Objective
The advent of recombinant DNA technique, provides us with the tools required to exploit bacteria for production of novel products of high biotechnological value. The potential of bacteria lies also in their ability to grow to high cell densities and to produce the required protein product as a large part of their biomass. Although there is a high degree of industrial interest, the number of recombinant protein products that are on the market or under development is low in comparison with the commercial expectations and the current level of investment.
When new industrial production strategies are being developed, severe time constraints imposed by commercialization, necessitates the use of empirical approaches. These are currently based on a small range of overexpression systems. Such approaches are only permissible if the final output is sufficiently high and valuable. After regulatory approval, it is generally too late and too expensive to modify the process. However, as the value of recombinant products declines with increasing competition, there is a demand for improved process optimization. A lack of knowledge of steering parameters does not, however, permit the optimization procedure to be performed on rational scientific basis. Additionally, the limited time available for process development does not, in most cases, allow for the control of unexpected variations in product quality and quantity caused for example by differences in batches and scale-up effects.
A basic concept of this project is that the strategy for process development is often constrained by a limited understanding of:
(i)recombinant protein overexpression in relation to the availability of intracellular building blocks and energy
(ii) the contemporaneous need for to satisfy the energy requirements for cell maintenance
(iii) the status of the intracellular building blocks and energy in relation to the possibilities of supply of exogenous sources.
From the above it is apparent that effective process development will involve the use of expertise ranging from molecular biology, microbial physiology to biochemical engineering.
The long term goal of this project is to derive a strategy that can be used for bioprocess development in order to: (i) arrive at regulatory approval with higher confidence; (ii) avoid wasteful and inefficient process performance and; (iii) provide knowledge of bottlenecks common to the general process. This will allow a true optimization procedure to be developed with a better understanding of the reasons for batch and scale-up variations.
The project strategy is based on prior knowledge that bottlenecks influencing process performance are to be found both within the cell in relation to the design of the bioprocess and from limitations in bioreactor capacity for oxygen and heat transfer.
In order to achieve the long term goal of the project we will focus on providing answers to the following issues;
1 the design of an optimal promoter and ribosomal binding site favourable for the induction of protein production under process conditions 2 the control of substrate uptake and intracellular metabolite balance to avoid energy and/or precursor limitation and to eliminate the waste of energy during production
3 the process optimization, based on the-parameters of the feed protocol and taking into account; (i) intracellular bottlenecks at selected growth rates and; (ii) limitations in oxygen and heat transfer at various cell growth and/or production rates
For successful evaluation and strategy development for production of recombinant proteins, it is necessary to derive the reasons why bacterial populations under the conditions described above often form in sub-populations some of which some are nonproductive and some not viable. We will therefore develop non-invasive techniques to measure the production capacity and viability per individual cell.
We believe this strategy to be generic since the regulatory elements are common to all living cells irrespective of environmental shifts. The strategy is therefore valid irrespective of whether the cells are grown in a reactor or in the natural environment. The present model system was chosen because it exhibits the highest level of prior knowledge and is combined with a system designed to diminish the effects of bottlenecks that are outside the scope of this project.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- engineering and technology environmental biotechnology bioremediation bioreactors
- engineering and technology chemical engineering biochemical engineering
- natural sciences biological sciences microbiology bacteriology
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences molecular biology
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Coordinator
100 44 STOCKHOLM
Sweden
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.