November 30, 2022

Organ on a chip: Part 1

By Conor McKechnie and Dodi Axelson

Organ on a chip: Part 1

In this first episode of a two-part series on organ on a chip technology, we discuss with Jan Turner, formerly part of Safer Medicines Trust, how these organoids can help us move away from the inefficient animal model.

Show notes

DODI: I'm hitting recording, and this is 'Organ on a chip' part one.

CONOR: We should start with the big organ music story. Dodi today I want to talk small.

DODI: Alrighty, how small? We've done quantum biology before, so are we going subatomic again?

CONOR: No, not that small. I'm talking about organ on a chip technology. We're going to take a really close look at how we can simulate organs on a small scale which means really big returns for developing safe therapies.

DODI: Okay, so it is organ on a chip technology that matters on today's episode of Discovery Matters.

CONOR: Today's episode, we start with an old friend and colleague, Jan Turner, who used to work with us. At the time of her interview, she was at Safer Medicines Trust, which is a charity focused on patient safety. She spoke to us about organ on a chip technology and why it might be a safer avenue for testing new drugs.

JAN TURNER: These are miniature models of organs on chips that originally came out of the bioengineering or engineering industry. They've been developed so that you can put human cells into small channels on these chips. These chips are probably about the size of a USB device, so they are very small. You can line channels within the chips with human cells, and you can also put fluidics through it like culture medium or in some cases a blood-like medium to recreate what would happen in a normal organ system. You can then read responses from it.

CONOR: These chips allow us to delve so much deeper into the biology of cellular mechanisms and the interplay between drugs and the different cell and tissue types.

DODI: Okay, so are you saying that drug development researchers can find out, through a tiny simulation, what the response of these cells or tissues would be to certain drugs?

CONOR: That's exactly right. So, researchers can build 3D models of tissues, called organoids or orgonites, and they build them on chips. They're much more efficient in comparison to the old, traditional 2D layers of cells on culture chips that people are more familiar with today.

DODI: Okay, so could this be a way to replace animal testing?

CONOR: You're right, it could be, and in some cases, it is. In human medicine, animal testing is not very effective, as it's not a great simulation of a human. So, we should phase out animal testing if we can, not because we love the bunnies, but because it's not as effective as a model of a human being. There are real limitations to it.

JAN TURNER: In the UK, nearly 3 million animals are used every year. Half of those are used for testing in either basic research or in regulated preclinical testing. But the main issue is translating any responses you see in mice, rats, even dogs into what that means in terms of humans. We've probably cured cancer in mice 30 times, but we haven't cured it in humans. That's the difference. The way disease forms in animals is different to humans. We can't recreate cognitive responses in rats who don't have a prefrontal cortex like we do. So, diseases like Alzheimer's and things like that are very difficult to recreate in a mouse model. Anything that can use human tissues, human organs, human cells, is going to give us an advantage as to what we have already.

DODI: Hearing cancer in mice 30 times over, kind of highlights that we're limiting ourselves. So how does it help humans to focus on finding ways to cure cancer in humans?

CONOR: Testing in humans presents greater danger. The long-term patient impact of using organ on a chip technology is that if we test on a platform with human cells, then patients won't suffer if things go wrong. So, let's look at the example of Vioxx, which had upwards of 100 000 deaths around a drug that was actually approved through the animal model and clinical trials.

JAN TURNER: In the UK, we have around 10 000 deaths from adverse drug reactions, which also has a cost to the NHS. The other benefit with these models is that we know statistically that drug development is very inefficient, around 90 to 95% of drugs actually don't make the market. I think what these systems can do is improve that efficiency. And therefore, increase the productivity of pharma and Emulatebased on that data that I just mentioned, have actually been able to show that you could increase pharma productivity by about USD 3 billion per annum by using these chips. So, you know, there's a financial cost, but there's also a human cost that can be addressed using these types of technologies.

DODI: Okay, so 90 to 95% of drugs don't make the market. That's huge.

CONOR: That's exactly right. And using an organoid, you're testing how we respond to the external inputs, whether it's a potential drug or treatment, and you wouldn't have to be concerned with if this works for mice, then we can start thinking about tailoring it to a human. You will have actually tested it on human tissues or on human cells, so it should save time, it should save resources. Ultimately, it should save lives.

