Transforming Drug Discovery: The Power of 3D Cell Cultures​​

This Transcript is AI-Generated

Jan Lichtenberg: In the 3D format, we are able to put all of these different cell types into a meaningful context, and that allows these models to be more predictive than a classical 2D cell culture. That's a huge win for research. 

Dana: We're witnessing a revolution in drug testing. 

Micah: The acceleration toward 3D cell cultures is improving safety, accuracy, and is shaking up traditional methods.

Jan Lichtenberg: If we could reduce animal testing by 90, 95 percent because customers see that They actually get better data and more relevant data and data at lower cost and faster using the solutions that we and others develop, that will be a huge win. 

Micah: As the adoption of this technology accelerates, could we be looking at a future where we can grow replacement organs?

In this episode, we explore how 3D cell cultures are changing the trajectory of the drug development and testing landscape. The ethical implications of this technology and how it all fits into the context of personalized medicine. 

Dana: I'm Dana Klemelsom. 

Micah: And I'm Micah Schweitzer. This is Balancing the Future from Mettler Toledo.

Dana: On this show, we delve into the world of science and technology and its transformative impact on our lives. 

Micah: Let's jump in.

Dana: One of the first people to develop animal tissue cell culture was Ross Granville Harrison, He was a professor at Yale and discovered that he could grow frog embryonic tissue in a plasma like substance all the way back in the early 20th century. 

Micah: The breakthrough proved that living cells could continue to grow and make connections outside of the body.

Dana: Others built on this work, leading to the widespread use of 2D cell cultures that we're familiar with today. 

Jan Lichtenberg: But this is how we did cell culture for the majority of biological science history, right? We are, we created surfaces, It's quite convenient. It's easy to do. It's easy to image, but it's not really representative of what happens in the, in the human body.

Micah: That's the voice of Jan Lichtenberg, CEO and co founder of InSphero. They develop a wide range of 3D cell cultures and three dimensional microtissues for drug development and screening. 

Jan Lichtenberg: Cells live in that 3D context. They need to. gradients, oxygen, uh, metabolites that are generated nutrients, but they also need the physical cues that they get from the cells next to them, right?

Sometimes it's stretching, sometimes it's chemical signaling. So if you are removing this, then the cells are not behaving as they should do. And again, hepatocytes, liver cells are a good example. If you take hepatocytes and you culture them in a quite advanced 2D sandwich culture, they still lose their liver specific.

Functionality after two to three days, they are not that, but they also not liver cells anymore. And what that meant for the industry, especially when it comes to safety testing for the liver, that researchers were limited to acute toxicity. So they would add the compound and then they would wait for 24 or 48 hours and then do a viability assay to see have the hepatocytes suffered any negative impact.

So that's great, right? But the majority of liver toxic effects. on the patient are not happening in 24 hours. They are happening after you take the drug for a week every day or two weeks. Sometimes you need accumulation in the liver to create that toxic effect. Sometimes the liver enzymatically chops up that drug of yours and then one of the metabolites that is coming out of that enzymatic reaction that is actually causing the effect.

toxic effect. So you don't see this immediately. And that meant that you would only see it maybe in the animal. But if you didn't see it in the animal, then you would see it in the clinic. And that's where you test it on humans, right? So it's already quite dangerous. So that's the 2D, 3D aspect. And then there is a second aspect to 3D cell culture, which is quite important.

And that is the possibility to do co cultures with different cell types. Again, if you would compare it to an orchestra, right? So every musician in the orchestra can play music, but it's only when the orchestra acts together as one unity that the true magic of an opera comes to light. And this is very similar to tissue culture.

In the liver, you have at least a handful of relevant cell types that work together, not just the hepatocytes, but also Kupfer cells and liver endothelial cells and so on. In the 3D format, we are able to put all of these different cell types into a meaningful context, That allows these models to be more predictive than a classical 2D cell culture.

And that's a, that's a huge win for research. 

Dana: Jan started his career as an academic, he's a microtechnology engineer by training, but was bitten by the entrepreneurial bug early on. 

