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                     <h1>Human practices</h1>
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In HEKcite we create an oscillating HEK-cell, but for what purpose? Therapeutic drug monitoring is our answer. In the treatment of multiple severe diseases, a stable concentration of drugs is crucial. Steady blood levels determine therapeutic outcomes and increase survival rates. Currently, the most common therapeutic drug monitoring technique is blood sampling. For patients who need lifelong observation, the numerous hospital visits and frequent blood samplings can have a negative effect on the quality of life.
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Therefore, we develop a system that allows patients to determine the level of drugs at home. Furthermore, the ease of these measurements allows for daily or even continuous analysis.</p>
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Using this dynamic data collection instead of the static measurements performed in hospitals today, we might increase both therapeutic outcomes and quality of life of patients. In order to investigate the different views on our projects we talked to specialists in several fields where therapeutic drug monitoring is of great importance: transplantations, psychotics and epileptics. Three specialists have provided insights in how they expect our project will influence the lives of their patients and future treatments. We used this information to further shape our project.
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                     <h1 style="text-align:center; padding: 30px; font-size:50px; color: white;">Human Practices - Silver</h1>
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                     <p class="head" style="text-align:center;color: white; padding: 10px 10px 60px 10px; font-size:15px;" ;>In earlier discussions with specialists, we gained first insights on how our project would influence the treatment of patients. But what do they themselves think of our idea? In order to investigate this, we proposed to invite several patients to discuss our project. However, talking to patients is not something you go over lightly.
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                        After receiving approval from the ethics committee of the UZ Leuven, we planned the overall course of the interviews in detail. The proposed questions were then reviewed by professor Monbaliu, who had already helped us earlier in the project. By performing patient interviews, we have gained insights in the daily lives of patients and learned of their opinions about HEKcite and the device, which would enable them to check the level of drugs (e.g. immune suppressants) continuously. This information helped us frame the impact of our project, allowed us to adapt the project to patients’ needs and could be interesting for future stakeholders.
 
