Silvia Mihaila
Description: Silvia Mihaila, Professor of Pharmacology at Utrecht University in the Netherlands. Her research focus lies in developing organ-on-chip models. These advanced in vitro systems can mimic the structure and function of many different organs. By utilizing these models, researchers can study specific biological processes without relying on animal experimentation, while also integrating multiple components of human physiology. Silvia and her team are particularly interested in studying chronic kidney disease and its impact on other organs in the body. In this episode, we talk all about her organ-on-chip research, the need for standardization & validation with these models, and the overall potential for regenerative medicine and how she is partnering with clinicians to better address the true needs of the people.
Websites:
Publications:
Kidney-based in vitro models for drug-induced toxicity testing
Organs-on-chip technology: a tool to tackle genetic kidney diseases
Co-axial Printing of Convoluted Proximal Tubule for Kidney Disease Modeling
Related Articles:
Successful Kidney-on-Chip Kick-off Meeting
Resources:
Utrecht Advanced In Vitro Models Hub (U-AIM)
Show Notes:
[0:00:03] Introduction and Background of Professor Aneesh Raghunandan
[0:03:53] Oversight and Regulation of ESG Funds
[0:07:08] The challenge of regulating non-financial performance metrics
[0:14:43] Decentralization and its impact on coordination across agencies
[0:19:16] Understanding the different scopes of a company's carbon footprint and outsourcing
[0:22:03] Challenges in Measuring Scope 3 Emissions
[0:24:00] Tax Arbitrage and Outsourcing Carbon Emissions
[0:30:59] Challenges with Data Accessibility and Standardization
[0:35:55] Requiring Standardized Disclosure: Importance and Trustworthiness
[0:36:30] Enforcing Misreporting for Transparent Company Disclosures
[0:38:53] Challenges with Third-Party ESG Data and Measurement Error
[0:44:18] Market Fix vs Regulation: Carbon Emissions Debate
[0:50:10] Different Perspectives on Company Virtue and Values
[0:52:59] The Complexity of ESG Ratings and Agency Weighting
[0:56:08] Tackling Specific Issues and Disaggregation in ESG Discussions
Unedited AI Generated Transcript
Introduction and Background Story of Professor Silvia Mihaila
Brent:
[0:01] Welcome, Professor Silvia Mihaila, thank you for coming on today.
Silvia:
[0:06] Thank you for having me.
Keller:
[0:07] We'd love to start off by hearing a little bit more about your story and how you got to Utrecht University.
Silvia:
[0:11] Well, it's a very long story and at times it doesn't have anything to do with science because science is not everything, so life happens.
So I am coming from Romania and I studied physics and chemistry and I was set to have a future as a teacher of physics and chemistry.
And I always had this curiosity, what is out there?
What is, I lived in a, I was born in a city that was surrounded by mountains and I always wanted to know what is behind those mountains.
So I had this ambition of see what is out there and during my studies I wanted to go abroad.
So a little bit of story on that because I could have, my choices were Germany, Spain or Portugal. and Germany was too close to Romania, so my parents would visit me too often and Idon't want that.
And at the time, Spain, there were a lot of Romanians in Spain, I just want to try something new, so I ended up in Portugal.
And at that time, I didn't know that much about the country, so I ended up in Portugal doing an Erasmus internship, so a six month internship during my final year of my undergrad studies.
And I liked it a lot. It was a very different experience academically, but also as a, yeah, coming at age, adulting, entering adulthood.
And I liked it a lot. So I decided to come back.
[1:40] I got an opportunity to work as a junior researcher. And my supervisor there asked me, would you like to do a PhD?
And I don't know what a PhD is, what does it mean?
And she invited me to be part of a program that at the time was called MIT Portugal.
[1:57] And that program offered me the opportunity to start a PhD in bioengineering, in a field that I didn't know that much.
But it turned out to be, yeah, to graduate from the program in bioengineering.
And then during that time, I met my husband in the lab, who he is Dutch.
And then we had this deal that, But yeah, he finished first his postdoc at the time and he came back to the Netherlands and then I followed him.
So it was not science that brought me to the Netherlands, but it was love.
[2:31] And yeah, while I arrived here, I applied for several scholarships and then there are some European scholarships that allow you to start, for instance, a postdoc in a different countrythat you have been before.
And this is how I kicked off my, let's say, scientific career in the Netherlands.
Love Takes Silvia to the Netherlands and a Scientific Career Unfolds
[2:49] And it was not in Utrecht, it was in a different place in Nijmegen, where I now live as well.
And then this postdoc ended and I was looking for another opportunity and there was this opportunity here at this department on a project called Bioartificial Kidney.
And during my PhD, I did bone.
During the first postdoc, I did bladder.
And now I moved into kidney, but at the the core of everything was this tissue engineering, biomaterials, stem cells, tools for the applications that in this case was about the kidney.
And while I was doing my second postdoc here, it was an opportunity of starting as an assistant professor in in vitro models of disease.
And this is how now everything is unfolding.
Brent:
[3:41] And then when you were doing your PhD in Portugal, correct?
That's when you went to Boston at MIT, it was a dual program.
Silvia:
[3:51] Yes, so this program, it was a collaboration with MIT, so part of this program was that you could have the opportunity to go to MIT.
And then during my PhD, I did go to MIT to the group of Alik Adem Hosseini for one year, and it was an amazing experience, I loved it.
Brent:
[4:12] Yeah.
Silvia:
[4:14] Again, it was a different lab, different culture, different way of doing things.
So that was amazing for me, was very important.
And what I really, really liked from those times is that there were a lot of people just like me there, but now we are all scattered around the world.
So we have that memory together of that experience. And then whenever we meet, we still talk about it. But then we...
Still keep contact and then somehow we still meet in a work context or not work context, social context and social gatherings and we still meet.
So we still keep those memories alive and yeah.
Brent:
[4:52] That's a lot of fun. So was that your first exposure to organs on a chip?
Silvia:
[4:57] Yes, yes. It was my first exposure and I think it was at the time where So I was then at MIT in 2010.
It was the very, very beginning of this.
So it wasn't, yeah, I didn't understand that much what it means.
Okay, it was just cool science at that time.
[5:19] And then as I moved, I came back from Portugal, to Portugal to finish my PhD, and then I moved to the Netherlands.
