Team:Heidelberg/Human Practices
Human Practices
Outreach of the project
Science communication
Science thrives on communication, whether among scientists or in general society. Proper communication is able to prevent social fear and rejection of new findings in synthetic biology. It was important for our team to actively communicate the relevance of synthetic biology and in particular of our project, to society. For this we used different forms of communications, for instance through online conversations or on Social Media. We reported regularly the progress of our project by uploading informative and creative posts on our Instagram page.
In order to reach even more people, we wrote an article about our project in collaboration with Biospektrum, which appeared in their science magazine.The major challenge was to explain our project and its relevance in a comprehensible way in a limited number of words.
BioSpektrum journal
BioSpektrum is a scientific journal aimed at students and postdocs and scientists. The range of topics covers a broad spectrum of biology from reports on new developments in molecular biology, genetics to biotechnology. BioSpektrum cooperates with several German professional societies such as the Society for Biochemistry and Molecular Biology (GBM) or the Society for Genetics (GfG). In our opinion the cooperation with BioSpektrum is a magnificent opportunity to reach another group of people that we cannot draw attention to ourselves for example via our social media account.
Eurofins Genomics online forum
Eurofins Genomics is a global life science company providing several laboratory services. Our team was not only supported materially by Eurofins but also got the opportunity to post a guest article on their blog to introduce our project to a larger audience.
Click here to see our Eurofins article
In writing this article we realized how many revisions of a text are necessary in order to arrive at a final text that presents our research clearly understandable and as precise as possible.
Dietmar Hopp Foundation contact
Our finance team looked for foundations that could possibly fund our project and therefore we sent a proposal to the Dietmar Hopp foundation. We started to connect with each other and answer all their questions in emails and during phone calls until they finally decided to sponsor us with. Furthermore, we were happy to engage in active discussions with Mrs. Fischer from the Dietmar Hopp foundation on how our project would align with the goals of the foundation. During these extensive exchange, we became more aware of other projects that are cooperating with the foundation. The foundation further connected us with Prof. Dr. med. Stefan Kölker, who works for the children's clinic in Heidelberg and is an expert in metabolic medicine. This gave us the opportunity to connect to a valuable expert and we asked his secretary for a meeting on which he agreed on.
Inspection of the diagnostics in newborn screening
After our great talk with Dr. Kölker about newborn screening, possible treatments for phenylketonuria as well as other inherited diseases and child-oriented drug design, we were allowed to take a look at the laboratory for newborn screening. Prof. (apl.) Dr. phil. nat. Jürgen G. Okun took over the guided tour and the detailed discussion. Thereby we got to know the sophisticated system in the laboratory and the administration. Among them there were steps which are still done by hand and others which are done automatically. We were able to see the equipment on which, for example, PKU is tested next to other genetic defects and get familiar with the overall workflow of the facility. On average, about 500 samples were screened per day. The catchment area was from the German federal states of Bavaria, Baden-Württemberg and Saarland. The interaction between diagnostics and research is widespread but can be observed very nicely side by side in the "Dietmar Hopp Stoffwechselzentrum".
Inclusivity
This year we delt with the topic of inclusivity in different areas. Fortunately, the topic has an increasing impact in on the society all over the world. Whether it is the Black Lives Matter, the #MeToo or the LGBTQIA+ movement, minorities or inequalities have definitely put into the spotlight a lot more. Even in the 2021 European Football Championship, football associations and football players showed soidarity presenting the pride flag. We discussed about how we could integrate this theme into our project. In our introduction on the landing page, we humanized a plasmid and portrayed them as a non-binary person. Time comes that peoples gender should not be defined by their biological sex or the gender assigned at birth. Gender should be considered on a continuum where people can define themselfes under the lable they feel the most comfortable with. We wanted to give a minority that is sometimes forgotten a space for representation: non-binary people. Some people assume that only male and female, man or woman exist, when there are actually many more genders and even the absence of one.
In addition, nowadays the inclusion of people who are hearing impaired and color blind is widely assumed. The promotion or presentation videos that must be submitted as a mandatory task are generally uploaded with subtitles. On the one hand this allows hearing impaired people to be included, on the other hand this serves for comprehensibility when the video has a poor quality. In videos without subtitles, hearing impaired people have to search for subtitles and in the worst case have to read and watch separately.
