Team:LMU-Munich/Rathenau

From 2014.igem.org

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In view of the possible BaKillus application process, we first plan to focus on the development of the diagnostic tool inside the university. Funding might be possible by DFG or SynBio- or entrepreneurship-funding organizations. Once our idea is able to leave the lab, we would start a business and develop a prototype with the help of an industry partner (e.g. a small engineering company) and venture capital funds.  Alternatively, we would look into the possibility of acquiring the necessary financial means through a crowdfunding campaign. Throughout the development process, we would apply rapid prototyping techniques such as 3D printing to quickly reach a market-ready product. At the same time, intellectual property (e.g. patents) will be built up to protect our invention and provide an income for the growth of our start-up.  
In view of the possible BaKillus application process, we first plan to focus on the development of the diagnostic tool inside the university. Funding might be possible by DFG or SynBio- or entrepreneurship-funding organizations. Once our idea is able to leave the lab, we would start a business and develop a prototype with the help of an industry partner (e.g. a small engineering company) and venture capital funds.  Alternatively, we would look into the possibility of acquiring the necessary financial means through a crowdfunding campaign. Throughout the development process, we would apply rapid prototyping techniques such as 3D printing to quickly reach a market-ready product. At the same time, intellectual property (e.g. patents) will be built up to protect our invention and provide an income for the growth of our start-up.  
Through the success of our diagnostic tool, we can convince further investor and finally could be able to afford the approval process of the BaKillus nasal spray. Once we have brought this product to the market, we can push for new legal regulations regarding the approval of SynBio products.
Through the success of our diagnostic tool, we can convince further investor and finally could be able to afford the approval process of the BaKillus nasal spray. Once we have brought this product to the market, we can push for new legal regulations regarding the approval of SynBio products.
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== Technomoral Scenario ==
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=== Autonomous nano-exterminator ===
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<i>BaKillus actively detects and kills pathogenic bacteria. The first version, the BaKillus nasal spray, was an overall success about twenty years ago. It is still in use to treat all kind of bacterial surface infections, e.g. of the skin or nose. Now, a modified BaKillus version that can treat intracellular pathogens like M. tuberculosis went into clinical trials in the last months. But the week before, several test persons reported the same side effect and all participants were asked to stay in hospitals for several days. Two friends, one of whom participated in this study, are talking. </i>
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 +
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...You know, it is not about that I lost an opportunity to fund my studies or that I have to be in hospital the next days. I have this stuff in my body now. What hit them could also hit me!
 +
 +
Ah, you are exaggerating. What is it they have? They are feeling a craving for huge amounts of proteins. They simply go and a have their protein shake and they are fine. Such as you. You’ll be home by weekend and you can have your shake. They did a good job on the new BaKillus, I would prefer having milk shakes all the time, than dying of Tuberculosis.
 +
Don’t try a trick on me, that’s not funny! We just don’t know what’s going on. Actually, most of the patients already lost their symptoms again. The other’s told me that they felt like not acting on their own. Really weird! And that’s the point. The doctors don’t know what it was or where it comes from. They just say BaKillus was perfectly designed not to interfere with the body system and they try to work out a solution. How can I still trust ‘em?
 +
 +
Oh, you have been to a company doctor? Better go to ask an independent doctor, they always have a different view.
 +
 +
No, I can’t. They barely have expertise because the company never release detailed information about products of this kind. Sure, you can read the patents, but I doubt that any outsider can really grasp what is going on there. I’m totally helpless. Can anybody help me? The thing is, that I have about a million BaKillus cells in my body system doing anything. I want them out!
 +
 +
Now I start to see your point. Remember my uncle, the old doctor and how he complained about the release of the BaKillus nasal spray twenty years ago? He never wanted to prescribe the BaKillus spray to people who had a middle ear inflammation. He said: Boy, you would never want to go on a plane without pilot, but you really want to put BaKillus in your nose? It is a complete black box to me, it doesn’t even tell me which infection you actually had!
 +
 +
Yeah, I remember! And we were always joking about him, saying that no one will need a doctor anymore with this new synthetic cells. Just go and get BaKillus, he will do the doctor’s work for you. Diagnosis and treatment within one shot of the spray. Did you know that the new BaKillus cells measure and react to more than dozens parameters of the body system? It is a data sampling monster, but a genius calculator allowing treatment with pinpoint accuracy! But God, the old man was right. With all those new nanotechnology stuff, you never know how it really functions. If only politicians would have slowed down this development.
 +
 +
Hum... but somehow it’s good that they didn’t. Just by the success of the first BaKillus have 60% less deaths by infectious diseases all around the world. Honestly, that was the only think that was important to us until last week. And indeed, the government was a bit reserved in the first year of BaKillus. On the one hand, the discussion whether we want to use BaKillus or not was dominated by the critics of the Doctors Association talking about the risks of SynBio, their jobs, the black-box issue and insufficient consumer protection. On the other hand, NGOs and industry praised the all over availability and efficiency of BaKillus. But as the first patients were cured, all patients just wanted to use BaKillus and were convinced that BaKillus will lead us into the post-antibiotic era.
 +
 +
But over the years we seem to forget what BaKillus changed, now we see the bad side more pronounced. NGOs started to work on a moratorium of BaKillus. This morning an independent doctor came to see me. He is in a sort of ethics committee that is collaborating with a NGO and consumer protection organisations. They want our story to show the downside of BaKillus-like technologies. We demonstrate that even the developers don’t know what is going on.
 +
 +
Uh wow, guess they have their point there. Are you going to support them? How, do you feel about it?
 +
 +
Oh, I feel so stupid and I guess even those BaKillus cells are more clever than me.
 +
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{{Template:Team:LMU-Munich/Playground/footer}}

