SBNet - Programme 1996-2000

Strategic Research in Structural Biology

Programme Plan

1996 - 2000

September, 1996

B. Nilsson (Chairman) & T.A. Jones (Director) on behalf of the Programme Board

G.J. Kleywegt (scientific secretary)

1. Executive summary

1.1 Introduction

Structural Biology research plays a central role in all biological sciences to explain biological function and activity in terms of structure and chemistry. The aim of research in Structural Biology is to elucidate the three-dimensional structure and dynamic properties of biological macromolecules (proteins, nucleic acids, and complexes) at atomic resolution. Structural Biology research is essential for several other biology-oriented programmes that have been or will be initiated by the Strategic Research Foundation. Structural Biology has already had a major impact in many areas (including medical and pharmaceutical science, food technology, forestry and plant technology) in most of the developed world. Swedish industry, however, lags behind by ~5 years in this process, even though some of the academic groups in Sweden are competing at the highest international level.

In order to strengthen the strategic value of Structural Biology in Sweden, the Structural Biology Network takes a four-tiered approach:

  1. To reinforce excellence ; by supporting new strategic research efforts of the groups that are competing at the highest international level.
  2. To remedy current weaknesses ; in particular, by building a protein-expression laboratory in Uppsala.
  3. To elevate graduate training to a world-class level ; by organising advanced courses and conferences open to all Nordic students and researchers with an interest in Structural Biology.
  4. To facilitate knowledge transfer ; by stimulating contacts between academic groups, contacts with industry, and participation of industrial researchers in the Network.
This document outlines a Programme to be funded by the Strategic Research Foundation during a five-year period (1996-2000) at a level indicated in the starting contract of November 1995 (total budget for the period 1996-2000: 65 MSEK). The Programme follows the directives issued by the Foundation at that time.

1.2 Programme aims

1.3 "Concrete" deliverables

1.4 End of the Programme

2. Introduction

2.1 Definition of the field

Structural Biology is defined here as the area of scientific enterprise which aims to elucidate the three-dimensional structure and dynamic properties of biological macromolecules (proteins, nucleic acids and complexes) at atomic resolution, in order to provide a structural explanation for biological function and activity. Such studies may be of benefit in many different areas, ranging from medical and pharmaceutical science, to forestry and plant technology. In the context of this Programme, Structural Biology is taken to include: biomolecular X-ray crystallography, biomolecular NMR spectroscopy, and near-atomic resolution electron crystallography.

To follow the directions of the Strategic Research Foundation, we have attempted to include research programmes on structural techniques within X-ray crystallography, and the modelling of macromolecular structure via computational methods. However, we believe that the area of bio-informatics and bio-computing is a broad one with a great deal of overlap with other programmes that are or will be supported by the Foundation. We have, therefore, chosen to concentrate on modelling groups that already are closely collaborating with the structural biologists that make up the core of this Programme.

Structural Biology was born in Cambridge, England in the 1950's where the first macromolecular structures were determined by Crick, Watson, Kendrew, Perutz and co-workers. Since then interest in the three-dimensional structure of macromolecules has exploded beyond the wildest imagination of even the most structurally-oriented biologist or chemist. In hindsight, the reasons for this are obvious. The atomic structure of a macromolecule is the skeleton upon which the biological function rests. Without this detailed knowledge of the structure, we are limited in our understanding of the biological process or event.

The methods that were developed in the 1950's and 1960's for the phasing of the diffraction data are still in use today, although new methods have been developed as well (MAD phasing, direct methods). Modern Structural Biology is a merging of different disciplines, which have greatly developed in the last ten years. X-ray crystallography has been the principal source of three-dimensional structural information. The time required to solve the structure of a medium-sized, soluble protein has shrunk in some cases to just a few months. The production of crystals has been greatly improved by the availability of large quantities of proteins, produced by over-expression systems, and by the experience gained in the last 30 years in how to grow crystals. Data-collection developments, in synchrotron-radiation sources, cryo-cooling of crystals, and area detectors, make that the new diffraction information can be processed easily and rapidly. The revolution in the computer industry has significantly reduced the time taken to process the diffraction data. Parallel developments in computer graphics allow for the simple manipulation of macromolecular structures.

In the last ten years, multi-dimensional nuclear magnetic resonance (NMR) spectroscopy has developed into an alternative to X-ray crystallography, at least for small proteins with suitable solubility properties. In addition, NMR allows the study of the dynamic properties of molecules, and the technique is well-suited for probing interactions between molecules.

