# What needs to be changed in the structure of the human body in order not to die from cyanide?

Cyanides are the most powerful poisons that affect the mitochondria of cells. A cyanide poisoned cell loses its ability to breathe. In mitochondria, cyanide acts on the cytochrome oxidase enzyme localized in the inner membrane, and specifically on the heme that is part of it (the same heme that is part of the hemoglobin). The mechanism is quite simple - the cyanide ion (CN-) forms a coordination bond with the iron "lying" in the very center of the heme.

Therefore, it is dangerous to ingest potassium cyanide in any form: both in the form of a dry substance and in an aqueous solution. The poison is dangerous if swallowed (passed through the digestive tract). Hydrocyanic acid - a relative of potassium cyanide - is dangerous if inhaled, as it is volatile.

And here we come to the purpose of my question: What do you need to change the human digestive and respiratory systems, which are the easiest method for these poisons to enter the body, in order to neutralize their danger (not poisoning)?

• If you are asking if something is realistic you cannot expect to have it documented in some scientific paper. That's why reality check and hard science are mutually exclusive. Please pick one – L.Dutch - Reinstate Monica Nov 9 '20 at 14:56
• This question is not proposing any mechanism to be checked versus plausibility. Which is when reality check comes into play – L.Dutch - Reinstate Monica Nov 9 '20 at 14:59
• (a) reality-check requires you, the OP, to provide a complete scenario based on the rules of your world and a complete description of those rules so we can judge whether or not the scenario is consistent with the rules. You have not done that. (b) hard-science requires answers to provide mathematics, journal/article citations, etc to prove the answer. We can't modify the human body for any purpose now (e.g., to permanently raise metabolism, which would sell like hotcakes) - what hard science are you expecting? – JBH Nov 9 '20 at 15:12
• (c) I'm an electrical engineer, so if I ask a EE question and tag it hard-science I can understand and judge the results. As an engineer, I can understand the results of most hard-science mathematics-based answers. But I can't even pretend that I'd understand the medical/biology/physiology hard-science that would meet the tag's mandate for this question. ... Are you qualified to understand such answers, which is required to judge a best-answer? – JBH Nov 9 '20 at 15:16
• The question AS ASKED has no answer. No "structure" change could grand cyanide immunity. You would need to fundamentally change the cellular biochemistry. – user79911 Nov 9 '20 at 20:28

Let's see if there is a possible way to immunize against CN on the basis of how CN affects the body:

# Immunity is impossible: you would need to change EVERYTHING

The chemical reaction cyanide - CN - has with the blood is cyanide poisoning. It results in the inability of cells to take the oxygen from the blood by inhibiting the cytochrome c oxidase enzyme. As a result, the blood becomes over oxygenated and the skin appears very red. In a non-fatal dose, the CN will get metabolized into thiocyanate and a complex aminoacid, which then get metabolized further over time. The first step occurs usually within one hour of exposure, unless the dose results in the death of the body from the inability to get oxygen to the cells.

As the effect of CN is on a crucial part of the cell membranes that is shared by every oxygen-consuming organism on earth, including most bacteria, you need a species that has a totally different genetic set up and does not use a molecule even remotely similar to cytochrome c oxidase. This means you need to start your alterations back with a totally different startup in evolution. To he immune to CN, the organisms would need to evolve in a CN-rich environment and have to cope with the naturally occurring CN in the phase of evolution when oxygen-consuming organisms started to evolve.

Lack of the cytochrome c oxidase (CCO) would immunize to CN, but there is no breathing life without it that we know of. So even if we could make a human without CCO (we can't!), we know of no other mechanism that can get the oxygen from the hemoglobin into the cells, so any tissue that is affected by such a modification (which we can't do in the first place) would be doomed to die from suffocation and ATP deprivation.

# Best available: reduced sensitivity

The best available method that could be implemented to increase the dose of CN that is non-lethal on a human body is a large dose of hydroxycobalamin / Vitamin B12 into the bloodstream, as it bonds more readily with CN than the CCO does. It is also the active resulting molecule in over-the-counter nutritional supplements to counter B12 deficiencies like Cyanocobalamin. In this application dosages of 1 gram are common.

