Virulence Management
Using evolution to make pathogens safer
Since infectious diseases like the cold or the flu have short generation times, you can actually see them evolve into different strains over a few months. Can we use this to our advantage? There’s an under-discussed approach to dealing with human pathogens that attempts to do just that, known as “virulence management”. The idea is to encourage pathogens to evolve into strains that inflict less damage.
I want to introduce this concept in more detail, but to do that, we have to understand why we have parasites that evolve in the first place.
Acquired Immunity
Our journey starts with the first of three papers by Stephen M. Hedrick on what he calls “Disease Ecology”. Of all of the papers I link here, his paper The Acquired Immune System : A Vantage from Beneath is the one I recommend the most. The final line of the abstract is perhaps the most striking:
By selecting for ever-more-devious parasites, the acquired immune system is the cause of it’s own necessity.
What does he mean by this? Hedrick reminds us that acquired immunity is a relatively recent invention. While all animals are beset by parasites, invertebrates lack an adaptive immune system, the network of immune cells that can target and destroy any possible disease.
How do invertebrates survive without an immune system that adapts to new threats? Hedrick’s answer: they don’t have to. Because pathogens rely on their host to survive, they face a strong evolutionary pressure to avoid killing them. If the host dies, the parasites go down with the ship.
In animals without an adaptive immune system, the host and pathogen find a stable equilibrium. As Hedrick points out, invertebrates are doing just fine despite carrying lots of parasites.
In animals with an acquired immune system (read: humans), the immune system is constantly adapting to new pathogens, forcing these pathogens to adapt as well. Pathogens mutate quickly and have short generation times in order to adapt to our changing immune system.
Hedrick argues that the short generation times of infectious diseases means that the work of the adaptive immune system is futile; we don’t have a way to out-adapt such a versatile threat.
But if the invertebrates are doing fine without acquired immunity, how did we get locked in this endless struggle?
Evolution only cares about you out-competing your neighbor. If you have an immune system that adapts to the flu and your neighbor doesn’t, you are going to have a better chance of passing on your genes. In this sense, adaptive immunity can be fitness enhancing. Competition to have a stronger immune system led to the adaptive immunity we have today. Unfortunately, this meant that adaptive immunity spread to the entire population, locking us in a wasteful struggle against an enemy we can’t defeat. It reminds me of an old joke:
Two guys are hiking through the mountains when a grizzly bear appears on the trail.
One guy takes off his hiking shoes, opens his backpack, and puts on his running shoes.
His friend says, "What are you doing? You can't outrun a bear!"
The first guy replies, "I don't need to outrun the bear. I just need to outrun you."
Virulence
With or without an adaptive immune system, parasites are a fact of life. But what determines how sick we get?
As we saw in the last section, pathogens and hosts co-evolve. Hosts evolve to mitigate the damage done by the pathogen, while pathogens evolve to dodge host defenses and steal resources. Pathogens have to avoid taking too many resources from the host; if they do, the host could die and bring the pathogen down with them. The degree to which a pathogen damages it’s host is called “virulence”, and the tradeoff between virulence and host health is the focus of optimal virulence theory.
The exact nature of the tradeoff between stealing resources and host health also depends on how the pathogen is transmitted. If the pathogen is transmitted by direct contact between people, it can’t make you too sick, otherwise you won’t come into contact with others.
The theory suggests that sexually transmitted infections should “hide” from their hosts by showing few symptoms. If someone is visibly sick, they (and their parasites) are going to have a hard time getting lucky. For example, Hedrick notes that HIV has relatively little effect on its host for years before finally culminating in AIDS. In fact, it’s common for people with STI’s such as chlamydia, gonorrhea, and HPV to show no symptoms, a nice validation of the theory (though its concerning if you have an STI; get tested!).
Infections transmitted though the air or surfaces have a different tradeoff. Their hosts have to come close to other people in order to be transmitted, but not too close. Touch surfaces can remain infectious for hours or days, and a sneeze can spread infectious particles across a room. I haven’t seen anyone say this explicitly, but I would guess that these diseases evolve to middling levels of virulence. They should make you sick enough to cough and sneeze, but not so sick that you avoid the office entirely.
Some pathogens don’t depend on people for transmission; malaria relies on mosquitos to transfer the disease between people. In fact, incapacitating people may make it easier to transmit malaria, since it’s easier for mosquitos to bite an immobile person. This explains why a malaria infection is so devastating for humans and so benign for mosquitos.
Hedrick closes by suggesting that medicine and the acquired immune system may not be up to the task of stopping pathogens. Anything we do, evolution will find a way to avoid it. Our continuing fight against antimicrobial resistance is just one example of this broader trend. Instead, our best chance to reduce the impact of infectious disease may come from sanitation, vector control, and education.
Virulence Management
So, the relentless nature of pathogen evolution means that infectious disease will remain part of our lives for the foreseeable future. On the bright side, thinking about pathogen evolution offers new opportunities for managing infections.
Paul W. Ewald has suggested that we might be able to make pathogens evolve lower levels of virulence. This is the guiding principle behind “virulence management”. If we can change the evolutionary context pathogens live in, we can modify them to be less harmful.
There are several ways to do this. Sanitation and eradication of insect vectors can ensure transmission only occurs when people are close to each other. By making close contact necessary for transmission, parasites have to be less virulent to ensure that their host actually leaves the house1.
Stronger behavioral responses to symptoms can help. If people who felt ill avoided contact with others, pathogens would face a strong incentive to leave their hosts unharmed. Another possibility: remote work makes it easier to stay out of the office when you’re sick, which should push parasites towards milder infections.
I find myself wondering if we could be more direct about breeding different strains of a disease. For example, we could quarantine people with a virulent strain but let asymptomatic people spread theirs around. We could even select for different traits, preferring, for example, a strain that causes congestion over one that makes people cough2. Could we domesticate pathogens just as we’ve done for so many other species?
Conclusion
What I like about this idea is how much it explains and how many new possibilities it generates. Virulence management seems like a promising way to control human disease, and I want to see more discussion in biosecurity circles. By switching our goal from eradication to domestication, we may discover a way to live peacefully with a problem that is almost as old as life itself.
Further Reading
For people interested in this area, here’s a list of relevant publications:
Stephen M. Hedrick’s series on disease ecology:
Understanding Immunity through the Lens of Disease Ecology
The Acquired Immune System: A Vantage from Beneath
Paul W. Ewald has a short talk about domesticating diseases and a textbook on the evolution of disease.
Some papers studying the evolution of human pathogens:
The evolution of transmission mode
Within-Host Population Dynamics and the Evolution and Maintenance of Microparasite Virulence
The evolution and expression of virulence
Worms and malaria: noisy nuisances and silent benefits
Some examination of the implications of vaccination for pathogen evolution:
The evolutionary consequences of vaccination
Imperfect vaccines and the evolution of pathogens causing acute infections in vertebrates
General reviews of virulence management:
Beyond killing: Can we find new ways to manage infection?
Darwinian interventions: taming pathogens through evolutionary ecology
Challenging the trade-off model for the evolution of virulence: is virulence management feasible?
This is another reason Far UV-C lighting is so exciting, with the ability to sanitize indoor air, airborne pathogens can only be transmitted when people are close to each other. This should slow transmission and lead to lower virulence.
It’s important to consider the impacts of vaccination in this context. Vaccines give the adaptive immune system a head start, making infections less deadly. However, vaccines may also encourage short infections and rapid mutation, which matches our understanding of the cold, flu, and coronavirus. Can we modify vaccines to encourage the spread of lower-virulence strains?