JENA, Germany - An impressive network of small and medium-sized companies, research institutions, and major industrial firms has grown around the town of Jena during the last three years.

The region, with traditional strength in the manufacturing of optoelectronic and precision instruments, glass and pharmaceuticals, has now become a center of innovation in biochip and high-throughput screening technologies.

When the German government organized its BioRegio contest in 1996 to speed up the development of biotechnology centers throughout Germany, the region around Jena qualified for special funding. The money was used to set up crucial links between the business community, scientists, policy makers and administrators. BioRegio Jena, a supporting organization, was formed and helped to start and run regional innovative projects based on the knowledge and skills already present throughout the region.

One of the main fields is laboratory miniaturization and automation. The Biotechnical Microsystems Department of the Jena-based Institute for Physical High Technology (IPHT) develops components for the lab on a chip: miniature-size flow sensors, extraction modules, calorimeters, switches, filters, etc.

In a joint venture with Biometra GmbH, of Gvttingen, the department developed a micro-thermocycler with 45l chambers which cuts the time to perform a PCR from hours to 10 to 20 minutes. A control accuracy below 0.1 K can be reached in less than a second.

"With this thermocycler, the performance of the polymerase and not the thermal properties of the instrument becomes the bottleneck," J. Michael Kvhler, head of the Microsystems Department, told BioWorld International. "As we manufacture our devices in silicon or silicon-glass technology we are able to integrate additional functions very easily."

As an example, the department developed a 100nl-well nanoplate with an integrated sieve so that automated experiments can be performed using single nanobeads.

"In basic research, our aim is to reach into molecular dimensions - to connect molecules to wires so that we can characterize electron transport phenomena through single biomolecules," he said. Using metallized microtubuli, the design of conductors the size of macromolecules is already possible.

"This sort of molecular nanotechnology is far away from the market," Kvhler said, "but with our microsystems we do aim at the mass market. However, before our vision to create a lab on a chip can become true, we need to have better fluid interfaces. We developed some ideas and partners and are looking for funding now."

In April 1998 one of Kvhler's collaborators, Eugen Ermantraut, founded Clondiag Chip Technologies GmbH (CCT) in Jena. Ermantraut holds a couple of patents to produce microarrays using microwet printing technologies. Based on this technology, CCT developed its "Total Analysis System (TAS)," which will be marketed next year for process control in reactors.

The biochips will carry oligonucleotides typical for prokaryotes. "However, they are designed not only to check for contamination but to monitor expression patterns of certain genes," Ermantraut told BioWorld International. "That way, the state of the cultures within the reactor can be checked and changes anticipated. With TAS, we are able to look into the future, and that will help us to be present with our product wherever there is a reactor."

The chips are designed as consumables and carry a fluid interface. An upstream module for the digestive process is under development.

In addition, CCT is developing biochips for medical and forensic diagnosis, pharmacogenetics and screening. "In these areas, very reliable, universal chips are needed, and there are only very few competitors," Ermantraut said.

The reader to analyze the chips has been developed in Jena as well. CCT cooperated with Jena-Optronik GmbH, a joint daughter company of DaimlerChrysler Aerospace and Jenoptik AG. As a space flight company, Jena-Optronik produces a "star sensor" to determine satellite positions. The device takes pictures of the starry sky and compares the patterns to a star catalogue database.

"Talking about the BioRegio concept some day," Werner Reiland, head of Jena-Optronik Product/Services said, "it came to our mind that our sensor could be redesigned very easily to screen luminescent spots on a chip instead of the firmament."

While conventional laser scanners can reads spots of at least 255m in diameter only, the Jena-Optronik biochip reader is able to analyze spots smaller than 55m and can detect one molecule per 5m2. It scans up to three frequencies, or wavelengths, in parallel and is suited for the measurement of chemoluminescence, absorption and transmission.

Jena Also Home To Biotech Innovations

Major industrial companies of the Jena area entered the biotechnology field, too. When Hoffmann-La Roche, of Basel, Switzerland, tried to step up its in-house high-throughput screening rate to more than 100,000 compounds a day, it looked in vain for a partner with experience and know-how in optics and system integration. Finally it placed an order for the development of a novel reader with the optics company Carl Zeiss Jena GmbH.

In only 18 months the Molecular Medicine Department developed an ultra high-throughput screening (UHTS) machine, which can process several microplates simultaneously and can read 96 probes in parallel in the 96-, 384- and 1536-well format.

To perform an assay it is not necessary to deal with the details: "The system is able to calculate the number of plates that can be processed in parallel and arranges the order of events," Thomas Handke, product manager, molecular medicine, of Carl Zeiss explained.

"Test runs are not necessary either, as the whole process can be simulated by the software. This saves considerable time and manpower in assay preparation."

The program calculates liquid levels, and reservoirs. and checks for errors and bottlenecks. If necessary, additional modules can be integrated by plug and play. Data are transferred and analyzed during the run, so that differences in data quality, hit rates or a breakdown of a reagent are recognized at once.

A first model was tested by Hoffmann-La Roche already. "However it is not an exclusive development," Martin Gluch, head of the screening product group, added. "Serial production will start early next year. Our customers will be the research centers of around 80 pharmaceutical companies worldwide."