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The Future of Alzheimer’s Prevention: Shedding Light on Probiotics and GMO

Now it’s time for a dive into the ethical and political landscape of probiotics and genetically modified organisms, GMO. The 2021 year’s iGEM team from Lund University, Sweden, aspires to prevent neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease. This will be done by genetically modifying the probiotic bacterium L. reuteri, an act that provokes discussion and questions.


During the course of 2021, team Cure-li from Sweden (Lund University) and team EndoSeek from France (Paris-Saclay University) partnered up to investigate the ethical and political aspects regarding each of our projects. This partnership was dubbed iGETHICS. As of August 2021, this is currently a work in progress and has so far resulted in an ethics video, this article below, and in the near future a panel discussion will take place.



Synthetic biology is a rapidly changing field. Breakthroughs in DNA technology altered the scientific landscape profoundly in the past decades; ranging from ancestry tracking to the engineered bacteria producing human insulin.


When implementing a new bioengineering solution, the outcome must clearly outweigh potential side effects. When these risks are somewhat unknown, this could prove to be quite difficult. This is the current situation that synthetic biology is facing, and with varying laws and legislations worldwide, the future is dependent on these discussions. In team Cure-li, we believe that ethics should be present in these discussions, every step of the way.


In the case that will be presented, we will connect the dots between a type of bacteria called probiotics, the bacterial amyloid Curli, neurodegenerative diseases and genetic engineering. Let us start with the bacteria. We’ve been told all our lives that bacteria is bad for us, but this might not be the whole picture.


In our gut, 100 trillion bacteria are thriving. These bacteria are known as the gut microbiota and can be both good and bad [1]. In team Cure-li are focusing on introducing good bacteria, namely probiotics, that decrease the amount of harmful bacteria in our gut.


Probiotics means “for life”, and are microorganisms that may help us all to improve our bodies' bacterial environment [2]. Natural probiotic cultures could, for example, be found in fermented foods [3]. With the help of DNA technology, we could genetically modify probiotics, to fit our needs.


Modifying the genes of an organism gives us the possibility to move genes among different species and to control the genes’ expression in terms of how they how and when they occur [4]. A genetically modified organism, GMO, is an organism that has been genetically altered in a lab in a way that does not occur naturally.


Before modern DNA technology, farmers selected certain animals or plants with desirable traits in order to produce desirable offspring. That practice spans over generations [5]. Equipped with DNA technology, we have the ability to tailor animals and plants in a much faster way. This applies to bacteria as well, and with the short generational span of bacteria, it’s beneficial for research.


In order to find out how a genetically modified bacteria could help us in preventing Alzheimer’s disease, let’s discover how a bacterial protein could interfere with our brain.


Studies in rats have found a direct correlation between the bacterial protein Curli, in the gut, and plaque buildup, in the brain. It is possible that some of these cases are connected with the Curli protein. Curli is produced in the gut by the bacteria E. coli and can cause misfolds in other proteins. Plaque arises when these bacterial amyloids travel to the brain and aggregate there. This type of plaque buildup could increase the risk of developing Alzheimer's or Parkinson’s [6]. What’s happening in the gut, also plays a role in the brain, known as the gut-brain axis.


Photo credit from left to right: Braňo, Fakurian Design, and Danie Franco.


A probiotic, in the shape of a pill or a yoghurt, could be the solution to prevent these diseases. In our project we’re aiming to genetically modify the probiotic bacteria L. reuteri, in order to inhibit curli formation in the gut. When Curli can’t form, we’re hoping to avoid plaque build up in the brain and thereby avoiding disease.


With this solution, we would be giving genetically modified bacteria to people, perhaps during a span of decades, and this raises many questions.


Is giving genetically modified bacteria to humans an act of medical progress, or is it potentially dangerous for our ecosystem and human health?

The first topic we would like to address is the complexity of the gut. Our genetically modified, GM, L. reuteri aims to inhibit Curli growth in our gut. It is extremely important that this does not impact the gut in a harmful way.


The gut microbiota is complex in nature, the good bacteria present in our gut should outcompete the bad to attain a good balance. Disturbing this balance can be quite problematic. As people consuming antibiotics might have noticed, the antibiotics are affecting all bacteria, including the good ones, which can lead to unpleasant side effects such as cramps, gas or diarrhea [2].


Our probiotic should decrease the amount of bad E. coli, but in doing so some of the good E. coli could also be affected. This problem might be exacerbated by horizontal gene transfer.


Horizontal gene transfer means that genes are transferred between bacteria which could lead to unintended consequences [7]. Our GM L. reuteri must be thoroughly tested before being consumed by the public in order to avoid these issues. Our aim is that our L. reuteri should be beneficial to consume, with no bad side effects. In order to prevent any harm to consumer health, we will discuss the next topic; safety regulations!


Today, in the EU, GMO food is strictly regulated by the European Food Safety Authority, EFSA [8]. While in the US, GMO food is regulated by the Food and Drug Administration, FDA, and is more freely available to the everyday consumer [9].


Photo credit: Guillaume Périgois.


Even though GMO is way more regulated and prohibited in the EU, there are some types of food that are available. Most of the GMO authorised foods belong to the EU agricultural sector [8]. We are gene modifying probiotics, not crops. As of 2021, it’s not legal to sell gene modified bacteria for consumption. This made us in team Cure-li wonder what the everyday person thinks about GMO and probiotics.


