Growing demand for pharmaceutical lipids is spurring interest in technologies that can make the production of these and other bioproducts more cost-effective. Because recovering intracellular bioproducts from yeast can be costly and energy-intensive, researchers are developing new approaches to reduce energy consumption and waste during downstream processing, one of the largest hidden costs in biomanufacturing.

A recent project has successfully demonstrated programmed lysis of cell walls during yeast fermentation to improve the recovery of intracellular products. This approach reduced the need to use hazardous solvents and demonstrated a reduction in mechanical energy required for recovering lipid products that accumulate inside the cell.

This BioMADE-funded project — a collaboration between bioalternatives company Manus and the University of Texas at Austin (UT Austin) — has also achieved improved product yields and safety, in addition to the benefits of enabling lower production costs, energy requirements, and improving sustainability.

Benefits of the programmed lysis 

Researchers at Manus and UT Austin successfully demonstrated programmed lysis technology up to pilot scale (300 liters) for two industrially relevant yeasts, according to published results of the program, which aims to make industrial yeast fermentation more efficient and sustainable. 

“In Yarrowia lipolytica, engineered strains enabled a reduction in mechanical separation energy requirements by more than 50%. In Saccharomyces cerevisiae, the team achieved autolysis in a relevant production strain. The work advanced the technology from laboratory demonstration to integrated pilot operation,” according to a release.

The two products used as case studies in the program were microbial oils for Manus (Yarrowia lipolytica) and a collagen protein for UT Austin (Saccharomyces cerevisiae), according to Joe Shaw, senior vice president of research and development at Manus. 

“This work uniquely combined academic and industrial settings to take bench-scale discoveries and more rapidly translate them to higher technology readiness,” says Hal Alper, professor of chemical engineering at UT Austin. “This technology finally helps to address the challenge of producing cheaper intracellular products that traditionally require high-cost separations and more laborious process steps.”

Shaw explained how downstream processing can account for 60% to 80% of the total manufacturing cost for intracellular products, with cell rupture representing a large portion of that expense. Breaking open yeast cells requires considerable mechanical force because of their strong cell walls — which he says can tolerate about 40 atmospheres worth of pressure before rupturing — emphasizing the energy and equipment requirements. 

“It’s quite a substantial cost center for biomanufacturing, and it’s often not addressed head-on in traditional biotechnology development,” Shaw says, adding cost reductions from the project should also be considered from a CapEx perspective, when factoring in the reduced need for expensive processing equipment like centrifuges.

Shaw also highlighted improved product recovery as a benefit of the program, noting that the engineered strains enabled high recovery rates without requiring solvents or harsh chemicals. 

“We were able to demonstrate a process that did not require any solvents or harsh chemicals,” he said. “We could basically take the biomass, process it in a water or dry basis, and get a very high recovery; over 90% in some cases of recovered product with the engineered cells.”

Shaw also emphasized the safety benefits of reduced solvent use, noting that it can lower the risk of environmental spills and other potential issues for biomanufacturing facilities.

Engineering yeast for product recovery 

Researchers from Manus and UT Austin, specifically Alper and his Alper Lab as part of the McKetta Department of Chemical Engineering, focused on creating an approach where cell lysis could be triggered late in the fermentation process as part of the project.

“At the end of fermentation, we turn on these different signals to weaken the cell wall and degrade it actively,” says Shaw. “Over the course of the program, we homed in from over 50 targets that we originally identified to really just two or three in our platforms that were able to give us really good benefits in cell wall degradation, while also retaining robust cell growth and health through most of the fermentation.”

This new project fits within a broader industry trend where advances in cell lysis are being explored to effectively recover yeast lipid without adversely affecting its quality.

Technology from this program has broad application across many products that are made and accumulate inside microbial cells, according to researchers. Cutting processing intensity and improving recovery strengthens the case for domestic biomanufacturing built on abundant, low-cost American feedstocks.

Advancing bioindustrial manufacturing 

The program is one of more than 100 projects supported by BioMADE, a nonprofit public-private partnership established with funding from the U.S. Department of Defense, says Penny Norquist, program director of technology at BioMADE. The organization aims to advance bioindustrial manufacturing technologies and help bridge the gap between laboratory research and commercialization.

She added that BioMADE’s membership includes more than 275 organizations that help identify technology development priorities for the industry, including ways to reduce manufacturing costs and advance bioindustrial processes to higher production scales while maintaining cost efficiency.

Other BioMADE projects exploring ways to improve biomanufacturing include a collaboration between Iowa State University and biosolutions company Novonesis to develop AI-controlled bioreactors that continuously monitor critical bioprocessing parameters in real time to boost enzyme production and improve product quality. 

Meanwhile, another project, a collaboration between Triplebar and the University of California, Berkeley, is focused on the creation of an AI genomic model capable of predicting genomic edits that improve commercial-scale protein production.