Gene therapy holds potential for treating a variety of brain conditions, particularly those with a genetic basis or where specific genes contribute to the disease process.
Some brain conditions that may benefit from gene therapy include:
Neurodegenerative Disorders: Diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS) are characterized by progressive degeneration of neurons. Gene therapy approaches aim to either slow down the progression of these diseases or replace damaged cells with healthy ones.
Monogenic Disorders: These are disorders caused by mutations in a single gene. Examples include Tay-Sachs disease, Rett syndrome, and various forms of hereditary ataxia. Gene therapy could potentially correct the underlying genetic defect or provide a functional copy of the faulty gene.
Epilepsy: Certain forms of epilepsy have a genetic component. Gene therapy may target specific genes or pathways involved in seizure activity to reduce the frequency and severity of seizures.
Brain Tumors: Glioblastoma and other types of brain tumors often have genetic abnormalities that drive their growth. Gene therapy approaches can target these abnormalities, either by directly killing cancer cells or by enhancing the body's immune response against the tumor.
Neurodevelopmental Disorders: Conditions such as autism spectrum disorder and intellectual disabilities may have genetic components. Gene therapy strategies could potentially modulate gene expression or correct genetic defects to improve cognitive function and behavioral outcomes.
Mood Disorders: While the genetic basis of mood disorders like depression and bipolar disorder is complex and multifactorial, gene therapy approaches may target specific neurotransmitter systems or signaling pathways implicated in these conditions.
Inherited Metabolic Disorders: Disorders such as phenylketonuria (PKU), mucopolysaccharidoses, and lysosomal storage disorders can lead to neurological complications. Gene therapy may offer a way to correct the underlying metabolic defect and prevent or ameliorate neurological symptoms.
Neurodevelopmental Disorders: Genetic abnormalities, such as Fragile X syndrome, can lead to neurodevelopmental disorders. Gene therapy aims to correct or compensate for these abnormalities to improve cognitive and behavioral function.
The effectiveness of novel therapies for brain disorders can vary widely depending on several factors, including the specific disorder being treated, the stage of development of the therapy, the complexity of the underlying biology, and individual variability among patients.
Here's a breakdown of some factors influencing effectiveness:
Targeted Approach: Novel therapies that target the underlying mechanisms of a brain disorder tend to be more effective. For example, therapies that directly modulate dysfunctional neural circuits or correct genetic abnormalities associated with a disorder have the potential to produce significant therapeutic benefits.
Stage of Development: Many novel therapies are still in the early stages of development, undergoing preclinical and early clinical trials to assess safety and efficacy. As these therapies progress through the development pipeline and accumulate more clinical evidence, their effectiveness may become more apparent.
Patient Heterogeneity: Brain disorders are often heterogeneous, meaning they can manifest differently from one individual to another. Novel therapies may be more effective for certain subtypes of a disorder or in patients with specific genetic or biomarker profiles. Personalized medicine approaches aim to tailor treatments to individual patients to maximize effectiveness.
Delivery Challenges: Some novel therapies, such as gene therapy or targeted drug delivery, face challenges related to delivering therapeutic agents across the blood-brain barrier or targeting specific regions of the brain. Overcoming these delivery barriers is crucial for ensuring the effectiveness of these therapies.
Long-Term Outcomes: Assessing the long-term effectiveness of novel therapies for brain disorders is essential, as some treatments may produce initial benefits but lose efficacy over time or lead to unintended side effects. Longitudinal studies are needed to evaluate the durability of treatment effects and monitor for potential adverse effects.
Combination Therapies: In many cases, the most effective approach to treating brain disorders may involve combining novel therapies with existing treatments or other complementary interventions. Combination therapies can target multiple aspects of the disease process and improve overall treatment outcomes.
Overall, while novel therapies hold promise for improving the treatment of brain disorders, rigorous scientific research and clinical trials are needed to evaluate their effectiveness, establish safety profiles, and identify optimal treatment strategies.
