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A proposal for funding – ACTIP

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A proposal for funding by the European Union of research in the field of animal cell technology and related areas, to be incorporated into the 6th Framework Programme

Executive Summary

Balancing fundamental and applied research for the future of the health and life sciences

ACTIP, the Animal Cell Technology Industrial Platform, comprises representatives of many major European companies as well as a number of SMEs. It was established in 1990 at the request of the Euopean Commission in order to follow the progress of research in ECfunded projects in animal cell technology, which is an important generic technology underlying many advances in health and the life sciences. Another objective was to liase with project contractors and to provide input to the European Commission regarding topics most likely to benefit from funding in this field. Through numerous meetings, networking activities and position papers, ACTIP has become a respected and internationally recognised forum of industrial expertise for European scientists and the European Commission.

The first century of this new millennium has been predicted from many informed sources, indeed from no less an authority than Bill Gates, as the ‘Age of Biotechnology’. The ACTIP membership, comprised of representatives of this technology from European Industry, will be pleased to remain a source of industrial expertise and a channel to facilitate technology transfer from academia to industry. ACTIP can and will provide a forum of communication, co-operation and co- ordination between government, academia and industry for an optimal exploitation of the scientific, technological and commercial success of biotechnology.

In order to support this role, the ACTIP members have prepared this position paper, intended as input for discussions with the Commission Services on Framework Programme 6. It contains ACTIPës view on a number of research policy actions and specific research topics likely to benefit most from EU funding in the area of health and the life sciences. The following Executive Summary contains a synopsis of our proposal; the underlying argumentation and full proposal follow in the position paper.

Continuing need for research in animal cell technology

Despite major achievements over the past 10 years, there is a continuing need for research in animal cell technology, a generic technology underlying many advances in health and the life sciences. The surface of this powerful enabling in-vitro technology has barely been scratched and many more important discoveries and applications are emerging as fundamental questions are being answered by basic research, performed in various interdisciplinary organisations.

Full social and economic benefits of new technologies can only be achieved against a background of solid scientific infrastructure and the ability to identify and transfer science to products, in particular since it is widely recognized that basic science gives new products! Further arguments in favour of an EUwide effort to support fundamental and missionoriented research in animal cell technology are the following:

* many fundamental questions relevant for technological applications remain unresolved, despite obvious progress in animal cell technology;

* basic skills and appropriate tools must be further developed in order to achieve meaningful academic, biomedical and industrial goals;

* a greater understanding of cell physiology is needed to take full advantage of the progress made in the human genome project;

* clinicians and industry are calling for more animal cell based approaches and products. These products and approaches are used:

  • for the production and safety testing of biopharmaceuticals and vaccines;
  • in tissue engineering
  • in cell and gene therapy approaches;
  • in advanced research programmes;
  • in human genome projects.
Recommendations

Because of the complexity of biopharmaceutical research, large pharmaceutical companies focus their research efforts on their core competencies. In addition, they frequently enter research alliances with specialized biotechnology SMEs to increase long-term innovation. Another solution to secure future growth is through fundamental research, since experience and history show that this type of research frequently generates new product concepts and the establishment of new SMEs. Both SMEs and larger pharmaceutical companies, the members of ACTIP, recognize the importance of pure and mission-oriented fundamental research; they therefore propose long-term approaches/developments in research with interest for applications, whereby research support should be on a pre-industrial level. The ACTIP membership in particular proposes support for:

  1. Fundamental research in addition to missionoriented research;
  2. Early identification of usable results, with a focus on:
    1. links between contractors of EUfunded research projects;
    2. practical applicability of results;
    3. good and meaningful cooperation, communication and coordination between academia, industry and the Commission Services;
  3. Increased funding and simpler procedures, in particular an improved balance between fundamental and applied research and separate evaluation procedures;
  4. Support for specific research topics, including suggestions for research topics to be financed by the European Commission in the field of animal cell technology in the Framework Programme 6 (2003-2007). These specific research topics can be divided into:
    1. the cell – new cell lines and model systems, stem cell technology, reverse genetics, metablic pathway engineering, expression systems;
    2. the process – i.e. new and reliable production processes, control methodologies, preservation methods;
    3. applications for the cells and/or their products – i.e. recombinant proteins, vaccinology, cell and gene therapy, artificial organs, functional genomics/proteomics, in vitro methodologies, virtual methodologies.

The full paper following this executive summary contains suggestions for specific research topics, as identified by the ACTIP members.

