> When he and his colleagues looked at the individuals’ immune cells, they could see encounters with all sorts of viruses—flu, measles, mumps, chickenpox. But the patients had never reported any overt signs of infection or illness.
Given that the article goes on to talk about mild persistent inflammation, is it possible that these individuals are sometimes asymptomatic but still capable of carrying/transmitting viruses at least temporarily? The article talks about potentially immunizing healthcare workers during a future pandemic, but if this was just allowing people to never develop symptoms (and not have to leave work) while having low-grade infections, would we accidentally create a work-force of Typhoid Marys?
Even worse, that type of chronic inflammation might cause premature death. Or cancer. Or other disease states.
> “In the back of my mind, I kept thinking that if we could produce this type of light immune activation in other people, we could protect them from just about any virus,” Bogunovic says.
This sounds terrifying. There's a reason our bodies do not regulate like this.
>Bogunovic’s therapy is designed to mimic what happens in people with ISG15 deficiency, but only for a short time.
Given the choice between 2 weeks of a moderate COVID infection (fever but no hospitalization), and 2 weeks of this therapy, I would guess that the moderate COVID infection gets you at least 10x the inflammation.
It also sounds like an episode of some televised sci-fi series where someone was exhibiting remarkable immunity to all sorts of diseases (including some nasty ones deliberately added for testing); but it turned out that this was no super-cure but instead the limited natural resources of the immune system being used up all at once, leading to a horrific death when they ran out.
Sounds very Outer Limits-esque, but I don't recall that specific episode. It's certainly at least an easy interpolation from many Outer Limits episodes, though.
On the other hand, let's aim for the juiced up immune systems portrayed in one of the Star Trek series. It gets so powerful it can reject acquaintances.
I think it was one of the offshoots like Next Generation that had a visit to some research station where all the scientists were dead or dying of premature aging. It was the immune systems of some (bioengineered?) children that were killing them.
I wonder if enough of them exist to even do a study like that.
I have encountered side effects that probably no one has seen before, simply because of rarity and peculiarity of behavior. You don't run into a ton of people using both interferon and doing karate, so if bruising more easily happens 10% of the time... would anyone notice?
Personally I would be more worried about persistent inflammation causing inflammatory disorders, of which there are many. If there are like 10,000 individuals with this trait then there just aren't enough to detect. But that seems direct... wouldn't you expect something like this to potentially even destroy viral reservoirs over time?
The fact that this is short term in the treatment made me 1000x more comfortable with the idea in any case.
They would still have too many other possible hosts.Or maybe they'd find a way to attack that very system, similarly how HIV attacks the immune system.
I am not a medical expert, but from what I read the last time I saw this being discussed, ISG15 deficiency also causes something called "infernopathy" that leads to inflammation across the entire body. I don't believe it's related to viral activity at all.
From TFA: "We only generate a small amount of these ten proteins, for a very short time, and that leads to much less inflammation than what we see in ISG15-deficient individuals,” Bogunovic says. “But that inflammation is enough to prevent antiviral diseases."
It seems that the goal is to learn to trigger the benefits, without triggering the bad parts. Which, should probably have been obvious to you without even bothering to read the article.
To the extent the disease is due to factors hurting the virus, I guess it's viable as a perspective, but I'd be surprised if it's deliberate in this case.
I would imagine the worker would be wearing protective gear. They're not walking around mask-off. Also, if you know you have gotten this treatment, you would obviously have to take different precautions.
Asymptomatic carriers are a concept I've always found interesting and honestly a bit confusing. When a pathogen can be present without ever causing symptoms it becomes much trickier to show causality.
This was a lynch pin of sorts in Koch's postulates. We can't properly go through those postulates with viruses like we can with biological pathogens, but it is odd to me that we don't have similar concerns when the presence of a replicable pathogen doesn't cause the symptoms they are expected to cause.
I am sure it does cause concern to many. I mean how scary is it that you can run into someone seemingly healthy and next thing you know you are sick?
I know as a health care worker I actually think about things like this. MRSA is a good example. Most people don't react to exposure but some do. Those that do get long term infections that are hard to get rid of if ever. Most think of this as a hospital issue. But the reality is that there are literally thousands of people with MRSA all over the world and they are carriers of it and they do things like go to the bank machine and touch it, open the door at 7-11, pick up items at the store and then put them back on the shelf and so on and so on. MRSA is literally everywhere. Some people contact it and suffer problems others do not.
With something like MRSA how do you determine that the virus is cause for disease when, as you said, many will be infected without showing symptoms?
That the root of the confusion for me. I haven't wrapped my head around how we can know a specific pathogen causes disease if a large number of people can be found to have that pathogen present without showing symptoms.