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Humans and aliens don’t mix
I love this concept, I might end up writing something, but for now I’m just gonna do some bullet points. If you’re unfamiliar with the idea, search up “humans are space orcs” and you’ll get an idea where this came from
Humans bond in a very complex social way
- other aliens probably don’t do this
- what if a human bonds to an alien?
- the human becomes very protective and fiercely loving of this alien. The alien probably loves them back, but in a very different and well, alien way.
- the human risks their own safety and goes feral to protect their alien friend. The alien appreciates it, but can’t fathom why they would risk themselves for someone else, no matter how much they like them. The human has done this repeatedly.
- at one point the human is in danger. In theory, the alien wants to protect their human friend, but isn’t willing to risk themself, even though the human is in greater danger.
- the human is in danger, and possibly in pain, and their friend is right there, capable of intervening. Imagine how crushed they are when their friend looks them dead in the eyes, and runs away. After all the human has risked and sacrificed for them!
- the alien feels a bit guilty, of course. The alien does feel they should reciprocate the kindness they were shown, and they really don’t want their friend to suffer. On their planet, friendships are more conditional, they benefit each other in times of peace, but when danger arrives everyone is for themselves. Or maybe their not social at all, and this is the first interpersonal bond they’ve had. Either way, anyone from this alien’s species would understand, and wouldn’t blame them. It’s not their nature, their brains don’t function like that. There are no protective instincts or courage, but the human doesn’t understand.
- anyway yeah, hurt feelings. The human feels betrayed and abandoned. Especially combined with the hurt of whatever happened to them in the first place.
- the alien knows that they hurt their friend’s feelings, and is pretty torn up about it. Despite the guilt, they’re also kind of angry. The human can’t expect them to do such extreme things for them! The human does so much more for them, but it’s still a crazy demand to ask!
-they probably reconcile, with the human understanding that this isn’t the alien’s fault really, it simply isn’t a function of their behavior. Even so, the human will have to accept that no matter how much they’d sacrifice for their buddy, they can never expect the same in return.
Also, a human meeting an actual space orc? HELL YES! This could be the same alien, or a different one, i’m just rambling. (Don’t know where I saw this idea, but I can’t find the post sadly).
- imagine being feared and considered immensely dangerous. Your planet being considered a death world and you being considered badass, tough, cutthroat and terrifying just for surviving it. Imagine the complex that would give you, especially if your species is rare and your pretty separate from them!
- the human is used to being feared. They’re used to the hushed whispers, they’re used to being one of “the scary ones from the death world”. From hearing this for so long, they’ve come to believe it. They subconsciously decided to fit the bill of how they’re perceived. They act tough, aggressive, feral. They know they’re scary and badass and they flaunt it, they like being perceived this way.
- the alien, also from a so-called death world, is the opposite. They’re friendly, they’re peaceful, and they hate their reputation. They hate how their species is perceived just because of where they hail from. They aim to break the stereotype, and show the gentle giant that they actually are.
Now have them meet >:D
The human Sofia sits at the bar. The seats within six feet of her are all empty. She guzzles her fifth drink - apparently most species are affected by it similarly to alcohol, and some weaker species would be dead by the fifth drink. Sofia remains unaffected. She could drink 30 and be unaffected. It doesn’t even taste good. She slams her empty goblet on the table, all for show. The conversations nearby hush even further, and the fearful whispers start up again. Good. She should be feared.
The door opens. In comes a gust of wind, and a hulking figure. No one in the bar is talking now.
Sofia slowly turns to face the door. She sizes up the newcomer. They’re big, not twice Sofia’s height, but a few feet shy. Not that it matters, when she’s wrestled creatures the size of bears before. The armor plating though, it sported a recognizable pattern. The forelimbs too, that were an odd combination of insectoid legs and tentacles, were a dead giveaway. This was a rragletatch. One of the most feared species in the multiverse, from one of the deadliest worlds known to the galactic community. They’re as rare as humans too. She smirks. Finally, a worthy opponent.
