It is not surprising that Oulu, Finland, a global center for wireless technology, has a vision of bringing biotech, information and communications technologies, as well as nanotech together. The Oulu region, however, is also strong in more traditional biotech areas such as bioprocessing, GMP manufacture, and drug discovery and development.
Oulu’s two leading assets are Biocenter Oulu (BCO) and Technopolis. BCO, founded in 1986 within the University of Oulu, was Finland’s first biocenter. It focuses on research in biotech and molecular medicine. BCO was also a driving force in the recent establishment of Biocenter Finland, a network of six Finnish universities.
Technopolis is the largest provider of operating environments for high-tech companies in Europe. The three Technopolis centers in the Oulu region have developed a growing interest in adding the life sciences to their high-tech profiles.
Creating a Strong Biotech Cluster
It is the job of Bioforum Oulu to bring together companies, interest groups, and infrastructure to build a strong biotech cluster, driving forward the regional innovation strategy in the life sciences. Bioforum is a member of the national HealthBio cluster in the Finnish Center of Expertise Program. It covers human genetics, diagnostics, drug discovery and development, gene therapy, pharmacogenomics, and regenerative medicine.
Finland’s bio business sector comprises 120–150 companies with a total turnover of E330 million, of which E185 million is in the Bioforum focus fields, says Tuula Palmén, Ph.D., Bioforum’s program director. The bigger companies include Orion, Thermo Fisher Scientific, GE Healthcare, Bayer Schering Pharma, and PerkinElmer. She explains that Oulu’s strengths in biotech include value-chain thinking and using strong and commercially interesting academic research as a source of innovation.
There are 33 biobusiness companies in the Oulu region. BioSilta, formerly Aurora BioTec, founded by Peter Neubauer, Ph.D., professor of bioprocess engineering at the University of Oulu, is one of the newest.
“A small country like Finland, unlike the U.K. or Germany, must focus,” he asserts. “This is well understood here. The cost of R&D per head may seem large, but the total amount is relatively small. We want to bring this region forward with clusters and platforms for discovery, such as the Bioforum.”
Dr. Neubauer has a long-standing interest in the manufacture of difficult recombinant proteins such as Wnts and collagen. He is closely associated with the BCO through his work in bioprocessing, emphasizing microbial production. “We can make E. coli better able to make all folded proteins. In the future, we will make the periplasm do the job of the endoplasmic reticulum. Even today, we can do a lot in this area.”
Currently, bioprocess development in E. coli takes a long time and is not straightforward. “In the future, we must integrate computer-based models and parallel approaches together with the competence from cell physiology and bioprocess development,” Dr. Neubauer notes.
He points out that one way around this may be to introduce fed-batch production earlier on in development to save optimization time later. His team has been developing such tools, which led to the founding of BioSilta.
For example, SENBIT® is a modular system involving the use of sensors in shake flasks based on a wireless system that allows it to be used anywhere in a facility. Another tool is a controlled-substrate delivery system, which enables cell cultivation to high density, avoiding the toxic osmotic effects of adding large amounts of glucose substrate. “This is an absolute breakthrough technology,” according to Dr. Neubauer.
He is also developing analytical methods for quantitative mRNA analysis from whole cell extracts, which will help to control and understand the transient and dynamic responses in a bioprocess.
Medipolis GMP, a privately held CMO, specializes in pilot-scale cGMP microbial fermentation of biologics in E. coli, P. pastoris, and B. subti. The company offers expression system and process development studies for biopharma companies, thereby converting bench-scale to pilot- and commercial-scale production for therapeutic proteins, enzymes, and vaccines.
Completed in 2001, the company’s biopharmaceutical facility comprises 2,300 m2 of space, of which 400 m2 is cleanroom. It meets FDA and EMEA requirements and is also approved by the National Agency for Medicine, Finland. The plant was upgraded for commercial production in 2006. “We want to become an expert group in recombinant protein manufacture within the next five years,” says Ashesh Kumar, Ph.D., director, biopharmaceuticals.
The Medipolis production site comprises two 15 L, one 150 L, and one 750 L fermenters. The firm says that it has manufactured the largest amount of therapeutic recombinant protein in Finland, successfully producing Phase II material for clients in the country and internationally, who partner for their fill-and-finish operations.
Dr. Kumar says there are some interesting new manufacturing opportunities on the horizon, such as biosimilars and new types of insulin. “Our mission is to help our customers bring their products to the market faster and more cost efficiently than other companies by offering reliable partnerships in manufacturing.”
