• N&PD Moderators: Skorpio | thegreenhand

How to create Congenital Insensitivity to Pain

Maybe with selective lesioning of the brain via radiation or manual surgery. Where exactly to aim is going to be the key problem you face there, I don't know if there is any one site that controls pain. Or a nerve block placed at just the right spot on your spine.

Total insensitvity to pain is not as wonderful as it sounds: pain plays a very important role in keeping our bodies from physical threats. If you break your ankle and then run a marathon anyway, I'm sure there'd be nothing left to save after the first few hundred meters.

wiki said:
People with this disorder are very likely to injure themselves in ways that would normally be prevented by feeling pain. For example, a patient could burn themselves severely and not even notice. The main features of the disorder are lack of pain sensation, painless injuries of the arms, legs and oral structures, [...] infection and scarring of the tongue, lips and gums, chronic infections of bones and joints, bone fractures, multiple scars, osteomyelitis and joint deformities, which may lead to amputation. Other common problems are eye related, such as infection due to the sufferers rubbing them too hard, too frequently or scratching them during sleep.

Now, I'm not a doctor, but a drug that led to people inadvertently destroying their corneas during sleep and waking up blind does not sound like the FDA would approve it, nor does it sound like anything I would want to take.

As far as I know, essentially every single painkiller will produce tolerance (as well as some degree of side effects) that will lead to you being forced to stop the "therapy" eventually anyway, and then fight through a miserable withdrawal.

Also, re: nerve blocks - injecting anything spinally is a bit of a tricky issue, which is why it's generally reserved for extreme cases like childbirths. And they're temporary to boot.
 
Aren't local permanent blocks possible?

That is to say, non-spinal blocks, targeting a peripheral pain nerve close to the area in constant neuropathic pain and giving an injection to destroy the pain feed to that area (by means of destruction of the pain signal-transmitting nerve(s) themselves)?
 
Don't local nerve blocks kill non-pain sensations, too? Also they would have to be done for the entire body, including for internal organs... so I'm not sure if that's possible... :?
 
People with that illness have a severely shortened lifespan. They constantly injure themselves but have no awareness that they are hurt. They can walk around complete unaware that they have broken their back or their appendix is about to burst. With all its drawbacks, pain also serves an important role.
 
Well I think it somewhat of an overstatement to suggest they would walk around having broken their back.

People who have snapped their back generally don't start tap-dancing in the streets.
 
˄Because it hurts, and the cognitive load involved in attempting to mimic the results of pain on actions is surely overwhelming. That's where those 'fake it till you make it' body-language folks fail too.

OP, you could go for fancy CRISPR editing of the SCN9A gene, to mimic the cause of congenital insensitivity to pain as closely as possible. Mull it over well before you jump in, although I suppose you can use the time spent designing the guide RNAs and making the virus for that.
 
CRISPR is interesting as hell.

Do you know if it can be used on fungi? (ascomycete species, macrofungus not smuts/rusts)

And not due to pain. Due to the minor inconvenience of having snapped their spine, and become at best, paraplegic and probably covered in their own faeces.
 
CRISPR is interesting as hell.

Do you know if it can be used on fungi? (ascomycete species, macrofungus not smuts/rusts)

Absolutely it can - the Cas9 enzyme is about as open minded as they come: DNA is DNA. There was a bit of brouhaha (or rather surprisingly little) over non-browning CRISPR'd mushrooms a couple of months ago.

And not due to pain. Due to the minor inconvenience of having snapped their spine, and become at best, paraplegic and probably covered in their own faeces.

That might be an issue, it's true. Mostly for the shame of the facial faeces - unfortunate that social pain remains intact in these folks.
 
Why would one voluntarily want to induce an extremely dangerous disease that drastically reduces life expectancy?

Normally people die before they get 3 years old and the extremely lucky ones still die before they get about 25 years old!

Congenital insensitivity to pain

CIPA is often seen as a condition exhibited in children as the life expectancy of patients with CIPA is very low. Most infants don’t pass 3 years and those that do, commonly do not make it past 25 years. The reason for death is due to the wear and tear done to their bodies as well as hyperthermia (Mardy et al., 2001)
 
Chances are it would take more than the minor bother of a severed spinal cord and broken back to outdo the pain from publicly covering yourself in your own shit, in a spontaneous DIY impression of donald trump.
 
As mentioned in the wikipedia article, the cause of this disorder is a SNP in SCN9A, which forms the alpha subunit to Nav1.7, a voltage gated sodium ion channel highly expressed on nociceptors. People who have this disorder need to be very proactive in avoiding injuries, and most have a short lifespan. In one case study, a 10 year old child with this disorder worked as a street performer in Pakistan, walking on hot coals and placing knives through his arms. He died at 13 from falling off a roof.
 
Thanks for the primer on CRISPR-Cas9 mate.

What I'd been thinking about, is that there are certain regulatory factors within the fungal genus Claviceps, a genus of ascomycete fungi that exist in the wild, as parasites on certain grasses. Most of the species have either a genus or a single species within which they are restricted to parasitizing, quite toxic for the most part, producing various mycotoxins, as well as lysergic acid derivatives, simple amides occasionally, clavines and lysergic acid peptides such as ergotamine, ergovaline, ergocristine and others. Although unlike most, one species, the one I have to work with, C.purpurea; the common or garden rye ergot has an astonishingly wide range. It isn't so much unfussy about that which it parasitizes, it is an absolutely whorish little bugger!