Jan Lichtenberg: I started the first startup company with a friend of mine. We never had a business plan. We never really had a strategy, but we had a lot of fun and we learned about how to build solutions that customers would buy and have fun.

And to me, it was kind of that springboard into turning science into technology and technology into, into products. I then moved on to do a PhD. In microtechnology here in Switzerland, and that's where I started to get interested in cell culture and combining biological cells with micro technological devices like chips and microfluidic systems.

And that's also where I met my two co founders at the ETH and at the University of Zurich, Jens Kelm and Wolfgang Moritz. We never thought about starting a company around this technology at the time. We just had a super exciting. scientific journey, trying to push the envelope of what was possible of culturing cells in the lab.

And then in 2009, in the middle of the financial crisis of all times, we started to work on the idea of turning that whole body of science and technology that we had developed into a startup company. And that's how we built Inspiro. 

Micah: So that's the perfect setup maybe to explain, just in fairly non technical language as far as is possible, can you explain what the work is at Insfera?

What do you do? 

Jan Lichtenberg: So, the problem that we tackle for our customers in drug development and drug discovery is to help them get the right information. get a reliable and early understanding of how a specific compound, small molecule and antibody works in the human body, right? This is, is the big question when you develop a drug, you are a bit of operating in the dark, right?

You have a hypothesis, you have maybe a specific therapeutic target that you want to address to, uh, kill cancer cells, but you need to make sure that it actually works and it works in a large portion of the population. But you also want to make sure that you don't have any side effects. And for a hundred years, people are doing this right.

They're doing it by trying to culture. It's human or animal cells in the lab and then figuring out what the impact of this molecule is on that cell. And then, of course, there is animal testing, which is still sort of our go to solution to understand whether something is efficacious. It has side effects or not.

And then of course there are the clinical trials. And that process is quite flawed. About nine of ten drugs that go into clinical testing are not making it to the market. In most of the cases due to safety concerns, in some cases because they are not efficacious enough to resolve the disease, then there are some problems.

more operational or commercial reasons for not continuing a clinical trial, but that's a huge expense. And it's part of the cost for the drugs that we pay every day. And so our, our interest was, could we recreate parts of the human body tissues in the lab in a way that is accurate enough to generate more meaningful data for pharmaceutical researchers to take better decisions at earlier times in that development process.

And do you see that changing the trajectory 

Micah: of 

Jan Lichtenberg: how drugs are developed? Definitely. So changing an industry and changing a paradigm in an industry is a marathon, right? It's not a sprint. Today, I think we're in the middle of a revolution in the way how cell based assays are used in that, in that whole process.

By the way, not just in pharma and biotech anymore, but also in cosmetics, in chemical industries, and so on. And I think there are a couple of drivers for this. When we started, our advanced in vitro models were, I think, considered to be kind of an okay alternative to animal testing, right? Not what you would want to do.

You would still want to test in the animal. But if it was not possible, then customers would kind of go this in vitro route, but kind of under protest and not a hundred percent convinced. But I think that has changed. And what has happened is that today I would consider human in vitro models to be that.

Gold standard, what customers are going for and the animal model is more what I would call a confirmatory study that you do later on. We are still scratching the surface, right? We are nowhere near totally turning the leaf in this book and moving to a complete in vitro first approach, but I think we are on a good way and, and there are a couple of reasons why this moves so quickly now.

I think the first reason is. That there are great and predictive human in vitro models on the market now, we are one of the leading companies in the field, but there are other, they are competitors, but at the same time, they are partners in crime for us because they are trying to change that status quo together with us with good science and with interesting solutions for the market.

Then there is a second important aspect and that is analytical tools. The 3D models that we develop, they are sand grain size. They consist of human cells, primary or IPS cells, but very often different cell types. So if you take a tissue like the liver, it does not just consist of hepatocytes, but but of a multitude of different cells that need to work together to generate the phenotype of the liver.

And so they are inherently quite complex, quite heterogeneous tissues. And you need new ways to analyze these tissues to understand what happens when you add the drug to these tissue models. And then at the same time, imaging has also come in. come a long way and with high content imaging with light sheet microscopy and other techniques, we can not only understand what happens in these tissues, but also where it happens, what happens to the cell cells next to them.