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                                 <h3>Professor Diethard Monbaliu</h3>
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                                 <p>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.</p>
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                            <h2>Epilepsy:<br> Patient interview</h2>
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                            <p class="head">During the interview, both the patient and her parents were present. All the questions were answered by the parents, since the patient is a 43-year-old woman who not only has daily seizures caused by severe epilepsy, but who also has a mental disability. Both parents are very active within IKAROS, a subgroup of the Epilepsy Liga. Within this organisation, they are in contact with several epilepsy patients and try to support and listen to as many patients as possible which gives them an overview of not only their own situation but also the lives of many other patients.</p>
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                                        <h3>Question 1: What is your experience using anti-epileptics?</h3>
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                                    <p style="text-align:justify">Their biggest challenge was finding the correct combination of drugs that reduced the amount of seizures. Most of the medicine they tried were not effective which means that new drugs had to be introduced and non-effective drugs had to be reduced. The changes of these dosages appeared to be dangerous, since this could substantially increase the amount of seizures their daughter experienced. These seizures could harm her not only because she could fall down but also because of the danger of Sudden Unexpected Death in Epilepsy (SUDEP). Additionally, these changes go together with several side effects such as weight gain, hair loss and problems with teeth and gums. However, they consider themselves lucky regarding the side effects, and when a stable drug concentration is eventually reached and no further dosage changes have to be implemented, the side effects disappear. </p>
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                                 <p>Professor Monbaliu confirmed our expectations 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.</p>
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                                        <h3>Question 2: Are there blood samples taken on a regular basis? If yes, would you like to see a decrease of the amount of blood samples that needs to be drawn?</h3>
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                                    <p style="text-align:justify; padding:-10px">When a stable dosage is reached and the medication is effective only one blood sample per year is drawn. This is not the case when drug dosages have to be increased or decreased, then more blood samples are needed. However, the parents do not see this as a discomfort for their daughter who has become used to the procedure. They also mentioned that nowadays the change of medicines is not strictly based on blood concentrations but is now more influenced by clinical symptoms such as a change in quality of life.</p>
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                            <p>After this question, we explained that it is important that blood levels of anti-epileptics remain constant. Our goal is to develop an easy method that enables patients to test their anti-epileptics concentration at home, at any given time. This would lead to a better follow-up, and would allow the doctors to react to unexpected changes in concentration that would otherwise remain undetected. This way, the amount of seizures could be reduced.</p>
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                                        <h3>Question 3: In which way do you think this device could influence your quality of life?</h3>
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                                    <p style="text-align:justify">Both parents agreed that our project could have an impact on both their daughter’s quality of life and theirs. Their daughter cannot take decisions regarding her disease herself. This means that her parents manage her illness. This responsibility is accompanied by a feeling of powerlessness and helplessness since they witness their daughter’s seizures and battles but they are not directly able to help. Our device could give them more control and insight in the different events taking place. As they said it themselves: “It would give us the feeling we can do something.”</p>
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                            <p>In order to do these daily measurements, a small device would be placed under the skin, containing living, genetically modified cells that respond to the concentration in the blood.</p>
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                                        <h3>Question 4: Would you be willing to undergo this procedure if this could lower the amount of seizures? What is your opinion about the device containing genetically modified cells?</h3>
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                                    <p style="text-align:justify">For them, everything that could help their daughter would be welcomed with open arms. Out of their experience within IKAROS and the different patients they have contact with, many of them are still searching for a way to reduce the amount of seizures and would try everything to achieve this. However, every patient has to make a compromise and accept that a minimum amount of seizures is unavoidable. This depends from person to person but many are still waiting for new solutions. </p>
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                                    <p style="text-align:justify">They have no objection to the fact that the device contains genetically modified cells, they look at these applications as the future. For them, the fact that this could improve life quality is more than enough.</p>
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                                        <h3>Question 5: Would you be willing to participate in a clinical study to assess this device if you do not know if it could lower the risk of seizures?</h3>
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                                    <p style="text-align:justify">They already participated in several clinical studies and are very compliant to try new possible solutions. The only thing that counts for them is that their daughter feels good and that she is not bothered by it.</p>
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                                        <h3>Question 6: Do you have problems with drug compliance? The device could alert you when you have not given the drugs yet by sending out notifications. Do you think this could be a helpful reminder for you when you forget to give their medicine or be helpful for giving their medicine at the same time on a daily basis?</h3>
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                                    <p style="text-align:justify">It does not happen often but they do sometimes forget giving their daughter her drugs even when they have multiple alarms set in their phone and around the house. Next to this, they themselves observed that patient compliance is inadequate in adolescents with epilepsy. They are often tired of taking their medicines and do not feel that the drugs actually help. This can seem harmless, but not taking your drugs or taking the drugs irregularly is the main cause of SUDEP. This is why our device could be a good stimulus for patients with poor compliance since they would actually see on their phone or computer that their drug level is too low. </p>
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                                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. </p>
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                                 <p>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.
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                        <h2>Organ Transplantation:<br> Patient interviews</h2> <div class="img"><img src="https://static.igem.org/mediawiki/2017/a/ac/Transplantation_HP_integrated_gold.svg"></div><img src="https://static.igem.org/mediawiki/2017/e/ef/HEKje_krijgt_orgaan.svg" style=" position: absolute; width: 25%; margin: -67px 0 102px -35px;;">
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                        <p class="head">Introduction about our team and an explanation about the iGEM competition.</p>
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                                    <h3>Question 1: What is your experience using immune suppressants?</h3>
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                                 <p style="text-align:justify">All participants have the same answer: There is more to organ transplantation than meets the eye. After the surgery, not all problems are solved as you would expect, but new ones arise. Some of these issues are side effects, caused by immune suppressants. Among the most frequent side effects are insomnia, easy bruising and bleeding, a tingling sensation on the skin, infection of the joints, et cetera…</p>
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                                <h3>Professor Chris Bervoets</h3>
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                                    <h3>Question 2: Would you like to see a decrease of the amount of blood samples that needs to be drawn?</h3>
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                                 <p>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.</p>
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                                 <p>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.</p>
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                                 <p style="text-align:justify">Most participants answered that they experience only mild discomfort from drawing blood. This is explained by the fact that blood drawings serve many purposes: When the participants go to medical consultations for blood drawings, the concentration of immune suppressants is just one of many variables analysed. This means that our device would most likely not reduce the total number of hospital sessions and the discomfort of blood drawing. This raises the question whether the device would be helpful for transplant patients. Luckily, this question was answered in the continuation of the interview.</p>
 
