Stopping a Disease from Evolving

Question

Some evil scientist, let's call him... Dr. BBEG, has manufactured a potent, powerful disease. He has full control over the bacteria's genome now, but once he releases it... not so much. However, in case some pesky group of Paladins, Wizards, and Rangers arrive and mess it up, he obviously needs a kill switch coded into the bacteria's genome. He doesn't want the kill switch to get evolved out, however unlikely this may be. In fact, he doesn't want the disease to change at all.

Can he create a bacteria disease that does not evolve and/or fixes errors in the genome of it's descendants?

Bacteria Details

• Similar to the Black Death in makeup and symptoms
• Vaccines don't matter, the world isn't at that tech level yet. He's using magic to make the disease.
• He can create anything that we can see today in the natural world, or that we can create with CRISPR and other genetic engineering methods.
• I don't think he can use artificial selection, because the whole goal is to STOP evolution, but if you can think of something, then sure, use it.
• He has ~250 years to create the disease.

Answer 1

The problem with proofreading

The simplest way to inhibit mutation is to insert error-checking mechanisms. Real organisms use these to make genetic damage less likely - but there is a significant problem with relying on these.

Any proofreading mechanism can fail. You can reduce the chances of these failures by increasing the number of error-checkers - but the more strict they are, the more they will inhibit the reproduction and survival of the organism itself.

If a bacterium has a mechanism that will cause it to self-destruct (or even become less efficient) if it detects even a small bit of corruption, it strongly benefits the bacterium to get rid of the error-detector itself. Which means that strains which mutate out your constraints will dominate, and you'll be right back where you started.

In nature, there is a fine balance between checking and repairing DNA damage that will inhibit the proper functioning of a cell, and being so strict that it reduces the efficiency of the cell. Multicellular organisms are usually more strict and may include self-destruct mechanisms as well - but this is because these mechanisms protect the entire organism from cancer, so there is strong selection pressure in their favor. For a free-living bacterium, self-destruct mechanisms are pretty much always detrimental and will be selected against.

But you don't really need to stop evolution entirely, do you?

Really, the only problem you have is the issue of the bacterium deleting the kill switch. So what you are really looking for is a mechanism to make the kill switch itself something beneficial (when it's not "activated") - and something that will become less beneficial if it mutates. That way, evolution will work in your favor - strains that delete or modify the kill switch will be intrinsically less fit (NOT due to an internal self-destruct switch) and weeded out by natural selection.

The question is, how?

Social bacteria

Yes, bacteria can be social. In fact, most of them are to some degree - conjugation, quorum sensing, and the formation of biofilms (colonies of bacteria, often involving multiple specialized roles) all involve chemical communication between bacteria. The ability to exchange information about one's surroundings, cluster into groups, and exchange resources is as beneficial for microorganisms as it is for us.

If you want to make sure the kill switch doesn't change, make the kill switch part of this chemical "language". Any bacterium that alters its switch will be unable to "understand" the information from its peers and will be unable to cooperate with them.

If you want to be really fun, you can even program the bacteria to recognize cells containing the switch as "allies" and make them hostile to organisms that are missing the switch. This will allow them to defend themselves against rival species (and their host's immune system) in addition to actively killing off their own mutant strains.

The kill mechanism itself is simply a toxin that mimics the chemical the bacterium uses to communicate. Metaphorically speaking, it's a "killing word" and the only defense is for the bacterium to be "deaf" - which will make it less functional.

As a bonus, if the ability to cluster into biofilms is a significant part of what makes the disease dangerous to humans (it often is), even if a strain becomes solitary and eludes the switch, it will be significantly less dangerous and therefore no longer a problem.

Answer 2

Error detection code

Cellular machinery already involves some error correction codes. This prevents quick death from accumulated harmful mutations while still allowing the right mutation rate to power evolution. The remaining bad mutations are eliminated by the affected line of descent dying out. Remaining good and neutral mutations are not eliminated, of course.

