Biology of Microbial Communities - Interview

So I'm Roberto Coulter. I'm a professor of microbiology and molecular genetics here at Harvard Medical School, and I've been here since 1983. I run a lab of about 10 people, all of them postdocs and interested in a number of areas of the microbial world.

And so if, if, I may just start out by saying very, because you may want to ask me some questions specifically, but if I may just start out my, my lab is a bit eclectic in the sense of the type of work that goes on. Some labs are very focused on certain areas. While I'm, if I would say anything characterized in my lab is that every postdoc that is here is focused on an area, but there's almost no overlap between postdoc to postdoc.

So it's, it may be difficult for me to tell you sort of what is my lab and what is my work, because it's not only a work that is very covering many areas, but it's also something that five years ago was Very different than now. 10 years ago, We were working primarily on what was known as stationary face physiology. That is what's happening to cells that are not actively growing.

And that at the time had been the combination of 10 years before that where we had sort of begun to ask those questions. And by then the field had the field, I mean, microbial physiologists in general had adapted to the idea that they should be looking at bacteria that were not growing, which was, and so I decided at that time to abandon that to some degree and enter bacteria that were not only well either growing or not, but were growing on surfaces or at least making a living outta surfaces. This was, this was the concept of biofilms and in, in the mid nineties, engineers were interested in that because of flow issues in tubes, et cetera.

But microbial physiologists and geneticists had not paid much attention to that. So we began to make mutants in back in model systems that were unable to attach to surfaces. And, and so now 10 years later, can I summarize what happened?

Now, I imagine for one, what we have done is focused a lot on basc settles one particularly wonderful model organism that makes spores and thus allows us to look at the very specific pathways of differentiation in the context of cells sitting on the surface as a field. I think what has the last 10 years has, has observed is that, that there's been a huge migration of people who were working on sales in suspension to now looking at what is it that they do when they're sitting on surfaces. So I think that what was a, an engineering centric view of biofilms is now very much taken on the, the, the, the attention of, of many, many different areas of people doing genetics, molecular biology, et cetera, in microbiology.

So what, what has that meant in terms of microbiology? I'm not so sure that it's made a huge difference, except that now there's great excitement in recognizing how different the existence on a surface is than when cells are In suspension. In assembling a Community, there is a level of organization that requires, or that, that this, we are finding that involves the, the communicating of cells with each other.

That is in studying bacterial physiology in a suspension, you and you can see how a cell changes because its environment changes. In no way does that cell need to be in contact in chemical contact or physical contact with the other cells in there. You just averaging across a population of, from what you see in the entire population, what you might surmise is happening in the single cell.

When you are shaking that population and they're all floating in, in, in a liquid, it really doesn't matter that the other cells are there. It matters for the investigator because then you derive the averages, but it really doesn't matter to the cell. Its physiology is, is defined by how it reacts to the environment, not necessarily how it reacts to other cells.

Once the cells settle down and begin to make an accelerator matrix begin to assemble into different cell types within that community, then what's happening is they're beginning to communicate with each other. So the whole area of sales cell communication opens up via the studies of Surface associated communities. The current day Challenges, I, I think in for us, in, in the, in the area of biofilm, say for what we are doing in my laboratory, the idea of being able to follow the lineage of, of an individual cell and what's its fate still requires techniques that we're just beginning to develop.

I say, how do you actually assess the physiological state of an individual cell in the context of thousands of other cells? So technically that's very difficult. We, we have reporter genes, we have ways of doing it, but that still represents a huge challenge to, without disturbing the cell, being able to assess what's happening to it physiologically in other areas that I'm involved with and which involve communicating between cells.

A large challenge is how do you, you you, you know, one of the things that we've come to recognize in microbiology in recent years is that the remarkable diversity that is out there and, and if you want to cast a net that tells you a lot, a very wide net that tells you a lot about the, the microbial world in, in, its in its true state. That is how many signals are out there, how can you cast a net that is even reasonably comprehensive? So a huge challenge conceptually is, is what we are doing with this completely artificial laboratory constructs that where we are observing the bacteria existing, do they really reflect anything of what they're doing in the real world?

I mean, or is it a completely a complete artifact that is that that is either at the level of molecules that they're sending to each other and even the structures that they're forming. So the, the anatomical descriptions that we make of these communities, are they valid for what they really do, what these organisms do in the real world? And, and we don't know because seldom have people been able to go out into the real world and observe what bacteria are really doing there at the level that we can observe it in the laboratory and when we go out there we can observe them, but it's a completely different way Of observation.

Yeah, I try not to be too, Try not to be too prophetic about, you know, what's the work that we're doing going to actually have to do with, with the real world because I'm not convinced that there is a direct connection. But lemme just tell you what people in generally perceive about two, about two areas. One of the areas is this biofilms and, and the other one is cell cell communication.

