Stephen Bentley: bacterial genomics and pathogen surveillance

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Professor Stephen Bentley, now Principal Staff Scientist, joined the Wellcome Sanger Institute in 1998. His team have laid the foundations for understanding and combating resistance to vaccines and antibiotics.

His work on bacterial pathogens has mainly focused on exploring the biological characteristics and evolution of Streptococcus pneumoniae, which can cause pneumonia and other severe infections. Here, Stephen explains how next-generation sequencing revolutionised his work, highlights his team’s strong global collaborations and shares his joy for mentoring early-career scientists.

During his undergraduate degree at Bristol Polytechnic (now the University of the West of England), Stephen studied Applied Biological Sciences. His fascination with microbial biochemistry led to his PhD at the University of Warwick on the molecular genetics of cell division in Escherichia coli (E. coli). He then moved to the University of Cambridge for his postdoctoral research.

“In both my PhD and postdoc, I spent a large chunk of time sequencing just two or three genes – it would take around 10 months with the old-style manual sequencing but it was great fun! During my postdoc, I saw an advert for a job at the Sanger Institute to annotate bacterial genomes. Annotation meant identifying the positions of genes and figuring out their functions from database matches, a task that was in growing demand as more genomes were generated,” said Stephen.

“After all that time in the lab spent sequencing (and annotating!) just a few genes, the idea of exploring a whole bacterial genome was amazing!”

Professor Stephen Bentley,
Principal Staff Scientist, Parasites and Microbes programme, Wellcome Sanger Institute

Years later, Stephen is still excited to be at the Sanger Institute leading a team that studies bacterial pathogen genomes. But his first project was not on a pathogen. It was a bacterium called Streptomyces coelicolor, which gives soil its characteristic earthy smell. S. coelicolor produces nearly all antibiotics available today, so Stephen describes it as “the enemy of pathogens!”

“That was a really cool way to spend my first four years at the Sanger Institute and I ended up as the first author on a Nature paper in 2002. It was such an exciting time for microbiology! But after that, the Institute adjusted its strategy to focus on the leading bacterial pathogens. This made me a little sad because I enjoyed that field – the Streptomyces community was nice to work with,” shared Stephen.

In the mid-2000s, genomic research drastically changed course with the arrival of Next-Generation Sequencing (NGS) technologies. These technologies enable scientists to sequence massive amounts of DNA and RNA in parallel. For context, Stephen explained that traditional Sanger sequencing of just one bacterial genome used to cost around one million pounds and take almost a year of laborious manual work. By contrast, scientists are now sequencing a bacterial genome for as little as £20 and running thousands at a time, taking only a few days.

Stephen said: “NGS absolutely revolutionised what we do. It meant we went from thinking about individual gene function and trying to relate that to the characteristics of the species, to looking at how entire species evolve. That technology shift was the biggest in my career, taking me from focusing on the function of individual genes within a genome to thinking about how a whole pathogen species evolves, particularly in response to the selective pressure of things like vaccines and antibiotics. What is really exciting is that we can now use this information to help us predict, control and prevent diseases from those pathogens.”

When NGS appeared, Sanger Institute scientists first used it to sequence human genomes. Stephen’s group were the first to apply the technology to bacteria.

The team carried out novel population genomics studies to explore the genetic diversity within single strains of two different bacterial species. Both of these strains often live harmlessly in healthy humans, but both are capable of causing serious diseases. These were the first published research applying NGS to bacteria. Their work appeared in the journal Science in 2010¹ and 2011², allowing scientists to understand how a bacterial strain evolved rapidly over just a few decades.

The first study was on Staphylococcus aureus, a bacterium that can cause severe infections such as pneumonia, meningitis, and sepsis. This  was the world’s first application of NGS technologies to track the evolution of the infamous strain, MRSA (or Methicillin-resistant Staphylococcus aureus), which is resistant to many standard antibiotics.

The second was Streptococcus pneumoniae, a major cause of pneumonia and other diseases including meningitis. This study revealed how the pathogen can evade vaccines by rapidly changing its genetics, with over 700 significant changes in this population alone. Often the changes affected genes related to its outer protective coating or polysaccharide capsule.

“I’ve mostly focused on S. pneumoniae ever since. It’s an interesting species because it only becomes a health risk when it reaches places such as the lungs or bloodstream. Research into this pathogen is vital because it’s a leading global cause of severe human infections and deaths, particularly in infants. Pneumonia kills around 2,000 children under five every day.

“This bacterium can successfully evade the human immune system because it can have one of over 100 types of capsule, referred to as serotypes. The vaccines also work by targeting these capsules.