And then if you put the two things together and you look into spatial biology, spatial transcriptomics, then you can get basically to the single cell level to see what's what's happening there. And that's a huge scientific advantage. And then there is a third aspect and that is the types of cells that we are have at our disposition to create these models.

There has also been a huge progress here, especially in the domain of induced pluripotent stem cells, which enable us to build models with very specific disease phenotypes, right? So we can get hepatocytes from, patients that suffered fatty liver disease or liver steatosis, we can get IPS cells from type one or type two diabetes patients.

And so again, it allows us to create models which are closer to the human patient. And when we mimic that human patient accurately in the lab, our customers have a much better chance to find the right molecules for a cure than if they were just basically using a shotgun approach. 

Dana: When a drug goes to market, what are the steps involved in that testing process?

Maybe you could walk us through that a little bit. 

Jan Lichtenberg: So, going to market is typically a three step process, so clinical phase one, two, and three. The phase one is the safety testing, it's the first step that is done, and that is typically done on a pretty homogeneous group of test subjects, right? So these are volunteers, they are healthy, typically they are male, they are Caucasian, and they are 35 to 40 years old.

And it is done for a reason, right? You do not have to take into account hormonal cycles of female test subjects, and that gives you a better chance to be successful in that first phase. But is it the right way of doing it? Most likely not. And especially in the US, there are a lot of discussions on the side of the regulators or the FDA, but also Political activist groups and patient activist groups who suggest we should be more inclusively represented in these clinical trials.

That would be a game changer, right? It would be a game changer for the industry. It would make phase one trials more complex and there might be a higher variation in terms of, of outcomes from such a trial. But so then even drives more interest from the pharmaceutical industry in in vitro solutions like we are offering them to understand how does the patient population behave, right?

So could we not do that? just test the drug on a single liver microtissue from Inspiro, but could you maybe create a panel of 40 different tissues from representing 40 different patients so that we get a glimpse into for who is it a safe solution and who might see a safety concern. Um, and that could allow to tailor these phase one studies in a more appropriate way 

Micah: down the line.

Moving to this flexible, tailored testing method seems intuitive, right? After all, every human has their own set of complex physiological traits that might affect the efficacy of any given drug. 

Dana: When Jan talks to customers, academics, and scientists, he finds consensus. Most can see the writing on the laboratory wall.

Using 3D cultures just makes sense. 

Micah: This is reflected in a changing tide of regulation. In 2022, the FDA Modernization Act 2. 0 passed the United States Congress. This bill instructs the FDA to recognize in vitro data as equivalent to animal testing data. At the time of this recording, the Modernization Act 3.

0 is also on its way. 

Dana: However, common ground and changing regulation doesn't mean that everyone is on board. 

Jan Lichtenberg: But then there is still that individual resistance of change, right? The resistance of change in an organization because, hey, we have been doing this for 30 years, um, takes too much time, too much money.

Some of our old data might not be valid in that new data. technology anymore. So I mean, there are reasons. And then, of course, there are the individual reasons for resistance to change of the head of drug safety or the lab manager or so says, you know, we're in a difficult economical environment. I do not want to take that risk.

At the moment, we are going to sit on the fence and see what's happening for the next year or two. And then we're jumping into it. I think this is then part of our job as a developer for a disruptive technology, we need to Help people see why it makes sense for them to take that chance and to implement the change that is, I think, our biggest job that I would see, right?

So we have a great technology. It works. It's reliable. But then spreading the word and understanding. Each individual situation to help guiding the organization to implement that change that is what's needed and you know, you can call it business development, but at the end of the day, it is part of this partnership that we have with our customers to analyze their situation to identify the benefits that make sense for that specific setup and then to to convince the stakeholders to give green light and to do it.

Micah: What are the broader ethical benefits, uh, for ethical implications of moving towards 3D cell culture technology? 

Jan Lichtenberg: So I think a big driver for us and for the whole team is that, uh, we are interested in reducing animal testing. And it is something that, that we are very open about. You know, we were not sure how much we should communicate about this because our customers use animal testing on a daily basis.

