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Genomics and knowing the enemy.

Updated: May 22, 2023

As Sun Tzu famously said: ‘know your enemy’, or more correctly: ‘If you know the enemy and know yourself, you need not fear the result of a hundred battles.’ This is true not only for human conflict but in what is probably the greatest and longest running battle the human race has ever engaged in: that between humans and their pathogens. Ultimately, COVID-19, our current enemy of focus, might kill 1%, but hopefully, many fewer now that there is a vaccine and better treatments established – and given that the elderly and most vulnerable populations exist in (and partly because of) the locations of the better health-care systems, this is probably not misplaced optimism. But, despite its impact, this is, in historic terms, a minor skirmish in a relatively short war. Before drug treatment, TB killed by some estimates around 1% every year. That’s across many age groups, not just the elderly. It killed my wife’s fathers’ sister at 2 years, her great aunt as an adult, and 1% scaled for the current world population would be around 70 million, compared to an estimated death toll from its start in 2019 to early 2021 of 2.5 million. And TB killed its 1% every year, year after year, but even TB is not as bad as it can be. Consider the plague called the Black Death? In less than 10 years, it is estimated to have reduced the European population by between 30 and 60%, and the world population from around 475 to between 350 and 375 million. An equivalent today would be a death toll in the billions.

When medical students learn about infection and pathogens, it is normal for them to be introduced as pathogenic species. For a few, normally just one, the idea is introduced that things can be more complex so that some strains of a species can be dangerous and others not. An example of this is E. coli which can be a harmless resident of the gut, perhaps even providing protection against other bugs that could make you ill (and even some strains used as health-promoting probiotics), while others cause increasingly unpleasant gut infections with one particularly challenging example that causes considerable deaths and kidney damage. This is a good example for teaching because the different ‘weapons’ the more dangerous strains are carrying are well known, and can be used as an introduction to how the causes of virulence (dangerousness) are investigated.

But, for the rest, it is pretty much a list of villains: the bad bugs you have to learn about: the infections they cause, some of the armaments and defences they carry, the list of enemies we need to know and contend with, and its fairly uncomplicated. If you have some bad bugs, it’s always bad news. If you have other bad bugs where they shouldn’t be or when you are particularly vulnerable – then that’s also something that has to be addressed. But, this model taught generation-to-generation, which is the structure and form of traditional lectures, exam questions, and textbooks – is it right?

The paper by Tong and colleagues is one of a number describing applying genomics to pathogen surveillance and control, which could be interpreted as suggesting a new and different perspective. Yes, you need to understand both the host and the pathogen; both ‘the enemy’ and ‘yourself’, because there is most certainly an interplay between the dangerousness of the pathogen and the vulnerability of the patient, but it is no longer necessary to be so simplistic as to how we define the enemy or fight it. What I see in this and other reports is an emergent pattern in which it is not ‘pathogen species’ but ‘more or less pathogenic strains’ that are evident. A subset of strains causes a disproportionate number of cases, and these have persistence and presence over time and in different settings. Of note in this study was that on several occasions, one clone of bacteria was replaced by a more dominant one in individual patients. It may even be that for the normally healthy, the less dangerous strains may be providing protective effects through their competition with the more dangerous versions. We have perhaps missed something else: that we face outbreaks, epidemics, and pandemics that are occurring in ways that we haven’t previously appreciated because they are mixed with each other and with less dangerous relatives; and perhaps exacerbated by travel, extensive population mixing, and food production and distribution systems. I think that this is exactly the situation. And this greater understanding of our enemy has the potential to transform our future strategies for both attack and defence.

Dr Nigel Saunders, Chief Scientific Officer



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