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From the bedside to the bench and back.

The shroud of silence was the most difficult to handle. This is how Nina Khanna from the University Hospital Basel felt in the days just before the NCCR AntiResist was made public. The physician is currently at the forefront of the NCCR. Together with her team, she manages the patient samples without which the project would not move forward.

She almost abandoned all hope, when it took so long for an answer to come. But then in December, when approval for the NCCR AntiResist was granted, all the more was Nina Khanna’s joy. “However, we were initially sworn to secrecy and it wasn’t easy to hide my delight.”The medical doctor and Professor of Infectious Diseases at the University Hospital Basel is responsible for the clinical part of the NCCR. 

Nina Khanna has already been working with the infection biologists from the Biozentrum for several years. This started when Dirk Bumann became the Faculty Representative for her PhD students. Later, joint projects arose, they discussed their work and developed new ideas together. “Since Dirk was very interested in the clinical side of things, I took him on the hospital round with me and showed him which pathogens and resistances cause problems in the clinic,” recalls Nina Khanna. “The great thing about the NCCR is that we can bridge the gap between basic research and clinical work. As a practicing physician, it would be immensely difficult to carry out basic research at the high level achieved at the Biozentrum.” In her opinion, the various disciplines are necessary in order to successfully run such a large and ambitious project. Shared with all in the NCCR, she has a great vision: “To uncover yet unknown targets or discover novel therapies and then to test them in the clinic, that would really be great. We are open as to whether we ultimately find a normal antibiotic treatment, a phage therapy or a way to intervene in bacterial communities.”

Nina Khanna started with her project even before the NCCR was launched, because everything is based on her work. She and her team provide the clinical samples and the data for basic research. They are responsible for bringing other hospitals and partners on board and for coordinating the whole thing. “We take specimens from lung secretions and urine, and take biopsies when patients undergo surgery. It is crucial, that we get the samples directly from the patients to study the environment in which the bacteria survive.” This work requires approval from the Ethics Committee, well-trained staff who are familiar with the exact procedures and know how to collect the samples, and a study nurse who coordinates everything. Nina Khanna also deals with antibiotic resistance in clinical routine. But in comparison with the worldwide epidemiology, such resistance does not occur very frequently at the University Hospital in Basel. Gram-negative bacteria, which are often resistant to many antibiotics, are not a local problem. It is rather patients from abroad who bring the multi-resistant pathogens with them. “We have patients from Thailand, Colombia and the Balkan countries. When they come to us from other hospitals, they also introduce resistant pathogens collected from there,” reports Nina Khanna. “We certainly come into contact with resistant bacteria every week but can successfully treat most infections with a broad spectrum of commonly used antibiotics. In cases of very serious infections, we sometimes have to request emergency antibiotics or new, not yet approved drugs.”

Nina Khanna experiences quite often that patients die from an infection. But this is not due to ineffective antibiotics but rather because the infection is already in a late stage. The pathogen has already spread throughout the patient’s body. Should the germ find its way into the blood circulation, it can lead to circulatory collapse and multiple organ failure, often with a fatal outcome. Especially at risk are individuals with a weakened immune system, including patients who have undergone chemotherapy or a transplantation. And also being elderly, diabetic or having serious injuries from an accident are risk factors for a life-threatening infection.

The Gram-positive bacterium Staphylococcus aureus causes most of the problems in the hospital,” emphasizes Nina Khanna. “It causes persistent infections that we can only manage with surgery. Although the antibiotic itself is effective, an operation is required to reach the site of infection.” Resistant pathogens are also a problem for patients with cystic fibrosis. In this hereditary metabolic disease, the lungs produce viscous mucus, which is a perfect breeding ground for germs. As those affected, often consequently suffer from chronic pulmonary infections, they are frequently treated with antibiotics for extended periods, which in turn promotes the development of resistance.

Basically, most pathogens met in daily hospital life are sensitive to antibiotics. But for patients infected with multi-resistant bacteria special protective measures come into force. “For this, it is of course important to know exactly how the pathogen is transmitted. All these measures lie in the responsibility of the Hospital Hygiene department. In my daily work, I am not concerned about getting infected,” says Nina Khanna. “Considering, however, the current developments in antibiotic resistance, there is no doubt that we urgently need to find new antibiotics. The NCCR is an important step in this direction.»

The Department of Biosystems Science and Engineering of the ETH Zurich in Basel (D-BSSE)  − another important partner in the NCCR AntiResist

Further to the Biozentrum and the University Hospital Basel, the D-BSSE is part of the NCCR core team. The bioengineers at the D-BSSE will apply the knowledge gained by physicians and biologists on the state of pathogens in the infected human body to develop model systems for the examination of bacteria under physiological conditions. With the further development of these laboratory models into high-throughput screening platforms, chemical libraries can then be systematically screened for potential bioactive compounds.

The research groups of Prof. Andreas Hierlemann, Prof. Petra Dittrich and Prof. Karsten Borgwardt are closely involved in this project. Andreas Hierlemann studies complex organ models and combines different organ functions on a chip. For instance, combining micro-tissues from intact liver and a tumor in a fluidic device facilitates studying both the activity and metabolization of anti-cancer drug candidates. His part in the NCCR will be the development and establishment of mini-organ models that simulate the physiological conditions of bacteria in the human lung, bladder and skin. These complex models will help the researchers to better understand how bacteria colonize these tissues and how this affects the efficacy of antibiotics.

Petra Dittrich works with so-called droplet-based microfluidics. This high-throughput method enables the simultaneous testing of a large number of conditions. The tiny droplets can be moved, sorted and analyzed and still remain an intact compartment. Basically, they are small reaction vessels into which substances can be transferred in and out. In these droplets, the researchers can grow bacteria and, for example, study how they respond to certain compounds. Or a collection of bacterial mutants can be treated in parallel to investigate which bacterial components are essential for survival. Ultimately, a whole canon of model systems is needed to identify the Achilles' heel of pathogens.

Clinical data such as the gender and age of patients, comorbidities, whether someone had an accident or surgery, are also analyzed because these parameters can provide information why a person suddenly becomes sick. Karsten Borgwardt from the D-BSSE is an expert in the field of machine learning and artificial intelligence. Using cutting-edge computational analysis, he can make correlations visible that our mind cannot easily recognize.

One of the objectives of the NCCR is to find out what information and what level of complexity is required for the models, on the one hand to be able to test innovative therapeutic approaches with regard to their efficacy, and on the other hand to comprehensively understand the biological processes behind an infection. This will stimulate the entire field of infection biology.