SBNet -Mid-term Evaluation Report

Abbreviations.

KI, Karolinska Institute
KTH, Royal Institute of Technology
KVA, Royal Academy of Sciences
LU, Lund University
SBNet, Structural Biology Network
SLU, Swedish University of Agricultural Sciences
SSF, Swedish Foundation for Strategic Research
SU, Stockholm University
UmU, Umeå University
UU, Uppsala University

1. Background, objectives, and organisation.

1.1. Structural Biology.
Structural Biology is defined here as the area of scientific enterprise which aims to elucidate the three-dimensional structural 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 are of benefit in many different areas, ranging from medical and pharmaceutical science, to forestry and plant technology. In the context of this report, Structural Biology is taken to include:
* biomolecular X-ray crystallography,
* biomolecular NMR spectroscopy,
* near-atomic resolution electron crystallography,
* molecular modelling.
Structural Biology was born in Cambridge, England, in the 1950's when 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 expanded interest are obvious. The atomic structure of a macromolecule is the skeleton upon which its biological function rests. Without detailed knowledge of the structure, we are limited in our understanding of the biological processes and events the molecule brings about or participates in.
The methods that were developed in the 1950's and 1960's for the phasing of the crystallographic diffraction data are still in use today. Modern Structural Biology is a merging of different disciplines, which have greatly developed in the past fifteen years. X-ray crystallography has been the principal source of three-dimensional structural information. The time required to solve the crystal 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 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 simple and rapid, yet sophisticated manipulation of macromolecular structures.
In the last fifteen years, multi-dimensional nuclear magnetic resonance (NMR) spectroscopy has developed into an alternative to X-ray crystallography, at least for molecules and complexes into the 30 kDa range, with suitable solubility properties. In addition, NMR spectroscopy allows the study of dynamic properties of molecules, and the technique is well suited for probing interactions between molecules.
However, the 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, to help us understand biological function, and (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 biomacromolecular structures is mandatory for a successful design experiment.

1.2. History 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 (UU) 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 last 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 on this line since his move to Lund University (LU) in 1987. Lars Liljas has continued the virus research and solved the MS2 and other virus structures. 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 development, and nearly all crystallographic models that have been described since ~1980 have been built with his computer graphics programs. His arrival coincided with the period of close cooperation between the two Uppsala 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. Several structures have been solved by Lindqvist and Schneider in the last few years.
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.
The transfer of scientists trained in Uppsala to other laboratories in Sweden had a slow start, but has accelerated rapidly in the past 10 years. Besides the move of Anders Liljas to Lund at the end of the 1980's, three of the original Pharmacia Structural Biology group were trained in Uppsala, and this recruitment trend has continued. Another former student, Pär Nordlund, has started a successful 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 been set up at the Solna campus, under the direction of Schneider and Lindqvist. Lennart Sjölin at Göteborg University set up a small group in the 1980's to study protein structures with a particular interest in neutron diffraction and electron transfer. 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. By around 1990, the first generation of modern 500 MHz spectrometers were installed in Swedish universities (Lund, Uppsala, Umeå, Göteborg 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. The Centre originally had a 500 and a 600 MHz NMR spectrometer, and 50 % of the machine time was made available to university scientists. Until the end of 1996, the operating costs were covered by Pharmacia. The NMR Centre is, and has been, an important resource for the whole biologically oriented NMR community in Sweden.
The situation as described above was essentially the one that existed in the autumn of 1994, when the original proposal to fund a Structural Biology Network was prepared for the Foundation for Strategic Research. Since then, structural biology has expanded even faster than could be foreseen at that time:
* Astra has set up a Structural Chemistry Laboratory, under the direction of Jan Hoflack, and employing a number of outstanding young structural biologists (e.g., Tomas Lundqvist, Karl Hård, Anders Åberg);
* the Swedish NMR Centre has moved to Göteborg, acquired a new 800 MHz spectrometer, and an excellent foreign candidate, Martin Billeter from Wüthrich's laboratory, has been selected for a new professorship in the area;
* the MAX II synchrotron in Lund has come on-line, and Anders Liljas and Anders Svensson supervise the protein crystallography facilities there;
* the combined groups of Schneider and Lindqvist moved from Uppsala to the Karolinska Institute's Solna campus;
* Janos Hajdu moved his group from Oxford to the Department of Biochemistry in Uppsala. In his new laboratory, So Iwata, a former post-doc of Hartmut Michel, has set up a unique facility for membrane protein crystallography;
* several other new professorships were instituted (in NMR spectroscopy: Sybren Wijmenga in Umeå, Torleif Härd at KTH; in crystallography: Pär Nordlund at Stockholm University, and Inger Andersson at SLU);
* Elisabeth Sauer-Eriksson has set up a small crystallography laboratory in Umeå, together with Uwe Sauer;
* through the Structural Biology Network and other granting agencies, several young people have been enabled to initiate their own independent research endeavours in the context of existing centres (e.g., Bryan Finn and Mikael Akke in NMR in Lund; Stefan Knight, Jerry Ståhlberg and Gerard Kleywegt in crystallography in Uppsala).
In this ever expanding field, the Structural Biology Network has been able to provide a significant impetus (through new student and researcher positions). In addition, the Network functions as the "cement" that links the entire Swedish structural biology community.

