Team:Marburg/Design
The cut-off capsule
As shown in the pictures above we are able to build a functional prototype that would grant the opportunity to use the CDI-system to modify guts. We can pelletize cells carrying our CDI-system and use the pellet as filling of capsules. The bacteria in this capsule have the ability to inhibit the growth of other cells. The prototype works at least in laboratory environment as expected. As a possible design for future applications freeze-dried CDI bacteria could be used in an acid resistant pill. The pill would then dissolve in the intestine and release the bacteria. In that scenario this system would be able to reduce proteobacteria which are associated with obesity or to establish permanently in the gut and produce beneficial compounds such as vitamins to treat undernourishment or to release appetite supressing lipids to fight obesity, respectively.
In a futuristic scenario it could even be possible to use the CDI cells to sense any change in health indicating parameters by either signalling the deviation or counteracting by producing the corresponding suitable substance.
Common treatments for undernourishment require permanent intake of drugs or dietary supplements. CDI bacteria that have established in the gut could in general produce any compound of interest continuously in the gut thus making the need for constant medication unnecessary. Additionally the effect of CDI is locally limited. Cells need to get in contact with other cells to perform their growth inhibitory function. Antibiotics that are used to target gut bacteria will certainly spread across the whole body and can cause side effects in other organs. CDI cells can only inhibit target cells that carry BamA. This Protein is conserved in gram negative bacteria but absent in gram positive bacteria, which make up more than two third of the microbiome and are therefore not affected by CDI cells.
Next to all advantages of using CDI cells instead of common treatments, we need to think about possible disadvantages as well especially ethical considerations. Should we use genetically engineered bacteria to permanently modify our gut? And what would happen if the bacteria spread into the environment? The ethical issues should be discussed by politicians and lawyers together with scientists. As a solution for safety issues we plan to implement a kill switch (link) that ensures that none of our cells is able to live after having left the gut.
Once we prove that our prototype is not only functional in a laboratory environment but also in animal testing it is only one last but protracted step until we are able to market our product to people all around the world and provide them with a tool to permanently improve their health conditions. This one last step is the clinical trial. By law, newly developed products have to pass four phases of clinical trials in order to get an approval.
In phase 0, the preclinical phase, the general research takes place including animal testing. In this phase no human experiments are involved.
In phase 1 the drug or treatment is tested in a small group of healthy people. The goal of this phase is to determine whether the drug or treatment causes severe side effects and what is a safe dosage range. Analyzing the desired effectiveness is no goal of phase 1 studies.
In phase 2 the drug or treatment is tested in larger groups of patients suffering from the disease to be cured by the new drug. An essential goal of this phase is to study the effectiveness of the drug in the dosage determined in phase 1.
In phase 3 the new drug or treatment is compared to standard drugs or treatments for this disease.
Phase 4 includes every study after the drug or treatment has been brought to market, including long-term side effects or effects in different parts of the population.
In general to carry out clinical trials in Europe the criteria and requirements of the EU pharmaceutical legislation for medicinal products for human use have to be followed. This legislation ensures the safety of all trial subjects. Additionally a vote of favour is needed by the ethics committee of the member state where the clinical trial is planned to be marketed.
If clinical trials are to be done for drugs that contain or consist of GMO´s it has to be decided if the drug leads to contained use which is defined as:
“any activity in which organisms are genetically modified or in which such organisms are cultured, stored, transported, destroyed, disposed or used in any other way and for which specific containment and other protective measures are used to limit their contact with the general public and the environment”
or as deliberate release which are all activities not rated as contained use.
If the clinical trial is classified as deliberate release an environmental risk assessment (ERA) has to be added to the application.
An ERA includes about five points.
- 1. Identification of potential adverse effects,
- 2. Estimation of the likelihood,
- 3. Risk estimation,
- 4. Risk management
- 5. Assessment of the overall environmental impact.
The final decision after a clinical trial if a product is released in the European Union is taken by the European commission. In the USA the FDA is the corresponding organization. After a product is launched further experiments are conducted as part of clinical phase 4 to observe long term side effects. The process from a prototype in a laboratory environment to a ready to market product including approval of all governmental organisations can take decades and probably costs millions of dollars. But every billion dollar blockbuster product started at the same stage as our project - as a prototype in the lab.
