Modern medicine is outstanding. Cancer survival rates have doubled in the last 40 years (Cancer Research UK), paralysed patients can walk again and there has even been a child born with the DNA from 3 parents. Unfortunately, modern medicine also has a dark side, and we are in the midst of a losing battle.
The enemy? Antimicrobial resistant micro-organisms.
As medicine advances, our desire and ability to treat numerous illnesses increases. In the last 50 years or so, we have developed hundreds, if not thousands of techniques for curing diseases caused by bacteria, viruses, parasites and fungi. These achievements, however, have not come without a cost – micro-organisms have begun to develop resistance to our medicines. In much the same way a person could grow tolerant to the effects of alcohol after multiple exposures, micro-organisms such as bacteria have begun to resist the drugs we prescribe to eliminate them. Antimicrobial resistant micro-organisms (ARMOs) are commonly referred to as superbugs.
Since the introduction of antibiotics in the 1950s, once life-threatening bacterial infections have become easily treatable. Antibiotics are so effective, in fact, that they have long been overprescribed, with some doctors even prescribing the drugs for illnesses which aren’t caused by bacteria at all; according to the CDC (2016), as many as 1 in 3 prescriptions of antibiotics are unnecessary, or even useless. On top of this, livestock are pumped full of antibiotics to allow the animals to survive in less than ideal conditions, and these antibiotics then pass into our systems when we consume animal products.
All of these extra antibiotics in our systems are providing bacteria with countless opportunities to develop antibacterial resistance. We are now in a situation where antibacterial resistant bacteria are responsible for 2 million infections and over 23,000 deaths in America each year (CDC, 2016).
As in all wars, in order to defeat our enemy we need to understand it. Dr Damien Keogh works at the Nanyang Technological University in Singapore and has been studying how micro-organisms behave in polymicrobial infections – the most common type of infection, where a host is infected by multiple organisms at the same time.
Dr Keogh’s aim was to investigate the role Enterococcus faecalis bacteria plays in facilitating the production of Escherichia coli bacteria in polymicrobial infections.
His study revealed that e-faecalis secretes an amino-acid called L-ornithine, which triggers e-coli bacteria to synthesise enterobactin siderophore. This is a molecule which binds and transports iron in micro-organisms, and e-coli requires iron in order to grow and multiply. Without e-faecalis, e-coli wouldn’t produce enterobactin siderophore and so would fail to thrive in iron-limiting environments (the environment created by the body during infection).
We spoke to Dr Keogh to find out more about his work.
1. Can you give us an overview of your job and research interests?
I’m a Senior Research Fellow at Nanyang Technological University in Singapore and I work in the field of bacterial pathogenesis. The Singaporean government invest a considerable amount of resources in scientific research here. I’m fortunate to work in this environment and get the chance to interact with brilliant scientists that are attracted here from all over the globe to one small island.
I have many roles and it is difficult to summarize a typical day. I’m expected to conceive, design, and execute research projects to answer important scientific questions. Although I work in a Research Centre of Excellence which is 100% research focused, I am also expected to mentor PhD students, or visiting undergraduates from the University. I have to write papers for publication or grants to get funding. I am also expected to travel and communicate the latest research work at international conferences.
For the past 3.5 years, my research has been focused on the contribution of bacterial biofilm (this is the most common state bacteria are found in) to diseases. Bacteria seldom live in isolation and I therefore investigate how groups or communities of bacteria interact and generate infections. So, I’ve created some useful models of biofilm in the lab to help me determine the components governing interactions between bacteria. And then, I translate these models to animals to prove that these are real events.
I am proud to be a total science nerd so I love all science from space exploration to the microbial world! But I work as a microbiologist, so one of my main research interests is the contribution of metals to the growth and response of bacteria. But I’m increasingly interested in how bacterial metabolism influences the other bacterial species or environments in which they interact. Without metabolism there is no growth, no virulence…just persistence. I think it’s interesting to see how bacteria upgrade their metabolism capacity by interacting with other species to fit the gap or to exploit their resources.
