🫀 The Future of Heart Repair: 3D Cell Models and Organoids 🫀

keywords
cardiac research, organoids, 3D cell models, IPS cells, personalized medicine, ethical concerns, organ transplantation, cardiac therapy, cell differentiation

Summary

In this episode of the Young Immunologist podcast - ImmunoChat, Nóra Balzer interviews Fabienne Becker, a PhD candidate at the University Clinic of Düsseldorf, about her work on the HEAL project (101056712 – HLA-homozygous iPSC-cardiomyocytE Aggregate manufacturing technoLogies for allogenic cell therapy to the heart; https://www.heal-horizon.com/), which focuses on using induced pluripotent stem cells (iPSCs) for cardiac repair. Fabienne discusses her background in chemistry and biochemistry, the process of manufacturing cardiac 3D cell models, and the differences between spheroids and organoids. She highlights the advantages of 3D models over traditional 2D cultures and animal models, the potential of iPSC-derived therapies in personalized medicine, and the ethical concerns surrounding the use of human cells. The conversation also touches on the cost and time implications of producing cardiac organoids, recent advancements in organoid technology, and the future of transplantable heart tissue. Fabienne shares her surprising discoveries in cardiac research and offers advice for aspiring researchers in the field.

Takeaways

• The HEAL project aims to develop cell therapy for heart regeneration.
• Induced pluripotent stem cells (iPSCs) can differentiate into various cell types.
• 3D cell culture is simpler than many believe.
• Spheroids contain one cell type, while organoids contain multiple.
• Organoids aim to mimic the complexity of real organs.
• Personalized medicine could benefit from iPSC-derived therapies.
• Standardized protocols are needed for consistency in research.
• Ethical concerns exist regarding informed consent for iPSC use.
• 3D models can reduce costs in laboratory settings.
• Patience and perseverance are key in scientific research.

Transcript

Nóra Balzer (00:01.132)
Welcome everyone to the Young Immunologist podcast. Today we talk about organoids and 3D cardiac cells models with Fabiana Becker. She's a PhD candidate at the University Clinic of Dusseldorf at the Institute of Transplantation, Diagnostic and Cell Therapeutics. Fabiana, thank you very much for joining this episode and sharing your thoughts. Would you introduce yourself?

Fabienne Becker (00:29.934)
Yes, Anna, thank you for having me. So as you just said, I'm Fabian Becker and I'm a PhD student right now. I'm actually in my third year already. And yes, as you've mentioned, I am at the University Hospital of Düsseldorf. I am actually working in the group of Professor Dr. Casino Kürtler. And I would like to say the name of my project that I'm involved in, although I know it's quite a handful. So I'm hoping for every listener that's...

Please bear with me because it's actually, because it's a new funded project. It's quite a long name, but generally what I'm working on with during my PhD is a project that's HLA Homozygous IPSC Cardiomyocyte Aggregate Manufacturing Technologies for Allergenic Cell Therapy to the Heart. And because it's such a long name, we actually just call it HEAL, very short.

Nóra Balzer (01:19.409)
wow.

Fabienne Becker (01:25.912)
just because no one can always say this kind of long name for such a big project. And it's actually quite interesting because we are not just my group is involved in it, but actually the consulting of people. So we have different university groups involved, but also companies who are working on this project together. So yes, that's on my background.

Nóra Balzer (01:48.898)
So what is the inspiration of this HEAL project? So if you would explain it with easy words, that would be awesome.

Fabienne Becker (01:54.574)
Yes, so generally, maybe the last part of the name, like heart repair is the main thing that you can focus on for maybe someone who's not in the field to really know what we're doing. So generally, we are trying to have a project where we are working with IPS cells towards cardiac repair and what this is. So IPS cells for people who are not in the field.

