The Biotechnology Resource Center at 27
Heat, Pressure, Enzymes
Every visit to the BioTechnology Institute features a tour of the Biotechnology Resource Center (BRC), the institute’s 4700 square foot R&D and contract services center. The BRC has grown from humble beginnings in the basement of the Gortner Lab into a state-of-the-art pilot plant performing fermentation process development, recombinant protein expression and downstream processing for clients within the University and beyond.
Celebrating its 27th year in 2013, the Biotechnology Resource Center (BRC) continues to support research at the University while serving as a resource for Minnesota’s biotech industry. Up to 80% of its business comes from Life Science companies ranging from one-person start-ups to some of the biggest names in the biotechnology business.
Income from fermentation services for outside companies helps the BRC fulfill its mission of providing services to the University community at cost, including new equipment and services like a French Press Extruder a Golan press, a Microfluidizer and 550L fermentation tank. Expertise provided by BRC fermentation manager Fred Schendel and his team help scientists involved in basic research develop methodologies for producing molecules at pilot scale—often producing batches of biological compounds at near commercial scale.
Strong connection to industry
Beyond the allure of the centrifuges and stainless steel, visitors quickly learn that the BRC serves an important role in supporting Minnesota’s growing Biotechnology and Life Science economy. And the BRC remains an important standard bearer for the University beyond the Midwest. In fact, The University of Minnesota alumni network is a primary driver of business for the BRC forming a national and international network from as far away as Uruguay.
Recently the BRC has played an important role in helping companies gear up for clinical trials for chemotherapy compounds and treatments for celiac disease.
From local companies like IGF Oncology, whose founder Hugh McTavish received his PhD from the University of Minnesota to Alvine Pharmaceuticals, a California based company with strong ties to Stanford University, the BRC is able to advance the projects of its partners while saving them capital equipment costs.
Like many of the companies served by the BRC, IGF Oncology has a direct connection to the BioTechnology Institute and the BRC. The company’s founder, Hugh McTavish is a PhD biochemist and patent attorney who received his PhD from the University of Minnesota in 1992 and co-authored a 2002 study with BTI’s Mike Sadowsky and Larry Wackett, which identified an enzyme which initiates the metabolism of the herbicide atrazine, a source of ground-water contamination from agricultural run-off.
McTavish is also a cancer survivor and his company seeks to increase the efficacy of existing chemotherapy by creating drug conjugates, which help target cancers cells while reducing damage
to healthy cells. If successful, IGF’s product holds the promise of lower dosages and fewer side effects than current chemotherapy compounds. Animal studies have shown the IGF conjugate to be effective at dosages 6 times lower than the chemotherapy drug methotrexate alone.
When IGF was planning Phase I clinical trials they turned to the BRC to produce a sufficient amount of the conjugate to conduct a trial on 20-30 patients. Using the strains provided by IGF,
the BRC scaled-up a fermentation and purification process from bench scale to production levels necessary first for animal studies and then to 250 liter scale to produce the material needed for a phase I trial.
Founded on technology licensed from Stanford University, Alvine Pharmaceuticals develops therapeutic compounds targeting autoimmune/inflammatory diseases. The company’s current focus is celiac disease, a chronic condition induced by the protein gluten found in wheat, and related grain species like rye, and barley. Gluten contains high concentrations of two amino acids, proline and glutamine, which are not broken down efficiently in the stomach and small intestine. Peptides absorbed through the small intestine cause an autoimmune reaction in individuals susceptible to the disease. Alvine’s flagship product, ALV003 contains protease enzymes engineered to digest gluten. In 2009, when Alvine entered Phase II clinical trials, it turned to the BRC to produce cell paste with the recombinant protein expressed. Using a working cell bank supplied by Alvine, the BRC grew the cells at pilot scale to Alvine’s specification in several 500 Liter reactor runs. The cell paste was then sent to Alvine for further purification.
Building on the success of the initial engagement, Alvine returned to the BRC in 2010 for assistance developing an economical process for scaling up to commercial production at Alvine’s own facility. The engagement, completed in 2012, underscores the value the BRC provides in helping bring novel products from early testing phase to commercialization and large-scale distribution.
“The BRC is not just a business running within the University,” according to BRC Director Tim Tripp. “Outreach to industry is essential to our mission. Another key component is our ability to provide training in processes not available elsewhere at the University.”
Coaxing an organism to produce a novel compound in a petri dish or shake flask doesn’t guarantee success at a commercial scale. A host of variables including feedstock, temperature, and acidity levels all contribute to the successful transition from lab bench to commercial scale. Through its short course, the BRC provides training in bench-top fermentation processed to students within the University and companies seeking to improve in-house fermentation capabilities.
The course is taught by Fred Schendel, a PhD level fermentation biochemist with over 10 years of experience in industry, along with BRC Director Tim Tripp, and a rotating group of faculty members from the BioTechnology Institute. The course is open to students within the University and industry.
In addition to lectures and lab visits, students work in teams to design and complete a fermentation using one of the BRC’s five liter bench scale fermenters. As Tripp points out,
“The BRC is the only place on campus where students can find structured, hands-on fermentation training, a valuable skill in Minnesota’s growing Life Science economy.”
