Infectious hallucinations?
August 26, 2011 2:45 AM   Subscribe

What would be the best way to create an infective agent that caused hallucinations? I was thinking a virus that modifed serotonin to psilocin - but how exactly would this take place in the cell, and how would a hypothetical virus catalyse that process? Is it realistic for a modern virology lab to design such a virus? I considered a bacterial vector, but I figure that bacterial infection of the CNS would probably just straight-up kill you due to the host response? Perhaps a bacterial species that just hangs out in your gut and squirts out psilocin that it synthesises itself, rather than having to methylate free serotonin? I know a fair bit of biochemistry but not much at all about microbiology, if that helps guide your explanations.
posted by nicolas léonard sadi carnot to Science & Nature (19 answers total) 13 users marked this as a favorite
Are you asking for real or for a novel?
posted by the fish at 3:23 AM on August 26, 2011

Response by poster: I'm just curious; I think I got the idea from a Joe Rogan podcast. Do I really need to post a disclaimer that I have no intention of carrying out an insane Bond villain scheme?
posted by nicolas léonard sadi carnot at 3:34 AM on August 26, 2011 [1 favorite]

Best answer: I know a fair bit of microbiology, but embarrassingly little biochem.

Is it realistic for a modern virology lab to design such a virus?
Short answer: Making a virus to express a given gene is pretty trivial, with complications coming in if you want to precisely control dose or timing of expression. If you can point to an existing enzyme that does the biosythesis step(s), my Evil Underground Facility can make a virus for you in a handful of weeks. But the constant problems in rational design of modifications to enzyme active sites mean we're into seriously hard territory if we need to modify or create de novo an enzyme to do that synthesis step. As the biochemist, I think that's your territory much more than mine.

Longer answer, for non-biologists:
Modifying a virus to express a given gene when it follows its normal routine and invades a host cell is pretty trivial. There are some challenges introduced by requirements to control the dose and not decrease the virus' infectivity/transmissibility too much, but they're probably not insurmountable. This is assuming that your hallucinogen of choice is one that can be manufactured anywhere in the body and carried by the blood into the brain (which presumably would be true for anything that works by ingestion); if you need to do your biosynthesis in the brain, you have a new suite of problems because getting infectious agents past the protective blood:brain barrier is tricky at best.*

The really hard part would be the biosynthesis of your hallucinogen. If there's already an enzyme or two that are known to take something abundant in the body and turn it into your drug, then we can just pluck the DNA sequence for that out of a database and stick it into our virus. Easy (although there are the standard problems that you get with gene therapy, notably immune responses against the virus or new genes, which limit how long the effect can last before your body mops it all up). But if we have to design a new synthesis pathway, we're somewhere between "seriously hard" and "currently impossible", depending whether we're trying to subtly modify an enzyme that almost does what we want, or design a completely new one from scratch.

So-called "rational design" of modifications to proteins is extremely difficult, as understanding the relationship between a protein's 3D structure and its function(s) is still almost as much an art as it is a science. The next stage of the problem is making the 3D shape that we want: a protein is a long chain of subunits that folds and coils up into a complex shape that's dependent on the sequence of the subunits and the environment that it's in. The relationship between a given protein's sequence and it's eventual structure is very difficult to predict (it's an NP-complete problem that occupies a decent chunk of the world's supercomputer processing time), so actually achieving the desired modification to a protein is tricky. By extension, designing a new enzyme completely from scratch is orders of magnitude harder again. There are a few work-arounds we can employ, e.g. pasting functional or structural chunks ("domains") of different proteins together to make a chimera, like a sort of Frankenstien's monster assembled from different parts. But this doesn't help with the key problem of modifying the functional site.

You'd also have to have a pretty relaxed attitude about safety, or at least the ethics of conducting animal research and eventually clinical trials for a non-therapeutic vector. Because chucking a new or modified biosynthesis pathway into cells seems likely to have all sorts of unintended consequences.

So: In a near-future science fiction story where (super)computer time is cheap and our biochem knowledge has come on a few leaps, sure. In a real-world grant proposal within the next 5-10 years, almost certainly not.