These are short for induced pluripotent stem cells. And these cells are actually very nice to work with because the pluripotency of the cell is making it able that if you work with these cells and you modulate the cells, so you give them certain triggers in culture, you can make any cell that you want out of them. So if you start with the cell, you can go into...

like we do into the cardiomyocyte region. So you do heart cells out of them, but you can also go into the brain cells, so can do neurons out of them. You can also go into blood cells. You can also go into immunocells, maybe for the listeners of the podcast. So this is IPS cells. And in the project, we take these IPSC cells and we make them into cardiomyocytes. So this is heart muscle cells.

Nóra Balzer (03:10.241)
Yes.

Fabienne Becker (03:21.866)
And the aim of the project is mainly that we just produce these cells to have a tool for cell therapy so that we want to administer these cells into the heart when patients have heart failure. Because for, well, in the most part, it's still quite a problem with heart diseases that there is in this day and age, sadly, it's quite a high mortality rate for people who suffer from heart disease. And we just want to...

have another tool for patients that they can have another option when they face the problem that they have a heart disease because for most people if they think about, I just had a heart attack, what are my options? Many people will maybe first think about, okay I can maybe get a new heart, an organ transplantation. But we just want to have another option available because not always you can get a heart transplantation. Other options would also be that you get a bioartificial heart.

or you need to face your whole life with strong medications. And just the HEAL Project is now as a new kind of side to this problem that we really want to have cell therapy-based approach for heart disease.

Nóra Balzer (04:36.108)
Very exciting. So may I ask what was your background before your PhD? What did you study?

Fabienne Becker (04:42.286)
Yes, I actually, maybe it's a bit strange because I actually started my bachelor in chemistry and then later switched my major for my master to biochemistry. And there actually started already in the group of Professor Dr. Koebler and I did my master's thesis with her. And then my project was actually on the stem cells of the hematopoietic stem cells. So the cells that do

Nóra Balzer (04:50.327)
Mm-hmm.

Fabienne Becker (05:10.434)
produce all of our blood cells. And she was kind enough to have this project available when I was finishing my master thesis, so I could immediately actually move into the IPS field. And it's actually quite interesting for me because I've never worked with IPS cells before. And it is such a big novel topic, maybe not as novel as many people think, because it's already been around since, I think, 2007.

But it's still such a big field in research and it's very interesting because of all of the applications that you can go into. So I really was excited to hear about the SEAL project and just have a new kind of topic for me, because like I said, I'm coming from chemistry, went to biochemistry, have worked, started working in cell culture. And now I was able to get this into this field of IPS and just see what I could do there in.

terms of cardiotherapy, actually.

Nóra Balzer (06:12.756)
Yeah, it's very exciting and as a biochemist turning into the organoids is, I can imagine it's a big challenge. So you just also just went to the lab with fresh hands to produce the cells. So could you explain the process of manufacturing cardiac 3D cell models and the main challenges that you faced?

Fabienne Becker (06:21.763)
Mm-hmm.

Fabienne Becker (06:36.334)
So most people, if you're already knowing about cell culture and all of these techniques, many people are working with the 2D culture. So it's actually that you just have a cell layer in your culture dish, whichever this might be. And for the 3D culture system now, it's in our part actually quite straightforward. So many people might think that it's challenging to go from 2D to 3D, but we have actually

thanks to our consortium partners, have been able to develop a quite easy approach of going from 2D to 3D, which is actually that we just have our cells and we just put them into a normal meteor in a culture dish or actually in some small uraniflux or even in bigger bioreactors. And we just simply by moving them either with a shaker so that they are always in movement or with a stirrer.

that they are always moving and that's actually the 3D culture system. So we just have our cells, put them into media, have them move around and that's actually our 3D culture. So I know many people also if they start with 3D culture, there are different approaches for people to go with. There are also that you can have 3D matrices where you can grow your cells in or microfluidic systems.

But for us, it's actually quite straightforward that we just have normal, plain media where we put ourselves in and that's actually it.

Nóra Balzer (08:10.464)
you are the first person who is telling me that the 3D cell culture is just a straightforward process. Maybe we can also make clear what is the difference between a spheroid and an organoid.