And more and more was, we talked about organon chips and advanced in vitro models and this idea of why exactly do we do that much research on animals.
And well, when I was in Portugal, I didn't do research on animals, but when I moved to the Netherlands, the group, the first group in which I worked, they were doing a lot of large animalexperiments.
So goats, so pigs as well. So there was a lot of discussion, do we really need this for the research question that we have?
Can we not refine better our research questions doing alternative methods and then come to the animals and so on?
So that there was starting to, this question start to arise.
And then when I moved in here in Utrecht, it, yeah, this was where the place where it exploded, I would say.
And that is because there was a lot of...
And desires from the society to come up with different methods.
There was a lot of desire from the scientists that were not happy with the methods that were in place, but also at the academic level there was a lot of push to try to think also inalternatives.
And that's how organs-on-chip technology started to kick in also here in Utrecht.
[6:47] Also in the Netherlands already, but very much here.
And this is how we also started here at the Department of Pharmacology to use these tools.
Keller:
[6:56] Yeah. So what are advanced in vitro models and why are they important?
Silvia:
[7:01] So advanced in vitro models are, well, they are in vitro, so there is no animals being used, but they are biological models in which we can probe, interrogate specific biologicalprocesses.
And then one of the, well, the classical is using cells, which are also good, to the still good, depending on the research questions, the research question that we have.
And what we want, what we understand by advancing vitro models is that we bring more components of the physiology, human physiology, that can be integrated in the system orreplicated in the system.
So, for instance, if you think about the kidney, kidneys produce urine, there is a lot of blood flow, can we have, can we replicate this interface between the blood flow and urine formation?
Always in the context of the research question that we have.
[7:56] So what we understand here by...
Advanced in vitro models can be either a 3D construct and that can be their cells are not growing on a 2D, but they grow in the scaffold or can be grown as organoids in that way.
And we are looking also at depending again, I will probably repeat myself many times saying, depending on the research question, you always have to look at what exactly do I want?
You cannot have it all. Well, you can have it all, but not at the same time.
So you can always, you need to pick your battles in that way, so then we look at what exactly do I want to interrogate?
And is flow relevant for my research question? Is it 3D relevant to my research question or not?
So this is what we are trying to do. And there are sometimes input that we have never thought of.
For instance, as I was mentioning a bit before, or that we work with a lot of kidney and chronic kidney disease and the underlying condition in chronic kidney disease, there is a lot ofcomponents that are in the blood that are not in the healthy population.
So do we take that into consideration when we culture the cells in this, let's say, diseased environment?
So that is also what we are addressing when we discuss about advanced in vitro models.
2D vs. 3D Models in Organ-on-Chip Technology
Brent:
[9:17] So when you talk about 2D, we're thinking like Petri dishes, is it's like on a single surface and then the, we mentioned it before, the organs on a chip, that's when we start getting 3D?
Silvia:
[9:29] It depends on how, well in the organs on chips you have the advantage of creating for instance perfusion.
You have the advantage of creating compartments and when you have this transport of molecules from the blood side to the urine side, you need.
Of an interface that is crossed by the molecules, right?
So then for instance, also in the models that we are generating, we are having a membrane and that membrane, you can think, we can engineer, we can have several designs of thatmembrane in which we culture cells and then we can apply flow and then from the blood side you see, oh, is this drug being eliminated in the urine Or is this drug affecting the barrier thatthe kidney cells are going to do.
[10:17] Should create, and so that they don't leak proteins.
So we should not have proteins in our urine or blood. That means that the barrier is broken.
So that is what we are looking at. But when you can also generate organs on chips having 3D structures, right?
So the membrane can have features like can have curvatures and it can have a certain the shape that will give this three dimensionality.
And we are working a lot of epithelial, so that means interfaces, so cells that create barriers, so there is a compartment of in and out, so this transport, so we work a lot with those ones.
Intestine, the kidneys, and one very interesting project that we have now, it's also bone, so back to the PhD time, so we also work with that.
And for bone, for instance, we are also looking at, so bones have to carry our body weight.
So that means that we cannot culture them in 2D, right? So they need to have a load.
So we are looking how we can create mechanical loads into 3D models of the bone.
So that we can see, for instance, in chronic kidney disease, bones are severely affected, and it's something that is called uremic osteoporosis.
And then many patients suffer fractures. And because it's a very.
[11:42] Patients with chronic kidney disease might be too sick to exercise, for instance, or to have a life of actively being, having an active life, then the bones might not remodel that often,often, and then you might, again, lead to more fractures.
So then we want to see how can the disease might, for instance, impair the sensitivity of the bone to feel mechanical stimulation, and that might lead to poor remodeling.
So we are looking at bioreactors, like physically stimulating or culturing the cells in 3D matrices that can generate these kind of mechanics.
And that, for instance, is a 3D model, but in those models, we don't need flow.
There's no need for flow. So then again, you will need to know very well what exactly you want to do in order to design the model.
Brent:
[12:36] And then could you give.
Silvia:
[12:39] Like a broad description of what the organ on chip looks like just as like a like the ones that you showed us in the lab today like what does that look like or like an image people canthink about.
[12:53] Well that would be very uh i i would not say that there is a recipe for it i
Designing Versatile Organ-on-Chip Models
[13:00] think it's a matter of imagination so we also try in the lab to be very creative so uh and obviously if you are going to Google organ on chips, you will see the chips that are generatedat Wyss Institute, the small chips made of PDMS.
So usually when we design what we call an organ on chip, it doesn't necessarily need to look the same as the one that colleagues from Wyss Institute prepared.
[13:27] So it can be anyhow the way you wish, but we take into consideration several aspects.
So we want to make them transparent so that we can make, we can image them.
We want to use materials that the cells will not die if they are in contact.
Materials that don't leach, they don't have traces of material that could kill our cells.
And very easy to achieve, preferably.
Easy to fabricate, easy to produce in the way that you would like to have a certain channel with or certain configuration that you can immediately do it.
So, some versatile materials that we are also looking at, and for instance, we collaborate a lot with colleagues that are material, that they do material design, and they help us also with thematerials that we can use.
Obviously, you want something that is autoclavable or something that is.
[14:28] You can use it multiple times and if not, it's not that expensive.