However, the single most important development for structural work has been the ability to produce large quantities of almost any protein of interest. These new molecular biology techniques also allow one to introduce changes in sequence at specific places, which help us understand biological function but also (possibly even more important) to modify function. The introduction of new functionality requires both selection and design. A deep theoretical understanding of the forces involved in determining protein structures is mandatory for a successful design experiment.

2.2 History and status of Structural Biology in Sweden

Protein crystallography has a long tradition in Sweden. Already in the first half of the 1960's two groups started in Uppsala, lead by Bror Strandberg and Carl-Ivar Brändén at Uppsala University and the Swedish University of Agricultural Sciences (SLU), respectively. Both had undertaken post-doctoral studies in Cambridge. On his return, Bror Strandberg initiated the structure determination of carbonic anhydrase, which was completed by Anders Liljas. He also began a programme to study the structure of spherical viruses which, at the time, were orders of magnitude larger than any structure that had been determined. The structure of satellite tobacco necrosis virus was eventually completed by Alwyn Jones and Lars Liljas. In the years prior to his retirement, Bror Strandberg has been working with Torsten Unge on the structures of HIV virus enzymes. Anders Liljas started investigations on ribosomal proteins and translation factors in Uppsala and has successfully continued this line since his move to Lund University in 1987. Lars Liljas has continued the virus research and recently solved the MS2 virus structure. Alwyn Jones came to Uppsala from Robert Huber's laboratory in Munich in 1979. After his virus work, he started his own research projects on retinoid-binding proteins, cellulases, lipases, etc. He is also interested in crystallographic methods, and nearly all crystallographic models that have been described since ~1980 were built with his computer graphics programs. His arrival coincided with the period of close cooperation between the two groups.

Brändén initiated structural investigations on alcohol dehydrogenase in the mid-1960's. He also solved the structure of a thioredoxin and a glutaredoxin. Hans Eklund participated in these projects and then formed an independent group which has mainly studied the enzyme ribonucleotide reductase. Brändén became interested in plant enzymes and initiated projects on the enzymes glycolate oxidase and ribulose-1,5-bisphosphate carboxylase/oxygenase. In this research Ylva Lindqvist, Gunter Schneider, Inger Andersson and Stefan Knight played important roles. These investigators have later formed their own groups which have continued these projects and started new ones. The Uppsala structural community has a healthy tradition of early scientific independence and of recruitment from outside Sweden. In 1990, Sherry Mowbray moved her laboratory to Uppsala from a Howard Hughes position at UTSW, Dallas. Her research interests are the molecular basis of chemotaxis, transport and signal transduction. More recently, structural biology at Uppsala University has been further strengthened by a new group, headed by Janos Hajdu who has taken up a Chair at the Department of Biochemistry.

The transfer of scientists trained in Uppsala to other laboratories in Sweden had a slow start, but has accelerated rapidly in the last 10 years. Besides the move of Anders Liljas to Lund at the end of the 1980's, four scientists of the Pharmacia Structural Biology group were trained in Uppsala. Another former student, Pär Nordlund, has recently started a group at Stockholm University. At the Karolinska Institute's Huddinge campus, a new crystallographic group was set up in 1991, led by Rudolf Ladenstein from Huber's laboratory. Another group has since been set up at the Solna campus, under the direction of Gunter Schneider who has been joined by Ylva Lindqvist. Lennart Sjölin at Gothenburg University set up a small group in the 1980's to study protein structures with a particular interest in neutron diffraction and electron transfer. The newest group to be set up is at Umeå University (UmU) where another former Uppsala student, Elisabeth Eriksson, has started this Summer. Crystallography in Sweden, therefore, has followed the expansion seen elsewhere (especially the USA) albeit with a delay of ~5 years.