1.3. Structural Biology Network.
In 1994, a committee consisting of Alwyn Jones, Björn Nilsson, Torleif Härd, Sture Forsén, Hans Eklund, and Gerard Kleywegt (scientific secretary) was invited by the Foundation for Strategic Research to prepare a proposal for a strategic programme in Structural Biology. The committee identified the following challenges for this field of scientific endeavour:
"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 proposed Swedish Structural Biology Network must be utilised in part to create organised connections with other national biology research networks, institutes and centres. 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.
2. Another challenge will be 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 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 future challenge will be 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."
The committee suggested that a Structural Biology Network be initiated to address these challenges, with the following objectives:
"The committee feels that the main objective of its proposed programme should be 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 transition 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 levels and 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. Symbicom has a fully equipped X-ray laboratory close to the Biomedical Centre in Uppsala, and there is 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 trained in either Uppsala (Lundqvist, Sundström, Kraulis) or Lund (Kördel). We expect this trend to continue with a transfer of educated 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."
The committee proposed to follow a four-tiered approach to reach its objective:
"* reinforcement of excellent research groups. These are groups with proven track records at the highest international level, adequate infra-structure, not dependent on a single excellent person, and firmly embedded in an academic setting.
* new efforts to try and remedy perceived current weaknesses. This means in particular, that each of the top groups should get a dedicated laboratory for protein expression and (in the case of NMR) for the labelling of proteins.
* to improve graduate student training in Structural Biology to bring it to a world-class level. This can be implemented through a Swedish Structural Biology Network. All research groups would be encouraged to join this Network, so that as many students as possible may benefit from it. The programme must be flexible enough to respond to changes in the quality landscape of Swedish Structural Biology, and to reward new initiatives which are perceived to be (or become) excellent. We will strive to ensure a close interaction with other Networks supported by the Strategic Research Foundation that will result in new structural projects.
* to stimulate contacts with industry to facilitate the knowledge transfer that is needed to keep Swedish companies on an equal footing with their foreign competitors."
An application was submitted to the Foundation, and it received favourable reviews from a committee of foreign experts (Profs. J. Drenth, G.G. Dodson, and I.D. Campbell), and was subsequently endorsed by the Foundation. Despite this, the level of funding tentatively allocated by the Foundation amounted to only ~2/3 of the level originally requested. This meant essentially that no equipment could be funded, and that only Uppsala received funds for a dedicated expression facility.

1.4. Start-up process.
The process of getting the Network up and running has essentially lasted from Summer 1995 (when the Network was adopted by the Foundation) until Summer 1997 (when the Network Coordinator could finally be appointed). This was due to some extent to the fact that the Network was the first initiative to receive funding from the Foundation, and in many respects served as a guinea-pig with respect to the development of procedures, contracts, policies, etc. Thanks to the fact that the Board and Programme Director were in place from the beginning, and the fact that Gerard Kleywegt was found willing to sacrifice some of his time to assume the task of pro deo coordinator ad interim, many of the essential aspects of the Network's operation could be implemented without significant delays (allocation of funding, web site, first conference, mailing list, etc.).