Furthermore, we have used plots with many colored lines, for example in the co-culture or selective advantage part. We take the ability to see all colors in most cases as granted, while in reality many people around us have color weaknesses. To make data visuably available to the largest group of people, one can proceed the color design in different ways. On the one hand, the selected colors can be chosen for people with red-green weakness or for color-blind people, so that the brightness of the colors varies. For this reason it is crucial to choose the right set of colors, so that each person can tell them apart. We have compared different variants with each other and finally decided for a color set on github that was designed to make matplotlib plots color weakness safe [1]. We asked people with color weaknesses, who gave us positive feedback. Thus, every sighted person should be able to tell the curves apart.
Integrated Human Practices
Interview with Prof. Dr. med Stefan Kölker from the “Dietmar Hopp Metabolic Center”
New ideas in medical research are essential for developing alternative therapies and thus advancing the medical treatment of diseases. Fundamental laboratory research is necessary for laying a foundation however, it is not everything. One should consider as early as possible to what extent methods, developed in the laboratory, can be implemented in clinical treatment. In order to get feedback for our project from a medical point of view, we met with the pediatrician Prof. Dr. med Kölker from the "Dietmar Hopp Metabolic Center".
We aimed to get an expert's assessment on how far the therapeutic approach we have developed, could be implemented clinically. Furthermore we evaluated where difficulties may appear and whether there are already other approaches. The main purpose of the meeting was to find out which other metabolic diseases our therapy approach could be used for. In metabolic diseases, such as phenylketonuria, which are a particular focus in our project, therapy is started immediately after birth, therefore we talked in particular about the special features of therapy for newborn and children.
The following sections summarize the key insights from the interview with Dr. Kölker
The treatment of phenylketonuria - previous methods, PAL as a new drug and further approaches.
Phenylketonuria (PKU) is an inherited disease where the patient can not degrade phenylalanine. The classic and most efficient therapy for people with PKU is still a diet low in phenylalanine and an additional supply of the essential amino acids.
For patients, this means a strong renunciation in everyday activities such as a visit to a restaurant.
The use of PAL directly has not yet been established as a therapeutic drug in Germany due to dangerous, partly life-threatening, immunological reactions that occur in many patients. This example shows that even if successful results in researching this topic have already been achieved, for physicians it is most decisive how safe a therapy method is.
This medical point of view, that has clearly been emphasized by Dr. Kölker, is: "Safety first!" If physicians have the choice between a therapy that may achieve slightly better results but carries a higher risk for the patient, they will opt for the already established therapy with lower risk.
The researchers goal must be not only to achieve better efficiency with a new therapeutic approach, but also to make new treatment methods as safe and comfortable as the established ones.
Dr. Kölker told us about another drug called Sapropterin, which is already being used in clinical treatment of PKU. It is a cofactor of PAH and can thereby enhance the efficiency of PAH in patients, where the enzyme is present, but only partially functional. Since a decreased functionality of PAH is the exception rather than the rule in PKU, it only leads to therapeutic success for a small group of patients.
With Dr. Kölker we also discussed other research approaches for the treatment of PKU. These include, for example, the modification of erythrocytes in the liver via non-inserting AAV8 vectors. The problem here is, that this treatment needs to be repeated, because non-inserting AAV8 are not suitable for long term treatment. Theoretically inserting AAV8 could be used, but here we have the risk of liver carcinomas. In the future more treatments will probably be possible with the help of mRNA, liposomes and gene therapy.
The use of PAL directly has not yet been established as a therapeutic drug in Germany due to dangerous, partly life-threatening, immunological reactions that occur in many patients. This example shows that even if successful results in researching this topic have already been achieved, for physicians it is most decisive how safe a therapy method is.
This medical point of view, that has clearly been emphasized by Dr. Kölker, is: "Safety first!" If physicians have the choice between a therapy that may achieve slightly better results but carries a higher risk for the patient, they will opt for the already established therapy with lower risk.
The researchers goal must be not only to achieve better efficiency with a new therapeutic approach, but also to make new treatment methods as safe and comfortable as the established ones.
Dr. Kölker told us about another drug called Sapropterin, which is already being used in clinical treatment of PKU. It is a cofactor of PAH and can thereby enhance the efficiency of PAH in patients, where the enzyme is present, but only partially functional. Since a decreased functionality of PAH is the exception rather than the rule in PKU, it only leads to therapeutic success for a small group of patients.
With Dr. Kölker we also discussed other research approaches for the treatment of PKU. These include, for example, the modification of erythrocytes in the liver via non-inserting AAV8 vectors. The problem here is, that this treatment needs to be repeated, because non-inserting AAV8 are not suitable for long term treatment. Theoretically inserting AAV8 could be used, but here we have the risk of liver carcinomas. In the future more treatments will probably be possible with the help of mRNA, liposomes and gene therapy.
