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An interview with Dr Alice Kleber and Dr Dirk Sombroek about unique BRAIN technologies and the development programmes TRiP2Sensation and TRiP2Taste developing new cosmetics and skin-care products.

BRAIN: What is the focus of BRAIN’s BioActives research area?

Dirk Sombroek: Our R&D work on bioactive natural substances focuses on two key subject areas; healthy nutrition and skin care. In the latter field, our aim is to identify substances that have a positive effect on the appearance of the skin in skin-care products and that promote well-being or prevent skin irritation. A wide range of specific problems need to be addressed in this connection. The integrity of the skin can be challenged by individual predispositions, stress factors, ageing processes or harmful environmental influences. We experience these in the form of inflammation, burning, itching, prickling or swelling.

BRAIN: What is the key element of this work?

Alice Kleber: We have long-standing experience in the development of cell models for simulating the skin’s sensory reactions, which are known as cell-based assays. These assays allow us to simulate physiological processes in the skin and thus to reliably assess even at the laboratory stage which reactions are caused by exposing the skin to a specific substance. We then try to adjust the cell-based assays as precisely as possible to the situation on and in the human skin cell. The more successful the assays are, the more successfully we can identify active ingredients that are suitable for skin-care products.

Dirk Sombroek: It goes without saying that this is no easy matter since the skin cells in question are differentiated. Their reproductive potential and life span outside the body are very limited. That is why we have to work with cell-based assays in the laboratory that ideally present the same physiological properties, but over a longer time span.

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We want to prevent skin reactions such as burning or itching right from the outset by choosing the appropriate active ingredient for a care product.

Dr Dirk Sombroek

BRAIN: What is the starting point for this research work?

Dirk Sombroek: Our work is very targeted. Right from the start, we focus on a specific problem, such as a specific skin reaction. Our aim is to prevent this reaction from the outset, whether it is a burning or itching sensation or reddening of the skin, using an active ingredient for a care product, or to subsequently alleviate the effects. We therefore study this specific problem and examine which molecular structures in the skin cells are responsible for the reaction.

Alice Kleber: To put it another way, we examine which skin sensors or receptors are activated in a given reaction and via which signalling pathways the stimulus is passed on. In our research, we call these sensors or receptors ‘targets’. Based on this knowledge, we then develop specific assays so that we can examine whether test substances have an effect on the target sensor in the lab.

BRAIN: What form exactly do these signalling pathways or targets take?

Alice Kleber: The skin sensors include, for example, ion channels such as transient receptor potential ion channels (TRPs for short), or so-called G protein-coupled receptors (GPCRs). The sensors perceive a stimulus and trigger biochemical or biophysical processes in the cell in which they are anchored. When such a signal cascade is activated, nerve channels tell the brain that the skin cell has entered into contact with a substance that might be harmful. We experience a burning or itching sensation as a protective measure. Based on these signalling pathways, we then look for substances that prevent or alleviate skin irritations.

BRAIN: What happens at molecular level?

Dirk Sombroek: In the TRP channels, ions flow over the cell membrane and produce a specific reaction in the skin cell, depending on the sensor channel. In G protein-coupled receptors, a stimulant is bound, frequently by means of a lock-and-key principle, and as a result specific messenger substances are activated in the skin cell metabolism, which in turn provoke a reaction. The end effect may be the same with both types of receptor. For example, the calcium level in a skin cell may rise. That is relevant because calcium performs an important signal function in cells and stimulates them to perform specific tasks, such as differentiating, synthesising or secreting specific substances.

BRAIN: Are there other targets that you use for cosmetics applications?

Dirk Sombroek: As well as various ion channels such as TRPA1, TRPV1 or TRPM8 and G protein-coupled receptors such as PAR2 and CNR1/2, which are each responsible for specific skin reactions, there are other assay systems which we are already working with or are in the process of researching or establishing. The ongoing fine-tuning and further development of this range of screening models is an important part of our research work.

BRAIN: How do you measure such changes?

Alice Kleber: We use very different methods depending on the cell-based assay. We can, for example, couple the activation of a receptor with a fluorescence signal in the cell-based assay. The cell then lights up and we can measure and evaluate this signal. Alternatively, we can measure the membrane potential, i.e. the electrical voltage between the fluid-filled spaces on both sides of the cell wall. There are different concentrations of charged particles in these fluid-filled spaces. Another possibility is to measure the level of specific messenger substances.

BRAIN: What is the advantage of the procedure you have chosen?

Alice Kleber: The cell-based assays enable us to screen virtually unlimited quantities of thousands of samples very fast. These can be pure substances or extracts from natural substances. There is no need to carry out extensive safety assessments beforehand. Such tests are then carried out with the substances that have shown an activity on our target sensor in the assay system. In our experience, after testing 20 thousand natural substances, about 20 development candidates are left that have shown reproducible specific effects to improve skin health in the cell-based assay.

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The cell-based assays enable us to screen virtually unlimited quantities of thousands of samples very fast.

Dr Alice Kleber

BRAIN: What sets your procedure apart from other approaches?