Instead of beefing up the existing error correction, your bio-engineer can do something simpler: Make sure all* mutations are very harmful. Implement an enzyme which traverses the whole DNA every now and then, and calculates some kind of checksum; Check the checksum, and if it does not match, trigger a kill switch. E.g. synthesize something poisonous right inside the bacterium.

To be sure, include several different mechanisms like that. Theoretically, a single error detection code can be made as safe as you please, but you know, life tends to find a way. This way, when one kill switch is disabled, another one takes out that bacterium.

* Actually, all except some astronomically improbable ones; No (practical) error detection code is perfect.

Answer 3

The bacteria do not replicate.

They are completely deficient in multiple pathways used for replication. They eat just fine but they do not reproduce at all. Thus they do not evolve. Each bacterium is synthetic, a product of the lab which uses machines, viruses, nonbacterial hosts and chemistry to make the bacteria.

The bacteria that infect a person are the ones they get. The bacteria will not increase in number. Those individual bacteria that get established are brutal little toxin machines and the toxins (which include human IL4 along with the typical Yersenia repetoire) leverage the excitability of the immune system to kill the host.

Fortunately the Black Death is a fine model for a disease like this. Your malefactor infects rats with loads of his synthetic bacteria, dusts them with fleas and releases them into cities. Infected fleas move the bacteria from rats to humans, infecting the humans with their attempts to feed: standard bubonic plague stuff.

Each outbreak will be limited by the number of rats released and will eventually peter out unless Baddy shows up with fresh rats. And sometimes he sprinkles bacteria over the sleeping city because he is that kind of guy.

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Background reading: synthetic bacterium. https://en.wikipedia.org/wiki/Mycoplasma_laboratorium

Answer 4

Can he create a bacteria disease that does not evolve and/or fixes errors in the genome of it's descendants?

A genome which doesn't get fixed leads to a quickly dead organism. Errors happen very frequently, because the nucleic acid is not stored in a safe buried in a concrete swimming pool under a granite mountain. It is subject to an environment with several aggression, each of which creates errors which need to be repaired to keep the code working.

In other terms, you can't wear a pair of shoes while wanting it always shiny without polishing them. With use comes dust. You have to wipe that away.

Answer 5

redundancy

To do this what you would want is at least five copies of all the DNA that is checked by at least four separate systems. This is needed, since if an error occurs in one it can be fixed, but if an error occurs in two strands and they match you need the remaining three to out vote the two wrong strands and fix the error. Luckily the chance of getting three errors in one base pair that are the same on three strands is very very low. You also need about four checking systems since if three of them fail due to a genetic error the remaining one will fix them all.

This will need to engineered from the ground up since nothing like this exists in nature. The only thing that is close is deinococcus radiodurans. This bacteria has two versions of its DNA and will repair double breaks with a very robust DNA repair system. It still get new mutations all the time. To make this more redundant we need to make a system that can do this but 5 way with a system that determines the most common base pair before recombining.

compromised system

Since this doesn’t evolve, people will become immune to it very fast. There are no strains, and anyone immune to one pathogen is immune to every other version of it.

Answer 6

A large bacterium could self-check its own DNA.

Otherwise, the bacterium uses a combination of protein receptors that allow it to recognize other cells and bacteria it passes by:

• no receptor match: foreign cell, do nothing
• complete receptor match: a sibling, do nothing
• partial receptor match: mutated strain, kill the cell by mutual annihilation

A substance permanently binding those receptors will neutralize the bug, and is your "kill switch".

Of course, the bacterium could mutate so that it loses the "kill mutants" code (B-form), and then other mutants could evolve; but the B-form would also need to out-compete the A-form.

Answer 7

In Larry Niven's Tales of Known Space Universe, one species in particular that stands out is the Bandersnatch. Artificially created billions of years ago, it was specifically designed to not evolve. They accomplished this goal by creating massive cells and DNA strands, as thick as a human finger, that were both robust and all but impervious to mutation. Scaled-down, that might be an angle worth pursuing.