Full text ACTIP position paper, August 2000

A proposal for funding by the European Union of research in the field of animal cell technology and related areas, to be incorporated into the 6th Framework Programme

Back to basics

Balancing fundamental and applied research for the future of the health and life sciences

In the late 1980s, the European Commission recognised the importance of animal cell technology for emerging biotechnology applications in the areas of biopharmaceuticals and vaccines. Between 19901999, it funded in its consecutive programmes a total of 18 projects in animal cell technology (including two large T and G projects) and 14 projects in the emerging field of gene therapy. In addition, 36 projects were funded in the area of transdisease vaccinology. ACTIP, the Animal Cell Technology Industrial Platform, was established in 1990 to follow the progress of research in ECfunded projects in animal cell technology, to liase with its contractors and to provide input to the European Commission regarding topics most likely to benefit from funding in this field. Through numerous meetings, networking activities and position papers, ACTIP has become a respected and internationally recognised forum of industrial expertise for European scientists and the European Commission.

In the past ten years, the efforts of the European Commission, the industry and academia to improve basic knowledge in animal cell technology has not been in vain. A critical mass of researchers has been created, networks between academia and industry have been established and fundamental and mechanistic knowledge of animal cells has increased substantially.

Continuing need for research in animal cell technology

There is, however, no reason for complacency. Full social and economic benefits of new technologies can only be achieved against a background of solid scientific infrastructure and the ability to identify and transfer science to products, in particular since it is widely recognized that basic science gives new products! Further arguments in favour of an EUwide effort to support fundamental and missionoriented research in animal cell technology are the following:

  1. Because of the complexity of animal cells, many fundamental questions in animal cell technology remain unresolved. This contrasts with the situation in other industrially important cell factories, i.e. those based on fungi, bacteria and yeast: in these systems molecular genetics, metabolic pathways, cellular biology and optimal cell culture conditions are much better characterised;
  2. Basic skills and appropriate tools must be further developed in order to achieve meaningful academic, biomedical and industrial goals;
  3. A greater understanding of cell physiology is needed to take full advantage of the progress made in the human genome project. Europe needs to maintain an intellectual and infrastructural critical mass so that the EU can respond rapidly to new opportunities rather than lose the initiative in this vital area of science and technology to the USA or Japan;
  4. Clinicians and industry are calling for more animalcell based approaches and products. These products and approaches are used for the production and safety testing of biopharmaceuticals and vaccines, in tissue engineering, in cell and gene therapy approaches, in advanced research programmes and in genomic and proteomic projects.

The area of animal cell technology is thus characterised by a market need which cannot as yet be fully met by the existing technology. To progress further, the field needs answers to fundamental questions: mechanistic knowledge is required to expand the set of skills necessary to develop novel approaches with emphasis on the translation of knowledge into products. In addition, a greater emphasis on basic research in animal cell technology is required to take full advantage of the knowledge generated by such initiatives as the human genome project.

Recommendations

The ACTIP membership proposes that increased support is given to research in animal cell technology and related areas, with emphasis on:

(1) Fundamental research in addition to mission-oriented research;

For the past 10 years, ACTIP has consistently emphasised the importance of fundamental research in addition to applied research in the field of animal cell technology. ACTIP published position papers to that effect in 1992, 1993, 1995, 1996, and 1997, and reinforced the message in letters and personal messages to representatives of the European Commission in 1998 and 1999.

Mainly through fundamental research will the science base be sufficiently broad to deliver the insights, which form the basis for new approaches and innovations in academia, the clinic and industry.

ACTIPs consistent call for reinforcement of fundamental research has been echoed by important academic institutions, such as ESACT (the European Society for Animal Cell Technology), the EUs own intergovernmental European Molecular Biology Organisation (EMBO), and most recently the ELFS (European Life Sciences Forum). All these organisations have emphasised the importance of basic research, and in several communications they argue that basic research and confidence in its value must be restored to a prime position on the agenda of research policy in Europe.

The call for reinforcement of basic research is also a recognised socioeconomic priority. In 1998, the US Committee for Economic Development found that US economic growth is fed by the enormous federal and industrial investment in basic research. In the same year, the US Congressional Budget Office concluded that the financial return on public investment in academic research and development is 2040%. In its January 2000 Communication, Philippe Busquin, EU Commissioner for Research, recognised the socioeconomic importance of scientific progress and argued that “…..Europe would be quite wrong to reduce its investment in this area”. As a consequence, he has put forward ideas of how to create a coherent, coordinated European policy on research, the European Research Area.

