When we walk into a shop, we hardly even notice how helpfully the door opens for us – since the spread of photocells, this has become an everyday occurrence. We have also grown used to controlling everything with remote controls, which operate using infrared light. But what would the world be like if similar light-controlled “remote switches” could be built into cells? At the University of Pécs, Hungarian researchers are studying light-activated molecular switches as part of the HU-rizon Programme. The international research project, funded by the National Research, Development and Innovation Office (NRDI Office), is led by Dr. András Szilárd Lukács.

Dr. Szilárd András Lukács, principal investigator

University of Pécs

In your project, you are developing a new generation of optogenetic tools – what exactly is optogenetics?

Optogenetics means that we can control biological objects using light. In practice, we introduce properties into a cell that it did not previously possess. In the name of the field, the “opto” part refers to light and vision, as in “optics,” while “genetics” refers to the fact that we produce modified proteins within the cell. We create fusion proteins: we attach a light-sensitive molecule – a photoreceptor – to another protein that performs an important function within the cell. This allows us to incorporate this light-responsive property into the cell. This is a relatively new field of science; so far, it has been applied mainly in neurons. Much of the research focuses on switching specific neurons on and off using laser pulses and light. However, we have taken a different, less explored approach: we aim to influence the molecules that make up the cell’s structural framework using optogenetic tools.

Why did you choose this particular direction? Why is it useful to make the cell’s structural framework, the cytoskeleton, controllable by light?

Here at the Institute of Biophysics, we have been studying the cytoskeleton for thirty years, so we know a great deal about it. What we see is that, practically, the cytoskeletal system determines almost everything in the cell. For example, if we are able to partially disrupt it in a bacterium, that bacterium ceases to function. It is an extremely sophisticated and complex system – built around an actin filament network – but beyond providing structural support to the cell, many proteins bind to it, and together they regulate how the cytoskeleton operates. Within this framework, continuous polymerization and depolymerization take place, with cellular protrusions forming and breaking down. As a first step, focusing on potential applications, we aim to influence this polymerization process by incorporating light-sensitive molecules.

This is also an important area from a medical perspective.

Does your research target any specific disease?

The long-term outcome of our project will be the development of optogenetic tools that can be applied both in therapy and in drug development. Light-sensitive photoreceptor proteins come in many forms and possess a wide range of properties, so they need to be carefully selected and tested to determine which ones are suitable for our purposes. For such a tool, it is essential that such proteins can be switched on and off repeatedly and that they function consistently every time. This is what we aim to achieve: from a drug development perspective, a version that is not too large, not overly complex, and reliably performs the same function under all conditions would be highly valuable.

I believe that within 10 to 20 years, this field will make it possible, for example, to release drugs at a specific location and at a specific time within the body. The idea is to deliver the drug into different organs or cells, and then release it using an appropriate light pulse in a way that maximizes effectiveness while minimizing side effects. Achieving this is not simple, and our research contributes to this goal by developing the necessary tools. At the same time, rapid progress is being made in parallel areas: for instance, delivering light into cells and tissues is also a crucial step toward making these applications a reality.

Photo: OPTOGenetika project

The HU-rizon Programme funds international research projects, meaning that, under Hungarian leadership, researchers from abroad also work together on a given problem. Which institutions are you collaborating with?

We collaborate with American, British, and French partners with whom we have a shared history going back decades. Since the changes occurring in photoreceptors are extremely fast – taking place on the nanosecond timescale – they must be studied using so-called ultrafast spectroscopy. This is carried out by one of our French partners at the prestigious École Polytechnique, where ultrafast spectroscopy has been applied to biological problems for some thirty years. Our British partner, based at the University of East Anglia – ranked among the world’s top 200 universities – is a pioneer in the application of ultrashort laser pulses, and their research also focuses on these rapid processes.

Our American partner, Stony Brook University (New York), has decades of experience in enzyme kinetics and drug development. When we modify proteins by introducing artificial amino acids and test their potential applications, they are responsible for producing these variants and effectively incorporating them into the proteins.

Another important aspect of the project is that we alter the structure of these molecules. These structural changes can be examined at the European Synchrotron Radiation Facility (ESRF) in Grenoble, a leading centre for X-ray crystallography in Europe.

The research led by the team in Pécs may ultimately enable active substances to exert their effects precisely where and when they are needed in the body. You can learn more about the development of these molecular switching systems and other fascinating details at the HU-rizon Roadshow event on 9 April, where the project of András Szilárd Lukács will also be presented. For further details on and to register for the free event, please, visit:   https://nkfih.gov.hu/hu-rizont-roadshow-pecs.

Photo: OPTOGenetika project