As B12 is generally safe, non-toxic even in large doses, and has only comparatively low impact side effects (compared to other antitoxins) it has become the standard treatment for Cyanide poisoning. Its closest competitors were Sodium Thiosulphate, which is considered more problematic and sometimes too slow as discussed in this paper, and dicobalt edetate or 4-dimethyl-aminophenol, both also quite problematic as discussed in this paper. Because of its nearly nonexistent toxicity, it is given in comparatively extreme doses compared to other antitoxins when used as emergency aid against acute CN exposure: a 90 kg person will get a dose of about 13 grams B12 to fight off an acute cyanide poisoning.

Why do I say it's a massive dose? Because measuring active ingredients in grams per milliliter is huge: Atropine, the counteragent for organophosphates (and a nerve agent itself!) is packaged in autoinjectors that contain 1.67 mg and the dosage information prescribes only at max 3 of these, so the total max dose is about 5 mg, or $$\frac {38} {1000}$$ of the dose that is considered safe and sane for Vitamin B12!

The least impact route would be to keep the hydroxycobalamin levels high and increase the tolerance would be a daily dose of B12, either in the shape of pills or, especially in high exposure areas, by injection. It might also be advisable to have some autoinjectors handy in case of acute exposure.

Currently, we are not able to modify humans in the degree needed to produce Vitamin B12 naturally, especially not in the doses needed to counteract cyanide.

• You suggested there is a mechanism the body has in non-fatal cases to deal with cyanide poisoning. Could that method be cranked up to ludicrous levels to make the non-fatal dose much much higher? – Rob Nov 11 '20 at 16:10

# Breathe Deep:

While we don't have a specific animal who is immune to cyanide, we do have a host of organisms that are, and we have a parallel toxicity that has evolved: that of oxygen.

One solution is to completely change out heme for a similar molecule that binds oxygen better than cyanide, but only weakly binds cyanide or at least reversibly. The problem is that cyanide binds extremely well to heme compounds, and typically irreversibly. Which molecule to use instead is problematic, as respiration is HIGHLY conserved and I'm not sure what alternate molecules would work.

Lots of plants make cyanide, and deal with the effects by binding it up in an inert form. If your people have enzymes that react with cyanide to convert it into an inert form not readily toxic, it will build up but not kill the person. Add a method to flush the resulting inert form out, and the cyanide goes away. We are not plants, so this may or may not work perfectly. While the mechanism for cyanide resistance is not elucidated yet, there is at least one beetle that has been recently identified as having an extremely high tolerance for cyanide.

Various bacteria have resistance to cyanide, and this can be attributed to specific enzymatic reactions that react the cyanide into less toxic compounds. If your world is soaking in cyanide, this won't work, but the functionality is very much like how eukaryotic organisms deal with the toxicity of oxygen. Our eukaryotic ancestors were anaerobic, and found oxygen toxic, needing complex adaptations to compensate, but the energy advantages were so great that they developed defenses and established a symbiotic relationship with mitochondria.

Biology is a little more difficult to nail down with hard science. Hope this meets your needs.

The only possibilities that come to mind are for the organism to carry and antidote to the cyanide already in its body fluids. Thiosulfate is the classic "antidote" to cyanide poisoning -- except the way it's usually shown in movies and fiction (for instance, in a MacGyver episode, in which Mac saves Peter after the latter has been sprayed in the face with cyanide, by draining fixer from a handy photographic mini-lab and getting the semi-conscious Peter to drink it) won't work. The thiosulfate needs to already be in the subject's blood and body fluids before the cyanide is introduced or injected IV quite quickly.

I've been reminded, however, that hydroxycobolamine, one form of Vitamin B12, is an even better blocker for cyanide than thiosulfate; it has virtually no toxicity and is an existing natural substance found in many foods already consumed by humans. It might be sufficient, depending on the environmental cyanide load, for your colonists to take daily supplements -- or they might be fitted with an internal dosing device (like an implanted insulin pump) to ensure that even if they don't or can't eat for a few days, they maintain protection for as long as the device's supply of the vitamin lasts.