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                         <p>After this question, we explained that it is important that blood levels of immune suppressants remain constant. Currently, blood samples are taken every week or in intervals of up to three months, dependent on the amount of time that has passed since the transplantation. Our goal is to develop an easy method that enables patients to test their immune suppressants at home, at any given time. This would lead to a better follow-up, and would allow the doctors to react to unexpected changes in concentration that would otherwise remain undetected. This way, the risk of organ rejection will be reduced.</p>
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                                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.  </p>
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                                <p>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.  
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                                    <h3>Question 3: In which way do you think this device could influence your quality of life?</h3>
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<p>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.</p>
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<p>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. </p>
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<p>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.</p>
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<p>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.</p>
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                                <p style="text-align:justify">Despite the fact that all patients agreed that our project could increase their quality of life, the opinions on how it would affect their lives differed among the patients. Some of them think it would influence their life in a positive way as it could offer them piece of mind. Risk of rejection by the body increases as more time passes, and by then, most patients only visit the doctor once every three months. Therefore, they think the possibility of checking the level of immune suppression on a daily basis would give them comfort and reduce their stress levels, and it would also enable the doctors to react quickly to changes that would otherwise remain undetected for three months. Others shared the opinion that, while our project would not influence their lives directly, they think that our device could be a general advance in the organ transplantation field. When the risk of rejection of an organ could be lowered, this would ease their mind indirectly. Hearing from patients that this device could have an impact on their lives motivated us even further to complete our project successfully.</p>
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<p>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.</p>
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                        <p>In order to do these daily measurements, a small device would be placed under the skin, containing living, genetically modified cells that respond to the concentration in the blood.</p>
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                                 <h3>Professor Wim Van Paesschen</h3>
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                                    <h3>Question 4: Would you be willing to undergo this procedure if this could lower your risk of rejection? What is your opinion about the device containing genetically modified cells?</h3>
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                                 <p>Professor doctor Wim Van Paesschen is a neurosurgeon specialized in epilepsy. He also is head of the epilepsy research laboratory, part-time teaches at the faculty of medicine and supervises thesis students.</p>
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                                 <p>Professor Van Paesschen confirmed that therapeutic drug monitoring is necessary for anti-epileptics and mentioned the importance of verifying patient compliance. He also showed us that our project has more potential than even we imagined by giving some more examples of possible applications.</p>
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                                 <p style="text-align:justify">All responses of the patients were positive. They were indeed willing to undergo the procedure if this could lower the risk of rejection of the transplanted organ. A crucial consideration is that the device would be placed during the transplantation process. Most patients were tired of the various medical interventions, and would like to avoid undergoing surgeries that were not strictly necessary, as they inflict a lot of pain and are a cause of frustrations. </p>
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                                <p style="text-align:justify">When asked about the genetically manipulated cells in the device, all patients reacted positively. As long as they are given sufficient information and are made aware of all the consequences and risks that result from the genetic manipulation, they would be willing to use the device.</p>
 
