Theoretical Cold Cure

[CommanderEspresso]

A week ago, my housemate got a cold. A few days after that, I caught it from him. A few days after that (ie today) He is nearly better, while I am in the middle of fighting the virus.

What I always wonder is; if we got some needles and tubes and hooked up our blood supplies (and assuming this didn't cause any new problems...) would his immune system cure my cold?

[screen317]

If the virus sufficiently mutated either prior to or during transmission, then no.

[yurell]

Your assumption is quite a strong one ... his immune system is more likely to kill you than the virus. And him, while it's at it.

[Gigano]

Doubtful, because for one the immune system is not just limited to the bloodstream (spleen, lymph nodes, thymus), and secondly his HLA is probably drastically different from yours assuming he is not directly related to you. Because of the latter his immune cells will then appear to be foreign material that needs to be removed from your body, and this will most likely result in a severe immune response.

[eSOANEM]

Still, if he's a different blood type, the chances of potentially fatal rejection are pretty high.

Also, there are much more important uses for blood than curing colds and, seeing as I've recently been told not to give blood for three years (during which I could have given 9 units), I urge you very strongly to use the blood for that rather than curing a cold.

Edit: on a purely hypothetical level, unless you're suggesting taking vast quantities of your friend's blood, I doubt that you'd get sufficient antibodies to provide much relief especially if the virus has mutated significantly whilst being transferred. At best, I think you'd just shave a small amount off the time you had the cold rather than having an instant cure and I doubt very much it would be sufficient to justify a blood transfusion.

[++$_]

Two people have suggested this already, but it makes no sense to me: why would the virus have mutated so much in being transmitted from a single person to another? If that happened regularly, you would be able to re-catch your own cold. Which basically isn't possible as far as I know.

Anyway, while you could probably suppress the virus with monoclonal antibodies from your friend or something, by the time you notice the symptoms I'm pretty sure the virus is already fairly well established, and your body is already producing plenty of antibodies of its own.

[poxic]

Don't some viruses have DNA (or is it RNA?) that code for functional proteins regardless of where the transcription starts? Or am I misremembering something?

[eSOANEM]

Two people have suggested this already, but it makes no sense to me: why would the virus have mutated so much in being transmitted from a single person to another? If that happened regularly, you would be able to re-catch your own cold. Which basically isn't possible as far as I know.

I was assuming screen317 knew more than I did.

Anyway, colds clearly mutate at spectacular rates or else, at which most people catch them, we'd all be immune by the end of the year and it'd die off. With this in mind, whilst it mutating significantly through one transmission is probably very unlikely, if you actually caught it through a slightly more indirect routes via a mutual friend(s) then it could become a significant effect.

[++$_]

I was assuming screen317 knew more than I did.

Anyway, colds clearly mutate at spectacular rates or else, at which most people catch them, we'd all be immune by the end of the year and it'd die off. With this in mind, whilst it mutating significantly through one transmission is probably very unlikely, if you actually caught it through a slightly more indirect routes via a mutual friend(s) then it could become a significant effect.

I think the reason we catch colds so often is that there are over 100 known strains of rhinovirus. They do mutate over time as well, so the rhinoviruses of 20 years ago are not the same as the ones today, but I very much doubt that they change that much over such a short time period.

[Gigano]

Don't some viruses have DNA (or is it RNA?) that code for functional proteins regardless of where the transcription starts? Or am I misremembering something?

Viruses can have either double stranded (ds) DNA or RNA or even single stranded (ss) DNA or RNA (positive sense or negative sense). Rhinoviruses contain single stranded RNA, hence their genomes are unstable and prone to mutations more than for example double stranded DNA viruses (e.g. poxiviridiae suchs as small pox). The trend of genome stability generally goes as follows, in order of decreasing stability: ds DNA > ss DNA > ds RNA > ss RNA. This explains why viruses such as small pox can be easily vaccinated against: they do no change their genome that much over time. "Unstable" genomes such as single stranded RNA (HIV, rhinoviruses) tend to experience changes in their genomes more often. However, these mutations do not happen so fast that the serotype, exterior protein mantle of the virus, changes dramatically after a single transmission to avoid detection. Rather, these viruses differentiate into various serotypes more quickly than slow mutating viruses, as ++$_ mentioned.

