With the ever-increasing potential of new technology and the exponential growth of the life sciences field, researchers are always running into new problems to solve. In this interview series, we get scientists’ opinions on the ‘Big Challenge’ in their field and the steps being taken to address it. From new and unique hurdles to fresh takes on common problems, we dive into the complexities of the research landscape.
In this interview, we chat to Craig MacLean (Professor of Evolution and Microbiology, University of Oxford) about the challenges surrounding antimicrobial resistance, and how understanding the bacterial genome could help in the fight against infectious disease.
FLG: What is your background and role?
Craig: My name is Craig MacLean, and I’m Professor of Evolution and Microbiology at the University of Oxford. My background is actually in evolutionary biology, I trained in very classic evolutionary theory. Then, I became interested in microbes; they gave me a really good tool to test evolutionary theory because of how quickly they could evolve. You can do experiments in the lab where you watch bacteria evolving in real time and use that to test evolutionary theory.
But as I moved along, I became more and more interested in understanding microbes in their own right, and antimicrobial resistance (AMR) really grew as a health problem. So, I’ve moved from studying very blue skies, evolutionary biology, to really working at the interface of evolution and infectious disease.
FLG: What is the ‘big challenge’ in your field?
Craig: AMR is a very complex and multifaceted problem, and there are many challenges. I’m going to focus on challenges that are related to genomics.
A long-standing challenge has been predicting AMR from genome sequences. There’s been a fundamental revolution in clinical microbiology that has been driven by increased sequencing of pathogen isolates, and just how much easier that has become. There’s a lot of interest in the ability to directly predict AMR from genome sequences, because that has a lot of potential as a diagnostic tool.
Where this is most important is in something like tuberculosis (TB). TB remains one of the leading causes of death due to infectious disease; mortality due to TB is greater than the combination of HIV plus malaria. When people have TB infections, measuring the resistance of the isolates phenotypically takes a few weeks, whereas by genome, theoretically, it can be done within days, maybe hours. That’s the clearest example of where there’s going to be a huge clinical benefit from being able to predict resistance directly from genome sequence.
But that’s not really what I work on, so I want to focus on another challenge, the challenge of understanding the bigger genomic context of AMR. Traditionally, people in the AMR field focus really strongly on a small number of genes that clearly have big effects on antibiotic resistance. The prototypical example of this would be horizontally transferred beta-lactamases that confer high levels of resistance to a whole range of beta-lactam antibiotics that are very important in the clinic. But what I want to focus on is understanding the bigger genomic context of AMR.
For example, how does the rest of the genome influence the ability of bacteria to acquire resistance genes? This is going to tell us something about how evolvable bacteria are, how readily they acquire new resistance genes and how the rest of the genome moderates the pleiotropic effects of those resistance genes. Resistance genes often have all kinds of important phenotypic effects on traits like competitive ability and fitness. If we understand how the rest of the genome moderates those, we can potentially identify the Achilles’ heel of antibiotic resistant bacteria. Say, for example, if we identify that there’s a gene X, and it makes a particular resistance gene really costly under these conditions, then we could potentially modulate the conditions in the clinic so that resistance becomes costlier to the bacteria.
FLG: Why should people care about this challenge?
Craig: I think AMR is going to be one of the biggest challenges that humanity will face in the 21st century. For most of human history, infectious disease has been a leading cause of death, and we’re tragically in a situation where we’re heading towards that being the case again. Resistant infections are predicted, by some models, to be the leading cause of human mortality by the mid-21st century, on par with cancer. The tragedy that those overall numbers hide is that if we compare AMR and cancer, we know that the risk of cancer increases exponentially with age, meaning that people who died from cancer are predominantly the elderly. But with resistant infections, it’s actually two groups who are very much at risk; the elderly and immunocompromised, but also children who are under the age of five. I think that this is something that often gets missed when people just look at the overall numbers.
FLG: What is being done to tackle the issue, or what should be done to tackle the issue?
Craig: I want to focus on the challenge that I’ve highlighted, which is really to understand how the rest of the genome impacts AMR. What are the costs and benefits associated with resistance genes, and how easily can bacteria acquire them?
I think that there are a number of challenges there, and what we really need to understand is how the rest of the genome influences phenotypes that are relevant to AMR. This is a big challenge. We know what some of those phenotypes are, for example, the level of resistance provided by a gene. We also know that, often, acquiring resistance genes comes with these pleiotropic costs. For example, acquired resistance genes make bacteria worse competitors, it makes them less virulent. So, we know that these costs are an important phenotype. In fact, epidemiologically, we think that these costs really are a key driver of the rate at which resistance spreads in populations and how sensitive or how stable resistance is after we stop using antibiotics. We know that these phenotypes are important, but we don’t understand much about the genomic basis underlying them, and this tends to be more subtle and quantitative effect on phenotypes that are quite different from the yes/no phenotypes that microbiologists usually think about. So, I think there’s a real challenge there for people in the bacterial genomics world to really understand this broader context of AMR, and how the rest of the genome influences all these other important phenotypes.
FLG: What is your advice to people breaking into the field?
Craig: My advice would be to think about problems broadly and outside the box, and to get good at working with other people. This is an area where a lot of the most exciting breakthroughs are made not by individual researchers or small teams, but by big teams of researchers. I think that is really part of the challenge for people breaking into the field, getting good at teamwork.
Enjoyed this interview? Craig MacLean is one of 250+ speakers joining us at The Festival of Genomics & Biodata in January. Here’s what he had to say about the event.
FLG: Finally, could you tell us what you’re looking forward to about the Festival and why you chose to speak?
Craig: I generally say yes to any opportunity to present my work, especially when presenting to people who are not part of the normal audience that I speak to. I think that’s always exciting. I’ve had a look at the lineup of speakers and it looks like there are going to be some interesting talks. I’m also looking forward to learning some new science and having the opportunity to present what we do to people who I haven’t met before and to maybe a slightly different audience than I’m used to speaking to.
Register here to hear more from Craig and the rest of our expert speaker faculty in January.