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Synthetic Biology Could Speed Flu Vaccine Production

Advanced genetic engineering is already changing vaccine development and could make inroads into other branches of medicine.

Synthetic biology is breathing new life into the old-fashioned world of vaccine production, raising hopes that manufacturers could release vaccines much more quickly when outbreaks occur.

At a meeting on synthetic biology held at MIT, the drug company Novartis said it has synthesized hybrid flu genomes in a process that could shave weeks off the time required to produce vaccines. When new flu strain emerges, government agencies normally send samples to vaccine manufacturers, who grow large numbers of the pathogen in chicken eggs as starting material for vaccines, says Philip Dormitzer, leader of viral vaccine research for Novartis. This process can take months and can miss the peak of an outbreak. But Novartis, working with synthetic biologists, has developed a way of chemically synthesizing virus genomes and growing them in tissue culture cells. That saves time and may produce more effective vaccines.

The idea is to build a synthetic virus based on sequence data that can be distributed much more quickly than actual viral material harvested at the site of an outbreak. The synthetic viral genome combines a genomic backbone common to many flu viruses with genes specific to the strains seen in a new outbreak. In 2011, the team tested its method in response to a mock outbreak of a bird-flu virus (one closely related to the H7N9 virus currently spreading in China). Starting at 8 a.m. on Monday that year, the team began to chemically synthesize a viral genome based on sequence data, says Dormitzer.  By noon the following Friday, the team had confirmed that it had live virus growing in cell culture.

Until recently, most synthetic-biology efforts have focused on engineering bacteria to produce desirable compounds such as drugs (see “Microbes Can Mass-Produce Malaria Drug”) or fuel (see “Bacteria Make Diesel from Biomass”); they haven’t involved humans or other mammals. But that is changing. Mammalian synthetic biology, which involves modifying mammalian genetic circuits, is still in “relative infancy,” says Jim Collins, a synthetic biologist at Boston University. “There are only a handful of groups in the space, and it’s very hard to do that engineering,” he says.

In other work described at the Cambridge meeting, Pam Silver, a synthetic biologist at Harvard Medical School, presented methods for “cell-based computing,” in which logic gates can be built from engineered proteins. One application of these tools is a genetic circuit that enables cells to remember if they were exposed to radiation, even after the radiation is gone. So far, she and her team have built such a circuit in yeast cells, but she says the technology could transfer to human cells. “That could be a useful situation in therapy and long term for space travel, and also for simply reporting on the experiences of cells in the body,” says Silver.

Some efforts to apply synthetic biology to health focus on programming stem cells to behave like naturally occurring cells that have been lost because of disease. Douglas Melton, a molecular and cell biologist at Harvard University, is programming stem cells to replace the glucose-sensing and insulin-producing cells lost in type 1 diabetes. This condition usually arises from an autoimmune reaction against the beta cells of the pancreas, which leaves the body without insulin.

Melton and his lab are working toward a technology in which the beta cells and other cells involved in regulating blood sugar could be replaced by encapsulated collections of mature cells derived from stem cells. The challenge will be to produce the final, differentiated cell types using hormones or other chemical signals to guide the development process. “What one wants to understand is how to instruct the cell as to which genes it should turn on and off,” says Melton.

But replicating the natural processes of cellular development isn’t easy. Melton says his group is able to make beta cells that produce insulin, but the process is imperfect. “About half of the cells do what you want to do,” he says. “We don’t know how to tell the cells to be only beta cells.” And the cultured beta cells do not have the finely tuned response to glucose that the body’s cells do: “Beta cells have to sense glucose levels and then squirt out the right amount of insulin,” he says. “Our cells will respond to glucose, but not with accurate sensing mechanisms. They usually dump insulin on the first [sign] of glucose.”

Other researchers are hoping to engineer entirely new circuits into cells to help diabetes patients. Martin Fussenegger, a bioengineer at the Swiss Federal Institute of Technology, described a molecular system in which cells are modified with genes that can detect low pH levels in the blood, a sign of a diabetic state. In response, he says, the engineered cells will produce insulin to better regulate blood sugar levels and calm the diabetic state.  

This kind of engineering typically depends on viruses to modify genes so that cells will perform useful tasks. But that method is risky: the introduced DNA could integrate into the genome at an unfortunate location that might lead to cancer. Harvey Lodish, a cell biologist at MIT, is working on a technology that could avoid that problem: lab-made red blood cells. After these cells are modified, they will kick out the virus in the course of their natural development process.

“The beauty of red blood cells is they are pretty much the only cell in body without a nucleus,” says Lodish. “By the time they get into circulation, they have lost their DNA and are stable for 120 days with no risk of tumors.”

In Lodish’s method, a retrovirus carries a new gene into the genome of progenitor cells that will eventually produce red blood cells. The cell uses that new gene to produce a modified version of proteins that sit on the surface of the mature red blood cell even after the cell has lost its DNA. The modified surface protein has been engineered so that other compounds can easily be attached to it—antibodies that could mop up toxic substances in the blood, or small-molecule drugs to attack cancers or other diseased cells. Lodish believes the technology is a safer approach to putting synthetic biology to use in the human body.

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