Recommendation:
ACTIP supports the initiative to arrive at a European Research Area and again makes the case to give priority to fundamental research in addition to missionoriented research, in particular in the life sciences. Animal cell technology, including research into non-mammalian species, should be one of the priorities in the life sciences because activities in this field have a wideranging impact on European citizens and society.

(2) Boosting early identification of usable results

To help science provide the tools to satisfy the commercial and sociological need, extensive focus should be placed on novel technology transfer schemes. In our perspective, technology transfer should embrace:

(a) Links between contractors of EUfunded research projects. In earlier (up to Framework 4 Programme) EUfunded programmes, there was a strong emphasis on clustering of projects on certain themes, whether in the form of T (tripartite), G (generic) projects or by means of sectoral meetings, where contractors working in related areas could exchange information and extend their network. For Framework Programme 5 such established channels have not been foreseen. Any links which have been forged have only developed due to the initiatives of the contractors themselves or through third parties such as ACTIP and other platforms. This approach leaves a great deal to chance.

Recommendation:
For FP 6, ACTIP supports the inclusion of established mechanisms that will facilitate exchange of information between contractors working on related topics. Preferably, such mechanisms take account of the International nature of research, allowing frequent and in some cases intensive exchange of European researchers with worldleading US and Japanese scientists. These goals fit extremely well into the ideas launched for the European Research Area, such as …”networking of centres of excellence”, ….” bringing together the scientific communities, companies and researchers of Western and Eastern Europe, “, ….”greater mobility of researchers in Europe”, …..”improving the attraction of Europe for researchers from the rest of the world”, etc.

(b) Practical applicability of results. In the past, many ideas have been put forward to promote technology transfer and industrial applicability of research. Many of the schemes have focused on the later stages of research such as stimulating patenting awareness or innovation and the creation of a more favourable climate for startup companies. Not enough has been done in the earlier phases of research projects, for example, providing guidance to researchers regarding potential applicability of their results. Experience has shown that 40% of fundamental research projects give rise to practical applications (EMBO, 1998).

Recommendation:
For FP 6, ACTIP supports a fixed percentage (i.e. 510%) of a project’s budget be allocated to assessment of technology transfer activities. ACTIP particularly favours the option whereby EUapproved consultants with industrial experience closely follow a project’s progress, preferably from an early stage onwards. Together with the project’s coordinator, these consultants may report back to a forum of scientists and industrialists, for example, industrial platforms, as was done for FP 4 but missing for FP 5. ACTIP would also favour official EU recognition of the function of an industrial platform, to allow early exchange of information and access to publiclyfunded research results.

(c) Good and meaningful cooperation, communication and coordination between academia, industry and the Commission Services is essential in order to fulfil expectations for the future industrial and socioeconomic wellbeing of Health and Life Sciences in the European Union.

Recommendation:
ACTIP, together with the Commission, would anticipate playing a pivotal role in the establishment and maintenance of good and meaningful cooperation, communication and coordination activities between industry, academia and Commission Services. ACTIP also offers the environment for the assessment of technology transfer activities.

(3) Increased funding, simpler procedures

During FP 5, the emphasis was on linking the ability to discover to the ability to produce. Thus the majority of projects selected so far are application orientated. While laudable in itself, this has reduced the chance that fundamental projects have been or will be selected for funding. In addition, the selection procedure is very time consuming, and when a project is finally started, its execution is accompanied by heavy administrative procedures. All this has resulted in an erosion of faith in the EUFP system among scientists working in academia and industry alike.

Recommendation:
ACTIP strongly proposes an increase in the budget for research and in particular an improved budgetary balance between fundamental and applied research. It also proposes that fundamental research projects be evaluated separately from more applicationoriented projects. While projects have to be executed in an accountable, transparent way, it is proposed that purely administrative procedures are lightened to free scientific minds for research rather than administration.

(4) Specific research topics

In addition to above general remarks, the ACTIP membership has identified a number of areas within the field of animal cell technology and closely related fields, where it believes that funding by the EU will be most effective.

Funding of these topics will stimulate research and serve to establish new networks among European scientists, including those from Eastern Europe. It will reinforce contacts between the industrial and academic research in Europe and create the opportunity for European industry to improve competitiveness, employment and growth in a global market.

As argued at length in the preceding paragraphs, we believe that fundamental research and applied research should be stimulated in concert. At the same time it is necessary to foster greater collaboration between academia and industry. Finally, an important aim must be the early identification of results with potential industrial applicability.