Alice Kleber: Our approach is target-based, i.e. we analyse which structure is responsible for a skin problem and try to find substances that have a beneficial influence. It doesn’t really matter what the substance is, at the outset. We only make a selection if a specific category of substances is desired, such as natural substances. We then select the candidate that offers the best range of activity and the most favourable properties in terms of compatibility, and then use it as our cosmetic ingredient. This ensures that we can really obtain the best possible effect. Other companies take a ‘substance-based’ approach; their research is based on a substance that promises to deliver an interesting marketing story, such as special provenance or a beautiful flower. They then examine which skin-promoting properties the substance has. Of course, such ingredients are also effective, but this approach does not usually provide the ideal candidate for the relevant skin problem.

BRAIN: What happens after the first screening campaign?

Dirk Sombroek: The typical procedure following screening is to retest and examine the substance on related targets. We call this counter-screening. That means we examine whether the effect is reproducible and whether there are side effects – i.e. whether the effect is selective. In technical terms, we can modify our cell-based assays using genome editing methods and switch specific functions on or off. This is an important option if we are trying to find out whether an active substance really only influences this one structure.

We then draw closer and closer to the in-vivo situation by using more specific assays, including primary cells from tissue samples, three-dimensional models or multi-layer skin simulations. For technical reasons, these methods are not suitable for high-throughput screening and are therefore only used for the further characterisation of development candidates that were identified during screening. To use a metaphor, the eye of the needle that the test substances have to pass through gets smaller with each screening step. Particularly with regard to three-dimensional cell-based assays, we are currently working with university groups on overarching research projects to use the systems in the health and cosmetics sector. Specifically, we are working with Mannheim University in this area [see article by Dr Rüdiger Rudolf in this issue of Blickwinkel, editor’s note].

BRAIN: Which criteria do you apply for selecting your screening resources?

Alice Kleber: That depends on the specific task in hand and the requirements of our cooperation partners. Do they want to work exclusively with natural substances, or are they also interested in synthetic substances? Are extracts or pure substances to be used? The preselection of test candidates is another special area of competency within the BRAIN Group. In this, AnalytiCon Discovery plays a significant role. This company is a global market leader when it comes to libraries of natural products with fully elucidated chemical structures, and has access to around 15% of all currently known natural products.

In the ideal scenario, the properties of the substances that are relevant as safe ingredients for subsequent use are already taken into account when compiling the screening resources. Further criteria for preselection are knowledge about the potential toxicity of a substance or about experience with specific manufacturing processes if the substance is to be provided later on via a production strain (a yeast or a bacterium). Questions of efficiency and cost-effectiveness therefore enter the scene at a very early stage in relation to specific product developments. The accessibility of the substance is also very important. At least 50 to 100 grams of a substance are needed for cosmetics developments on a laboratory scale.

Dirk Sombroek: Within the BRAIN Group, we can also access the expertise of L.A. Schmitt GmbH for our product developments. This company was established in Leipzig in 1925 and looks back on a long tradition of manufacturing cosmetics and wellness products.

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BRAIN: Do you work exclusively with natural substances to develop these products?

Dirk Sombroek: As far as research for foods and beverages are concerned, we work solely with natural substances that we can directly extract from bio-based materials. That is one of the core competencies of AnalytiCon Discovery. But if possible, it may indeed be more efficient and sustainable to carry out biological fermentation using microorganisms. Whether or not the active ingredients are natural is not a crucial criterion for developing ingredients for cosmetic and care products. Here we can use synthetic molecules, depending on the customer’s wishes. Such molecules can also be produced in large quantities by means of chemical syntheses.

BRAIN: How do you enter into business with your potential development partners?

Alice Kleber: We gathered together our offers for industry partners in our development programmes TRiP2Sensation and TRiP2Taste. We have tried-and-tested cell-based assays and a wealth of resources that we can test on this basis. We can use them to compile a qualified list of top candidates for various applications, and carry out initial safety assessments for these candidates, and try them out on test persons.

Industrial partners can test our top candidates in their own product systems and use them for their own care products if they prove successful. We decide together on a case-by-case basis how this business can be contractually arranged.

BRAIN: Can you name an example of such a successful industrial partnership?

Alice Kleber: One example of a successful development partnership is the cosmetic active ingredient SymSitive® 1609, which we developed with Symrise. This active ingredient is now used in a number of skin-care products, for example in Beiersdorf’s Eucerin UltraSENSITIVE range. It reduces overreactions in the skin and has a soothing effect. Our target when selecting the active ingredient was the TRPV1 ion channel that is activated by capsaicin. This causes a burning and prickling sensation on the skin, such as occurs when using ABC heat plasters. This effect can be reduced using Sym- Sitive® 1609.

Kleber Sombroek Brain

Dr Alice Kleber studied biology at Saarland University and at Eberhard-Karls-Universität in Tübingen. She obtained her doctorate in 2000 in pharmaceutical/medical chemistry with a thesis on cell-based assays. She has worked at BRAIN since 2001 as a research scientist and project manager. In 2012 she took on the additional role of programme manager for System Products Cosmetics. 

Dr Dirk Sombroek studied chemistry at Albert-Ludwigs-Universität Freiburg and obtained his doctorate at Ruprecht-Karls-Universität Heidelberg. During this time he performed research at the German Cancer Research Centre (DKFZ) in Heidelberg. He joined BRAIN in 2010, where he now works as a project manager and platform coordinator. Within the BioActives & Performance Biologicals research area, Sombroek coordinates the activities of the NatLife 2020 innovation alliance.

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