Executive summary
Strategic importance and scientific challenge
Research areas within the program
Bioinformatics
Admission of graduate students and economic support
Graduate courses and annual meeting
Industrial collaborations
Equal opportunities

The council of the Foundation for Strategic Research (SSF) has evaluated and approved a proposal for a five-year program in the field of Cell Factory for Functional Genomics. The program involves protein and proteomics research spanning from protein expression to combinatorial approaches. One of the main objectives with the program is to develop technology platforms to facilitate the understanding of the function of proteins encoded by genes discovered in the various international genome projects. Methods to explore interactions between proteins and protein domains are of particular importance.

As suggested by the international reviewers and decided by the Programme Board, the program consists of three research areas of strategic importance for biomedical and biotechnological research.

I. Protein expression in different recombinant hosts.

II. Combinatorial protein chemistry, including phage display techniques.

III. Proteomics, including protein characterization and analysis.

The national network will provide graduate student training in these three research areas with an emphasis on basic problems or technology platforms that are of direct or potential interest for pharmaceutical and biotech industry. Collaborative and multi-disciplinary projects covering two or three of the areas listed above will be encouraged. Graduate students will be admitted to the program and the program will ensure funding for the first three years of the graduate training. The university is expected to provide faculty funding for the last year of the training.

The background of the research program is the strategic importance of exploring the products of expressed genes in all areas of biology, medicine and biotechnology. Obviously, the need for functional studies of proteins is eminent in the genome research area where many thousands of genes with unknown functions will be available within a few years. In addition, protein expression is still a major bottleneck in other important research disciplines, such as structural biology, molecular recognition, combinatorial biochemistry, neurobiology, tumor biology, immunology and vaccine engineering.

One of the major challenges of the post-genome era will be to assign functions to all of the unknown gene products discovered through the genome and cDNA sequencing efforts. Important efforts in this emerging field are to perform homology studies with known genes and/or proteins, but also to produce "transcription maps", where the mRNA levels in different tissues, organs or cell types are characterized using various approaches (differential display, subtractive hybridization etc.). However, it is obvious that the structural/functional analyses must also involve protein analysis. This will be a major effort and will need to incorporate several overlapping strategies. One such strategy is to use 2-D-gel analysis, which allows the comparison of protein products from cells under varying conditions (stress, differentiation etc.). The use of mass spectrometry and modern image analysis hardware/software systems has made these methods potentially very powerful. A more specific assay to analyze protein function is to use expression systems designed to detect protein-protein interactions, such as the 2-hybrid system of yeast. Using such systems, protein complexes can be characterized and potential interactions of heterodimers or multimers can be defined. Another important aspect of proteomics-related research is to systematically assign cellular and/or organell localization of gene products to facilitate a functional determination. Thus, the ultimate goal for this research is to combine protein expression and purification with protein analysis and characterization to allow structural/functional studies of partial (EST) or full-lenght genes. The combined use of different expression systems, powerful analytical tools, such as MS, 2-D gels and high resolution HPLC and combinatorial protein chemistry based on phage display and other   in vitro evolution techniques will provide a technology platform of strategic importance in post-genome research.

The national network will provide graduate training in three sub-programs.

I. Protein expression in different recombinant hosts. The goal of this subprogram is to perform research in areas such as (i) in vitro and in vivo expression, (ii) secretion and intracellular expression in various recombinant host, and iii)  in vitro folding strategies for aggregated proteins. Research projects devoted to high-through-put systems for expression of proteins for functional and structural analysis will be encouraged. In addition, expression systems to select for interacting proteins, such as 2-hybrid systems, is an important part of this program. More specific projects can involve cell engineering to obtain optimal production, novel gene fusion systems, novel promoter systems for regulated expression and new technology for expression and purification of membrane proteins.

II. Combinatorial protein chemistry, including phage-display techniques. The goal of this subprogram is to perform research in areas such as combinatorial protein and peptide libraries. Development of cell and phage display techniques are important parts of the program as well as development of in vitro selection systems. An emphasis will be on research devoted to functional analysis of gene products, including selection of bindning molecules (antibody-fragments or other protein domains) to proteins of unknown function to allow localizations studies and affinity purification of proteins from biological materials. Another interesting area for research is efforts to develop selection systems for proteins that interact with each other.