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                                In light of our group focusing on drug monitoring as our target for human practices, anti-epileptic drugs seemed to be a quite interesting to research. Given that, we set a meeting with Doctor/Neurologist Wim Van Paesschen, a specialist in epilepsy. Prior to the meeting, our main interest was figuring out if drug monitoring was in fact needed for patients being treated from epilepsy, and it case it was, how could the concept of HEKcite come in handy for said patients. During the meeting, Prof. Van Paesschen showed a great deal of excitement and enthusiasm about the concept of HEKcite, assuring us that drug monitoring of anti-epileptics is indeed necessary, especially for patients suffering severe forms of epilepsy. There have been already various attempts to implement drug monitoring in epilepsy patients but none were quite successful. Since the concept of HEKcite mainly relies on different ion channels, his advice wasn’t to necessarily work with the most used anti-epileptics, but instead focus on those directly linked to the ion channels we are working with. Some of those include: Retigabine which opens potassium channels or ethosuximide which influences T-type calcium channels. Furthermore, some epileptics bind partially to albumin which hinders their activity. Nowadays laboratory tests can only measure the total concentration of anti-epileptics in the blood and not only the free, active concentration. Our system would be able to distinguish between the free, active versus the bound, non-active drug compounds. Another crucial point that was discussed during the meeting was what the patients would think/react to idea of an inserted monitoring device. He proceeded to say that field of “biosensors” is now a very interesting, growing field, and due to its simplicity and accuracy, it would be most welcome by patients. Prof. Van Paesschen was also so helpful, shedding light on a very important matter related to drug monitoring, that is, checking patients’ compliance. He mentioned how that is such a big problem especially with epilepsy patients, and that HEKcite could also be used to solve that problem. Last but not least, he gave a few suggestions for other useful applications that HEKcite could be used for. First of all he gave the idea of using our system as a form of personalized medicine. By using ion channels who contain the exact mutation of the patient, we could use our system to verify which drug is most effective specifically for the mutated channel of the patient. Next to this, he mentioned that epilepsy is often the result of multiple mutations in multiple channels. Our system could study the interactions between different ion channels and their mutation to further understand the mechanisms that can lead to epilepsy. These examples of the professor show again the diversity of our project and the great range of possible applications. All in all, the meeting was extremely helpful to us. We were able to leave the meeting with an answer to our original inquiry, that is, if the concept of HEKcite could be useful with patients with cases of epilepsy. We were also able to realize the full potential of the project and its various applications, giving us extra motivation and drive to move forward with our human practices.
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                                    <h3>Question 5: Would you be willing to participate in a clinical study to assess this device during a case in which you do not know if this could lower the risk of rejection?</h3>
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                                <p style="text-align:justify">The interviewed patients told us they would like to help scientific advances to improve the lives of future transplantation patients. Some of them mention that they have already participated in clinical studies in the past, and indicate that they are open to new developments. Therefore, two of the four patients would be willing to participate if a trusted transplantation doctor, such as professor Monbaliu, supported the study. The other two patients were more hesitant and they would only consider participating in case the risks were minimal and well known.</p>
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                                <h3>professor Iemand anders</h3>
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                                    <h3>Question 6: According to professor Monbaliu, patient compliance is a problem in the organ transplantation field, especially some years after the surgery. The device could alert you when you have not taken your drugs yet by sending out notifications. Do you think this could be a helpful reminder for you when you forget to take your medicine or be helpful for taking your medicine at the same time on a daily basis?</h3>
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                                 <p style="text-align:justify">The patients we talked to have received their transplants 2 to 7 years ago. However, they all told us that they have never forgotten to take their drugs, and this is no issue for them. However, the immune suppressants have to be taken at specific time points. The patients admitted that, as more time passed after the organ transplantation, they tended to take their drugs at less specific time points. These inaccuracies occur especially on holidays or special occasions, as it is difficult to take a medicine at the exact same time every day. Therefore, the patients see our device as a useful system, as it could give out a notification on their computer or smartphone.</p>
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                    <h1 style="text-align:center; padding: 30px; font-size:50px; color: white;">Ethics</h1>
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                    <p class="head" style="text-align:center;color: white; padding: 10px 10px 60px 10px; font-size:15px;" ;>When our team was assembled and we started brainstorming about our project, we already appointed several persons as our ethics team. They had to try and keep an eye on the different topics we were focusing on and steer us in the more ethical direction. After our definitive project was chosen, the ethical work was far from done. What we, as a team, thought to be ethical might not be received as ethical by other experts or the general public. That is why we decided to go one step further and we addressed different ethical specialists. However, we wanted to incorporate different perspectives and not only the view of biotechnological companies. This is how, we started our search for spokesmen who could give us more insight in the ethics of our project but also in the more general ethical view on genetically modified organisms. </p>
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                    Our first meeting was with René Custers who is a regulatory and responsible research manager at VIB. VIB stands for Vlaams Instituut voor Biotechnologie, it is an important Flemish institution that conducts research in biotechnology and is an important partner of different companies and Flemish universities. René Custers helped us by giving us several important questions we should consider before proceeding with our project.
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                <li>-      HEK cells originated from an aborted human embryo, is this ethically correct?</li>
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                <li>-      HEK cells were immortalized with different adenovirus genes, what would be the effect if these cells were introduced into the body?</li>
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                <li>-      Is it ethical correct to gain money from widely used cells in research such as HEK cells?</li>
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                <li>-      Would we need to test our device in animals before starting clinical studies?</li>
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                <li>-      How invasive is our device? Resembles it the implantation of a pacemaker or does it come close to cell therapy?</li>
 +
                    </ul></p>
 +
 +
            <p style="text-align:justify;">
 +
            All these questions seemed very relevant to us which is why we decided to do a small ethical debate within the team. This debate made us more aware of the different difficulties that go together with research in general but also specifically the ones regarding HEKcite. We based the debate on the different questions we received from René Custers, every question was asked one by one and every team member was allowed to give his/her viewpoint about the topic.</p>
 +
            <br>
 +
            <br>
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                          HEK cells originated from an aborted human embryo, is this ethically correct?
 +
                    </p>
 +
                    The whole team was quite level-headed regarding this question, we all agreed that using these cells should be allowed. For instance, HEK cells helped in answering many scientific questions that could might have remained unanswered if these cells were never used. However, there are strict regulations needed before using cells from human embryos is ethically correct. First of all, we all thought that consent from the mother was of utmost importance. Next to this, anonymity of the origin of the cells should be guarded at all times which protects the mother from possible discoveries in the embryo’s DNA and from possible societal reactions to her decision.
 +
                    <br>
 +
                    <br>
 +
                    <p class="border text" style="font-size:medium; text-align:center;">
 +
                    HEK cells were immortalized with different adenovirus genes, what would be the effect if these cells were introduced into the body?
 +
                    </p>
 +
                    This question was not answered by the team but by Bernard Schneider who gave us valuable information regarding the encapsulation device. He notified us that HEK cells are not allowed to be introduced into the human body for the main reason that they are immortalized with adenovirus genes. HEK cells in our capsule could become infected with adenovirus, if the adenovirus genes already present within the HEK cells come in contact with the infectious adenovirus, the possible consequences are not yet known. We as a team fully support that decision which is why we did more research about other cell types that can be used in the capsule. (link naar encapsulation text?)
 +
                    <br>
 +
                    <br>
 +
                    <p class="border text" style="font-size:medium; text-align:center;">
 +
                    Is it ethical correct to gain money from widely used cells in research such as HEK cells?</p>
 +
 +
                    This question was answered by René Custers himself, he said that it has recently been approved to patent findings with HEK cells or other commonly used cells. The team supports this decision since we know that patents are crucial to stimulate innovation. Genetic modification and synthetic biology are the future which means that using certain cell types for genetic modification has to be allowed.
 +
                    <br>
 +
                    <br>
 +
                    <p class="border text" style="font-size:medium; text-align:center;">
 +
                    Would we need to test our device in animals before starting clinical studies?</p>
 +
                    Again, the whole team agreed, we would use biocompatible materials that are already extensively researched in clinical studies and animal testing. However, we think safety studies in animals are of great importance to verify the effect of the cells on the body if they could escape the confinements of the capsule.
 +
                    <br>   
 +
                    <br>
 +
                    <p class="border text" style="font-size:medium; text-align:center; text-align:justify">
 +
                    How invasive is our device? Resembles it the implantation of a pacemaker or does it come close to cell therapy?</p>
 +
                    On this topic, the team did not quite agree, some members thought it resembled the implantation of a pacemaker while others thought it leaned more towards cell therapy. The biggest concern was: what if the capsule breaks and cells enter the body? Every team member agreed that first research had to be conducted to establish the possible consequences. However, some of them agreed that if this appeared to be safe, our capsule would more resemble a pacemaker. While other members were of the opinion that if indeed cells escaping was not dangerous, these were still genetically modified cells. In the end, we did not come to a consensus. Not reaching this consensus was not regarded as a negative point but as something we can still learn from. Using genetically modified cells in medicine is a difficult topic were ethics and science have to go hand in hand to determine the new way forward.
 