Not all smokers get lung cancer. But with large enough samples, smokers turn out to be much more likely to get lung cancer than non-smokers. That's why we say that smoking causes lung cancer. It's not as if someone has actually watched a particle of tobacco interact with someone's lung cells to turn them cancerous in real time.
I always wonder this and maybe people in the comments here know the answer: If humans had the technology to eliminate all viruses on Earth, what would be the outcome? Do viruses keep other bad things in check? Would there be bad consequences if we eliminated all viruses?
The world of viruses is wide and beyond our current understanding. 50 years ago one might have dreamily wondered whether "eliminating all bacteria" would improve the world. Now we know we'd all die quickly without bacteria (e.g. gut biome). I think we're about at that level of understanding today regarding viruses.
For one thing, viruses keep bacteria in check. Bacteria populations live in an equilibrium standoff with bacteriophages (viruses). The human gut contains more bacteriophage virions than bacterial cells. So eliminating all viruses could lead to bacteria overgrowth
Eliminate all viruses: Population issues in other organisms down to bacteria is my guess. We break a link in a significant food chain, basically.
Eliminate human-tropic viruses: We have to monitor for outbreaks when new viruses mutate and jump species to successfully infect humans. If there's zero mass immunity across the population at every outbreak, we're still in a high-risk situation.
Loss of genetic diversity overtime will happen as well as a different path of evolution. Much of what you see on earth today is the result of virus-host interactions shaping evolutionary outcomes. Viruses are capable of providing horizontal inheritance of genetic material.
Viruses have had a lot to do with the evolution of life and specifically us, where perhaps our distant ancestors were bestowed with a system of transcribing short term memory into long term memory via the hijacked machinery from a virus. This is only one example that I could remember off the top of my head, there are surely many more. Would that matter going forward? I feel like we'd better be sure that we aren't causing more problems than we are solving.
Viruses are part of other biological processes as well as keeping things in check. For example, there is a bunch of viral activity involved in human pregnancy. A quick web search found this:
On the other hand viral infections themselves can instigate autoimmunity. After all, your body now has to fight your own cells (in contrast to other foreign infection)
Not really. Races don't exist biologically. There are certainly traits within populations but that's a bit like my cousins tend to be fatter than my family. It's not something that can be accurately targeted.
You'd be surprised. There is quite a bit of polymorphism within the human species that is very much distinguishable per population. E.g. haplogroup analysis or microsatellite analysis is remarkably accurate in this regard due to a lack of interaction between far flung populations until quite recently in human history. Now, does this imply all the bullshit eugenicists and other racists tend to preach about with race? Hell no, social factors are responsible for most of that variance, but to suggest there would be no biomarker for "race" in its colloquial definition as proxy for population of origin is inaccurate.
This is also why there is a big focus now to seek out underrepresented populations in genetic analysis, because there may be population specific biomarkers that are relevant in disease that you miss if you limit yourself to the handful of widely sequenced homogeneous populations (e.g. there are Utah and Iceland datasets that are popular to use for this).
Not an expert but I don't think that still qualifies as biological differences in races. I mean, obviously we are all biological different and it seems obvious as well that if a group of people stays isolated enough it will develop and reinforce differences to other groups.
For example the Basque population has clear genetic differences to the rest of the Iberian and Westerner population [1] but that doesn't make them a different race.
Race is just a social construct, mostly based on visual traits.
Sure there are. An easy example is Australian aboriginals. They were geographically isolated for tens of thousands of years. Their subgroups are more related to each other than to other subgroups.
There is, due to the way humans migrated and geographically isolated themselves over human history where founder effect, genetic drift, and evidence for introgression (both within our species and from hybridization with other species of hominids) is easily appreciated among populations even today.
Depends on the group. Oldie but goodie (1). Salient quote: "The Mormon gene frequencies are similar to those of their northern European ancestors. This is explained by the large founding size of the Mormon population and high rates of gene flow. In contrast, the religious isolates (Amish, Hutterites, and Mennonites) show marked divergence from their ancestral populations and each other, due to isolation and random genetic drift. "
The historical conception of race doesn't translate simply to human genetics.
There is more genetic variation within a what we might call a race than between them. And it's interesting to note that the genetic diversity of Eurasian populations is in large part contained within the much greater diversity of Africa. In some sense we're all Africans. On top of that there has been a good amount of mixing, both historically and in the present day.
To think in terms of "races" might lead one to hold a mental model of impermeable boundaries between populations that in many cases were never present, and certainly aren't today. Geneticists tend to use the word "population" instead, since it doesn't connote any unhelpful assumptions about uniform or fixed phenotypes within a well-defined species subgroup.
Of course there are certain obvious environmental adaptations that have been selected for in different geographies/climates, as well random genetic drift between distant populations. Sometimes those difference might have medical relevance, and you can make statistical generalisations about the prevalence and distribution of genetic markers within any group you like. But for most medical and public policy applications it is likely most useful to focus on populations within an administrative area, and increasingly, individualised medicine.
