Synthetic glycobiology

The latest Interface Focus issue focuses on synthetic glycobiology — a fusion of the fields of synthetic biology and glycobiology. Synthetic glycobiology involves re-engineering carbohydrates and their protein receptors for useful purposes. We spoke with the organiser of the issue, Professor Bruce Turnbull from the University of Leeds, to learn more.

What is synthetic glycobiology?

Synthetic glycobiology is a fusion of two rapidly advancing areas of science. Synthetic biology is defined as re-engineering biological molecules and organisms for new and useful purposes. Glycobiology is the biology of carbohydrates, in particular the forest of complex carbohydrates that coats the surface of living cells.

Anything that approaches the cell membrane, for example another cell or a virus, needs to descend through this forest — so nature has evolved proteins that can interact with specific sugar structures at the cell surface to mediate adhesion and entry into cells.

Synthetic glycobiology involves re-engineering the carbohydrates and their protein receptors for useful purposes.

Why is synthetic glycobiology important?

Glycobiology is really important for many biological processes — from fertilisation to inflammation — and interactions between carbohydrates and proteins provide the mechanism by which many viruses and bacteria latch on to healthy cells.

The ability to manipulate any of these processes with re-engineered sugar-binding proteins (called lectins) or re-engineered carbohydrates opens the possibility of mimicking or intervening in these important biological processes.

The specific carbohydrates that are displayed at the surfaces of cells differ depending on the type of cell, and often they change when a cell becomes cancerous. This opens opportunities for diagnosis of cancer if we can develop protein probes that can recognise specific tumour-associated glycans. Such probes could also be useful as targeting agents for drug delivery.

What is the aim of this Interface Focus issue?

We were delighted that the Royal Society agreed to fund the first conference that was focused on the emerging field of synthetic glycobiology. This issue of Interface Focus contains research articles and reviews written by some of the scientists who contributed to the conference.

Our aim in both the conference and Interface Focus issue was to start to define the field of synthetic glycobiology; to review the state of the art in the field; and to promote synthetic glycobiology as a new strategic direction for glycoscience.

What are the challenges of synthetic glycobiology?

The challenges of synthetic glycobiology are much the same as the challenges of glycobiology.

Carbohydrates are much more structurally complex than nucleic acids, and proteins and glycosylation is not a templated process that can be manipulated directly using classical molecular biology techniques.

Protein-sugar interactions are often quite weak, and physiologically useful binding requires many individual weak interactions working in concert to achieve the high affinities and selectivity that nature demands. Re-engineering such systems is therefore also very challenging, and often requires multidisciplinary teams of chemists, biochemists, and biophysicists to work together on projects.

However, many talented glycoscientists have responded to the challenge by developing innovative new chemical biology methods, such as biorthogonal ligations and synthetic biology systems for heterologous expression of mammalian glycoproteins, while advances in analytical and structural biology methods have revealed a huge amount of detail of the glycocalyx and its interactions. All these innovations underpin our ability to rationally re-engineer glycobiology systems for new purposes.

What is the future for synthetic glycobiology?

Our first steps in synthetic glycobiology were supported by an EU ERASynBio grant that brought together an international and interdisciplinary team to explore methods to recreate complex cellular phenomena like adhesion, endocytosis, and membrane fusion in simple artificial systems. We see the future of synthetic glycobiology involves moving these ideas towards applications in medical diagnostics and drug delivery.

I am co-ordinating a new EU Marie Sklodowska-Curie initial training network called synBIOcarb that aims to do exactly that, while training 15 early stage researchers in the underpinning technologies that make synthetic glcyobiology possible — lectin and glycan engineering, biophysical and cellular studies, and new medical diagnostic technologies.

We feel it is time to set aside the old narrative that glycoscience is difficult, and to develop ‘Synthetic Glycobiology’ as a new narrative that will be a forward-looking and inherently creative strategic direction for the glycosciences in the decades to come.

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