The potential of NMR spectroscopy was recognised early on in Sweden, and the first two instruments were installed in 1957. Around 1970, Forsén and his co-workers at Lund University became engaged in studies of quadrupolar nuclei, and these endeavours gradually became the port of entry into biological systems, phospholipid membranes and proteins. Around 1980, the work in Lund had largely become focused on the structure and function of calcium-binding proteins of the calmodulin superfamily. After the seminal papers of Wüthrich and co-workers on the determination of solution structures by 2D NMR methods, the lack of suitable equipment forced a search for international collaborations. An important benefit from this period is that most Swedish biologically-oriented NMR spectroscopists now have close links with many international NMR laboratories. Torleif Härd spent time with Robert Kaptein in Utrecht, returning to set up his own group at the Karolinska Institute in Huddinge in 1991. He has recently accepted a Chair at KTH, but remains based at KI. Around 1990, the first generation of modern 500 MHz spectrometers were installed in Swedish universities (Lund, Uppsala, Umeå, Gothenburg and Stockholm). In 1992, the arrival of Gottfried Otting from Wüthrich's laboratory to the Karolinska Institute in Solna further strengthened Sweden's NMR competence.

As a result of a donation from the Swedish Tobacco Company, the Swedish NMR Centre (SNC) was set up in Stockholm in 1992. From the spring of 1997, the Centre will be located at a new site at Gothenburg University. A recent donation from the Wallenberg Foundation has allowed the purchase of the first 800 MHz machine in Sweden. The NMR Centre is, and has been, an important resource for the whole biologically-oriented NMR community in Sweden.

2.3 Analysis of strengths and weaknesses today

2.3.1 Challenges for the future

Structural Biology research has become a central tool in most biological research areas. The main reason for this is the fact that the techniques allow for the determination of atomic resolution structures of relevant biomolecules. These structures often reveal key features that explain the biological response in chemical terms. In addition to an increased knowledge, such understanding has the potential to generate a vast number of industrial applications, e.g. in rational drug design for the pharmaceutical industry.

Today, Structural Biology is a strong field in Sweden. However, there are a number of challenges in the next ten years to strengthen the strategic value of structural biological research in Sweden, both within the national research environment and in society:

  1. Most importantly, the atomic-resolution techniques must strengthen their interfaces to the various national research programmes in biology. Typically, it takes from months to years to solve atomic-resolution structures. Therefore, all such efforts must be considered early in strategic research programmes, and relevant molecules must be produced and purified. The Swedish Structural Biology Network will attempt to create organised connections with other national biology research networks, institutes and centres (see section 2.7). In addition, the Structural Biology groups (both in protein crystallography and NMR spectroscopy) must build their own support groups for the production of recombinant proteins. In this way, the necessary production and purification of gene products that are targets for structural analysis can be carried out near the structural groups. Unfortunately, sufficient funding has been granted for only one expression centre, at Uppsala.
  2. Another challenge is to transfer Structural Biology technology and trained personnel to relevant applications in the industrial sector. To date, only corporations in Sweden with pharmaceutical interests are utilising Structural Biology techniques in-house (Pharmacia and the branch of Astra that was formerly Symbicom). The needs of the pharmaceutical industry will expand, and in the future, we predict, many more applications linked to biotechnology will find new use for macromolecular structures, e.g. in improving enzymes for the paper industry, in ligand design for different diagnostic purposes, and in the food industry.
  3. A third challenge is to strengthen the technology platform in Structural Biology; to maintain and further improve the technological and methodological strongholds that exist in the field in Sweden today, to spread state-of-the-art techniques to the smaller groups, and to develop leading-edge technologies in new areas that are considered to be important for biology and industry, such as structural analysis of membrane-spanning proteins.
These challenges are addressed in the present Programme in Structural Biology.

2.3.2 Protein crystallography

The major stronghold consists of the combined groups of Uppsala University and the Swedish University of Agricultural Sciences. Taken separately, the Uppsala groups are much smaller than the best American groups. This follows, in part, from the traditions and form of the Swedish granting system and the large increase in funding for Structural Biology in the USA from the Howard Hughes Foundation. Taken together, however, Uppsala is a centre of excellence within Europe, and in some areas is unique. The main weaknesses we perceive are a lack of access to the latest protein-expression systems, lack of expertise in studying integral membrane proteins, and the lack of in-house NMR expertise. The latter problem cannot be remedied in the context of this Programme. The first two shortcomings, as well as the issue of size, will be addressed, however.

On a smaller scale, the group at Lund also operates at an internationally competitive level. The opening of a dedicated beamline at the MAX II synchrotron in Lund will be very beneficial for maintaining this position. At the present time, there is a severe shortage of synchrotron radiation beam time in Europe. Access to much larger periods of beam time will, therefore, be a major advantage for Swedish groups. This will require the purchase of suitable area-detector equipment and suitable computers to process the data from other sources. This beamline may not be suitable for multi-wavelength anomalous dispersion (MAD) phasing (developed by Wayne Hendrickson and co-workers), but fortunately a dedicated MAD beamline (BL19) is being developed at ESRF, Grenoble. We plan to develop expertise in this new phasing method by organising workshops within the Network.

