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Engineered endosymbiosis: what would be some amazing collaborations?

Image credit: National Institutes of Health (NIH)

Darko Savic
Darko Savic Oct 14, 2020
Could we engineer endosymbiotic collaborations with other microbial species?

Our cells got lucky with Mitochondria and the resulting abundance of energy that came out of it. Our evolution skyrocketed when one of our predecessor cells ingested a bacteria that for some reason survived and started collaborating with its host cell. Mitochondria turned out to be amazing at converting glucose to useable energy for its host. This abundance of energy resulted in the cell being able to achieve greatness.

Modeling by our own Mitochondria we could get similar symbiotic relationships going. Let the professionals take care of demanding jobs while the cell takes care of them.

  • What are some microbial species with amazing superpowers that would be beneficial to our cells?
  • How could we ensure symbiosis? The newly introduced symbiont should not turn on the host cell somewhere down the line.
  • What are the obstacles to work on before something like this can become a reality?


Creative contributions

Mimic endosymbiosis: models and example

Antonio Carusillo
Antonio Carusillo Oct 17, 2020

I wanted to start this contribution from a broader point of view; since, after finding the best fit microorganism, we will have still to think how to achieve endosymbiosis and then provide an example where I think we may find a quicker application.

So the contributions can be divided into two parts, equally important:

Part 1: how to model Endosymbiosis

Discovering a way to recreate endosymbiosis in humans may enable countless possibilities ranging from fighting diseases to survival in extreme conditions. Engineered bacterial strains already exist and some of them will be even used for the upcoming mission to Mars! However, endosymbiosis is yet to be explored in humans although only some small attempts have been done in the past year, which I will talk about later. But still, to do so we would need to model it first. As for any approach whose final goal is to go into a human, we would need experimental models to understand:
  • How do we make it?
  • What are the side-effects, if any?
  • What are the benefits, if any?
  • Do the benefits outbalance the side-effects?
So my first step would be to identify a way to model this “synthetic symbiosis “. To this end, a very interesting paper was published in PNAS .
One of the milestones - in eukaryotic evolution - has been the mitochondrial acquirement. According to the “Endosymbiotic theory “, the mitochondria were free-living prokaryotes which entered the host cell and were retained as endosymbionts. Such an event is thought to have occurred more than 1.5 billion years ago. In the paper from PNAS, the investigators tried to recreate an “ endosymbiotic event” by using E. coli and S. cerevisiae. What they did was very smart, they took an E. coli strain and modified it to be able to provide ATP to S. cerviase with defective mitochondria ( i.e. no ATP ) while in return the S. cerevisiae would provide the E. coli with the essential nutrients that the E. coli could not acquire itself ( the thiamin pyrophosphate). This way a mutual dependency was achieved. So, they introduced E. coli in the cytosol of S. cerevisiae but they soon found out that S. cerevisiae was not growing, even if E. coli was supposed to provide ATP. After further experiments, they realized the reason was that E. coli was being attacked by the lysosomal degradation system in the cytosol of the S. cerevisiae. To circumvent this, they turned to the intracellular pathogens fields. In particular, those can escape lysosomal degradation by expressing SNARE-like proteins that hijack the host vesicular trafficking machinery and allow the pathogens to escape the lysosomal degradation pathway. By equipping the E. Coli with this SNARE-like proteins they were able to grow Yeast with defective mitochondria.
They pushed the system even further, by engineering the E. coli or - rather - “de-engineering” it by removing other E. coli genes that would make the bacteria even more dependent on the Yeast. This was done to mimic another process part of the endosymbiotic theory: the genome reduction. Meaning that the mitochondria DNA, throughout its evolution as a symbiotic organism, underwent further loss of genetic information that could be taken over by the host organism. They could replicate the same process.
Ultimately this proves that Yeast may be a starting point for investigating synthetic symbiosis.