Humans are animals, adaptable animals. We have seen how pigment faded when people moved out of Africa and the energy cost of melanin was saved as men lost melanin to allow Vitamin D internal synthesis, and as they went to Asia they regained melanin in the South-East and even changed to another pigment in China etc - might be dual pigments.
Hot climates often had ample food = over-population and competition for food = war and internecine conflict for resources and people optimised for combat. As you went North food became seasonal and people starved at time = crops/storage = less fighting = Eskimos are non combative against people, but their enemy was the climate = they learned to combat that quite intelligently with tooth/bone/sinew - also animals are high calory food, but deficiencies can lead to 'rabbit starvation' can occur, but in Eskimos was abated by fat from seals etc. https://en.wiktionary.org/wiki/rabbit_starvation
So we are like cats/dogs/hamsters and the same for birds = hundreds of chicken variants. We are just meat in varied shapes/minds
I recall an SF book by Jack Vance called 'Dragon Masters' where there were 2 habitable planets, one with Earth men and one with smart lizards and every few thousand years they would pass nearby and the higher tech lizards with space ships would raid the 'Earth' for slaves/plunder and would also lose some lizards to Earth capture. In the long period between orbital intersections, each side would breed their captured slaves into combat beasts of varied types. The lizards bred variants from massive Gorilla types to medium and smaller warrior variants, much like we bred cats/etc. The lizards also bred Juggers, Fiend, Blue Horror, and Murderers - all optimised for combat role against the other race. Vance created many highly creative novels, many with race variants as well as species on various planets. Often they had devolved from fallen interplanetary societies, near savagery, in a complex web of interspecies trade/conflict after the ancient fall when space travel was lost. SF in those days differed a lot from now. Even so, I found Vance's novels fascinating as a teenager. He is long gone, but not forgotten but his novels live on as e-books/audio books and are worth reading.
Wont viruses just adapt and now we've got worse viruses as a result? Isn't this kind of why doctors don't like to prescribe antibiotics too often, because they become ineffective in the long run.
I'm genuinely asking, I'm a simple software dev not a doctor.
Maybe, maybe not. Antibiotic resistance develops because antibiotics are only somewhat deadly to bacteria, so natural selection can occur and bacteria develop resistance over time. There are some antibiotic/bacteria combinations where this doesn't happen, because the respective antibiotic is so deadly to that special kind of bacteria, that no survivors can pass on their slightly increased resistance.
And bacteria self-replicate, whereas a virus needs to infect a cell and be reproduced by that cell. Some antiviral mechanisms attack the reproduction proteins that the human cells use, which the virus cannot do without. And the human cells don't have reproductive pressure to replicate viruses, quite the contrary.
Is a fair analogy, antibiotics kill, whereas antivirals use birth control? So viruses would have to find a way to circumvent the replication inhibitors or potentially find a noval way to replicate.
Some classes of antibiotics use birth control - rather than killing bacteria directly, they inhibit reproduction.
I think the biggest difference is that bacteria can react to a treatment, while viruses don't have the capacity to react. If you've stopped a virus from replicating, it's essentially dead. A bacterium may have defensive measures it can take. It could form an endospore and try to wait things out. If you've stopped it from reproducing, as it ages it might start accumulating free radicals that increase DNA damage, leading to a higher chance of it mutating to resist the antibiotic. Etc.
> I think the biggest difference is that bacteria can react to a treatment, while viruses don't have the capacity to react.
Bacteria also swap genes between themselves [0], whereas two viral particles sitting on the same Petri dish are too inert/simple for that. That represents an additional way for adaptive tricks to spread.
Antibiotic resistance costs bacteria dearly. The proteins they lose (typically related to cell membrane building) are honed by millions of years of evolution. The resistance mutations end up being inferior, slowing down growth and perhaps other capabilities.
Antibiotics are related to bacteria, which have different mutation mechanisms than viruses. I'm also a tech guy, so someone may correct me.
Also, this seems to influence the human end to make protective material, not act on the viruses directly.
OT: Just replying to myself to ramble a little bit more.
The Crick, Brenner et al. paper that I cited above
* studied mutations in a viral gene called "rIIB"
* the authors used those rIIB mutations to determine that the genetic code was a non-overlapping triplet (now called codons) -- a pretty fundamental discovery.
* What's amazing to me is that they still have NO IDEA what the rIIB gene actually _does_, mechanistically.
It's like learning a little bit about God using an enigma machine (sorry, shitty simile).
I'm honestly confused about what the OP could be getting out of a drive by comment so obviously and verifiably wrong. Seems like a poor use for even cheap AI inference tokens. It doesn't even have trolling value.
Is it so wrong of me to demand competence of my spammers?