*Come to think of it, certain kinds of epileptic seizure damage the BBB next to the affected brain regions, allowing stuff like viruses through. So you could have a two-stage approach, somehow inducing a seizure that then allows your hallucinogen or virus into the brain. Not sure how you'd induce the seizure though; there are chemicals that do it, but this gives you another tricky delivery/biosynthesis problem to solve.
posted by metaBugs at 4:20 AM on August 26, 2011 [7 favorites]

Well, ergot poisoning from contaminated rye satisfies all your requests. It's not a viral infection, but a bacterial one, and it affects rye and grains, not human. But, it is 'an infective agent that causes hallucinations'.
posted by smoke at 4:27 AM on August 26, 2011

Complications with transfecting bacteria with code for a protein exist. How big is the code for the hypothetical enzymes that catalyze psilocin production? Does the host have the metabolites for catalyzing psilocin production? Are the hypothetical enzymes and their various catalysis products toxic to the bacteria making them (or to the host at large)? The bacteria also need a cellular mechanism for expelling psilocin into the host, where it can be absorbed. Magically engineered bacteria that make psilocin but are evolved to living on your skin probably wouldn't get you high, when the common absorption route is usually oral.
posted by Blazecock Pileon at 4:27 AM on August 26, 2011

Response by poster: Yeah, excellent point about enzyme design. That said, you shouldn't have to struggle to find appropriate enzymes from nature. DMT is meant to be endogenous in humans, I think: all you'd need there is the gene for tryptophan decarboxylase and then whatever turns tryptamine into DMT, which has probably been characterised somewhere.

And, thinking about it, psilocybin-expressing fungi should have a pretty similar pathway going on that you could crib from. For natural hallucinogens that aren't indole alkaloids, it might be even simpler! I bet there's a well characterised pathway for tyrosine to mescaline, for instance.

Does tinkering with viruses like this to get them to induce expression of whatever enzyme reduce their virulence? Can you just choose an existing, highly infectious virus as your vehicle, like a flu?
posted by nicolas léonard sadi carnot at 5:03 AM on August 26, 2011

Best answer: metaBugs covered a lot of the biochemistry, but another issue is that the enzymes that produce the hallucinogens are not beneficial to the bacteria or virus you engineer*. Having extra coding DNA, and wasting energy making functional proteins takes energy and slows replication, leading to the bacteria or virus being outcompeted by clones that have looped out the extemporaneous DNA, or shut off synthesis of the unnecessary enzyme. It's easy enough to force a bacteria to keep extra genes in vitro by linking the genes to a drug resistance cassette, but this selection is lost in a non-drug treated host. Thus, its likely that your microbe of choice would not be hallucinogenic for very long, and would not spread person to person very well.

If this is for a book you are writing, you could make something up about the hallucinogen-enzyme also providing a metabolic benefit (unlocking a new carbon source? Causing tissue damage that provides a new niche?) but you couldn't count on the for real world applications.

I'm not a neurologist, but it seems like a lot of hallucinogens are made from things already in your body - it makes sense if you think about it - though the accessibility of the precursors may be an issue. Here's a paper I skimmed on the biosynthesis of ergotamine if you want to think about that as a possibility**.

*On preview, this answers your latest question. Bacteria are probably easier to get to express extra proteins on their own, where as viruses generally have much less DNA to start with and are often used to get your own cells to do something weird. A virus could potentially take over and alter an existing cell pathway.

** for thought experiments
posted by fermezporte at 5:20 AM on August 26, 2011

Response by poster: For the curious, looks like tryptamine to DMT is catalysed by indolethylamine n-methyltransferase. Anyway, fermezporte, that is definitely a huge stumbling block I hadn't considered: competition from wild types! It's very difficult to imagine any of these synthesis enzymes giving a bacterium or virus a competitive edge.
posted by nicolas léonard sadi carnot at 5:29 AM on August 26, 2011

Response by poster: What about a virus that just somehow induces the upregulation of genes responsible for an already present hallucinogen synthesis pathway? Possible?
posted by nicolas léonard sadi carnot at 5:35 AM on August 26, 2011

Best answer: Does tinkering with viruses like this to get them to induce expression of whatever enzyme reduce their virulence?