III. Proteomics, including protein characterization and analysis. The goal of this subprogram is to perform research in areas such as 2-D-gel analysis, mass spectrometry (MS), high-through-put HPLC and biosensor analysis. Protein analysis systems to study the global expression of proteins in cells and tissues is an important objective of the program. This allows comparison of protein products from cells under varying conditions (stress, differentiation etc.). Another aspect of the program is to analyze heterogeneity of proteins from different sources and post-translational modifications of proteins using high-throughput methods.

An importnat part of the program is to develop bioinformatics tools to faciliate for reseachers within the program, but also for other scientist interested in protein expression, combinatorial protein chemistry and proteomics. We therefore plan to set-up a home-page where the principal investigators are encouraged to present results from the research programs, matched with information available from the public databases. An Oracle-based database will be set-up,which includes (i) protein expression information, (ii) results from the different combinatorial approaches and (iii) protein localization information. The objective is to create databases and database-applications related to protein functionality, but with a focus on the various projects funded by the program.

To direct the graduate students to the best available projects on a national scale, researchers active in Sweden will be invited to each year propose graduate student projects within the areas specified above. Projects will be selected by the program board according to their scientific quality and strategic importance for Swedish industry. To facilitate and ensure quality on the selection procedure, the board will appoint a reference group of experts for each of the three areas. These reference groups will perform an initial screening and the top-ranked projects will be presented to the board which selects a total of 10 each year (during 1999 and 2000).

The projects selected by the program board for funding will be presented this Home Page. The first year students in the six local graduate schools in biomedicine (Umeå, Uppsala, Stockholm, Linköping, Göteborg and Lund) are invited to apply for these projects. Also other students can apply. The applicants to each project will be ranked by the project leader/supervisor. The resulting combination of projects and graduate students (coordinated by the program director) will be presented to the program board for approval. Before the end of the first semester, the student and the supervisor should have prepared a detailed research plan, which is presented in a written form to the reference group. The students will register as regular graduate students at the respective department.

Each student will be supported for three years which includes two years "utbildningsbidrag" followed by one year "doktorandtjänst". The funding is 160,000 SEK for utbildningsbidrag and 280,000 SEK for doktorandbidrag. After three years, the recipient department/faculty will assume the economical responsibility. The students are expected to graduate after 4 years.

Each position will be accompanied by a "bench fee" support during the first two years, which should cover costs for visits to collaborating laboratories and to contribute to the running costs of the project. The bench fee support has been set to 120,000 SEK annually. In addition, 70,000 SEK is paid annually to contribute to over-head cost (rents, administration etc). The total economic support for each project will thus be 350,000 SEK annually for three years.

During the fourth year of the projects, we plan to give "bech-fee" support for some of the projects. The supervisor is expected to apply for this additonal funding together with a progress report. The ranking will be performed by the Program Board.

Two graduate courses of relevance for one of the different sub-programs will be a arranged every year (starting 1999). These courses will be 2 weeks in length and focus on topics of particular relevance for at least one of the subprograms. The program director, the executive coordinator and the local contact person will plan the course program for each year and present a plan that must be approved by the board.

Each year, an annual meeting will be organized to allow each graduate student/supervisor to present results. International scientist will also be invited to these meeting. To encourage interactions with the genome research program, the meeting will be held in conjunction with the annual genome meeting.

The links between industry and academia in this field are already close. Many of the groups supported by the first round of applications already have contacts with industry. To ensure industrial relevance and participation, we will encourage contributions from industrial researchers both on the courses and workshops as well as the annual meetings. In addition, projects with relevance for industry will have priority in the selection of projects to be funded by the program.

The instruction for the program plan from the SSF stipulate that at least 20 % of the graduate students recruited should be women. Our ambition is to try to recruite approximately 40-60 % women as graduate students, although this figure might vary from year to year.