Brain cell, Cell, Neuron, DNA damage, Genetics YSP BlueSciCon 2021: Aditi Nayak – Mitochondria, Brain Organoids, and Space Travel

Why would someone especially researching astrobiology not want to go to space? Well, i have two reasons. First, im, terrified of roller coasters and space flight seems like the most intense roller coaster at universal, except instead of universal. Our theme park is the entire universe, ill admit, thats, not the best reason. Eventually, i do get the courage to go on roller coasters and i even end up enjoying it, but im more hesitant because of my second reason, by observing astronaut help. We know this journey changes. The human body whats scary to me is that we dont fully understand why, this summer, through reading literature and designing experiments on mitochondria brain organoids and space travel, i began to find my answer. Last year, in 2020, the cell journal published this piece written by 38 authors. What they sought to do is take existing data available through the genelab database at nasa, which collects data from previously conducted spaceflight experiments. These experiments included those with mouse models and human models on the organismal tissue and cellular level upon analyzing these available data. The researchers stumbled upon a unexpected finding across all organisms and cell types. They noticed that the mitochondria consistently had something changed about it after space flight. Now this figure depicts that trend specifically in human cells. Each oval here represents a different type of human cell. That was analyzed through this experiment, and each color represents a different grouping of genes. The genes that are included in this were actually significantly altered in their expression levels.

When you compare space, flight amounts to at earth amounts where you see two ovals overlapped. That means that gene at the overlap was changed across both or multiple cells, where all four of these ovals overlap. There is four four genes that were consistently changed as a result of space flight, and what was interesting is that all four of these genes had some function related to the mitochondria. This was true not only of human cells but also of mice, cells, also of mice and human tissues, and even mice as a full organ organism and humans, as a full organism now not pictured here, but another very interesting. Finding from the study had to do with the different types of dna that create the mitochondria in the human body, so mito so dna for the mitochondria come from two places. First, they come from the mitochondria themselves in the form of empty dna or mitochondrial dna, but they also come from the nucleus in the form of n dna or nuclear dna. What this study had found that i found very interesting was that the levels of nuclear dna and mitochondrial dna expression were both changed as a result of space flight, but it was not necessarily in the same way or in the same way across different organisms. This is important because this dna relates directly to how the mitochondria functions, for example, this dna encodes for proteins that are involved in the oxidative phosphorylation and the electron transport chain, which are processes by which the mitochondria produces energy.

The cell paper, the cell paper, also found altered levels of calcium and oxidative stress as a result of space flight, and both of these values are typically regulated by the mitochondria. This lack of calcium, homeostasis and different oxidative stress levels could impact the fourth function of the mitochondria, which is to start apoptosis or cell death. Now the mitochondria have different functions and can infect a lot of organs throughout the body. So if its true, that mitochondrial dysfunction is at the core of space flight impacts, then this gives us a sort of unifying framework to understand all the different health consequences we see with space flight and try to backtrack backtrack them to a root cause which we can Address through through medicine and therapies, now, if only the answer was that simple, of course, things get complicated specifically in here, mitochondria play a lot more functions than just the four that i laid out. Furthermore, mitochondria actually have take different shapes and different organs in the body and even amongst the same organs, they can look very different, even within the same cell. So what we want to do is try to understand how space flight impacts, specific types of mitochondria and try to find a more clear solution, because the cell paper could only look at a at a bulk analysis of mitochondria. And perhaps by doing so, we hope to create more targeted countermeasures that address mitochondria and prepare us to to help and ensure astronaut health isnt damaged as a result of spaceflight.

Now, in addition to astrobiology, there is also some evolutionary biology applications of our work. More specifically, it could apply and give us more clues about the endosymbiotic theory, which was popularized by lynne. Margulis, now to understand this theory, i want you to consider this question. What if i could absorb another organism and then take on its abilities? So imagine two billion years ago there was a prokaryotic cell with a nucleus and it came across this aerobic bacteria which could use oxygen to create atp or energy. At some point, this prokaryotic cell could have engulfed and encompassed that aerobic bacteria inside the larger host cell. This aerobic bacteria would continue to divide, as it always had, it would continue to produce energy as it always had, but now their existences are somewhat linked. This process of engulfing is known as endosymbiosis, and this aerobatic aerobic bacteria is what we think is today. The modern mitochondria now im happy to discuss more evidence for this endosymbiotic theory after the talk, but one important piece of support is that modern mitochondria actually have their own dna and ribosomes. In fact, their dna has a circular structure that is very similar to the dna of the aerobic bacteria, so dna for mitochondrial function comes from two places: mitochondrial dna and nuclear dna. Thus, when we see space flight impacting nuclear dna differently than mitochondrial dna, maybe this differing response actually has to do with where these dna originated from and if so, what makes one origin less susceptible to space flight than the other, and can we take advantage of that To create therapeutics to protect the more vulnerable one to get us to this level of understanding, we decided to use organoids to help us understand how mitochondria are impacted by space flight now derived from stem cells.

