TIBTECH - DECEMBER 1987 [Vol. 5]

structures are being determined each year. As new ones are published, one looks keenly to see how they fit into the emerging picture, and in what ways the new data allow us to test, probe, and extend our current ideas.

Against this background, several projects at EMBL are aimed at the analysis of known sequences and structures to elucidate basic princi- ples. Looking towards the future, these will, sooner or later, support serious attempts to move to the ulti- mate goal of predicting tertiary struc- tures of proteins from amino acid sequence alone. Specific projects in- clude:

• Sequence-structure correlations: the conformational variation of individual oligopeptides found in native structures, improvements

in methods of prediction of secondary structure from se- quences, the analysis of newly determined gene sequences, and the search for 'fingerprints' by which structures and functions may be recognized from amino acid sequences. Analysis of known structures: the course.~and mechanism of evolu- tion in protein families (how can very different amino acid se- quences produce similar struc- tures?), and mechanisms of con- formational change. Protein design (this is the inverse of the folding problem - in pro- tein design one starts with a target structure in mind and tries to sug- gest an amino acid sequence that might form it): This involves im-

proved methods of prediction of structure from sequence, col- laboration with experimental groups in planning modifications of known proteins, and the pre- diction of novel proteins with new functions or structures. Pro- tein design was the subject of a major international workshop held at EMBL in 1986. An amino acid sequence devised during that workshop - a modification of the protein ROP - is now being synthesized at the Gesellschaft ffir Biotechnologische Forschung (GBF) in Braunschweig, FRG.

Compiled by A R T H U R M . L E S K

EMBL, Meyerhofstrasse 1, 6900 Heide}berg, FRG.

[ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ]

European Laboratories Without Walls: focused precompetitive research

Robert van der Meer, Etienne Magnien and Dreux de Nettancourt

The most striking aspect of bio- technological research in Europe is its vitality, which springs from the variety and diversity of the subjects studied and the approaches adopted. Over the last few years, many countries in Europe have accorded high priority to biotechnology in their national R & D stimulation programmes, with the result that there has been a significant growth in biotechnological research.

In many subject areas, however, fragmentation of research among

Robert van der Meer is at the HOM business and venture development, Hol- landse Ontwikkelings Maatschappij voor bedrijven by, Scheveningseweg 9, 2517 KS, The Hague, The Netherlands; Etienne Magnien and Dreux de Nettancourt are respectively a member and the head of the Biotechnology Division at The Com- m&sion of The European Community, DG XII for Science, Brussels, Belgium.

member states can result in duplica- tion of effort. Individual national projects can be condemned to isola- tion and relative insignificance. In order to solve this problem, the Commission of the European Com- munities (CEC) has set up research and training programmes to under- pin existing achievements and elimi- nate weak points. The Commission's R & D programmes are intended to improve the international competi- tiveness of European industry and agriculture while increasing environ- mental awareness. They must also complement national initiatives. Therefore, calls for research pro- posals for the Community pro- grammes BEP and BAP* stipulated transnationality of joint projects as the main criterion of acceptability. Consequently, transnational coopera- tion in European biotechnology is now a reality. Many of the BAP

© 1987, Elsevier Publications, Cambridge 0166-9430/87/502.00

projects involve more than two laboratories (Table 1). From the outset, all the cooperative projects distributed tasks among laboratories in different Member States. Now, where the competitive advantage of integrated work under the Com- munity programme has become par- ticularly obvious, multidisciplinary collaborative associations have been brought into being. These are the European Laboratories Without Walls (ELWWs).

An ELWW is larger than a simple cooperative project, but smaller than a research programme. It is an open- ended, transnational association of cooperating European groups with a common commitment to target- oriented multidisciplinary research.

With their origin in the biotech- nology R & D programmes of the CEC, the ELWWs are clearly European in character. But what of 'laboratories without walls'? From the outset it has been stressed that these associations are open to any researcher with either an industrial or a university back- ground who can contribute usefully

*Biomolecular Engineering Programme (1982-1986) and Biotechnology Action Programme (1985-1989), respectively; for a more detailed description, see Trends in Biotechnology (1987) 4, 277.