And so it is well recognized that many of the infections that you see today that deal with that involve bacteria, involve bacteria that are very difficult to treat with con conventional therapies. And it's not that they are genetically resistant at all and they're all conditions, but actually that these bacteria, when they're in these biofilms, the surface associated communities physiologically, they become resistant or tolerant to the treatment of antibiotics. And so for example, you might have an, an indwelling device like a catheter that gets infected, and once that happens, that infection is very difficult to eradicate because those bacteria that are sitting on the catheter are quite resistant to known therapies.

So one of the things that people would hope is that by understanding better the state of cells in the biofilm, that they'll be easier to develop new strategies to deal with those bacteria that conventional strategies do not do not eradicate. So that's one possibility. You can also argue that if we learn how bacteria are behaving in these biofilms will be able to get them to produce better things for us in the future.

Sort of the, the whole concept of bioprocessing, and this goes beyond, beyond therefore medicine. You can imagine in, in many industries that are utilizing bacteria that if we knew how, how to get them to produce things better as as biofilms, they'll, they'll, they could be more effective, more efficient, et cetera. This idea of covering surfaces with bacteria, actually it's, it's interesting it covers almost any surface in the planet.

And so even people who are involved in, in, in shipping lanes can think of, you know, how do you keep the bio performing on their ships so that the ships can be running more efficiently. So the, you can imagine that just understanding the, the, that the natural setting of how bacteria are interacting with surfaces has great impact in, in sort of everywhere. But I don't try to think that what we are doing is eventually going to lead to, to improvements because I, you know, I let that happen on its own.

The other area that I wanted to tell you about was the, the cell cell communication. And, and that's an interesting one because, because we do have things that we call antibiotics and, and the, and the bottom line is that what I was telling you before is in the laboratory and in medicine we know what these compounds are. They're called antibiotics, right?

So it's because they kill bacteria. Now they're actually made by bacteria. Most antibiotics are made by bacteria.

And, and the funny thing is we ha we as, as, as a, as a community of scientists, we are really clueless as to what these compounds are doing in nature.Yeah. We don't have any direct evidence that the bacteria that are making them make them because they want to use them as antibiotics, right? And so they are lots of indications that in fact they are serving as signaling molecules not to kill each other, but to signal.

And so the nice thing about that is that you can sort of turn it on its head and you can say, well, maybe if we discover new signaling molecules, they might actually end up being useful antibiotics. So one possibility of translational research would be, okay, discover new signaling compounds and see if by either jamming the signals, you might actually come up with new therapies or might maybe some of the molecules themselves that you discover as a signaling molecule could eventually become a useful Therapeutic agent. Yeah, that's always tough.

I mean, I can tell you what I, what I might be doing five years from now. I don't know if that's necessarily the most important. You can never predict five years into the future, I think.

But, but I'll come back to something that I said before. I think in terms of microbial ecology, and that involves making communities that are elaborate, looking at interspecies interactions. I believe that we have to really exploit this idea that we can now have better and better handles at the single cell level.

So, so if we can, I think the direction that we need to head is to explore microbial ecology, not by, I mean, it's still useful to go out there into the oceans and to the forest, and I sort of do the stamp collecting that people have been doing for the last 20 years, which has been very useful. But we need to actually begin to see what are these, this myriad species, how are they interacting and how are they're, they're interacting not in the typical scale that we've been looking at thus far in terms of population sizes that are enormous, but rather in population sizes that are germane or real at the level of a single cell. So I think going back to the, to, to the analysis of microscopic analysis of small numbers to see how they're interacting.

So I think that the, the more we do of that, the more we'll learn about the, the, the real interactions and then we can extrapolate that to the communities that, you know, that are happening in the ocean, et cetera. But I think we need to go back in there and look at, at, at scales that are relevant to the size of the bacteria. Most everything right now is being done by averaging through scales that are really whole universes for this organism, right?

So people think a small scale is a centimeter, but in a centimeter, in a cubic centimeter you can have 10 to the ninth organisms and, and 10 to the fourth species in soil, right? So, so we really need to go in there and look at, you know, cubic micron scales and see how are these cells interacting? What's their physiology there?

How are they seeing their world in In that context? If I were starting my Postdoc today, I I to, to, I I am now serious. I do think that every time a new postdoc arrives in my lab, I'm restarting my lab.

And that's very different than most labs, right? So in a sense, I do have that experience every time a new postdoc arrives here, it, yes, there's some tradition of what I've done, but I'm think I'm seeing the world fresh. I think microbial ecology is, is the, is the area that I would do it, but I would do it in the context of either experimental ecology where I can really manipulate and control the populations and the species that I'm looking interacting, not microbial ecology in the sense of, of serving what's out there.

I mean, that's not an area that I think it's important that people do it, but I don't think it's, it's the, is the, is the answer to all of the questions. We really need to look at mechanism, mechanistic basis for interactions between the species. And you've gotta make it simple enough so that you can tackle it.

In fact, my belief is that the whole field of ecology, not just microbial ecology will benefit greatly from experimental ecology. That will come from, from looking at bacterial systems where you have a species that are manageable, where you can really control things. So that's, that's what I would choose to do now.

That is what I'm doing.