Some chatter starts up again as the rragletatch begins to walk up to the bar, pretending to ignore Sofia. It was still eerily quite, considering this was a bar, and people were drunk. A few gasps and screams echo when Sofia abruptly stands up, knocking over her stool. Her smirk widens into a grin. She stalks confidently up to the rragletatch stranger, and stands close enough that they can’t ignore her. Several people began filing out of the building, while others chose to stay.
“So.” The alien greets her.
“You’re one of those infamous rragletatchen I hear of, no? The ones who are supposedly suuuuper scary?”
“Yes, I am rragletatchen. You’re human, right?”
“Damn right.”
“well then.”
A long pause. Practically the whole bar was listening in anticipation.
“Fight me.” Sofia’s expression didn’t waver. On Earth, she never could have looked so intimidating while staring so far up at someone.
“No.”
what?
“Oh? You scared? I thought you were supposed to be tough or something.” The stranger didn’t look scared, but they must be. Why else would they not want to fight?
“I’m not scared.”
“Then square up bitch. See who’s stronger. Finally put it to the test.”
“No.”
The whispers now were not of fear, but of confusion.
“I will not engage in needless violence,” the rragletatch continued, “contrary to the stereotype of my kind, I will not harm others if at all avoidable. Attack me if you will, I refuse to fight you.” The rragletatch stood still in a wide, but open stance, as if preparing to be hit.
Sofia felt a flash of guilt. Something about attacking an opponent who refused to fight back felt wrong.
“You don’t want to see? Find out who the real champion is?” Sofia pushed aside her feelings and stared up. Unafraid, taunting as ever.
“No. My parents, grand parents and great grandparents before me have embraced a sacred philosophy of pacifism. It saddens me that my kind is known only for cuttthroat violence, only because of our home and biology. I refuse to hurt you. Do you truly wish to hurt me?”
Sofia was a bit shocked to say the least. When she realized her jaw was open and her head cocked, she quickly schooled her expression. That question though... she thought she did. But usually she just liked to brawl. Scare people. Assert dominance. When faced with an unwilling opponent who would not be scared of her... she realized she did not wish to cause harm. She never liked hurting people, that was never the fun of it.
“No.” Sofia sighed. She slouched from her offensive stance and backed over to her seat. “Come, sit with me.” It was phrased like a command, but really it was an offer. Everyone knew Sofia would have a hard time forcing this stranger to do anything. The rragletatch followed reluctantly. Sofia picked up her stool and plopped herself haphazardly on it. The stranger sat more eloquently on one of the many seats next to her.
“I’m Sofia.”
“Yal-sre.”
People moved their seats even farther from the Death-Worlders, or as some call them, orcs.
Suddenly, Yal-sre relaxed their whole body.
“Wow.” Yal-sre almost whispered
“What?” Yal-sre made a sound that, in aliens with exoskeletons, tended to equate to a soft laugh.
“To be completely honest, I thought you were going to kill me.”
Sofia barked a laugh.
“hey! I’ve never met a human before! I didn’t want to judge based on reputation due to my own, but you came on pretty aggressively!”
“Yeah, I’m the apex predator ‘round these parts, and I plan to keep it that way. Still though, I ain’t gonna fight you if you don’t wanna.”
“That’s a relief.”
Neither knew what to say next, and suddenly the nearby silence was so loud. Fortunately, a few conversations began to pick back up now that they were talking peacefully.
“What’s your planet like?” Sofia asked.
“My planet, Challrk, is beautiful. It has vast plains of purple vshink, glowing with bioluminescent insects. Sure, they bite. Sure, I’ve been stung, bitten, chased and harassed by many a critter, but Challrk is a truly incredible place. It has high mountains that stretch beyond the atmosphere, and colors some planets can’t imagine. Our sky is orange and pink, if you can believe that. What’s Earth like?”
“Earth. It’s a rough and tumble place, you can’t survive there without being Hardy. I’ve been chased by swarms of wasps and stung repeatedly more than once. I stepped on a bee and couldn’t walk properly for days. I’ve been stung by jellyfish, and went back into the bay knowing they were there with no protection. Unafraid. Earth is rough, our fauna is often hostile and transmits thousands of deadly ailments, much of our flora is poison. Our weather conditions alone could wipe out an entire species instantly. Earth is extreme.”