2. You have recently had a study published in the prestigious Cell journal. Congratulations! Could you give us an overview of your research?
Much of my work in Singapore focuses on a bacteria called E. faecalis which has two different lives – as a commensal bacteria (colonizing our gut immediately at birth and staying with us throughout life) and as an opportunistic pathogen (found in UTI, CAUTI, wound, gut, and heart infections). This bacterium is frequently found together with E. coli and other bacterial species in many infections. For this paper, we investigated why this co-occurrence with E. coli is prevalent.
During infection, our body implements an immune response by withholding iron from the infection site. Iron is an essential growth nutrient for almost all living things. This iron-limitation puts the invading bacteria under pressure and they must produce systems/mechanisms to overcome the limitation. E. faecalis is unusual in that it doesn’t have a significant growth requirement for iron, unlike E. coli which does. My work takes advantage of this difference. I created experiments to mimic this iron-limiting environment that these bacteria experience during infection and tested their interaction with each other. We used sequencing technologies to determine what genes were doing during the interaction, deletion mutants to test if particular genes were important in the bacterial-bacterial interaction, metabolomics to identify molecules that were present in the bacterial samples, and a mouse model for wound infection to validate the mechanism.
The general picture of this discovery is that bacteria are sensing ‘metabolites’ (i.e. L-ornithine in this work) in their environment and responding accordingly. Together they could share and cooperate (as in this project) or alternatively they might take advantage of one another.
3. The study looks at the behaviour of bacteria in polymicrobial infections. Prior to reading your paper I’d never heard of such an infection, but it is my understanding that they are caused by a number of different infectious agents working ‘in tandem’ with each other to attack a host. They sound like quite formidable opponents to modern medicine. How common are they, and how much do we really know about them?
The majority of bacterial infections are polymicrobial. Either two or more pathogens invade a host, or a single pathogen interacts with the host’s microbiome during infection. In this work, two bacterial species were studied during polymicrobial infection. Polymicrobial could also refer to interactions between a bacteria and virus, fungus, yeast, etc etc. From a clinical perspective, often it is the dominant pathogen that is measured and determined to be the causative agent of an infection with less abundant species being classified as ‘contaminants’ – this perspective has now changed.
Bacteria are rarely found in isolation. Traditionally, for microbiology it was important to isolate a species and investigate it on its own (referred to as Koch’s principles). Current research technologies (microbiome research, next generation sequencing technologies, metabolomics, data analytics) are now sophisticated enough to study bacteria together as groups or communities of species. By investigating bacteria in communities we can better understand the mechanisms governing their actions.
Many of the early studies from pioneers of microbiological research such as Louis Pasteur and Alexander Fleming were actually the result of polymicrobial research – Fleming’s discovery of penicillin from a contaminated nutrient agar plate being an example.
4. How useful will your findings be to the general public? For instance, might there be clinical applications to your work?
Drugs to treat bacterial infections are limited and very nearly exhausted due to the emergence of antibiotic resistant bacteria. This really is a serious problem with fundamental implications for modern medicine. Very soon even the most routine operations or simplest cuts and abrasions will be a serious concern. We need smart strategies to best use the current set of drugs. Understanding and mapping synergistic interactions that facilitate polymicrobial infections will help us to best use current antimicrobial drugs.
Investigating polymicrobial interactions will also help identify new targets for antimicrobial drugs, and possibly lead to the discovery of new antibiotic-like compounds that could be clinically useful (such as antimicrobial peptides).
5. Research can take months or even years to complete. How long have you been working on this project, and throughout that time were there any points when you doubted that you would achieve a ‘positive result’ at the end?
I have had some of the ideas included in this work for a long time. But 3.5 years ago I was invited to interview and moved to Singapore for this position and proposed this work. This is definitely one of those big projects. Research is full of doubt, and it is this doubt that drives a good researcher on further. Without it, you would simply accept things without question, by faith. It is the questions that doubt raise that opens our mind to new knowledge, or at least, the desire to obtain it. This is the starting point for science.