This poses other questions:

  • How can we maintain a stable endosymbiotic situation? SNARE-like proteins may be an answer. May we look at our microbiota to understand which would be the key factors in terms of expressed genes that are amenable? To this extent models using Drosophila melanogaster are already available to study the host immune system control over gut microbiome .
  • What kind of dependency should we install in the selected microorganism? Those will be GMO and we have to avoid a horizontal genetic transfer. So we should develop a control system not readily available in nature, to avoid an undesired "escape".
A step closer to humans could be using organoids which can mimic the 3D-organ tissue organization on a small scale. So, we may be able to use these as a possible way to investigate possible interactions between specific organs and the microorganism of choice .

Part 2: example of engineered bacteria to fight Cancer

Leaving aside the already mentioned the Deinococcus radiodurans, I will step back in my field regarding a more "boring" microorganism we already know, E. coli.
Researches have indeed managed to turn a no-pathogenic E. coli strain in a cancer-killer! .

Yes, that’s right.

They reported that they were able to engineer a non-pathogenic Escherichia coli strain
to specifically lyse within the tumour microenvironment and release an encoded nanobody antagonist of CD47 (CD47nb)12, an anti-phagocytic receptor that is commonly overexpressed in several human cancer types. […] delivery of CD47nb by tumour-colonising bacteria increases activation of tumour-infiltrating T cells, stimulates rapid tumour regression, prevents metastasis and leads to long-term survival in a syngeneic tumour model in mice. […] local injection of CD47nb-expressing bacteria stimulates systemic tumour-antigen-specific immune responses that reduce the growth of untreated tumours, providing proof-of-concept for an abscopal effect induced by engineered bacterial immunotherapy. Thus, engineered bacteria may be used for safe and local delivery of immunotherapeutic payloads leading to systemic antitumor immunity. “

Wouldn’t be cool to have a patrol of those guys looking around for cancer cells to toast?

[1]Engineering yeast endosymbionts as a step toward the evolution of mitochondria Angad P. Mehta, Lubica Supekova, Jian-Hua Chen, Kersi Pestonjamasp, PaulWebster, Yeonjin Ko, Scott C. Henderson, Gerry McDermott, FrantisekSupek, Peter G. Schultz

[2]Ludington WB, Ja WW (2020) Drosophila as a model for the gut microbiome. PLoS Pathog 16(4): e1008398. https://doi.org/10.1371/journal.ppat.1008398

[3]Nigro G, Hanson M, Fevre C, Lecuit M, Sansonetti PJ. Intestinal Organoids as a Novel Tool to Study Microbes-Epithelium Interactions. Methods Mol Biol. 2019;1576:183-194. doi: 10.1007/7651_2016_12. PMID: 27628134.

[4]Chowdhury, S., Castro, S., Coker, C. et al. Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med 25, 1057–1063 (2019). https://doi.org/10.1038/s41591-019-0498-z

Subash Chapagain
Subash Chapagain7 months ago
Elegantly framed concept.

While engineering endosymbiosis, not just horizontal gene transfer, immunogenicity can raise some problems (if we are looking to using non-native microorganisms). How would this approach address the potential risks of hyper-immune reactions?

Coming to the second case of using engineered E.coli against cancer cells, as far as I know, the receptor CD47 is not specific to tumours but it is needed for angiogenesis in normal tissues also (the only difference being overexpression in cancer cells). How does the engineered system (E.Coli) discriminate between the normal and cancer cells? Is it based on the CD47 marker only? Or are their other determinants which influence the recruitment of these E.coli cells against tumor?

Hence, the next stage in this pursuit would be to determine the specificity and efficacy of targeting and tagging non-normal cells.
Antonio Carusillo
Antonio Carusillo7 months ago
Subash Chapagain 1- Since the microrganism will be engineered - something easier and easier to do - I think that we may identify the motifis used by our immune system to recognise them and eliminate them or change them in a way they won't be detected. We may even - that's why I have suggested it - look at our microbioma and see how our microbioma avoids to be attacked by our system ( what do they express and what not ) 2- As you well pointed out we will need more studies to better control the specificity of such microrganisms, in a way that they are directed only towards the target. Maybe by rendering them dependent ( auxotrophic ) on components present in a tumor environment only, so taht they can act only where the tumor is and only until the tumor is there. But this is a pure guess.