Organoids are these tiny self assembling 3d structures which can recapitulate the structure and function of a human organ, possibly even its mitochondria? Now for this experiment, we specifically decided to look at the cerebral or brain organoids, and this is a decision im happy to talk about more during our q, a section with organoids, as our platform were hoping to change some environmental conditions to start predicting. How mitochondria in these organoids would respond to spaceflight like conditions, but before we get to this point, we need to understand how the mitochondria in these organoids on earth just in a baseline. What do they look like? What is their health like in these normal conditions? To do so were looking at four things: first, the morphology or the shape of these mitochondria; second, the membrane potential and third and fourth, the levels of oxidative, stress and atp. Now the reason we picked these four measures of mitochondrial health in particular is because the experiments we can do to measure these levels are actually simple enough. Where maybe one day we can do them in space with current technology. Thats available with this established baseline well then expose these organoids to one of three simulated space flight conditions listed here, so that includes radiation exposure, high co2 levels or microgravity. After exposure to one of these three simulated space, flight conditions, well reevaluate the mitochondrial health and compare it to the baseline. With this comparison, we can make better and stronger predictions for how these mitochondria will actually respond to real space flight, and that leads us to our next point.

Sending these organoids to space now pictured here are a few different extraterrestrial locations where we can send these brain organoids and conduct more targeted, mitochondrial, chondrial experiments, and with this we can actually see how these brain organoids and their mitochondria are responding. Not to just one aspect of space flight, but space flight as a whole, as i mentioned before, mitochondrial dysfunction can impact a lot of different organs, and this is true whether that abnormality is caused by space flight or otherwise. The effects of mitochondrial dysfunction can vary organ to organ and as as listed here, there are many ways that the abnormality can manifest in the human body: understanding how space flight leads to mitochondrial dysfunction and in turn health impediments. Maybe we can develop therapeutics for astronaut health that way we are one step closer to a future where everyone who wants to go to space. Even those of us a little too scared for roller coasters can feel more confident for takeoff, and on that note, id love to launch into some questions, job of dt uh. I see some claps coming in the reactions. Uh well open it up to questions. Can i just say, though, um how awesome it is that you looked at the camera almost the entire time um? That is fantastic im, so glad to see that the change from the practice to now um you did such a great job uh. We have a question from sanjoy. I think you actually have many.

This is a really interesting presentation and so, first of all, im gon na. Take you up on it. What are brain organoids and why are those your your cells of study and, secondly, um? Can this work have some applications to uh radiation treatment on earth like cancer disease, for example, to make the treatment more bearable, then our radiation treatment is very brutal on the human body um. Does your work have some applications that could make radiation treatment uh? You know less less of a chore to bear yeah. Those are both really good questions. I guess ill address them in parts. So the main reason we decided to go with brain organoids. I guess its theres a few reasons behind it, but when were looking at mitochondrial dysfunction, mitochondria im actually so proud that i didnt say mitochondria is the powerhouse of the cell thats. What everyone knows them for um, so high energy expenditure organs such as the or such as the brain are probably the most likely to be affected by mitochondrial dysfunction or wed expect them to really show a large difference as a result of mitochondrial dysfunction. Thats. One reason we decided to look at brain organoids um on top of that in the in the initial cell paper study they actually couldnt, look at the brain as an organ being being affected by space flight, um, so kind of to address that gap. We wanted to put brain organoids in to fill that gap of knowledge in terms of the applications to radiation, um, radiation therapy and other like cancer treatments.

That specifically, is a very interesting application that i hadnt thought of, but i do know they are actually using organoids. As a way, i mean its really hard and its very unethical to just take a human brain and see how it reacts to all these treatments right, so organoids are being used. They are a relatively new platform, but they are being used in similar ways to kind of test out what things might look like on the brain before actually putting them into action yeah. I hope that answered both of your questions. Absolutely thank you. It makes sense now because brain requires a lot of energy and mitochondria, either powerhouse of the cell um. Could you generate brain organoids from stem cells to try and avoid the ethical? Well, minimize the ethical uh challenges yeah, so thats thats, the exact process by which it happens were actually very lucky. We have two collaborators who run labs, that specialize in organoid generation and like working with organoids um, so they both know a lot more about this, and i do.

What do you think?

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