I actually wish I could publish all of the ‘negative-results’ because often these are far more informative. In my mind, results are just results and need to be interpreted.
6. How does it feel to work on a project for so long and not only have positive findings to show for your efforts, but to have such a high-quality journal recognise your work?
Immense relief! The academic system and how it measures work progress is outdated and unfair. So having a cool project like this was very lucky from the beginning but yes, it took a lot of hard work by a lot of talented people to bring this together. I feel very fortunate to have had the chance to work on my ideas like this.
7. In your opinion, what was the most exciting part of this project?
The day (by day I mean 3am in the morning!) I came up with the idea for the “proximity assay”. I couldn’t wait to get to the lab and set it up. To see this develop over the coming days and show the growth enhancement for E. coli was awesome!
8. There is always further research required after any study – what’s next for you?
This is just one of my projects. I have another due to be submitted this month and it characterizes a new form of metabolism that I’ve discovered in bacterial biofilm. I think the link between metabolism and virulence are the next scene for microbial pathogenesis and I’m very excited to take my work in that direction.
9. Clearly no two days are the same in the life of a research scientist, but I wonder if you can you give us an idea of a working day for you?
Stress, never enough time, project management, communication, creation, and data interpretation.
There is a constant pressure to balance the lab work that’s needed to run the experiments with the office work that is equally important. Simply – there is never enough time.
10. You are originally from Dublin but have since moved to Singapore – how does life compare, both as a scientist and a citizen?
Singapore is a great place to live but it does take time to adapt to life in South East Asia. Throughout the year it is constantly hot, making trips outside from the aircon-security of home or office a sweaty challenge. But you get used to this and learn to deal with it. Singapore is very convenient once you can afford it (one of the most expensive countries in the world!) and I thoroughly enjoy all the sports activities, sights, events, and experiences it has to offer. Definitely the most rewarding experience here is being able to make so many friends from all over the world! Singapore is a tiny country but has attracted people from all over. I’m lucky to have friends from all over Asia, Europe, Australia, Canada, and USA. If you are open-minded and interested you can learn so much about other cultures while living in Singapore.
I was educated and trained as a research scientist in Dublin. I was extremely lucky to have the mentors that I had. But the academic system and funding just can’t compare to the investment the Singaporean government has made in research and development here. I use my Irish-acquired experience in a Singapore funded environment. It’s not without its challenges but it is working well for me.
11. What inspired you to pursue science as a career? Did you ever consider another career path?
I have always questioned things and imagined alternative hypothesis. I’ve been doing this since very young although I didn’t always realize it. The Biotechnology degree I took at university really gave me a strong broad science foundation and set me up for the field of science I work in now. But it was my PhD advisor and mentors from Dublin who inspired me. Everything about the Dublin research team and our work convinced me to pursue a career as a research scientist.
I have not had the most direct career path so far! After earning my PhD, I worked for some years on a BioPharma-funded project (based within University) and later on a commercialization program that resulted in a StartUp Company establishing. Now, having gone back to ‘true academic research’ the university system seems not to know how to measure this alternative contribution (the classic academic approach is to do academic research and publish and repeat….). I think you always need to be open and ready to switch career direction or be ready for new opportunities. I love the idea of working in the private sector and regularly interact with colleagues/friends in these areas.
12. Is there anything else you think our readers may be interested to know, about your research, the career of a scientist, or even life for an Irishman in Singapore?
South East Asia is one of the most beautiful and culturally diverse regions in the world. Singapore is a fantastic place to set up and explore the surrounding environment. It is definitely different to Europe and there are a lot of challenges to face when moving here, but once you learn to live with these challenges (or avoid them) life is great.
It’s hot! Dublin is cold! That’s not going to change so you must embrace it. I love doing sports in the heat now. It’s much more effective.
You can read more about this research in the published article from Cell.