So the main problem is not whether the virus with which the second person is infected can be recognised by the donated immune system of the first infected person, rather whether the second person is able to survive the invasion of foreign immune cells.

[screen317]

Two people have suggested this already, but it makes no sense to me: why would the virus have mutated so much in being transmitted from a single person to another? If that happened regularly, you would be able to re-catch your own cold. Which basically isn't possible as far as I know.

It does happen regularly. That's why there is no "cold vaccine." Both rhinovirus, adenovirus, and others are responsible for "colds." Yes, you don't catch "your own cold" because where would it come from? When you sneeze or cough, you expel virions far away from you, or into a tissue, or something. Viruses don't mutate in the air. They mutate when the newly created viral genome isn't identical to the one that entered the invaded cell.

Not exactly cold related, but viruses that encode their own polymerases are especially susceptible to mutation (see HIV etc.); its reverse transcriptase is incredibly inaccurate since it doesn't have a self-checking mechanism. Take-home message: viruses evolve at an alarming rate.

[Izawwlgood]

My description of this is going to be flawed, maybe Angua or Gigano can chime in with more specifics:

Two people have suggested this already, but it makes no sense to me: why would the virus have mutated so much in being transmitted from a single person to another? If that happened regularly, you would be able to re-catch your own cold. Which basically isn't possible as far as I know.

Many viruses have what I can only describe as 'sloppy replication'. They intentionally do a poor job duplicating parts of their genome, either by splice variation or by using 'less accurate' polymerases. The idea is to create some variation every time they're duplicated, leading to greater diversity.

This may only apply to certain particularly nasty viruses (I think HIV does this, and the Plasmodium parasite does something similar in terms of splice variants for it's external coat). But yes, it's possible that a virus mutated significantly between individual cases.

[++$_]

Two people have suggested this already, but it makes no sense to me: why would the virus have mutated so much in being transmitted from a single person to another? If that happened regularly, you would be able to re-catch your own cold. Which basically isn't possible as far as I know.

It does happen regularly. That's why there is no "cold vaccine." Both rhinovirus, adenovirus, and others are responsible for "colds." Yes, you don't catch "your own cold" because where would it come from? When you sneeze or cough, you expel virions far away from you, or into a tissue, or something. Viruses don't mutate in the air. They mutate when the newly created viral genome isn't identical to the one that entered the invaded cell.

I understand what you're saying. I just don't believe it is correct. In a very cursory search of the literature I can't find any evidence for this.

There is no cold vaccine because there are 100 serotypes of rhinovirus. (And, as you point out, adenoviruses and coronaviruses can also be implicated.) Maybe there is also no cold vaccine because apparently immunity is mediated by antibodies in nasal secretions, which might not be as easy to induce as serum antibodies.

Sure, sneezes expel viruses away from you, but when you have a cold, unless you exercise perfect hygiene everything in your home will become heavily contaminated with cold virus. (At minimum, personal articles like toothbrushes will become contaminated.) But most importantly, even with the best hygiene your nasal cavity will be contaminated. If there were any viruses in there that are not recognized by the antibodies specific to the original strain, the host would be reinfected immediately.

[WarDaft]

Just because the RNA has changed, does not mean it has changed enough to be unrecognizable by antibodies. Small changes can easily leave it functionally identical externally. But the period between when you catch a cold for the first time and when you might catch a descendant of the cold you already had is close enough to unbounded as to be indistinguishable. In fact you might say it is at least as long as is needed for it to mutate into one you are no longer immune to.

The fact that there are 100 varieties, or even 1000, would not prevent them each from being systematically immunized against. Well, 1000 might end up with it being deemed too expensive to be practical, but there's no technical reason, and if there were were no technical reasons you couldn't vaccinate against all of the common colds, there would be research papers looking into fixing the non-technical reasons and organizations espousing how we should just do it anyway. But when you prove that not only do you have to vaccinate against X many number of viruses, but vaccinate everyone against all of them within a small window of time Y or you wasted all that money, then you aren't going to have many people advocating it.

