SBNet - Programme 1996-2000
Strategic Research in Structural Biology
1996 - 2000
B. Nilsson (Chairman) & T.A. Jones (Director) on behalf of the
G.J. Kleywegt (scientific secretary)
1. Executive summary
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:
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.
- To reinforce excellence
; by supporting new strategic research efforts of the groups that are competing at
the highest international level.
- To remedy current weaknesses
; in particular, by building a protein-expression laboratory in Uppsala.
- 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.
- To facilitate knowledge transfer
; by stimulating contacts between academic groups, contacts with industry, and participation
of industrial researchers in the Network.
1.2 Programme aims
- to guarantee a world-class status for Swedish Structural Biology research.
- to reinforce excellent research groups.
- to carry out academic research of the highest calibre.
- to make new efforts to try and remedy perceived current weaknesses. In the first
instance, this means establishing a dedicated laboratory for protein expression at
- to strengthen academic research in areas that will be of direct interest to Swedish
industry. In particular, we will encourage projects to study integral membrane and
receptors proteins, drug design and structures of high medical relevance.
- to improve graduate-student training in Structural Biology, to bring it to a world-class
- 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.
- to improve interactions between the different structural biology groups working
- to interact with other programmes supported by the Foundation.
1.3 "Concrete" deliverables
- all students are expected to get their doctorates within 4 years of starting their
research. By the end of the first five-year period, therefore, we expect 17 new
doctorates. More than 20% of these will be female.
- each student supported is expected to publish 3-4 papers in international, top quality
journals during their thesis work. The Programme should, therefore, result in the
publication of ~75 papers.
- there will be 3-4 technique oriented "small" meetings each year and one larger
- interactions between the structural groups will be improved. Each Ph.D. student
will have 2 advisors from other institutions, who will closely monitor the progress
of the research.
- we will make a major move into work on membrane-bound proteins and receptors. We
will use B and/or X-ray methods for structure determination, as appropriate.
1.4 End of the Programme
- we intend to have a "lektor" in charge of the day-to-day running of affairs. An
oral promise from the Dean of the Science Faculty (UU) has been received that this
person will be taken on by the faculty. A contract will be drawn up before creating
- no promise has yet been received from the Faculty to take on the expression lab
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
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
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
These challenges are addressed in the present Programme in Structural Biology.
- 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.
- 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.
- 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
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,
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
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
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
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
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:
- reinforcement of excellent research groups.
These are groups with proven track records at the highest international level, adequate
infrastructure, 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 that a dedicated laboratory for protein expression is being built in
- to improve graduate student training in Structural Biology
to bring it to a world-class level. This is implemented through the Swedish Structural
Biology Network. All research groups are encouraged to join this Network, so that
as many students as possible may benefit from it. The Programme is 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 strive
to ensure a close interaction with other Networks supported by the Strategic Research
Foundation that may 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.
2.5 Summary of the Programme
- Reinforcing excellence.
The top groups in Sweden are quite well equipped with measuring instruments, and
have easy access to national and international facilities Funding limitations do
not allow us to invest in major equipment purchases except for the Uppsala expression
laboratory. Therefore, the total investment in new equipment constitutes only ~5% of the
proposed budget (see Appendix I). Instead, the bulk of the investment is in "human
capital", plus defrayment of the costs of small laboratory equipment, chemicals and
other running costs. Rather than applying the "inverse cheese slicer" principle (i.e.
, dividing resources equally, regardless of track records), the Programme has invested
initially in those groups that have already demonstrated that they are capable of
operating at the highest international level, both with respect to skills and choice
of research subjects. Naturally, some flexibility to adapt to unforeseen developments
has been built into the Programme by budgeting later calls for proposals. Support
to the groups comes in the form of graduate students, researcher positions ("Forskar
Assistent" or "Forskare"), laboratory technicians ("Laboratorie Assistent"), and research
engineers ("Forskningsingenjör"). It is important to note that all research groups
in Sweden benefit from this investment, even those that do not receive initial, direct support,
due to the transfer of competence and knowledge within an active and open
Network. Naturally, the "excellent" groups are expected to make significant contributions
to the methodology of their respective areas of expertise, and to disseminate their expertise
nationally and internationally. Substantial new funds will be used
to stimulate research in areas which can be foreseen to become increasingly important
in the next few years (such as membrane-bound proteins, receptors, protein dynamics).
In order to address relevant biological questions, the Structural Biology Network will
initiate very close interactions with other national biological programmes that are
initiated within the Strategic Research programme (see section 2.7).
- Remedying weaknesses.
The Board does not feel that any of the important areas of Structural Biology are
absent in Sweden, which implies that no major new research efforts need to be initiated
at the professorial level. On the other hand, dedicated protein expression and labelling
facilities are virtually absent in academia. While this may be understandable
to some extent (since this largely involves service-type activities, which give little
scientific credit), it also means that the choice of subjects that can be studied
may be somewhat ad hoc
, depending on the availability of material, and personal networks. In particular
with respect to the most prestigious projects, structural biologists are critically
dependent upon usable quantities of sufficiently pure (and, for NMR studies, isotopically
enriched) material. In such cases, the laboratories that have dedicated expression
(and labelling) laboratories usually have the edge. A new protein expression laboratory
is being set up in Uppsala, and we strongly recommend that extra funds be made available to
set up expression and labelling laboratories both in Lund and at KI.
