Structural biology is a common thread running through many major biological advances, opening novel opportunities for impact, including:
- discovering the structure of DNA
- research into the treatment of diabetes using insulin
- our understanding of the COVID-19 virus
- the development of animal vaccines
- the 2024 Nobel Prize-winning AlphaFold technology
UK researchers are at the forefront of structural biology, a field that has rapidly developed due to increasingly sophisticated technologies.
What is structural biology, and why is it important to us?
Since Biotechnology and Biological Sciences Research Council’s (BBSRC) formation in 1994, we have invested over £690 million in research relating to structural biology.
Structural biology helps us to understand the structures of the building blocks of life. This includes DNA and proteins, such as the hormone insulin. The structure of a biologically important molecule is closely related to its function. For example, the virus that causes COVID-19 has protein spikes that cover its surface to enable the virus to bind to and enter human cells. Analysing these protein structures provides insights into their function and ultimately enables effective vaccine design.
Tackling coronavirus: understanding the structural biology. Video credit: UK Research and Innovation
Video transcript and on-screen captions are available by watching on YouTube.
Structural biologists use various technologies that have advanced over the years to support their work, including X-ray crystallography, spectroscopy and microscopy. X-ray crystallography images of DNA created by Rosalind Franklin led to the discovery of its helical structure by Watson and Crick.
Since then, cryo-electron microscopy has become an increasingly popular tool to create high-resolution images of biomolecules. From the 1980s, advances in nuclear magnetic resonance spectroscopy enabled further great strides in understanding the structure of biomolecules and their dynamic functions.
A paradigm technology shift and a Nobel Prize: AlphaFold
Crucially, structural biologists worldwide have been sharing their research data openly for decades, using public data resources such as those managed by the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI).
BBSRC funding has supported these open data resources, which enable scientists to build on existing data and advance knowledge faster than ever before. Such publicly available, high-quality datasets are also being used to train the next generation of artificial intelligence (AI) and machine learning models.
AlphaFold is an AI model that can now accurately predict protein structure in minutes. These predictions are then validated using experimental methods. High-quality predictions significantly speed up progress, allowing researchers to make discoveries and impact much more quickly.
This is not just for describing the structure of important proteins; it also assists research that designs proteins for our needs, like industry processes or medical applications.
Predicted the structure of nearly 200 million proteins
AlphaFold was developed by Google DeepMind, an AI research lab led by Chief Executive Officer (CEO) Demis Hassabis. In 2024, Hassabis and John Jumper were co-awarded the Nobel Prize in Chemistry for their work developing AlphaFold. They also shared the prize with David Baker, who won for his work in computational novel protein design.
AlphaFold predicted the structure of nearly all 200 million proteins known to science, and these predictions were made openly available through the AlphaFold Protein Structure Database, co-developed by Google DeepMind and EMBL-EBI. More than two million researchers worldwide have used these predictions to accelerate research and impact across the life sciences.
Building structural biology research and data infrastructure
The success of AlphaFold is built on the availability of thousands of experimentally determined protein structures using the techniques described previously. This is a result of long-term research funding, infrastructure investment and data-sharing policies supported by funders and journals. Enabling open access to these research data through open data resources such as those managed by EMBL-EBI has been key.
Structural biology research and data infrastructure has paved the way for major advances in this field, supported by:
- UK Research and Innovation (UKRI), including BBSRC, Medical Research Council (MRC), Engineering and Physical Sciences Research Council (EPSRC), and Science and Technology Facilities Council (STFC)
- other UK funders like the Wellcome Trust
- international funders, such as the EU and National Institutes of Health (NIH)
Two BBSRC-funded researchers, Professor Rod Hubbard (University of York) and Professor James Naismith (University of Oxford), share their excitement about this transformational AlphaFold technology.
Read our full case study: Open data key to solving the protein structure prediction problem.
