Microfactories in the body

No longer any need to swallow tablets or take antibiotics that also attack the intestinal flora. The tiny factory would produce only as much as necessary – and at the exact point in the body where it was required. This may sound like science fiction, but for chemist Wolfgang Meier at the University of Basel, it is by no means far-fetched.

Meier has been working on miniscule nanoreactors for more than 10 years, microscopic synthetic bubbles in which targeted biochemical reactions can take place. The factory stage is still a long way off, but the initial steps have proved promising. Together with his colleagues, Meier has already developed a precursor to a microscopic antibiotics factory. He works with polymers – special synthetic materials. In his laboratory, he has mastered the art of forming the synthetic molecules into tiny beads structured in a similar way to living cells or cell components. Meier allows these beads to absorb various substances, which then react with one another inside the bead to produce the desired product – such as antibiotics.

The trick? First, the beads absorb substances that are a precursor to the actual agent. Only when the substances in the bead react with another substance is the end product – and the desired agent – produced.

Antibiotic production on the spot

In the case of antibiotics production, Meier filled the beads with the enzyme penicillin acylase, which has the ability to convert a precursor substance into an antibiotic. In a laboratory test, Meier showed that this was possible. First, he mixed the bead filled with penicillin acylase with a culture of Escherichia coli bacteria. At first, nothing happened. But when he added the precursor substance for the antibiotic, the bacteria began to die off. Meier explains the principle of the process: “First, the inactive precursor substance penetrates the bead through the lightly porous shell and is then converted to an antibiotic by the penicillin acylase. The finished antibiotic then leaves the bead and kills off the bacteria.” The experiments are still taking place in laboratory vessels. However, Meier will soon be using cell cultures to test whether this antibiotics production works in living cells too.

Meier has an extensive support network on which he can rely. He is Director of the large-scale National Center of Competence in Research (NCCR) Molecular Systems Engineering (MSE), which has been working on the molecular factories of the future since mid-2014. A total of 29 research groups are involved from the University of Basel, the Federal Institute of Technology (ETH) and other academic institutions. The Swiss National Science Foundation is providing CHF 16.9 million to support the first four years. The size of this National Center of Competence in Research alone indicates the importance of developing molecular systems. If they succeed in building microfactories, the potential would be enormous. Synthetic vesicles could be placed in the direct vicinity of cancer cells and then administer inactive precursor substances to the patient. These would be converted into the active agent in the synthetic vesicles directly at the tumor site and the patient would be saved the strain of chemotherapy with all its side-effects.

Meier envisages combining different synthetic vesicles to produce a complex chain of production: “Substance A would be produced in the first vesicle. This would then move to the neighboring vesicle and be transformed into substance B, and so on.”

Although Meier has already shown that this works in principle, there are still some obstacles to overcome. The questions to be answered do not just relate to chemistry, which is why the NCCR MSE brings together biologists, chemists, engineers and physicists. For example, biophysicist Daniel Müller from the Department of Biosystems at the ETH in Basel is working to optimize the reactions in the microfactories. “In a living cell, the site of a biochemical reaction and the number of molecules involved are precisely defined to ensure an optimal procedure. We want to find out how to ensure optimal process control in our synthetic cell factories by regulating them in this way.” So far, it is also unclear how the energy for the chemical reactions would be generated in the microfactory, says Daniel Müller, Co-Director of the NCCR MSE. In living cells, many biochemical reactions are driven by high-energy molecules. The researchers do not yet know whether they will be able to use these energy suppliers for the microfactory too.

Center for development of microfactories

Funding for the NCCR MSE is initially limited to four years. However, this can be extended twice, allowing the NCCR to be funded for a maximum of 12 years. The funds are currently being used to finance several professorships and a whole range of doctoral work. “This ensures that the doctoral and postdoctoral students involved dedicate themselves entirely to MSE and can work without other academic commitments,” says Meier. “We consider research into molecular systems to be so important that we are currently developing our own Master’s degree program in Molecular Systems Engineering, which students at the University of Basel and the ETH will be able to attend in the future. By doing so, we want to train experts in our field in good time to be able to drive forward our basic research.” The NCCR MSE is also providing support specifically for female scientists. Among other things, a scholarship is available to female researchers with children to allow them to combine research with family life.

Meier and his colleagues know that new technologies can present risks. For example, the potential hazards of genetic engineering and nanoparticles have been the subject of public discussion for many years. From the outset, the NCCR MSE will therefore thoroughly investigate the possible consequences of using microfactories in the human body. An ethics board has been set up, and at the University of Zurich, an entire project team is explicitly focusing on the potential ethical, social and political consequences of molecular systems engineering.