So, these are kind of aspects that we are addressing, and then we come also with the biology and the biological questions that we have.
But in principle, these are the aspects that it's easy to use, very easy materials, easy to fabricate, that you can adapt.
Easily, because if you have a material or a system that you just need to change a parameter and it's not possible, then it's not versatile anymore.
So then it kind of constricts you.
So we try to be sometimes to create systems that we can build ourselves like a plug and play system that gives you a little bit of flexibility.
Brent:
[15:10] Yeah.
Keller:
[15:11] And with these models, they're coming as a result of a move away from animal models.
Could you talk a little bit about the efficacy between the two models?
Silvia:
[15:20] Yes. So, besides the fact that scientifically and in the field of in vitro, these are very nice models, there is a very, very strong push to move away from animal experimentation.
And that is not because, oh, we don't want to work with animals anymore.
Yeah, it's because there is evidence that many of the findings that in animals didn't apply to humans.
And And that has to do also a lot with this drug development pipeline.
And that is where we as scientists, we are in contact a lot with companies that develop drugs, so pharma companies.
[16:05] And many times they also say that, well, we need to find a model that answers our questions.
And if that model is a 2D, then we use the 2D, but then we need to challenge the model. And then many times we had these discussions with them, what can we as scientists do so that themodels that we are preparing are appealing for their screenings?
So that we just don't do for the sake of doing, but there will be also follow up on this.
[16:31] And then we, for instance, because we are talking about kidney, there are many drugs that are eliminated by the kidney, so into urine, and then you create these profiles that arecalled clearance.
And then you make this assessment, okay, the clearance of this compound is of this number.
So then you go to humans and you see that it's something else.
And then you realize that the predictions that you had in rodent models, which are the most used, didn't fit.
What you found later on. And then you could have done a better refinement before the animal was put in, you used it.
So now what we want to use with this advanced in vitro models is like to be a kind of a buffer zone before we even reach animals.
So did we do everything that we could do that can be done with the tools that we have to kind of refine much better the conditions that we are going to test so that we don't do just animalsbecause this is what we have done all the time and we cannot draw conclusions because it's too complex a system.
[17:36] So at the moment, especially in the Netherlands, there is a very strong desire to develop alternatives and to move away from animals, from animal testing.
So for that we develop humanized models, human models.
[17:53] In which we address this kind of different questions, biological questions, and then, And although the ambitions are high not to use animals at all, we also have to be realistic andthis will not happen overnight.
And it's not only about people not working with animals anymore, it's also about changing the mindset, creating the frameworks in which these results that are coming from the non-animal experiments are valid, validated, and then accepted by the society as valid.
Scientific society as well, but also the civil society, and then we are doing a lot on that.
Creating a Sustainable Transition and Collaborating with Hospitals
[18:34] So we have the support, not only academic, but also governmental support, the non-governmental organization that support the work that we are doing, and then basically it's anentire ecosystem that aims to...
[18:49] Bring sustainable innovation. It's almost like when you want now that we are changing to alternative energy.
So you cannot just do it overnight. So it has to be sustainable, long-term goal, a vision.
So I know that sometimes we are just rebellious and I don't want to do any more experiments anymore, but these things don't happen like this.
They only last three days and then you have to go back to your old ways.
So now what we try to do is develop the platform, the framework in which this transition is sustainable and it can have, it's here to stay rather than just being a fling of a moment and thengone.
Brent:
[19:29] And it seems to be way more useful from my perspective, at least from the standpoint that you could go get a sample from the hospital, from a patient who has a certain disease, acertain genetic background, who might be different than the models we currently use, and then you put that on the membrane, and you culture that and then you put that specific sampleonto the chip and then run tests with different drugs or different conditions and it just seems to be a way to create way higher efficacy for whatever you're using.
Silvia:
[20:04] So we, this is not anymore a one man show science.
So we are always, what is the greater goal?
What do we want to achieve? I think many people that are scientists, they want to do something, they want to contribute to the society.
So we are working a lot in collaborations. We cannot do science on our own.
Science doesn't exist anymore.
So we are always teaming up.
It's about team, altruism and empathy to what we want to achieve.
It's not okay, we want to find out a cure for chronic kidney disease or to find how we can delay the progression of the disease, so there is there an interest to help somebody.
So for that we collaborate a lot and we collaborate with the hospital and that's why it's very important that for instance this is the university and then across the street is the hospital.Sometimes we just need to cross that street.
[21:03] For many it can be very difficult to cross, but sometimes we just say okay, it's a hospital, maybe the setting is different, the discussions are different and the way they do work isdifferent, but we just are in the moment which are so open and ready to let's embark in this together because we all want the same thing.
So why trying to work towards the same goal but in different routes, let's do it together.
And then you multiply the efforts.
And this is what we are doing at the moment. We collaborate a lot with the hospitals.
The hospitals are very open.
They create the framework in which they explain to the patients why, why is it important.
Increasing Awareness and Openness in Research Community
[21:44] And then there is an increased awareness in the community about why do we need to do this kind of models.
And then whenever you have this conversation, nobody's scared, oh, what are you going to do with my cells?
Are you going to, what are you going to do with them?
So then there's, people are very forthcoming. And obviously, when you are needing cells from patients, they are in a place where, yeah, it's a very difficult time for the family.
If you have to work, for instance, with the children hospitals, it's very difficult time.
But then if the, we have these colleagues that are preparing these kind of explanations and people are much more aware of what we do.
And here is where outreach is very important, where we go out of the lab, put the lab coat in a hanger, and then you just go out in the lab, from the lab and explain to people, what are wedoing? Why are we doing?
And why are we doing it like this and not the other way around, so that we are very close to the society and basically we want to serve the society, then people are much more for comingto support in your research.
And then it's not only the hospitals that are involved, it's also the people that are talking about what is the impact of innovation.
[22:59] Who is going to pay the bill at the end of the day? Who is, okay, we discovered a very, very fancy treatment, but that will cost, will be very expensive.
Who is going to make sure that this is a viable option for the insurance companies or the government to cover.
So these colleagues are also involved in this discussion.
Brent:
[23:21] Yeah, it seems like a much more holistic view of impact.
It's not just I can get a paper published. It's no, like this discovery will genuinely impact lives.
