Uni-Tübingen

Listening to cells at work

Peter Jones and Udo Kraushaar test pharmaceutical compounds on individual human cells. Jones develops the miniaturized chips which are used by Kraushaar in his experiments. The method helps to significantly reduce the number of animal experiments required before drugs are approved.

Human cardiac muscle cells pulse rhythmically under the microscope. They are arranged like a mini 3D heart on a chip, known as a microelectrode array (MEA). Every few seconds, the heart muscle cells contract and relax again. All at the same time. Rhythmically. Tiny electrodes measure the voltage discharged by the cells.

Dr. Udo Kraushaar disturbs them by adding substances and observing if they still pulse regularly, lose their rhythm or stop pulsing altogether. A monitor records the voltage discharged from the cells on a curve, like an ECG. Udo Kraushaar would rather test the effects of particular substances on the heart cells now before “someone falls off their bike because they can't tolerate a painkiller pill,” he says. This is not a fictitious example: Udo Kraushaar tests possible side effects of new substances on human cardiac organoids and cells from many other organs and helps to sift out unsuitable candidates for new drugs. 

When a pharmaceutical company wants to develop a new agent, it starts with 100,000 to 200,000 substances and systematically reduces the number to the most promising candidates. When there are about fifty to a hundred left, Udo Kraushaar and his team come into play. Organoids resemble a small white lump, large enough to be seen by the naked eye on the microelectrode chip under the microscope. Cells for forming the organoids had to be removed from a volunteer’s skin once by biopsy and then grown into heart muscles using adult stem cells. The cells behave as expected: They contract and relax again. Like a heart.

In this phase of drug development, usually between five and ten years have already passed. Only when two to five drug candidates remain does the clinical phase, the test on humans themselves, begin. “If a pharmaceutical company puts a substance into the clinical phase and fails, a billion euros is wasted,” says Udo Kraushaar. That’s why his work is essential in selecting the right substances. Animal testing also takes place before the clinical phase. The experiments in Udo Kraushaar's lab at NMI Natural and Medical Sciences Institute however, are closer to the physiology of humans and reduce the need for animal experiments.
Udo Kraushaar can only measure the cells’ electrical activity because the cells are on a chip with microelectrodes. Under the microscope, they are about the size of a cell and evenly distributed in the center of the board. From there, 60 electrically conductive tracks lead in uniform patterns to a square formation of contact pads. From here, the voltage pulses are amplified and digitized. 

“We listen to individual cells,” says Udo Kraushaar, “and groups of cells and amplify their signals together.“ He moves a slider to the right with the cursor on the screen. Now the convulsions of the heart organoid can be heard as a rhythmic murmur. Microelectrode chips are custom-made four floors below in the NMI Natural Sciences and Medicine Institute at the University of Tübingen in Reutlingen. The name of the institute is complicated, but can be explained by the combination of basic research, which very often takes place in cooperation with the University of Tübingen, and application-related research close to industry at the Reutlingen site and far beyond. In his laboratory on the first floor, engineer Dr. Peter Jones and his team produce the microelectrode arrays. First, they start with a glass substrate, on which they apply and structure several layers in succession. The first layer is conductive, typically made of titanium or the transparent conductor indium tin oxide (ITO) and forms the connections to the microelectrodes. The second layer is an insulating layer, usually made of silicon nitride, which covers the conductor tracks. The insulator is then opened, forming microelectrodes by precisely etching tiny holes. Depending on the application, the holes have a diameter of 10 to 30 micrometers. The third layer consists of the electrode material, often titanium nitride (TiN), to give the microelectrodes excellent electrochemical properties. Finally, a chamber is glued to the substrate, which serves as a dish in which cells or tissues can live.

Peter Jones has been experimenting with materials and manufacturing processes for years. An NMI subsidiary company produces the microelectrode arrays in large numbers, and another company in the Reutlingen Industrial Park delivers them to research laboratories in science and industry all over the world. “New human 3D in vitro models such as organoids and organ-on-chip models require new technologies. We develop our chips according to these needs, resulting in both scientific papers and products that are used in laboratories worldwide,” says Peter Jones. Without the microelectrode chips, Udo Kraushaar would not be able to test potential drugs on cardiac organoids. Two unequal components of inanimate and animate matter.

Udo Kraushaar (left) und Peter Jones work for the NMI, a non-university research institution and conducts application-oriented research at the interface of biological and materials sciences. With its two hundred employees, the institute is aimed at the healthcare industry and at regional and international companies from the automotive, mechanical engineering and toolmaking industries. At the same time, the NMI supports spin-offs of start-ups. In research, the NMI cooperates with institutions such as the University of Tübingen, the University Hospital Tübingen and theinstitutes of the Baden-Württemberg Innovation Alliance (innBW).

Text: Tilman Wörtz


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