From the epic high fantasy novel written by J. R. R. Tolkien to the two outstanding researchers, Prof. Chris Schofield and Prof. Wilfred van der Donk, there is only one small step to take for a bright chemical biologist mind. If you don’t know why, read through this masterpiece to discover the link, and get inspired before attending the Symposium where you will hear these two ring leaders!

 

Rings in the human imagination

Rings occupy a privileged position in the human imagination. These classic forms were even central to rituals enacted by Neanderthals hundreds of thousands of years ago^[i]. Both modern and classical literature make reference to unnatural gifts conveyed to the wearers of rings. Often rings provide their owner with special “dark” powers. Socrates and Cicero both used the Ring of Gyges, which grants its wearer invisibility and hence the opportunity to behave as they please, as the basis for a discussion of human morality. More recently, Tolkien made the “One Ring”, a horcrux infused with the evil of Sauron, a theme around which his masterpiece, The Lord of the Rings, revolved. Conversely, in Ancient Egypt, the Shen-ring (a circle with a cord below it) was a symbol of protection and longevity, particularly for the pharaoh. And if none of the above rang any bells, you are probably familiar with the halo, that continues to signify beatification or similar concepts in numerous religions. Today, we see that our fascination with the perpetuity of rings lives on in the jewelry we wear and the ceremony we ascribe to it, the infinity symbol, and indeed the Olympic rings that have their spiritual home not so far away from us.

However, it is often forgotten how science also has had a longstanding fascination with rings. For instance, the concept of Ouroboros, another ring-like ancient symbol denoting protection and the cyclic nature of life, may have provided the spark of inspiration for Kekulé’s structure of benzene. Given this backdrop, we should really come full circle and ask, how are ring structures greasing the wheels of inspiration for contemporary scientists? This session of the 2020 International Symposium on Chemical Biology has assembled two ring masters to discuss their work with us.

 

Ring master 1: Prof. Schofield

Professor Schofield is a professor of organic chemistry at the University of Oxford, where he is currently chair of the department. Professor Schofield’s research has centered on two areas that zero in on behaviors of cyclic structures. The first area is β-lactam-based antibiotics, of which the non-ribosomal peptide derivative, penicillin, is the poster child. These studies have also led his laboratory to investigate biosynthesis, and enzyme engineering with a goal to generate new antibiotics, particularly based around the β-lactam, carbapenem. On the flip side of the coin, Prof. Schofield’s laboratory is also interested in designing inhibitors of β-lactamases, enzymes that hydrolyze β-lactam antibiotics. These ring breakers are often responsible for antibiotic resistance. Another of Prof. Schofield’s active areas of research is protein regulation through oxidation, particularly oxidation of proline. Proline oxidation, which occurs at ostensibly unactivated carbon-hydrogen bonds, is particularly important as a degron, and regulator of the hypoxia response. Misregulation of this signaling pathway is increasingly implicated in disease etiology, including cancer. Thus, the Schofield laboratory addresses a spectrum of problems all of which require application of the gamut of biological and chemical approaches.

 

Ring master 2: Prof. van der Donk

Our second ring master is Prof. Wilfred van der Donk. Prof. van der Donk is a Professor at the University of Illinois at Urbana-Champaign, and is an Investigator of the Howard Hughes Medical Institute. Similar to Prof. Schofield’s group, the van der Donk laboratory is multidisciplinary and seamlessly blends concepts and techniques from chemical and biological fields. The van der Donk laboratory is also focused on understanding ring-containing antibiotics. However, the van der Donk laboratory does not work on 4-membered rings, but rather macrocyclic peptide-based antibiotics, such as lantibiotics and glycocins. These classes of antibiotics are ribosomally synthesized, but their structures are post-translationally modified to create the mature, cyclic antibiotic. Prof. van der Donk’s group tackles all aspects of these interesting molecules, from discovery, bioengineering, and mechanism of action to how producers avoid autotoxicity. Thus, Prof. van der Donk is another researcher who has had to adopt a holistic approach in order to unlock the secrets enchained in cyclic biomolecules.

 

Join us in Geneva!

We hope that this teaser has stimulated you to round up yours friends and colleagues to come and listen to these two ringleaders of chemical biology together. So, step right up into the auditorium (Campus Biotech, Geneva), perhaps bring a donut, party ring, jammie dodger, bagel, or even some snoepkettingen to fuel your thoughts while these two fascinating scientists regale you with their outstanding work. Although it will be a little late, this session promises to be a perfect way to ring in the new year of chemical biology together!

 

[i] Nature volume 534, pages 111–114 (02 June 2016)