Silvia:
[23:32] Yes, and that was, yeah, 10 years ago when I was doing my PhD, there was this, oh, we just publish, it's printed, and it's done.
But now it's much more than this.
We don't want something, a thesis in a bookshelf. It will not do anything if it sits in a bookshelf. Only gain dust.
So now we are, what is very important for us as researchers and the next generation, the generation that is coming, okay, let's say maybe we are too rusty at our edges and might not be, wefeel that we are just too old to innovate as much, but we really want to encourage the next generation to be as courageous as possible.
Of course, young people are ambitious, but sometimes you need to take some risks and we really encourage them to take those risks.
I think at the university, the safety net is there. So if the project doesn't work, it's fine.
Encouraging rebellion and youth participation in the conversation
[24:36] Trying is very important. So we We try, especially with the younger generation, to make them aware of the possibilities, to challenge the system, to create a sort of rebellion, acalculated one, not very strong.
No, but we are really, really encouraging the young generation to really be part of the conversation.
And for that, we do have, in the Netherlands, there is a young chapter.
It's for people until 35. I still feel that I am 35, I feel young at heart, but there is this group of young people that really want to be at the table.
This is their future.
[25:23] So they want to be part of the discussion. This is how they see it.
They want to be heard and they are giving this spot at the table.
So then it's very back and forth and a lot of listening ears.
And so there's not the right way to do things, but there's nobody having a better idea than the other ones.
All ideas are listened and we decide together in this.
So that's what we really, really encourage, not only the collaboration, academic collaboration, but also collaboration with industry, with the people that are in between industry andacademia.
There was a time when we were saying, yeah, when you finish your PhD and you move to industry, ah, yeah, you went to the dark side. And there was the other side.
You betrayed the academia, but now those lines are very blurred.
[26:17] And we really talk a lot with also people from industry and people that tell us, well, for a model to work, you need to have it validated, it has to be standardized.
I was like, oh, I never thought about standardization. and I thought it was just a publication and done.
I was like, okay, but it worked three times and that's it.
But then also the standardization and implementation, how is it going to be used? How do you envision?
Because if you have to connect a gazillion cables, I'll forget it.
So sometimes, for instance, in the meetings that we have with the clinicians, they say, no, it will not work, it will not work. Why? Because it doesn't fit the system.
[26:56] You have to make it very easy to adapt to what we have, right?
Keller:
[27:00] And with the youth chapter, is that isolated to youth in academia, or could anyone within the age group of 35 come in and express their opinion?
Silvia:
[27:09] So this is a program that in Netherlands is called TPI, so it's Transition to Animal-Free Innovation, and that is at an academic level, so all across the Netherlands. science.
And it's a governmental program, so that means that every university can have a center on this so that they can contribute to this.
And then they have this young chapter, which is for the younger generation, PhDs, bachelors, masters, whoever feels that they can be part of it.
But it doesn't have to necessarily be biomedical.
It can also be people that are doing more science of innovation, that are more, let's say, philosophical in their approach, that don't necessarily have to be the ones pipetting in the lab, let'ssay, hardcore, but that are part of the discussion and then can be also people doing law and governance and how does governments work and how laws are put into place and who makessure that the law is being followed.
So they are also, but I think it all has to be in an academic setting, so that it's more organized.
But at the same time, for instance, there are also other initiatives that are called help-a-thons.
When one researcher says, I have a problem, I want to.
[28:34] Create a Kinyon chip that is doing testing all these drugs and I don't know how to do it, where to start.
So I'm launching the question to the community and then the community gathers for two days and then they help this person that came with this question as I did you think about whatdrugs did you think about what material but look from my experience I learned this maybe you should take it into consideration did you think where you are going to use it who's going todo it Do you have any sponsor? Do you have finances?
So things that you might have not thought of, but the community comes together and then help you to refine your question, to find the methods, to think about the impact in a more in-depth way.
And can be any questions related to animal alternatives in that way.
So it's, again, very nice here in the Netherlands, this organized.
Brent:
[29:27] Yeah, definitely seems very collaborative and very useful, especially as we progress a little bit more.
And now, kind of jumping back into your specific work, why did you focus on kidney models and maybe what are you hoping to answer?
Silvia:
[29:44] Yes, so this group in which I am at the moment, well, it's the Department of Pharmacology and in the subgroup that I'm part of is Experimental Pharmacology and it was alreadydedicated to kidney.
So that was already the core business, let's say, of the group.
And for that, we are looking, and in the way kidneys, in the setting of pharmacology, it's very important because it's the root of excretion of many, many drugs.
And then there are cancer drugs that are being eliminated by the kidneys and they can damage the kidneys.
So then you also need to look into these kind of aspects, for instance, when we discuss about certain treatments.
And then, as I started to, obviously, when I started, I didn't have that much kidney experience.
I knew that everybody has them, right?
That it's important to have them. And I learned more and more.
And one of the things that I realized, and it always comes to create your own niche, to create your own space, I did my PhD in bone.
And I had, I understood how to make bone models and so on.
And then as I was reading, I realized that one of the complications in chronic kidney disease, like it's also this situation with the bones that they become very fragile.
So now one of the focus that we had in our group was also, to understand how, when the kidneys are failing.
[31:12] With the failing of the kidneys, the certain metabolites that have to be eliminated via urine, so that are generated because we are just existing and are alive, so metabolic waste is noteliminated and remains in the blood.
And blood circulates everywhere.
And this is how all these kind of compounds that should have been eliminated reach everywhere.
So that's why when we discuss about chronic kidney disease, we don't discuss only about the fact that the kidneys are not working is that the system is slowly falling apart.
So one of them is the kidney, the intestines, the brain, a lot of cardiovascular complications.
So then you end up having this kind of very complex system in which, okay, how can I, it's very tempting to use animals for this because then if you do a kidney injury, then you realizehow other organs are being affected.
And this is also why we are thinking about working a lot with organs on you because then we can connect different chips.
And then you can, for instance, use patient plasma.
So that's why we have the collaboration with the hospital, because they can give us plasma from patients that are having the disease.
And then we can culture ourselves with this plasma, for instance, and then you can see, okay, what is happening in the bones, what is happening, for instance, in the brain, because we alsohave brain models, and what is happening with the intestinal cells, and then it could create these kind of connections.
