ONE THOUSAND AND ONE IDEAS

How Professor Dr. Ute Schepers uses biochemical research as a basis for application-oriented product ideas.

For one thousand and one nights, Scheherazade told the well-known stories of Aladdin, Sindbad and other adventures. She thus stands for wisdom and the will to change the course of history with the power of the mind. The creative mind of this fairytale figure and her helpers is extraordinary – but what connects Scheherazade with science at KIT? “Inventiveness and the right attitude”, says Professor Ute Schepers, “are needed to generate socially relevant innovations. Well-founded research is a good basis for this, but it's the ideas from which you can make something useful that are crucial.”

This is the strength of her research group at the Institute of Toxicology and Genetics of KIT. Her team focuses on biochemistry, genetics and peptide research. The resulting innovation projects sound more tangible: Hair growth from the printer, removal of tattoos with light, selective destruction of tumor cells. A wide range of applications that are not always immediately apparent. “Doctoral students often ask me what to do with this or that discovery under the microscope. Then you have to think outside the boy”, says Schepers.

A spin-off company called vasQlab is one of the most important current innovation projects of the professor and her team of fellow scientists and entrepreneurs. The founding team set out to change drug development and has already won over several expert juries with its miniaturized organs on body-on-a-chip systems, its artificial blood vessels and the 3D printing of human organs – including at the Cyber Champions Award 2016.

“Our idea is based on the production of different human organs on a miniaturized “body on a chip” system. We have already been able to print three-dimensional organs such as the liver, intestine, brain, skin or lungs on an artificial blood vessel system with the help of 3D printers and reproduce them in miniaturized form."

Prof. Dr. Ute Schepers

“Although it has become easier to produce new drugs, the subsequent clinical trials are lengthy and often cost more than 1. 2 billion euros. Moreover, the number of laboratory animals in Germany alone has increased to 2. 8 million in recent years, while the approval of new drugs by the Federal Institute for Drugs and Medical Devices has not increased significantly. On top of that, testing new drugs on humans during the clinical phases frequently results in serious health damage and even death. Results from animal experiments are not always transferable to humans”, explains Ute Schepers. Miniaturized human 3D tissues and organs from different cells can already provide indications of drug tolerability in humans in the preclinical phase, thus minimising the risk in the clinical phases. A highly relevant project with great potential for the pharmaceutical industry.

While vasQlab is due to be founded by a notary in August 2017, Prof. Schepers has already launched new ideas: “We are just starting projects on the photodynamic therapy of cancer and light-activated inks, both of which could lead to spin-offs. The biochemist is also open to collaborations with the industry to further develop her ideas and bring them to market. “Our creative ideas are interesting for a wide range of industries. As a scientific group, we cannot and do not want to take all the way to market ourselves. For industrial partners, however, our projects offer promising new business areas,”says Schepers.

Winner at the innovation contest

The scientific team around Ute Schepers has already participated several times in the KIT NEULAND innovation contest and won - among others with the topics anti-MSRA agents and "With light against cancer".
From left to right: Vice President of KIT Prof. Thomas Hirth, project members Carmen Seidl and Eva Zittel, Prof. Ute Schepers, Prof. Claus Feldmann at the award ceremony of the Innovation Contest 2016 for the project "With Light against Cancer".

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INNOVATIONS PROJECTS

Body-on-a-chip combines “mini-organs” in a small space, for example to perform drug tests. The chip shown contains the intestine, liver, kidney as well as the blood-brain barrier. Other organs, such as the skin, lungs or heart, are also already in production. An expansion of the chip to ten organs is planned.

PEOPLE ON THE CHIP

Drug testing on humans repeatedly results in adverse health effects, sometimes even fatal. Animal experiments, on the other hand, are ethically questionable and their results are not always transferable to the human body. Miniaturized human 3D tissues and organs made from different cells, so-called body-on-a-chip, can already provide indications of of drug tolerability in humans in the preclinical phase, thus minimizing the risk in the clinical phases. There is a need for in vitro systems in which supplying blood vessels can be grown in combination with 3D tissues and which meet the physical and mechanical demands of a blood vessel system. Today, there are few microfluidic chip systems, which however consist of angular channels and do not represent the curved environment of a blood vessel or the flow profile of the blood vessel. Prof. Schepers' research group was able to develop a three-dimensional microfluidic blood vessel system consisting of round, porous and branched channels through microthermoforming, onto which miniaturized 3D organs can be 3D bioprinted from human cells. Resulting low-cost disposable products can reduce the cost of pharmaceutical research and minimize the number of animal experiments.