             </div>
 
             </div>
 +
           
 +
            <br>
 +
            <br>
 +
            <p style="text-align: justify">
 +
            After this ethical debate, we were more determined to dig a little deeper into the world of ethics but also look at the different regulatory processes needed to start a clinical study. This is why we scheduled an appointment with the ethical committee of the university hospital of Leuven. The ethical committee gave us more information about the different juridical and regulatory procedures needed to start a clinical study, if you want to read more see below. On the other hand, they also gave us some more aspects we could think about. Such as the benefit-risk analysis, you should always keep in the back of your mind. It is important that patients always receive more benefit from the capsule than they are in risk of different complications. We did think about the complications such as the breaking of the capsule, infection or possible wrong read-outs. However, the ethical committee also pointed us in the direction of the psychological effect of our device. Some patients may find it beneficial to have more control regarding their illness but this may have the opposite effect on others. Patients could experience difficulties with having this much control or maybe would not like to know about their physical status every moment of every day. This made us think about the fact that with our device also an important psychological assessment should be made. The benefit should always exceed the risk and this is the psychical risk as well as the psychological risk.
 +
            <br>
 +
            <br>
 +
   
 +
            After our meetings with the René Custers and the ethical committee, we assessed the information we already received and the different angels we received it from. René Custers gave us some more insight in the ethical view of a biotechnological company while the ethical committee gave us the viewpoint of a hospital. We felt that another important perspective was missing: the government. After sending various e-mails to a wide range of authorities, we were able to schedule a meeting with Johan Hanssens, the secretary-general of the department of economy, science and innovation in Flanders.
 +
            <br>
 +
            <br>
 +
   
 +
            Johan Hanssens was able to give us more insight in the role of the government regarding genetically modified organisms. However, he told us that in Belgium the ethical decisions were mostly made by the different institutions and hospitals themselves. When it comes to regulatory decisions all of these are made by the European Union and are eventually implemented in the Belgian law. Momentarily Europe is very focused on responsible research and innovation, RRI. This new form of research implements the opinions of the different stakeholders such as doctors and patients in very early stages of research, to ensure that the conducted research has societal relevance. Johan Hanssens told us that Belgium as well as Flanders are searching for a way to have a more global body that could oversee the different ethical questions that are now overseen by the different hospitals and institutions themselves. Which means that the ethical debate could be done in a more structural and global way to ensure that Flanders and Belgium react in a unified way concerning difficult but also important topics regarding genetically modified organisms.
 +
            <br><br>
 +
   
 +
            A biotechnology company, a hospital and the Flemish government, three different meetings and three different perspectives on genetically modified organisms. We, as the KU Leuven team, were very honoured to be able to hear these different perspectives and have the possibility to integrate these angles into our research: from different ethical questions, regulatory necessities from the ethical committee to RRI from the European Union. We discussed the different ethical questions given to us by René Custers in an ethical debate, we did research about the regulatory conditions to start clinical studies and by talking to doctors and patients we tried to do RRI as suggested by the European Union. All these aspects made not only our science more valuable but also taught the team that science is not something that stands alone but is also determined by the needs of society and that we have the honour to answer to those needs.
 +
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Latest revision as of 00:09, 2 November 2017


Human Practices - Silver

In earlier discussions with specialists, we gained first insights on how our project would influence the treatment of patients. But what do they themselves think of our idea? In order to investigate this, we proposed to invite several patients to discuss our project. However, talking to patients is not something you go over lightly.
After receiving approval from the ethics committee of the UZ Leuven, we planned the overall course of the interviews in detail. The proposed questions were then reviewed by professor Monbaliu, who had already helped us earlier in the project. By performing patient interviews, we have gained insights in the daily lives of patients and learned of their opinions about HEKcite and the device, which would enable them to check the level of drugs (e.g. immune suppressants) continuously. This information helped us frame the impact of our project, allowed us to adapt the project to patients’ needs and could be interesting for future stakeholders.

Epilepsy:
Patient interview

During the interview, both the patient and her parents were present. All the questions were answered by the parents, since the patient is a 43-year-old woman who not only has daily seizures caused by severe epilepsy, but who also has a mental disability. Both parents are very active within IKAROS, a subgroup of the Epilepsy Liga. Within this organisation, they are in contact with several epilepsy patients and try to support and listen to as many patients as possible which gives them an overview of not only their own situation but also the lives of many other patients.

