Distinguishing between Self and Other: Q&A with Dr. Karine Gibbs

Dr. Karine Gibbs
Dr. Karine Gibbs

How do you distinguish between self and other? That’s the question Dr. Karine Gibbs, an Assistant Professor of Molecular and Cellular Biology at Harvard, is trying to answer. Using the bacterium Proteus mirabilis as a model, Gibbs and colleagues are working to understand how bacteria discriminate self from non-self.

P. mirabilis is the culprit in most catheter-related urinary tract infections (UTIs). But UTIs aren’t the bacteria’s only talent. When migrating as a swam across a surface, populations of the bacteria display a remarkable phenomenon: swarms of the same strain merge, while swarms of different strains form a visible boundary between each other. This behavior suggests that P. mirabilis swarms are capable of self vs. non-self recognition leading to territoriality .

Looking for the molecular mechanisms underlying this ability, the Gibbs lab has identified a set of genes in P. mirabilis that encodes the components necessary for self vs. non-self recognition. Martha Henry sat down with Dr. Gibbs in her office in Harvard’s BioLabs to talk about the work.

 Martha Henry: What do you mean in of terms self and non-self in regards to bacteria?

Dr. Karine Gibbs: I don’t think that the definition for self in bacteria has been well defined. That’s one of the active questions. In my group, when we talk about self vs. non-self, it really is about kin. We’re talking about things that are closely related genetically, meaning that they have nearly identical genomes—mostly siblings.

Non-self can be easier to define, such as different bacterial species, different bacterial isolates. Large regions of the genome may be different.

What does Proteus mirabilis do when it distinguishes something as being other?

Mature swarm of P. mirabilis
Mature swarm of P. mirabilis

In the laboratory, when P. mirabilis is in liquid, it can swim using appendages called flagella. When on a surface that has at least a little bit of a wetting, P. mirabilis will differentiate: instead of being short, one-to-two-micron long cells with few flagella, they grow into a single cell that’s anywhere from ten to 80 microns long with many flagella. These long cells, if they’re next to other neighboring long cells, can move outwards together forming a single larger colony called a “swarm”. When this set of swarming bacteria meets another set of P. mirabilis that’s swarming, the two populations merge if they are self and form one single super swarm. If they meet a P. mirabilis strain that is different, a boundary forms.

Is it each bacterium for itself, or do bacteria work together for the good of the genetically identical group?

 That’s a hot debate. With the isolate that we work with, we see competition with bacteria that are different, but we also see elements of cooperation among cells that are siblings.

Why does an organism need to recognize itself? What advantage does a bacterium have in being able to differentiate self from others?

When you look at sentient animals, there is an advantage for those that are closely related to work together, for example, wolf packs, ant colonies, and honey bee colonies. Not all organisms are social, but for those that live in social packs, there appears to be an advantage for coordinating resources for survival.

There’s a theory, as described in E. O. Wilson’s book Sociobiology, that the most intense competition in animals isn’t between species, for example, wolves and elk, it is actually within a species, for example, between two wolf packs; in other words, within family groups of the same species. Competition within a species is particularly fierce because both populations likely have relatively equivalent fitness for a given environment. I would imagine that for most organisms, the choice is either to share the environment or to dominate.

Cells from two populations of P. mirabilis intermingle on a surface.
Cells from two populations of P. mirabilis intermingle on a surface.

To extend this to bacteria, when faced with organisms that are quite different (for example, a different species), it’s likely that this foreign bacterium will have a different fitness for the environment and likely inhabit a different niche within that environment from one’s own, and that’s fine. But if you have two bacterial isolates that have one niche for which they are both optimized, then it is likely that only one can dominate as the evolutionary pressure is to ensure the propagation of each bacterium’s genetic material. We think that’s where self and non-self, as well as competition within a species, comes in.

What happens if foreigners come into your population? How do you know if everyone around you is actually helping out? That’s where cooperation likely comes in. One active question is, within a given environment, do groups that are working with each other have a slightly higher fitness than the groups where it’s just about killing?

So basically, what you’re saying is that bacteria behave like a season of Game of Thrones.

Mass of P. mirabilis swarming cells (dark objects) on a surface
Mass of P. mirabilis swarming cells (dark objects) on a surface

Yes. (Laughs) We like to think of bacteria as single cells, but they’re also single organisms. Each bacterium itself is a single organism. Evolution is driving that its genomic material moves forward, or if it’s going to die, at least its clonal sibling needs to survive.

I think cooperation amongst cells is the hardest concept for we as humans to understand. If you think about any complex animal, it’s all about cooperation between cells. For example, in the vertebrate immune system, cells work together to migrate to sites of infection, to communicate invasion to other cells, to recruit pathogen-fighting cells, and to recruit cells for the restoration of the cells damaged at the site of infection.

When talking about single bacterial cells, there are advantages to working together such as the formation a biofilm or a migrating swarm mass. One benefit when you’re a single-cell organism is dividing the work amongst the group and likely providing added protection for survival within the environment. That’s cooperativity.

At what level of complexity do organisms begin to display self-recognition?

That’s a great question. I don’t know. It’s goes back to how one defines “self,” and that, as we discussed earlier, is still up for debate.

Has your work on the mechanisms of self-recognition in bacteria changed the way you look at current events?

 I would say it differently. What studying bacterial self-recognition for the last nine years has done is make me think about how much of what happens in the world is actually driven by evolution and evolutionary pressures versus intent.

It’s really easy for someone to take our research and say, “Well, if bacteria tell the difference between self and non-self and their colonies combat each other, then humans are tribal, too.” I think that’s a gross simplification. One of the major differences between bacteria and cognitive beings is that we have thought. We have intent.

We can choose to work against what might be an evolutionary driving pressure. We can reason through it. It doesn’t mean that we don’t have inherent biases. Everyone has inherent biases. But just because you have an inherent bias doesn’t mean that you have to act on it. As cognitive beings, we can think about it, acknowledge it, and then actively work against it.

What’s the danger of people like me trying to anthropomorphize the self-recognition behaviors of bacteria?

By far the biggest danger is we don’t know enough yet. The field is incredibly young. So I would just say, tread carefully. It’s great to pose the questions. There are few answers.

One can discuss and analyze self from multiple levels of complexity. What’s self on a single cell level? What’s self when you start talking about groups of cells that are working together? What’s self in a simple animal organism? What’s self in a large animal?

I think self is an underlying component of cooperativity, allowing one to know who cooperative partners are vs. those who aren’t. For every organism, the definition of self will likely be different.

Further reading:
Genetic Determinants of Self Identity and Social Recognition in Bacteria, Science, 2008

Two Proteins Form a Heteromeric Bacterial Self-Recognition Complex in Which Variable Subdomains Determine Allele-Restricted Binding, MBio, 2015

Title photo of individual P. mirabilis cells in which a membrane protein is highlighted using epifluorescence microscopy (Left, phase; middle, gfp; right, false-color overlay). All photos in this post owned by Karine A. Gibbs, all rights reserved. Do not distribute without written permission.

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