Perhaps because studying the proteome has become a crowded endeavor, an East German startup called MelTec has set its eyes on a new “ome:” the toponome. Determining all the structural networks that proteins form within a single cell — MelTec’s description of the toponome — and how their composition changes at different stages, will be more meaningful for drug discovery than just looking at differences in protein expression levels over an average of many cells, according to Walter Schubert, the company’s founder and CEO. “The cell depends on quick changes of functions by very quick changes in the protein assembly,” he said.
To map the intracellular protein networks, MelTec uses an imaging technique that involves sequential staining of proteins with specific ligands like antibodies, lectins or aptamers. Last month it published its first results in two articles in the Journal of Theoretical Medicine. However, the data is not recent: both articles were first submitted almost two years ago. Moreover, they do not reveal any details of the imaging method, although Schubert said another publication planned for the near future will do so.
Schubert, an MD by training, started developing the method in the 1980s, while heading a research laboratory at the university clinic of neurology in Bonn. At the time, he was studying the invasion of T cells into muscle tissue and found that patterns of cell surface proteins were linked to the T cells’ migratory potential. With a research grant from the DFG, the main German public funding organization for academic research, he continued developing the method at the University of Heidelberg. When he moved to the University of Madgeburgurg as an associated professor in 1994 to lead a molecular pattern recognition research group, he started developing a robotic system to perform the assays and take the images, along with pattern recognition algorithms.
In order to scale up the technology and apply it to drug discovery, he founded MelTec in May 1999. By the beginning of 2000, the company had four employees; later that year it received $13.8 million in venture capital, and $3.7 million from the federal and regional governments. Since then, the company has grown to 30 people and has filed or been granted 60 patents on functional protein networks and various parts of the technology. It occupies 16,000 square feet but is hoping to double its space in the near future.
Although the concept of a toponome may sound mysterious, it refers to the three-dimensional distribution of up to thousands of different proteins in a single cell. A robot applies an antibody or other ligand to cultured cells or a tissue section from a biopsy. Once a ligand has bound to its epitope, its position is recorded by a microscope. Although Schubert’s group routinely measures binding via a fluorescent tag, MelTec also uses a label-free method, although Schubert declined to reveal the underlying principle.
By using large numbers of ligands sequentially — so far MelTec has used more than 1,000 — a computer can detect structural protein networks that exist in a cell at a specific moment and compare them with those of other cell types or of disease states. Up to 60 proteins can also be visualized simultaneously. The protein members in these networks are often unexpected, said Schubert. “You find [all] of a sudden proteins which are linked together topologically in a way that has never been seen,” he said. And he believes that it is the precise pattern of proteins in these networks that determines their function. “Losing one protein could mean the opposite [function],” he said.
Schubert is not the only one to buy into the concept. MelTec has entered a number of collaborations to put its technology to use in drug discovery, primarily focusing on immune-mediated diseases and cancer. Last September it began developing new toxicity assays for Evotec OIA, a German-UK company offering assay services to pharmaceutical companies. Eventually, a small number of proteins changing their location in response to a toxin will constitute the assay, Schubert said. In a collaboration begun last month with Basel-based MyoContract Pharmaceutical Research, MelTec is trying to define a toponome in skeletal muscle cells specific to Duchenne Muscular Dystrophy. Two additional collaborations with undisclosed pharmaceutical companies are ongoing, Schubert said.
MelTec is also developing its own drug leads, he added, targeting proteins that play a major role in the protein networks involved in disease. It already has two such leads in pre-clinical development, one targeting amyotrophic lateral sclerosis, a progressive neurodegenerative disease, the other one against a rare frorm of cancer, Schubert said.
In addition to commercial applications, MelTec is involved in an academic project. Last year it received grant of $4.1 million from the German government for a toponome project, which will involve collaborations with academic groups in Berlin, Bielefeld, Heidelberg, Magdeburg and Stuttgart. “We are developing a routine to decipher the human toponome systematically,” Schubert said. The project — determining protein networks in migratory cell models and integrating several data mining algorithms — is just about to start.
— JK