Endosymbiosis engineering for containing anti-oxidant producing bacterial species

Subash Chapagain
Subash Chapagain Oct 15, 2020
Increased levels of intracellular oxygen radicals can cause damage to lipids, proteins and Nucleic Acids, resulting in oxidative stress to the organism/cell . Reactive oxygen species (ROS) like superoxide anion radicals, hydroxyl radicals and hydrogen peroxide are such highly reactive oxygen free-radicals that can cause oxidative damage to the cellular system. Though most of the organisms have evolved to possess enzymatic defences like superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and non-enzymatic antioxidant defences like Vitamin C, Vitamin E, these systems are not enough to fully protect the living organisms from the effects of oxidative damage. A number of synthetic antioxidants are available, for example, butylated hydroxyanisole and butylated hydroxytoluene, however, their safety and efficacy has been questioned in relation to liver damage and carcinogenicity .

Hence, the search for safer and natural antioxidants from biological resources is indeed a very promising field of research. If we could engineer to include microbial species known to produce anti-oxidant molecules in our cellular systems, we could possibly limit the damage done to our cells by oxidative stress. This can be particularly helpful to fight ageing as one of the main features of senescence is the accumulation of ROS.

In recent years, finding safer and natural antioxidants from bio-resources to replace synthetic antioxidants has received a great deal of attention. In regard to the proposed idea of endosymbiotic engineering, a number of bacterial species could be used. For example, Lactobacillus Plantarum AR113, Pediococcus pentosaceus AR243, and Lactobacillus plantarum AR501 which are screened from Chinese fermented foods have high scavenging activity of α, α-Diphenyl-β-Picrylhydrazyl (DPPH) free radical and hydrogen radical, stronger inhibition of lipid peroxidation, and better protective effect on yeast cells in vitro. Moreover, when the strain L. plantarum AR501 was orally administered, it improved the antioxidant status of oxidized oil-induce oxidative stress including a decrease in lipid peroxidation, renewing the activities of SOD, GSH-Px, with an overall enhancement of total antioxidant capacity (T-AOC). Another striking feature was that L. Pantarum AR501 caused alleviation of oxidized oil-induced injury of liver cells in mice. This was found to include nuclear factor erythroid 2–related factor 2 (Nrf2), one of the regulators of cellular resistance to oxidants, which also controls the expression of a lot of phase-II enzymes downstream, involved in antioxidant activity .

What if we could engineer the symbiotic relationship between our gut cells and these strains of LAB so that we could harness the anti-oxidant capacity and use these microbes as an army against oxidative stress?

[1] Schieber M., Chandel N.S. ROS function in redox signaling and oxidative stress. Curr. Biol. 2014;24:R453–R462. doi: 10.1016/j.cub.2014.03.034

[2]Luo D., Fang B. Structural identification of ginseng polysaccharides and testing of their antioxidant activities. Carbohydr. Polym. 2008;72:376–381. doi: 10.1016/j.carbpol.2007.09.006.

[3]Lin, X., Xia, Y., Wang, G., Yang, Y., Xiong, Z., Lv, F., Zhou, W., & Ai, L. (2018). Lactic Acid Bacteria With Antioxidant Activities Alleviating Oxidized Oil Induced Hepatic Injury in Mice. Frontiers in Microbiology, 9, 1–17. https://doi.org/10.3389/fmicb.2018.02684

What causes parts of symbiont's DNA to move to the host cell's nucleus?

