SCIENCE CORNER

Dr. Pam's Q & A with Dr. Manfred Schmolz and 
Dr. Oliver Engelking

Two interviews with German scientists regarding in vitro models developed for studies on human skin and the immune system 


February 22, 2012

As you know, NAVS believes strongly that science can move forward without the use of animal models. While some scientists believe that the similarities between animals and people justify the use of animal models in biomedical research, we know that the differences between species can severely complicate data interpretation, and that better, more predictive ways of performing these experiments exist or can be developed. In an effort to learn more about the innovative, in vitro technologies that are available now to biomedical researchers, I contacted several companies around the world to inquire about their sophisticated, animal-free models.

Below are two interviews I had with German scientists regarding the in vitro models that they developed for studies on human skin and the immune system. I hope you will enjoy reading about these innovative technologies and are as encouraged as I am that scientists are working hard to develop models which can accurately recapitulate what happens in humans.

- Dr. Pam Osenkowski, Director of Science Programs

This week I had an opportunity to discuss in vitro models with Dr. Oliver Engelking, Business Development Manager of CellSystems Biotechnology in Germany. CellSystems has partnered with researchers in the life science community for over 20 years. They have developed complex in vitro models, including 3-dimensional skin models for toxicology studies, experiments that test the effects of chemicals on living organisms. These models are also used in efficacy testing and research. When scientists discuss in vitro cell cultures, often times we are referring to a single layer of cells growing in a petri dish. Many times, these in vitro models are criticized because they are not as complex as the cell networks in the body. However, scientists at CellSystems are working with a more sophisticated in vitro model of the skin, one with several layers of cells and surrounding proteins which more closely mimic the complexity of human skin.

The generation of in vitro models has long been supported by the European Council, the European Union’s strategic body which is tasked with defining "the general political directions and priorities" of the European Union. In 1976, the European Council came out with a Cosmetics Directive, a piece of legislation whose main goal was to ensure that cosmetics are safe for consumers. One of the initiatives of this directive is to try to reduce, refine, and replace (3Rs) animal testing in this process. Because of this goal, much effort has been made developing in vitro models to serve as alternatives to traditionally-used animal models. Historically, animal models have been the main way to evaluate the harmful potential of substances on the skin. But more sophisticated in vitro models, including the human epidermis model EST1000 (Epidermal Skin Test 1000) by CellSystems, provide a highly predictive alternative system to perform such studies, with the added bonus of having human relevance. Because the goal of developing a scientific model is to create a system that can accurately recapitulate what happens in nature and can predict what would happen under certain conditions, it makes sense to generate models with direct human relevance, as they have the greatest potential to accurately predict what will happen in humans given that we don’t have to extrapolate data among species.

In 2009, the European Center for the Validation of Alternative Methods (ECVAM) validated the EST1000 as a stand-alone method to perform skin corrosion assays. Skin corrosion assays are those that look for the production of irreversible tissue damage on the skin after a test chemical is applied. This is in contrast to skin irritation models, which look for the production of reversible inflammatory changes on the skin after a test chemical is applied. EST1000 is currently being reviewed by ECVAM’s Scientific Advisory Committee (ESAC) to see if it can also meet regulatory requirements to serve as a stand alone model for skin irritation assays.

NAVS supports the development of in vitro technologies that advance science without harming animals, and would like to thank Dr. Engelking for taking the time to inform us about the EST1000 model of human skin from CellSystems.

Q. Why was your company interested in developing in vitro assays?

A. There was growing interest from the cosmetics industry and from CRO [Contract Research Organization] looking for reconstructed human skin. We had developed expertise in this field and responded to these demands.

Q. What is your model mainly used to test? Can you describe your assay in more detail?

A. Our reconstructed epidermis EST1000 is mainly used in two fields: in vitro toxicology (for skin irritation and skin corrosion testing) and for efficacy testing.

The in vitro test for skin corrosion and skin irritation is relatively simple: A test item is applied topically to the EST1000 (onto the stratum corneum, i.e. the top of the model). After different exposure times and culture periods the viability of the tissue is measured by MTT Assay [a test that can quantify the cells’ mitochondrial activity; mitochondria are like “energy factories” in cells-they produce the energy cells need to perform their functions]. Depending on the percentage of viability to a negative control [a test condition known to give a negative result- in this case, not adversely affect the cell’s ability to live] the item can be classified as skin corrosive, skin irritative or non corrosive, non skin irritative.

Q. Aside from your model, what other models are commonly used by researchers who are studying skin corrosion and irritation?

A. For cosmetics, this [skin irritation and skin corrosion testing on scientifically validated reconstructed skin] is compulsory in Europe. For chemicals (in the context of the REACH legislation [Registration, Evaluation, Authorization, and restriction of Chemical Substances] testing), even these tests are still carried out with rabbits.

In research – the alternative is to work with standard cell culture. This means skin cells growing in cell culture medium. This does not allow application of substances on the top of skin, in contact with the air (as it is in reality).