TIBTECH - DECEMBER 1987 [Vol. 5]

Genetic engineering of dairy starter cultures

i~ Goals To devise genetic techniques for application to :~ ..... lactic streptococc= in order to develop superior strains for

dairy fermentations. To develop vector systems and transformation techniques of bacteriophage-host

interactions, cloning and the characterization of proteinase activities.

Participants Ch. Daly, (Eire), M. J. Gasson, (UK), M Teuber, (FRG),

W. M de Vos and G. Venema (The Netherlands)

Expertise Strain selection, the gen-

etic improvement of starters cultures, resis-

tance to phase infections; the molecular biology of

proteases and flavours.

Achievements The discovery of a Streptococcus cremoris ptasmid that also

replicates in E. coil. The isolation of highly phage resistant strains and the cloning of

phage-resistance genes from resistance- associated plasmids. The cloning of the proteinase

region, and the discovery of a demethiolase enzyme with prospects for accelerating cheese ripening.

Molecular genetics of phytopathogenic Erwiniae

Goals Understanding the utilization of plant cellulose and pectin by Erwinia m the course of the plant-

pathogen interaction: production of anti-tumoral enzymes; construction of secretion vectors for

the production of engineered polypeptides; exploitation of Erwinia pectinase/cellulase

genes to increase substrate utilization of industrial microbes; identification of mechanisms underlying plant

phytopathogenicity.

Participants J.P. Cham- best, A. Kotoujansky and

J.M. Robert-Baudouy, (France), G.P.C.

Salmond, (UK), A. Toussaint-Pour-

baix, (Belgium)

Expertise Plant path- ology, biochemistry, enzy-

mology and molecular genetics.

Achievements The cloning of genes involved in cellulolysis and

pectinolysis; characterization of mutations inhibiting secretion of both pectinase and

cellulase with a view to studying secretion mechanisms in Gram negative bacteria; analysis

of phytopathogenicity; avirulent mutants were shown to have altered lipopotysaccharide (LPS) profile and

in proteins associated with iroh transport.

Molecular genetics of mitochondrla in relation to crop improvement

Goals To understand the structure and expression of the mitochondrial genome and of its

recombinational mechanisms to devise vectors of general applicability to the transformation of

mitochondria.

Participants M Briquet, (Belgium), A. Cornu, F. Quetier, (France), A.P. Czernilofsky, (FRG), D. R. Davies

and C. J. Leaver (UK), H. J. J. Nijkamp, (The Netherlands).

Expertise Structure/ expression studies of

the mitochondrial genome of major

crop plants, meth- ods of mitochondrial

transfer (fusion, micro- injection, wide-ranging

sexual crosses), characteri- zation of native plasmids and

construction of synthetic plasmids for transformation purposes.

Achievements Elucidation of the molecular basis of cytoplasmic male sterility;

-" described recombinational events in mito- chondria giving rise to aberrant reading 4-rames.

Accumulating knowledge of the mitochondrial genome.

In-vi tro cell manipulation of crop species

Goals The genetic manipulation of four economically important crop plants by means of an array of methods for

the transfer of genetic elements and complexes vary- ing from cloned DNA fragments to complete nuclei

or chromosomes.

Participants M.G.K. Jones, (UK), M. J. Tempelaar and L. van Vloten-Doting,

(The Netherlands), M. Jacobs/ I. Negrutiu, (Belgium), F. Sala, (Italy), M. Caboche and Y. Dattee (France), H. Lerz.

(FRG)

Expertise Charac- terization of select-

able mutants, synchronization of

the cell-cycle, cell- mediated gene trans-

fers, chromosome-, DNA- and liposome-mediated gene

transfers, cytological and molec- ular analysis of transformants and

regeneration techniques.

Achievements Production of new hybrid plants from Solanum tuberasum and Solanum

brevidens (potato) through electrofusion; the application of y-fusion to the production of asymmet-

ric hybrids, e.g. combinations of Nicotiana plumbagim- foil and Atropa belladonna or Beta spp. Transformations

of cereal protoplasts with transient expression of the reporter genes have also been repeatedly achieved.