Since the beginning of BBSRC
BBSRC’s founding Chief Executive, Sir Tom Blundell, is a structural biologist and was a member of Dorothy Hodkin’s team, which, in 1969, solved the structure of insulin. Solving protein structures is a basis for drug design, and this early work on insulin later led to the development of synthetic ‘human’ insulin. Identical in structure to natural insulin, this artificial form is now manufactured and used instead of cow or pig insulin to treat diabetes.
Sir Tom founded Astex Technology (now Astex Pharmaceuticals) with the late Professor Chris Abell and Dr Harren Jhoti. Based on an X-ray structure-guided, fragment-based approach to drug discovery and building on several successful research grants supported by the research councils, Astex was a great success.
Based in Cambridge, Astex has partnered over the years with major pharmaceutical companies like GSK, AstraZeneca, and Novartis in the discovery and development of drugs in oncology and diseases of the central nervous system.
In 2011, it merged with SuperGen Inc. and was sold in 2013 to Otsuka Group for £600 million. Astex currently has several compounds in its clinical pipeline for treating certain types of cancer.
Leading the way
Under Sir Tom’s guidance, BBSRC provided excellent leadership to UK structural biology research alongside MRC. In 1995, BBSRC led a comprehensive review of UK structural biology. This resulted in the establishment of six centres for structural biology across the UK and influenced a major investment in a new synchrotron radiation source, Diamond, a joint venture between STFC and the Wellcome Trust.
Diamond Light Source Ltd was formed in 2002, and Diamond was operational in 2007. It’s an extremely powerful microscope that accelerates electrons to create bright beams of light.
Diamond continues to develop with the Diamond-II project, which will deliver new infrastructure and run from 2023 to 2030. This project is a £519 million investment from the UK government, funded predominantly by UKRI and the Wellcome Trust.
BBSRC and other UKRI stakeholders pioneered the construction of the Research Complex at Harwell in 2009. Located adjacent to Diamond, it is a base for convening users of Harwell facilities, including structural biology.
Developing new methods for protein structure determination
The Research Complex and STFC are also the home of the Collaborative Computational Project Number 4 (CCP4). CCP4 is a suite of programmes for determining structures with X-ray crystallography and other experimental methods. It is a community and not-for-profit resource and aims to develop new methods for protein structure determination.
It is a long-running project, starting in 1979 when it was originally supported by BBSRC’s predecessor, the Science and Engineering Research Council.
CCP4 is funded by BBSRC, MRC and STFC. UK universities, pharmaceutical companies and international organisations use CCP4 for research, including drug development.
Diamond and the Research Complex offer advanced complementary structural technologies that are particularly suited to exploring the cell biology of virus-host interactions and how viruses replicate.
Structural biology of animal viruses
BBSRC has a long history of supporting structural biology research into animal viruses, and scientists at the Pirbright Institute have been at the forefront of this, collaborating with scientists at Diamond.
Using these facilities, Pirbright scientists, in collaboration with other academic institutions, are studying how animal viruses replicate, cause disease, and interact with animal immune systems. Several farm animal diseases are being studied in this way, including bovine respiratory syncytial virus, Marek’s disease virus and infectious bronchitis virus.
Pirbright researchers have used Diamond to study the outer shell of the foot-and-mouth disease virus (FMDV). Work in collaboration with the universities of Oxford and Reading has produced an FMDV vaccine that is safer to produce, easier to store and is now licensed with MSD Animal Health.
Professor Bryan Charleston, Director of The Pirbright Institute, said:
The long, mutually beneficial association between Pirbright and Diamond has allowed our scientists to study viral diseases in greater detail, resulting in vital research developments such as the visualisation of the FMDV capsid, bluetongue virus and bovine antibody structures.
An essential part of the UK’s national capabilities, the partnership represents a conscious effort to increase research resilience and innovation identified by UKRI’s Infrastructure Programme.
From one virus to another: combating COVID-19
BBSRC-supported structural biology research has also proved pivotal in more recent years in combating emerging zoonotic diseases, including during the COVID-19 pandemic. Many researchers who were historically funded by BBSRC were able to quickly pivot their research to combat the disease and learn more about the virus.
