3D cell culture systems – towards primary drug discovery platforms: An interview with Heinz Ruffner (Novartis) and Jan Lichtenberg (InSphero)

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Abstract

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Advanced cell culture systems for regenerative medicine, drug efficacy and toxicity testing, enabling technologies to create and analyze 3D cell culture systems were the topics of the 3D cell culture meeting taking place in March 14–16, 2012 at the Technopark in Zurich, Switzerland. At this meeting Biotechnology Journal had the pleasure to talk to Dr. Heinz Ruffner, Novartis AG, and Dr. Jan Lichtenberg, co-founder and CEO of InSphero AG, about challenges and perspectives in using 3D cell culture systems as primary drug discovery platforms.

Advanced cell culture systems for regenerative medicine, drug efficacy and toxicity testing, enabling technologies to create and analyze 3D cell culture systems were the topics of the 3D cell culture meeting on March 14–16, 2012 at the Technopark in Zurich, Switzerland. At this meeting Biotechnology Journal had the pleasure to talk to Dr. Heinz Ruffner, Novartis AG, and Dr. Jan Lichtenberg, co-founder and CEO of InSphero AG, about the challenges and perspectives in using 3D cell culture systems as primary drug discovery platforms. Dr. Ruffner is Senior Investigator at the Novartis Institutes for Biomedical Research, Developmental and Molecular Pathways, and is actively working on establishing 3D cell culture systems for drug screening purposes. InSphero is a provider of 3D cell culture solutions in the form of microtissue spheroids for efficacy and safety studies (see for example recent articles [1, 2]).

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UG:

Dr. Lichtenberg, your company InSphero is prominently displayed at this conference, with several applications presented in scientific talks and on many posters. What contribution does your company make towards a wider applicability of 3D cell culture systems?

JL:

We would like to add 3D cell culture systems as a standard to the portfolio of cell-based assays. Instead of replacing 2D with 3D systems, we believe that there are many applications were 3D technologies can give valuable additional information that is not available from 2D culture systems. The problem is, however, that many 3D systems are not yet at a level that can be used commercially. The whole manufacturing process as well as assay systems have to be stable, simple and available at a competitive cost, so that high-throughput applications are possible. We would like to drive innovation in this area, so the user can decide which model system, be it 3D or 2D, is the method of choice for his or her purpose.

UG:

Dr. Ruffner, what is the aim of your work? Why do you want to use 3D cell culture systems for regenerative medicine applications?

HR:

In our department we want to develop innovative therapeutics that ultimately reach the patients. For many of our questions 2D cell culture systems are not able to give us satisfying answers, because our studies strongly depend on the context of different cell types and their crosstalk. Thus, it is important to look at more complex systems to find candidate drugs. We are currently working on verifying already known drugs in newly developed 3D culture systems, as well as establishing new stable systems that can be applied for drug screening in 3D systems. The next steps will be to use these systems for target finding and molecule screening, once they are established.

UG:

I suppose that there are many challenges to overcome, before you can actually use 3D culture systems as a primary drug-screening assay. Where do you see the most important limitations?

HR:

First of all the tissue availability, especially in the context of a certain disease. We have to find out first whether we can get particular cells or tissues that can be used to build a model system. Then, we have to make sure that the model is actually able to answer the questions we would like to address. Especially when working with human tissue we may have a high variability between different samples and the expected results may vary to a great extent, thus limiting the use of any data generated from these systems. Another area is of course the technological challenges mentioned already by Dr. Lichtenberg, such as using 3D systems in high-throughput assays. The more complex a systems is, the more complicated it gets and the longer it takes to be manipulated in a controlled manner.

UG:

Is InSphero addressing some of these problems and where do you see additional areas that need to be worked on?

JL:

Our main interest is to use the existing workflows and assays a customer has already established in his or her lab. With our spheroid microtissues we are trying to make 3D systems as simple as possible. Also for us tissue availability is one of the main limiting factors. Therefore we are looking at ways to reduce the number of cells needed to produce one microtissue. For example, in liver models we are using between 1000–1500 hepatocytes; this is 5-10% of the amount currently used for sandwich culture systems. Thus, we can generate 10–20 times more data points from one tissue sample. Of course we also need to work together with assay developers to be able to deliver more sensitive readouts that are applicable for our microtissues at a smaller scale.

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UG:

Many of the presentations at this meeting discussed the use of stem cells in their 3D cell culture systems. Can stem cells be instrumental in overcoming tissue availability problems?

HR:

This always depends on the disease and model system you are looking at. For our regenerative tissue models stem cells are a substantial part of our work, since we would like to find drugs that are working on survival and protection of stem cells within a tissue. We still have very limited knowledge on the factors that influence stem cells, especially in the context of other cells, where crosstalk and factors that drive differentiation are important. There is a lot of work to do in order to establish the molecules that are needed to manipulate stem cells in our assay systems.

JL:

At InSphero we are currently actively working on incorporating stem cells in our microtissue models. For example, we are taking part in a large EU project where we study cardiotoxicity. I believe that stem cells will play an important role in overcoming tissue availability problems.

UG:

How far do you think are we away from using 3D cell culture systems as standard systems for primary drug discovery? Do you think we can replace animal models with these advanced cell culture systems?

HR:

The journey has begun. We are already working on systems that are able to reduce animal testing, maybe not for all diseases but for many. The main problem is to determine whether the results generated with 3D systems do translate into clinical settings. Therefore, we test compounds for which we already know the effects in animal models and human, as well as in 2D and 3D cell cultures; and then we analyze if there are clear correlations. I am very optimistic that we will soon have systems available that are widely applicable and can be used to get a better prediction whether these drugs are effective and safe in the clinic. I think we can achieve a lot with 3D systems to streamline currently applied pre-clinical testing and make them more efficient.

UG:

What can this meeting offer to drive innovation in 3D cell culture and why do you think this meeting was so well received in the community?

JL:

I think an important point is that this is a very concentrated gathering of researchers working in 3D cell culture. Usually you only have smaller sessions at bigger meetings where only one topic is discussed in detail. It is a great forum to work on common issues and problems and build collaborations between companies and academic researchers to solve them.

HR:

I totally agree. I also think that it is a good idea to have such a meeting in Switzerland, because of the regional closeness to pharmaceutical companies, which are often neglected at scientific meetings. This will definitely result in fruitful collaborations.

UG:

I sincerely thank you for taking the time to share your insights with our readers.

Uta Göbel

Assistant Editor, Biotechnology Journal

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