Revision as of 19:39, 16 October 2014


Collaboration with the Rathenau Institute

Application Scenario

Download our application scenario as a PDF here.


The BaKillus Concept

Increasing bacterial resistance to classical antibiotics remains a serious threat and urges the development of novel pathogen-killing strategies to treat infectious diseases. Exploiting bacterial communication mechanisms such as quorum sensing is a promising strategy to specifically target certain pathogens. Towards this goal, the synthetic organism BaKillus was designed to specifically target respective QS-dependent pathogenic bacteria. Here, the core element is a pathogen-detection device to detect Staphylococcus aureus and Streptococcus pneumoniae. By utilizing QS-dependent promoters, BaKillus will activate pathogen-killing devices like the production of antimicrobial peptides or biofilm degrading enzymes in the presence of target pathogens (see Fig. 1 for details). As a safety measure, a delayed suicide-switch guarantees non-persistence of genetically modified B. subtilis in the absence of pathogens.

Figure 1: Basic concept of BaKillus: S. aureus and S. pneumoniae use autoinducer-peptides (AIP) for cell-density dependent regulation of gene expression (quorum sensing), e.g. regulation of pathogenicity. BaKillus with the respective two-component sensing systems AgrAC and ComDE is enabled to activate killing devices in an AIP dependant manner. Uncommon antimicrobial peptides like subtilin or the cannibalism toxin, the peptidase lysostaphin and the hydrolase dispersin will be used to ensure effective killing of the targeted pathogens.

Application

BaKillus could be applied in two independent ways, first as a point-of-care diagnostic tool to identify pathogens and second, as a drug-producing microbe to treat bacterial infections.


Pathogen-identification diagnostic tool:

Problem:

Current tests to identify S. aureus (e.g. coagulase) require a time-consuming (18-24h) culturing step.

The BaKillus S. aureus diagnosis tool:

If the S. aureus detection device is sensitive enough, a smear of a patient into the BaKillus diagnostic tool would be enough to verify a S. aureus (MRSA) infection. This culture-independent detection provides results within 1-2 hours (just limited by the time for BaKillus spore germination and gene expression) and subsequent treatments could be initiated more quickly. We are planning to develop a ready-to use diagnosis tool for point-of-care testing by the professional staff in hospitals, pharmacies or medical offices (see Fig. 2). We are looking into collaboration with the iGEM-Team Aachen, who are planning something similar (https://2014.igem.org/Team:Aachen).


Figure 2: Basic concept of the BaKillus diagnostic tool. BaKillus spores are stored separately in a self-contained device. About one hour before use, spores and medium are mixed and incubated for the germination of the spores. The sample of a patient (e.g. a smear) can be applied into the culture and after about 30 minutes the result can be analysed with a simple camera-computer-station.