Llama antibodies against SARS-CoV-2
Professor James (Jim) Naismith was the first full Director of the Rosalind Franklin Institute, a leading life science institute on the Harwell Campus funded by EPSRC. The institute specialises in structural biology tool development, as well as AI, mass spectrometry and other technologies. He is now the Head of Mathematical, Physical and Life Sciences at the University of Oxford after a long career in structural biology research, teaching and mentoring.
Professor Naismith has received significant funding from BBSRC, with grants totalling over £8 million awarded as principal investigator. BBSRC has supported his early research across a wide range of topics, including:
- understanding the replication process of adenovirus
- understanding how mutations in E. coli surface proteins affect resistance to antibiotics
- a multidisciplinary programme of work using the Structural Proteomics Facility shared by the universities of St Andrews and Dundee, including technology development and infrastructure improvement
During the pandemic, Professor Naismith collaborated with researchers at:
- University of Oxford
- Diamond
- Research Complex at Harwell
- Public Health England
The collaboration was supported by:
- MRC
- EPSRC
- Wellcome Trust
- EPA Cephalosporin Fund
It also involved engineering llama antibodies to produce nanobodies that could neutralise the SARS-CoV-2 virus.
Diamond’s advanced imaging capabilities were key to checking whether the antibodies could bind and neutralise SAR-CoV-2.
Finding fatty acids to block SARS-CoV-2
Professors Christiane Berger-Schaffitzel and Imre Berger at the University of Bristol were pooling their teams’ expertise to study how membrane proteins fold.
Their work was supported by BBSRC responsive mode and ALERT research equipment funding, the Wellcome Trust, and BrisSynBio, one of six synthetic biology centres in the UK. BrisSynBio was funded by BBSRC and EPSRC, and Professor Imre Berger is the director of the centre.
When the pandemic started, they pivoted to COVID-19 as part of University of Bristol’s UNCOVER, a COVID-19 emergency research group led by Professor Adam Finn from Bristol Medical School (PHS).
Using cryogenic electron microscopy, where researchers freeze samples and fire electrons to image proteins, they determined the 3D structure of SARS-CoV-2’s spike protein. They discovered a pocket in the spike protein that they showed contained linoleic acid, an essential fatty acid with key roles in regulating the immune response.
Collaborating with virologist Professor Andrew Davidson and his team, they found that binding linoleic acid to the spike blocked the virus from infecting and replicating, acting as an antiviral. Two medical doctors in the US began using linoleic acid as an emergency COVID-19 treatment. Work is ongoing to develop this technology and establish full regulatory approval for this therapy in the UK.
To achieve approval and bring the drug to patients, University of Bristol spin-out Halo Therapeutics Ltd was founded by Dr Daniel Fitzgerald (CEO), Professor Christiane Berger-Schaffitzel (Chief Technology Officer) and Professor Imre Berger (Chief Strategy Officer).
Halo is developing structure-based drugs to target unmet needs around disease treatment. The spin-out is leading the application for clinical trials for the fatty acid antiviral drug on patients.
If successful, the drug could be used to treat early infections or for those who have been in contact with an infected individual to prevent infection and transmission.
Halo is also not stopping at COVID-19, turning its attention to other respiratory infections and potential obesity treatments based on fatty acid metabolism, too.
Looking to the future
Discoveries from structural biology have made great advances in revealing the intricate mechanisms at work in our bodies. This has led to major impacts on fields like infectious disease and drug development.
Novel technologies and improved methods, such as in sample preparation and AI tools, will continue to develop, allowing researchers and innovators to address ever more sophisticated questions. This includes areas such as in situ structural biology, where scientists can study the molecules, their dynamics, and modifications inside living cells.
Increasingly, researchers will also harness fundamental insights from structural biology in the design of novel biomolecules, contributing to the green economy and new bio-based solutions to problems.
Top image: Credit: nicolas_, iStock, Getty Images Plus via Getty Images