WITH LIGHT AGAINST CANCER

Despite advances in cancer treatment, there are still problems with many chemotherapeutics, such as drug resistance or serious side effects due to the simultaneous killing of stem cells and proliferating tissue. Likewise, it remains a challenge with radiation therapy to avoid damaging surrounding healthy tissue. Photodynamic therapy is an innovative treatment method for cancer based on light-inducible active substances, so-called photosensitizers. The photosensitizer is injected into the patient’s bloodstream and is initially completely harmless to the body. Only when irradiated with light of a certain wavelength does the photosensitizer develop its toxic effect: Local exposure of the tumour results in the formation of reactive oxygen species that destroy the tumors.

However, conventional photosensitizers such as titanium dioxide are not suitable for the treatment of deep-lying tumors, as they are activated with UV light, which has a low penetration depth in the human body and is cell damaging. Photosensitizers, which are activated with longer-wave light, are therefore of great interest for tumor therapy. The research group has developed light-sensitive β-tin tungstate nanoparticles, which, in contrast, are very stable under physiological conditions. Since they are activated with visible light, deeper tumors can also be treated.

FLUORENSCENT SPRAY AGAINST MELANOMA

Malignant melanoma, the black skin cancer, is one of the most dangerous types of skin cancer. If detected in the advanced stage, there is little chance of recovery. If a malignant melanoma is detected early, there is a good chance of recovery. Early detection is mainly performed by surgical removal and histological examination of degenerated liver patches. This method is complex and allows only random examinations of patients.

One of Prof. Scheper’s product ideas is based on the development of a contact gel or a spray for the whole body treatment and the subsequent detection of degenerated skin areas using a commercially available and inexpensive UV lamp that stimulates the fluorescence of the dye and makes the degenerated liver spots visible. Any unintaken substance can be removed by washing it off beforehand. The idea is based on a fluorescent substance synthesized by the research group, which is selectively absorbed only by cells of the malignant melanoma. Screens on human cells do not show uptake in healthy skin cells or in other cells or tumors.

The picture shows the frequency of detection of MSRA in human blood. The group headed by Professor Schepers is researching drugs against the widespread hospital germ.

ANTI-MRSA ACTIVE SUBSTANCES

In Germany, the number of infected patients is around one million per year, with the number of deaths rising to up to 40,000. The reason for this is an infection with one of the three most common hospital germs MRSA, ESBL or the intestinal germ VRE. Multi-resistant germs have adapted over time to the presence of antibiotics. The cells develop strategies to disable their mechanisms of action and then react only poorly or no longer at all to the active ingredients. Multi-resistant germs are found globally, especially in hospitals and nursing homes. There are increasingly fewer treatment options available for multidrug-resistant germs, such as Salmonella or Staphylococcus aureus (MRSA). At present, therefore, it is impossible to contain the formation and spread of these so-called super germs by conventional means.

Prof. Scheper’s team has discovered a new class of compounds based on fat-soluble peptide-like structures that show very good efficacy against MRSA. Unlike conventional antiobiotics, the peptidomimetics do not attack the bacterial metabolism but destroy the bacterial cell membrane, causing the MRSA to dry out. This kills and eliminates the bacteria. Resistance does not develop.

In a research collaboration, Prof. Schepers has developed an alternative to painful hair transplantation. This is based on genetic reproduction of the hair roots and on a biodegradable foil, which is attached to the scalp and then painlessly dissolved with hair roots.

3D HAIR PRINTING AND HAIR TRANSPLANTATION

In Germany alone, around ten million men suffer from hair loss and about one in three women are affected. Usually, the only remedy is a hair transplant. The surgeon removes a strip of skin from the crown of hair at the back of the head. Several thousand hair follicles are located on this skin lobe, which is now broken down into small grafts. The individual hair follicles are transplanted into small holes in the scalp, which the surgeon either cuts, stings or burns with a CO2 laser. About 3000 individual hairs are often transplanted. This procedure is very painful and cannot be performed in patients with little own hair in the wreath.

In collaboration with a group from the Institute of Technical Chemistry, Professor Schepers has developed a procedure that avoides a surgical procedure and allows the insertion of several thousand hairs at a time. In this procedure, a few hair roots are removed from the patient's hair crown by a biopsy at the family doctor's office. Several thousand hair roots are then multiplied from two to three follicles. In order to place these follicles on the scalp in a simple process, the cells are printed on a special polymer foil with small hair-root-like recesses using a newly developed 3D laser printing process. The edges of the recesses are chemically modified so that they act like a velcro tape to which the hair root cells can adhere. Since it is a foil material that is biodegraded by a special enzyme, several thousand follicles can now be transplanted in one step without surgery.

After detachment of the epidermis by fruit acid peeling, as it is done in cosmetic treatment of aging signs, the foils are glued on large areas with fibrin glue. After 48 hours the skin is regenerated and the hair roots are ingrown. Within a short time, the foil decomposes into FDA (Food and Drug Registration) approved products.

