From studies of cells at the molecular level to a rapid diagnostic test for antibiotic resistance
Professor Johan Elf’s research group has developed methods that make it possible to study life’s processes in real-time at the molecular level. With this knowledge, scientists have now developed a rapid diagnostic test for antibiotic resistance in urinary tract infections.
About twenty percent of all antibiotics prescribed in Sweden concern urinary tract infections. The test now being evaluated at two healthcare centres in Uppsala is expected to provide answers to which antibiotics are most effective within just 30 minutes. It can thus make both treatment more precise and counteract the development of antibiotic resistance.
“I think it’s especially exciting because the diagnostic test is a very clear example of the value of independent basic research,” says Johan Elf, whose research team developed the technology on which the test is based.
Johan is firmly rooted in basic research in the natural sciences. With the help of further developments of the microscopy technique that was recognised in the 2014 Nobel Prize in Chemistry, he has made several notable discoveries about the smallest building blocks of life. That the work his research team performs would be directly useful was not at all planned.
“We primarily try to understand how life’s processes work at the molecular level. Such research is in itself a prerequisite for medical applications, but not necessarily in the short term.”
Johan’s research team works in the traditional way: making models, predictions and experiments. What distinguishes the group from many others in the biological sciences is that the models are based on physics, the predictions are quantitative, and the measurements require self-constructed microscopes to be sufficiently accurate. The latest instrument, the Minflux microscope, has been developed by the research team together with Stefan Hell’s group in Göttingen. It took five years to complete, but at the beginning of 2017, they described in Science magazine how this new type of microscope makes it possible to study exactly what single molecules do in living cells on a time-scale of one hundred-thousandth of a second.
“Since we develop techniques to study fundamental biological processes in harmless bacterial cells, it’s usually not so easy to explain what they could be beneficial for.”
It was the terms of a research grant from the Swedish Foundation for Strategic Research (SSF) that raised Johan’s awareness of the usefulness of his research: three percent of the grant is, in fact, earmarked for investigating how the research could be utilised. Furthermore, an offer of mentorship is also included.
“Initially, these terms did not feel so good, especially since money was allocated for something other than research. However, I got the opportunity to get to know a highly competent and insightful individual, Ove Öhman, who is well-versed with the biotech world. We got along well. We also quickly realised that there is no commercial interest in our previous research methods: they are way too complicated and expensive, no matter how powerful they are”.
During the same period, Johan discussed possible collaborative research with colleague Dan Andersson, Professor of Microbiology, who works with antibiotic resistance. Together they concluded that it would be interesting to study cell-to-cell variations in growth rate at low doses of antibiotics, particularly whether it would be possible to understand how antibiotic resistance occurs and why some bacteria become resistant while others do not. One of Johan Elf's doctoral students, Özden ‘Ozzy’ Baltekin, was particularly interested in this experiment since he had already developed microflow channels to measure growth rates for many individual bacteria in order to study evolution.
“Already in Ozzy’s first experiment, we could clearly see how antibiotics affect bacteria in just minutes. Above all, the differences between various antibiotics were clearly reproducible. It was obvious that the method’s time resolution for the antibiotic reaction was superior to that of the bacteria themselves”.
Johan and his colleagues immediately realised that it should be possible to perform a rapid diagnostic test to see if the bacteria that have infected a patient are resistant to an antibiotic or not. Above all, it was a simple measurement to perform: an ordinary microscope, a microfluidic plastic chip and some statistics were all that were needed. The fact that the chip is microfluidic means that fluid can pass through in microscopically small channels. A chip contains a total of 4000 channels so small that they each capture one bacterium. Antibiotics are then added to half of the channels and after just a few minutes, it is possible to see if an antibiotic inhibits growth or not. The results, which for the first time demonstrate that an antibiotic resistance test can be done in less than 30 minutes, were published at the end of the summer in the US Journal of the National Academy of Sciences.
But even though researchers can see how fast an antibiotic affects a bacterial cell in the lab, it’s still a complicated pathway to a simple and inexpensive routine test that can help patients at a healthcare centre”, says Johan.
“It’s also a project that’s better suited to run in a company than a university. UU Innovation and UU Holding have provided good help. But without Ove’s support and Ozzy’s enthusiasm, the company would not have become a reality”.
The test is now being developed by the company Astrego Diagnostics AB. Johan Elf is one of the founders but does not work in the venture, unlike the other two: Ove Öhman is CEO and Özden Baltekin Chief Scientific Officer. UU Holding is a partner and the company also managed to attract other investors early on. In total, Astrego has about ten people developing the microfluidic chip and testing it on patient material at healthcare centres. Half of the staff comprise PhDs from Uppsala University and half Uppsala’s biotech industry.
“I hope that Astrego can develop a first user-friendly test for urinary tract infections within a couple of years. Obviously, it is extremely satisfying if we can help patients with antibiotics that have a direct effect at the same time as healthcare can avoid using broad spectrum antibiotics”.
Text: Lisa Thorsén
Besides the Foundation for Strategic Research, Johan Elf’s research team has also received support from the Knut and Alice Wallenberg Foundation, the European Research Council and the Swedish Research Council.