And we, of course, do not want to confront them with a very different view on things. Personally, I believe there will be animal testing for a very long time. And if it is confirmatory before we go into a human patient, it might be something that we will do forever because the animal is a full organism, right?

It's not just an isolated tissue type. Even if we combine several, we are not reaching the conclusion. complex interplay of biology in a test animal. But if we could reduce animal testing by 90 95 percent because Customers see that they actually get better data and more relevant data and data at lower cost and faster using the solutions that we and others develop, that will be a huge win.

The other two aspects that I wanted to mention is we believe that because we can create very specific disease phenotypes also for rare diseases. That this technology can help rejuvenate interest in curing diseases that currently are not of commercial interest to a lot of pharmaceutical companies because they are rare, which not only means that the patient population and therefore your market is smaller, but it's also more complicated to do the research because you just don't have that Biological information that you need.

The third aspect is the diversity that I already mentioned, right? We, I believe that, you know, some populations are underrepresented when it comes to drug testing, safety testing and efficacy testing. And because we are doing this on a patient centric way, we start and we end with the patient and the patient tissue in our philosophy of how drugs should be developed.

And that is enabling that we are. covering a much broader cross section of the population in our research than what's possible so far. 

Dana: And we're hearing a lot about personalized medicine or, you know, cell therapy, gene therapy could in spherus technology also play a role in this making drugs that are specific for certain individuals.

Jan Lichtenberg: Definitely. And it's a very exciting topic, right? So personalized medicine or precision medicine already starts with the drug development. Again, understanding what type of patient will benefit from that treatment and which does not. This also has an economic impact, right? Because these drugs are getting more and more expensive.

And if the drug maker is able to better isolate, which type of patient will benefit, the payer is going to be more likely to pay for it than if it's a bit of a shotgun approach and we say, hey, two out of 10 will benefit and it's going to cost 150, 000 per treatment, then this is is a treatment that might not be approved in many countries.

So there is a bit of a sort of, companion diagnostics aspect that goes hand in hand with that. And there was some great research by Professor Hans Clevers in the Netherlands. He's one of the inventors of the organoid technologies or a specific type of 3D cell culture. That's quite amazing because you can isolate a small number of cells from the patient and then over a period of 40 to 60 days, grow little organoids, again, the size of a sand grain, maybe up to one millimeter.

that are reflecting the physiology of that patient extremely well. And so one of the projects that he published, and I'm not sure whether it has become part of the way how the drug is described in the Netherlands, but what he did was for cystic fibrosis patients that were considered for treatment with the Vertex triple combo, which is quite expensive, he developed It's basically a test where you would take cells from this patient and then incubate them with the drug to see whether there is a reduction of mucous formation of these cells.

And then only if this was successful, there would be a recommendation to, to take the drug. So again, I'm not sure whether it made it into that whole catalog of compendium diagnostics in the Netherlands, but I think it's a fantastic way to, be more mindful with the financial resources that the public health system has at its disposition, but then at the same time, still make it possible that the patient who could benefit from such an expensive treatment gets the treatment because the likelihood of success is so high.

We've taken a little bit of a different approach in oncology. where we are currently investigating to take primary tumor tissue, either from a biopsy or from a resection, and then create hundreds of tumor microtissues using our technology so that we can test standard of care drugs alone, but also in combinations, which I think super exciting to see which combination is most powerful to the patient.

Eliminate tumor growth, or even kill the tumor altogether. 

Micah: If you've been listening carefully, you might have wondered about the potential of organoids. If we can grow tiny versions of organs, does that mean we should be able to grow full sized ones? Microtissues. 

Jan Lichtenberg: could be a fantastic vehicle for cell based therapy, right?

Instead of trying to inject single cells into the human body, which are easily washed out physically or have issues in grafting themselves in the target tissue. The spheroid is already a little tissue, right? So it is much more robust. This is much more stable. It is larger physically so that it could stay more likely at the point where it's placed non invasively.

But because of its tissue structure, it's extracellular matrix, right? So the adhesion proteins that are built around the cells to form the tissue, there is some compelling data that these organoids and spheroids are engrafting much better in a target tissue so that you could replace insulin secretion in a patient that has lost that capability or maybe Enhance the cardiac output of the heart after a heart infarction.

