Complex Proteins Made in Algae

Photo: Algae

Scientists used algae to produce complex pro-
teins to fight cancer in large amounts and
much more cheaply than is currently possible;
© Kreutz

“Because we can make the exact same drug in algae, we have the opportunity to drive the price down dramatically,” said Stephen Mayfield from the University of California San Diego. Their method could even be used to make novel complex designer drugs that cannot be produced in any other systems - drugs that could be used to treat cancer or other human diseases in new ways.

“You cannot make these drugs in bacteria, because bacteria are incapable of folding these proteins into these complex, three-dimensional shapes,” said Mayfield. “And you cannot make these proteins in mammalian cells because the toxin would kill them.” The advance is the culmination of seven years of work in Mayfield’s laboratory to demonstrate that Chlamydomonas reinhardtii, a green alga used widely in biology laboratories as a genetic model organism can produce a wide range of human therapeutic proteins in greater quantity and more cheaply than bacteria or mammalian cells.

The scientists genetically engineered algae to produce a complex, three-dimensional protein with two “domains” - one of which contains an antibody, which can home in on and attach to a cancer cell and another domain that contains a toxin that kills the bound cancer cells. Such “fusion proteins” are presently created by pharmaceutical companies in a complex, two-step process by first developing the antibody domain in a Chinese hamster, or CHO, cell. The antibody is purified, then chemically attached to a toxin outside of the cell. Then the final protein is re-purified.

“We have a two-fold advantage over that process,” said Mayfield. “First, we make this as a single protein with the antibody and toxin domains fused together in a single gene, so we only have to purify it one time. And second, because we make this in algae rather than CHO cells, we get an enormous cost advantage on the production of the protein.”

The fusion protein the researchers in his laboratory produced from algae is identical to one that is under development by pharmaceutical companies with a proposed cost of more than 100,000 dollar. This same protein could be produced in algae for a fraction of that price. And the UCSD researchers confirmed that the compound worked like the more expensive treatment: it homed in on cancer cells and inhibited the development of tumors in laboratory mice.

Mayfield said such a fusion protein could not have been produced in a mammalian CHO cell, because the toxin would have killed it. But because the protein was produced in the algae’s chloroplasts - the part of algal and plant cells where photosynthesis takes place - it did not kill the algae. “The protein was sequestered inside the chloroplast,” Mayfield said. “And the chloroplast has different proteins from the rest of the cell, and these are not affected by the toxin. If the protein we made were to leak out of the chloroplast, it would have killed the cell. So it is amazing to think that not one molecule leaked out of the chloroplasts. There are literally thousands of copies of that protein inside the chloroplasts and not one of them leaked out.”

Mayfield said producing this particular fusion protein was fairly straightforward because it involved fusing two domains—one to recognize and bind to cancer cells and another to kill them. But in the future, he suspects this same method could be used to engineer algae to produce more complex proteins with multiple domains.; Source: University of California San Diego