The structural group around Schneider and Lindqvist is a self-contained unit of international class. The drawbacks they will encounter caused by leaving the Uppsala environment will be met by the close interactions that we intend to foster within the Network. Structural Biology is a recent enterprise at Stockholm University, but it has had an excellent start. This group, the one in Gothenburg, the one at KI Huddinge, and the one being set up in Umeå around Elisabeth Eriksson are small and they will, therefore, greatly benefit from interactions within the Network.

2.3.3 Protein NMR

Biomolecular NMR spectroscopy is a much younger technique, but nevertheless there are at least two groups in Sweden who are able to compete at the highest international level (at Lund University and the Karolinska Institute).

A major limitation to the NMR structural work has been the virtual absence of dedicated laboratories for protein expression and isotopic labelling. Isotope labelling of proteins (uniform as well as specific, with 15N and 13C) has become an indispensable technique in NMR spectroscopy, for the structure determination of larger proteins, for studies of large protein complexes, and for studies of protein dynamics. Specific labelling may require the use of specifically labelled amino acids, as well as auxotrophic strains of the producing micro-organism. Whereas several prokaryotic expression systems presently are well documented and adequate for the production of a large body of proteins, they are unsuitable for the production of glycosylated eukaryotic proteins or proteins with post-translationally modified amino acids.

Experience from a large number of biophysical laboratories involved in structure-function studies of proteins strongly indicate that expression and labelling facilities should be closely integrated with the research activities. Again, it has been the hard-learned lesson in many biophysical laboratories that samples delivered to the laboratory have been far from suitable for NMR studies. We have argued that funds be allocated to support expression/preparation facilities at both the Karolinska Institute and Lund University, but this has been ignored. We still believe that extra resources are needed within this area.

2.4 Philosophy, objectives and strategy

2.4.1 Philosophy

The Board considers the best approach is to reinforce groups with a proven track record by injecting extra funds without requiring an initial major realignment of their research efforts. This may be best described as supporting curiosity research in areas of strategic interest. Of course, a precondition is that there are excellent groups already; if not, one would have to try and attract researchers from elsewhere. These groups must also commit themselves to making methodological contributions to their field, and to disseminating knowledge and expertise to other research groups in the country.

Simultaneously, graduate education will be improved substantially in order to guarantee continuity in the future. The national Structural Biology Network will organise courses for all Swedish graduates in particular areas of Structural Biology (with foreign as well as Swedish tutors), and an annual conference at which the students will be able to present and defend their work.

2.4.2 Objectives of the Programme

The main objective of the Programme is to guarantee a continued world-class status for Swedish Structural Biology research. The area has become exponentially more important in the past decade, both because of basic scientific interest and curiosity, and because of the many potential industrial applications.

The transfer of Structural Biology from an area of academic interest to a field with important commercial applications is now far advanced in Europe, Japan and the USA. Foreign industry has relied almost totally on academia to produce their structural biologists. Many of the new industrial laboratories are competitive at the very highest international level, and they are an active part of the Structural Biology community. Swedish industry lags behind most developed countries by at least 5 years in the build-up of their structural groups. Two Swedish companies have invested in setting up their own structural groups to date. The Astra division that was formerly Symbicom, has a fully equipped X-ray laboratory, which was originally close to the Biomedical Centre in Uppsala, but has since been moved to Gothenburg. It has had and continues to have a close interaction with the academic groups. Pharmacia has more recently invested in both an X-ray and an NMR group. A large part of this group was educated in either Uppsala (Lundqvist, Sundström, Kraulis, Ogg) or Lund (Kördel). We expect this trend to continue with a transfer of well-trained structural biologists from academia to industry. We will encourage industrial groups to take an active part in the setting up and running of the Network.

We plan to strengthen our curiosity research in the following strategic areas: membrane proteins, receptor-ligand interaction, protein design, development of computational methods to study enzyme catalysis and drug design. This should be of major interest to the pharmaceutical industry and to those involved in the industrial applications of enzymes.

