Researchers report full humanization of therapeutic proteins from yeast

Sep 07, 2006

Researchers at Dartmouth's Thayer School of Engineering, Dartmouth Medical School, and the biotechnology firm GlycoFi, Inc., report a significant advance in the production of therapeutic proteins. Reported in the Sept. 8 issue of the journal Science, the Dartmouth/GlycoFi team announced the complete humanization of the glycosylation pathway in the yeast Pichia Pastoris.

"We've successfully completed one of the most complex cellular engineering endeavors undertaken to date," said Tillman Gerngross, chief scientific officer of GlycoFi and professor of engineering at Dartmouth.

Protein-based therapies represent more than half of all the drugs currently in development, and they have to be manufactured by living cells, which are genetically engineered to produce a given protein of interest. However, most of these proteins require the attachment of sugar structures, a process known as glycosylation, to attain full biological function. To date, this has required the expression of such proteins in mammalian cells that have the ability to attach human-like sugar structures.

This new finding replicates all the steps of human glycosylation within a yeast cell, eliminating the need for mammalian cells. Plus, report the researchers, the technology offers numerous advantages over the conventional use of mammalian cell cultures, namely reduced risk of contamination by pathogens and infectious agents along with improved drug performance and manufacturing efficiency.

"Humanizing glycosylation in yeast was a tour de force of genetic engineering, requiring the knockout of four yeast genes and the introduction of over 14 heterologous genes," said Stephen Hamilton, the lead author on the study and a senior scientist at GlycoFi.

The study details the genetic engineering of the yeast Pichia pastoris to secrete human glycoproteins with fully complex, terminally sialyated N-glycans. The researchers demonstrated the effectiveness of this approach when the glycoengineered yeast strain was used to produce functional erythropoietin, a protein widely used in the treatment of anemia, and considered to be the most successful biotech drug to date.

Gerngross noted that the GlycoFi/Dartmouth research team previously demonstrated the importance of glycosylation structures on other commercially relevant therapeutic proteins such as antibodies (published in Nature Biotechnology earlier this year). Like with most glycoproteins the researchers were able to show that, by controlling glycosylation, they could significantly improve an antibodies ability to kill cancer cells.

"By engineering yeast to perform the final and most complex step of human glycosylation, we will be able to conduct far more extensive structure-function investigations on a much wider range of therapeutic protein targets," Gerngross said.

Source: Dartmouth College

Explore further: How do our muscles work? Scientists reveal important new insights into muscle protein

add to favorites email to friend print save as pdf

Related Stories

'Mind the gap' between atomically thin materials

11 minutes ago

In subway stations around London, the warning to "Mind the Gap" helps commuters keep from stepping into empty space as they leave the train. When it comes to engineering single-layer atomic structures, minding ...

Seychelles poachers go nutty for erotic shaped seed

25 minutes ago

Under cover of darkness in the steamy jungles of the Seychelles thieves creep out to harvest the sizeable and valuable nuts of the famous coco de mer palm, and their activities are threatening its long-term ...

Recommended for you

Genomes of malaria-carrying mosquitoes sequenced

5 hours ago

Nora Besansky, O'Hara Professor of Biological Sciences at the University of Notre Dame and a member of the University's Eck Institute for Global Health, has led an international team of scientists in sequencing ...

Bitter food but good medicine from cucumber genetics

5 hours ago

High-tech genomics and traditional Chinese medicine come together as researchers identify the genes responsible for the intense bitter taste of wild cucumbers. Taming this bitterness made cucumber, pumpkin ...

New button mushroom varieties need better protection

10 hours ago

A working group has recently been formed to work on a better protection of button mushroom varieties. It's activities are firstly directed to generate consensus among the spawn/breeding companies to consider ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.