eLife Episode 57: Malaria and Myrmecophiles

Compared with “summer babies”, individuals born in the winter months have a higher risk of a range of different diseases, including neurological and neuropsychiatric conditions. Why though, we don’t know. A tempting theory - but one that’s very hard to test - is that the higher rates of infection that prevail in winter might be to blame. Now, as she explains to Chris Smith, Oregon University’s Adrianne Huxtable has come up with a way to explore how inflammation in early life affects the way at least one part of the nervous system develops and operates…

Adrianne - So what we're showing in this paper is that one bout of sickness early on in life can lead to permanent changes in how the neural circuitry that controls breathing functions into adulthood. We know that early life inflammation is really common, but what we don't know is what lasting effect that might have on this important neural circuitry that controls breathing.

Chris - What's the neural circuitry that you're referring to?

Adrianne - The neural circuitry I'm referring to is housed within the medulla, and the drive for breathing begins here and is then transmitted to relevant respiratory-related motor neuron pools, which innervate the muscles that control your breathing. And we're specifically looking at how these motor neurons that are housed in the spinal cord are influenced by early-life inflammation.

Chris - So if you look at an individual that's been subject to some early life inflammation, or some kind of infection, how does their respiratory effort, or their pattern of respiration, change in line with that past infection or inflammation?

Adrianne - What we're seeing is that it's not necessarily the baseline breathing that's changed. What's changed is the ability of this system to learn, and then respond to subsequent challenges to breathing. So here we're seeing that the system fails to learn properly, so it does not exhibit any plasticity, which could undermine the system in response to disease, or injury, or other challenges to respiratory control.

Chris - How did you do the experiments?

Adrianne - We did the experiments in a rodent model, since most people don't like their central nervous system poked and prodded. Four days after the rats are born we give them an inflammatory challenge; so it's mimicking aspects of a bacterial type infection. Once they're adults, we can then stimulate the respiratory system with changes in oxygen, changes in carbon dioxide, and see how the respiratory system responds. The main stimuli that we're using is repetitive episodes of low oxygen to induce one form of learning within the system. And what we find, is that that one inflammatory stimulus during the neonatal period undermined the ability of the system to learn in adulthood.

Chris - So what should happen in response to that bout of low oxygen exposure in a healthy non-inflamed individual first?

Adrianne - In a healthy, non-inflamed individual, you should see this lasting increase in respiratory motor output. And we don't see that increase if we treated the animals at postnatal day four with an inflammatory challenge.

Chris - Is there anything you can do to reverse this, to try and put them back to the situation that they should be in?

Adrianne - Interestingly, we can reverse it by applying sort of a general anti-inflammatory - sort of analogous to an Advil or a Tylenol. We use ketoprofen in the rodents, and we can reverse one form of learning, but not the other. So we think that there are different pathways to this learning and plasticity, and that they seem to be impaired differently in response to early-life inflammation.

Chris - Where do you think then, based on these observations, that the seat of the problem is? What is being hit during this critical postnatal period, during that bout of inflammation, which leads to this respiratory learning deficit down the road?

Adrianne - I would love to know the answer to that right now. We don't know yet. But we do think that it is related to how different cell types in the central nervous system communicate with each other.

Chris - Presumably it's not the nerve cells themselves? Because the fact that you've got messages being conveyed out of the central nervous system and to the muscles that drive respiration - these animals are aren't stopping breathing, so they must have intact nerve pathways, so that can't be it. So is it something upstream of that?

Adrianne - Yeah, exactly. We don't think it's the neurons themselves that are impaired, and we think it's likely to involve other cell types in the CNS known as glia. We are specifically targeting whether there are changes in microglia, the resident immune cells of the central nervous system, and astrocytes. Astrocytes were largely thought to be support cells within the CNS, but we now know that they can play pretty active roles in how the cells communicate with each other within the CNS.

Chris - And not just for respiratory issues as well, because it strikes me that if one looks at sort of public health data, individuals who are born in the winter characteristically are at risk for a whole raft of conditions compared with people who are not born in the winter. I'm thinking things like schizophrenia. Could it be, then, that actually the phenomenon you've discovered here could be broader than just changes to the way the respiratory networks work; and in fact, you could be finding what underpins why some people are at higher risk when they're born in winter?

