Team:KU Leuven/Description

Project

HEKcite! Inspired by the human heart rhythm, we aim to create an electrophysiological oscillator from eukaryotic cells. Rhythmic contraction of heart cells is coordinated by a small group of cells located in the sinus node, which have an intrinsic frequency of de- and repolarization. This frequency of electrical oscillation is influenced by environmental parameters as well as certain molecular substrates. The oscillator that we aim to create consists of genetically modified excitable Human Embryonic Kidney (HEK) cells, altered to contain the intrinsic pacemaker ability found in sinus cells. As witnessed in heart cells, the rhythm would be dependent on substrate-activated ion channels in the membrane. As there is a great variety of ion channels available in nature, the oscillator could be modified to measure concentrations of many specific substrates. By integrating a certain ion channel into the oscillating system, specificity for a substrate can be chosen. Building an electrical oscillator from cells has several advantages. Intra- or extracellular changes that influence the conductance of ion channels in the membrane have an immediate impact on the frequency of oscillation. Once these cells are connected to each other (by for example gap-junctions), they generate an electrical signal that can easily be measured from a distance and non-invasively—similar to the way electrocardiography (ECG) and electroencephalography (EEG) measure electrical activity in the heart and brain. A multi-purpose sensor suitable for this system could be developed for medical and biotechnological applications. One such application is the measurement of drugs that interact with ion channels, such as antipsychotics, anti-epileptics or a certain class of immunosuppressants.

Professor Diethard Monbaliu MD, PhD

Professor Monbaliu is a reputable abdominal transplant surgeon, at the department of microbiology and immunology at UZ Leuven. He is also responsible for a course on topographical and radiological anatomy and supervises several thesis students.

Professor Monbaliu confirmed our suspicion that there is a need for a more dynamic measurement. In addition, he suspects that it could lead to a better evaluation of patients’ compliance. Together, these advances could result in fewer transplant rejections. He has also brought our attention to a novel and more prevalent immunosuppressant drug, tacrolimus. Finally, he mentioned that patient variability is an issue in his field, and that our device should take this into account. Want to learn more? Press for more details.

Before this meeting, we were investigating the immunosuppressant cyclosporine, as we thought this compound was commonly used after transplantations in order to reduce the chance of rejection. However, professor Monbaliu clarified that this is no longer the case. Instead, he brought our attention to the compound tacrolimus, which has taken cyclosporine’s place in transplantation medicine. Both drugs have the same mode of action, but tacrolimus has a better clinical outcome and less side effects. We were interested in using this novel drug for our research, but unfortunately, the compound is too expensive for us to use. Therefore, considering our financial situation and the input of the professor, we chose to use cyclosporine in our experiments.

Lastly, according to professor Monbaliu, a possible reduction of blood sampling could be a great advantage. However, he mentioned that every patient is different, which means that finding the optimal concentration of immunosuppressant for each patient could a challenge. As a result, our device should be calibrated individually for every patient. Together with professor Monbaliu, we suspect that the individual differences and the problems that go with them could be assessed during clinical studies. As soon as different patients and their different values can be assembled, it can lead to the procedures needed to determine the optimal drug concentration and calibrate our device.

Professor Chris Bervoets MD, PhD

Professor Chris Bervoets is a psychiatrist. He is responsible for the department of transcranial magnetic stimulation, the department of deep brain stimulation and the department of compulsive disorders within the UPC (University Psychiatric Center) of KU Leuven. Additionally, he conducts research on neuromodulatory treatments for various psychiatric disorders.

While investigating different branches in medicine that could benefit from improved therapeutic drug monitoring, our attention was drawn to psychiatry. In this field, there are several drugs, for example lithium, that affect ion channels and could therefore be measured directly by our system. These aspects spiked our interest, and to learn more we contacted the specialist professor Chris Bervoets, who gave us some valuable insights in the difficult world of psychiatry.

After explaining our project, professor Bervoets shared his enthusiasm about the possible advantages of our device. He mentioned three ways in which HEKcite could further shape the field of psychiatry.

First of all, he described the current problems concerning treatments using dopamine antagonists. These dopamine antagonist are blockers of the so-called dopamine receptors, and are used for a wide range of psychologic disorders, among which are depression, psychosis, and many more. At present, researches lack detailed information about the correct dosage of these dopamine antagonists: The amount of receptors that have to be occupied to achieve a certain clinical effect is not yet known. In some cases, doctors see a more favourable clinical outcome when patients take dopamine antagonists irregularly, while for other patients, this is not the case. Therefore, a better understanding of how the correct dosage correlates with dopamine receptor occupancy could be extremely valuable.

Nowadays, this occupancy can only be measured using expensive PET scans. If we could find a way to insert the dopamine receptor in our HEKcite cells and genetically design a correlation of the electric rhythm and the occupancy of the receptors, it could generate valuable information concerning different drug concentrations and their corresponding receptor occupancies. Not only would this measurement be less expensive than a PET scan, it would also provide a more dynamic measurement of the receptor occupancy, which could result in additional insights in dopamine antagonist metabolism.