So when we presented the business plan, I think in 2020, nine or 2010 in Switzerland, right? And this is, I think, an important aspect here where things are a little bit more conservative. Also on the investor side, people were like, okay, you guys are crazy, right? So this is, it's a nice idea, but you know, be realistic.

You need so much money and you have no track record that this is going to work. And we, you know, we want to invest into solutions that can show traction. very soon, right? We're not interested in moonshot projects. And so in that process, we were getting in touch with Novartis and Novartis told us, Hey, we need these liver models for safety testing.

This is a fantastic technology. So we pivoted, we wrote the business plan. And I think we're happy with, with having done that because we clearly identified a very valuable market that was ready to engage with us. But interestingly, we are now starting the first projects to look at the applications of our technology for regenerative medicine.

And in fact, it's in the metabolic disease space. It's a small project. It's um, Yeah, it's a proof of concept, but you can imagine with the production capabilities that we have for these uniform microtissues with cryopreservation technologies that we work on, which could be quite important to make sure that they're safe.

This self therapeutic entity, whatever it is, can make it safely from the manufacturer's side to the clinic where it's going to be administered or implanted. So it's a fantastic opportunity and we are very grateful that we have a customer who is willing to engage with us and to explore whether that's a possibility or not.

But it's a proof of concept. 

Dana: As we come to the end of our interview, and that's, you know, you went from academia to entrepreneurship and, you know, have a startup of your own. And what would your advice be to other academics who might just be starting in their careers and want to do something like you're doing now?

Jan Lichtenberg: So I think two aspects. One is the personal one, right? Where is your road taking yourself and always be aware of the choices that you can make it at every time, right? So for me, it was clear through my academic career that I wanted to work in industry, not necessarily as an entrepreneur, but I wanted to work in industry.

I did not plan a purely academic career. A, because I think there are tons of people who are smarter than me in taking professor positions, and I don't want to fill one that somebody else would be excellent in, but B, because My passion is to make technology available so that people can use it, right? I'm, I'm 100 percent convinced that living on this planet, technology is a solution to many of the problems that we have, but only if the technology is developed.

And then available for use, and that means that it needs to work. It needs to be scalable. It needs to be safe, and it needs to be cost efficient. And so that's where I see my capabilities, and that's where I decided to invest my working life. And, and I think. Thinking about what you want to do with your life instead of just following reflexively, whatever the next step seems to be, I think that's an important advice that I give to a lot of younger people that I work with because you only have that one life, right?

And if you want to be you. Really impactful. You have to love what you do and it needs to also fit with your mindset and your capabilities.

Micah: We've been speaking with Jan Lichtenberg. He's CEO of Inspiro. 

Dana: So Micah, that was a really fascinating conversation. I think Jan did a really great job articulating this innovation and its impact that it will have on all of our lives. 

Micah: Absolutely. I think that what's really interesting in what he explains is how it can revolutionize processes that have been in place for quite a long time.

And at the same time, the potential is, is perhaps not even fully Imaginable at this point. I mean, where this could go if we're talking about organoids, the size of a grain of sand that really feels like the smallest building block. And it'll be fascinating to see where this develops in future. 

Dana: Another point for me, Micah, that was very interesting is How Jan explained how drug testing works now and that the common subject would be a male in his 30s and 40s of Caucasian ethnicity and how that really is an unfair judgment of the entire population.

Micah: Exactly. I mean, if you look around, that's not, these are not the only inhabitants of the world, right? And, and so the accessibility I think is remarkable, the way that can be expanded. So that medicine really is for all different kinds of people and not sort of homogenized or, you know, ultimately most effective for a certain type of person.

Dana: This has been Balancing the Future from Mettler Toledo. 

Micah: What questions about science and technology do you want answered in future episodes? 

Dana: Let us know by leaving a review or if you're a Spotify user in the comment section. 

Micah: And be sure to subscribe wherever you get your podcasts. 

Dana: We'll be back in two weeks with our next episode.

See you then.