This month, we sat down with Dr. Elvira Weber, adipose tissue organoid pioneer, expert in regenerative medicine, and Head of Lab at the CURE 3D lab in Düsseldorf.
Who are you and how did you get into the field of 3D culture?
Dr. Weber: My name is Elvira Weber. I’m a biologist. I did my PhD in biochemistry and then moved on to a postdoc in virology. At that time, I started working a lot with animals. I switched to the lipid field in 2014. I wanted to study the interaction between macrophages and adipocytes. I started working with adipocytes in 2D cell culture, but I realised that they didn’t look anything close to what they would look like in-vivo.
So, I decided to start a side project to find another method for culturing adipocytes without going back to animal experiments. Around the same time, I heard a talk from Hans Clevers for the first time. He was working with organoids, which sounded interesting.
I started checking to see if it was possible with adipose tissue. I found all sorts of organoids, but not for adipose tissue. That’s still a problem today, because a lot of people don’t realise that adipose tissue is a full organ. They normally think of it as something that is between your other organs, but few realise its important function.
It’s the most communicative organ. It sends out adipokines through our body, communicating with every organ. It doesn’t matter which pathology you’re looking at. You will always find a connection to adipose tissue because it surrounds everything.
When you check which kind of pathologies you find with adipose tissue connected, it’s not just cancer or cardiovascular diseases. It’s also Alzheimer’s, Parkinson’s, and even blindness. It’s involved everywhere.
So, I decided to try making adipose tissue organoids myself. I was a bit naive. I thought it was something you just do. It turned out to be more difficult.
It was several years ago, so we were really in the beginning of the organoid movement. First, I needed to decide whether to use a scaffold or not. I realised that I wanted to do lipid metabolism, which is better without a scaffold. Then I thought about using hanging drops, magnetic beads, or whatever else – I tried them all.
None of them worked.
It took me about four years to find the solutions. And I can just say thank you very much to my old boss, Professor Christoph Thiele. I came every week saying I was going to try something new and super fancy. And the week after I would come and say that it didn’t work out so well… for years. It was crazy.
In the end, I created the first adipose tissue organoid that was able to develop its own immune cells.
That was the starting point for how I came to CURE 3D. The head of the clinic for Cardiac Surgery, Professor Lichtenberg, had this innovative idea that a clinician, in this case Prof. Hug Aubin – a heart surgeon – and a basic researcher – me – lead the lab together. It’s a wonderful concept since we learn a lot from each other, and it helps our research improve a lot.
What is your main focus now?
Dr. Weber: Our lab has several working groups. One is working with bioprinting. The plan is to print small tissues, like vessels and valves. We are focused on different bio inks and cross-linking.
Another group is working on decellularised aortic valves. Professor Lichtenberg was already involved in developing the method to remove intact valves from a patient with heart failure, decellularise it, and implant it into another human. Because there are no cells, there won’t be an immune rejection.
And that is working seriously well. It’s an amazing project because you don’t need any anticoagulants anymore. It also grows with the patient, which is important for transplantation into children. We’re still improving the process by testing different coatings and understanding the immune reaction in the patient.
We also have a biobank. Patients who come to our clinic sign a consent form that allows us to collect tissue samples and store them in the biobank. This is important because we can use patient material to better understand what organs and tissues consist of and how they function.
And then there is one working group that works with organoids. Our focus here is on adipoids, the importance of adipose tissue for cardiac function, and to understand the differences between different adipose tissue fat depots.
How are 3D models helping you answer your key research questions?
Dr. Weber: For example, when I work with fat that has been removed from the body of a patient, I have a limited time to work with it. And I’ll just have a small piece, enough for a few assays. But when I take the stem cells out of this adipose tissue, I can generate several hundreds of adipoids, as I call them, which I can store for a long while.
It means I can do a lot of functional assays directly on patient derived material. If you, for example, had somebody with a genetic disease that’s influencing the adipose tissue, but you don’t know how or why. Adipoids give you the chance to understand because you have a lot of material, because you can do many more functional assays and standardise your experiments.
What are the key challenges when it comes to scaling up your work?
Dr. Weber: You always have to be careful with standards. Your models have to be the same so you can compare them and standardise your testing. How they’re handled is also important. We’re thinking of using robotics, but it’s difficult for us because adipoids are the only organoids that swim. Once you have a nice adipose tissue, it will swim up. It’s a good quality control for us because we know they really have fat inside. But it makes it hard when you’re trying to use robotic pipettes. So, it’s something you need to do manually at the moment.
I’m still waiting for somebody to develop a cool robot that can find my adipoids, avoid sucking them up, and still do a medium change. It would be lovely to have a tool like this.
What’s the process for culturing your adipoids?