Question 1: What is your experience using anti-epileptics?

Their biggest challenge was finding the correct combination of drugs that reduced the amount of seizures. Most of the medicine they tried were not effective which means that new drugs had to be introduced and non-effective drugs had to be reduced. The changes of these dosages appeared to be dangerous, since this could substantially increase the amount of seizures their daughter experienced. These seizures could harm her not only because she could fall down but also because of the danger of Sudden Unexpected Death in Epilepsy (SUDEP). Additionally, these changes go together with several side effects such as weight gain, hair loss and problems with teeth and gums. However, they consider themselves lucky regarding the side effects, and when a stable drug concentration is eventually reached and no further dosage changes have to be implemented, the side effects disappear.


Question 2: Are there blood samples taken on a regular basis? If yes, would you like to see a decrease of the amount of blood samples that needs to be drawn?

When a stable dosage is reached and the medication is effective only one blood sample per year is drawn. This is not the case when drug dosages have to be increased or decreased, then more blood samples are needed. However, the parents do not see this as a discomfort for their daughter who has become used to the procedure. They also mentioned that nowadays the change of medicines is not strictly based on blood concentrations but is now more influenced by clinical symptoms such as a change in quality of life.

After this question, we explained that it is important that blood levels of anti-epileptics remain constant. Our goal is to develop an easy method that enables patients to test their anti-epileptics concentration at home, at any given time. This would lead to a better follow-up, and would allow the doctors to react to unexpected changes in concentration that would otherwise remain undetected. This way, the amount of seizures could be reduced.

Question 3: In which way do you think this device could influence your quality of life?

Both parents agreed that our project could have an impact on both their daughter’s quality of life and theirs. Their daughter cannot take decisions regarding her disease herself. This means that her parents manage her illness. This responsibility is accompanied by a feeling of powerlessness and helplessness since they witness their daughter’s seizures and battles but they are not directly able to help. Our device could give them more control and insight in the different events taking place. As they said it themselves: “It would give us the feeling we can do something.”

In order to do these daily measurements, a small device would be placed under the skin, containing living, genetically modified cells that respond to the concentration in the blood.

Question 4: Would you be willing to undergo this procedure if this could lower the amount of seizures? What is your opinion about the device containing genetically modified cells?

For them, everything that could help their daughter would be welcomed with open arms. Out of their experience within IKAROS and the different patients they have contact with, many of them are still searching for a way to reduce the amount of seizures and would try everything to achieve this. However, every patient has to make a compromise and accept that a minimum amount of seizures is unavoidable. This depends from person to person but many are still waiting for new solutions.

They have no objection to the fact that the device contains genetically modified cells, they look at these applications as the future. For them, the fact that this could improve life quality is more than enough.


Question 5: Would you be willing to participate in a clinical study to assess this device if you do not know if it could lower the risk of seizures?

They already participated in several clinical studies and are very compliant to try new possible solutions. The only thing that counts for them is that their daughter feels good and that she is not bothered by it.


Question 6: Do you have problems with drug compliance? The device could alert you when you have not given the drugs yet by sending out notifications. Do you think this could be a helpful reminder for you when you forget to give their medicine or be helpful for giving their medicine at the same time on a daily basis?

It does not happen often but they do sometimes forget giving their daughter her drugs even when they have multiple alarms set in their phone and around the house. Next to this, they themselves observed that patient compliance is inadequate in adolescents with epilepsy. They are often tired of taking their medicines and do not feel that the drugs actually help. This can seem harmless, but not taking your drugs or taking the drugs irregularly is the main cause of SUDEP. This is why our device could be a good stimulus for patients with poor compliance since they would actually see on their phone or computer that their drug level is too low.



Organ Transplantation:
Patient interviews

Introduction about our team and an explanation about the iGEM competition.

Question 1: What is your experience using immune suppressants?

All participants have the same answer: There is more to organ transplantation than meets the eye. After the surgery, not all problems are solved as you would expect, but new ones arise. Some of these issues are side effects, caused by immune suppressants. Among the most frequent side effects are insomnia, easy bruising and bleeding, a tingling sensation on the skin, infection of the joints, et cetera…


Question 2: Would you like to see a decrease of the amount of blood samples that needs to be drawn?

Most participants answered that they experience only mild discomfort from drawing blood. This is explained by the fact that blood drawings serve many purposes: When the participants go to medical consultations for blood drawings, the concentration of immune suppressants is just one of many variables analysed. This means that our device would most likely not reduce the total number of hospital sessions and the discomfort of blood drawing. This raises the question whether the device would be helpful for transplant patients. Luckily, this question was answered in the continuation of the interview.

After this question, we explained that it is important that blood levels of immune suppressants remain constant. Currently, blood samples are taken every week or in intervals of up to three months, dependent on the amount of time that has passed since the transplantation. Our goal is to develop an easy method that enables patients to test their immune suppressants at home, at any given time. This would lead to a better follow-up, and would allow the doctors to react to unexpected changes in concentration that would otherwise remain undetected. This way, the risk of organ rejection will be reduced.