Darko Savic
Darko Savic Nov 06, 2020
Aphids and Buchnera
This video covers a few cool symbiotic relationships between bacteria and animals. The first relationship it describes is between Aphids and Buchnera aphidicola. Aphids have specialized cells - bacteriocytes within which they grow the Buchnera bacteria. Buchnera have lost parts of their DNA (70% of the genes) - including the genes for responding to environmental changes and building cell walls. They do well without those genes because the Aphid bacteriocytes provide what is needed.

We see something similar in our mitochondria, but there, some genes have moved into the host cell's nucleus instead of being thrown out. This now serves as a way for the cell to keep mitochondria under control.

Vesicomyid clams and their sulfur-oxidizing bacteria
As mentioned in the same video above, the vesicomyid clams host their symbiont - sulfur-oxidizing bacteria within their gill epithelial cells. Likewise, these bacteria have lost large chunks of their genome and have the lost functionality taken care of by the host cell.

Blue-ringed octopus and their "domesticated" toxin-producing bacteria species
According to the same video, the Blue-ringed octopus seems to be good at establishing symbiotic relationships with various bacterial species. How does it do it?

This makes me wonder:
  1. What mechanism "decides" to cut out parts of a bacterial cell's DNA?
  2. Does the decision come from the bacteria or the host cell?
  3. What mechanism "decides" whether to incorporate the genes into the host cell's nucleus or throw them out?



Make the symbiont's DNA incomplete without the host cell's DNA

Dragan Otasevic
Dragan Otasevic Oct 14, 2020
In our cells, some of the genes required for mitochondrial replication are present in the nuclear genome but missing in the mitochondrial genome. This effectively makes the mitochondria an obligate mutualist - dependent on the host cell's nuclear DNA for replication.

Move the key genes required for symbiont replication onto the host's DNA so that the "decision" to multiply is directed by the host cell.

Nitrogen fixing bacteria within our skin cells

Darko Savic
Darko Savic Nov 22, 2020
Nitrogen is essential to life because fixed inorganic nitrogen compounds are required for the biosynthesis of all nitrogen-containing organic compounds, like amino acids, proteins, etc. We get the nitrogen by eating plants or other animals that contain nitrogen. Even though the air is 78% molecullar nitrogen, we can't use it directly. We depend on other lifeforms to convert it for us.

Biological nitrogen fixation is the conversion of atmospheric N2 to NH3. Legume plants form a symbiosis with nitrogen fixing bacteria by growing root nodules which provide the bacteria with energy and in return get the nitrogen.

Could we bypass one or two middlemen and incorporate a suitable nitrogen fixing bacteria species as endosymbionts in our skin cells?

Deinococcus radiodurans as safe-keeper of the host cell's DNA

Darko Savic
Darko Savic Oct 14, 2020
Deinococcus radiodurans is amazing at protecting its DNA from anything that would damage it. It's one of the most radiation-resistant organisms known to us. It keeps several copies of its genome. Even if several are shredded to pieces, if just one copy remains unchanged, it can survive and restore itself. D. radiodurans also has extremely efficient DNA repair mechanisms.

  • Could it somehow be turned into an organelle that keeps our nuclear DNA safe and makes sure that the master copy is not damaged?
  • Could it be repurposed to do the job of Mitochondria? If so, its function would not be prone to damage with age.

[1]Minton KW. DNA repair in the extremely radioresistant bacterium Deinococcus radiodurans. Mol Microbiol. 1994 Jul;13(1):9-15. doi: 10.1111/j.1365-2958.1994.tb00397.x. PMID: 7984097.

Magnetosomes from Magnetotactic bacteria

Darko Savic
Darko Savic Nov 21, 2020
Magnetosomes from Magnetotactic bacteria could give us the ability to sense magnetic fields.

Other than having an in-built compass, would this ability be useful to us in other ways?

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General comments

Dragan Otasevic
Dragan Otasevic7 months ago
Take a look at these photosynthetic animals https://www.youtube.com/watch?v=AcX2n1rC4W4