New software called TARDIS reveals for the first time the movement of multiple particles in a bacterial cell. This allows scientists to monitor proteins and DNA in living cells and study their functioning, according to biophysicist Johannes Hohlbein and his former PhD student Koen Martens.
The software offers new opportunities for biological research, such as testing the effectiveness of antibiotics and other medicines. ‘Some antibiotics work by blocking molecular machines in the cell,’ says Martens. The software makes it possible to study the behavior of several of these machines simultaneously. This gives researchers a quick and clear insight into how an antibiotic works.
All the TARDIS program needs are coordinates of the molecular particles at different times, determined with a microscope. The program then calculates all possible paths of those particles. ‘TARDIS takes into account, among other things, biological dynamics and physical forces,’ says Martens. The result? A precisely mapped out route of the particles in a cell. As a proof-of-concept, the researchers used the software on known movement patterns such as diffusion. ‘Our program calculated exactly the right movement,’ says Martens. This worked even under more complex circumstances than was previously possible.
Previously, researchers could make particles visible in a cell using biological techniques, for example by attaching a fluorescent ball to them. But this only allows them to track one particle at a time. Biomolecules move very quickly; faster than cameras can capture. This results in a kind of stuttering film with jumping frames. If you follow one particle, that’s no problem: you can fill in the missing movement yourself. ‘But if two or more identically appearing particles jump, you cannot say with certainty which particle in the first frame corresponds to which particle in the next frame,’ says Martens.
Using computer computing power, scientists can now clearly measure global movement patterns in the cell for the first time. However, Hohlbein points out a limitation: “The software allows us to process data faster, but live monitoring of one specific particle, such as a protein, is no longer possible with this method,” he explains. ‘Think of it as a top view of a flock of sheep: the computer predicts how the flock moves, but does not follow the path of each individual sheep.’
The idea for the software arose in 2020 when Martens was doing PhD research in Wageningen, under the supervision of Hohlbein. “His thesis was so long that there was no more room for this research,” says Hohlbein. That’s why Martens and Hohlbein later developed the idea, together with colleagues from Carnegie Mellon University and the University of Bonn, where Martens currently works. During his current research, Martens is already using TARDIS to study DNA repair in single-celled organisms. “I don’t have a biological interpretation yet, but with my software I can now monitor the repair kit in the cell from minute to minute for the first time,” says Martens.