Making mini kidneys

26 November 2019

Interview with 

Jamie Davies, Edinburgh University

KIDNEY

KIDNEY MODEL

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One of the organs in high demand is the kidney. Here's Phil Sansom with the quick fire science...

Kidney transplants are in especially high demand in the UK. The wait time is between two and a half to three years. The most common reason for them is kidney failure, where the kidneys no longer filter waste products out of your blood. This is most commonly a consequence of poorly controlled diabetes and high blood pressure. Dialysis can help. It involves three, four hour sessions a week connected to a machine that takes over the role of the kidneys, removing waste from the blood. But dialysis places a strain on your body over time and people can die on dialysis if they don't eventually get a kidney transplant. Most people who need the kidney transplant are capable of having one no matter how old they are. But there are some reasons it might not be safe or effective. Like if you have an ongoing infection that needs to be treated first or heart disease or cancer that is spread to multiple places in your body or AIDS.

Jamie Davies from Edinburgh University is working on growing new “mini kidneys” in his lab. Chris Smith asked him how he's trying to tackle the donor kidney shortage...

Jamie - Well, we're tackling it by trying to turn stem cells into kidneys. So these are cells that we can make from patients and we can turn the cells back into an embryonic state and then try to walk them forward in the same kind of path they would have taken when a baby forms in the womb, the part of the baby that will form the kidney. We try to walk these stem cells through the same sequence of events so that they want to form a kidney.

Chris - And the benefits of doing that, presumably Jamie, if you do it with a person's own stem cells, is that they end up with tissue which is genetically matched to them. So we don't have one of the problems, which is an issue with organ transplantation, which is finding a match.

Jamie - Yes, exactly. And that's very important. People who have transplanted organs in the number of pills they have to take a day is quite phenomenal just to control immune rejection. So yes, that does help a lot. So we can take these cells out into culture dishes and use their own ability to organize themselves to make very small versions of the kind of organs that we want to make, in our case, the kidney.

Chris - How do you do it?

Jamie - Well actually it's the cells that do all of the clever stuff and this is the remarkable thing about this that what we have to do is to provide conditions for the cells that seem to the cells like being inside an embryo and then they're capable at least of making the small anatomical structures of the kidney on their own. And we just have to sit back and watch, which is amazing. What they can't do is make the broad scale anatomy of the kidneys. So for example, they can make all of the detailed little pipes that are found in the kidney, but the broad arrangement of pipes, they can't do it. It's a little bit like being able to make a street but not being able to have these streets organized like a proper city that you want. We now know a little bit about how to get the broad organization and again, it's going back to the embryo and it's mimicking signals that come from adjacent spaces in the embryo. And when we find we get the mimicking right, then we start to get this very large scale anatomy starting to form properly. We haven't formed a full size kidney yet. The best we can do is only a few millimeters across, but it's still quite exciting to see those forming.

Chris - And when you look at your miniature kidney, a few millimeters across, is it a miniature version of the whole thing or have you got very good at making just one part because the kidney is a collection of things. You use the analogy of a street just now. Well, if I could build on that. So we've got houses, we've got roads, but also there are water mains, there are electricity supplies, the internet comes in so you can watch Netflix and other rival stations, etcetera. Have you got all of that being reproduced and recapitulated in your mini kidneys?

Jamie - We have all of the parts that carry urine in the kidney. The kidney makes urine from blood by cleaning up the blood. What we're now struggling to do is to get the blood system into the kidney in the right place. One of the things which is a problem to us is that the way that kidneys work, the blood vessels have to have a very, very special arrangement. And although we can get a kind of random hodgepodge of blood vessels and into our kidneys perfectly well, we are at the moment struggling with finding ways to get the arrangement exactly right.

Chris - Do you know why?

Jamie - Well, we know from going back to the embryo again, because we have this cycle of of doing some tissue engineering, getting stuck, going back to the embryo and asking better questions about what the embryo does, and then going back to the engineering. We, again, we understand that this is to do with asymmetries in the embryo and a special environment where the blood vessels come in. So we've published a whole series of papers about normal blood development where some students have been discovering new things. And what we're now having to do, working with engineers, is to work out how to create that special environment in a culture dish.

Chris - How would one apply what it is you've discovered? Would it be that you would say, I'm now going to grow a whole new kidney for someone who's got kidney failure? Or could you go down the road of saying, well, we're going to do some in-situ repair, because rather than build a whole new road, we keep returning to housing estates and houses here, don't we? But rather than build a whole new road, I can fill in potholes and I can make the road a much smoother ride. So which is it? Or can you do both?

Jamie - I think we can do both. We had originally imagined we would have to build the entire new kidney, and I suppose that's still our main aim, but very recent work, which we've not yet published, so this is, this is kind of in a provisional and not yet checked by peer review, but we found that these new kidneys can hook up to existing kidney tissue. You know, that's given us, at least it's given us a new direction to do our research. We've got a lot more to do before we can properly nail that down and say yes, we're absolutely sure. But it's meant that both strategies are now alive.

Chris - So you may be able to take someone who's got, say, a shrunk and not very healthy kidney and refresh it by putting new cells in which will then organize themselves into healthy functional tissue inside that kidney and restore its function.

Jamie - That would be exactly one of the ways of doing this. The other thing as well in our aim for making whole organs which is the first tree we were doing this is, we may not need to make something at the whole scale of an adult organ. Other scientists have been working showing that it's possible to transplant fetal kidneys into animals and have them grow up and take on function, and that's given us some hope that actually we only need to make a really good copy of a fetal kidney and that might be enough because a lot of kidney diseases are slow. You have a lot of time before knowing that a patient is starting to suffer kidney disease to the point that she might need a transplant.

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