Q. Does your assay have advantages/disadvantages over other currently available models?

A. Advantage is: use of human skin not animal skin; animal skin might react differently to certain chemicals.

Q. Does use of this type of assay replace/reduce animal testing? If so, can you approximate by how much?

A. It does reduce animal testing, not a large percentage taking into account the large number of animal tests that are carried out. However, irritation and corrosion testing on animals are very cruel and painful tests for the animals.
For skin corrosion and skin irritation testing, the very cruel method – using rabbits – is replaced.

Q. Is data from your model more likely to predict what happens in humans than data from animal models?

A. RHE [Reconstructed Human Epidermis] are validated against data from rabbit (which still acts as the gold standard in toxicology). It is known, that some test chemicals which are toxic for humans are not correctly detected by rabbit, but by RHE.



*Dr. Osenkowski adds: It is exciting to learn that predictive in vitro technologies are on the market and continue to be developed. These models hold the potential to replace the use of animals in such studies.

For more information on human-relevant, in vitro skin models generated by CellSystems, please click here.




Monday, February 6, 2012

This week I had an opportunity to touch base with Dr. Manfred Schmolz, founder and CEO/CSO of Experimental and Diagnostic Immunology (EDI) in Germany. EDI is a contract research and development laboratory that works for pharmaceutical, cosmetics, and chemical companies. Formally trained as a microbiologist, Dr. Schmolz focused his studies on human immunology for over 30 years. In that time, he developed innovative in vitro assays to model the human immune system. As you know, NAVS supports the development of technologies that advance science without harming animals, and we were impressed that the inventive models Dr. Schmolz has developed can do just that.

Modeling the human immune system is a challenge for scientists, because this system is extremely complex. The body has several types of specialized immune cells that need to communicate with other cells in various tissues and organs, in addition to responding to a wide variety of signals. One of the major criticisms of in vitro models of the immune system is that they lack the complexity of the in vivo immune system, and scientists in favor of using animal models believe that the complexity of animals makes them more useful models in these studies. And that is where Dr. Schmolz comes in -- he has recognized the issues that come with in vitro models that are too simplified, and has helped overcome this problem by inventing more elaborate cell culture models that more closely mimic the complexities of the human immune system.

I had an opportunity to speak with Dr. Schmolz about his cell-based models, and here is what he had to say.

- Dr. Pam Osenkowski, Director of Science Programs


Q. Why was your company interested in developing in vitro assays?

A. Mouse and rat immunology formed the basis of immunological research in the past decades. Nevertheless, the availability of immune cells in the peripheral blood makes it so easy to isolate human cells from the immune system for in vitro investigations that there is actually only little reason to use non-human cells. The main reason, however, is that despite the similarities between human and mouse/rat immune cell activities, there are a lot of differences. In many situations these latter prevent a reliable prediction of what drug activities will be found in the human body when animal cells are used in pre-clinical experiments.

Q. Does your assay system have advantages/disadvantages over other currently available models?

A. Reliability in the prediction of drug effects in vivo to my opinion depends mostly on the complexity of the testing environment that can be created in vitro. Thus, our focus from the beginning on (more than 15 years ago) always was on complexity. The co-culture systems we developed around immune cell cultures still can be considered second to none. The basis for each of these is a thoroughly developed human whole-blood culture that is combined with differentiated human tissue cells in the second, communicating compartment.

Q. Can aspects of this assay be transitioned to the development of other in vitro assays?

Absolutely: The adding of complexity should become a major goal also for other types of in vitro systems.

Q. Does use of this type of assay replace/reduce animal testing? If so, can you approximate by how much?

A. We actually didn't develop these systems to replace animal testing, but just because we were convinced that these add the quality of being totally human. They surely do have the potential to reduce animal use (and I would be more than happy about that). However, I am not able to judge the size of this effect.

Q. Is data from your model more likely to predict what happens in humans than data from animal models?

A. To our opinion, this [is] surely the case. Nevertheless, there are other situations, where a whole organism still has the advantage of higher complexity (providing for example the link between the CNS [central nervous system] and the immune system), despite the inter-species differences.* However, this speaks in favor of a careful and thorough stepwise testing in humans, wherever possible, rather than for using animals with all their inter-species differences, causing new imponderability.



*Dr. Osenkowski adds: It should be noted that the higher complexity of animal models does not ensure that they accurately predict human response. Even non-human primates, our closest relatives, have failed to accurately predict drug response in humans. Additionally, the heterogeneity of humans (with respect to our unique genetic profile and environmental exposures) is not well represented in animal models, and one major reason drug candidates can fail during late stages of drug development.

NAVS would like to thank Dr. Schmolz for his contribution to Science Corner and for his hard work developing in vitro technologies. NAVS agrees that more complex, in vitro models have great potential to accurately mimic in vivo human conditions. As these models are based on human cells, they have greater relevance to the human condition than animal models. Complex in vitro models have great potential to accelerate the process of drug development and increase the rate of clinical success. For more information on human-relevant, in vitro models generated by Dr. Schmolz of EDI, please click here.

 
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53 West Jackson Blvd., Suite 1552
Chicago, IL 60604
(800) 888-NAVS or (312) 427-6065
Fax: (312) 427-6524
navs@navs.org
© 2013 National Anti-Vivisection Society is a
501(c)3 non-profit organization