[++$_]

Just because the RNA has changed, does not mean it has changed enough to be unrecognizable by antibodies. Small changes can easily leave it functionally identical externally. But the period between when you catch a cold for the first time and when you might catch a descendant of the cold you already had is close enough to unbounded as to be indistinguishable. In fact you might say it is at least as long as is needed for it to mutate into one you are no longer immune to.

Yes. The question is, how long is that period? Is it weeks (as suggested by screen317) or years (as suggested by me)?

The fact that there are 100 varieties, or even 1000, would not prevent them each from being systematically immunized against. Well, 1000 might end up with it being deemed too expensive to be practical, but there's no technical reason, and if there were were no technical reasons you couldn't vaccinate against all of the common colds, there would be research papers looking into fixing the non-technical reasons and organizations espousing how we should just do it anyway. But when you prove that not only do you have to vaccinate against X many number of viruses, but vaccinate everyone against all of them within a small window of time Y or you wasted all that money, then you aren't going to have many people advocating it.

Developing vaccines against 100 different strains is a very significant investment. There are fewer strains of influenza than there are of the cold, yet you don't see anyone saying "just vaccinate against all the influenza strains."

Every paper I have read indicates that the main barrier to developing a vaccine against the common cold is the diversity of the viruses that cause it, not some ungodly large mutation rate.

Keep in mind that there are many highly successful vaccines against RNA viruses. Measles, mumps, rubella, polio, and rotaviruses are all RNA viruses that have been very successfully suppressed by vaccination programs.

[WarDaft]

Suppose it is years. It takes more than just a few years to eradicate a strain, so if that strain mutates into something that your vaccine is ineffective against, your entire eradication efforts were in vain. Many different viruses that mutate on less than decade spans basically guarantees you will have several ineffective eradication attempts, and one is all it will take to stifle the program by loss of public trust and cries of wasted money. Worse yet, if the eradication is not totally complete on a global scale, then it will still have been a waste of money. Less transmittable higher visibility infections are much more feasible for eradication, but less visible more transmissible diseases can still be targeted, so long as the goal post doesn't keep moving.

The WHO wouldn't advise surveillance of the seasonal flu for mutations if they didn't think it was at least something to worry about, and as you said, there are fewer strains of that.

[screen317]

The question is, how long is that period? Is it weeks (as suggested by screen317) or years (as suggested by me)?

I never said weeks...

Every paper I have read indicates that the main barrier to developing a vaccine against the common cold is the diversity of the viruses that cause it, not some ungodly large mutation rate.

What causes viral diversity?

[++$_]

The question is, how long is that period? Is it weeks (as suggested by screen317) or years (as suggested by me)?

I never said weeks...

Well, what you said was, "If the virus sufficiently mutated either prior to or during transmission, then no," in answer to the scenario "A week ago, my housemate got a cold. A few days after that, I caught it from him. A few days after that (ie today) He is nearly better, while I am in the middle of fighting the virus."

That timeframe definitely falls into the category of "weeks".

[gmalivuk]

What causes viral diversity?

Read my post from 24 Feb 2012, and you'll know.

[Karantalsis]

What causes viral diversity?

Read my post from 24 Feb 2012, and you'll know.

I think Screen317 was asking another poster to think about their own answer (regarding viral diversity) and thus come to the conclusion taht high diversity = high mutation rate, essentially. I also get the impression that Screen317 knows the answer.

A quick Pubmed search gives the following information. Riboviruses (of which all cold viruses are subtypes) have a mutational rate of around 0.76 mutations per genome per replication. This is massive. This indicates that every single cell infected will result in multiple mutated virus strains, meaning that once an infection is established you could be looking at 100s of strains a minute, admittedly with minor diffrences and noen viable strains being eliminated. Each of these then begets more strains and so on. A single patient therefore does not have a single strain of cold, let alone any two patients.

