Sixty years of the Colworth Medal

I've always been fascinated by the natural world, and cell biology in particular captured my imagination at school. I chose to study biochemistry at university, and for my Master’s thesis, I used quantitative imaging to study centromere propagation in live Drosophila embryos. I really enjoyed using this approach to tackle biological problems, which led me to do my PhD in Jan Ellenberg’s lab at the European Molecular Biology Laboratory in Heidelberg. At the time, there were no high-resolution studies of mammalian oocytes, so I saw a lot of potential in developing microscopy methods for live mouse oocytes. Jan gave me the opportunity to establish these methods, and fortunately it worked well. I have continued to work on meiosis in mammalian oocytes ever since, and I am still very passionate about this topic because it has a huge impact on our society and the many couples who struggle to conceive.

My research focuses on how mammalian oocytes develop and how aneuploidy, a major cause of miscarriage and female infertility, occurs. We have been able to visualize for the first time how human oocytes assemble a spindle and segregate their chromosomes. We found that spindles in human oocytes are often unstable, leading to chromosome segregation errors. This instability is due to low levels of a spindle-stabilizing protein, KIFC1, which, when added to human oocytes, can reduce chromosome segregation errors. We also found that mammalian oocyte spindles are rich in actin and contain a liquid-like spindle domain that stores spindle assembly factors and that both structures are important for spindle assembly and chromosome segregation. In addition, we have shown that aneuploidy often occurs in the one-cell embryo when the parental genomes join at the first mitotic spindle. My lab is also interested in why female fertility declines with maternal age. We have identified a number of changes in chromosome architecture that predispose chromosomes to aneuploidy in aged oocytes. Other work in our lab has focused on method development. For example, we have developed a strategy for performing RNAi screens in mammalian oocytes, and the Trim-Away method, which can be used to acutely remove proteins from cells without prior modification, and now allows mechanistic studies in cell types that are not genetically tractable, including human oocytes and embryos, to name just a few examples of our work.

My research has helped explain why so many human eggs are aneuploid and why IVF success rates decline with age. We are now investigating how oocytes are able to reset the biological clock with each generation and how they can promote something as fascinating and complex as the development of a new human being. For example, we have recently discovered how oocytes store mRNAs and proteins for embryonic development. We are also developing new strategies to improve IVF outcomes. We are hopeful that we will be able to help more couples and women over the age of 35 to become pregnant.

The Colworth Medal is a highly prestigious award, and I am honoured to be among the many outstanding recipients. Winning the Colworth Medal has given me a platform to share my research with a wider audience. It has also helped me to attract funding for my research and to recruit talented students and postdoctoral fellows to my laboratory. Overall, the Colworth Medal has had a very positive impact on my career, and I am grateful for the recognition it has brought.

I would encourage future molecular bioscientists to be bold and innovative in their research. Don’t be afraid to try new things, even if they seem challenging. It is also important to be collaborative and to work with others. Science is a team effort, and the best discoveries are often made by people from different backgrounds working together. Finally, be passionate about your work. Science is a demanding career, but it is also incredibly rewarding. If you are passionate about what you are doing, you will be more likely to overcome challenges and achieve your goals.

I studied chemistry and biology and got into structural biology quite early. One choice I had to make early on in structural biology was to choose which technique to specialize in. I decided on cryo-EM back in 2006, and I am amazed how much the field has taken off!

We are working to understanding how bacteria form infectious aggregates called biofilms and how they evade antibiotic treatment, using electron tomography as the primary tool. We have recently solved the first complete structure of a bacterial surface layer (von Kügelgen et al, Cell, 2020), as it is found on Gram-negative bacterial cells, bound to abundant and important immunogenic glycolipids called lipopolysaccharide. Another recent contribution from the laboratory (Tarafder et al, PNAS, 2020) describes phage molecules secreted by Pseudomonas aeruginosa bacteria that modify their external environment to promote virulence. The key discovery we made was that the secreted phage molecules form liquid crystals that encapsulated bacterial cells and protect them from antibiotics. Similar phage molecules have since been identified in several Gram-negative human pathogens (in addition to Pseudomonas aeruginosa) of relevance to biomedicine and for the treatment of bacterial infections.

I guess one of the biggest motivations to study prokaryotic cell surface molecules is that there is so much unknown out there to discover. We typically work with different microbes and different model organisms, which really enriches our inquiries and makes our work exciting as there is always something new to learn!