- -Tab le 2

TIBTECH - DECEMBER 1987 [Vol. 5]

Industrial affil iation of BAP projects in the different research sectors

to the collective activity. Thus ELWWs are not exclusive clubs, although the intention is to involve as many top-ranking research scientists as possible in their work. Participa- tion by industry is usually wel-

N u m b e r of Number of projects companies To ta l in w h i c h

I ndus t r i a l i n t e r e s t e d n u m b e r o f i n d u s t r y is Sector contractors* in sector projects interested

Subprogramme I C o n t e x t u a l measures

Bioinformatics Biotic materials

Subprogramme II comed.

Figure 1 indicates how four of the ELWWs have operated. To address specific goals within an area of technology, expertise and resources from several laboratories have been

4 : 4 2 19 12 8 0 : 1 3 7 5 5

harnessed. Although one can never know what might have happened without ELWWs, the list of their achievements to date indicates the effectiveness of collaborative re- search on this scale.

Fruits o f integrat ion The integration of work is more

apparent in ELWWs than in the original bilateral collaborations of BAP and BEP. Three facets of this integration are particularly note- worthy: information from the fore- front of research is circulated freely; there is a iramework for the con- tinuous exchange of materials, data and staff; and there is regular joint planning and evaluation of experi- ments.

Divers i ty - Input from various European countries gives ELWWs a variety of research approaches and expertise across a wide range of disciplines. This particularly bene- fits biotechnology since ELWWs can

~ T a b l e 1 Number of projects Programme (BAP)

E n z y m e e n g i n e e r i n g 4 : 4 5 35 17 14 P lant cel ls 4 : 64 43 23 20 Microorganisms 1 : 35 31 13 12 Risk a s s e s s m e n t 0 : 7 5 3 1 A n i m a l ce l ls 3 : 40 19 16 14 In vitro t o x i c i t y 0 : 16 10 6 3

Total 1 6 : 2 6 2 169 95 77

* N u m b e r o f i ndus t r i a l c o n t r a c t o r s : total number of contractors

provide combinations of skills rarely available within the confines of an individual university, institute or company.

Information exchange and tech- nology transfer- Participation in ELWWs of leading scientific groups has led to increased exchange of information: healthy competition be- tween national groups has been superseded by healthier collabora- tion. The dissemination across state boundaries in Europe of the views of experts will now more readily influence the direction of new avenues of research. Open and rapid transmission of biological data and materials have been facifftated by ELWWs as has the exchange of scientific staff involved in highly innovative experiments. They also provide a platform for information

funded under the Biotechnology Action

N u m b e r o f p a r t i c i p a t i n g l a b o r a t o r i e s

exchange and technology transfer between academics and with inter- ested industrialists. Each ELWW addresses the complexity of scien- tific and industrial structures in different member states and attempts to overcome the physical and psy- chological barriers to horizontal (between disciplines) and vertical (between academia and industry) technology transfers. It is, perhaps, less likely that European biotechno- logical discoveries will be exploited only on some other continent.

Catalysis of research - Through limited funding under BEP or BAP (approximately one researcher plus operating costs for each participating laboratory), the skills of highly qualified research groups are merged in functional, target-oriented co- operative projects. Thus the funds act catalytically, guiding and tuning the research work performed. It is research strategies and not just individuals which benefit. Moreover, the distribution of tasks among the European member states can help in harmonization of national stimula- 1 2 3 4 5 6 a n d o v e r To ta l

C o n t e x t u a l m e a s u r e s 1 7 - 4 4 1 17 E n z y m e e n g i n e e r i n g 1 8 4 4 - - 17 Genetic engineering of - 15 2 2 3 1 23

agricultural species Genetic e n g i n e e r i n g o f - 6 6 - 1 - 13

i ndus t r i a l microbes Risk a s s e s s m e n t - 2 1 - - - 3 G e n e t i c engineering of 1 7 5 1 2 - 16

a n i m a l h u s b a n d r y / n o v e l m e t h o d s a n i m a l cel l cu l t u res

In vitro e v a l u a t i o n o f t o x i c i t y - 4 1 - 1 - 6 and p h a r m a c o l o g i c a l a c t i v i t y o f m o l e c u l e s

To ta l 3 49 19 11 11 2 95

tion programmes. There is a degree of overlap

between ELWWs, especially where techniques are shared. This results in further cross-fertilization between disciplines and applications giving additional impetus to scientific and technological progress.