“There are effective vaccines that have helped reduce infections over time, although these only target 13 of the most dangerous serotypes due to limitations in manufacturing. However, we’ve seen that the pathogen can evolve resistance through genetic changes to the capsule, which limits the effectiveness of these vaccines.

My team uses genomics to understand how that's happening and aims to forecast the outcomes of its evolution. This helps us think about designing better vaccines.”

“A key person in my career has been Keith Klugman; a big player in the pneumococcal field and an all-round good person. I met up with Keith at a pub in London one Sunday in 2009 – he was travelling from the US to his home country of South Africa.

“Over a few beers, we discussed NGS technologies and I shared my views on its potential for pathogen genomics. He was very enthusiastic about the science, as well as being generous with his time, advice and sharing his connections.

“We hatched a plan that lead to the creation of The Global Pneumococcal Sequencing (GPS) Project. It’s a global genomic survey of the impact of vaccination on pathogens. This project continues to inform pneumococcal disease control.

“The GPS project has partners in over 50 under-served countries³ and I’m proud that we have helped the community to build capacity. Several partners can now do genetic sequencing locally, and many more carry out their own data analyses.”

This capacity building is important for countries that struggle with infectious diseases because they typically have the highest disease burden.

The data are freely available in the European Nucleotide Archive⁴ and have helped inform the design of vaccines by identifying new bacterial targets.

Stephen’s team recently started using genomics to understand pathogen transmission and link this to human migration. For example, by combining information on the serotype, genotype and drug resistance of one pneumococcal strain his team have measured its rate of spread across multiple countries in Africa⁵. This approach will help scientists estimate how long new outbreaks will take to spread and inform a global treatment strategy.

Another useful NGS technology is deep sequencing within a species. This involves sequencing the same genomic region, sometimes thousands of times. Deep sequencing can reveal a sample’s full genetic diversity and indicate transmission events. For example, if person A has transmitted a pathogen to person B, then a nose swab will reveal person B has less genomic diversity than person A. This is because person B harbours a subset of the bacteria present in person A. This can also be used to understand how multiple strains are evolving.

The team also uses metagenomics, which involves analysing the DNA of a mixed community of organisms all at once (such as everything on a nose swab), rather than isolating individual species. They use metagenomics to explore how the human respiratory microbiome develops from birth and identify the differences between healthy and unhealthy infants⁶. This could indicate how the diversity of the human microbiome affects the likelihood of infection by a pathogen and may reveal a preventative treatment through creating a healthier microbiome.

Stephen recently won the Robert Austrian Lectureship in honour of the American physician who first developed a pneumococcal vaccine. This award recognises Stephen’s outstanding contributions to the field, spanning his scientific findings, their impact on public health and extensive student mentoring.

“I get a kick out of seeing people’s careers develop! I usually meet my mentees when they are PhD students and they are a joy to work with. I think the Sanger Institute’s PhD students are the real innovators of our science – they are super smart and fearless. They all go on to do great things.”

Professor Stephen Bentley

“One outstanding mentorship was with Chrispin Chaguza. I met him during his Masters when we collaborated with his group in Malawi. He joined my team for a three-month research project during the early days of NGS and I co-supervised him through his PhD and first postdoc and remains a close collaborator of my group. He is now heading towards a senior researcher position at a leading university. It’s been so enjoyable to watch him develop into a confident world leader in his field.”

Stephen reflects on his experience at the Sanger Institute and shares his advice for early-career scientists:

“I absolutely love working here, there is such an exciting atmosphere. I remember deciding within two weeks of joining the Institute that I would never leave! We offer researchers access to resources and technology at a scale that just isn’t available elsewhere. Our infrastructure makes it possible to do really cool and difficult research.

“I’d advise genomic scientists at the start of their careers to make the most of the generosity of others and to communicate and share openly. This will help you to learn as quickly as possible. It also allows people to benefit from each other’s work and fosters open research practices.”

Antimicrobial resistance has drawn widespread scientific and media attention. It is an inevitable consequence of antibiotic use because they provide selective pressure for pathogens to become resistant. But if researchers develop preventative vaccines then hopefully fewer people will become infected and need antibiotics.

Stephen emphasises how mathematical models will drive the design of future vaccines and computer simulations will predict how a pathogen population will respond to a vaccine before it is even manufactured. This should result in getting the best vaccines to market faster.

Whilst Stephen has focused most of his career on a single bacterial pathogen, researchers are now generating large amounts of data on many different pathogens. There is scope to improve how these data are used, especially through collaborations with large pharmaceutical companies.

Continued research into bacterial pathogens is vital for supporting global public health. Achieving successful surveillance and treatment of devastating diseases such as meningitis and pneumonia will require equitable collaboration with the countries most affected. Stephen’s research continues to benefit scientists working across the globe.