Fabienne Becker (08:24.142)
So if you first start in the field of actually if you go into 3D culture you have different options for your cells. So as you said spheroids or organoids and a spheroid is kind of like the more simple version of the cell model because you have just one cell type in your spheroid. So for us this would be the cardiomyocyte, so the heart muscle cells which makes out the spheroid.

And for an organoid, you would typically first have all your cells of a component already differentiating into different cell types. So not just one cell type, but different cell types. And then you would kind of, well, maybe to say like you mix these kinds of different cell types and then put them together and let them form an organoid. So an organoid is really trying to aim to mimic a whole or the real organoid as we find them in our bodies, but in like small scales.

Compared for spheroids, you have different type of cells interacting in an organoid, rather than just one cell type as we have for our catecholamides in a spheroid.

Nóra Balzer (09:34.964)
I see. And what are the key steps in ensuring that the cardiomyocytes develop and organize within an organoid?

Fabienne Becker (09:43.47)
What I have just said, so going from 2D to 3D is already quite simple and actually that they develop in these spheroids or organoids is also at least from what I feel is also actually quite simple because you don't have to really trigger the cells into doing something, but rather they just self-assembly. So for us, of course, we do the shaking that they find each other, but I know from other protocols where people just have them in small U-bottom wells.

that they also just find each other by close contact and then they self-assembly into this kind of small cell ball. So it's actually not very difficult if you have the right protocols where the cells really just self-assembly. it's maybe also very straightforward and easier as many people might think because you just have your cells, let them have some time of course because they don't really like immediately.

find each other, it does take a few hours to a few days for the self-assembly, but other than that, it's quite straightforward.

Nóra Balzer (10:49.258)
I see. So for me, when I was in the lab, I was always facing with difficulties of reproducibility. So sometimes I do the same experiment and it looks just somehow different. So how do you achieve scalability in the production and the consistency? So how do you do that?

Fabienne Becker (11:08.27)
Yes, so I think, especially if you know it already, I feel like especially if you are working or just starting to work with this specific cell line and you're trying to establish a protocol that no one maybe in your lab has worked with before as well, it can be quite challenging to have consistency between different like batches where you are doing the runs and the differentiation. And we are actually, this is also part of the

partners that we are working with, they have really done quite a lot of work with the existing protocols because for the cardiac field, it is actually quite well published and there are quite a few protocols out if you want to have your IPS cells and want them to go into the cardiomyocyte differentiation. So you do have quite a lot of options, but we thought that because we have our own IPS cell line.

that we needed a protocol that is actually really targeting this consistency because we do want to have a clinical trial one day and really have a self-product easily available for patients. So we really needed to figure out how do we both get the scalability but also have a very consistent protocol. And so we actually optimized just existing protocols. So if you really want to have

If you see that your cell line is not performing as consistent as you would like it to be, then you might have to really take a step back, look at the protocol, have a look at all of the steps that are involved in your process, and just think about, at which step could I maybe optimize something that my cell line is maybe having troubles with, because especially in IPS cells, because they are...

quite different depending how you get them. So they are available for purchase from different companies. And if you just have a different cell line than what is used in the protocol that you're working with, you could face that the cells kind of behave a bit differently. So you really need to know what your cells are. Like the cursor is just, sorry.

Fabienne Becker (13:34.016)
like the characteristics of yourselves and you just need to know what you're working with and then just optimization. And it can be quite a tedious process and you have to do it again and again. But at one point we have now actually achieved quite robust and optimized protocol for our production. And I feel like we can in our project confidently say it's actually already also published from our partners that we have now acquired optimized protocol that's really.

If we also give it to our partners, other people in the lab, that they can easily reproduce it. And we have this consistency now that no matter who does it and no matter at which time point or like with which cells we do have consistent outcomes of our chymiocyte differentiation.

Nóra Balzer (14:23.19)
And it's great that you are working with a published protocol already. So that's something we can also put into the show notes for sure for other scientists who are still struggling with the point.

Fabienne Becker (14:26.54)
Yes.