1.5. Organisation of the Network.
Early in 1997, Prof. Uli Hacksell (Astra Draco, Göteborg) announced that his increased workload made it impossible for him to stay on as a member of the SBNet Board. In his place, Dr. Jan Hoflack (head of structural biology research at Astra SCL, Mölndal) was co-opted. The other Board members stayed on: Dr. Björn O. Nilsson (at the time head of structural biology research at Pharmacia & Upjohn; currently director of research at Amersham Pharmacia Biotech; Chair), Prof. Guy G. Dodson, F.R.S. (University of York), and Prof. Iain D. Campbell, F.R.S. (University of Oxford). The Programme Director, Prof. T. Alwyn Jones, F.R.S. (Uppsala University), continued to function as a non-voting qualitate qua member of the Board. The main responsibilities of the Board involve strategic directions, finances, and peer-review. The Board met twice during 1997 (in February in Windsor, and in December in London); in the future, it will continue to meet twice a year, once during the Annual SBNet Conference (in Sweden), and once in the Winter (in the U.K., if possible). Important matters that arise in between meetings are dealt with by means of electronic mail or telephone conversations. Matters involving the day-to-day running of the Network are handled by the Chair, Director, and Coordinator.
The position of Network Coordinator was advertised in the Spring of 1997 (until that time, Dr. Gerard J. Kleywegt, UU, had acted as ad interim Coordinator). Three applications for this position were received. They were reviewed by the Chair, and he recommended that Dr. Kleywegt be appointed. Unfortunately, Uppsala University has been unwilling to promise to take over this position after SSF funding ceases. Hence, the position is one as "forskare" rather than "lektor", despite the fact that the Coordinator possesses both "lektorskompetens" and "professorskompetens".

1.6. Allocation of funds.
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. The Network has allocated substantially more than the 10% originally suggested as a renewal fund. This has been allocated in application rounds 3 and 4 of the Network.
Allocation of funding within the Network has been organised in a series of application rounds ("tranches"). At its first meeting on 20 January, 1996, the Board awarded eight student positions to the following PIs and projects:
* Schneider/Lindqvist (KI): Protein Secretion.
* Otting (KI): Expression and NMR analysis of triply-labelled proteins.
* Härd (KI): Protein-protein interactions: structural studies of Bruton's Tyrosine Kinase
* A. Liljas (Lund): Ribosomal proteins and factors.
* Forsén (Lund): Initiation of blood coagulation: interaction between Factor VII and Tissue Factor and the role of non-catalytic domains.
* Jones/Mowbray (UU/SLU): Structural studies on the Platelet-Derived Growth Factor Receptor and its complex with Platelet-Derived Growth Factor.
* Eklund (SLU): Ribonucleotide Reductase holoenzyme complexes.
* L. Liljas (UU): Structure of viruses and viral components.
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 by the Board, 5 student and 4 researcher positions were allocated to the following projects:
* Lindqvist/Schneider (KI), student: Time-resolved crystallographic studies of an ATP-dependent carboxylase: dethiobiotin synthetase.
* Härd (KI), student: Protein-DNA interactions: structural and biophysical studies of runt homology domains.
* Hebert (KI), student: Structural studies on microsomal glutathione transferase by electron microscopy.
* A. Liljas (Lund), researcher: Crystallography at MAX II.
* Forsén (Lund) researcher: Experimental studies of biomolecular dynamics by NMR spectroscopy.
* Nordlund (SU), student: Structural studies on protein phosphatases.
* Mowbray/Jones (SLU/UU), researcher: Structural studies on Membrane Protein Receptors.
* Åqvist (UU), student: Computational approaches to structure-based drug design and enzyme catalysis.
* Unspecified PI (UU/SLU), researcher: Strategic research in Structural Biology.
The researcher position, under Liljas' guidance in Lund, devotes roughly half of the time to user support at the macromolecular data-collection station at the MAX II synchrotron. The unspecified researcher position at Uppsala was to be allocated to a young independent scientist to set up his/her own research project in a strategic area of structural biology. After advertising the position, Dr. Stefan Knight was judged to be the best candidate.
In the first two rounds of funding, the allocations were 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 allowed us to broaden our options in the third and fourth tranches.
During 1997, the Board allocated the remaining seven student positions (these constituted the "contingency fund" of the original proposal). This process took place in two rounds, for both of which open calls for applications were issued. For tranche 3 (four positions), the Board decided that preference should be given to proposals that were based on a multidisciplinary approach and/or involved a collaboration with industrial or other laboratories. In addition, the Board decided to set priorities in four strategic research areas, namely integral membrane and receptor proteins, drug design, structures of high medical relevance, and methods development (in any of the areas of structural biology). Twenty proposals were received and reviewed by the Board (excluding the Director). After this process, the following four proposals were selected for funding:
- Dr. Holland Cheng (KI): Structural Studies on Virus-Host Interactions.
- Dr. So Iwata (UU): Structural studies of human multidrug resistance protein (MDR) and multidrug resistance-associated protein (MRP).
- Dr. Gerard J. Kleywegt (UU): Crystallographic studies of monoamine oxidase, a drug target in the treatment of clinical depression and Parkinson's disease.
- Prof. Sybren S. Wijmenga (UmU): Development of Methods for Improved Structure Determination of Larger Systems by means of NMR.
For tranche 4 (three positions), the quality of the applications, as determined by their scores in the peer-review process, was the most important overall criterion. In case of equal scores, PIs that were not already funded by the Network were to be prioritised. Proposals that involved collaboration with another network or programme funded by the Foundation for Strategic Research were viewed upon favourably. A total of 25, often excellent, applications was received, many more than there were positions available. After a difficult review process, the Board decided to award the student positions to:
- Dr. Jerry Ståhlberg (SLU): Structural studies of cellulases and other enzymes with potential for use in the cellulose industry and bio-organic synthesis.
- Dr. Mikael Akke (LU): Protein structural dynamics, interactions, and drug design.
- Dr. Stefan Knight (SLU): Structure/function studies of virulence associated adhesion organelles from pathogenic Gram negative bacteria.
In retrospect, essentially all seven "contingency fund" positions have been awarded to young and talented people who were not operating independently (in Sweden) at the time of writing of the original proposal. It can therefore be concluded that the idea of having a contingency fund was an excellent one, and that it worked extremely well in practice to foster new efforts by young and promising scientists.