[32:41] And this is how I'm now looking, especially with what I'm doing in my research, as a research focus, is to understand these comorbidities associated with the failing of the kidneysand how one organ is failing as affecting the other one, and this kind of communication that exists between the organs.
And that is via the blood, in this case.
But as I said, it goes everywhere. So there are many organs that are being affected when you have this kind of diseases.
Keller:
[33:12] Yeah, and are any, theoretically, are any organs able to become chip models?
Microphysiological System Summit: Advancements in Organ-on-Chip Technology
Silvia:
[33:18] I was recently, I think at the end of June, there was a very, very big conference.
It was the Microphysiological System Summit. And there were about 1,300, researchers doing organ on chip.
And it was a very interesting meeting. It was a worldwide meeting.
So, and then it was, what was very interesting is that there were organs that I never thought, and it was also like stroke.
So, okay, you can do organs, but you can also do certain diseases, seizures.
[33:59] How, how seizures? So it was very, very interesting because it was again coming back to what is your research question?
What exactly do you, who are the key players in for instance this disease?
And then what was also very important was eye, so cornea, retina, how?
And then there are many, for instance one of the things that we discussed, we discussed also with the colleagues that we have here, we have colleagues that are working a lot with autism.
And then it's very difficult, autists, to do in vitro, because autists is behavioral.
So you can do animal autistic mice, and then you see how socially they are just different than non-autistic ones.
So that is also a very big discussion, yeah.
We talk about it, how, is it possible to have in vitro models for this kind of situations?
[35:00] What are the limitations? Because in vitro models are not the answer of everything.
So we need to also acknowledge their limitations and where that limitation gives power to the in vivo models in this case.
So I would say that theoretically it should be possible to have all systems that we have in our body, even hearing.
Yeah, so it's now being developed, or in Maastricht even.
So, theoretically, yes. Now, again, do you have the right tools?
Or should we still have to develop more tools to address certain limitations that we currently face?
The cells, the systems, how do you measure hearing?
Keller:
[35:47] What is hearing?
Silvia:
[35:49] What is behavioral traits in vitro, like is it all the biology and chemistry and molecules moving or again is an entire system that behaves in a certain way?
So again, obviously we need to look at the limitations as well and then to see how we can push further the boundary so that we can incorporate even more.
Keller:
[36:14] And you mentioned the communication pathways between the different organs.
Replicating Communication Pathways between Organs in Models
[36:17] Could you explain a little bit how that's replicated in the models?
Silvia:
[36:21] So now what we, as I was mentioning a little bit before, we, for instance, we have a project that is about the connection between the gut and the kidney.
So we have two chips, one is the gut part and so it contains intestinal cells that are cultured either on the membrane or in a tube, on a hollow tube, and then we can perfuse.
And what comes from the inner perfusion, let's say that would be the blood compartment, which is the kidney.
So that it reaches in the chip that has kidney cells, again on the membrane or on a tube, and it reaches the kidney cells from the bottom.
So that will be like as the blood will reach the cells and then you see how what comes out into what we call the urine compartment.
So if for instance you can think about, okay, I eat something, I have the microbiome, there's a bacteria that is in our guts that processes these nutrients and then they are passing the barrierinto the intestine, into the blood, then it's circulated and reaches down to the kidney.
So, we are looking, especially in our research, we are looking at molecules, like how molecules travel.
[37:31] And for that we look at either drugs, either metabolites, either cytokines, and so on.
So for that, it's very important for instance to have detection methods, real time detection methods.
So for that we work with colleagues that are doing sensing platforms that you can do this biomarker discovery and real time imaging or real time detection of certain compounds.
Compounds. And also a little bit, I was mentioning also, we collaborate with other colleagues that are kind of doing movement of compounds on porous surfaces, but are not necessarilybiological.
So the colleagues from geology, that they are also looking at movement of through the soil, how water penetrates the soil.
So then we work with them, for instance, in understanding how certain molecules, pass the barrier of the intestine, reach the kidney, and then from the blood go into the urine, so they passthe barrier of the kidney.
So this is how we are working at the moment. And for that, obviously, molecules have different sizes, and it's very nice that we can have them colored, because then we can easily detectthem, so we can image them one by one.
So then you can see how they are being.
[38:54] Moved from one side to another, and at the same time you can play with the flow, so then you can see how flow affects.
And in chronic kidney disease, one of the complications is hypertension, so then there's higher blood flow.
So there is much more high, it's much higher blood flow through the kidney, so that's why they can also get further damaged because of this high blood flow.
Personalized Dosing and In Vitro to In Vivo Extrapolation
[39:17] So this is also something that we are looking into it. So it's playing with this kind of, Yeah, with flow in this case, but communication for us at the moment means molecules beingmoved from one side to another and how you can see that, okay, one compound, it was in the intestine and somehow ended up in the urine compartment of the kidney and that is via thetransporters of the cells.
So basically the in and outs.
Brent:
[39:45] And then before this, when we were talking, you talked about the models of flow and diffusion across the membranes, that might be able to be used to personalize dosing formedicine and treatment.
Could you maybe expand a bit on that here?
Silvia:
[40:01] Yes, yes, that is a very important thing because we are not a chip.
We are very different, very diverse, very, and many times, this is also something that we are doing again in collaboration because, okay, as I said, we can be expert in, we prefer to beexpert and very good at what we are doing, and then collaborate with other colleagues and what is called this in vitro to in vitro extrapolation, where the data that we generate, because wecan generate a lot of data, but it's a...
Sort of, and so what, kind of. So what is the meaning of this data?
What can we do further with this data?
So then we have these colleagues that will say, okay, but if you have, for instance, a one kilo kidney, you only have a few cells, but this is the weight of a kidney of an adult.
But what is the weight of a kidney that is of a child, and so on.
So this kind of adaptation of the system that we need to do, and these are already pre-established equations.
Embracing Learning and Collaboration in Research
[41:03] Sometimes researchers that are doing hardcore cell experiments might be a little bit scared to see these kind of things and they run away.
But one of the things that we try to encourage, don't be scared.
Everybody, as long as you are willing to learn, there should not be anything to be scared of.
I am still learning a lot of things, so I think we should start to worry when we don't want to learn anymore.
Then I think it's a issue. And then if you think that we know it all, it's not true.