A Biotech Catalyst
In addition to its weeklong short course on bench-scale fermentation and services offered through the pilot plant, the BRC is also home to a growing number biotech companies through Lab Use Agreements offering affordable, small-scale lab space and direct access to experts within University’s academic community and the BRC.
Founded in 2008 by Don Mattsson, PhD, a former UMN student, and one of the first three graduates of the BioTechnology Institute’s Masters in Microbial Engineering (MicE), Butrolix (www.butrolix.com) was one of the first companies to rent space from the BRC.
While completing his doctoral and postdoctoral training at the University of Minnesota, Mattsson discovered the molecular components used by butanol-producing bacteria to regulate biobutanol formation. In 2008, after spending time in industry, Mattsson and his wife, Attorney Lisa Mattsson, formed Butrolix with the goal of developing a patentable process for biobutanol production from low-cost sugar feedstocks. In fact, Butrolix was the first company to patent the use of quorum sensing peptides to synchronize bacterial populations and increase the speed of butanol production.
Dr. Mattsson sites the resources offered by the BRC as a key factor in getting Butrolix off the ground. After researching facilities closer to his native Duluth, Mattsson choose the BRC because of the access it provided to the BRC’s fermentation facility and the expertise of the BRC staff and faculty.
When Butrolix sought a Phase I SBIR award from the National Science Foundation (NSF), Mattsson was able to draw on BTI director Mike Sadowsky, who provided a supporting letter for the NSF, while the BRC was listed as subcontractor.
CTE Global Inc. is a manufacturer of industrial enzymes with production facilities in the U.K., China, and Brazil and 150 enzymatic preparations used in over 15 industries in 48 countries. Its fermentation products are produced from plant material, microbes, and fungi including an Aspergillus derived enzyme that facilitates the fermentation of ethanol, butanol, organic acids and other specialty chemicals. Preparation used in ethanol production help producers reduce hazardous chemical inputs and use costly feedstocks more effectively, improving the bottom line while reducing energy use and improving air and water quality.
As the company sought to extend its market share in they increasingly competitive ethanol industry, they began looking for a Midwest facility to focus on outreach, quality control, and product development.
Proximity to clients played a major role in CTE’s decision, but the BRC provided a number of other advantages, which sealed the deal, including affordable, move-in ready lab space with critical infrastructure, logistical and administrative support from Director Tim Tripp, and the availability of contract services through the fermentation pilot plant.
Add to this access to the expertise within the University and a wide variety of sample feedstocks available at the University’s St. Paul agricultural campus, and the BRC was a perfect fit for CTE’s first U.S. Quality Assurance facility.
In the U.S., one of the primary goals is to protect against contamination in transit. Staffed by Dr. Sandra Lobo, a biochemist with strong Minnesota ties, CTE has stocked its St. Paul facility with state-of-the-art equipment to help ensure its enzymes preparations are protected against contamination in transit. Beyond quality control and assurance, Lobo plans to use the facility to develop new enzymatic formulations to enhance biocatalysis for the wide variety of cellulosic feedstocks used in ethanol production.
Lipodome, the most recent company to enter a lab use agreement with the BRC, was founded in 2001 by Tarun and Napur Ghosh. The company is currently focused on developing and marketing its product line, used to facilitate the study of proteins and lipids in the development of therapeutics for inflammatory diseases and cancer. In addition to its platform technology for solubilizing detergent sensitive membrane bound proteins and enzymes, Lipodome also markets products which allow the retention of protein functionality in a stable, non-detergent buffer medium. LLS KitsTM allow for the separation and quantitative analysis of lipids 10-20 times the rate of conventional assays.
The National Center for Food Protection and Defense, a U.S. Department of Homeland Security Center of Excellence, recently awarded $1 million to a group of researchers headed by Larry Wackett, Distinguished McKnight University Professor with the BioTechnology Institute. The grant was made for the development of a generalized method to test for food adulterants using enzymes. The Department of Homeland Security has a strong interest in protecting the public from possible attempts to contaminate food with toxic chemicals.
Wackett was instrumental in the recent development of an enzyme-based test kit for detecting melamine contamination in milk. He and fellow researcher Michael Sadowsky utilized an enzyme that altered the chemical structure of melamine and caused it to release detectable amounts of ammonia. The test kit was developed in collaboration with Bioo Scientific over a 6-month period in response to a call put out by the World Health Organization for a simple field test for melamine contamination.
Since the introduction of the melamine test kit, Wackett has continued to investigate other nitrogen-based potentially toxic manmade chemicals to find enzyme reactions that could help release colorimetrically detectable traces of ammonia. His efforts at enzyme detection came to the attention of the National Center for Food Protection and Defense in their search for a general method of testing for toxins that could potentially be introduced into the general food supply by terrorists.
“I think they were impressed that in six months we helped a prominent food testing company put a product on the market,” explained Wackett. “They thought it would be great if other tests like that could be developed to address potential terrorist threats.”
Wackett will be working with Sadowsky and Dr. Mani Subramanian, former global head of biotechnology for Dow Chemical Company currently directing the University of Iowa Center for Biocatalysis and Bioprocessing, on lead research to apply known and novel enzymes for the detection of toxins.
“Together, we probably have the best academic fermentation and enzyme purification facilities in the country,” said Wackett of the partnership between the researchers at the BioTechnology Institute and the University of Iowa Center for Biocatalysis and Bioprocessing. “It made sense to combine our efforts.”