Fabienne Becker (14:32.334)
and

Nóra Balzer (14:39.38)
so.

Fabienne Becker (14:45.678)
Of course.

Nóra Balzer (14:50.312)
I had a thought but it's gone now.

Fabienne Becker (14:53.91)
Maybe it comes back in a second.

Nóra Balzer (14:55.644)
Yes. Yeah, so when I used to work with mice and other models and in natural sciences, we usually work with models and not with the real organ. And then

People usually ask, yeah, it's just a model, it's very simpler. So what are the biggest hurdles in mimicking the complexity of native cardiac tissue in spheroids and also versus in organoids?

Fabienne Becker (15:28.43)
So it's actually good that you also bring up animal models because for cardiac development and actually if you go from the cell-based model where you do the cardiac differentiation, if you also look into literature, what's been a problem for I think the main part of the last few years is that no matter what, if you start with your iPS cells and make them into the cardiomyocytes,

They most often resemble fetal-like cells, so very young cells. And we have the problem if we want to, of course, look into the adult heart and have an adult-based model, we have the problem that the cells that we produce in the lab, they don't match this maturation step. So they are quite fetal in their maturation. And this can affect the phenotype of the cells, the functionality of the cells. So we do have

the problem that in most cases that we need to think about, can we somehow mature ourselves in a simple way? And I know there are quite a lot of protocols out there that are trying to mimic this maturation and it actually is quite difficult. And I feel like this is actually something that's good about both spheroids and organoids because recent papers have shown that the structures of the connectivity

in these, let's call them cell balls, no matter spheroids or organoids. So because the cells are quite connected in a 3D environment, they actually show first signs of this maturation. So they are at least going into the right direction of becoming a bit more adult-like. And this actually helps, of course, but we are still definitely needing to put more focus into bridging this problem if we...

want to maybe even at one point not use animal models at all that we actually need in the cardiac field. We need to think about how can we really make organoids as a cell-based model that really resembles the adult heart. And a different problem that I've also heard that many people are having problems with if they talk about the organoids as a disease model is that actually, although we do have all of the

Fabienne Becker (17:50.734)
different tissues or different cell types in the organoid and they can quite nicely mimic the heart model. do often, not only neglect, but we do often forget that our organs are not just the organs itself in our body, but there's also the microenvironment. So we also have interactions with other cells that are just important also to think about if we want to.

have organoids as a disease model, that we often forget that the microenvironment might also play quite a big impact on the disease of drug toxicity. And this is something that we, at this point, think, either not always focus on, but also just sometimes forget that these factors can also play quite a big role if we want to use organoids, phosphorides in these kind of situations.

Nóra Balzer (18:48.288)
Right. We had in one of the previous podcasts on animal experiments, the question whether organoids one day can replace all animal experiments, because of course, from a bioethical perspective, it would be just much better. So what are the main advantages of using cardiac 3D models over the 2D cell cultures or even animal models for studying heart diseases?

Fabienne Becker (18:58.766)
Mm.

would be great.

Fabienne Becker (19:14.254)
So as I just mentioned before, what we really have with the organoid, and this is mainly to compare 2D with 3D, is that thanks to this 3D model, we do can at least more or less closely resemble a simplified version of the whole organ, because we have all of these different cell types from cardiac cell types in the organoid. So we do have...

the connectivity between different cells and we can mimic more or less a simple version of an organ. And in 2D we just have like a monolayer, so the cells are just spread out in your dish and although the cells are connected with each other, this 3D model just gives a whole other base to everything because we have different kinds of connections, not just in a plane 2D.

a way, but in a 3D manner, it's quite better. And well, for the animal model, because we've just talked about, are still, I feel quite far away from really saying, okay, we can use these organoids instead of animal models. But I feel like if we are, as researchers trying to really, if we want to make the step at one point in our lives that we maybe at one point can say confidently say,

that, okay, instead of animal models, we want to have a cell-based model. We still at this point need to do quite some research into that field. But also just thinking about quality control measurements, because actually, for my part, we are thinking about, of course, going to clinical trials and these essays and these safety measurements that are actually that we do with the animal studies, at this point, we cannot

simply do them in an organoid model because it's just not possible to really see if the safety of our product would affect the host when we transplant the cells. This is just not possible at this point with a simple 3D cell model.

