Modelling! Medical mimicry

27 June 2013

Interview with

Kelly BeruBe, Cardiff University

Modelling. Not the catwalk variety, but medical mimicry!Chest x-ray showing lung cancer in the left lung

When researchers want to peer inside the human body to understand it better, one option is to create an artificial model of the area they're interested in: be it lung, heart, or breast. They can then tweak this artificial system to test drugs and see how it reacts, in order to understand it better. We were joined by Kelly BeruBe, a researcher at Cardiff University, who's doing just this for lung tissue.

Chris - So, what's involved in trying to make a model lung in a dish?

Kelly - A lot of work, that's for sure and a lot of innovation, and a lot of patience. But first, I should begin by probably telling you what a model is. With modelling, I would say it's basically like being a hobbyist. You reproduce an item of interest. So, in my case, we're looking at building a replica of the airway region of the lungs and that's the conducting part of the lungs, the big tubes where air moves in and out because that's the area where, when you inhale something, it takes the biggest hit. So, we like to focus on that region for any kind of inhalation studies. For using models, well, they're useful because you can replicate them endlessly, very quickly, usually, very economically whereas if you compare that with animals, they're very expensive. You'd have to let them live their whole life span if you wanted to make a comparison with the human situation. The other thing is that, with using models that you create, you can then change little parameters on those models and then measure those. That gets rid of the problem with extrapolating animal data to the human situation because if you're using human tissues like we use, we use lung cells and tissues donated from patients then you have human endpoint data.

Chris - So, you make a number of compelling positives for why this is a good idea, but it's presumably not trivial to make something that behaves, looks, and functions as a lung in a dish.

Kelly - Yes. I mean, we've been working on this now for 10 years and we used to work with animals for the past 15 years and weren't getting anywhere. And then I think about 2003, we were able to buy human tissues, you could procure cells from human tissue banks. We started dabbling with them and all of a sudden, questions that were eluding us for years, we were getting the answer to those very quickly in a matter of a year or so. So, we decided that we were going to leave the animals and move right into human tissues and it was like a Lego system. We just started playing with different cells, different media, different bioreactors because we needed to make the cells in 3D to work. If they're in 2D like in a petri dish, you don't get the same reactions that you would get if it was in the human body.

Chris - How do you get the cells to grow into that 3-dimensional structure that the lung is (first point) and second point, if you look in a lung, they're not just one type of cell. There are many different types of cell, aren't there? There are muscle cells, glandular tissue, epithelial cells that line the airways, and then special surfactant making cells that make the air sacs where the respiratory exchange takes place. It's really complicated.

Kelly - Chris, you could work in my lab. You sound like you know a lot, but yes, there's over 40 different cell types in the lung and they're divided into 3 different regions. You have the upper respiratory system which traps things and tries to prevent them from getting into the lower lung, then you have the thoracic region where we work in that has a lot of defence mechanisms. Then in the lower lung, the distal lung, you have the alveolar region where you breathe, where people exchange oxygen and CO2. You don't want anything in that area because you'll get inflammation. So, we work in the thorax where it has the highest number of defence cells in that area because its job is to stop things from getting into where you actually breathe. Now, in that region, there's about 7 key cells and what we do is we take the basal stem cells from donors and the cool thing here is that we can use medical waste tissues. So, if you have an operation and they open you up, and they have to nick out some tissue, and they throw it away, we can buy that. They usually incinerate that so we buy it, we take out the stem cells or the cells that we're interested in and then we regrow them in bioreactors. These are special membranes in, they look like little petri dishes, like little cups about the size of a pea and the top part is open to the air, and the bottom part you feed. That's just like how we breathe. When we breathe in air, it goes over the tissue and you'll get your nutrients from below.

Chris - Do the cells know where to go?

Kelly - Yes. This is like a military secret. I could tell you, but then I have to kill you type thing because it's all patented technology, but I'm sure the other people will tell you this. Using the 3D culture media that we created, it has the right amount of hormones and chemicals that tell the cells when and what to turn into basically, at what time and it grows a multilayer into 7 different cell types and you get your mucus secretion, you get your cilia doing the samba, beating back and forth. It looks just the piece of tissue that you would take out of a person.

Chris - And what sorts of questions can you ask and answer with this that you couldn't do previously when you were working with say, mice or other rodents, other experimental animals?

Kelly - We know we can accurately dose ourselves because when we used to do installation work, where you inject a fluid with a particulate matter or something into the lung. We were never really sure where the compounds were going. We would just put it in and faithfully think we've put a milligram in and we're hoping it's dispersing throughout the whole lung, but you'll never know. So, this way, we can accurately put a dose on that's environmentally relevant. So, we're not overdosing the cells.

Chris - And it's very reproducible and very consistent. So I suppose, getting the numbers up to a way that you can say this is statistically valid is easier.

Kelly - Absolutely. We buy in about 500,000 cells from donors and we'll get about 400 pea-sized lungs to work on and they last for about 2 weeks which is rare, so you can do acute, chronic, and repeat toxicity testing. In terms of cosmetics, this is a big deal now because in March this year, the EU had this directive where they ban the sales of any cosmetics that were tested in animals. So, it's often an alternative device now to industry where they've always relied on animals.

Chris - And you can do that testing for them.

Kelly - That's the whole idea now. We're trying to develop a model where people can test compounds that are going to be used for cosmetics and beauty purposes as well as obviously safety testing for medicines. Think of all the stuff that's in the air - air fresheners, aerosols, pesticides, perfumes, make up. It's an endless list of things that we're inhaling into our lungs.

Chris - The fact is that my lung is a part of me and I have an immune system. A petri dish doesn't. it doesn't have a blood flow. There are other aspects of the model that you can't reproduce with your dish. So, how do you know that you're not missing something, even though you're using human cells?

Kelly - Very good question. The thing is that people have to realise is that when you're working with alternatives, it's a reductionist type model and the whole idea is that if it's not complex, you can avoid a lot of confounding factors. So, you can tweeze out little delicate things that you would miss. For example, the immune system or if it's a female and the hormones are in the way, those reactions could mask things that you're trying to find. So, what these alternative methods do is they give you a look at the least complex situation and something of interest should stick out. You can build up and use more complex models to try to answer your question such as using in silico or other in vitro models of different tissues in the body.

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