Professor Dr. Wilfried Weber hitches molecular, light-sensitive switches to other molecules. In the CIBSS – Centre for Integrative Biological Signaling Studies at the University of Freiburg, he has created a gel which changes state from hard directly to soft, depending on the light. Weber and his collaborative partners aim to use this tool to enable certain immune cells to penetrate hard tumors and combat them from inside.
Some immune cells try to push the living tissue aside to get into solid tissue – as if trying to pass through dense bamboo thickets without a machete. “How hard can they push?” Wilfried Weber wants to know. A biotechnologist and part of the CIBSS Excellence Cluster’s representative team, he interested in molecular slide switches. Together with his CIBSS partners, he hopes to find these signaling pathways and learn to control them. This would enable human immune cells to penetrate and fight hard tumors which would otherwise have defeated them. Weber's research group is building molecular tools for this and other projects. To simulate the tissue, Weber has developed a special gel that can be switched from hard to soft within seconds, using light.
Sticking together macromolecule chains
“It looks like a plate of spaghetti,” says Weber. When the pasta is properly cooked, a fork can stir it easily. But it's a lot more difficult if the spaghetti is stuck together by a lot of cheese. Weber, of course, works not with spaghetti but with chains of macromolecules, also known as polymers. Instead of cheese, he adds light-sensitive switches. Depending on the strength of red light, the switches bind and link up the molecule chains to a greater or lesser extent. The chains form a loose or more solid gel. Conversely, dark red light dissolves the bonds. The gel softens and may even liquefy.
“For example, doctors might one day implant a gel into patients and release the drugs in it at the desired time,” Weber says. This molecular toolmaker, who completed the trinational biotechnology course in Freiburg-Strasbourg-Basel, is doing basic research. But, he says, “it is my great wish that one day one of our tools will contribute to the benefit of people - for example, by improving the treatment of a disease.
Switchable gels have been around for some time, but conventional gels change their consistency depending on heat, chemicals or pH. Cells do not tolerate this at all. That's why Weber uses biological protein switches, saying “We let nature inspire us.” His light-sensitive switches, for example, are photoreceptors from plants and bacteria. Weber attaches these proteins to biomolecules, mostly other proteins, but also to macromolecules or analysis chips. He can switch the coupling products on and off. Control signals are natural or manmade substances, or – in the use of optogenetics – light. Light can issue an order to transcription factors, for example, to read certain genes; to make proteins start or interrupt certain signaling pathways - or to stick molecular threads together, in the case of switchable gels.
Skillful irradiation creates easy pathways for immune cells
Weber finds it relatively easy to combine different proteins: “To do this, we link up their genes and introduce them into cells, which then produce the fusion protein.” However, the researchers have to connect their protein switches to macromolecules themselves. For the “spaghetti” gel, Weber uses the red light receptor Cph1 from blue-green algae. “We had to produce grams of it,” he says. This is followed by the combination of two chemically different substances - Cph1 protein and polymer threads made of polyethylene glycol. Chemists like to cook up mixtures like this to create bonds. Sometimes they add aggressive acids or bases. But proteins do not tolerate this. “We had to do a lot of optimization until the bonding was successful and the gel circuit worked,” says Weber, “We did a lot of pioneering work in this area.”
