CPSA Digest 2001

Proceedings -Wednesday, October 10, 2001

WOA2

The Emerging/Future Role of Proteomics in Drug Discovery:
Industrial-Scale Proteomics at GeneProt

Background:
The goal of the GeneProt Company (also known as Geneva Proteomics), founded in Geneva in spring 2000, is to become the international leader in proteomics. GeneProt will generate and commercialize proteomic and related biological and medical information to accelerate the understanding of biological processes and to assist pharmaceutical, biotechnology and life science research efforts. In April 2001, GeneProt announced the opening of the world's first large-scale proteomic discovery center in Geneva, Switzerland. Strategic partnerships have been secured with Novartis and with three providers of essential tools to their business-- Bruker, Micromass and Compaq Computers. A team of 60 scientists and bioinformaticians has been assembled. A second site has been secured for a large-scale proteomics facility near Princeton, New Jersey to be operational in 2002.

GeneProt was founded in close association with the principal figures in the world-leading bioinformatics company, GeneBio. GeneBio's founding group, the leading proteomic scientists Denis Hochstrasser, M.D., Amos Bairoch, Ph.D. and Ron Appel, .D., joined with Robin Offord, Ph.D. and Keith Rose, Ph.D., world leaders in the field of protein chemistry, to found GeneProt. These individuals are known internationally in the fields of bioinformatics, mass spectrometry, protein chemistry and protein databases. As a result of a background as medical faculty, they expect to provide a unique expertise to focus on the medical applications of proteomic information.

Premise:
GeneProt's Mission Statement is to:

• Obtain massive quantities of proteomic data by analysis of chosen biological fluids and tissues in healthy and sick individuals
• Enhance the value of the information obtained through bioinformatics
• Make "it" (i.e., useful information) available to their customers
• Shorten the path to drug development

While Genomics links genes to their biological functions, Proteomics is the complementary discipline that correlates genetic sequences to the proteins that they encode. Unlike the genome, which is fixed for each organism, the proteome changes with the state of development, the tissue or even the environmental conditions an organism is exposed to. The term "proteome" refers to the PROTEins expressed by a genOME or tissue. Many more proteins are expressed in a proteome than there are genes in a genome. More proteins are possible because a gene can be spliced many different ways and still result in a functional messenger RNA expression. It has been estimated that from the 30,000 genes in the human genome perhaps as many as a million proteins may be generated. Thus, the proteomic project is a much more difficult task than the now completed project to sequence the human genome.

It is at the protein level that most regulatory disease processes primarily occur and where many drug targets are found. There are over 250 tissues in the human body, each with their own proteome and each depending on age, sex, state of health, diet, medical treatment, time of day, etc. By measuring the amounts of the expressed proteins and how different proteins are interacting, a greater understanding of how cells operate under normal and diseased states can be learned. This knowledge can accelerate diagnostic and therapeutic product development and identify important biomarkers and novel drug targets. The anticipated result of proteomics research will be the identification of early disease markers, better diagnostic tests and targeted drug therapies. It is anticipated that the developed treatments will have greater success rates than present therapies.

Value of the Technology
In a practical sense, GeneProt aims to detect, identify and characterize as many proteins as possible that are present in concentrations of 10-12 M or higher. Another aim is to produce an annotated protein database that will help discover protein therapeutics, targets and biomarkers. Clearly, an industrial scale proteomics factory is being established.

The technology platform for bioinformatics is described as follows.

• Proprietary developments--from peak detection to complex database design through LIMS, MS data identification and sequence automatic annotation
• Several integrated biological databases
• Global data mining across the proteome; able to provide comparisons
• Manual annotation of results to further improve the quality of information
• Selection of interesting proteins

The technology platform for synthesis is described as follows.

• Total chemical synthesis
• … State of the art multiple fragment ligation with ThioPro, native chemical ligation and general chemical ligation
• Covalent capture purification
• Final refolding
• Protein size range--160 residues and beyond; SeMet, tags etc., chips
• Expected yield is 5-20 mg at >95% purity

The Future
The future of GeneProt will be made at their two facilities (Geneva, Switzerland and The Technology Centre of New Jersey, North Brunswick) that will coordinate and integrate all functions and data. Production mode is the nature of their business now, involving the functions of Separation, Analysis and Synthesis. Future technological improvements need to be made in the following areas: protein separation, mass spectrometry, computing, bioinformatics and synthesis. An important objective of their work involves the demonstration of speed, sensitivity and reliability.

Links
GeneProt Milestones

Major Novartis investment confirms Geneva as key center of excellence in world biotechnology

Geneva's GeneProt enters technology partnership with US Waters

Geneva Proteomics selects Compaq as it supplier

GeneProt and Bruker Daltonics plan large-scale deployment of MALDI-TOF/TOF mass spectrometers for high-throughput proteomics

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