Dr. Weber: They’re super small, around 400 micrometers and they swim, which was a problem at the beginning. I would treat them with an adipogenic cocktail, and then one day I would come, and they would all be gone. Just gone. And I was freaking out.
I repeated everything exactly the same and it happened again. I noticed that it happened the day after I started differentiation. So, my idea at the time was that they died because of differentiation. But what happened was they just swam up. They were out of focus.
They look like little white fluffy balls on the top across the plate.
Are you just buying commercially available primary cells and seeding them into a plate and waiting for them to grow?
Dr. Weber: No. In the beginning I worked with a 3T3 cell line. Then I switched to primary mouse cells from the visceral fat. But it was always my plan to switch to human primary cells directly. Now that I’m working at the department of cardiac surgery, I have access to fresh human adipose tissue from which I remove all adipocytes to start with the stromal vascular fraction, including the stem cells.
What are some of the missing pieces when it comes to tissue regeneration that have yet to be solved?
Dr. Weber: We’re in the beginning right now. I’m super optimistic, but there’s a lot to do. First of all, your starting material. You can’t do this with cell lines. A lot of people go for iPSCs. I’m not a huge fan of them myself, since it’s difficult to go back to human with them because of their possible tumorigenicity. They also don’t fully mature.
Standardisation and immunogenicity as well. One thing will always be time. You need to think of how long it will take you to regenerate new tissue from a patient’s sample. Typically, you have an acute injury, and you can’t wait. So that will always be a problem.
Vascularisation hasn’t been solved, so you can’t go big. And the regulatory side when you want to go back into human.
There are still a few things left in the way.
From your perspective, how do we go about incentivising key stakeholders from academia, the clinic, and pharma to work together towards the goals that we want to achieve?
Dr. Weber: One big thing I like is clinicians and scientists working closer together, and on the same level. We can be far more creative together because we can approach problems from completely different angles, which leads to innovation.
I think what we’re missing are joint congresses. They are normally either for clinicians or scientists. There aren’t many good mixtures. And industry is often outside trying to sell, but not trying to collaborate enough.
We also need far more funding opportunities, resources, and IP policies for projects between industry and academia.
It’s important that we have clear rules in these collaboration projects on who owns what, and what will happen when results are commercialised. As a researcher, you don’t know. Somebody has to explain it to you. There needs to be far more work explaining to scientists how these collaborations can be set up as a win-win and what to expect.
What do you see people get wrong when they try to commercialize new products in the field of tissue regeneration, or 3D culture more broadly?
Dr. Weber: I have less experience here than you would probably think, because my outputs have never been patented. Now, I see that a lot of companies are trying to do it. At the time, I thought I should, but like many young researchers, I didn’t know how.
I’ve seen good and bad things from the people who do it. It always depends on the company and the researcher. How well they work together. I think it’s far more important that researchers from industry and from academia connect with each other. And that it’s not all for selling, but also for developing tools.
Don’t get me wrong, I’m always happy about industry being at conferences, because I learn a lot there about new products and I love talking to my colleagues. It would just be great to engage more on the development side. To see how we can help one another.
Because people don’t have to make the same mistakes. We might try something that doesn’t work, so we don’t publish it. But we can share that information, so others don’t do the same. This is missing at the moment.
In 10 years, if a patient needs a new heart valve, what kind of treatments will they have access to?
Dr. Weber: I think that we’ll see a big change in the next five years. Bioprinting just started and you can see how much progress they’ve made.
I remember when I first looked for meetings about tissue engineering and 3D cell culture. I hardly found one.
Now there are so many per year, and they are packed. I’m convinced that there will be fast progress now. Because of the regulations, 10 years is a tough timeline, but there are already plenty of things in progress, like the heart valves I mentioned before.
Outside of your own lab, who are the people, groups, or organizations that you look to for inspiration?
Dr. Weber: I was a huge Twitter fan before it changed because there was a great science community there. LinkedIn also works well. Most of my inspiration comes from conferences. In Germany we have a good one from EMBL called Organoids. There is also a huge international one, the IMPSS.
My most favorite one is organoidspheroid.com. It’s a website. They started in the field early and I love what they’re doing. They’re collecting all papers together, so you just click on your organ of interest and then you can see the newest relevant papers. They have a conference once a year called World Organoid Research Day+ (WORD+). It’s amazing! It’s a great group of scientists who all want to share and collaborate with great ideas.
What was it that happened with Twitter that forced you to leave?
Dr. Weber: The changes Elon made. A lot of people decided they didn’t want to support that, so they started to leave. It makes sense, but it made my community a bit smaller. Now we are trying to make it bigger again somewhere else.
Any final thoughts to share?
Dr. Weber: No, but I really like what you’re doing here because newsletters from companies will get more interest from people like that.
Want to connect with Dr. Weber? You can find her here:
LinkedIn: Elvira Weber