Nóra Balzer (21:22.004)
I see. But maybe at one point we can also mimic all the environmental changes. Maybe we can also just mimic an obese heart or an aging heart. I think that's all the future that will and should come.

Fabienne Becker (21:27.628)
Yes, hopefully.

Mm-hmm.

Fabienne Becker (21:35.692)
Yes, definitely.

Nóra Balzer (21:38.444)
So how do you see the the IPSC derived cell products contributing to personalized medicine, particularly in cardiac disorders? Is it a hype or are there significant new insights gained from this technology?

Fabienne Becker (21:54.036)
So I feel it's not just a hype, it's definitely a needed feel that we really need to put our focus in. As I've mentioned in the beginning, cardiac disorders are still connected with a very high mortality rate. So if you have the problem that you have a heart disease, you actually, you just need new options and modern technologies. And I feel like these IPS based therapies can have

a new outlook on everything. So for personalized medicine, can of course think about donating your cells and people are making IPS lines out of these cells to then make them again into a cardiac model. And this maybe can really help to see individual genetic background of your heart, but also just of your cells and to maybe at one point really if we have these three organoids and do disease modeling.

with patient derived cells that we can maybe really at one point see, which drugs, which new drugs or just drugs that are available already just from the clinical side, that we can really test all of these different drugs and combinations of drugs and really in this, with this 3D cell model, just find the best working regime for the patient. I'm actually at this point not quite well versed into how

far away we are really from doing something like this, but at least from a very maybe naive standpoint of just being a student, I think it would be very nice because then you can, at least if it's not too expensive for patients to do something like this, that you can really just get personalized medicine because we know that not every patient is having the same treatments or like the same outcomes with different medicines. So we do need to think about

What's the best outcome for the patients?

Nóra Balzer (23:53.642)
Wow, yeah, the way that you just mentioned drug screening indeed, think for that one, organoids would be just amazing. what progress has been made in this field and what are the limitations there?

Fabienne Becker (24:01.571)
Mm-hmm.

Fabienne Becker (24:06.754)
Yes. So the progress is definitely, in my opinion, one of the biggest progress is of course that we've made so far is that these organoids, as I've mentioned before, or again and again in this talk, is that they just, thanks to these organoids, we do have a model that is showing more or less the real tissue, so the real how our organ is really behaving. And we do have with this

a quite improved physiological relevant model, even though I've just mentioned that it's a bit lacking in the sense of that we have fetal cells instead of mature cells. But still we do have with these intracellular interactions in an organoid, we are definitely working towards a more real organ that we are working with in a lab. But still the limitations are not just the maturation.

But also if we said before how we face the scalability and consistency, it's just that it's actually still, I think, quite a big limitation that we don't have real standardized protocols out there. So like every lab is maybe picking up what they have known from colleagues, like what has worked with their cells. It's just everyone has like their own protocol that they know that works with them. But if someone like starts a new protocol right now or is completely...

starting a new project that maybe they need to think, okay, I have so many protocols available online from publications, which do I choose? So it's like, there are sometimes even actually in cardio field, there are just sometimes very slight changes in different protocols. So for you, you're like, okay, which would be best for me? So I feel like this is definitely still one of the biggest limitations that we need to think about, maybe standardizing everything a bit more.

to have more standardized versions of protocols, both for organoids, but also actually for 2D culture. So yes.

Nóra Balzer (26:10.69)
Yes, I think it's valid for almost all types of research in natural sciences, especially in the academics. I work now in the organ transplantation field and I see how many people have bioethical and religious issues with receiving or also donating an organ, especially heart or eyes.

Fabienne Becker (26:15.884)
Yes.

Yes, everyone's doing their own.