“i’m sure that’s true, but that’s what you’ve been told. By people who have never been there. People who are scared because they couldn’t survive there. But what is it actually like? What do you remember?”
“I- I remember the heavy storms. I remember punching a goose and having to go to the hospital. I remember- I remember the blue skies. Fluffy white clouds, flocks of songbirds. I remember walking barefoot because I loved the green grass under my feet, not because I was trying to face danger. I remember a loving family, playing with friends. Warmth and love. I remember going in the bay because I loved the feeling of swimming and playing in the water, not because I wanted to be tougher than the jellyfish. Earth is- Earth is a BEAUTIFUL place and it makes me ANGRY” Sofia slammed both her fists on the table, “that all it’s known for is being dangerous.” A few satisfying screams and gasps rang off in response.
Sofia looked over at Yal-sre. When they didn’t say anything, “I can’t read your face or body language. Can you give me a description?” This was actually a normal question to ask, in places where species were mixed.
“Uh, understanding, I’ve been there. Pleased that we’re getting somewhere. Uhhhhh, still kinda scared of you though. Sorry,” Yal-sre answered. Sofia gaped for a second, before she gave another rough laugh, knowing she probably sounded unhinged to the alien. “Ah!” Yal-sre yelped, “What- what are yours?”
Sofia laughed harder. “laugher can mean many things, in most cases it means ‘amused’. Right now, I am laughing at you, meaning I’m being rude because I find your fear amusing. If there was any non-human who wouldn’t be scared of me, I thought it would be the damn rragletatch. You guys are supposed to be tough shit, but you’re pathetic.”
Yal-sre paused. “Well, yeah. Some of us are tougher than others.”
“Hm, yeah I guess it’s kinda the same with humans. That makes sense. Obviously if you put a fearless human who’s tougher shit than most together with the most timid rragletatch, of course you’d be scared.”
“I’m not the most timid! I’m normal! I’ll bet most humans would be scared of me too, after hearing how “dangerous” we are for so long.”
“Maybe. Humans are tough, but I’ll admit they’re not all like me.” Yal-sre did an odd motion with their... shoulder?
“Translation? I don’t speak shoulder,” Sofia attempted to mimic the motion.
“Understanding, but now amused. Anyway, does it bother you?”
“Does what?”
“The fact that everyone is afraid of you? ... even me?”
“I like being feared.”
“Do you?”
Sofia took a long sip of her drink - which probably made it look like she was drowning her sorrows - to avoid answering the question. When she was done, she placed the goblet face down on the bar to signal to the bartender that she was ready for a refill. The metal was dented... she had put it down too forcefully.
“Oops.” Though it had been an accident, her voice held no remorse.
Anyway, might continue this, might not! I’ve had the “humans are space orcs” idea in my head for a long time, I might later separate this into its own post and make it longer lol.
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Revisiting P2 since the docu epilogue dropped and your AMV (<3) popped up as a sign for me to ask something that hopefully you haven't already spoken about years ago: What did you think of the in-game psych explanation for Maligula, that she's the primitive savage part of the mind? P2 is a weird mix of sketchy Freud/Jung concepts that Tim likes meshed with modern psych, and Maligula's deal seems like something they probably wrote a lot of different versions of but never quite solved elegantly
yeah, i think you totally hit the nail on the head - it's always felt like one of the parts of the story that they couldn't quite give enough polish to before they had to finalize it and move on with development. like - i went to go get my artbook to see if it had any insight into the writing process, and did you know that Nona and Maligula being the same person was apparently added way later in development? that's wild! i didn't know that until literally right now! i may or may not have skipped straight to my favourite characters when my artbook arrived and then put it on my shelf without reading the whole thing
ANYWAY, retrospectively i think it being a twist that was added later actually makes a lot of sense in the context of everything you mentioned. the Maligula problem, to me, is the fact that they're trying to juggle a bunch of different things that she has to be in the story. there's Maligula, the ruthless big bad, and Nona, the beloved grandma, and if you suddenly have to also make them both the same person... well, it ends up being kind of a thorny writing problem to make that work, haha.