Team Cure-li conducted a survey to find out what the average person knows about GMO and probiotics. The average respondent in the survey was a European below the age of 30. Now, one might ask why asking young adults would be a good idea when researching a Alzheimetr’s prevention. Well, the answer is that research and development takes quite many years and the consumers might have to start eating this probiotic decades before the average age of Alzhemier’s diagnosis. So, this age group might actually be the target audience in a decade or two.


75% answered that they know what GMO is, and 50% know what probiotics are. So, while GMO seems to be quite well known, fewer people know what probiotics are.


In the survey we provided a definition for both probiotics and GMO. With our GM L. reuteri in mind, we asked them whether they would take a GMO probiotics if it was properly regulated, 74 percent said they would consider doing so. What was learned here was that the safety aspect is super important from the consumer's point of view and that the average young consumer trusts EU regulations.


Now we might ask ourselves how GMO probiotics are discussed, and perhaps how the current EU legislation might determine that scientific discussion. A 2021 study by the European Commission found that today’s strict regulation has a negative impact on research of GMO in the EU. The study also points out that there’s a lack of scientific knowledge on how applications in animals and other microorganisms are affected, especially from a safety perspective [8].


So, right now, the EU is faced with two problems; GMO research is being held back and we are not aware of the potential risks. This brings us to the next topic; potentially releasing GMO into our ecosystem and the risks that follow along.


Photo credit from left to right: krakenimages, Aurelien Romain, and Annie Spratt.


All things considered, we need to poop. As we do this, our engineered L.reuteri enters the outside world. Now, life outside of the gut is a harsh place. The temperature is no longer the comfortable 37 degrees L. reuteri is used to in the human body. It would likely not survive and it would even less likely multiply significantly.


More angles need to be scrutinized. If the new DNA we are introducing spreads through horizontal gene transfer then it could do things that we did not anticipate it to do. This is something that has to be investigated thoroughly. Since the EU focuses the GMO conversation heavily on agriculture, we would like to broaden the conversation to also include GM bacteria.


We do not want to harm the natural microbial community in the gut. Our modified L. reuteri should be safe to consume and not cause harm in nature. This shows us how important it is to get a proper testing framework.


We in team Cure-li acknowledge that the GMO question is complicated. The EU chose to go with the precautionary principle in order to protect the citizens and we agree that it’s important to stay safe. However,


we cannot just turn a blind eye and drop the discussion and research.

We would also like to stress the importance of ‘knowledge’ and staying up to date with the most recent GMO developments. Another reason is that GMO is not only crops, it can also be bacteria. We need to broaden the conversation.


A number of respondents in our survey claimed that they thought GMO was dangerous due to the EU’s strict control. This fact from the survey, together with GMO research being held back in the EU, shows how important it is to have an open discussion. We would like to advocate for a scientific reliable testing framework that will assess the new GMOs in order to protect both the environment and human health.


Photo credit from left to right: Jonas Von Werne, Johnny Cohen, and 傅甬 华.


Team Cure-li aims to prevent Alzheimers and other neurodegenerative diseases. The key in our project is a genetically modified bacterium, and if our GM L .reuteri is thoroughly tested and proves to be both safe and to be of help in our fight against neurodegenerative diseases, we believe that this is an ethical approach.


We would like to end our video on two key takeaways. Open up for broader GMO research and build a dependable testing framework for new genetically modified organisms.


We believe that if done properly and with safety in mind, GM bacteria can be greatly beneficial to human health!

About the Author


References

[1]

“Can gut bacteria improve your health?”; Harvard Health; October 14, 2016;

https://www.health.harvard.edu/staying-healthy/can-gut-bacteria-improve-your-health


[2]

“The benefits of probiotics bacteria”; Harvard Health; June 7, 2017; https://www.health.harvard.edu/staying-healthy/the-benefits-of-probiotics


[3]

“Technological challenges for future probiotic foods”; Harvard Health; December 29, 2020; Technological challenges for future probiotic foods


[4]

“Releasing genetically modified organisms: will any harm outweigh any advantage?”; Journal of Applied Ecology; May 13, 2002; https://besjournals.onlinelibrary.wiley.com/doi/full/10.1046/j.1365-2664.2000.00502.x


[5]

“Genetically Modified Organism”; Britannica; July 25, 2021.

https://www.britannica.com/science/genetically-modified-organism


[6]

“Exposure to the Functional Bacterial Amyloid Protein Curli Enhances Alpha-Synuclein Aggregation in Aged Fischer 344 Rats and Caenorhabditis elegans”; Scientific Reports; October 6, 2016.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052651/


[7]

“The advantages and disadvantages of horizontal gene transfer and the emergence of the first species”; Biology Direct; January 3, 2011.

https://biologydirect.biomedcentral.com/articles/10.1186/1745-6150-6-1


[8]

“EC study on new genomic techniques”; European Commission; April 29, 2021.

https://ec.europa.eu/food/plants/genetically-modified-organisms/new-techniques-biotechnology/ec-study-new-genomic-techniques_en


[9]

“How GMOs Are Regulated for Food and Plant Safety in the United States”; Food & Drug Administration; April 22, 2020.

https://www.fda.gov/food/agricultural-biotechnology/how-gmos-are-regulated-food-and-plant-safety-united-states




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