Fabienne Becker (26:33.07)
Mm-hmm.

Fabienne Becker (26:38.958)
Mm-hmm.

Nóra Balzer (26:39.776)
And in this way, I'm just wondering what are the ethical concerns which are unique to IPS derived cells and how do they influence your research?

Fabienne Becker (26:50.898)
So maybe from the sample you just mentioned that we don't always have real organs available for if someone has a heart disease. So I feel like IPS cells or IPS based cell therapies can definitely bridge this hurdle of we don't have any organs available, hopefully at one point. And for me personally, at least the most ethical concern that I would have.

is that we often forget where we get these iPS cells from because it's still human cells that we're working with. often patients that do donate just a few cells of their body to then be produced into iPS cells, sometimes if you donate your cells for research, you're not always completely in the loop of what can be done with your cells. Or especially if you're not in a research field and you just want to donate your cells as a normal

human cell donation, you not always know what the researcher means if they tell you, yeah, we can do an IPS based model or we can do this and that. So I feel like informed consent is still quite challenging because there are so many options that you can go with IPS technology. So from a standpoint that you just donated your cells, you, it's quite challenging to really be completely in the loop of

what is all possible because the field is so broad. So you can kind of like do everything with yourselves. And I think this is maybe not for everyone, but I feel like this is an ethical concern that really where you have your cells from that the people who donate are also informed what can possibly happen. And maybe I'm not sure if it's counting as an ethical concern, but of course, because it's a human cell based product, there's also of course the concern of safety.

And because if you transplant from a donor, your cells, you of course have immune responses, but also especially because it's an IPS based product. IPS cells, they do have the capacity of differentiating into different cells that you might not want them to differentiate into. But also these IPS cells just grow quite strongly. So if we have any of these, I'd say unwanted native IPS cells left in our product,

Fabienne Becker (29:17.304)
when we want to just administer cardiomyocytes, for example, we really need to find tests to really ensure that the product is safe. Because if we have any iPS cells left in our product and we administer these into the patient, there could be the risk that tumors are formed. So this is something also for the patient to always note. If they also have the option, do you want an organ transplantation or do you want a cell-based therapy?

that you're just informed what are the risks of everything and that we also as researchers focus on really safety testing with our self-products.

Nóra Balzer (29:54.562)
Yeah, very interesting topic. And here comes a bit also science communication as well, because I think many patients also don't really understand who are not in this field, what's going on or how to make a good choice about it, about their own life and health. And that's why I think it's also important to talk about it in an easy language that everyone can understand.

Fabienne Becker (30:10.072)
Mm-hmm.

Fabienne Becker (30:15.702)
is.

Nóra Balzer (30:18.092)
Yeah, so after ethical concepts, we just come to the question of money. So you just mentioned that it's not a super extensive technology, but just roughly what are the costs and time implications of manufacturing cardiac organoids and how could these be reduced? I think in health, we can always just need to reduce the cost.

Fabienne Becker (30:23.79)
you

Fabienne Becker (30:42.774)
It's actually because I know from other labs that they are still working with 2D based cultures and this is actually one of the cost reduction factors that we are doing because I feel personally with this 3D based models you're already reducing your cost because from a very simple standpoint if you're working in the lab and you have like a well played like a dish you have a certain amount of media in it.

And whether you are working with a 2D layer or a 3D culture, you have the same amount of media for different types of or different numbers of cells. So in the 2D field, have, I'd say, less cells that are laying at the bottom and a certain amount of media. But for the organoids or the spheroids, they are because they are floating, they have more space and the same amount of media. So this is already like a cost reduction that you have just more cells that are

taking up less of the materials that you use. And of course, you always need to think about how or where we can reduce more of the costs because yes, especially if you're starting a new project or if you're new to the cardio field, you do have to maybe like at the first step, you do have to put quite a lot of effort into what you need to buy. And there are quite a few things that you will need to buy. And this could at the first like

stage put your cost quite high. But I think, especially with optimized protocols, this initial cost is paying out in the sense that you can produce quite a lot of cells with it. And time-wise, at least in our hands, I think the most time-consuming part is actually the IPS culture, because you have to have them readily available that they can go into the cardiac

differentiation, but for us at least we have optimized the protocol of pure cardiac differentiation to be as quick as nine days. So in nine days you go from the IPS cell and you have readily available heart muscle, real heart muscle cells. So it's actually quite easy. quite, quite fast.