2. Research within the programme.

2.1. Participating researchers.
Scientists who have received funding through the Network are listed in section 1.6. However, the Network attempts to unite all Swedish structural biologists and, hence, the number of participants in the Network is considerably larger. A listing of PI-level scientists involved in the Network is included as Appendix I.
SBNet funds the position of 27 structural biologists in Sweden, which constitutes a significant fraction of the academic community (~15%). Appendix II contains a list of all positions and the PIs to whom they have been allocated, as well as a research report over 1997 for each. Seven positions have not been filled yet. Of the remaining 20 positions, 9 are taken up by females (45%). Twenty positions are student positions (74%), and four are researcher positions (15%). Two of the remaining three positions have been allocated to the Uppsala expression laboratory, and the final position is that of the Network Coordinator.
In terms of disciplines, 15 positions are related to X-ray crystallography, 7 to NMR, 2 to electron microscopy, one to modelling, and two to the expression laboratory. In terms of geographical spread, LU and SLU have each been awarded 3 student and 2 researcher positions, KI and UU both have 5 student positions, KTH has 2 student positions, and SU and UmU each have one student position. The Network Coordinator and the expression laboratory personnel all reside administratively at Uppsala University.

2.2. Scientific results.
Since most students and researchers employed through the Network have only been working for at most a year and a half, the total number of publications is still small. However, we rapidly expect this to change during 1998 and 1999. Concise scientific reports for the year 1997 from all of the supported scientists and students have been collected in Appendix II.

2.3. Future research plans.
Regrettably, the Network funds for supporting new research efforts have now been exhausted, precluding further commitments. However, the Board would like to point out that the quality of many of the proposals that had to be rejected in the various allocation rounds due to limited funds was excellent. Many more proposals could have been funded from a purely scientific point of view without compromising the quality constraints on the programme. The major task for the remainder of the first five-year period is to follow-up supported students, and to organise activities to strengthen the national network. Given the success of this programme and the importance of the Structural Biology area, we are convinced that the Network ought to continue beyond the first five years. In a second mandate period, it will be important to identify further areas of strategic importance. One such area could be the link between Structural Biology and Bioinformatics, where a systematic structure determination of unknown folds ("high-throughput structural biology") will have a major impact on the structural annotation of novel gene sequences.

2.4. Relevance of the research programme.
Structural Biology has an intrinsic high visibility in the bioscience area because of its unique importance in explaining biological mechanisms at the atomic level. This programme in structural biology drives research in Sweden to the frontiers of modern biology. In the short term, the benefits to industry and society lie in the strengthening of the academic competence, and its dissemination from the more prominent laboratories to the smaller and newer ones, both in academia and in industry. These laboratories are kept at the forefront of developments through the Network's courses and its annual conference. In the longer term, the broad reservoir of top-notch structural biologists that is being built up will function as a primary recruitment pool for further expansion and novel initiatives in structural biology, both in academia and in industry. In addition, many of the PhDs being trained in the Network at present will make excellent candidates for positions in related areas, such as structure-based drug design and bioinformatics.