After the startup phase of the Network, extra weight will be given to support projects working in areas of supreme strategic relevance, such as integral membrane proteins, structures of great medical interest, and drug design (both theoretical developments and in practice)

2.4.3 Suggested strategy

The Board proposes to follow a four-tiered approach to reach its objective:

2.5 Summary of the Programme

2.6 Expected results and spinoffs

The Programme is expected to produce results of high scientific interest and quality that will be published in the leading scientific journals. Some of the results that we expect to obtain will be of immediate interest to the Swedish pharmaceutical industry. However, the most important impact on industry will be the transfer of state-of-the-art techniques from the academic groups to industrial participants in the Network. Short-term benefits of the proposed Programme include:

In a longer time perspective, the Programme is expected to have the following impact:

2.7 Interactions with other programmes

Structural Biology research has become central in most biological research efforts world-wide. Structural information can be used to explain detailed biological mechanisms at the atomic level. Therefore, we suggest that the Structural Biology Programme will be directly interfaced to other Strategic Research Foundation programmes. In a sense, in the Structural Biology Programme we are suggesting a strategic programme to make structural techniques nationally available. We are confident that this Programme will have a major impact on all biological programmes supported by the Strategic Research Foundation. To realise this, we suggest to create an active forum of scientists that meets regularly under the Strategic Research Foundation umbrella, and that this forum will be launched once the funded programmes have been decided. The proposed interface between this and the other programmes would in practice serve to define key molecules that could be targets of structural analysis, and to make firm plans as to how to express, purify and structurally analyse these molecules.

2.8 Interactions with industry

Many of the Structural Biology groups are already involved in projects that interact with industrial partners. At the present time, most of these interactions are with companies from outside Sweden.

In Uppsala, Jones has set up a small company to market computer graphics and other computer programs that are of interest to structural biologists. These programs are used by more than 30 companies world-wide, but particularly close interactions have been maintained with the Pharmacia-Upjohn group. Via EU-supported projects, he is involved in structural work on epoxide hydrolases with collaborators from Rhone-Poulenc (France) and DSM Research (the Netherlands), and on cellulases with collaborators from Primalco (Finland). Unge at UU has a close collaboration with Medovir to study HIV proteases.

In Lund, A. Liljas has a collaboration with Pharmacia on structural studies on superantigens. It is expected that the structural groups from both Pharmacia and Astra will be users of the X-ray station at the synchrotron. Forsén's industrial connections are mostly with Novo Nordisk.

At KI Huddinge, both Nilsson and Härd have close ties with KaroBio, mostly concerning modelling of nuclear receptors. At KI Solna, the closest ties of Scheider and Lindqvist are with Du Pont, USA. Otting also has a number of collaborations with European firms, Hoffman La Roche (Switzerland), and via an EU grant MorphoSys (BRD).

We expect interactions with Swedish industry to improve within this Network. This will initially take the form of knowledge transfer within the educational porgrammes that are planned. We will also be open to joint research proposals involving academic and industrial groups.

3. Swedish Structural Biology Network

3.1 Organisation

The organisation structure of the Programme is outlined in the following scheme:

The Network is run under the direction of a Programme Board with the following members:

Uppsala University is the "host authority"; the Chairman of the Board has established and maintains contact with both the Rektor at UU and with the SRF. Now that the Programme is up and running, it is estimated that the Board needs to meet only once or twice a year. The Programme Director chairs the Network Council. This Council initially consists of all Principal Investigators (PIs) who were recommended for support in the original Programme Proposal. A PI is defined as a person with responsibility for other scientists (in practice in the Swedish system, this means a "Lektor" or Professor). A list of Network Council members is included in Appendix II.

All PIs funded within the Network automatically become members of the Council. In addition, the Board can appoint PIs to the Council at its own discretion. The Network Council has the following tasks and responsibilities:

Participation in the Graduate Courses and the Annual Conference is a matter for the entire Network, i.e. the assembly of all Swedish structural biology PIs and students who wish to participate. All PIs have direct access to the Board (e.g. , in case of disputes) without having to proceed via the Director. The Annual Conference will be organised along the lines of a Gordon Conference, where all interested scientists are welcome (other SRF programmes, industry, other Nordic countries). Organisation of the Graduate Courses and the Annual Conference is the responsibility of the Programme Director, and will be managed by the "Network Coordinator" (with secretarial assistance).