Generally, yes. Viral particles tend to be pretty densely packed, without much room to fit much in the way of extra DNA. If you just add your transgene to the existing genome, it generally results in a reduction of the proportion of the virus' progeny that are properly assembled and able to start a new infection: either the virus' capsid is deformed to accomodate some of the extra packing, or some of the DNA is left behind. The solution to this is to delete parts of the viral genome that you deem inessential; this can leave you with infectious virus, but of course it's less efficient, or less able to dodge the immune response, or more dependent on getting into cycling cells, etc. One workaround to this problem is to go for a co-infection: if you have both the wild-type virus and a virus lacking key genes but containing your transgene, genes expressed by the wild-type should be able to work in trans to support replication of the mutant virus. This obviously works better with e.g. cell-cycle regulation genes than with structural proteins, whose availability is likely to be a limiting factor in producing new virus.

Of course, this cuts in half the number of viral progeny that are carrying your transgene, and means that your mutated virus can only infect people that are already infected with the wild-type. But if you went for something extremely common and transmissible -- like influenza in the winter, adenovirus, etc -- you could still get a decent proportion of your target population. If you're clever, you can take into account the fact that a virus isn't dependent on a specific protein, it's dependent on that protein's function. So make sure that the gene you delete is responsible for some really common viral function (e.g. fiddling with p53 or Rb), and just assume that your targets will have *something* in them that also has that goal.

Most of the effort going into gene therapy recently has been in the opposite direction: we need to be confident that it *can't* be transmitted into the general population or find its way into the germline, so the viral gene therapy stuff tends to be based on viruses with huge deletions of key genes. The oncolysis (cancer-killing) folks often work with replicating viruses, but even then the transgenes tend to be locally lethal and the infections are expected to be short and contained within the patient.

What about a virus that just somehow induces the upregulation of genes responsible for an already present hallucinogen synthesis pathway? Possible?

No reason you couldn't just have it synthesise the relevant transcription factor(s). Probably have weird side-effects though, depending what else that txn factor controls. You might want to get fancy and look into mopping up any naturally-occurring RNAi targeted against your pathway, too.
posted by metaBugs at 5:58 AM on August 26, 2011

I don't know the science at all, but instead of synthesizing hallucinogenic compounds, would it be possible to use a virus to perform gene therapy on the host to have more 5-HT2A receptors (2ARs), or some way to alter the brain so that they are susceptible to hallucination from naturally occurring serotonin? Alternatively, viruses that cause schizophrenia or some other disorder?

This reminds me of the sci-fi book with the guy who had the machine in his lung that dripped hallucinogens (Gibson? Effinger?).
posted by BrotherCaine at 6:19 AM on August 26, 2011

Your question seems to presuppose a purely viral or bacteriological vector. But actual hallucinations have many sources and immediate triggers. Normally there will be some kind of physical or psychological trigger that combines with brain state to produce a hallucination. The exact nature of the hallucination produced is much harder to predict. A purely viral or bacteriological agent that caused a specific hallucination would need to both increase susceptibility and also provide a trigger event that was activated in a particular way (that is - if you care about the nature of the hallucination you wish to pass on). No easy.

You might just find it easier to found a religion.
posted by rongorongo at 6:30 AM on August 26, 2011

This thread scares me.
posted by hamandcheese at 11:39 AM on August 26, 2011 [1 favorite]

What about a virus that just somehow induces the upregulation of genes responsible for an already present hallucinogen synthesis pathway? Possible?

You might not need anything as exotic as a virus or bacterium for that. Steroids like glucocorticoid, for example, trigger changes in gene expression by binding to various receptors. Find the right pathway and agonist...
posted by Blazecock Pileon at 12:01 PM on August 26, 2011

If you managed to make a virus that would turn tryptamine into DMT in normal health cells... you wouldn't need a vector. There's a certain demographic who would queue at the door to your Evil Lair waiting for the final product.

Also, thinking of helper viruses: why not delete something expressed in one of the more ubiquitous herpes serotypes? Something something excessively high, passive HSV# infection in humans something something.