Additional diseases and microbiome-based therapeutic approaches
So far, we have mainly focused on PKU as a metabolic disease. Dr. Kölker had drawn our attention to other amino acid metabolism related diseases that could possibly be reached with our approach. These include maple syrup urine disease and Glutaric aciduria. Further considered could be urea cycle disorders, for which liver-based therapies are already in development.
According to Dr. Kölker, it is currently more challenging to develop therapies for fatty acid oxidation disorders because the malfunctions occur in the mitochondria and are thus difficult to reach. Even with our approach of therapy through transformation of the gut microbiome, it will be difficult to reach this area. However, another application we had considered was the lung, since there is also a microbiome and diseases such as cystic fibrosis could possibly be treated there. For questions in this topic area Dr. Kölker referred us to the DLZ ("German Center for Lung Research").
According to Dr. Kölker, it is currently more challenging to develop therapies for fatty acid oxidation disorders because the malfunctions occur in the mitochondria and are thus difficult to reach. Even with our approach of therapy through transformation of the gut microbiome, it will be difficult to reach this area. However, another application we had considered was the lung, since there is also a microbiome and diseases such as cystic fibrosis could possibly be treated there. For questions in this topic area Dr. Kölker referred us to the DLZ ("German Center for Lung Research").
Microbiome-based therapeutic approaches
However, Dr. Kölker also reported on some medically promising microbiome-based therapeutic approaches. One example given is the attempt to inhibit the growth of ammonia-producing bacteria in the intestine as a new approach for treatment of urea cycle disorders. The aim hereby is to prevent the production of additional ammonia, since ammonia levels are strongly elevated in this clinical picture anyway.
Child-orientated forms of application
Dr. Kölker was very pleased with our question about what particularities are required when developing a treatment of children. He and many physicians wish from the pharmaceutical industry to take these questions under consideration. According to him, it has always been criticized by paediatricians that often no child-orientated forms for new medications are provided.
Many drugs are administered in tablet form, which causes major problems in pediatrics, especially in the treatment of newborns. On the one hand, children can only swallow a tablet from a certain age - before that, one has to work with juices or suppository drugs - on the other hand, the dosage has to be much more specifically adapted to the child's developmental state, weight and body size. To address this issue divisible tablets, or even better juices are used. The importance of consistency and taste in the administration of medicines to children should also not be underestimated. A current approach as an alternative to tablets that is being tested in Heidelberg is so-called 2d or 3d printed postage stamps. These are absorbed via the buccal mucosa and thus bypass the first pass of the liver.
Many drugs are administered in tablet form, which causes major problems in pediatrics, especially in the treatment of newborns. On the one hand, children can only swallow a tablet from a certain age - before that, one has to work with juices or suppository drugs - on the other hand, the dosage has to be much more specifically adapted to the child's developmental state, weight and body size. To address this issue divisible tablets, or even better juices are used. The importance of consistency and taste in the administration of medicines to children should also not be underestimated. A current approach as an alternative to tablets that is being tested in Heidelberg is so-called 2d or 3d printed postage stamps. These are absorbed via the buccal mucosa and thus bypass the first pass of the liver.
Our take home message
During the joint considerations on the application in the lung microbiome for the treatment of cystic fibrosis, Dr. Kölker mentioned the drug Pulmozyme®. It is used to hydrolyze DNA present in mucus in order to make it more fluid. It contains the enzyme DNaseI. We therefore researched to what extent we could have this enzyme expressed by the lung microbiome. We found out that bacteria are not able to express a functional DNaseI. During our search for alternatives, we came across micrococcal nucleases.
In addition, we realized that since our therapy tends to be used in children, we would also have to think about child-friendly forms of application when transporting our DNA via a capsule into the intestine. The first resolution was that a capsule should be used as a one-time treatment. We further talked about the design of capsules which are suitable for children. In the case of supplementaries such as agarose or β-galactose for the selection advantage, one could work for example with gummy bears or sugar containing juices. We brought these new considerations to the MicrobioCOSMOS meetup while discussing ethics in child-treatment and drug design.
In addition, we realized that since our therapy tends to be used in children, we would also have to think about child-friendly forms of application when transporting our DNA via a capsule into the intestine. The first resolution was that a capsule should be used as a one-time treatment. We further talked about the design of capsules which are suitable for children. In the case of supplementaries such as agarose or β-galactose for the selection advantage, one could work for example with gummy bears or sugar containing juices. We brought these new considerations to the MicrobioCOSMOS meetup while discussing ethics in child-treatment and drug design.
References
[1] A color blind/friendly color cycle for Matplotlib line plots, https://gist.github.com/thriveth/8560036 (retrieved on 21.10.2021)
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