GlycoTrackers – chemical precision tools to understand protein glycosylation

This idea has been around since the year 2000, so for us to be here 20 years later and to have got the tools Prof. Carolyn Bertozzi (principal investigator) envisioned to work in living cells is an amazing thing to see come to fruition. It also required a huge amount of people and skills – combining the biological aspect of the cells with the chemistry of making molecules, so it’s really exciting and shows us the power of collaboration and combining science.

On the project itself, this is the first time the glycans and enzymes we’re studying have been able to be connected with an engineered gain of function. This allows us to see cells working as normally as possible while the enzymes incorporate modified structures into complex glycans which is really cool.

All along the project we had to take a lot of informed leaps of faith. It’s sometimes years before we knew if any of the experiments would work. Waiting to see if the things we’d made would fit together was a challenging process – so many pieces had to come together. Also, the length of the project meant that when we started, a lot of what is available now – like protein crystal structures or knock-out cell lines to drive our ideas forward and test our findings - didn’t exist at the time.

It's important to be interested and excited about what you're working on, but I think what I've learned from this experience, more than anything, was to be equally excited about the people you're working with. I am just so grateful for having other people bring their energy, their passion, their creativity and their drive to the project and to help move it forward.

Traditionally, studies on glycans up until now have been slightly incomplete and we haven’t had the whole story when it comes to the complex world of glycoproteins. Now we have a toolbox to ask the right questions on the activities of glycosyltransferases and test hypotheses in a complete manner.

Before this project, I only knew enough chemistry to get the work done, as my background is in molecular biology. When I joined the team, I started to notice how much chemistry is central in being able to study the function of enzymes in the cell. I didn’t realise before how much we need chemistry to make the entire project work.

Glycans are altered in pretty much every disease that has ever been studied. They change structures all the time, so getting a handle on this is so informative to help us diagnose and treat diseases. We’ve now got an incredible molecular view on how things change in disease.

Prof. Carolyn Bertozzi always says that diverse science leads to the best science – including diverse people from all backgrounds and walks of life. To me, this also includes people from different scientific backgrounds who bring different perspectives and creative ideas stemming from their own scientific expertise.

Our Horizon Prize lists 49 different scientists from five different countries - it's never just one person who makes something work right. For this project to work it starts with the chemist who makes the molecule, but you also need structural biologists who model the enzymes, crystallographers, enzymologists, biologists who set up the living cell approach, people who can create elaborate model systems, mass spectrometry experts to dissect the glycoproteins – you need experts in pretty much every facet of chemical biology!

The whole field of glycobiology – despite 100 years or more of work – is still shrouded in mystery, because there are so many experimental obstacles to unravelling the roles of glycans. By combining chemistry and biology, we hope that our Precision Tools will provide a way to complement existing approaches in the biosciences. There are so many aspects of our work that we think of as textbook knowledge but is actually still the “dark matter” of biology. Ultimately, the objective to make tools is the provision of knowledge that might cause us to rethink what we know.

We coined the term ‘Chemical Precision Tools’ because it will give us the capacity to answer questions we couldn’t tackle before to dissect the fundamental mechanisms of physiology and discover new markers of disease.

The breadth of applications and fields that the project crossed. As an undergrad I was brand new to research, learning something new every day and getting experience in applications like crystallographic data collection, molecular modelling and experimentation. Each step is a whirlwind and I’m lucky to have great mentors and collaborators to learn the techniques.

A good research environment or culture is one that fosters growth and learning amongst everyone involved, even someone brand new to science and research. 

Chemistry provides a very unique and interesting perspective in breaking down problems into very distinct and trackable parts. It’s easy to get lost in the complexities, but when you take a chemistry perspective you can be more targeted and precise and start thinking about questions in a more accessible way.