So that's why I think for us it's very important to collaborate with these colleagues that are expert. Okay, this data of yours has meaning in this context.
So as I said, we can generate a lot of data, beautiful graphs, IC50s, okay, the cells are dying at this dose, beautiful chips, another model, another and another.
So you end up having a novel model, a novel model. But then, okay, and what's next?
So then we need to give relevance to the data that we have and relevance to the context that we want to be used for.
So that's why I think you always need to have this context of use.
What exactly do you want to use it for?
Again, you cannot have a chip that will do everything.
[42:17] So, again, the research question that you have in mind, and then what are the experiments that you need to do in order for your claims to be valid?
Because sometimes you say, oh, this chip has the potential of revolutionizing drug development, is it?
And what are the tools? What do we need to do in order for us to disrupt what is being done at the moment?
What steps do we need to take further? So this is something that again comes because we talk with companies, the pharma industry, they are also coming to us and say, okay, let's do thistogether.
[42:57] We have programs in which companies are paying for instance, giving scholarships for PhDs to do the PhD with us, but then to further develop the pipeline or the models that theyare using while still in an academic setting.
So, it's not the good side and the bad side, the bad cop, good cop anymore, this is, we are all in this together.
And again, with the assistance of the regulators, of the developers that are kind of, okay, make sure that this is in a certain context that you are clearly describing what you are going to usethis for, what are the expected outcomes, what are the limitations, as again, you cannot have it all.
And in which context you want to use the model that you have just developed.
So that is how we are at the moment looking at.
Challenges in Model Development and Standardization
Keller:
[43:51] And what are some of the biggest challenges facing the development of these models? Like what are some of the issues that you guys are working through now?
Silvia:
[44:00] Okay, I will be very honest about it. I think there are several challenges, okay?
So let's say in the academic setting, The old way was like, okay, we need publication.
I'm doing a PhD and I need to publish in order to finish my PhD.
So many times it's like, I'm going to start again from scratch.
I'm going to develop a new gut on chip.
But aren't the other models gut on chip already good enough?
[44:27] Do we really need another one? So then you end up having flavors of the same kind.
Yeah, many things of the same kind, but they are very different in a way that one has the seeding density is different, the other one has a material that is a polycarprolactone and the otherone is SPCL.
So these kind of differences in between, but then the question is like, you tested drug A and I tested drug B, you tested drug A at concentration X, you tested drug A at concentration Y.
So very different, and then the idea is like, Shouldn't we just have everything in one room?
Platform, so that if I am developing a new model, I'm going to test drug A, B at concentration X, Y, and then we are, so that I can compare the data that I have with what is already there.
And that makes sometimes very difficult the comparisons.
Is my chip better than the other one? Because I don't have a reference.
So this is what we are also very much looking into. And this has to do with the entire community.
So it's not a university or it's not a country. We as a community of developers of this kind of models, we look at, okay, we need a framework, and we say, okay, if you want to show thatyour chip is used for proximal tubal nephrotoxicity, you need to test 20 drugs at these concentrations for this amount of time, and these are the.
The Need for Output Parameters and Comparisons
[45:56] Output parameters that you need to look at. All is the same.
So then, if you are developing a new one, you go and match it to this kind of matrix, so that you can compare with the developments of another colleague.
Obviously, everybody will say that their chip is better.
It's obvious, you have to sell it.
But sometimes I think that there are some efforts that might not be necessary in that way, only if we would have this kind of regulations around it.
And this is happening, so it is happening.
And then we just need to accumulate more information to see exactly what are the reference drugs that we need to use or the assays that we need to do.
So for that there are a lot of what are the key events that we are interested in and for that there are other big, for instance, consortia that are looking at it to create, to facilitate my researchso that I say, okay, what kind of drugs do I need to show?
Well, there is this list, ABCD and so on.
[47:00] Another challenge in this field is that there are colleagues that they have done this for 20 years in the same way.
And sometimes, now the challenge is coming of changing and implementing alternatives.
But then it requires a little bit of, it's an uncomfortable position to be like, I have done this the same this way, my entire career, and now I need to change that will require an investment, alearning moment.
[47:31] A time where you feel vulnerable and maybe not the smartest person in the room because you don't know a lot of things.
And that requires a little bit of being a little bit humble.
Say, okay, I'm accepting, I'm embracing, it's happening.
What can I do to gracefully be part of it?
[47:51] And sometimes this is happening, a bit of a resistance of, ah, I'm lost if I don't do it the way I know I did it 20 years, and this is how I know how to do it. These are the protocols.
So that can be for sometimes an issue.
And for instance, when we publish, if we have published something that doesn't have animal experiments, and then you get a comment from the reviewer, well, but where is yourvalidation in the animal models?
Oh yeah, I just describe my goal was not to use that.
So then you also have this kind of interventions from the reviewers.
And that's why it's very important to have this kind of validation framework in which you can say, okay, but I passed my model through this validation framework and I can say that it'sokay.
Like I can use this as a, to bypass for instance, some animal experiments or at least to contribute to the reduction of the, the replacement of this kind of experiments.
Empowering the Young Generation and Preparing for the Future
[48:52] And I think, and that's why, for instance, in this kind of discussions, it's very important for the young generation to already be aware of this kind of models.
And then when they are in discussions, to say, okay, but what about this?
To put it in the discussion. And I totally understand that sometimes when you are young and you only hear, you are afraid to say things.
[49:16] But I think we appreciate most when young people, they do. talk.
Because we know that sometimes it takes a lot of courage, because of course you feel you are at the beginning, maybe you don't know enough, and you feel that what you know is notappreciated.
But I think we really, really encourage, young people to speak up, there is no, as I said, I am still learning, so I want to learn, so I want to hear, and yeah, learning is also feeling, as I said,being in a position of, vulnerable and acknowledging the fact that you don't know, but you are also in a position of, okay, I'm ready to know, so please tell me.
So I think that is very important for the young people, and for that, we need to have educational systems in place that prepare the young generation for what is to come.
So one of the things that we have is that, okay, we say, the old way, let's call it.
Yeah, they are too young, they don't understand these kind of things.
But what we are, the decisions that we are making now, the young generation is going to live in five years or 10 years, the consequences of our decisions.
[50:33] All the older people decisions.