My understanding is that there's often at tradeoff between fitness and antiviral resistance. The virus starts on a fitness local maximum, and it has to pay a fitness cost as it evolves resistance to the antiviral (due to stepping off the local maximum). If the antiviral is ineffective, and the virus continues reproducing, over time it will evolve "compensatory mutations" which allow it to regain some or all of the lost fitness.
So yeah, I wouldn't be super worried about the virus evolving to become worse in absolute terms as a result of antiviral exposure. Virii are evolving all the time anyways. Antivirals can also reduce evolution speed by fighting an infection: A more severe infection means more virions means greater evolution speed. I believe some new COVID variants were thought to have evolved in the body of someone who was severely infected. (However: Note that it's not necessarily beneficial for fitness for the virus to evolve greater infection severity, especially if that interferes with transmission.)
Same deal with vaccination, right? We saw this with covid; as new variants evolved to evade the vaccines, they tended to result in less severe infections (even to the unvaccinated) than the original.
After some reading, it appears it's more of a mixed bag. Evolutionary pressure from vaccines can have that effect, as appears to have been the case with Omicron, but it's not guaranteed, and some variants appear to have been more virulent than the original virus. See the "Relative Severity of Variants" section of this paper: https://www.nature.com/articles/s41579-022-00841-7?utm_sourc...
1) Viruses don't adapt instantly nor perfectly - that's why viruses can be animal-specific. Influenza (or recently SARS-CoV) are famous because they are malleable enough to adapt to new hosts, human or animal, within a few months or years, but not all viruses have this ability.
2) To further illustrate, some viruses have been nearly eliminated with a single vaccine. Polio didn't manage to adapt before going almost extinct. And a good reason why is:
3) Viruses can only evolve inside contaminated hosts. If you find a cure that stops quickly the virus from multiplying and contaminating, you are also curtailing its ability to adapt. A contaminated host is a giant casino machine, allowing the virus to mutate until it hits a new evolutionary step. A strong enough vaccine or treatment is like throwing out the virus before it has time to play much.
Two viruses have been entirely eliminated in the wild, one (Smallpox) still exists in government research facilities the other (Rinderpest) I believe is just gone because it wasn't useful as a direct weapon (humans aren't affected) and nobody actually wants Rinderpest, it was just killing cattle and while poor farmers need their cattle or they'll starve the rich want to drink milk and eat steak so they weren't keen on this virus either and helped fund its eradication.
Probably, currently it's just 15 people that have it, but if you started giving it to more people there would be incredible advantages to any virus that could adapt and viruses mutate fast.
Of course. Given unlimited time, viruses will develop resistance. Resistance = evolution = descent + modification + selection. You can quibble about whether viruses are alive, but they definitely evolve.
But so what? Anti-pathogen drugs are useful in the period during which resistance hasn't become universal, and if and when it comes a problem, we'll have other drugs.
Besides: sometimes you get lucky and the virus goes extinct before it can develop resistance (e.g. smallpox)
That's not really true. Evolution is constrained by physics, so while bacteria can evolve to live in 100C water, they can't evolve to live in molten magma, or the surface of the sun. Similarly, they can evolve to live off of isopropyl alcohol, but they can't evolve resistance to sufficiently concentrated bleach (sodium hypochlorite).
I'm not sure what you consider "sufficiently concentrated" but some existing viruses (which form spores) can already survive a 1% sodium hypochlorite solution cleaning, which is pretty crazy-high. At that point you're risking damage to surfaces/skin. Doesn't seem impossible it could go higher if bleach exposure was consistently selected for.
Surviving in 1% bleach doesn't demonstrate the supremacy of evolution over physical constraints, and it's important to keep the eye on the ball of what this whole point was about. There are circumstances such as the temperature of the Sun, where DNA, or any molecular structure, or even atoms, can't hold together, and so there's no evolutionary pathways that can iterate toward survival. You can't have molecular biology without molecules.
It's an extreme example, but it demonstrates a fundamental constraint that can't be evolved around. Ideally vaccines can find an equivalent in the space of mechanistic interactions that cut off any evolutionary pathway a virus could reach, either exterminating the virus before it has enough time to complete the search, or by genuinely leaving no pathway even with infinite searching.
Contrary to what you may have heard from Jeff Goldblum life does not always find a way.
And the really, really bad part about abusing natural parts if the immune system to provoke pathogen resistance against them is that the resistance will target part of natural immunity.
Normally they don't get to try that with a strong selection pressure for a handling a particular monoculture.
Admittedly the method in the present article is probably better than the idiocy of extracting antibacterial peptides from context for use as drug products, since at least this will always be used in the context of a full immune system and they trigger a number of genes which probably regulate a whole subcomponent of measures rather than just one or two mechanisms.