Not just genus-wide host range but entire orders of grasses, Arundinoids, Pooids, even sedges IIRC.

Rye was the classic (and favourite) host species, and it used to get into the bread in the middle ages before it was understood, and is thought to have been responsible, possibly, for the epidemic of witch-mania and inquisitions, courtesy of hallucinations, seizures and severe vasoconstriction resulting in gangrene. Not really ideal for a sandwich. But the alkaloids it produces are useful, once one manages to engineer a productive strain, using various mutagens on cultures, along with colorimetric testing with Van Urk or Erlich's reagents to determine alkaloid levels.


Problems are twofold-one is, once the strain is there in front of someone, KEEPING it there is another matter, because the little sods become senescent after several subcultures usually. And also, its difficult to store because productive strains usually, but not universally, do not produce conidia.

And ascospores of course are less useful because they will not then breed true. I wish to have a shot at at least knocking out the regulatory factors involved in senescence, along with a negative feedback mechanism controlling tryptophan biosynthesis. And the more available to the fungus, given the lysergic acid is biosynthesized from dimethylallyltryptophan the better the yield. Quite a lot of things I wish to try, mind you but the senescence, and conidiation are the two primary targets for attempted manipulation.
 
Your ideas sound good. I imagine that, Claviceps being an ascomycete like S. cerevisiae, all the CRISPR-Cas9 refinements developed for yeast should help you in your system. And the fact that you're more interested in knockout than mutagenesis makes guide RNA design a doddle. There are a ton of good tools for that, and others to check for potential off-targets etc.

I see that your species of Claviceps already has 2% of dry-mass as ergotamine. Is the precursor concentration the main bottleneck?
 
Well I think it somewhat of an overstatement to suggest they would walk around having broken their back.

People who have snapped their back generally don't start tap-dancing in the streets.

Fracturing the vertebra in your back is not the same as transecting your spinal cord. You do understand that it is possible to fracture a vertebra without being paralyzed?

In the situation where you break a vertebra, bone, etc, the one thing that stops you from continuously re-injuring it is the severe pain. They don't have to be "tap dancing in the streets" -- depending on the injury, just continuing to move would be enough to cause severe damage. That is why they put patients in traction.
 
Last edited:
the easiest way to get close to that is to contract leprosity. contrary to popular belief the disease does not make your limbs fall off. instead it kills the nerve cells responsible for feeling pain. as a consequence people hurt themselves and get serious infections which lead to the loss of limbs.
 
Last edited:
Umm I'm genuinely wondering, is the fungi stuff above related to CIP? 8( If not, I'd like to just ignore...

And isn't CRISPER not really supposed to work on adults yet?

Anyway CIP patients don't have working Nav1.7, but they also have constantly high endogenous opioid level, which researchers think contribuetes to their pain insensitivity. So if i have a constant mega high internal opioid, I may become CIP %)
 
Umm I'm genuinely wondering, is the fungi stuff above related to CIP? 8( If not, I'd like to just ignore...

And isn't CRISPER not really supposed to work on adults yet?

Anyway CIP patients don't have working Nav1.7, but they also have constantly high endogenous opioid level, which researchers think contribuetes to their pain insensitivity. So if i have a constant mega high internal opioid, I may become CIP %)

It was an offshoot from the CRISPR suggestion, so ignore away!

CRISPR hasn't shown to be safe for use in humans, but the technology is there, and it most certainly works in adult animals. I expect the most serious problems to be secondary effects of single gene manipulation, not probelms caused by CRISPR per se. It's a pretty straightforward technique.

I think there are a variety of independent causes of CIP. Do patients with the sodium channel mutation have elevated opioid levels?
 
Umm I'm genuinely wondering, is the fungi stuff above related to CIP? 8( If not, I'd like to just ignore...

And isn't CRISPER not really supposed to work on adults yet?

Anyway CIP patients don't have working Nav1.7, but they also have constantly high endogenous opioid level, which researchers think contribuetes to their pain insensitivity. So if i have a constant mega high internal opioid, I may become CIP %)

Only in some of the cases do high endorphins contribute to symptomotology. Administration of naloxone, as a result, only works in a few cases.
 
Wildtype C.purpurea doesn't have anything LIKE that. 2/3-10mg per liter is more like it.

Think I'm likely to fuck about with nitrosamines, DMSO4/EMS, strong alpha/gamma sources and the likes just for the fun of it? :p Because you must be shitting on my breakfast if so. Not things I am prepared to have more to do with than absolutely necessary. Hydroxylamine is about the only one of the planned for mutagens that isn't downright evil stuff. Use if needs be, sure but...I don't REALLY like the thought of getting cancer or dropping dead.

There is very little point at all messing with wildtype purpurea ergot, not unless you happen to have a rye field and are content to build a self-propelled pricker machine (these are something vaguely similar to a combine in basic theme, only instead of harvesting, they run the heads of grain through a pair of spiked rollers that are sprayed with culture) but with unmutated wild type C.purpurea and simple infestation and alkaloid harvest you'd have fairly poor results. So the answer is almost certain to be liquid, solid cultures, or better, encapsulation in alginate microspheres doped with a perfluorocarbon inert type solvent that acts as an oxygen transport enhancer (this enhances stability, and helps shield the encapsulated culture from one of the number one enemies, mechanical shock, Worse than many other insults by quite a long way. Claviceps spp. are sensitive as hell little buggers.
 
Top