So what we try, for instance, here is to do at the university is also to empower the students, be part of the conversation, come to meetings where we are discussing science, not onlylistening to lectures that prepared, that are very, very sugar-coated.
[50:52] Everything is beautiful and it works and look how, but also to see, okay, not every time it works, to see that scientists are vulnerable and can admit, well, this was a major failure.
I wrote a grant and I didn't get it then you have to see a little bit of my disappointment when these kind of things happen, because then they also understand the value of the science and ofthe effort that you put when things go well, that is indeed a celebration, and that we need to acknowledge, but also that sometimes things don't work.
And then it is important to acknowledge that things don't always work, and that is not necessarily a defeat, but then it's a push to move forward.
So, that is what we try here to do in Utrecht to involve students from already their bachelor time.
So, when they are 20 and partying, but to make them aware, okay, these are the possibilities, this is what is happening.
Be sure that you are in the train, take the ride, enjoy the ride, but then to embrace it as much as possible so that it doesn't come as a surprise when they are already ahead of a PhD andyeah.
So this is very, very important for us.
Regenerative Medicine: Past Development and Future Possibilities
Brent:
[52:08] And then on that note, could you talk maybe about the space of regenerative medicine as a whole, kind of what the field is doing and where you see it going and maybe wherestudents might find, the new path forward to be like very interesting or very exciting.
Silvia:
[52:25] Yeah, so regenerative medicine is a tissue engineering regenerative medicine is already here for a long, long, long time.
So also when I did my PhD, it was tissue engineering, tissue engineering, but then at the end of the we talk so much about it.
But if we look a little bit, there's nothing there's not, we don't know much of a tissue engineer product that is available old to be used, so it's not, I don't know, any of something that isalready approved and ready to use.
So it was a lot of development, development, a new material, a new thing, a new thesis, a new, you work with stem cells from the umbilical cord, but then another PhD thesis stem cellsfrom the bone marrow.
All of, and then it was, okay, but what for? This is what I think was missing.
And I think what now the field is trying to do is like, okay, we did a development, we have the materials, we believe we have some good models, now it's time not to go back to, like not toreinvent again, but with what we have to push forward.
And that is, for instance, we, there are all this, where the collaboration with the clinicians is very, very, very important.
The importance of implementation and clinical relevance
[53:40] So, this is what we, I think the field is embracing this part of clinical relevance.
Is it important? Is it a need?
How we are going to do it? Who's going to use it?
This part of implementation, which is not very sexy to discuss if you are a scientist.
How it's going to be implemented? How it's going to be packed?
What is going to be the size? We don't think about these kind of things.
And that is very important now.
And then I think eventually if we push and advance towards the implementation of it and the real use, how we are going to use, then we can have some very, very nice advancements inthe field.
So basically the point is not to start to reinvent again another material.
I think we have all the tools in place.
I think we do have good materials. I do think we have good cells, or at least to pro, we have now all sorts of methods to evaluate.
So now it's just more into the application and into the implementation phase.
Brent:
[54:47] And then do you, so that sounds like a kind of an academic towards clinical route, bottom up.
Do you think the current healthcare industry and the doctors and the clinicians and the hospitals, are they accepting of all these new technologies and wanting to work with the academicsto start to implement these new treatments and technologies?
Silvia:
[55:07] Yeah, so in the Netherlands we have the academic hospitals, so they also do research.
There are a lot of clinicians that do research and they are very open towards research and towards academic minds, I would say.
So we are trying to, there is a synergistic space in which we give room for everybody to speak.
And then as I mentioned also when we developed our model, the clinician would say, why are you using this drug? We never prescribed this drug to patients.
So why would you even try it? So then there are a lot of clinicians that are passionate about science I'm passionate about research.
They have patient duties, or the cleaning duty, and they have this part, then they also have these discussions with us.
And what is very, very important, what we have here in the Netherlands is also the patient organizations.
So we have meetings with patient organizations. And many times, we were in a meeting one time and we are discussing about this very fancy machine that you can do dialysis at homeand it will help your life.
A very fancy scientific, from a scientific, the chemistry of it and the thing that was very cool.
And then one of the patients to them was like, but do I need to plug it in?
Yeah, you will have to plug it in because how much will be the electricity bill?
I was like, we never thought about it.
[56:31] So if you cannot afford, you can have the fanciest thing and is the health insurance going to cover it? And we never thought about it.
So it was also very interesting for us to see how patient come forward and say, well, this is not my major concern.
I can do dialysis, I don't mind if I do it takes this.
These are my concerns. I don't like that I need to eat, cannot eat steak.
That I need to restrict my bread intake. and there are other things that they are bothered.
And we were inventing problems, no, we were inventing solutions to problems that might have not been there, just because we don't go through the situation.
And that's why the collaboration with clinician also brings us in the context in which we can see and we can meet these patients that we aim to help with our research. And then it givesyou a totally different perspective.
Engaging with patients for moral and ethical motivation in science
[57:23] So if there is any possibility for whoever is listening to us and wants to know what is the relevance, to go and see and talk and engage with people that are suffering and we want tohelp, then you will get also a sort of a moral and ethical motivation to really do good science.
And really, if this is what motivates you that you want to help.
[57:49] I think that is very important.
And that's how, if I wouldn't have been in contact with the clinicians, I would have never, ever.
I've seen, for instance, a dialysis ward or talked to a dialysis patient and for that person to tell us, these are my challenges, I have a lot of itch, I'm frustrated, I cannot eat a steak.
[58:10] And I was like, I didn't know about this kind of things.
And then it gives you a different perspective and boosts you with a different type of energy.
It's not only, okay, I want to do good science and I want to publish high, but for who am I doing this? and then you really steer your research towards that. That way.
Keller:
[58:29] Yeah, it seems like that collaboration can really help align the problem solving.
Silvia:
[58:33] Yes, yes, and again, it's about, it's what we do that takes the stage. It's for who we do and how we can help those people to have a better life, a better outcome of their lives.
Many are, now that we are talking about the dialysis these patients, they cannot enjoy a holiday on a remote island because they always need to be close to hospital where they can dodialysis.
So then it gives you, as a researcher, you say, okay, I have a duty, almost, that my research, that I'm doing, that I'm invested in my work, that I really want to make a change, to support, tohelp, and then the decisions that you are making are more going there.