Table 1: Discussion of the BaKillus diagnostic tool.
Strengths Weaknesses
Detection & Identification of AIP dependent pathogens Application is limited to targets that exhibit QS-dependent pathogenicity.
Initial assessment of the sensitivity of the test and tests for reliability of the tool required
Self-contained/tightly closed device prevents release of GMO and thus a product possibly has little legal barriers for approval. (This is topic of an ongoing discussion with Dr. Ulrich Ehlers (Commissioner for GMO-release in Germany, BVL) and Dr. Hans Schrubar (Commissioner for Bio-Safety in Bavaria)
Easy engineering and handling of the detection devic Maybe too cost-intensive due to the need of high-end technology for measurement, especially for the utilization in developing countries. We seek to minimize this hurdle by using low-cost hardware (e.g. Raspberry Pi instead of a conventional computer).


Pathogen treatment tool:

Problem:

Unreasonable use of antibiotics reinforces the propagation of bacterial resistance and globalization of the failure of classic antibiotics to treat bacterial infections.

The BaKillus pathogen treatment tool:

Based on the pathogen-detection device, BaKillus will activate its pathogen-killing devices (see Fig. 1) to kill S. aureus or S. pneumoniae. Both are often associated with surface infections of the human body system and thus BaKillus could be used to cure infected patients. We discussed potential applications with doctors and immunologists and plan an application as a nasal injection to treat chronic inflammation of the ENT tract.

LMU14 Application Rathenau BaKillus Nasal Spray.png


Table 2: Discussion of the BaKillus nasal spray.
Strengths Weaknesses
Novel antibiotics allow treatment of resistant superbugs like MRSA Unknown efficiency and interaction of the drugs with the human body system, therefore individual evaluation and approval required for each novel antibiotic.
Local treatment dependent on presence of pathogen => no need for broad spectrum-antibiotics
Combination of drugs allows effective killing and little survival of resistant subpopulations Strong legal regulations to use GMOs on humans could make the approval a long endeavour and obstruct the substitution of sensing and killing devices for personalized needs, as individual approval is required.
Low production costs Immense costs to fulfil legal regulation for approval and clinical studies
Bacillus subtilis is Generally Recognized As Safe (GRAS status, FDA), so BaKillus is probably non-pathogenic. Additionally, the Suicide Switch and the Trytophane auxotrophy add addtional safety layers.


The gene safety discussion:

Using GMOs for any kind of application requires a detailed consideration about risks and legal regulations. The diagnostic tool does not release the GMO and the approval might be feasible in near future, whereas the use of BaKillus as a nasal spray faces huge legal barriers to be overcome and is unlikely to come into the market in the near future. Necessary steps (timeline) and legal regulations (paragraphs) for an approval of both products will be part of our application wiki. We are in an ongoing discussion with Dr. Ulrich Ehlers (Commissioner for GMO-release in Germany, BVL), Dr. Hans Schrubar (Commissioner for Bio-Safety in Bavaria) and Dr. Gabriele Wanninger (Expert for clinical studies in Bavaria).


Realisation:

In view of the possible BaKillus application process, we first plan to focus on the development of the diagnostic tool inside the university. Funding might be possible by DFG or SynBio- or entrepreneurship-funding organizations. Once our idea is able to leave the lab, we would start a business and develop a prototype with the help of an industry partner (e.g. a small engineering company) and venture capital funds. Alternatively, we would look into the possibility of acquiring the necessary financial means through a crowdfunding campaign. Throughout the development process, we would apply rapid prototyping techniques such as 3D printing to quickly reach a market-ready product. At the same time, intellectual property (e.g. patents) will be built up to protect our invention and provide an income for the growth of our start-up. Through the success of our diagnostic tool, we can convince further investor and finally could be able to afford the approval process of the BaKillus nasal spray. Once we have brought this product to the market, we can push for new legal regulations regarding the approval of SynBio products.


Technomoral Scenario

Autonomous nano-exterminator

BaKillus actively detects and kills pathogenic bacteria. The first version, the BaKillus nasal spray, was an overall success about twenty years ago. It is still in use to treat all kind of bacterial surface infections, e.g. of the skin or nose. Now, a modified BaKillus version that can treat intracellular pathogens like M. tuberculosis went into clinical trials in the last months. But the week before, several test persons reported the same side effect and all participants were asked to stay in hospitals for several days. Two friends, one of whom participated in this study, are talking.

...You know, it is not about that I lost an opportunity to fund my studies or that I have to be in hospital the next days. I have this stuff in my body now. What hit them could also hit me!