Prof. Dr. Ute Schepers

Prof. Schepers has been working at KIT since 2009 and since then heads the Chemical Biology Research Group at Institute of Toxikology and Genetics at KIT. From her studies of chemistry in Bonn, her path to Karlsruhe led her through scientific positions in Bonn and at Harvard to her habilitation at KIT in 2011.

Her research focuses on molecular transporters, cell recognition of polycationic transporters, antibacterial transporters and RNA interference techniques. The research group has a large library of molecules. Many product ideas are the result of current research projects, for example in the context of doctoral theses, and are in some cases followed up to commercialization on the market. This led, among other things, to the creation of the spin-off company vasQlab, with which a team of entrepreneurs around Prof. Schepers develops and sells body-on-a-chip systems.

Prof. Schepers has received several awards for her scientific work. Her wealth of ideas in the field of applied research and innovation has been awarded several times with the NEULAND Innovation Award at KIT.

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INTERVIEW WIRH PROF. UTE SCHERPERS

Prof. Ute Schepers heads an interdisciplinary team with a high percentage of women. She advocates women's greater involvement in research and innovation. Private and professional life planning demands can be reconciled - as long as the right steps are taken at the right stage of life.

Prof. Schepers, you explicitly encourage a high proportion of women among your doctoral students. Why?

Because I think that women should also explicitly support women in order to motivate them to take on leadership positions, even if they want to start a family. If we as women don't show that you can reconcile both, who else will? If female employees see that it works, they may be more willing to take the next career step.

Why is it that fewer women than men pursue their scientific careers very consistently?

Up to the doctorate, women and men are now on an equal footing, even in STEM subjects. After that comes the big drop. This depends on three main factors: The first is entry into the workforce. Women dare less and go for secure jobs, even if that means getting a lower-paid position. As a result, very few women venture down the path of starting a business either. Women are definitely less location-flexible in their job search because they are more family-affine. There was once an assessment by work psychologists that women also place less value on status symbols in their professional lives. For example, their own office is often smaller than that of their male colleagues of the same rank, which leads to a loss of respect among colleagues and employees. I take your word for that. The very fact that women are still paid significantly less than their male colleagues with the same or in some cases even worse qualifications gives them a much poorer starting point for equal career opportunities. Unfortunately, due to the lack of female applicants in appointment procedures for professorships, mostly men are appointed because they are a better fit for a position. Women also do not use so-called networking because they usually think that they can do it on their own thanks to their achievements. As a result, they miss out on a great many opportunities. The second and perhaps even essential factor is starting a family. Women plan the family into their career from the very beginning. Unfortunately, this is still a contradiction of sorts for a steep scientific, career with many temporary contracts and changes of location. Successful female professors are, unfortunately, often childless due to the time it takes to pursue their careers, which means they are also not perceived as role models. If we succeeded in creating long-term (beyond kindergarden) and self-evident childcare, then family planning could also be included in career planning. The third factor is not quite obvious and has to do with creativity. The scientific career is not only the career itself: i.e. doctorate, postdoc, habilitation but also a creative space. Women are very determined. This is already evident in the doctorate. They pursue the research question until they have reached the goal on the direct path, while men very often get distracted on this path and thus also make very interesting discoveries and are inspired by them. This creates a larger creative space in which one is also more strongly perceived and promoted. This promotes not only your career but also your own will to stay in science. I try to get my female doctoral students to develop their own ideas and pursue them. We then submit them to the innovation competition. That's motivating.

How can women balance the demands of a time-intensive academic or research-related career with family planning?

As already mentioned, longer-term childcare beyond kindergarden is still missing. This already works very well at KIT, but not at all at many other institutions.

If you look closely, a scientific career is easily compatible with a family. We as women just have to set an example for our doctoral students. Everyone knows that writing publications or acquiring third-party funding does not fit into an already busy daily schedule and requires a lot of overtime. But the nice thing is that you mainly work for yourself, have a lot of flexibility in working hours and location (home office, mother-child office, etc), work with a lot of talented young people, and every day is different. This means there is a lot of co-determination in how to shape one’s work.

It's a different story with spin-offs:

Thinking in phases - early mid-30s is a bad time for women to start a business - here, women's willingness to take risks is very low. Factors such as an uncertain salary, capital to be raised, uncertainty as to whether the whole thing will work at all are no-go criteria for starting a family at the same time. Men are more attracted by this risk. They find the entrepreneurship scene attractive because men like to meet and network. Women are less attracted to it: they see it more as a waste of time.

From the age of 40 onwards, things change again, and women then look for interesting fields of activity. They are more settled and take a more relaxed view of things because they have had more experience. And: family planning is usually accomplished and this pressure is falls off.