Even so, it lifts up a particular part from the diffuse field of defenses as salient and particularly worthwhile to defeat.
Also, keep in mind that many species of virus have so small genomes they have to overload the readings of parts of the nucleic acid sequences to get a full set of proteins.
Evolve to evade the immune system, certainly. But if you're implying that it will happen in the same ways, at anything like the same rate and to the same extent regardless of what we do, no that's not right.
By your logic, we'd be better off if we gave patients a cocktail containing small amounts of many different antibiotics. By giving a single antibiotic in a large dose, we are "lifting up a particular part of our field of defenses as salient and particularly worthwhile to defeat". Sounds bad.
Willing to bite the bullet and sign on to this kitchen-sink approach, of offering patients a cocktail containing small amounts of many antibiotics?
The problem I see with the cocktail approach is that a pathogen can gradually evolve defenses against everything simultaneously, in parallel. With a cocktail, every element of the cocktail provides a distinct glide path for a virus to increase its contextual fitness. That also sounds bad! The main way I see this situation improving is if two elements of the cocktail happen to act as a sort of clamp, where any virus which begins to defeat one ends up increasing the effectiveness of the other.
Azithromycin (rhinovirus, influenza A, Zika), clarithromycin (influenza A, rhinovirus), doxycycline (dengue, Zika), minocycline (West Nile), teicoplanin/dalbavancin (Ebola, MERS/SARS-CoV and SARS-CoV-2), rifampin/rifamycins (orthopoxviruses), aminoglycosides (HSV-2, influenza A, Zika), salinomycin/monensin (influenza A/B, coronaviruses incl. SARS-CoV-2), nanchangmycin (Zika, West Nile, dengue, chikungunya), nitroxoline (mpox), and some fluoroquinolones have all shown antiviral properties.
I think they used “generally” on purpose, to make a general observation. Of course, there exist viral infections that are worse than the most common bacterial ones.
There’s some ambiguity in their comment because it isn’t obvious what we’re sort of… averaging over, but I think they clearly don’t mean that there no serious viral infections exist.
It was already invented [0], but the patents were bought by a small company in New Zealand (some kind of big pharma shell company?) who isn't seriously developing it and now appears to be defunct.
Both are broad spectrum antivirals, but completely different mechanism.
DRACO "is a chimeric protein with one domain that binds to viral double stranded RNA (dsRNA) and a second domain that induces apoptosis when two or more DRACOs crosslink on the same dsRNA." (Ridder et al 2011). This article is about packaging mRNA for a set of 10 interferon-stimulated genes that express multiple proteins that target various stages of viral replication.
"""
In March 2024 Kimer Med announced it has signed a contract valued at up to USD$750,000 (NZD$1.3 million) with Battelle Memorial Institute (Battelle), the world’s largest independent, nonprofit research and development organization. The contract is focused on the discovery and development of new antiviral drug candidates for the treatment of alphaviruses.
"""
The cynical part of me wonders: if this has been a promising approach for 10+ years, why weren't they able to secure VC funding years ago (or nonprofit biomedical research funding from places like the Gates Foundation that care a lot about infectious disease)?
This. Claims of a universal antiviral are as old as western medicine itself. Literally the only reason anyone knows what the Hippocratic oath is is because Hippocrates was already famous at the time for promoting elderberry as the universal antiviral.
My understanding is that the _concept_ of a virus wasn't even established until the late 19th century, because we first needed the germ theory, and then we needed to understand bacteria well enough to have a filter whose pores were known to be smaller than bacteria could pass through, but which some _other_ infection agent could still pass through.
And the part where he says people with this mutation are more prone to bacterial infections is not worrying, because…?
In a world of more and more antibiotic resistant bacteria, that does not seem like a good trade-off…
This is researched as a potential treatment to an acute viral infection. For the duration of the treatment, you can accept the increased risk of bacterial infections.
Just like you accept the risk of increased yeast infections while treating bacterial infections with antibiotics, or the risk of any infection while treating a cancer with chemotherapy.
One of the effects of ISG15 deficiency is a disease called "Type I interferonopathy".
Among the symptoms of this disease includes things like necrotic lesions and severe multi-systemic damages.
From what I gather the fact that these people are not more susceptible to viral infections was a surprise. Which probably relates to why the doctors in the parent article were investigating its possible anti-viral properties.
Probably the issue is microphages being wiped out which allows bacteria to thrive. But you wouldn't take this _all the time_, only when you had a specific viral infection to get rid of.
It seems to me that the point is to induce the inflammation only when someone is exposed to a virus or developed a viral infection, not to have a persisting one. Just like you take antibiotics if you get a bacterial infection, but only for the time needed to treat the infection. You don't take antibiotics every day "just in case".
Exactly my thought. There must be a reason that evolution didn't auto-optin us to these proteins. Everything is a trade-off. It's possible with the prevalancy of viruses in the modern world that we would, on balance, benefit from a more vigilant immune system.