Size and l i fe t ime o f an ELWW The level of participation in

ELWWs (3-12 participants) is easily manageable. Research can be co- ordinated for optimum efficiency and scientific productivity and for

T I B T E C H - D E C E M B E R 1987 [Vol. 5]

- - F ig . 2

Precompetitive loose associations of academic laboratories

Stratiffed in volvement o f industry

the exchange of techniques, results and people.

The lifetime of ELWW is the period required to attain the common scien- tific objective for which it was set up. It is dissolved if this objective proves to be unattainable or if the research has been brought to a successful conclusion. If new avenues for further development are opened, an ELWW will cease to exist. It becomes split into narrower associa- tions based on direct bilateral, con- tractual agreements with interested firms,

Industrial interest in ELWWs Many academic research groups in

biotechnology have contacts with one or more companies. The creation of an ELWW, therefore, can widen the interest and involvement of European industry, perhaps initially without much in the way of con- tractual commitment. How should industry's involvement be developed further? As yet there is no precedent for evolution of an ELWW into a series of bilateral contracts with European firms. At Commission level, this question is being discussed by the Management and Coordina- tion Advisory Committee (CGC) on Biotechnology and Working Party 5 of the Industrial Research and Development Advisory Committee (IRDAC) and also at industrial round table meetings with various firms that have expressed their interest in projects implemented under the BAP.

Industry has indicated consider- able interest in the BAP, and provides written (and sometimes more con- crete) support for the research pro- jects in progress, frequently hiring scientific staff initially from contract- ing laboratories (Table 2). Many firms have attended the contractors' meetings recently organized by the Commission which marked the start of the BAP projects. It is important for interested firms to be able to monitor the progress of cooperative research in the ELWWs.

Ideally, each ELWW should have its counterpart in the industrial community; a group of firms pre- pared to explore commercial pros- pects in the relevant areas. Any research results with commercial possibilities could thus be trans- ferred effectively to industry. In turn, the industrial partners can steer the ELWW along lines of strategic inter- est towards important commercial breakthroughs. For the time being, however, the strategic research in ELWWs will continue to be directed largely towards precompetitive gen- eric technologies.

In certain cases, the cooperation between firms and ELWWs could benefit from having a legal basis, addressing questions of cooperation between firms, and between firms and their academic partners. A legal framework recently devised by the Commission for 'European Economic Interest Groupings' might serve as a model for enhancing the relationship between the European biotechno- logical industry and the R & D infra- structure.

Both the CGC on Biotechnology and the Commission will strive to establish effective links between the ELWWs and the European biotechno- logical industry so that the research results obtained under the BAP can more easily reach the targets for which the programme was set up. To

m Haemophi l iaand biotechnology

m Secondgenerat ion monoclonal antibodies

this end, it is recommended that a stratified form of research partner- ship (Fig. 2) be adopted.

Two aspects of this stratified involvement are important. Firstly, ELWWs are destined to be replaced by narrower industrial agreements when firms become sufficiently in- terested. Hence there is a need for industry to be involved at an early stage. Secondly, ELWWs simple constitute one layer in the stratified research partnership: a motherlayer which gives birth to new ideas and developments in response to real industrial requirements and con- t inuously feeds the layers repre- sented by company-based industrial research.

In short • ELWWs should initially deal with

precompetitive research subjects, addressing limiting factors such as methodological bottlenecks or gaps in knowledge.

• ELWWs must be open-ended to facilitate joint experiments and the exchange of forefront informa- tion and researchers.

• There must be mechanisms for dissociation of ELWWs into smaller units for competitive in- dustrial development projects when the transition from basic to applied research has taken place.

• Each ELWW should be backed up by its counterpart in industry. In this connection, closer attention should be paid to the organ- izational structure of and the legal basis for such groups.

[] Recombinant virus vaccines m The future ofar~imal cell cuFture

n Growthhormone m Crossf low filtratTon