2.5. Interdisciplinarity.
Structural biology is an inherently multidisciplinary area of science, in which biology, chemistry, physics, computer science, and information technology coexist in a symbiotic and synergistic relationship. The Network will monitor relevant developments in related areas, and, where this is deemed opportune, undertake initiatives to bring such developments to the attention of the structural biology community. For instance, at the second annual conference of the Network in May, 1998, one session will be devoted to the field of bioinformatics.

2.6. Quality control.
The quality of the research carried out with Network funding is monitored in various ways. The student and researcher positions were allocated in a process involving applications and peer review by the industrial and foreign members of the Board. All students and researchers funded by the Network submit an annual report of their activities. These reports (Appendix II) are scrutinised by the Board, and will be published on the SBNet Web site. Further, the progress of students is assessed at least once a year through the mentor mechanism. Finally, all students present a poster or lecture at the annual conference of the Network, which represents an informal, but public review-type process.

3. Graduate training within the programme.

3.1. Recruitment of Ph.D. students.
For the first round of student position allocations, a joint advertisement was published in the journal Nature. However, this approach had some disadvantages, so that for subsequent rounds the advertising was left to the individual PIs.

3.2. Organisation of graduate training.
There have been several developments in this area involving the Network in 1997:
* One of the first noticeable effects of the Network coming into operation has been the fact that people at the various institutes have begun to open their local courses to students from other institutes. For example, several students from Stockholm and Umeå participated in the Biomolecular Structures course in Uppsala, and students from Uppsala attended a course on enzyme structure and function in Stockholm. Currently, several such courses are regularly advertised through the SBNet WWW site and the SBNet mailing list.
* KVA awarded the 1997 Aminoff Prize to Prof. Wayne A. Hendrickson (Columbia University). After the ceremony and symposium in Stockholm, the Network (through Prof. T. Alwyn Jones) organised a short course on the MAD technique. The course was held in Uppsala, and included lectures and computer practicals. Speakers included Dr. Janet L. Smith, Dr. Gérard Bricogne, Dr. Venki Ramakrishnan, Dr. Craig Ogata and Dr. Eric de la Fortelle.
* A course in NMR spectroscopy organised in Göteborg was co-sponsored by the Network.
For 1998, a one-week graduate course on "Protein Structure & Analysis" has been planned (22-26 June; organiser G.J. Kleywegt), as well as a course on "Macromolecular Crystallisation" (16-25 September; organiser T. Bergfors). In both courses, top foreign experts, complemented with national and local ones, will ensure that the teaching level will be state-of-the-art, in keeping with the original goal of the Network's graduate training programme. In addition, there are plans to organise a workshop on drug design in collaboration with some of the industrial Network participants.
There are also more subtle aspects to the graduate training programme. For instance, during the student-mentor meetings, students have to present their work face-to-face with expert structural biologists. Similarly, all students who attend the annual national conference of the Network present either a poster or give a talk on their work. Student who are awarded a foreign travel award, have to write a report that is published on the Network's web site.

3.3. Mentor system.
For the students who are funded through the first two allocation rounds, a mentor system was set up in 1997. The idea of the mentor system is to assign two mentors to each student funded through the Network. Student and mentors meet at least once a year, at the Annual Conference of the Network, to discuss the student's progress, problems, new ideas, etc. In order to obtain a large enough pool of mentors, all PIs who have been allocated one or more positions are required to act as mentors. In addition, many other PIs, both from industry and academia, have volunteered as mentors, which is a very encouraging development, in line with the increased spirit of cooperation and collaboration that the Network has engendered. The pool of mentors is now indeed sufficiently large to also provide two mentors for each of the students funded through the last two rounds of allocations. In order to target the mentor system more precisely (a wish expressed by the PIs at the First Annual Conference), the Board is currently reviewing both the initial experiences and the expectations of the students who have already had their first student-mentor meetings.

3.4. Awarded degrees.
Since all students have been working one and a half years or less, no Ph.D.s have been awarded to any of them yet. The first Ph.D. to be "produced" by the Network is Tomas Hansson (UU, PI Åqvist) who will defend his thesis in May, 1998.