Adrianne - Yes, exactly. And things like Sudden Infant Death Syndrome also go up during the winter months. So there may be more here than we know just yet, but it really suggests that there are these really important windows for development of respiratory control; but also more broadly, as you mentioned, neuropsychiatric disorders are also associated with early-life inflammation. There's been a lot of excellent work done recently looking at these different regions of the brain, and trying to understand how different regions are susceptible to early life inflammation. So I think this is a pretty exciting new area of research that might lead us to better understand both some of this acute mortality that you see in infants, as well as some development of things like obstructive sleep apnoea in adults and other disorders as well.

When students are learning to be scientists, the pictures they learn from are often just a few static images. But in reality, things happen continuously, so still images are always going to miss something. So a group at the University of Exeter decided to get together to represent the process of cell division in a radical new way. Combining the expertise of artist and researcher Gemma Anderson, cell biologist James Wakefield and philosopher of biology John Dupré, a new image was made. An image that shows the whole process of cell division, and not just a few steps. Talking to the team, Adam Murphy heard how the project came to be, beginning with James Wakefield...

James - I never really thought about how I did the science that I did. And as I’ve gone through my 20 years of research, I think it kind of became apparent to me that the default way in which we do science is through this kind of a historical reductionist approach: where you are looking at a live process, something that's going on in the cell - in my case cell division - but you're trying to reduce that down to its component parts. And although that's incredibly useful, there is something missing in terms of what that meant for the cell, if you like. And when I first got to know of John's work, it struck me that the processual view of life was one that had been under-explored in terms of scientific practice, especially in the world of cell biology.

Adam - But how do you create these new images? Artist Gemma Anderson takes me through it.

Gemma - What we're trying to do is to reintroduce drawing into scientific practice, but in a new way, if you like. Because we're not trying to represent scientific objects so much as we're trying to represent scientific processes. So we're trying to think about the process - say, for example, mitosis, or protein folding - as dynamic. We start off with the entire lab; that might be, you know, around six people, postdocs and PhD students and researchers in the lab, and then the P.I. of the lab. So I bring along materials, and questions, and suggestions, and structures that we can use to draw; and then we use the drawing to sort of create a consensus about understanding; then we find new ways of drawing the processes that emerge throughout the session. So they're very productive, they're very collaborative, and they're very helpful to sort of generate new questions for both the scientists and for me as an artist.

Adam - But how hard is it to snap out of your old modes of thinking and look at these images as they were meant to be looked at? James Wakefield.

James - Yes, it is very difficult to do that. And I think that's that's reflected in our publication, in the first two or three of the drawing labs. Both Gemma and I worked incredibly hard to try to release the PhD students and the postdocs from the habit and the learned practices of drawing what you see in terms of things, rather than in terms of processes.

Adam - But philosopher John Dupre seems to think this might not be a bad thing.

John - I think it probably is hard, but I think that may be one of its great virtues: that if people go to the trouble to try and work out why we ended up representing the process the way we did, then it may be really helpful in reflecting on the extent to which they are thinking in an appropriately static ways about the phenomena.

Adam - But what did other academics in the field think of these images? Back to James Wakefield.

James - I think that was one of the one of the most rewarding parts actually of the project. The approach that we took was to show them the final picture first, without any words, without any clues, and without anything to guide them as to what it might represent, apart from saying, “this is a representation of mitosis and cell division”. And so the response that we got from those four individuals was, as I say, incredibly gratifying in one way: in that they were able to really articulate the essence of what we were trying to represent, even though we haven't really told them what it was at all.

Adam - And what are the implications of this work? John Dupre.

John - We hope that it will encourage an awareness that drawing isn't just a way of producing pictures which you could produce much more easily by using some kind of automated technology, but that it’s a way of interacting with phenomena in knowledge-generating ways.

Adam - And finally, Gemma Anderson takes me through the wider implications.

Gemma - When you think about art and science, and how lots of students in school quite often feel a bit torn between, “I like biology and art”. One is more about studying the creative process of, you know, life; and the other is more about engaging in creative processes. And I think what's nice about this project is how we're actually encouraging learning and understanding living processes through the engagement of creative artistic processes, and that seems to work very well.