When it comes to fighting drug resistance and other emergent health threats like Ebola, AIDS, H1N1, SARS, time is of the essence.
“It’s amazing to think that by 2050, antibiotic resistance will threaten 10 million lives per year which is more than cancer kills today.” Says Michael Jewett, a resident faculty member of the Chemistry of Life Processes Institute, “That’s a staggering number.”
These figures come from a 2016 report by the Review on Antimicrobial Resistance that warns unless we respond quickly with new interventions and a ready supply of new antibiotics, the devastating impacts of antibiotic resistance will be felt across every society and healthcare system.
Accelerating drug manufacturing
“One of the things we’re keenly interested in doing is developing next generation tools and technologies for manufacturing medicines in a resource-limited setting,” says Jewett, the Charles Deering McCormick Professor of Teaching Excellence, professor of chemical and biological engineering, and co-director of the Center for Synthetic Biology, “Could we, for example, make a therapeutic directly where it is needed, or a vaccine against an emergent pathogen on demand?”
Most factory-produced protein therapies take months to reach consumers. By thinking differently, Jewett and collaborators have discovered a new way of synthesizing proteins outside of cells that turbo-charges time to market and may offer a highly modular, safe and cost-effective way to manufacture new drugs.
He likens the process to lifting up the hood of a car and taking out the engine.
“We use cell-free systems to manufacture therapies without living cells,” says Jewett. “The idea is that we take the guts of a cell, the molecular machinery that you want to make a medicine, and then, whenever you need to make the medicine, you feed the machinery substrates it needs to make the product.
“What’s surprising is that using our approach, we can make therapeutics in just hours,” he said.
Until very recently, a key gap has limited the cell-free protein synthesis approach: the inability to glycosylate proteins, or decorate them with sugars. 70 percent of FDA approved protein biologics are glycosylated proteins. For cell-free systems to enable a new paradigm of on demand medicine, tools to boot up the machinery involved in glycosylation are needed.
Enter Jewett’s lab
In collaboration with Matthew DeLisa, the William L. Lewis Professor of Engineering in the Smith School of Chemical and Biomolecular Engineering, Cornell, the researchers closed the gap. Specifically, Jessica Stark, Ph.D. student in the Jewett Research Group, and Thapakorn Jaroentomeechai, Ph.D. student in the DeLisa Research Group, developed a way to selectively enrich their cell-free system with glycosylation components. This work was published in Nature Communications.
The resulting extracts enabled a simplified reaction scheme for efficient, targeted protein glycosylation that the researchers have dubbed cell-free glycoprotein synthesis, or CFGpS. In addition to its speed and simplicity, the CFGpS method is highly modular, allowing for the use of distinct and diverse extracts for the production of a variety of glycoproteins bearing both bacterial and eukaryotic carbohydrate structures, including glycosylated versions of an antibody fragment and the protein therapeutic erythropoietin.
“This is the key first step to enable biomedicines on demand,” says Jewett. “While we are just at the beginning, we are excited about the potential of our new method, especially for enabling new forms of personalized medicines.”
Proximity of Jewett’s lab to two CLP core facilities, the Recombinant Protein Production Core and the Proteomics Center of Excellence, give his team access to advanced technologies that enable protein purification, high resolution analytics and other capabilities. What draws him most to CLP is the Institute’s “larger ethos that thinks about making medicines,” an environment that encourages investigators to think big.
“Imagine a time,” says Jewett, “when you go to the doctor and somewhere back in behind the counter you sit for an hour while someone makes a therapeutic designed just for you.”
by Lisa La Vallee