It felt absolutely fantastic. We had several hardships in our laboratory at the time, and this award provided me with the motivation to strive to achieve more in the coming years. In particular, the award gave our work a spotlight and led more recruitment to the Laboratory of Molecular Biology. So I really cannot be more grateful!

From personal experience, I think working on a problem you feel passionately about is the most fruitful.

I think it was a deep curiosity around how chemistry could be applied in living systems. My undergraduate degree was in medicinal and biological chemistry and during this time I spent one year at GSK as a medicinal chemist, which really opened my eyes to the impact that (bio)chemistry could have in the real world. After a PhD in chemical synthesis, I was determined to follow my newly found molecular curiosity and creativity into cells. After a postdoc at the LMB in Cambridge developing bio-orthogonal reactions, and a postdoc at Harvard in microbial chemistry, I was hooked and utterly convinced by how microbes could be used to solve many of the grand challenges facing science and society today. The rest was inevitable, and indeed history.

My lab is having a lot of fun in two main areas of research right now. The first involves the design of new biosynthetic pathways in bacteria to transform ‘waste’ feedstocks to value-added chemicals. This research is also highly industry-focused and we’re currently collaborating with over 20 companies on projects in this area. I’m fascinated (and horrified!) by how wasteful our modern-day society is, and how much of what we buy, use and dispose is simply incinerated or sent to landfill. My inner organic chemist sees all this waste as carbon, and my new-found inner biologist wants to design microbial pathways to transform this into something useful. The second area is an emerging idea that we’ve called ‘biocompatible chemistry’. This involves developing chemical, non-enzymatic catalysts that can be interfaced with microbial metabolism in vivo. For example, we’ve recently co-localized metabolites and chemical catalysts within the bacterial cell membrane and demonstrated that you can perform new chemistry in these cells that Nature has never evolved before. I genuinely believe that this flavour of research at the interface of synthetic biology and synthetic chemistry has vast untapped potential for innovation. We just need organic chemists, metabolic engineers and biotechnologists to interact and collaborate more often!

I feel a great sense of privilege and pride being an academic scientist. Engaging every day with my group and being scientifically creative with them is the best part of my job. Seeing them develop into independent and creative researchers and watching them at conferences and in seminars enthusing others about microbiology, chemistry and biotechnology fills me full of immense pride in my work. Scientifically, my background in chemical synthesis and my journey into biochemistry and biotechnology hasn’t been easy but has left me laser-focused on how biotechnology can impact the way the chemical society is today, and needs to be in the future. Our society’s transition to a more sustainable and circular economy in the future is going to undoubtedly take a concerted effort of scientists from many disciplines, with chemical biotechnology at the core of the technologies that will take us there. Playing a small part in this journey is my career goal.

It might sound odd, but it really doesn’t feel like there have been any highlights per se! I have always felt incredibly privileged to have been given so many amazing opportunities to work on exciting research questions at the interface of chemistry and biology with so many inspirational leaders in my field. My time in Oxford as a PhD student taught me how to think about molecular reactivity and synthesis; my time at the LMB taught me how cellular processes and chemistry could be coerced using an expanded genetic code; and my time at Harvard and MIT introduced me to the utterly fascinating world of microbial chemistry, synthetic biology and metabolic engineering. All in all, I feel very confused about what ‘sort of scientist’ I am now after all that, but at the same time I feel incredibly fortunate to have been given so many opportunities to diversify as a scientist and to embark on my own path as an independent researcher.

Receiving the Colworth Medal from the Biochemical Society is an incredible honour and one I’d like to share with my amazing lab and all of the trailblazing scientists who have mentored me through the years. I think we’re only beginning to glimpse what microbes can achieve in the field of sustainable chemical synthesis and so this award is a tremendous motivation for me and my team to keep pushing forward our work in this area.

To the older scientists: I often hear hollow questions and comments from colleagues and students, like “what will get me the most funding?” or “which project will get me published the quickest?” or “I’m not going to research that, it sounds too difficult”. Forget all this. Focusing on being successful before doing your best science will ultimately result in failure. Focus instead on doing what you love to do. Because it’s your interest that drives your creativity, and creativity that drives innovation.

To the younger scientists: The chemistry of biological systems underpins everything you see in the natural world. If you want to help save or impact the environment, you must first understand it. A career in science will enable you to understand Nature at a molecular level, and to then change it for the better.