Although... if you made it viable when co-infected with rhinovirus, people would get the best colds ever.
posted by Slackermagee at 1:00 PM on August 26, 2011

No reason you couldn't just have it synthesise the relevant transcription factor(s)

If you're activating a pathway through de-repression (i.e., repressing a repressor) you might be able to get away with an siRNA. They're shorter than protein-coding genes and don't need to be translated, so I'd imagine the fitness cost would be lower, though IANAvirologist.
posted by en forme de poire at 2:22 PM on August 26, 2011

Best answer: Delirium causing hallucinations is very common in older people who are hospitalised - wiki tells me 30-40%. Any infective agent will cause hallucinations in a vulnerable section of the population, and there isn't a good understanding of why it affects some people and not others. Age and severity of illness increase the risk, but you still can't pick out who will or won't become delirious.

Understanding delirium would vastly improve hospital care, and probably reduce stay times (with the side effect of knowing how to enact your Bond villain scheme). So, you know, if this random question turns into serious scientific research that's where I'd suggest aiming it.
posted by Coobeastie at 3:21 PM on August 26, 2011

Best answer: What you want the agent to produce is not an enzyme (too much trouble) but a protein that binds to and activates the relevant serotonin receptors directly. This is actually not as hard as it sounds. Run a large and diverse protein library through a series of high-thoroughput assays until you get some good candidates, then maybe try and tweak the best ones until you get strong enough activation.

The tricky part with this strategy is 1) getting the protein past the BBB and 2) evading the immune system and the scavenger proteases in the bloodstream. The rabies virus might be a good place to start. It'll get your package where it needs to go without raising alarms. The trouble there is lowering the destructive properties of the virus without sacrificing too much pathogenicity.

Another approach would be to start with tetanus or botulism. The toxins they produce (tetanospasmin and botulinum, respectively) are both accomplished at getting from the bloodstream to brain, and could conceivably be modified to deliver your protein package instead of their vicious little endopeptidases.

With either the rabies or the neurotoxin approach, you'll be coming in from the cytoplasmic side of the neuronal membrane, so it's important that your protein be screened to activate the relevant receptors allosterically, from below, rather than at the external receptor site, as would a traditional drug.
posted by dephlogisticated at 8:36 PM on August 26, 2011

Best answer: I am a gene therapy researcher. We work with adeno-associated virus, which is fortuitously not-pathogenic by its very nature. AAV is almost like a gift from nature for use exclusively in gene therapy, because as a virus it is considered "defective" in as much as aside from delivering its genome to a given cell type, it doesn't do much of anything at all. No hijacking of cellular equipment or killing of the cell, etc. Due to its non-pathogenicity, it also elicits no immune response (though there can always be an immune response against the final protein product of whatever gene you intend to deliver).

In your case you are likely looking at delivering a gene to the central nervous system. This is an immune-privileged area of the body, which means that an immune response to your protein of interest is very very unlikely. AAV also comes in many different flavors - or serotypes - which are characterized mainly by their natural tropisms - or types of cell in which they ultimately like to reside. metaBugs gave you excellent answers about regarding potentially inducing a seizure to get a virus across the BBB, but there are plenty of AAV serotypes that cross the BBB with no prompting, if you inject them intravenously.

So, just to echo above, getting a virus to package a gene of interest is no problem. Getting a virus to infect a given cell or tissue type is no problem. The real question here is what gene you would use.

I like the idea of constitutively activating a neuronal receptor. If you'd like to do something like this, you could choose a peptide or protein known to activate that receptor (or potentially design one, which would be much easier imo than designing an enzyme from scratch) and simply attach a known secretory sequence to the activator peptide. So your design would look something like this: virus is packaging say (for example) specific serotonin-activating-peptide-conjugated-to-known-neuronal-secretory-sequence. Virus has been chosen specifically to evade immune response and cross BBB (I'm thinking AAV serotype 9, aka AAV9, but there are many other choices here). After an IV injection, the virus travels into the CNS, infects neurons, and begins expressing its genome. Cells recognize secretory sequence and begin secreting your peptide, which then goes on to activate receptors on cells. And so on.

If you wanted even finer control, you could then start looking into what promoter you'd like to stick in front of your gene. Do you want high expression or low expression? Induced expression? All things that can be optimized.

I may or may not have looked up whether THC was the final product of an enzymatic pathway in the past, fwiw. (It is - not that this would be hallucinatory, but it does make for interesting thought experiments)

In summation, I don't think this would be a very difficult problem at all intellectually. It would just involved tinkering and time.
posted by corn_bread at 6:52 AM on August 27, 2011

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