I'm guessing the deployment ends up being less mass-population and more "oops, this guy with a viral disease just coughed on me." Though I can easily see long-term, preemptive use being worth the risk for people dealing with, say, ebola patients.
I like the turn of phrase "sentencing" here. The jury gave its verdict, guilty as all hell, and now we're ready for the sentencing hearing, Your Honor.
Interesting, and potentially very good. But I can't help but wonder, like at least one other commenter, that this might have unexpected effects if applied at a larger scale. I know some viruses kill bacteria for instance. I don't know, something about universal applicability makes me a little uneasy.
Bacteriophages don't infect things which aren't bacteria.
In fact they're so absurdly specific that while you could bathe in a solution of them and not get sick, they also frequently fail to infect slightly different members of the same species, which is why ultimately they never become antibiotic alternatives: having the right one on hand ranges from difficult to impossible.
Yep, in cheese making, we regularly rotate between very similar strains of starter culture for phage resistance. The company we buy from even lists what cultures to use for anti-phage rotation.
Are you saying that this antiviral would not kill bacteriophages? Or are you saying you think the effect would be small because the population in our bodies is small?
There are not bacteriophages in your body, except where bacteria are. And since they don't infect human cells, they're being constantly destroyed already by the primary immune system even if they get there.
Viral infections only successfully persist by replicating faster then the human body destroys them, and by hiding in human cells.
This isn't a system which is some sort of toxic to viruses, it's an immune booster.
When you get a viral infection, immune cells make a signalling protein called a IFN-1 (Type I Interferon) cytokine, and this flips a boolean flag to True on a bunch of genes (interferon-stimulated genes or ISGs) that produce a bunch of proteins (hundreds) that control the infection. ISG15 is one of them and its role appears to be to downregulate and to limit the inflammation.
The paper title refers to a ISG15 deficiency, meaning if you are dificient in ISG15 that inflamation limitation goes away. But the paper is actually about how in people that naturally have a ISG15 deficiency, there is an always-on low level expression of some of these pro-inflamation genes. So they take that as a safe level.
The did RNA sequencing on experimental ISG15 deficient cells and from heatlhy individuals, identified the mutations, narrowed down to 10 genes (antiviral ones not inhibitors) that in combination significantly inhibited viral replication. They stuck the RNA for such genes in lipid nanoparticles such that they enter host cells, whose ribosomes happily read the RNA like a turing head reads a tape in base 20 and produce proteins encoded by these genes, similar to how the mRNA vaccine works.
So why not dose with the IFN-I directly? Three referenced papers show its "poorly tolerated with significant side effects" and all those downregulators that get expressed limit the inflammation response.
Disclaimer: IANAB (not a biologist) corrections might be due..
This is typical of "why not just one drug/treatment" for something big like viruses, cancer, etc.
I think we'll never have this "one shot," but continue to find tailored treatments for individual conditions. There's no way out of this complexity with "one simple trick," which seems really appealing to the people who determine what gets popular in social media and seemingly politics now. Its just going to be boring and grueling academia and medical trials that are hard for the layperson to understand, hence the important of funding these programs. The recent right-wing election wins and thus a right-wing government cutting all manner of medical grants is supported by the "one weird trick" crowd. Hopefully, the USA will have better leadership in the future to get us back to actual science and to find actual new treatments.
Already, even on HN, the top comments are conspiracy-culture coded, "but, but this one company bought the patent and disappeared with it!" Sigh.
Don't we already have treatments for the rabies virus but the problem is that it's too late once the virus gets to the central nervous system which is when symptoms show? How would this new antiviral be different?
What is the “current” scientifically approved and unbiased understanding about the negative effects of the COVID vaccines?
There seems to be a lot of information, misinformation, conspiracy theories, and information hiding at least in the perception, if not in reality.
I cannot imagine what society at large will have to deal with or what the reaction will be for or against an “everything” therapy, given what happened with Covid.
The current understanding is that you're 15 to 20 times more likely to suffer severe eye damage from taking Viagra than even the highest risk group (young men) is to encounter a serious adverse effect from the COVID vaccine.
The information has not changed dramatically since a few months after its release, and the myocarditis risk was not detected in clinical trials because it is an unbelievably rare event. Detecting it would've required trials orders of magnitude larger than any clinical trial ever.
Broad-based inflammation delivered by lipid nanoparticle chock full of mRNA: what could possibly go wrong? I'll stick with monoclonal antibodies, thanks.