4. Collaborations.

4.1. Inter-disciplinary and inter-academic.
In order to foster inter-laboratory collaboration, the Network operates a scheme under which students and post-docs can apply for funding for laboratory-rotation visits (e.g., if a student from Lund wishes to visit the NMR group in Umeå).
Starting in 1998, the Board has also allocated funds for foreign travel awards. These awards are intended to fund travel and subsistence for a trip (1-4 weeks) to a foreign centre-of-excellence in any of the areas of (or related to) structural biology, or (occasionally) to a foreign facility (e.g., a synchrotron) or a particularly germane conference. In general, the purpose of the trip must be to acquire expertise or know-how that is not readily available within Sweden itself. Candidates who receive an award should write a short report of their trip (these reports are published on the SBNet web site), and be prepared to travel to other interested laboratories in Sweden to give a presentation about the results of their trip.

4.2. Other SSF programmes.
Some PIs have applied for, and been awarded, funds and/or student positions from other SSF-funded programmes and networks. However, the Structural Biology Network does not keep statistics in this respect, since this is largely a matter of personal interests, contacts, and qualifications.
Unfortunately, contacts with other Networks to date have been few and far between. In our opinion, the Foundation should play a more active role to facilitate this process. The Structural Biology Network is fortunate to have a coordinator who takes private initiative. Through searches on the web, and accidental encounters of advertisements etc., he often finds information that is relevant to structural biologists, but not disseminated by the Foundation. Examples of this include several calls for applications from related Networks which have been forwarded to the structural biology PIs by the coordinator. Similarly, he has taken the initiative in disseminating information regarding the calls for proposals, courses and conferences of SBNet to other graduate schools and networks.
In the future, we foresee intimate interactions with the Swedish centre for bioinformatics that may be established (in particular, if it were based in Uppsala), for instance:
- many structural biologists will be interested in hands-on courses organised by the bioinformatics centre.
- some of the PhDs and PhD students produced by the Network will be excellent candidates for a possible "crash-programme", and thereby become part of the first wave of qualified bioinformaticians that the new centre produces.
- structural biologists can help identify areas and problems that are key to making the most efficient use of biostructural information, and thereby help guide some of the research at the bioinformatics centre into relevant directions.
- given the overlap between structural biology and structural bioinformatics, there is a significant scope for joint courses and workshops.
- students who are trained at the bioinformatics centre and aspire to improve their knowledge of experimental structural biology (which, in our view, is a prerequisite for structure-oriented bioinformatics research) could take part in courses organised by SBNet and at structural biology departments throughout the country.
- structural biology researchers would make excellent co-supervisors for PhD students at the centre who do research in structure-related areas.

4.3. Industry and society.
The structural biologists from the industrial laboratories at Pharmacia & Upjohn and Astra are active and valued participants in the Network (e.g., annual conference, mailing list, mentor system). Some of the student positions sponsored by SBNet also involve close collaboration between industry and academia. During 1997, several students and post-docs from Swedish structural biology laboratories have found employment in industrial laboratories. In the future, the Network also intends to involve the industrial participants more closely in its educational activities (e.g., through a workshop on drug design co-organised by industrial scientists). Such initiatives are beneficial to both students (who get to know leading scientists in Swedish industry) and the industrial scientists (who get to know students interested in their line of research). At the annual conference, Pharmacia & Upjohn and Astra have made financial contributions in the form of best speaker and best poster awards. In the future, the Network will attempt to attract industrial scientists from companies that are not (yet) actively involved in structural biology research (e.g., the wood and cellulose industry) to its annual conferences.

4.4. International.
Essentially all groups that participate in the Network have national and international collaborations, and many participate in one or more EU-funded programmes. Since these collaborations usually arise from personal networking, merits, and research interests, the Network does not play a significant role in this process. However, through the SBNet WWW site, occasionally a request comes in from foreign scientists interested in collaborations with Swedish structural biologists. Such requests are brought to the attention of the participants by posting them on the SBNet WWW site.

