Dr Laura Spagnolo joins Research Complex this year to start off a group focusing on her research in enzymes, in particular, serine integrases, which continues to be of great interest to scientists due to its highly ‘one-way’ reactions.
She obtained her MSc in Pharmacy at the University of Trieste and doctoral studies at University of Padova and EMBL Heidelberg. After obtaining her PhD in Pharmaceutical Sciences, Laura moved back to Trieste for a short postdoc at ELETTRA, the Italian synchrotron. Fascinated by the study of protein machines working on nucleic acids, she undertook postdoctoral work at the Institute of Cancer Research, before establishing her own research group in 2009 at the University of Edinburgh, supported by an appointment at the Centre for Science at Extreme Conditions.
At Edinburgh, the Spagnolo group continued work on DNA damage and repair, as well as starting new projects on gene editing machines. In 2016, Laura moved to Glasgow, where she continues to be based and now at Research Complex, will use our resources to discover the structures of the protein and DNA ‘complexes’ that serine integrases form.
To mark International Women’s Day 2023, Communications and Engagement Officer Alison Oliver talk to Dr Spagnolo about her career.
1. What first piqued your interest in science as a child?
As a child I was more interested in the classics than science. My first recollection of reading about scientific research was a biography of the Curies when I was at primary school but my interest was more historical than anything else. In secondary school, I chose a course of studies that included Latin, Ancient Greek, philosophy, lots of literature, but only some science. However, I developed a strong interest in physics towards the end of secondary school, thanks to a very engaging teacher (a woman, with 4 young children). I chose physics as my elected subject for the final year exam, which was a rather unusual choice in a “liceo classico” (an Italian secondary school with a strong focus in humanities). My favourite subject in school was by far philosophy. My interest in chemistry, and biochemistry in particular, only developed later during university.
2. Did you have a role model that influenced your decision to work in science?
During my MSc project on the anti-inflammatory properties of non-glycosilated flavonoids at the University of Trieste, I worked with a really talented and motivated researcher. I started the project with a great deal of curiosity, not really knowing what to expect from experimental science. It was then that I realised that this was something I wanted to pursue.
3. What led to your interest in pharmaceutical sciences?
I felt that a STEMM (science, technology, engineering, mathematics and medicine) degree would lead to job security, initially without any ambition of embarking in an academic career. I didn’t expect to enjoy my studies as much as I did. It was much more of a practical choice. My degree in Pharmacy gave me a very interdisciplinary background, which I still benefit from. At the University of Trieste, I was taught by inspiring teachers and had my first taste of ‘life in a lab’. Trieste is a rather unique and beautiful city and hosts the Italian synchrotron. After my MSc, I was awarded a PhD studentship in Padova, whose pharmaceutical sciences department has a strong research portfolio in protein chemistry. Part of the research work during my thesis was done as a DAAD-funded exchange student at the EMBL-Heidelberg. There, I started working on how proteins fold and how they interact with other chemicals, be it small molecules or polymers. Broadly speaking, this is still the core of my research.
4. Your fascination of the study of protein machines led to your postdoctoral work at the Institute of Cancer Research. What inspired this fascination?
I realised that structural biology is key to unraveling fundamental biological mechanisms at the molecular level, which in turn is essential in the design of strategies to fine-tune these mechanisms when they go wrong, e.g. due to disease. The ICR gave me an opportunity to work in a bench-to-bedside environment, which I found motivating, using cutting-edge research facilities including cryo-EM, well before the “resolution revolution”.
Research Complex is the ideal place to tackle the more difficult parts of this specific project, because the expertise and facilities available on site are unparalleled. Over the years, my experience of Research Complex as a facility user has always been that of a place where difficult problems were tackled with the most appropriate technologies, which is generally not available at home institutions.
5. What led to establishing your own research group at University of Edinburgh in 2009?
I moved to Edinburgh because they were hiring specifically for structural biology and they were looking to start a cryo-EM initiative. I was hired as a member of the Centre for Science at Extreme Conditions (CSEC), a truly interdisciplinary centre bringing together scientists from the Schools of Physics, Chemistry, Geosciences, Engineering and Biology. They use large facilities such as those here at Harwell Campus quite a lot – squeezing/heating/cooling materials to probe the fundamental properties of matter. It is thanks to scientific conversations with colleagues at CSEC that I got to know the campus here better.
6. What led to the move to Glasgow?
The move to Glasgow had two equally important drivers: a scientific one and a family-related one. As it happens, they are intertwined. Glasgow was setting out to build a cutting-edge cryo-EM facility to which I wanted to contribute as their research in genome biology perfectly aligned with my scientific interests, and it is the place where my husband already worked. I was sad to leave CSEC, but at the same time I knew that this was an excellent opportunity to further my research. Cutting down on my husband’s commuting meant that I got more help on all-things-practical with the children, and he did not miss out on their childhood. This might sound menial, but it made my work life both more effective and more enjoyable and Glasgow is a beautiful city, full of life and events – a very welcoming place.
7. Here at Research Complex, you are now establishing a group to work on deciphering the directionality mechanism of PhiC31 integrase. Please could you explain your research and what you hope to achieve here?