As to why you don't catch your own cold, although mutations rates are very high the antibodies against the "original" strain and its various derivatives produced in the first host are likely to be effective agains tthe closely related strains in the second. A blood transfusion as indicated above is more likely to harm the patient for a number of reasons. Further identifying and isolating the relevant antibodies and administering them would take so long the intended recipient would be better by the time the cure was available, and any tertiary infection incidents would be unlikely to respond strongly due to the mutation rate.

Mutation rates among RNA viruses
John W. Drake*† and John J. Holland‡

For the numbers, experience, logic and remembering other papers for the rest.

[WarDaft]

I doubt it is likely that most colds mutate that quickly, otherwise once any airborne cold got into a reasonably large population dwelling with common areas (say a small apartment building, or even better a dorm) it would persist in the building for quite a long time. Each tertiary case would probably be a mutation in a different direction, and fourth and fifth generations would be even more dissimilar. You would go from one cold in the building to dozens of overlapping colds and most of the people would be sick with several at once. This would last until a sufficient fraction of the building's residents built up a strong enough immune system to simply not get infected by any of the colds in the first place, even if they hadn't already had that particular strain. The exact fraction of the population and required increase in immune strength would depend on particulars of the building. If you increase the expected number of generations to re-infect the same person even by a small amount, you can avoid this particular case, but scaling up to cities, you'd still have a rather sick population overall. You would need a couple of constant sized jumps as population size increased to get prevalence down to real world levels. It still wouldn't have to be decades, but it would be more than just a couple generations.

[Angua]

There is an element of heterogenous immunity to the immune system - antibodies can help protect you against similar mutations, but generally this is much more effective just after infection (ie wait a year and give a slightly different strain, and you will probably catch it then). However, just giving antibodies transferred in sera probably won't be that helpful - there are also T cells which are especially important against viral immunity. Finally, while the mutation rate may be high, you have to remember that not all mutations are advantageous to the virus (actually, a lot of them are pretty deleterious), so you don't end up with that many different strains so quickly. A method looking at trying to make antivirals against RNA viruses is finding a method to push their rate of mutation even higher, so they are no longer able to keep a coherent genome. This is known as lethal mutagenesis.

[EricH]

The problem of rejection dwarfs the original cold, but--suppose CommanderEspresso's housemate is, in fact, his identical twin. Now, could simple (albeit, potentially massive) cross transfusion cure the cold?

[screen317]

I think Screen317 was asking another poster to think about their own answer (regarding viral diversity) and thus come to the conclusion taht high diversity = high mutation rate, essentially. I also get the impression that Screen317 knows the answer.

The question was, in fact, rhetorical. Thank you Karantalsis.

The problem of rejection dwarfs the original cold, but--suppose CommanderEspresso's housemate is, in fact, his identical twin. Now, could simple (albeit, potentially massive) cross transfusion cure the cold?

That depends on whether or not the memory T and B cells which developed during the infection are present in the serum, and aren't already hidden away in lymphoid organs. That is what confers immunity to "repeat" infections. True that there may be virus-specific antibodies present in the serum, however it may be more efficient (if the memory cells themselves cannot be isolated quickly enough) to treat with (genetically identical) virus-specific CD4 T cells (in particular, the B cell helping T follicular helper cells), which may mediate faster viral clearance through increased B cell activation.

The whole cross-transfusion thing just seems odd to me in general. How much would you need to transfer/would it even help is certainly up to debate/experiment, but I wouldn't personally volunteer for it.

[Soralin]

Well simple, see, you just:

Take the same artery on both people, sever it
Connect the upstream section of the artery of the first person, to the downstream section of the artery of the second person.
Likewise, connect the upstream section of the artery of the second person, to the downstream section of the artery of the first person.

That way you can end up with just one big circulatory system with a pair of hearts (at least partially so).

I'm guessing the most likely outcome of this is death, by all out warfare between each person's immune systems. Possibly identical twins would fare better.

[Angua]

This still seems like an awful lot of effort to avoid a cold, even if the person was an identical twin. People with immune deficiencies get injected with serum from a bunch of people every so often so they at least get some passive immunity from common infections, so you already have proof of concept.