Nóra Balzer (32:47.928)
Okay.

Nóra Balzer (32:58.718)
It's super fast. I mean, the mouse has, for example, like three weeks of pregnancy or so. So yeah, it takes already longer. And also, guess also with the maturation process or with aging, you are much quicker.

Fabienne Becker (33:05.71)
Mm-hmm.

Fabienne Becker (33:12.366)
Yes. If we think about that, then of course we will take quite a bit longer, purely the cardiac differentiation nine days, and that's like it. Of course, if we're thinking about putting them then into the organets, because I've just said for spheroids, you just have cardiomyocytes in our case. But if you want to go into the organoid, you also need different cell types. Then of course it can take maybe two to three weeks, of course, also because first you have to

make all of the individual cells and then have them self-assembly. But all in all, think it can be quite straightforward if you have these optimized protocols and you know it.

Nóra Balzer (33:54.442)
I see. Yeah, exciting. So what are the recent advancements in the organoid technology that you are most excited about? And how might they impact on your work on cardiac 3D models?

Fabienne Becker (34:08.59)
So for me, I feel like because we are mainly focusing actually on spheroid development rather than organoids, so I feel at least for me as an accept, if possible of course, I'd also like to contribute to real organoid research because I'm not actually quite sure how long organoid models have been around, but I feel it's still quite a novel approach to cell culture.

And I feel like there can be quite a few improvements, but also in the recent years, many groups have done quite a lot of research on these 3D models just to have a cell model available for maybe as a, circumvent these animal models as we've talked about before. So for me, it would be most interesting to see if we can ever really bridge this gap of animal models and the purely cell culture. So.

For me, would be the most interesting to see if other researchers are already able to do this in the coming years, or if maybe I can also go more into this field and really see what we can do in regards to that.

Nóra Balzer (35:24.84)
Indeed, think it also has a very important social impact because I think in Europe it's...

heavily discussed whether we really need animal research and I think from the scientist perspective we know that yes we still need but we still need like alternative ways to at least before going into animal research we could use we can use organoids to to see if our hypothesis works or not.

Fabienne Becker (35:42.552)
Yes.

Nóra Balzer (35:56.024)
So now we are coming to a question that no one can really answer, but maybe you can speculate or we can speculate together. So how far are we from generating a fully functional transplantable heart issue using organoid based technologies? What do think?

Fabienne Becker (36:13.969)
So, also coming from an EU project, so as I've said before, we also wanting of course to go into clinical trials with our cells. I do know that different groups that they are already actually going into clinical trials and they are, I'm not sure in which phases exactly, but there are definitely groups out

who are doing clinical studies already with, I'm not sure if they really are using organoids, but at least cardiac tissue. So I know that there are different groups that are also like, we are thinking about doing spheroid administration. So just with one cell type, so we're doing the cardiomyocytes instead of the whole organoid. But I feel like sometimes, or especially if you're thinking about what exactly we need to actually do.

If someone is suffering a heart disease, for example, ischemia or something like this, maybe we even don't need to really transplant a whole organoid, but we just need the specific cell type, like in our case, the cardiomyocytes. That's maybe something that you need to really look into, like, do we really have to transplant an organoid or is it just as a model for us to really look into disease modeling or as animal studies?

And then if we want to go into clinical trials, if we really need an organoid to be transplanted off, it is enough to like just transplant one of the cell types, in our case, decaromyosides. And because I know that there are clinical trials out there, we are actually going into the step of adding cell-based therapies, at least for testing in these kinds of cases.