(a) The cell

In order to allow for further progress in its applications, cellular research should focus on:

  1. Development of new, mammalian virus-free cell lines that are not transformed;
  2. Identification of factors involved in the immortalization of cells; establishment of conditional immortalization procedures;
  3. Development of stem cell technology, thereby e.g. facilitating tissue engineering and target finding;
  4. Development of (non-tumorigenic/virus free) continuous cell lines from other species than vertebrates, e.g. invertebrates (insects, crustaceans) or avian cell lines;
  5. Development of methods allowing isolation or induction of cell lines that keep their differentiated characteristics and that can be grown in large scale culture;
  6. Development of efficient methods for site specific modifications in mammalian cells (other than embryonic stem cells);
  7. Improvement of efficient expression systems, especially for toxic proteins;
  8. Development of reverse genetics as a tool to develop defined RNA and DNA viruses for use in vaccinology and gene therapy programmes;
  9. Metabolic pathway engineering;
  10. Identification and removal of the bottlenecks in cellular secretion pathways including intracellular transport, intracellular degradation and folding;
  11. Wherever possible, use of yeast (or an other eukaryotic organism like Drosophila or C. elegans) as a model system to take advantage of the vast knowledge of microbial genetics and the complete genome sequence (especially relevant to points 1 and 2)

(b) The process

In order to develop novel production processes meeting industrial requirements, the ACTIP membership suggests:

  1. Development of new efficient, safe, largescale expression systems allowing high productivity combined with a short development time;
  2. Development of animal cell cultures using serum-free/animal product free media to avoid possible contamination of industrial production processes with animal derived material;
  3. Development of improved reliable measurement and control technologies;
  4. Development of improved bioseparation systems;
  5. Development of novel protein ‘tags’ permitting the design of efficient and versatile integrated bioproduction, downstream processing and validation of product;
  6. Development of methods that permit the viable preservation of very large numbers of animal cells or organs;
  7. Development of technologies for gene therapeutic virus production;
  8. Development of organ-like cell culture.

(c) The product and applications

The following research topics have been identified by the ACTIP membership to promote the development of specific products or applications based on animal cell technology:

I Recombinant Proteins

  1. Study of the in vivo function of posttranslational modifications including N and O linked glycosylation.

II Vaccinology:

  1. Transdisease vaccinology with emphasis on both prophylactic and therapeutic vaccines;
  2. Continuing study of the immunology of vaccination;
  3. Development of new efficient adjuvants;
  4. Further development of nucleic acid vaccination for both human and veterinary applications (see also under III);
  5. Identification of vaccine targets;
  6. Studies on host-pathogen interactions.

III Gene and cell therapy:

  1. Alternative direct DNA therapies (using the injection of ‘naked’ DNA for the delivery of recombinant proteins);
  2. Development of celltargeted specific vectors;
  3. Development of safe, immune nonreactive cells;
  4. Development of new packaging technologies;
  5. Further development of expansion technologies for primary cells;
  6. Methods for the storage and in vitro and in vivo expansion of stem cells (i.e. from umbilical cord) to be used in human therapy;
  7. Further development of cellmediated gene transfer.

Biosafety aspects will have to be an integral part of the projects funded.

IV Artificial organs

  1. Studies leading to the development of artificial organs such as liver, pancreas etc;

V Functional genomics/proteomics

  1. Development of the cell as a vehicle for functional genomics;
  2. Methodology to translate genomics into diagnosis and therapies including improving methods of gene expression from newly discovered chromosomal DNA (verification of genes, exploration of gene function) and improvement of knock-out technology on cells to explore gene function.

VI In Vitro methodologies:

  1. Development, and validation, of in vitro toxicology methods;
  2. Development of in vitro methods for the study of drug metabolism and pharmacokinetics;
  3. Studies aimed at the (partial) replacement of in vivo preclinical drug development by in vitro methods;
  4. Development of cellular models for metastasis induction, tumour and normal function;
  5. Studies on cellular signal transduction pathways leading to the development of in vitro models that are used for the identification of lead compounds;
  6. Development of tools that will facilitate High Throughput Screening and assay development in today’s drug discovery programmes;

VII. Virtual methodologies

  1. Establishment of a virtual database of certified cells and vectors used in the industrial production of marketed therapeutics and diagnostics to foster R&D, exchange of material, standardisation of cell lines and regulatory procedures.

Inishturkbeg, August 2000

 

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