[eSOANEM]

Well simple, see, you just:

Take the same artery on both people, sever it
Connect the upstream section of the artery of the first person, to the downstream section of the artery of the second person.
Likewise, connect the upstream section of the artery of the second person, to the downstream section of the artery of the first person.

That way you can end up with just one big circulatory system with a pair of hearts (at least partially so).

I'm guessing the most likely outcome of this is death, by all out warfare between each person's immune systems. Possibly identical twins would fare better.

IIRC, when they first started doing transfusions they did something like this although I think they connected it artery to vein because severing arteries is generally a bad idea and because the heart already has to do work to get through the tube so by the time it gets to the other person the pressure will have dropped to below normal arterial pressure. This type of transfusion isn't used very often because it's a pain to do and requires that you have the donor available when you want to do the transfusion rather than having them give the blood first.

[++$_]

I think Screen317 was asking another poster to think about their own answer (regarding viral diversity) and thus come to the conclusion taht high diversity = high mutation rate, essentially. I also get the impression that Screen317 knows the answer.

A quick Pubmed search gives the following information. Riboviruses (of which all cold viruses are subtypes) have a mutational rate of around 0.76 mutations per genome per replication. This is massive. This indicates that every single cell infected will result in multiple mutated virus strains, meaning that once an infection is established you could be looking at 100s of strains a minute, admittedly with minor diffrences and noen viable strains being eliminated.

No it doesn't.

For one thing, the vast majority of the mutations either do nothing or cause the virus to stop working.

For another, unless the mutation changes the surface proteins of the virus in a significant way, it doesn't count as a new "strain" (serotype).

[screen317]

No it doesn't.

For one thing, the vast majority of the mutations either do nothing or cause the virus to stop working.

For another, unless the mutation changes the surface proteins of the virus in a significant way, it doesn't count as a new "strain" (serotype).

Oh good Lord will you give it a rest? Yeah, missense and nonsense mutations happen all the time, but do you know how many copies of virus are made before each cell lyses??

[Karantalsis]

I think Screen317 was asking another poster to think about their own answer (regarding viral diversity) and thus come to the conclusion taht high diversity = high mutation rate, essentially. I also get the impression that Screen317 knows the answer.

A quick Pubmed search gives the following information. Riboviruses (of which all cold viruses are subtypes) have a mutational rate of around 0.76 mutations per genome per replication. This is massive. This indicates that every single cell infected will result in multiple mutated virus strains, meaning that once an infection is established you could be looking at 100s of strains a minute, admittedly with minor differences and none viable strains being eliminated.

No it doesn't.

Yes it does. Whilst the majority of the mutations are irrelevant or none viable, the rest are still a significant portion especially in something as information dense as a virus. This is covered in the paper I referenced, as well as in several others.

For one thing, the vast majority of the mutations either do nothing or cause the virus to stop working.

I did point this out whilst making my earlier post (you even quoted it). We agree here.

For another, unless the mutation changes the surface proteins of the virus in a significant way, it doesn't count as a new "strain" (serotype).

You are mistaken, serotypes and strains are quite different things, as can be seen in the title of the below paper.

Evolution of human influenza A viruses in nature: Recombination
contributes to genetic variation of H1N1 strains

Young et al. 1979

[Gigano]

No it doesn't.

For one thing, the vast majority of the mutations either do nothing or cause the virus to stop working.

For another, unless the mutation changes the surface proteins of the virus in a significant way, it doesn't count as a new "strain" (serotype).

Oh good Lord will you give it a rest? Yeah, missense and nonsense mutations happen all the time, but do you know how many copies of virus are made before each cell lyses??

He's right though; most mutations do not create some new immediately discriminable serotype that can evade the immune system. It doesn't matter how many viroid particles are created in a single cell lysis, if the viral DNA/RNA is integrated into the genome then the mutation rate pretty much becomes zero. The mutations most dominantly arise because that integration goes awry. It's not like every single viroid particle receives its own unique DNA/RNA sequence.

[screen317]

It's not like every single viroid particle receives its own unique DNA/RNA sequence.