3.2 Funding

Because of the reduction in the size of the budget from that suggested in the original Programme Proposal, support within the Network does not include funding for equipment. The salary associated with each position is shown in the Network Budget in Appendix I, and is based on NFR and Uppsala University norms. Each student, research assistant, researcher, and lecturer supported by the Network has the same consumables budget (50 kSEK p.a. plus overhead costs). Each student and researcher position is funded for a period of 2+2 years. After the first two years, a detailed account of the research must be presented to the Board before funding for the second two-year period is granted. Each person and PI funded by the Network is committed to take part in conferences and courses organised by the Network.

Funds have been allocated as directed in the Initial Contract in Structural Biology to cover resources for education in the form of courses, an annual conference, travel grants, administration, trips to MAX/SNC and the expression laboratory at the Departments of Molecular Biology in Uppsala. These are itemised in the detailed budget in Appendix I. We have allocated more than the 10% suggested as a renewal fund. This will be allocated in rounds 3 and 4 of the Network for funding from January 1997 and 1998, respectively.

Allocation of funding within the Network has been organised in a series of proposal rounds. At its first meeting on 20 January, 1996, the Board awarded 8 student positions to the following PIs and projects:

For Schneider/Lindqvist and Jones/Mowbray responsibilities for the student position are shared by the PIs. The Jones/Mowbray student is registered at UU.

Tranche 2 applications were by invitation, based on all PIs in the original Programme Proposal. After scientific evaluation, 5 student and 4 researcher positions were allocated to the following projects:

The researcher position, under Liljas' guidance in Lund, will devote roughly half of the time to user support at the macromolecular data-collection station being developed at the MAX II synchrotron. The unspecified researcher position at Uppsala will be allocated to a young independent scientist to set up his/her own research project in a strategic area of structural biology.

In the first two rounds of funding, the allocations have been made to Sweden's world-class structural biologists who have been carrying out independent work in Sweden for a number of years. Because of the continued expansion of the field in Sweden, we have restricted the tranche 2 allocations to just half of the projects outlined in the original Programme Proposal. This allows us to broaden our options in the third and fourth tranche calls.

Our budget estimate at the level of funding indicated by the Strategic Research Foundation, allows us to fund a further 4 student positions from January, 1997. In this third tranche, new applications will be encouraged in the most strategic areas of structural biology, in particular integral membrane and receptor proteins, drug design and structures of high medical relevance. The fourth and final tranche of the first five year Programme, will comprise 3 new student positions to be funded from January, 1998.

To even out the cash-flow, we request that the 1998 and 1999 funds each be increased by 1 MSEK while those for the year 2000 be reduced by 2 MSEK.

3.3 Education and courses

The Swedish Structural Biology Network will improve and broaden the level of training of Swedish graduate students. The Network is open to any academic or industrial structural group that wishes to join. The major educational purpose of the Network is to organise advanced graduate courses at the highest level, where necessary by inviting international speakers. Each course will take ~1-2 weeks and will involve theory, exercises and practicals where appropriate. Each course will be given according to a 3 year rolling schedule. If ~40-50 students were to take part in each course, then every Swedish graduate student would be able to participate once in each course during his or her graduate period. Since the courses will be given for students from different sub-disciplines, the potential for cross-fertilisation (e.g. , between X-ray and NMR students) is large, something which is missing in present-day graduate education. In 1997, we plan to organise basic courses on crystallography and NMR. The crystallography course will be modelled on EMBO courses previously organised by the Uppsala groups.

Smaller courses, lasting only 2-3 days and aimed at a more specialised audience, will also be supported. In the first year, we plan a course on MAD phasing, and another on the derivation of NMR structures from experimental data.

We expect to organise 2 large and 2-3 small courses each year. Once a year, the Network will also organise a graduate conference. The format of these conferences will be modelled on the Gordon Conferences, i.e. with 3-4 invited foreign speakers and all other lectures exclusively by the students. PIs will not give lectures, but they are expected to question the students after the lectures and during poster sessions, thereby training them to defend their work. In addition, the conference provides an opportunity for the Programme Board to meet with the PIs of all Swedish groups that participate in the Network. Finally, each student who is funded by the Programme will be assigned two mentors from other institutions. The annual conference provides an opportunity for the students to meet with their mentors and to discuss their progress and plans. Travel grants will be available for workers within the research Programme to allow for working visits to other laboratories, both in and outside Sweden. Applications are to be made to the Board of the Network.

4. Miscellaneous issues

Appendix I

Proposed budget 1996-2000

Appendix II

Network Council members

SBNet Latest update at 12 February, 1998.