Having invested $84 million almost a year and a half ago to launch a drug discovery collaboration with GeneProt, Novartis might not seem the most likely big pharma candidate to establish a strong and growing internal proteomics research program of its own. After all, the deal with GeneProt is still most likely the largest of its kind, dwarfing Oxford GlycoScience’s cumulative $22.5 million deal with Pfizer, and represents a massive capital and human resource investment for GeneProt’s 110 Geneva-based employees.
But the deal with GeneProt only covers three disease areas — which remain undisclosed — and Novartis has more proteomics research up its sleeve, according to Dalia Cohen, the global head of functional genomics for Basel, Switzerland-based Novartis. In particular, the company has established a central proteomics laboratory at its Basel headquarters, where researchers are working to increase the sensitivity of 2D gel electrophoresis techniques, and developing non-2D gel methods for separating proteins that the group then tries to integrate into Novartis’ platform for identifying and validating potential drug targets.
“All of the collaborations that we have are a huge add-value for what we are doing,” said Cohen. “But the only way to integrate — this is not only for GeneProt, this is in general — and bring value [is] we have to have people internally who are skilled and know the technology and can make the best of it for our environment.”
To add to GeneProt’s efforts outside the company, which Cohen said has met Novartis’ expectations so far, and to apply proteomics to other disease areas within the company, the in-house proteomics group has developed techniques for using narrow pH gradient gels, similar to the approach espoused by Angelika Görg of the Technical University in Munich. In this way, she said, Novartis scientists can zoom in on closely clustered proteins in a gel, and potentially pick up proteins expressed only in low abundance. “It’s really a step-wise, narrow pH analysis to cover everything at a given time, when a protein is expressed in a tissue or cell.”
Novartis isn’t currently using the highest-end mass spectrometry equipment to identify the proteins it finds, preferring instead to rely heavily on MALDI-TOF mass spectrometers, Cohen said. However, the company definitely has a need for precision instruments, such as the MALDI-TOF/TOF mass spectrometer, she said, and is looking into purchasing one or more. In addition, Novartis is devoting resources to automate “everything that can be automated,” including the spot picking, spot digestion, and preparation of samples for MALDI analysis.
As part of the company’s strategy for validating the protein targets it finds, Novartis scientists are also engaged in running yeast two-hybrid and protein complex pull-down techniques, Cohen said. But unlike MDS Proteomics and Myriad Proteomics, which have developed high-throughput platforms for running similar protein-protein interaction experiments, Novartis’ approach is to only study the interactions of proteins it has first identified as being differentially expressed in a disease tissue through its 2D gel platform.
Cohen said Novartis has also found proteomics experiments to be of value in trying to determine how and why a particular protein is phosphorylated in a particular cell type or state. At this point, she added, only proteomics experiments are capable of providing this type of valuable information for gaining insight into biological pathways and drug mechanisms of action.
In addition to developing its own in-house expertise, Novartis’ proteomics group in Basel is also busy integrating technologies developed elsewhere, Cohen said. The group is already using Ciphergen’s ProteinChip platform to screen specific types of proteins “quite successfully,” she said, and is currently evaluating other types of protein microarrays, although she declined to elaborate.
“We are constantly looking at what’s out there that we can internalize,” she said. But the question is “how much is this going to bring value, and how much resources are we going to divert in order to integrate this technology,” Cohen added.
But that’s not to say that proteomics stands alone as a separate entity within Novartis. Researchers involved in the discipline work hand-in-hand with biologists with expertise in specific disease areas, she said. In addition the company’s scientists are starting to take an interest in more systems-oriented approaches to understanding disease.
Proteomics falls under Cohen’s control as head of functional genomics, and she stressed that proteomics was only a part — a nevertheless important part — of the company’s strategy for discovering drugs.
“Proteomics is one complement of this whole puzzle when we ask what genes are involved in disease,” she added. “[But] proteomics as an entity is extremely important because they are the ones doing the job in the cell at the end of the day.”
— JSM