- Guaranteeing continuity.
In order to maintain an internationally competitive role, training of graduate students
should be at the highest level. At present, there is little cooperation and coordination
between the individual universities. The Board plans to initiate a Graduate Network which
organises advanced courses (with international as well as local tutors),
and an annual conference at which the students present and defend their research.
In addition, each student who is funded through the Programme will have two mentors
from other institutes who annually discuss and assess the progress made by the student.
Participation in the Network is open to all Structural Biology groups in Sweden,
so that even the groups that do not receive direct financial support will benefit.
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:
- The training for all Swedish graduate students in Structural Biology will be improved
through the courses organised by the Network.
- The cooperation and coordination between the various research groups will be improved.
- The capability to compete at the highest scientific level will be improved.
- The attractiveness of Sweden as a country of high-quality Structural Biology research
will be increased (this may attract excellent researchers to come and work in Sweden,
as well as high-biotech companies to set up shop here).
- The availability of highly skilled people to knowledge-intensive Swedish industry
will be increased.
- The dissemination of knowledge and expertise from the competence centres to other
research groups in the country will be improved.
- The other medical and biological Networks supported by the Strategic Research Foundation
will be strengthened by the Structural Biology Programme (see section 2.7).
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
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
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.
- Dr. Björn Nilsson, Pharmacia & Upjohn (Chairman)
- Prof. Uli Hacksell, Astra Draco
- 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)
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).
- communication (via the World-Wide Web)
- connections with other networks
- organisation of graduate courses
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.
- 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
- 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
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.
- 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
- A. Liljas (Lund), researcher: Crystallography at MAX II
- Forsén (Lund) researcher: Experimental studies of biomolecular dynamics by
- 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
- Unspecified PI (UU/SLU), researcher: Strategic research in 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,
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
4. Miscellaneous issues
- Students and researchers funded by this Network will be required to spend the same
amount of time in teaching duties as others holding similar positions in their department.
This is to ensure that the Network does not create "A" and "B" class positions
- Personnel will be affiliated with the university of the PI. Students will take part
in the graduate training programme of the participating university as well as the
courses organised by the Network. All allocations are to be to PIs; in other words,
if a PI moves to another university within Sweden, the funds and personnel will move
to the new institute as well
- At present, the fraction of women of the PhD-level researchers in the groups involved
in the Programme is ~30 % (for non-PhDs, this fraction is ~35 %). We strive to improve
this through active encouragement in advertising the positions which will be funded through
- The PIs of this Network are involved in an extensive international Network of collaborations
and organisations (for details, see the original Programme Proposal of December,
1994). Apart from the usual scientific collaborations, they are also involved in European
Union networks. Jones has been a member of the steering group of an ESF-funded
Network supporting crystallography in molecular biology. This Network has created
a biannual conference in Como, Italy. Many of the Swedish Structural Biology groups now
participate in programmes initiated in the new Framework IV of the European
- The Network is amenable to interacting with industry at a number of different levels.
Members of the Network will offer expertise in state-of-the-art methods and techniques
to industrial laboratories. Industrial scientists will be able to work in the laboratories
of Network members for limited periods for educational purposes. We
expect to see the development of a number of joint projects during the lifetime of
this Network. Industrial scientists are welcome to join the Network as equals to
academics. They will be able to take part in, and to contribute to, both courses
- We are confident that Structural Biology will expand enormously in the next ten years,
both in academia and industry. We expect that some of the people trained in the
Network will find their way into academia while others will opt for a career in industry.
Moreover, we believe that one of the positive effects of the Programme will be
to stimulate Swedish companies to initiate work in Structural Biology or related
areas. Therefore, we expect that all students trained within this Programme will
find productive positions
- In the event of a major reduction in Foundation support, the Structural Biology Network
would be crippled. It would not be possible to find continued support for those
students and post-doctoral scientists to continue their research activities
- An initial World-Wide Web site for the Network has kindly been set up by Dr. Gerard
Kleywegt in Uppsala (URL: http://onyx.bmc.uu.se/sbnet/srf.html). In the future,
this site will be maintained by the Network Coordinator
- We expect that the position of the Network Coordinator will be advertised in September,
and an appointment made shortly afterward. Uppsala University has agreed to continue
the funding of this position once the Network ceases to exist
Proposed budget 1996-2000
Network Council members
- Prof. T Alwyn Jones, Uppsala University
- Prof. Hans Eklund, Swedish Agricultural University
- Dr Sherry Mowbray, Swedish Agricultural University
- Dr Inger Andersson, Swedish Agricultural University
- Dr Lars Liljas, Uppsala University
- Dr Johan Åqvist, Uppsala University
- Dr Torsten Unge, Uppsala University
- Prof. Anders Liljas, Lund University
- Prof. Sture Forsén, Lund University
- Prof. Torbjörn Drakenberg, Lund University
- Dr Torleif Härd, KTH/Karolinska Institute
- Dr Hans Hebert, Karolinska Institute
- Dr Lennart Nilsson, Karolinska Institute
- Prof. Rudolf Ladenstein, Karolinska Institute
- Prof. Gunter Schneider, Karolinska Institute
- Dr Ylva Lindqvist, Karolinska Institute
- Prof. Gottfried Otting, Karolinska Institute
- Dr Pär Nordlund, Stockholm University
Latest update at 12 February, 1998.