Our guest blog, written by longstanding Friend and Collaborator Steve Trim, CSO and Founder of Venomtech is presented below.
An early career at Pfizer, Sandwich
“Why spider man is joining forces with ion man” is a newspaper headline I’ll never forget, and one of the few puns about my work that I really liked. This heralded the announcement of Venomtech partnering with Metrion Biosciences in 2017, but my interest in ion channels goes back much further.
After my degree, I moved to East Kent as a molecular biologist at Pfizer Global Research and Development in 1999. Prior to this I only knew of Sandwich as my favored portable lunch, but now I know it as the nearest town to this cutting-edge research institute. It was an exciting introduction to the drug discovery process and included preparing delicate scientific instruments for the oncoming millennium bug. In the mid 2000’s I got the opportunity to join the pain therapeutics team and this started the journey leading to me writing this blog nearly 20 years later.
The involvement of ion channels in pain
Pain affects most of us at some point or another throughout our lives and if you are lucky, this is only acute pain from the mild trauma of misadventure such as stubbing your toe or a hangover. But for millions of people worldwide, pain is a debilitating disease that is difficult to control. Pain processing is a complex conglomeration of pathways ending with even more complex interpretation and emotional overlay in the brain. Ion channels are critical components all along the process from detection to final interpretation of painful sensations. When this process goes wrong chronic pain can become a debilitating disease in itself and this is the front line of therapeutic development.
The role of venoms in ion channel drug discovery
Ion channels are very complex transmembrane proteins and often have conserved structures around ion pores and drug binding domains, making modulation a significant challenge but also an intriguing one. Drugs like Lidocaine deliver good target engagement and local anesthesia without involving motor neuron ion channels, however Lidocaine also does a good job in blocking cardiac ion channels and hence is not systemically useful. This lack of functional and tissue selectivity highlights the challenge of ion channel drug development and is where venoms come in. Evolution has produced endless forms most beautiful and most wonderful at both the species and protein levels. Natural selection is relatively quick to build on any opportunity and modulating ion channels has turned out to be a very common method of subduing prey and warning off predators.
‘Poisonous’ versus ‘Venomous’
Tetrodotoxin is a famous toxin from the Fugu sp pufferfish which blocks sodium ion channels and thus is a formidable defense, and intriguingly it is also found in other aquatic animals such as blue ringed octopus. However, even though the toxin is most likely produced by similar microbes, these animals differ in their delivery of this toxin. Puffer fish are poisonous (the predator does the biting) whereas the octopus is venomous, actively delivering the toxin through a beak-like mouth. Correcting people on the difference between poisonous and venomous has become a constant amusement having called the company Venomtech (and not poisontech 😊). Evolution has had millions of years to hone venoms to block ion channels to stop prey escaping or open pain signaling ion channels to give predators a strong message. So, it’s not a surprise that having only had about a hundred years of concentrated drug discovery, humans are lagging behind nature in selectively and efficaciously modulating ion channels.
The importance of venom-based screening libraries and the creation of Venomtech
It was the abundance of scientific papers on venom peptides, particularly those from Theraposidae (aka tarantula) spiders, that seeded the idea that venom-based screening libraries were needed to unlock the full potential of venom peptides for drug discovery. So, when I got made redundant from Pfizer, I found myself with an idea and some key skills. This included an understanding of the need for better drugs, an understanding of venoms and venomous animals, combined with pharmaceutical health and safety training. I formed Venomtech in March 2010 with the brave ambition to help research around the world to find new tools to treat the most challenging diseases, especially pain. In order to do this, I had to solve the problem of supply and thus had to go back to the source.
Creating a diverse collection of venomous animals
This involved building a lab with the capacity to safely house a varied collection of venomous animals in order to have the diversity needed in the compound library I was assembling. Amazingly enough, acquiring the venomous animals was actually the easy bit, and innovating the safe systems of work was relatively straightforward with my safety training, but was not in common use. We published several papers and even a patent on these novel safe systems which put us in good stead as I grew the team and our customer base.
The next stage was in separating out this phylogenetically and geographically diverse collection of venoms to get the compound library I needed to hit diverse ion channels and nearly all other targets. People often ask us how do you collect the venom and how safe are the animals to work with? Well, my top answer to the first question is always carefully! And the second answer is venoms are a lot safer in the plate than when they are packaged with a brain and injection system! So, it was a steep learning curve to build a lab and then populate it with a large collection of venomous animals, to then safely and recoverably collect their venom. But we did and eleven years later, I’m still fascinated with ion channels, have developed a cosmetic ion channel blocker and spend a lot of time working to develop venom peptides from hits in plates into drug-like molecules.
Adoration of the natural world
Managing any company through the pandemic is tough, but our venomous chemists still got the same care and attention as always, and the global spotlight on science and drug discovery has also been useful. I still relish those opportunities to work with the animals as it keeps my adoration of the natural world fed at a macro level in between the daily fascination of the molecules of biology. I don’t think I’ll ever loose the fascination of ion channels at the interface between biology and electricity. Even though I work with many targets and disease areas, neuroscience has a special place in my own bundle of neurons producing these words.
Metrion and Venomtech have collaborated on a poster, entitled: “Identification of novel scorpion venom peptide inhibitors of the Kv1.3 ion channel and their potential as drug discovery leads for human T-cell mediated disease.” This can be found here (2nd poster, 2018).