Question 3: In which way do you think this device could influence your quality of life?

Despite the fact that all patients agreed that our project could increase their quality of life, the opinions on how it would affect their lives differed among the patients. Some of them think it would influence their life in a positive way as it could offer them piece of mind. Risk of rejection by the body increases as more time passes, and by then, most patients only visit the doctor once every three months. Therefore, they think the possibility of checking the level of immune suppression on a daily basis would give them comfort and reduce their stress levels, and it would also enable the doctors to react quickly to changes that would otherwise remain undetected for three months. Others shared the opinion that, while our project would not influence their lives directly, they think that our device could be a general advance in the organ transplantation field. When the risk of rejection of an organ could be lowered, this would ease their mind indirectly. Hearing from patients that this device could have an impact on their lives motivated us even further to complete our project successfully.

In order to do these daily measurements, a small device would be placed under the skin, containing living, genetically modified cells that respond to the concentration in the blood.

Question 4: Would you be willing to undergo this procedure if this could lower your risk of rejection? What is your opinion about the device containing genetically modified cells?

All responses of the patients were positive. They were indeed willing to undergo the procedure if this could lower the risk of rejection of the transplanted organ. A crucial consideration is that the device would be placed during the transplantation process. Most patients were tired of the various medical interventions, and would like to avoid undergoing surgeries that were not strictly necessary, as they inflict a lot of pain and are a cause of frustrations.

When asked about the genetically manipulated cells in the device, all patients reacted positively. As long as they are given sufficient information and are made aware of all the consequences and risks that result from the genetic manipulation, they would be willing to use the device.


Question 5: Would you be willing to participate in a clinical study to assess this device during a case in which you do not know if this could lower the risk of rejection?

The interviewed patients told us they would like to help scientific advances to improve the lives of future transplantation patients. Some of them mention that they have already participated in clinical studies in the past, and indicate that they are open to new developments. Therefore, two of the four patients would be willing to participate if a trusted transplantation doctor, such as professor Monbaliu, supported the study. The other two patients were more hesitant and they would only consider participating in case the risks were minimal and well known.


Question 6: According to professor Monbaliu, patient compliance is a problem in the organ transplantation field, especially some years after the surgery. The device could alert you when you have not taken your drugs yet by sending out notifications. Do you think this could be a helpful reminder for you when you forget to take your medicine or be helpful for taking your medicine at the same time on a daily basis?

The patients we talked to have received their transplants 2 to 7 years ago. However, they all told us that they have never forgotten to take their drugs, and this is no issue for them. However, the immune suppressants have to be taken at specific time points. The patients admitted that, as more time passed after the organ transplantation, they tended to take their drugs at less specific time points. These inaccuracies occur especially on holidays or special occasions, as it is difficult to take a medicine at the exact same time every day. Therefore, the patients see our device as a useful system, as it could give out a notification on their computer or smartphone.

Ethics

When our team was assembled and we started brainstorming about our project, we already appointed several persons as our ethics team. They had to try and keep an eye on the different topics we were focusing on and steer us in the more ethical direction. After our definitive project was chosen, the ethical work was far from done. What we, as a team, thought to be ethical might not be received as ethical by other experts or the general public. That is why we decided to go one step further and we addressed different ethical specialists. However, we wanted to incorporate different perspectives and not only the view of biotechnological companies. This is how, we started our search for spokesmen who could give us more insight in the ethics of our project but also in the more general ethical view on genetically modified organisms.

Our first meeting was with René Custers who is a regulatory and responsible research manager at VIB. VIB stands for Vlaams Instituut voor Biotechnologie, it is an important Flemish institution that conducts research in biotechnology and is an important partner of different companies and Flemish universities. René Custers helped us by giving us several important questions we should consider before proceeding with our project.

  • - HEK cells originated from an aborted human embryo, is this ethically correct?
  • - HEK cells were immortalized with different adenovirus genes, what would be the effect if these cells were introduced into the body?
  • - Is it ethical correct to gain money from widely used cells in research such as HEK cells?
  • - Would we need to test our device in animals before starting clinical studies?
  • - How invasive is our device? Resembles it the implantation of a pacemaker or does it come close to cell therapy?

All these questions seemed very relevant to us which is why we decided to do a small ethical debate within the team. This debate made us more aware of the different difficulties that go together with research in general but also specifically the ones regarding HEKcite. We based the debate on the different questions we received from René Custers, every question was asked one by one and every team member was allowed to give his/her viewpoint about the topic.



HEK cells originated from an aborted human embryo, is this ethically correct?

The whole team was quite level-headed regarding this question, we all agreed that using these cells should be allowed. For instance, HEK cells helped in answering many scientific questions that could might have remained unanswered if these cells were never used. However, there are strict regulations needed before using cells from human embryos is ethically correct. First of all, we all thought that consent from the mother was of utmost importance. Next to this, anonymity of the origin of the cells should be guarded at all times which protects the mother from possible discoveries in the embryo’s DNA and from possible societal reactions to her decision.