Oh, and here's what the ISG15 deficiency (the condition these mRNAs are there to simulate) does:
> Patients present...with infectious, neurologic or dermatologic features. Basal ganglia calcification is observed in all patients... The basal ganglia calcifications may cause epileptic seizures... The IFN-I inflammation may also manifest early in life as ulcerative skin lesions in the armpit, groin and neck regions. Finally, ISG15-deficiency leads to mendelian susceptibility to mycobacterial disease... [t]hese infections present as fistulizing lymphadenopathies and respiratory symptoms following BCG vaccination.
> When he and his colleagues looked at the individuals’ immune cells, they could see encounters with all sorts of viruses—flu, measles, mumps, chickenpox. But the patients had never reported any overt signs of infection or illness.
Given that the article goes on to talk about mild persistent inflammation, is it possible that these individuals are sometimes asymptomatic but still capable of carrying/transmitting viruses at least temporarily? The article talks about potentially immunizing healthcare workers during a future pandemic, but if this was just allowing people to never develop symptoms (and not have to leave work) while having low-grade infections, would we accidentally create a work-force of Typhoid Marys?
Excellent point, and it seems plausible in my opinion.
https://www.frontiersin.org/journals/immunology/articles/10....
Oh, and it's probably worthwhile pondering what the viruses will do if this mechanism comes into widespread use.
While I was looking for the reference above this also came up:
https://www.sciencedaily.com/releases/2020/02/200210144854.h...
when bat cells quickly release interferon upon infection, other cells quickly wall themselves off. This drives viruses to faster reproduction
Quite a way from whole-animal physiology in the referenced research, by all means, but it's a fair point, right.
Even worse, that type of chronic inflammation might cause premature death. Or cancer. Or other disease states.
> “In the back of my mind, I kept thinking that if we could produce this type of light immune activation in other people, we could protect them from just about any virus,” Bogunovic says.
This sounds terrifying. There's a reason our bodies do not regulate like this.
The article states:
>Bogunovic’s therapy is designed to mimic what happens in people with ISG15 deficiency, but only for a short time.
Given the choice between 2 weeks of a moderate COVID infection (fever but no hospitalization), and 2 weeks of this therapy, I would guess that the moderate COVID infection gets you at least 10x the inflammation.
Yeah, constant low-grade inflammation is a hallmark of auto-immune disease, diabetes, etc. It's a glide path to degeneration and death.
If that was what the article said, your point would be on topic.
But the article didn't talk about imposing constant low-grade inflammation. In fact, they specifically said they were talking about 3-4 days.
But if this was something you could activate as needed..
It also sounds like an episode of some televised sci-fi series where someone was exhibiting remarkable immunity to all sorts of diseases (including some nasty ones deliberately added for testing); but it turned out that this was no super-cure but instead the limited natural resources of the immune system being used up all at once, leading to a horrific death when they ran out.
I can't remember which series it was, though.
Sounds very Outer Limits-esque, but I don't recall that specific episode. It's certainly at least an easy interpolation from many Outer Limits episodes, though.
On the other hand, let's aim for the juiced up immune systems portrayed in one of the Star Trek series. It gets so powerful it can reject acquaintances.
I have always been a huge fan of the show but sitting here trying to figure out what you specifically are referencing?
I think it was one of the offshoots like Next Generation that had a visit to some research station where all the scientists were dead or dying of premature aging. It was the immune systems of some (bioengineered?) children that were killing them.
I wonder if enough of them exist to even do a study like that.
I have encountered side effects that probably no one has seen before, simply because of rarity and peculiarity of behavior. You don't run into a ton of people using both interferon and doing karate, so if bruising more easily happens 10% of the time... would anyone notice?
Personally I would be more worried about persistent inflammation causing inflammatory disorders, of which there are many. If there are like 10,000 individuals with this trait then there just aren't enough to detect. But that seems direct... wouldn't you expect something like this to potentially even destroy viral reservoirs over time?
The fact that this is short term in the treatment made me 1000x more comfortable with the idea in any case.
I wonder if large numbers of humans acquire this mutation, how viruses would adapt to this evolutionary pressure?
They would still have too many other possible hosts.Or maybe they'd find a way to attack that very system, similarly how HIV attacks the immune system.
I am not a medical expert, but from what I read the last time I saw this being discussed, ISG15 deficiency also causes something called "infernopathy" that leads to inflammation across the entire body. I don't believe it's related to viral activity at all.
From TFA: "We only generate a small amount of these ten proteins, for a very short time, and that leads to much less inflammation than what we see in ISG15-deficient individuals,” Bogunovic says. “But that inflammation is enough to prevent antiviral diseases."
It seems that the goal is to learn to trigger the benefits, without triggering the bad parts. Which, should probably have been obvious to you without even bothering to read the article.
The weird thing about this quote: is the inflammation enough to prevent viral diseases, or antiviral diseases?
To the extent the disease is due to factors hurting the virus, I guess it's viable as a perspective, but I'd be surprised if it's deliberate in this case.