So I think it's very, very important, this collaboration, and we, everybody wants, the clinicians want to help, we want to help, everyone wants to push forward, and I think it's alwaysimportant to do it together, because then you have much more momentum and much more strength, force.
[59:43] Sometimes you need the funding and if you are the pushes from many people, then the funding becomes available and so on.
Because at the end of the day, also the research that we are doing is paid by public money.
So we are becoming accountable to the taxpayer in that way. So they can come, what did you do with the money?
I wanted you to test a new way for dialysis. Were you able to do it?
So then you become really, really sort of you have this duty to do the good, good science.
Online resources and opportunities for students in the field
Keller:
[1:00:20] And for students looking to get involved in this space, do you have any advice on places they can go, whether online, research opportunities, any summer classes that might beavailable?
Silvia:
[1:00:30] Yes. So there are, I think one of the good things that came out of the pandemic was that there were many things that moved into the online space.
So, if for instance at conferences, conferences are always a nice opportunity for you to start to see what is happening in the field and do some networking and so on.
But not everybody can go to conferences or traveling is a hassle and so on.
So now there is a lot of things that are happening online, even on YouTube.
By the way, I love YouTube.
Because I also go on YouTube and I'm looking for answers there.
And I found all sorts of recorded lectures and you have this series of the teacher talks from Columbia University. They are very, very, very good.
I almost religiously follow them.
[1:01:23] And that is also for me to freshen up my knowledge.
Oh, what are colleagues from MIT doing? Let's Or other colleagues from other places which otherwise I would have not had the possibility to listen to them.
And it's always a moment of inspiration. Sometimes you have this writer's block and then you really want to push forward and then you just need a little bit of inspiration and then an ideacan come and so on.
So there are all sorts of online webinars and so on.
What we do, for instance, here in the Netherlands, there are some national initiatives in terms of education, so open education, it's not only open science, but also open education.
So that means that you are kind of in the driving seat of your own education, and if you, for instance, you study in Utrecht, but you know that there is a very interesting course at anotheruniversity, what stops you from taking it?
And why should the system, the education system, stop somebody from taking a course like this?
So, and we also have challenges, so that means that students from different universities, they can come together.
[1:02:40] A very nice opportunity for students to also meet colleagues from different universities that learn different things so that they put their knowledge at use.
And obviously, if you are studying biology and you are going to meet with somebody that is doing a little bit more biomaterials in the team, you are the expert in biology.
So you have a word to say at the table. So this kind of projects we do.
[1:03:09] And I think this is also.
The Challenge of Finding Visible Information
[1:03:13] Sometimes the information is not visible, it's not there.
You will not find a catalog where you see, you Google, it's like, where I can find, and then you get a lot of information.
So sometimes it's also very important to ask, and then what we do, what I personally do, I have some researchers that I follow.
So I follow, I see their updates and usually, okay, they are, for instance, say, okay, I managed to have this grant or I'm going to do this project.
So that means that there will be an opportunity or an opening soon on this kind of projects.
European Research Council (ERC) Grants and PhD Opportunities
[1:03:50] For instance, now there were the ERC, which are the European Research Council, big grants in Europe.
The results have just been released. So, these are projects in which the PI, the person that submitted these kind of projects and was awarded, is going to look for PhDs and postdocs. So,you know that it's coming.
So, you just need to be ready for when the call for an open PhD position is coming.
And I think it has to do also, trying to, what I do, for instance on LinkedIn, I see a lot of researchers because everybody likes posts and then you say, oh, I didn't know about this person.
And then I usually engage with them or I really try to write comments because if somebody achieves, manages to get a very, very big run, this is something to congratulate about.
It's not only a thumbs up, but it's also congratulations on this massive achievement, and so on, and this is how you create a little bit also of a network.
And then you become a little bit visible in the space.
[1:04:58] And then you see how others are moving, for instance, on LinkedIn, you see what is happening.
And then always take a little bit of a proactive role in that way to engage with people.
No, from my experience, I think researchers are very happy when they get a email, oh, I'm really curious about your work, and I think we are even feeling flattered about it.
Overcoming Barriers and Finding Motivation
[1:05:26] So I think it's whatever fears or barriers or I'm just too young, oh, I'm not experienced, no, out.
Do some, a little bit of pep talk to yourself, and say, no, just do it.
And I think for us, the message that comes to us is like, okay, they passed by, they put aside this barrier, they put aside the fear, they put aside the fact that they might, the insecurities thatthey might not know, everything, and they reached out to me. That I can appreciate.
That means that you are really motivated, that you really are capable of putting aside what you think that is a barrier and say, okay, but I really want it, so I'm going for it. So for me, it'smotivation.
That's what I read, right? For maybe for the young people doing this, well, yeah, maybe it's too bold, maybe, oh.
No, for us, it's really motivation, determination, ambition, and you want people like this in your team that will not be afraid to push a little bit, to put barriers aside.
Brent:
[1:06:35] Yeah, well, that's a very inspiring message to kind of wrap this up on.
Do you have any other partying words of wisdom or advice?
Silvia:
[1:06:42] Well, I don't know if you have words of wisdom.
But I think it's, I would really like to say that the future belongs to you. So, Embrace it, take it, be part of it. And then, yeah, you might think, okay, the future, for you to live the future thatyou want, you need to be part of the present now.
So you need to speak up now because you will live that future.
So I think it's very important. The same thing I'm saying for myself.
So if the same discussions we have, for instance, with the professors that are retiring that probably make certain decisions for my future, so I want to be part of the conversation.
So, I think with this mindset, I think we can really achieve a lot.
We are all in this together.
There's no need for competition and elbow, making grooms and so on.
There is room for everybody. Everybody I think is unique and has something to say that is unique.
So I think it's, yeah, the opportunities are there. the stage is open for this kind of opportunities.
It's just a matter of, just do it, eh?
Brent:
[1:07:59] Yeah.
Keller:
[1:08:00] Beautiful. Thank you very much.
Silvia:
[1:08:02] Yeah, it was very nice to have a chat with you and for you to challenge me to verbalize sometimes what I also think and doesn't come out because I'm not being asked.
So now it was nice to have this chat with you as well.
Brent:
[1:08:15] Perfect.