Microbes that cannot normally be grown in the lab may harbour new antibiotics.
Nature is ingenious. Somewhere in its vast diversity there are bacteria making better antibiotics and fungicides than we could ever invent. The problem is, only one per cent of bacteria species can be grown in the laboratory, which is the first step in any investigation of their abilities. The other 99 percent are a closed book to us.
Bactobio was set up to get over this hurdle, and to identify compounds with the potential to become powerful new antibiotics. This is a hot topic because infectious bacteria are increasingly resistant to existing antibiotics. “Some 1.2 million people die every year because of antibiotic resistance, and that number is expected to increase to 10 million by 2050,” says Dr Daniel Hansen, founder and chief executive of the company. “This is one of the biggest problems facing modern healthcare.”
Our strength is to generate new biological and therefore chemical diversity. Dr Daniel Hansen Founder and chief executive, Bactobio
The challenge of antimicrobial resistance caught his imagination when he was looking for a PhD topic in biotechnology. After an undergraduate degree in human sciences at the University of Oxford, Dr Hansen went to Madrid for a master’s degree in finance, then spent two years in investment banking. “But I’ve always been more impact-driven than money-driven, and I realised pretty quickly that this wasn’t the route for me,” he recalls. “And biotechnology looked like an area where you could make a huge impact.”
He chose to pursue this new direction at Imperial, first with a MSc in applied biosciences and biotechnology in the Department of Life Sciences, then a PhD focusing on to how cultivate unculturable bacteria and screen them for antibiotics.
Bacteria want to grow
The cultivation barrier is difficult, but not impossible, to overcome. “It’s a much-debated view in the field, but I believe that all bacteria want to propagate, so at a basic level it’s just about finding the right conditions,” Dr Hansen explains. In addition to identifying chemical and biological factors that persuade a bacteria species to grow, it is also possible to make genetic changes that unlock growth. “In some cases, we help them a bit, guiding that process and driving evolution towards them being easier to culture.”
Dr Hansen built on his PhD work with a post-doctoral fellowship at the Ludwig Maximilian University of Munich, then began to raise funds for a startup. “That funding allowed me to come back to London, where there is a pool of very innovative young researchers who are driven by impact and cool technology.”
The first person he hired was Dr Mark Wilkinson, another Imperial alumnus. He had completed an MSc and a PhD in the Department of Chemistry, developing a biosynthetic platform for antimalarial drug discovery and a single-molecule method for studying protein folding. He went on to work at GlaxoSmithKline’s Drug Discovery Unit in Madrid, then briefly joined another startup before moving to Bactobio as chief scientific officer in 2020. “Mark has been incredible in setting up the team and setting up the lab,” says Dr Hansen.
Instruments to get started
In those early days, Bactobio lacked the top-flight scientific equipment it needed to make a start. So, it turned to SynbiCITE, the national synthetic biology accelerator established at Imperial. This has a wide range of analytical equipment in the Agilent Measurement Suite, which is now at Imperial’s Molecular Sciences Research Hub, part of the White City Innovation District.
“We had our bacterial library, in its infancy, and we were beginning to build our compound screening and identification platforms, but we didn’t have the resources we required for the full pipeline,” Dr Wilkinson recalls. “So we started working with Dr David Bell and Dr Marko Storch on the compound identification side, using the Agilent facilities at SynbiCITE. Since then, we’ve gained more funding and been able to bring those facilities in-house, but in terms of establishing that part of the pipeline it was really helpful.”
The benefit goes both ways, according to Dr Hansen. “Being able to lend equipment to startups, and to be a partner to them, means that those startups look to Imperial for collaborations and talent later on, and this helps in Imperial’s goal of making London a biotech hub.”
As for the bacteria, they also came from close to home. While some researchers have scoured the world looking for novel bacteria, this was only necessary because only a few of the species they found could be grown in the lab. They were barely scratching the surface of what each ecosystem had to offer. “The bacteria they found were dominated by just four groups of genetic diversity,” says Dr Hansen. “But if you go to your local forest and go deep, as we can, then what you find is 60 to 120 different distinct groups of genetic diversity.”
“Now we have someone with a PhD in soil microbiology and plant-pathogen interactions, from Imperial, who chooses our sites for us,” Dr Wilkinson adds. “And as much as I would like weekly trips to the Amazon rainforest, these sites often end up being a half-hour drive from London.”
Building the team
In building the rest of the Bactobio team, it has been important to find people who are familiar with microbiology and synthetic biology on the one hand, and the power of computing and bio-informatics on the other. “We’ve hired a lot of emerging scientists with recent Master’s or PhDs from Imperial. They have a skill set that did not exist until recently,” says Dr Hansen.
This is a result of the way the joint Master’s and PhD programmes at Imperial are built, with each student often getting a primary supervisor who is a ‘wet-lab’ scientist, and a secondary supervisor who is an expert in computing, or vice versa. “So their training merges the two fields, and they lend themselves perfectly to what we are trying to create here.”
Machine learning is particularly important, helping in small but significant ways at almost every stage of Bactobio’s process. “We are using it to find the chemical and biological components that are missing for cultivation, to assemble our genomes, to filter-out compounds that have already been found, and so on,” says Dr Hansen. “Machine learning is almost ubiquitous in our pipeline now, and our team is part of the new generation that feels very comfortable using these tools.”
Bactobio has been able to apply its innovative approach thanks to a series of awards from Innovate UK, a government agency that supports business-led innovation. “These grants enable us to target additional bacterial and fungal pathogens,” says Dr Wilkinson. “They also help us expand our network, bringing in additional collaborators, and they send a signal to private investors that we are recognised, by experts, as doing innovative science, and doing it well.”
Getting to work
The company’s latest Innovate UK grant, worth £416,000, is the largest to date. It will fund 21 months of work looking for compounds that are active against Pseudomonas aeruginosa, a bacterial pathogen that often becomes resistant to conventional antibiotics. It is a leading cause of sickness and death in people with cystic fibrosis, and the most frequent hospital-acquired infection among critical patients in the UK.
Our Innovate UK grants send a signal that we are recognised, by experts, as doing innovative science, and doing it well. Dr Mark Wilkinson Chief scientific officer, Bactobio
The goal of the project is to find between five and ten promising pre-clinical antibiotic compounds. These will then be licensed out to pharmaceutical companies for further investigation. “Our strength is to generate new biological and therefore chemical diversity, it’s not to take things through clinical trials,” says Dr Hansen.
The other product that he wants the company to generate is young entrepreneurs, people who will add to the crop of startups in synthetic biology that have their roots at Imperial. In addition to Bactobio, this includes LabGenius, created by Dr James Field; Basecamp Research, co-founded by Dr Glen Gowers; and Baseimmune, co-founded by Dr Joshua Blight.
“That is a super-impressive record, and it tells you why we take so many people from Imperial,” says Dr Hansen. “Our belief is that if we bring them in here and empower them to do good science, they will drive our company forward and then, in three or four years, they will leave to set up their own biotech companies and strengthen the network. And Imperial is at the epicentre of that development, in the UK, if not in the whole of Europe.”
Photos: Acacia Diana © Bactobio 2022
Article text (excluding photos or graphics) © Imperial College London.
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