Bacteriophages (‘phages’) are viruses that infect bacteria. To ensure their long-term survival, many phages integrate their own DNA with that of their host cell. The phage DNA then gets copied each time the cell’s DNA is copied. Integration is brought about by a mechanism called site-specific recombination: an enzyme (integrase) promotes breaking and rejoining of DNA strands at two sites in the phage and the host DNA, thus splicing the two together. At some point the phage re-forms infectious virus particles by cutting its DNA back out of the host genome, and this is also promoted by the integrase. One family of these enzymes, called the serine integrases, has proved to be of great interest to scientists because of its highly ‘one-way’ reactions; on its own, a serine integrase promotes integration but not excision, whereas when another phage protein called RDF (recombination directionality factor) is present, it behaves exactly the opposite, promoting excision but not integration.
The big aim of the research I will carry out at Research Complex is to reveal the structures of the protein + DNA ‘complexes’ that serine integrases form when they recognize their DNA target sites, bringing them together to perform DNA strand breaking and rejoining. To do this we will use cryo-electron microscopy, which involves the imaging of individual protein-DNA complexes and the analysis of individual copies of these assemblies to obtain a three-dimensional structure. This structural information will reveal for the first time how the integrase enzymes bring about one-way recombination. We can then test our new ideas about the mechanism via experiments in the lab, where we can modify the proteins or the DNA and see what the effects are on the recombination reactions. This will be done in collaboration with the Stark and Colloms labs. Once we know these details, we can design new integrase-based systems for optimum performance in synthetic biological devices, and potentially think of ways to incorporate serine integrase modules into larger/more complex systems.
8. What are the hardest parts related to this research?
From a technical point of view, the hardest bit of my part of the project is tackling the structural movements of the assemblies involved in ensuring directional DNA recombination. These are important in the mechanism of integrates, but structural heterogeneity can limit the level of detail that one can achieve in 3D-reconstructions. We have devised strategies to both limit the flexibility of the assemblies, as well as embracing it to provide us with sequential snapshots along the pathway, which are extremely informative of the mechanism. Biophysical techniques are also very powerful in ‘detangling’ complex dynamic events in macromolecular recognition. Research Complex offers a unique setting in combining the structural work with the biophysics, allowing simultaneous grasping of the fine detail of a structure as well as understanding the dynamics of the process.
I hope that increased awareness will lead to more research and better tools to address under-representation in science, not limited to gender. That we can find solutions to the current difficulty to get back into academia after a career break or enter via non-linear career paths.
9. Why did you choose Research Complex for your research base?
Research Complex is the ideal place to tackle the more difficult parts of this specific project, because the expertise and facilities available on site are unparalleled. Over the years, my experience of Research Complex as a facility user has always been that of a place where difficult problems were tackled with the most appropriate technologies, which is generally not available at home institutions. As a user of several facilities on campus, I saw first-hand how visits to Harwell campus are not only important for the experiment that you come to perform, but also for the new ideas and strategies that spark from conversation with world-leading scientists at the cusp of research in physics/chemistry/biology. One goes home with brilliant data for one experiment performed, as well as ideas for three new ones. A longer visit will exponentially increase the amount and importance of our findings. At the same time, we will contribute our know-how and expertise to the nurturing environment at Research Complex, and we will build a productive link between Research Complex and the University of Glasgow.
10. Is there any scientific topic (outside of your field of research) that you think should have more scientific attention? Which one?
Climate change is a very urgent issue, with consequences on health, economy and society. Any aspect of research in this field would be important, from the biology of climate adaptation, to decontaminating the environment, renewable energies, strategies to limit energy consumption and so on.
11. What were the biggest obstacles you have had to overcome? Did you ever have the impression that it would be easier/harder if you were male?
The biggest obstacle I had to overcome was by far combining a career with a family. My husband is not a colleague, which could have mitigated some aspects of the whole thing, but also contributed to keeping me sane. We lived far from those who could have offered some support when the children were very young.
Data suggests that it might have been easier had I been male. Having said that, I had lots of encouragement from colleagues around me, both male and female. Seeing that other female colleagues succeeded in combining family with a strong career profile was definitely inspirational.
12. In your opinion, which changes, if any, are needed in the scientific system to be more attractive to women in science and possible future scientists?
I don’t think that science is less appealing to under-represented groups: I live under the illusion that science is thrilling to everybody. There is clearly a problem with the hiring and retention of diverse talent in the scientific system. This is an unfortunate waste of resources, because diversity boosts innovation.
The scientific setting I am more familiar with is the academic one. Be it a leaky system, a faulty lattice, a glass ceiling, a sticky floor, or a combination of the above, some aspects of it are better studied than others. With respect to the poor retention rate, research suggests that women initially decide to move away from a system built on short-term contracts, long hours, mobility. Upon tenure, many women take on contracts with heavier teaching/admin/support loads, and even for research-focussed roles, career progression tends to be slower for women.
Recent data from my institution show that, in 2020, 55% of employees on grades 6-9 were women, but only 31% of professors were women. While that’s just under 1/3 of the total, it is a big leap forward compared to the 20.5% reported in 2013, so that’s good news. It would be interesting to know the split among disciplines: are these figures the same for STEMM and humanities? While the impact of starting a family on a woman’s career progression is a very easy one to spot, the detailed aspects of this phenomenon are difficult to measure: female scientists without children are still less than male scientists without children. Some studies suggest that male scientists with a family thrive more because they benefit from the emotional support. Also, they don’t experience a pay gap (well, they do, but it has a + sign…). It is a complex problem, where variables are often difficult to unpick.
I hope that increased awareness will lead to more research and better tools to address under-representation in science, not limited to gender. That we can find solutions to the current difficulty to get back into academia after a career break or enter via non-linear career paths. Besides, creating a more productive, diverse environment makes science even more interesting and enjoyable. And fair.