Novamass is a contract research organization (CRO) specializing in ADME studies and was formed as a spin-off from the University of Oulu in 2000. The firm received funding from TEKES, the national development agency for technology and innovation, to develop in vitro models and analytical methods to investigate lead compounds for Juvantia Pharma and Hormos Medical, its first clients.
“The company emerged from our customers’ needs,” says Jouko Uusitalo, CEO. “We solved problems for them, developed new service products, and offered them a good package of in vitro ADME.”
Novamass’ services focus on late discovery and early development. Its products carry out studies such as those on the basic properties of a compound and in vitro metabolism, with the identification of metabolites being a speciality. “We can also predict whether a customer’s compound will interact with other drugs,” Uusitalo says.
“We create added value to the customer by tailoring our methods to their compounds,” he continues. “If there are problems, they get to know about it sooner.” He explains that most companies, especially those in high-throughput sequencing (HTS), deal mainly in numbers and don’t explain results that can be hard for small biotechs to understand. “Our reports are more like a scientific article. We explain what has to be done next.”
Novamass is the only company in the Nordic region with 45 biotech customers in 11 countries including India and many in Europe like KuDOS Pharmaceuticals and Cyclacel. The firm is on the verge of expansion with new ownership and the purchase of an in vivo business.
Uusitalo says they want to grow organically and through M&As. Novamass is currently negotiating with companies in Finland that are involved in areas like GLP and animal as well as clinical trials organizations. The firm also plans to work on HTS in India. “We will do studies in Europe that need to be close to the customer, and India can be cost effective,” he says.
Besides manufacturing and drug development, there is a great deal of interest in drug discovery in Oulu. The collagen research unit (CRU) at the BCO consists of three groups. Studies on collagens and collagen enzymes was instrumental in setting up FibroGen, the recombinant collagen specialist with a focus on biomaterials and fibrotic diseases.
Recently, the CRU, in collaboration with FibroGen, has shifted its attention to anemia and ischemia, according to Johanna Myllyharju, professor of molecular biology. They have been investigating an enzyme known as collagen prolyl 4-hydroxylase (P4H), which is essential for processing collagen into its correct triple helical structure.
More recently, a separate P4H family with another role was discovered. Under normoxic conditions, this newly identified P4H group helps break down a transcription factor called HIF, which otherwise regulates EPO and VEGF and helps the body to survive hypoxic concentrations.
There are many potential therapeutic opportunities for HIF in conditions associated with hypoxia, such as anemia, myocardial infarction, stroke, renal hypoxia, and cytoprotection. The strong background of the CRU in collagen P4Hs has enabled them to look for inhibitors of mechanistically similar HIF P4Hs that would allow HIF to survive and carry out its role. “Essentially, such an inhibitor wou ld help to mimic the state of hypoxia response in tissue,” explains Myllyharju.
Working on Lab-in-Pocket Devices
At the VTT Technical Research Center of Finland, Markku Känsäkoski, senior research scientist in the biomicrosystems section, and his team are developing devices involving printed-intelligence. They predict that these could be used in rapid diagnostics in medical and environmental applications with advantages of low cost and high repeatability.
The instruments involve the use of micromechanical components such as pumps fixed in micrometer-scaled channels. “There is still a big gap between biotech and hardware engineering,” Känsäkoski points out. “We are currently working with model assays in areas such as cardiac markers. The hope is that the research could lead to the lab-in-pocket type of disposable diagnostic, a vision that will involve several VTT groups in printed electronics, microfluidics, optics, and antibody libraries.”
To help build and strengthen the Oulu cluster, Finland recognizes the need to create the best possible networks of financing, market analysts, and customers in the main markets. Additionally, using the best expertise and contacts to make the R&D period shorter is important, Palmén adds.
The country differs from its Scandinavian neighbors as it has less of a home-grown pharma industry. Yet, they all face the same challenges in obtaining financing for early-phase innovation. Finland would like to have more access to funds such as Inveni Capital, a new VC company with offices in Finland and Germany. A recent example of progress in this area is a partnership between the University of Oulu and IP Finland, bridging business and financing networks to innovations.
Palmén recently returned from a trade mission to India, a country seen as an increasingly important partner for Finland. “It is a huge, emerging market with additional features important to us,” she says. Finland’s bio sector also collaborates extensively with North America, Germany, and the U.K. Nationally, the HealthBio cluster is seen as an important partnering organization.