5. Implementation.

5.1. Organisation and management of the programme.
The organisation structure of the Network is outlined in the following scheme:

The Network is run under the direction of the Programme Board with the following members:
* Dr. Björn Nilsson, Amersham Pharmacia Biotech (Chair)
* Dr. Jan Hoflack, Astra Structural Chemistry Laboratory
* Prof. Guy Dodson F.R.S, University of York
* Prof. Iain Campbell F.R.S, University of Oxford
* Prof. T. Alwyn Jones F.R.S., Uppsala University (Programme Director)
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 SSF. The Board meets once or twice a year. The Programme Director chairs the Network Council. This Council initially consisted of all Principal Investigators (PIs) who were recommended for support in the original Programme Proposal, but has been extended to include all PIs who wish to participate. A PI is defined as a person with responsibility for other scientists (in practice in the Swedish system, this usually means a "Lektor" or Professor). The Network Council has the following tasks and responsibilities:
* communication (via the World Wide Web)
* connections with other networks
* organisation of graduate courses
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 is organised along the lines of a Gordon Research Conference, where all interested scientists are welcome (other SSF programmes, industry, other Nordic countries). Organisation of the graduate courses and the annual conference is the responsibility of the Programme Director, and is managed by the Network coordinator.

5.2. Handling of intellectual property rights.
The handling of intellectual property rights is governed by national and international law where applicable (e.g., the "lärarundantag" in Swedish law), and further adheres to the policy of the local institutes and universities. However, essentially all research in structural biology is pre-competitive, and is therefore unlikely to yield patentable proceeds.

5.3. Continuation of the programme.
Three of the 27 positions funded by the Network were intended to be permanent positions, namely the two positions in the Uppsala expression laboratory and the position of the Network coordinator, which was planned to be a "Lektor" position at Uppsala University upon termination of SSF funding. Unfortunately, Uppsala University has so far been utterly unwilling to make any firm commitments in this matter. This feat may have disastrous consequences for the expression laboratory which is tremendously valuable to the entire structural biology community in Uppsala. Further financing will therefore be sought after termination of the programme. In general, the Board would like to suggest to the Foundation that future contracts with universities include explicit clauses concerning future commitments.

5.4. Budget and financing.
The budget we presented with our "Programme Plan 1996-2000" has been essentially adhered to. A minor surplus has been used to fund a new foreign travel award scheme for PhD students.

6. Internal and external communication.

6.1. Annual Conference.
For many Swedish structural biologists, the First Annual Conference (held from 6 to 9 June, 1997, in Tällberg) has been the first tangible spin-off of the Network. Although organised by volunteers and under great time pressure (the Network Coordinator position had not been filled yet), the Conference proceeded not only without a flaw, it was also an enormous success, judging from all the positive feedback received from both speakers and participants during and after the meeting. The format of the Conference was similar to that employed during Gordon Research Conferences, with morning and evening lecture sessions. Each session included one or two prominent foreign speakers and further talks by Swedish students and post-docs.
The meeting was attended by 120 people (the maximum number that could be accommodated), both PIs and students, from all disciplines of structural biology, from academia and industry, and from all over the country. The atmosphere was extremely friendly, enthusiastic, and one of community, and many new contacts have been made across the borders of disciplines and institutes. Students and post-docs were offered a very attractive conference fee provided they presented a poster. This resulted in a high-quality session in which over 70 posters were presented. The Pharmacia & Upjohn Poster Award for the best poster went to Mathias Eriksson, SLU ("Ribonucleotide reductase"). Also the lectures (both by the invited speakers and by the young persons) were generally of high quality. The Astra Structural Chemistry Laboratory Award for the best presentation by a young person went to Helena Berglund, KTH ("Structural studies of the ribosomal protein S15").

6.2. Electronic communication.
For the intra-Network communication, two major instruments are used. The first is the SBNet mailing list (sbnet@xray.bmc.uu.se), through which the Swedish structural biology community is regularly informed about Network matters (e.g., calls for proposals by related SSF-funded networks, Network Conference), scientific matters (e.g., upcoming conferences, new software), educational matters (e.g., upcoming courses), and more. The current mailing list contains addresses of around 150 Swedish structural biologists (PIs, researchers, post-docs, students). Recently, the scope of this mailing list was extended by enabling any structural biologist in Sweden to broadcast messages directly to all subscribing participants.
The second instrument, which is also the Network's "face" to the outside world, is the SBNet site on the World-Wide Web (URL: http://xray.bmc.uu.se/sbnet/). This site is updated continuously (typically, two or three times a week) and contains a large amount of information about and related to the Network. The site has been "advertised" by contacts with related networks and organisations, by submitting it to some of the major web-based search engines, and through a short article in the newsletter of the Protein Data Bank.
The mailing list and the web-site, together with the First Annual Conference, have made that SBNet is now generally considered to be "the hub" of Swedish structural biology.