Ah, you are exaggerating. What is it they have? They are feeling a craving for huge amounts of proteins. They simply go and a have their protein shake and they are fine. Such as you. You’ll be home by weekend and you can have your shake. They did a good job on the new BaKillus, I would prefer having milk shakes all the time, than dying of Tuberculosis. Don’t try a trick on me, that’s not funny! We just don’t know what’s going on. Actually, most of the patients already lost their symptoms again. The other’s told me that they felt like not acting on their own. Really weird! And that’s the point. The doctors don’t know what it was or where it comes from. They just say BaKillus was perfectly designed not to interfere with the body system and they try to work out a solution. How can I still trust ‘em?

Oh, you have been to a company doctor? Better go to ask an independent doctor, they always have a different view.

No, I can’t. They barely have expertise because the company never release detailed information about products of this kind. Sure, you can read the patents, but I doubt that any outsider can really grasp what is going on there. I’m totally helpless. Can anybody help me? The thing is, that I have about a million BaKillus cells in my body system doing anything. I want them out!

Now I start to see your point. Remember my uncle, the old doctor and how he complained about the release of the BaKillus nasal spray twenty years ago? He never wanted to prescribe the BaKillus spray to people who had a middle ear inflammation. He said: Boy, you would never want to go on a plane without pilot, but you really want to put BaKillus in your nose? It is a complete black box to me, it doesn’t even tell me which infection you actually had!

Yeah, I remember! And we were always joking about him, saying that no one will need a doctor anymore with this new synthetic cells. Just go and get BaKillus, he will do the doctor’s work for you. Diagnosis and treatment within one shot of the spray. Did you know that the new BaKillus cells measure and react to more than dozens parameters of the body system? It is a data sampling monster, but a genius calculator allowing treatment with pinpoint accuracy! But God, the old man was right. With all those new nanotechnology stuff, you never know how it really functions. If only politicians would have slowed down this development.

Hum... but somehow it’s good that they didn’t. Just by the success of the first BaKillus have 60% less deaths by infectious diseases all around the world. Honestly, that was the only think that was important to us until last week. And indeed, the government was a bit reserved in the first year of BaKillus. On the one hand, the discussion whether we want to use BaKillus or not was dominated by the critics of the Doctors Association talking about the risks of SynBio, their jobs, the black-box issue and insufficient consumer protection. On the other hand, NGOs and industry praised the all over availability and efficiency of BaKillus. But as the first patients were cured, all patients just wanted to use BaKillus and were convinced that BaKillus will lead us into the post-antibiotic era.

But over the years we seem to forget what BaKillus changed, now we see the bad side more pronounced. NGOs started to work on a moratorium of BaKillus. This morning an independent doctor came to see me. He is in a sort of ethics committee that is collaborating with a NGO and consumer protection organisations. They want our story to show the downside of BaKillus-like technologies. We demonstrate that even the developers don’t know what is going on.

Uh wow, guess they have their point there. Are you going to support them? How, do you feel about it?

Oh, I feel so stupid and I guess even those BaKillus cells are more clever than me. …


Hi there!

Welcome to our Wiki! I'm BaKillus, the pathogen-hunting microbe, and I'll guide you on this tour through our project. If you want to learn more about a specific step, you can simply close the tour and come back to it anytime you like. So let's start!

What's the problem?

First of all, what am I doing here? The problem is, pathogenic bacteria all around the world are becoming more and more resistant against antimicrobial drugs. One major reason for the trend is the inappropriate use of drugs. With my BaKillus super powers, I want to reduce this misuse and thus do my part to save global health.

Sensing of pathogens

To combat the pathogenic bacteria, I simply eavesdrop on their communication. Bacteria talk with each other via quorum sensing systems, which I use to detect them and trigger my responses.

Adhesion

The more specific and effective I can use my powers, the lower the danger is of provoking new resistance development. So I catch pathogens whenever I get hold of them and stick to them until my work is done.

Killing

Talking about my work - killing pathogens is finally what I am made for. In response to quorum sensing molecules of the pathogens, I export a range of antimicrobial substances leading to dissipation of biofilms and the killing of the targeted bacteria.

Suicide switch

When the job is done and all the bad guys are finished, you don't need a super hero anymore. So after fulfilling my work I say goodbye to the world by activating my suicide switch.

Application

Of course I'm not only a fictional hero, but a very real one. In two different prototypes, I could be used for diagnosis or treatment of pathogen-caused diseases. However, there is still a whole lot of regulational and economical questions that have to be answered before.

See you!

So now you know my short story - and it is time for me to return to my fight for a safer world. Feel free to take a closer look on my super powers, the process of my development or the plans for a medical application.