here's some art i made so this isn't just a wall of text, rest of the answer under the cut
i think one thing they could have done when they needed to rehabilitate a mass-murderer into a lovable old lady was pull back on either end of the spectrum. make your villain softer and more sympathetic, or give grandma a mean streak like she's one bad day away from a tragedy at the crochet club. and to give the story credit, i'm really glad they didn't. Nona is relentlessly sweet and endearing - and that's great! she needs to be in order to make the audience care about her, otherwise the emotional beats are never going to land. likewise, Maligula is a great villain, she's vicious and ruthless and at the culmination of her arc we see she simply does not give a shit about murdering hundreds of people. i love that for her, honestly, you go girl
but then, like - how do you connect the dots? how do you frame grandma having a violently murderous streak in a way that doesn't make the ending of "but she's over it now" feel kinda weird and hollow? and how do you do that while also being sympathetic to the game's themes around mental health? Maligula's informed by the traumatic things that happened to Lucrecia during the war, but she can't just be a manifestation of trauma, because the moral of the story being that trauma makes you a mass-murderer (until you beat up your trauma and shove it in a giant pit) would feel... really tonally dissonant!
so i think you're totally right that the sprinkling of pop-psych concepts we get ends up feeling a little bit like an awkward band-aid. Maligula's story is about how the horrors of war can shape you into a terrible person, who does terrible things - ...but there's also, like, special circumstances, so it doesn't feel weird that she goes back to being Raz's sweet grandma afterwards. special psychic circumstances! she's not just any war criminal, she's the fight or flight response gone out of control!
which - i dunno, i think that line in particular always stood out to me, because that's not really what the fight or flight (or freeze or fawn) response is, right? it's a temporary boost of adrenaline to the system to rev you up for getting out of a dangerous situation. an overactive fight or flight response is called chronic stress and anxiety. i know the games are pop-psych and not actual science, but it always stood out to me as a little awkward.
if it were me in the writer's seat - with the benefit of all the time in the world to workshop it, and no looming deadlines, and the hindsight of having a full completed game in front of me to think about - i might have tried to frame it around connection. i think you could swing the lens to instead focus on how violence, stress, trauma etc., make it harder to understand and empathise with the people around you. the tragedy of Lucrecia's story is that she came home to try and help her countrymen, the people she cared so dearly about. but the more time passed, the less she cared, the less she was able to see them as people. after Marona's death, the Maligula that remains is one who's unable to even care about killing her own sister. the alternative is too raw, too painful - instead, she sheds her last vestiges of remorse, and throws herself into the easy relief of violence. (we see this again, when Nona "awakens" as Maligula - when confronted with the baggage of her past, she chooses to wash it all away with force, unable and unwilling to care about the people she used to call friends.)
and i think shifting the focus like that ties it in thematically, too. a big theme (of both games, but especially the sequel) is how important connection is, how being able to understand and reach out to and rely on other people is a lifeline during hard times. PN2 touches on how there aren't really "good people" and "bad people" - everyone has the capacity to do wonderful or terrible things, and i think Raz's line to Maligula about how "everybody's got something like you" works. Lucrecia was never a monster, no matter how everyone tried to pretend she was. she was just a person, the same as everyone else - and just like everyone else, she could be pushed to extremes under the right circumstances. it just feels kind of odd when the implicit context is "everybody's got a mass-murderer hidden in the primal recesses of their brain", hahaha.
but like, again, that's the privilege of hindsight, right? i've definitely also been on the other side of the creative process, stuck with something i suddenly need to make work in a story and having to come up with a solution that feels like a band-aid. sometimes you just gotta call it good enough, and move on. and i think the game is overall much stronger for having Nona and Maligula be the same person - it plays into the wider themes, it sets up some great emotional beats, and i think it's overall well-executed, even if there are one or two hiccups in the writing.
anyway, great ask! thank you for the invitation to ramble, this is something that stuck out to me on my first playthrough of the game and it was fun to sit down and get my thoughts in order
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