Sure it does. The polymerase only makes one at a time...

[Angua]

He's right though; most mutations do not create some new immediately discriminable serotype that can evade the immune system. It doesn't matter how many viroid particles are created in a single cell lysis, if the viral DNA/RNA is integrated into the genome then the mutation rate pretty much becomes zero.

Retroviruses and maybe some dna integrate into the genome - the viruses responsible for the common cold do not come under these categories, therefore will be constantly mutating.

[Gigano]

It's not like every single viroid particle receives its own unique DNA/RNA sequence.

Sure it does. The polymerase only makes one at a time...

Multiple polymerases actually but those polymerases have proofreading abilities, minimising the errors made in the copied DNA. And they replicate the same RNA/DNA strand again and again. It's PCR on a small scale.

Retroviruses and maybe some dna integrate into the genome - the viruses responsible for the common cold do not come under these categories, therefore will be constantly mutating.

Reverse transcriptase, the enzyme capable of producing cDNA from RNA to allow insertion in the genome is actually wholesomely inaccurate compared to endogenous polymerases of host cells. The template RNA strand is even destroyed after replication, destroying the original source material. The inaccuracy comes from the fact that reverse transcriptase does not have proofreading ability.

[inserted white line]

Rhinoviruses are picornaviruses, containing single stranded RNA, so their mutation rate is higher than most DNA viruses but upon transduction their genome is almost immediately made into a double strand to prevent further degredation of their genome. Why? Because their RNA genomes are directly transcribed by endogenous ribosomes via IRES sites; major errors in the RNA transcript (i.e. proteins) will result in non viable viroid particles.

Because of the intrinsic instability of a viroid genome they mutate at a faster rates than most other organisms also depending on whether they have a single/double stranded RNA/DNA genome. But they still have to produce viable consistent products with minimal change to allow for their own viability. What's more, they still have to be able to escape the host before they're able to spread.

Bottom line, most viruses mutate quickly, but not at the alarming rate of a completely new serotype per transmission.

[Angua]

Picornaviruses don't use reverse transcriptase. They never turn their genomes into DNA.

http://viralzone.expasy.org/viralzone/all_by_species/33.html

[Gigano]

Picornaviruses don't use reverse transcriptase. They never turn their genomes into DNA.

http://viralzone.expasy.org/viralzone/all_by_species/33.html

I never said they did.

[Angua]

Then you weren't very clear with what you've been trying to say.

[Gigano]

You implied that integrating an RNA genome into the hosts genome via reverse transcriptase does not result in a genome that mutates constantly, unlike what is the case with the rhinovirus. I merely remarked that reverse transcriptase does not necessarily provide accuracy in genome replication, because it lacks proofreading.

Maybe an extra white line between that remark and the one on picornaviridae can clarify it. It was a remark in general, quite unrelated to our discussion concerning the rhinovirus.

[Angua]

No - you implied that first, and I was saying that it didn't happen in the common cold.

No it doesn't.

For one thing, the vast majority of the mutations either do nothing or cause the virus to stop working.

For another, unless the mutation changes the surface proteins of the virus in a significant way, it doesn't count as a new "strain" (serotype).

Oh good Lord will you give it a rest? Yeah, missense and nonsense mutations happen all the time, but do you know how many copies of virus are made before each cell lyses??

He's right though; most mutations do not create some new immediately discriminable serotype that can evade the immune system. It doesn't matter how many viroid particles are created in a single cell lysis, if the viral DNA/RNA is integrated into the genome then the mutation rate pretty much becomes zero. The mutations most dominantly arise because that integration goes awry. It's not like every single viroid particle receives its own unique DNA/RNA sequence.

[Gigano]

Pah, poo, piss and pants. I see what you are getting at.

I did not mean to imply that this happens with the rhinovirus. It was somehow suggested in the posts that I quoted that every single virus receives its own uniquely mutated genome. This is most unlikely as all new genomes are transcribed from a base template; be it an integrated genome in the case of retroviruses or a stabilised ds RNA genome as is the case with picornaviridae.