Bottom line, the only practical way to manage persistent environmental exposure is to ensure that the subject always has enough blocker/binder present to neutralize the commonly encountered levels of cyanide and its compounds. Fortunately, this is within current technology -- give us another few centuries, and it might be possible to produce (for instance) a symbiont to produce hydroxycobolamine without equipment (and its capacity limitations). The symbiont would limit your dramatic options (but what if someone's immune system attacked their symbiont colony?), but would make an otherwise uninhabitable planet possible to colonize.

• Thiosulphate was massively outpaced by hydroxycobalamin - Vitamin B12. Less counterindications, and you can pretty much not overdose it. – Trish Nov 9 '20 at 15:52
• Thanks, @Trish -- I'll edit that in as an alternative. – Zeiss Ikon Nov 9 '20 at 16:50

On some reflection, I agree with Trish that immunity in a biological context probably isn't possible for cyanide, but, with some heavy modifications, it should be possible to engineer an organism that is resistant to all levels of cyanide it is likely to encounter. You're not going to achieve this with just a single modification, but a number working in concert should get there.

Modification of Cytochrome oxidase C would be possible - there's probably an enzyme alteration that would prevent cyanide from binding to the iron ion in the enzyme. This would be hard, though. Cyanide is a very strong binder of Fe+3 ions, and this is likely to be hard to defend against. This paper suggests that swapping in an alternative version of cytochrome C into the pathway confers good resistance, and is well tolerated in mammalian cells. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456879/)

An easier method is to do what, classically, the body does with toxic compounds, which is to have specialist enzymes to break down or manage them - In cyanide's case, it might be as simple as having a lot of molecules with Fe+3 ions to mop up the cyanide - a modification of hemoglobin would do this, and, in fact, one of the antidotes creates a modified form of hemoglobin (but causes a drop in oxygen transport in the process, because it uses existing hemoglobin). An enzyme would probably be involved in recycling the modified hemoglobin. Thiosulfate cyanide transsulfurase might work without modification, to convert the cyanide into a much less toxic substance, which can then be excreted.

Finally, although I've not found an example for cyanide with a quick search, the other, classic, method for control of toxic substances is to remove them from the location in which they'll be harmful - I can't find something like a cyanide pump, but this would be another, biologically plausible mechanism to add resistance

The modifications would be pretty energetically expensive, though, and are unlikely to evolve in a normal environment. Your proposed organism would have to be full of modified hemoglobin, requiring a large amount more iron. Getting this would probably require an increase in food, particularly red meat (being a good source of bioavailable iron)

• We know of no misconfiguration of Cytochrome Oxidase C that does work in transporting oxygen and at the same time being insensitive to cyanide. Regarding the other part of the answer, Sodium Thiosulfate (metabolised into Thiosulfate-cyanide), was already mentioned. – Trish Nov 10 '20 at 16:51
• Hi Trish, this paper: ncbi.nlm.nih.gov/pmc/articles/PMC1456879 suggests at least that swapping in cyanide-insensitive alternative oxidase (AOX) from Ciona intestinalis works in mammalian cells to substantially increase cyanide resistance. I don't think we'd get to immunity from one modification, but this, combined with upregulation of the enzymes in the thiosulphate pathway might give a decent level of resistance. I think we'd also need to define "immunity" in a biological context :P – lupe Nov 11 '20 at 13:51
• resistance is the right word: immunity means it can't ever bond with CN - and that is outright impossible. Immunity in biological context is nigh impossible. If you incorporate that paper into your answer and explain that it only increases resistance, that's a 2 point swing. – Trish Nov 11 '20 at 13:59
• that's fair - I guess total immunity is not something I'd normally think of in biology -most things are toxic at high enough concentrations, if only from osmotic pressure! – lupe Nov 11 '20 at 16:40