting people. Still, the Berkeley researchers will need to investigate how an animal's immune system responds to the viral scaffolds and prove that they encourage nerve regeneration once inside the body. Lee hopes that the viral system will eventually be used to regenerate neurons in patients with spinal-cord injuries.