JAN TURNER: I think that's the beauty of it. You can actually look at the biology of that system in vitro outside the body. So, you can see the mechanisms, you can investigate the mechanisms that are taking place, but then that also gives you an understanding of the mode of action of a drug causing some toxicity. Therefore, you can then use the same model to test a drug or to test a potential treatment. So, we are removing a lot of that difficulty. We know that so many drugs go on to the market that cause adverse drug reactions and things like that, and we need to stop that. We need to be able to do something about that and continuing to use animal models has not really helped us there. Whereas if we can move to a more human model, then hopefully we can start to pick up these sorts of reactions that are human relevant rather than animal.

DODI: I wonder, has there been an instance when the animal model did not pick something up?

CONOR: Yeah. So, Jan mentioned a study that reviewed drugs developed through animal models, and the results are really troubling.

JAN TURNER: There's actually just been a publication posted on a preprint server from a company called Emulate. Emulate is a US-based company that has come out of the Wyss Institute in Harvard, and they've just produced a paper looking at 780 liver chips. They've looked at LiverTox compounds for toxicity. I think they tested 27 of them. So, these are compounds, drugs that have gone through animal models, and have proven to be toxic in the human when they've reached the market. And they've taken those 27 compounds and put them through these 780 liver chips. In terms of sensitivity and specificity, they've been able to get numbers around a sensitivity of 80%, which can actually be increased to about 87% when you take into account protein binding, and a specificity of 100%. So, what that means is they've been able to really show which compounds were toxic in these models, which is incredible. Whereas animal models, we're probably talking about 70% sensitivity and specificity depending on the model. So, this is just a really powerful technology, and something that's really exciting in terms of what we can do, in terms of preclinical testing, and removing the costs be it human costs or monetary costs from putting drugs out there that are going to cause toxicity.

DODI: So, that's pretty shocking. It drives home the importance of a move away from animal testing, but also the interplay of different organs and their response to drugs is another factor that we just can't ignore.

CONOR: Well, there have been developments since 2010, around including immune cells on organoids to view the immune response effects and so on, but there's obviously no animal or human as a whole organism with cognitive responses that you can build on a chip. So, there are limitations. But the chips can include immune cells, hormonal responses, andcan even include the microbiome that contain all sorts of human models.

DODI: Well, so we've come around to another one of your favorite topics, Conor, if it couldn't be mushrooms let it be the microbiome.

CONOR: Totally guilty.

DODI: So, we're starting to understand the influence of the microbiome and how we metabolize drugs, and their impact on the body, but Jan is saying there are limitations.

JAN TURNER: There are also other limitations that are inherent with any cell culture: the stability of the cells and the reproducibility of the cells that we need to consider. There are numerous groups that bring the developers, the pharma groups, and the regulators together to really look at these chips and understand the criteria for using them and their robustness and reproducibility. The other thing to think about is that there's an awful lot of computational power that goes behind these as well. The machine learning that's coming through now can also be applied to these chips. So, you can actually look at pharmacokinetics so drug metabolism and recreate that using the data from the chip, translating that into what would happen in the human will using computational methods. It's not just the biology on its own, there's the in-silico piece as well, which is almost bridging that gap between those more advanced mechanisms that take place in the human.

CONOR: Organs on a chip have real potential in the steps before drugs enter into clinical trials.

JAN TURNER: I would love to see these used more regularly in preclinical testing; I think they do offer a huge opportunity. But I do think there's a lot of education that needs to take place be it with regulators or even with people who are issuing grants to people using this technology. There's a lot more understanding needed there in terms of education. But I really do think there's a huge potential in terms of moving away from animal models and coming up with more human relevant approaches. The fusion of engineering and cell biology is all coming together at the right time. The stem cell piece is really allowing us to have continuous cultures of the cells that are human relevant and not altered in any way in terms of genetics. So, I think it's a really powerful technology. I really hope that we can include this more in preclinical testing because I think it's going to offer us a whole lot more in terms of productivity and treatments for humans going forward.

DODI: Okay, we need to keep talking about this because I feel like we've just scratched the teeny tiny surface of this topic.

CONOR: Next week, we'll have part two on organ on a chip technology, and we'll be talking to Professor Alice White and Christos Michas on their use of this technology to tackle cardiac arrest.

DODI: Our executive producer is Andrea Kilin. This podcast is produced with all the work by Bethany Grace Armitt-Brewster. Editing, mixing and music by Tom Henley and Banda Produktions. Coming to you live is Dodi Axelson and...

CONOR: I'm Conor McKechnie, I have organs with my chips. Make sure you rate us on Spotify or whichever platform you use. If you are listening on Spotify, please answer the poll under the episode description. It helps us get a better episode next time. We'll see you when we come back with another one on Discovery Matters.

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