HEK cells were immortalized with different adenovirus genes, what would be the effect if these cells were introduced into the body?

This question was not answered by the team but by Bernard Schneider who gave us valuable information regarding the encapsulation device. He notified us that HEK cells are not allowed to be introduced into the human body for the main reason that they are immortalized with adenovirus genes. HEK cells in our capsule could become infected with adenovirus, if the adenovirus genes already present within the HEK cells come in contact with the infectious adenovirus, the possible consequences are not yet known. We as a team fully support that decision which is why we did more research about other cell types that can be used in the capsule. (link naar encapsulation text?)

Is it ethical correct to gain money from widely used cells in research such as HEK cells?

This question was answered by René Custers himself, he said that it has recently been approved to patent findings with HEK cells or other commonly used cells. The team supports this decision since we know that patents are crucial to stimulate innovation. Genetic modification and synthetic biology are the future which means that using certain cell types for genetic modification has to be allowed.

Would we need to test our device in animals before starting clinical studies?

Again, the whole team agreed, we would use biocompatible materials that are already extensively researched in clinical studies and animal testing. However, we think safety studies in animals are of great importance to verify the effect of the cells on the body if they could escape the confinements of the capsule.

How invasive is our device? Resembles it the implantation of a pacemaker or does it come close to cell therapy?

On this topic, the team did not quite agree, some members thought it resembled the implantation of a pacemaker while others thought it leaned more towards cell therapy. The biggest concern was: what if the capsule breaks and cells enter the body? Every team member agreed that first research had to be conducted to establish the possible consequences. However, some of them agreed that if this appeared to be safe, our capsule would more resemble a pacemaker. While other members were of the opinion that if indeed cells escaping was not dangerous, these were still genetically modified cells. In the end, we did not come to a consensus. Not reaching this consensus was not regarded as a negative point but as something we can still learn from. Using genetically modified cells in medicine is a difficult topic were ethics and science have to go hand in hand to determine the new way forward.


After this ethical debate, we were more determined to dig a little deeper into the world of ethics but also look at the different regulatory processes needed to start a clinical study. This is why we scheduled an appointment with the ethical committee of the university hospital of Leuven. The ethical committee gave us more information about the different juridical and regulatory procedures needed to start a clinical study, if you want to read more see below. On the other hand, they also gave us some more aspects we could think about. Such as the benefit-risk analysis, you should always keep in the back of your mind. It is important that patients always receive more benefit from the capsule than they are in risk of different complications. We did think about the complications such as the breaking of the capsule, infection or possible wrong read-outs. However, the ethical committee also pointed us in the direction of the psychological effect of our device. Some patients may find it beneficial to have more control regarding their illness but this may have the opposite effect on others. Patients could experience difficulties with having this much control or maybe would not like to know about their physical status every moment of every day. This made us think about the fact that with our device also an important psychological assessment should be made. The benefit should always exceed the risk and this is the psychical risk as well as the psychological risk.

After our meetings with the René Custers and the ethical committee, we assessed the information we already received and the different angels we received it from. René Custers gave us some more insight in the ethical view of a biotechnological company while the ethical committee gave us the viewpoint of a hospital. We felt that another important perspective was missing: the government. After sending various e-mails to a wide range of authorities, we were able to schedule a meeting with Johan Hanssens, the secretary-general of the department of economy, science and innovation in Flanders.

Johan Hanssens was able to give us more insight in the role of the government regarding genetically modified organisms. However, he told us that in Belgium the ethical decisions were mostly made by the different institutions and hospitals themselves. When it comes to regulatory decisions all of these are made by the European Union and are eventually implemented in the Belgian law. Momentarily Europe is very focused on responsible research and innovation, RRI. This new form of research implements the opinions of the different stakeholders such as doctors and patients in very early stages of research, to ensure that the conducted research has societal relevance. Johan Hanssens told us that Belgium as well as Flanders are searching for a way to have a more global body that could oversee the different ethical questions that are now overseen by the different hospitals and institutions themselves. Which means that the ethical debate could be done in a more structural and global way to ensure that Flanders and Belgium react in a unified way concerning difficult but also important topics regarding genetically modified organisms.

A biotechnology company, a hospital and the Flemish government, three different meetings and three different perspectives on genetically modified organisms. We, as the KU Leuven team, were very honoured to be able to hear these different perspectives and have the possibility to integrate these angles into our research: from different ethical questions, regulatory necessities from the ethical committee to RRI from the European Union. We discussed the different ethical questions given to us by René Custers in an ethical debate, we did research about the regulatory conditions to start clinical studies and by talking to doctors and patients we tried to do RRI as suggested by the European Union. All these aspects made not only our science more valuable but also taught the team that science is not something that stands alone but is also determined by the needs of society and that we have the honour to answer to those needs.



Hahahah