Organoids: Miniature Organs

11 April 2017

Interview with

Dr Hans Clevers, Ubrecht Institute

Adult tissues contain stem cells, which means that, under the right conditions, they can be cultured and turned into new miniature organs - called organoids -  to study how diseases happen and what drugs might best benefit an individual patient. One of the pioneers of this approach is Hans Clevers from the Ubrecht Institute in the Netherlands who spoke to Chris Smith...

Hans - Organoid is a very small artificial version of a real organ grown in a dish, typically from stem cells. These organoids represent many aspects of the original organ from which they were taken.

Chris - Why would you make one?

Hans - There are various reasons to make organoids. One would be that you’d like to study an organ in great detail, which can be done in animals. It can be done in people  but can be very difficult. It’s much easier if you take some cells out of a human being and culture them in the form of a mini organ and study them with great care.

Chris - Now you make that sound very easy - I’m sure it’s not. So what steps do you have to go through in order to take a bit of my tissue and make a mini intestine of mine, for example?

Hans - The best example would probably be a mini gut that we could make up of your colon or you small intestine. We learned about ten years ago what the stem cells are and what they look like in the inner lining of your gut. Stem cells are the cells that will repair or replace lost cells that wear out or when you’re sick you lose them. Stem cells become active and they divide and replace the lost cells.

So we’ve learnt where they are. We then learnt how to keep them active, how to mimic the situation that occurs in your gut. Mimicked in a petri dish, which means that we grow them 3D in a gel and we have to give them growth factor. What we grow is the lining of the intestine so this is the tissue that helps you digest food and take up the nutrients and pump it into your blood and lymph vessels. We do not produce the muscle that surrounds the lining and helps to move the food through your intestinal tract, and also we don’t have blood or lymph vessels. So, in that sense, they are somewhat incomplete.

Chris - But nonetheless, because there are lots of diseases that affect the lining of the intestine, being able to produce this in a dish means that you could then model what a disease does or how it works in a dish rather than having to go to the patient?

Hans - Yeah. We call the lining the business end of the gut; that’s where all the gut stuff happens. Many diseases are, indeed, associated with a complex set of functions that’s located there and often diseases are associated with a loss or changes of these functions.

Chris - What sorts of things, once you’ve taken a sample of these stem cells and made an artificial mini gut lining in a dish, what sorts of things can you test on it?

Hans - Probably the best example I could give is an application where we use this to advise doctors who treat cystic fibrosis patients. Cystic fibrosis is a simple disease and always affects the same gene. The problem is there are lots of different flavours of this disease and only for the more common flavours is there a drug. These drugs are extremely expensive, up to half a million US dollars per year per patient, and it’s very unpredictable for who they will or will not work.

What we found out is that you can actually test whether a drug works in a patient that was known but it’s very expensive if you have to treat a patient for about a year to figure out if it’s okay or not for that particular patient. But we could create an avatar of that patient (a mini gut). So we take a small rectal biopsy; it’s a painless procedure; grow it for one or two weeks in petri dish and get maybe 50 or 100 small mini guts. Expose these mini guts to the drugs and there is a one to one, black and white correlation between restoring the response with the drug in the petri dish and then giving it to a patient and see the patient respond.

Chris - Can you pull off the same trick with pretty much any organ in the body or are you confined to just studying the guts?

Hans - The gut was the first one that we tamed in the lab but, since then, we have come up with protocols for almost any internal organs, so lungs, liver, stomach, prostate, ovary. In all cases, if we play around with the conditions a little bit, we can come up with conditions where the stem cells from that particular organ will make a mini organ in culture. The exceptions, we think, are going to be heart where we fear there is no real stem cell, and brain where there is very little, if any, stem cell activity.

Chris - Notwithstanding that, that means you can then produce miniature versions of those organs to do things like test drugs, or test disease processes, and give people predictions about the diseases?

Hans - Exactly. And one other major field that we can actually do this with normal tissue, which was essentially impossible before we developed this technology but we can do it more easily with the cancers that develop in those tissues. And there again, the promise is (and we are currently testing this) that one could grow a cancer, for instance of the colon, of the pancreas, side by side with the normal tissue from that same patient. Expose the mini organs and the mini cancers to a variety of cancer drugs and then score, much like we do with cystic fibrosis, for the best cancer drug for that individual patient, knowing that overall probably a third of the patients benefit from their first chemotherapeutic treatment but all of them will get the side effects.

Chris - So we might be able to come up with much kinder chemotherapy regimes in the future, thanks to that work. That was Hans Clevers from Rotterdam.

Chris - With me Katherine Brown, executrive editor of the journal development. Those things are being used to understand processes, and diseases, and drug treatments, but they’re not actually being used therapeutically are they?

Katherine - No not yet, and I think we’re quite a long way from that. People have shown, in fact, in a mouse, taking Hans’s mini gut as an example that if you injure a mouse intestine and you put one his mini guts into that intestine, it will engraft and it will restore some functions. But that’s in a mouse, and that’s very early work but that is some promise that we may be able to use that in a subset of cases to treat certain diseases.

Chris - But what is the key difference between an adult stem cell and the embryonic stem cells that Roger was talking about. If adults have stem cells, why do we need to every use embryos?

Katherine - There are various differences. I think the most important thing is that not all of our tissues have large populations of stem cells and we don’t necessarily understand them very well. As Hans said, the heart for example, as far as we can tell the adult human heart doesn’t have stem cells in it.

The other big difference I think that is really important is that adult stem cells can only become certain kinds of cells, so they’re much more restricted in what you can do with them. Whereas an embryonic cell, because in normal life it has to make everything, when you put it into a dish it can also make everything.


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