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Have Some Sugar with Your Protein

A tiny company engineers yeast to make better human therapeutics, a technique that could transform biotech manufacturing



COURTESY OF GLYCOFI
Merck paid $400 million in cash for a small New Hampshire company last May, the largest sum ever reported for a privately held biotech. One venture firm that invested $10 million in the start-up received a $100 million payout, according to the Boston Globe.

The purchase is part of a larger trend by pharmaceutical companies to scoop up biotechs, an acknowledgement that the future for blockbusters may be closely tied to protein-based drugs. One of the reasons that Merck shelled out hundreds of millions for GlycoFi of Lebanon, N.H., was detailed in a paper published in Science on September 8.

Investigators from GlycoFi and Dartmouth-Hitchcock Medical Center--the company is an offshoot of research at the college--reported on a technique capable of genetically engineering the yeast Pichia Pastoris to stud a broad range of therapeutic proteins with the same sugars found in human proteins. Attaching sugars is required to ensure that the protein folds into the proper shape and that it is thermodynamically stable. Moreover, if a protein carries the wrong sugars--from yeast, for instance--the human immune system goes on the offensive. Yeast has routinely been used for decades to make insulin and other proteins that do not undergo glycosylation, the process of coupling sugars to the surface of the protein. But it has not been deployed for glycosylated proteins like erythropoietin, the antianemia compound (also frequently used for sports doping) that the researchers report on in the Science paper.

"The availability of such yeast cell lines may eliminate the need for mammalian cell culture in the future," the researchers write. Currently, glycosylated proteins are produced by inserting a gene for a pharmaceutical protein in Chinese hamster ovary cells or other mammalian cells. In principle, yeast offers many advantages, including cost savings from shorter production times and higher yields as well as avoidance of contamination from residues from animals.

Tillman Gerngross, GlycoFi's co-founder, chief scientific officer and professor of bioengineering at Dartmouth, notes that the biggest benefit accruing from glycosylated protein production using yeast is unrelated to this list of selling points. "A lot of attention has been paid to making it cheaper," Gerngross says of yeast-based production. "That's gone by the wayside because of the ability to improve mammalian cell cultures." Rather, he contends, the real payoff will come by increasing a protein drug's potency--selecting only the sugars that increase a pharmaceutical's effectiveness (a much more difficult task in mammalian cells). "You will be able to use less of the drug and treat patients who currently don't respond because a drug is not strong enough," he says.

From a technical standpoint, fiddling with the yeast's innards was a feat that Gerngross characterizes as "massive replumbing of an organism," and one of the most technically challenging genetic engineering accomplishments ever, requiring the removal of four yeast genes and the introduction of 14 new ones. Before the research detailed in Science, GlycoFi had already been producing proteins that carry simpler sugars, such as antibodies, providing them to Merck and other major drug companies that were thus able to perceive the power of the technology.

The recent report described the most difficult reengineering step, the addition of the sugar sialic acid, which allows for the production of virtually any glycoprotein. "Now we've expanded the scope to all glycoproteins, not just antibodies," Gerngross says.

"Engineering yeast for production of humanized glycoproteins was the holy grail in biopharmaceutical manufacturing and its implementation a scientific masterpiece," remarks Martin Fussenegger, a professor of biotechnology and bioengineering at ETH Zurich and an expert in mammalian cell cultures. Fussenegger observes that even if yeast protein production eventually prevails, mammalian cells have a "bright future" because of their prospects in tissue engineering and gene therapy, an arena where yeast cells obviously have no application.

Donald Jarvis, professor of molecular biology at the University of Wyoming, asserts that production of glycosylated proteins in yeast must still overcome steep hurdles, because firms have heavily invested in mammalian cell lines. "Many large biotech companies are dedicated to recombinant glycoprotein producing in CHO [(Chinese hamster ovary)] and other mammalian cell lines," Jarvis says. "These companies have mammalian cell strains that can produce large amounts of at least some glycoproteins, they have huge investments in infrastructure, they have FDA approval for their processes, and they have a comfort zone with these systems. In my experience, this will be difficult to overcome."

Jarvis, however, acknowledges the possibility that alternative technologies may play a role and has himself published papers on glycoprotein production using insect cells. Commercialization, however, lags behind GlycoFi's work. From university campus to giant pharma subsidiary, the GlycoFi experience demonstrates that the esoteric endeavor of applying gene manipulation to the biology of sugars holds the potential of providing enabling methods for a new generation of biotechnology drugs--and an outsized deposit slip for venture capital investors.

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