GlycoTrackers – chemical precision tools to understand protein glycosylation
Winner: 2021 Chemistry Biology Interface Division Horizon Prize:
Rita and John Cornforth Award
For the development of chemical precision tools for the new era of quantitative glycobiology.
A team from Stanford University, Imperial College London and the Francis Crick Institute, working with colleagues in an international collaboration, has won the Chemistry Biology Interface Division Horizon Prize.
Every cell in the human body is covered by a layer of sugar molecules, also called glycans, which are involved in processes that are essential for life. Glycan molecules come in different shapes and sizes, small changes of which can have a profound impact on metabolism or on mounting an immune response against pathogens.Read more
Unlike other biomolecules, glycans are not directly encoded by DNA in the genome. Instead, they are built from simple building blocks by molecular machines called glycosyltransferases. When glycosyltransferases are dysfunctional, this can have drastic consequences and facilitate cancer formation.
It is becoming increasingly clear that studying the role of glycans will provide a detailed view into the basic functions of a cell and help developing the next generation of diagnostics and therapeutics. However, due to their non-DNA-encoded nature, glycans are much more challenging to study than other biomolecules.
The GlycoTrackers team has developed a set of chemical “Precision Tools” that allow the direct mapping of glycans by taking a detailed look into the activity of glycosyltransferases. After a two decade-long effort, the team can now map the products of individual glycosyltransferases by using state-of-the-art techniques, for instance in mass spectrometry and microscopy, to detect any abnormalities.
Twenty years ago we set out on a journey that we knew would require many new inventions, combing expertise across the spectrum of chemistry and biology, and a diverse and dedicated team who understood that this would be marathon, not a sprint. Here we stand today having assembled the components of a powerful new platform that can transform our understanding of glycobiology.
The teamSee full team
Anthony J. Agbay, Undergraduate student, Stanford University
Jon Agirre, Research Fellow, University of York
Nikolaos Angelis, PhD student, Francis Crick Institute
Aristotelis Antonopoulos, Postdoc, Imperial College London
Michael C. Bassik, Assistant Professor, Stanford University
Carolyn R. Bertozzi, Professor, Stanford University
Ganka Bineva-Todd, Senior Laboratory Research Scientist, Francis Crick Institute
David C. Briggs, Senior Laboratory Research Scientist, Francis Crick Institute
William M. Browne, PhD student, Imperial College London
Jacob Bush, Scientific Leader, GlaxoSmithKline
Beatriz Calle, PhD student, Imperial College London, Francis Crick Institute
Junwon Choi, Postdoc, Stanford University
Anna Cioce, Postdoc, Imperial College London, Francis Crick Institute
Marjoke F. Debets, Postdoc, Stanford University
Holly L. Douglas, Senior Laboratory Research Scientist, Francis Crick Institute
Daniel Fernandez, Research Associate, Stanford University
Helen Flynn, Principal Laboratory Research Scientist, Francis Crick Institute
Douglas M. Fox, PhD student, Stanford University
Acely Garza-Garcia, Senior Laboratory Research Scientist, Francis Crick Institute
Jase Gehring, PhD student, University of California, Berkeley
Thomas A. Gerken, Professor, Case Western Reserve University
Melissa A. Gray, PhD student, Stanford University
Stuart M. Haslam, Professor, Imperial College London
Gaelen T. Hess, Postdoc, Stanford University
Ramón Hurtado-Guerrero, Professor, Universidad de Zaragoza
Svend Kjaer, Deputy Head, Structural Biology Science Technology Platform, Francis Crick Institute
Jennifer J. Kohler, Professor, University of Texas Southwestern Medical Center
Zhen Li, Postdoc, Imperial College London, Francis Crick Institute
Vivian S. W. Li, Group Leader, Francis Crick Institute
Liang Lin, Postdoc, Northwestern University
Yi-Chang Liu, Postdoc, Stanford University
Stacy A. Malaker, Postdoc, Stanford University
Leonhard K. R. Moeckl, Postdoc, Stanford University
W. E. Moerner, Professor, Stanford University
Milan Mrksich, Professor, Northwestern University
Nicola O’Reilly, Head, Peptide Chemistry Science Technology Platform, Francis Crick Institute
Keyvon Pedram, PhD student, Stanford University
Jessie Peh, Postdoc, Stanford University
Chloë Roustan, Senior Laboratory Research Scientist, Francis Crick Institute
Katrine Schjoldager, Associate Professor, University of Copenhagen
Benjamin Schumann, Group Leader/Lecturer, Imperial College London, Francis Crick Institute
Ambrosius P. Snijders, Head, Proteomics Science Technology Platform, Francis Crick Institute
David Spiciarich, PhD student, University of California, Berkeley
Tyler J. Stewart, PhD student, University of Alabama at Birmingham
Megumi Takashima, Undergraduate student, University of California, Berkeley
Omur Y. Tastan, Senior Laboratory Research Scientist, Francis Crick Institute
Suzanne Timmermans, Master’s student, Radboud University
Hans Wandall, Professor, University of Copenhagen
Lauren J. S. Wagner, PhD student, University of California, Berkeley
Philip Walker, Head, Structural Biology Science Technology Platform, Francis Crick Institute
Simon P. Wisnovsky, Postdoc, Stanford University
Thomas M. Wood, Master’s student, Universiteit Utrecht
Mia Zol-Hanlon, PhD student, Imperial College London, Francis Crick Institute
Lauren Wagner, PhD student at University of California, Berkeley
What makes this so exciting?
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.
What were the biggest challenges?
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.
What advice would you give to someone starting their career in chemistry?
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.
Omur Tastan, Senior Laboratory Research Scientist, Francis Crick Institute
What makes this so exciting?
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.
Why is chemistry important?
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.
Stacy Malaker, former postdoc at Stanford University (now Assistant Professor at Yale University)
How will this be used in real life applications?
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.
How important is international collaboration?
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.
Ben Schumann, Group Leader at the Francis Crick Institute and Lecturer at Imperial College London
What strengths did people bring?
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!
Where do you think the biggest impact will be?
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.
How do you see this developing over the next few years?
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.
Anthony Agbay, undergraduate student at Stanford University
Did you face any challenges?
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.
What does good research culture mean to you?
A good research environment or culture is one that fosters growth and learning amongst everyone involved, even someone brand new to science and research.
Why is chemistry important?
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.