Nóra Balzer (37:57.836)
very exciting project and you have been working on this project now for three years. So I'm sure you had many shocking moments when you were really surprised or didn't expect that something has happened. So what was the most surprising discovery or insight you have gained by working on this project?

Fabienne Becker (38:16.974)
Yes, so maybe because I'm like I said in the beginning from a chemistry background and then just like not being pushed into but by choice going into more of a cell culture based project because it was always quite interesting and as also you mentioned when I talked about how easy it is to go into 3D Cell based therapies or like the models I think this was the most surprising discovery how easy it can be if you at least have

Nóra Balzer (38:21.4)
Mm-hmm.

Fabienne Becker (38:47.0)
partners who have worked with them with these kinds of models before and who can provide you with good protocols. So if you have a good group available, it's, it can be quite nice and easy to from like start from scratch because I didn't know anything about or like very little about IPS technologies and the cardiac field. And going into that with like kind of zero knowledge, it was thankfully for me a quite nice start.

because it was working quite nicely and well. And maybe one of the most, I'm not sure if it can be called surprising discovery, but also just, feel like for every PhD project that if you encounter hurdles or like problems in your project, in your protocol, wherever that you can at least with time overcome these problems and that patience is really needed in s-

project like this, especially if it's a long project like three years now, that you just need to be patient and really try and try again, especially when you're working with cells, because they, we sometimes maybe forget that these are living cells, so they sometimes have a mind of their own and you really need to like think about or like get a feel for how your cells just behave to really make your project work.

Nóra Balzer (40:12.952)
So for me the biggest surprise was today to meet a PhD candidate in her third year who is actually saying that yeah it's pretty straightforward and with time it can be solved and also that you are coming from a slightly different field. I love it so I think you have just shown now to many listeners that yeah it's also a question of mindset and just doing and keep on going and it's gonna work out. So what advice would you give to students or researchers who want to contribute to the field of

cardiac science.

Fabienne Becker (40:45.428)
And so I hope I'm not being too naive and saying, it's so easy for everyone to go into, because I know from, course, if you're talking to other students, other PhD candidates, that depending in which group you are, it can be quite difficult to like going from the university life of a master's student where you have different courses and you have a clear line and guidance what you are supposed to be doing at which stage of the master program.

And then going into a PhD program, you're kind of like on your own. So you have to first like really think about, okay, what is there already available as research literature, especially in the cardiac field I've said before, it has been quite well published already. So maybe if you're thinking about doing it to cardiac science, you may be like, I see all of these publications already out. Can I even?

still do any real relevant work in this field because I so many publications. I don't even need to do anything anymore. especially because maybe I also thought that in the beginning I was like, okay, I'm reading up on all of the things that have been published and what's relevant to the project. And I was like, hmm, there's already so many things out there from different groups. What can I really do? But with the project was prolonging, like going through all of these years now.

Nóra Balzer (41:45.674)
Everything is done.

Fabienne Becker (42:12.386)
You do have to do quite a lot of reading, but you do find that there are always certain things that are still missing or lacking. Like I've said before, maturation, for example, in the cardiac field, that we go from a fetal-like model to more adult versions of ourselves, something like this is still lacking. But just generally that you really find, or you do have to be passionate about your topic.

I think if you really like to do science and research in the university setting, in a PhD setting, then you can really make the work. So even if there are hurdles, you can really try and find your niche where something's maybe still lacking or where you want to go into. And then you can just really make the science work.

Nóra Balzer (43:01.24)
Thank you very much. It was a very inspiring thoughts and insights into organoid research. I wish you the best of luck and yeah, all the best for your future career and looking forward to see the clinical trials and all the future advancements in this field.

Fabienne Becker (43:10.71)
Thank you.

Fabienne Becker (43:22.038)
Thank you for having me and I hope maybe I've hopefully in this short amount of time tried to really bring forward what cardiac field research can be like and maybe someone wants to go into the field now and I hope I can could bring the topic into a bit more perspective of a student who's just doing basic research.

Nóra Balzer (43:44.374)
Definitely. Thank you very much.