The skin as a gateway to connective tissue disorders

Interview with Dr I. Korkmaz

Dr Ibrahim Korkmaz is a university lecturer and researcher at Amsterdam UMC, VUmc location. As a medical biologist, he focuses primarily on burns, wound healing and scar formation.

What do burns and collagen connective tissue disorders have in common?

At first glance, these appear to be very different problems, but the underlying processes show clear similarities. Burns often result in excessive scarring. This means that too much collagen is produced and deposited. As a result, the tissue becomes thick, stiff and less functional. In other connective tissue disorders, such as fibrosis or certain bone diseases, collagen is also poorly organised. Sometimes there is too much collagen, sometimes too little, or it is built up incorrectly. This causes problems in, for example, the skin, bones or organs. It is precisely these similarities that make it interesting to study these disorders together."

Why is the skin a good model for studying connective tissue problems?

The skin is very accessible: you can easily get to it. For our research, we use skin that is left over after plastic surgery, for example after tummy tucks. We isolate cells from these pieces of skin and grow three-dimensional skin models in the laboratory. Under the microscope, these models closely resemble real skin, although they do not contain blood vessels or immune cells, for example.
In these models, we can study wound healing and scar formation in a very controlled manner. This is much more difficult with bones or organs. Fortunately, skin research can also provide insights that are relevant to connective tissue problems elsewhere in the body.

What is the focus of your current research?

My research can be divided into two main areas. Firstly, I study how wounds heal and why that process often goes awry in the case of burns. We see that the inflammatory response in burn patients lasts far too long, sometimes even months or years, and not only at the site of the burn, but throughout the entire body. This hinders normal healing.
Secondly, we are working on new skin models in which we can simulate the processes involved in wound healing as realistically as possible. This allows us to test which factors improve or disrupt wound healing.

You are also working on potential new treatments. What is the idea behind this?

Together with colleagues, including Dr Nathalie Bravenboer, we are investigating whether we can influence the formation of collagen bundles. In fibrosis and scarring, an imbalance between collagen production and breakdown leads to the accumulation of stiff, strongly cross-linked collagen with an abnormal structure, resulting in loss of elasticity and function of the tissue. This makes the tissue hard and immobile. We are investigating whether we can reduce the production of certain proteins that play a role in this process using so-called siRNAs. These are small molecules that inhibit the production of specific proteins in cells. The idea for this came from Prof. Ruud Bank from Groningen, who has since retired. Our goal is not to halt wound healing, but to make the process more orderly. In osteogenesis imperfecta, which Nathalie focuses on, the collagen is not of good quality. That is why you would not so much want to put the brakes on it, but rather stimulate processes that ensure stronger and better-structured connective tissue.

What is required to take that next step?

Funding. We have clear ideas for pilot experiments: small, targeted studies to test whether this concept is promising. That requires money for laboratory materials, but also time and people—for example, a junior researcher who can get started on this.

Why is it so difficult to obtain funding?

Public funding bodies often focus on large-scale clinical research with clear and direct applications for patients. Our work comes before that: we first try to understand whether a particular mechanism can be influenced at all. We call this fundamental or preclinical research.

It is difficult to obtain funding for this type of research because you cannot yet guarantee that it will actually lead to a treatment. Subsidies from organisations such as ZonMw are usually strongly focused on clinical studies, while large NWO subsidies require extensive, well-developed research programmes.

What we need now are relatively small amounts of money for pilot studies: initial experiments to test whether an idea has potential. It is precisely this type of research that often falls between two stools. That is also exactly where a foundation such as Power of Reflection can play such an important role: by enabling this early research and thus laying the foundation for larger subsidy programmes in the future.

What does the Power of Reflection foundation mean for your research?

“The foundation acts as a connecting factor. Founder Cindy Wan brings together researchers who might otherwise never meet. She is also actively involved in finding funding, for example through contacts with pharmaceutical companies and investors. This is invaluable for early-stage research, such as the pilot studies we want to conduct.”

What do you hope to achieve in the coming years?

“My first goal is to actually carry out these initial experiments. If we can demonstrate that we can influence how collagen is built up and arranged in the tissue, we will have an important starting point for further development. Ultimately, I hope that this will lead to new treatments that limit scarring and may also be applicable to other connective tissue disorders. Power of Reflection can play a crucial role in this.”

The skin as a gateway to connective tissue disorders

Written by: Diana de Veld, science journalist