Furthermore, Chris Bervoets told us about a novel way of clinical assessment, called the experience sampling method (ESM). Patients are asked to answer ten or more questions a day regarding their emotional status. The answers to these questions are then used to improve diagnosis or foresee psychotic episodes. Professor Bervoets suggests that our device could complement this method by combining the answers of the patients with the exact drug concentrations at a certain time. This could lead to a better comprehension of the connection between symptoms and drug dosage, and help further treatments.

Finally, professor Bervoets mentioned safety monitoring, which was our original motivation to investigate the field of psychiatry. With our device, we could verify the concentration of certain drugs that only have a small therapeutic range in which they are effective. Furthermore, Professor Bervoets explained to us that lithium may cause side effects even in the right doses. As a result, many patients visit the hospital unnecessarily. Our device could prevent these avoidable hospital visits by reassuring the patient that the experienced symptoms are due to a benign lithium intoxication. On the other hand, it could also warn the patients when their lithium concentrations are dangerously high and a hospital visit is required.

After discussing these interesting possibilities for our project, we asked professor Bervoets if he thinks whether patients would accept to undergo the implantation of a small device. He suspects that our project would most likely only reach a select group of patients. For instance, patients who experience severe symptoms are often treated by transcranial magnetic stimulation and are used to medical interventions. This group of patients would not mind a minor subcutaneous implantation, if this would decrease their symptoms. Additionally, our device could help determine which drug is most suitable for a patient and optimise doses to reduce side effects.

To conclude, professor Bervoets confirmed our speculations that therapeutic drug monitoring is important in psychiatry. Furthermore, he opened our eyes to other potential applications of HEKcite in this branch of medicine and research. We are very interested in investigating the correlation of ESM and drug concentrations and the possibilities of developing a system to analyse dopamine antagonists. However, due to time and resource constraints, we have to remain focussed on therapeutic drug monitoring. Thanks to professor Bervoets’ enthusiasm about the project and the possible applications, we have become even more motivated to investigate the possibilities of safety monitoring, and believe it could bring science and medicine a substantial step closer towards solving important problems in psychiatry.

Professor Wim Van Paesschen MD, PhD

Professor Wim Van Paesschen is a neurologist specialized in epilepsy. He also is head of the epilepsy research laboratory of the UZ Leuven, and is a lecturer at the faculty of medicine.

Professor Van Paesschen confirmed that therapeutic drug monitoring is important for anti-epileptic compounds and mentioned the necessity of verifying patient compliance. He was very enthusiastic about the project, and even suggested other possible applications for the HEKcite cells.

As our group focuses on drug monitoring as an application, anti-epileptic drugs seemed to be interesting to research. Therefore, we set a meeting with doctor and neurologist Wim Van Paesschen, who is a specialist in epilepsy. Our goal was to discuss the importance of drug monitoring for patients being treated from epilepsy, and whether the HEKcite project could be useful in this regard.

During the meeting, professor Van Paesschen showed a great deal of excitement and enthusiasm about the project, and assured us that drug monitoring of anti-epileptics is indeed necessary, especially for patients who suffer from severe forms of epilepsy. There have been various attempts to introduce therapeutic drug monitoring for epilepsy patients, but none have been successful so far.

Since the concept of HEKcite mainly relies on different ion channels, professor Van Paesschen advices us to focus on the anti-epileptic compounds that directly influence ion channels, even though they are not the most commonly used. Some examples are retigabine, which opens potassium channels, and ethosuximide, which influences T-type calcium channels. Additionally, he mentions that some anti-epileptics can bind to the blood protein albumin, which hinders their activity. Laboratory tests can only measure the total concentration of anti-epileptics in the blood, and are unable to detect the amount of free, active compound. Using our system, we would measure the concentration of free drugs that are able to interact with the ion channels in vivo, which would be a great advantage.

Furthermore, we asked professor Van Paesschen whether he thinks patients would agree with an inserted monitoring device. He proceeded to say that biosensing is a very interesting and growing field, and that it would be most welcome by patients, due to its simplicity and accuracy. He also mentions that checking patients’ compliance is crucial for epilepsy treatment, and that the HEKcite project could be used to solve that problem.

Last but not least, he gave a few suggestions for other useful applications of the HEKcite project. First of all, he suggested using our system as a form of personalized medicine. By using ion channels that contain the exact mutation present in the patient, we could use our system to verify which drug is most effective for his or her exact condition. Additionally, he mentioned that epilepsy is often the result of multiple mutations in several channels. Our system could study the interactions between the different ion channels and their mutations to further improve the understanding of the mechanisms that can lead to epilepsy.

These examples further illustrate that the project could be used for multiple applications. All in all, the meeting was extremely helpful to us, as he was able to confirm our suspicions that HEKcite could be useful for patients of epilepsy, and shed some more light on the further possibilities within this field.

professor Iemand anders

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