Probably just a mistake. I don't believe there is such a thing as an "antiviral disease".
A virivore infection could count I guess? But probably not what they meant.
I would imagine the worker would be wearing protective gear. They're not walking around mask-off. Also, if you know you have gotten this treatment, you would obviously have to take different precautions.
Asymptomatic carriers are a concept I've always found interesting and honestly a bit confusing. When a pathogen can be present without ever causing symptoms it becomes much trickier to show causality.
This was a lynch pin of sorts in Koch's postulates. We can't properly go through those postulates with viruses like we can with biological pathogens, but it is odd to me that we don't have similar concerns when the presence of a replicable pathogen doesn't cause the symptoms they are expected to cause.
You can show transmission pathways with a combination of epidemiological evidence and sequencing data.
Epidemiology can never show causation or evidence, at best it shows correlation that is a useful indicator for future research.
I am sure it does cause concern to many. I mean how scary is it that you can run into someone seemingly healthy and next thing you know you are sick?
I know as a health care worker I actually think about things like this. MRSA is a good example. Most people don't react to exposure but some do. Those that do get long term infections that are hard to get rid of if ever. Most think of this as a hospital issue. But the reality is that there are literally thousands of people with MRSA all over the world and they are carriers of it and they do things like go to the bank machine and touch it, open the door at 7-11, pick up items at the store and then put them back on the shelf and so on and so on. MRSA is literally everywhere. Some people contact it and suffer problems others do not.
With something like MRSA how do you determine that the virus is cause for disease when, as you said, many will be infected without showing symptoms?
That the root of the confusion for me. I haven't wrapped my head around how we can know a specific pathogen causes disease if a large number of people can be found to have that pathogen present without showing symptoms.
Statistics.
Not all smokers get lung cancer. But with large enough samples, smokers turn out to be much more likely to get lung cancer than non-smokers. That's why we say that smoking causes lung cancer. It's not as if someone has actually watched a particle of tobacco interact with someone's lung cells to turn them cancerous in real time.
Smoking isn't a contagious pathogen.
Second- and third-hand smoke mimic contagion.
That has nothing to do with contagion, that's just a sign that the impact of smoke inhalation isn't limited to the one sucking on a cigarette.
Contagion would mean that the smoke can infect the host, replicate, and spread to others. That's not how second hand smoking works.
Why doesn't that get dismissed with the usual universal dismissal "correlation != causation"?
Worse, what if they actually are sick, but don't have the immune response so it's not obvious they are sick until their organs fail?
(I may have watched too much House)
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I always wonder this and maybe people in the comments here know the answer: If humans had the technology to eliminate all viruses on Earth, what would be the outcome? Do viruses keep other bad things in check? Would there be bad consequences if we eliminated all viruses?
The world of viruses is wide and beyond our current understanding. 50 years ago one might have dreamily wondered whether "eliminating all bacteria" would improve the world. Now we know we'd all die quickly without bacteria (e.g. gut biome). I think we're about at that level of understanding today regarding viruses.
There's a hypothesis that a viral gene made mammalian placenta possible: [pubmed](https://pubmed.ncbi.nlm.nih.gov/10693809/).
And there's not even the only one (there are other syncitins).
Disclaimer: I'm not a medical professional
For one thing, viruses keep bacteria in check. Bacteria populations live in an equilibrium standoff with bacteriophages (viruses). The human gut contains more bacteriophage virions than bacterial cells. So eliminating all viruses could lead to bacteria overgrowth
Most viruses are bacteriophages, so I imagine bacteria would run wild!
Aren't bacteria generally much larger than viruses?
Phages don't devour bacteria, they get inside and hijack them, like viruses tend to do with cells.
Seems strange to call them that, then; but such is English I suppose.
Sometimes when phages get enough copies inside bacteria. The host will explode and release all phages inside it.
Eliminate all viruses: Population issues in other organisms down to bacteria is my guess. We break a link in a significant food chain, basically.
Eliminate human-tropic viruses: We have to monitor for outbreaks when new viruses mutate and jump species to successfully infect humans. If there's zero mass immunity across the population at every outbreak, we're still in a high-risk situation.
Loss of genetic diversity overtime will happen as well as a different path of evolution. Much of what you see on earth today is the result of virus-host interactions shaping evolutionary outcomes. Viruses are capable of providing horizontal inheritance of genetic material.
Viruses have had a lot to do with the evolution of life and specifically us, where perhaps our distant ancestors were bestowed with a system of transcribing short term memory into long term memory via the hijacked machinery from a virus. This is only one example that I could remember off the top of my head, there are surely many more. Would that matter going forward? I feel like we'd better be sure that we aren't causing more problems than we are solving.
Viruses kill a lot of bacteria. We might trade viral infection for increased bacterial infections
We aren't the target of most viruses.
It could be chaotic, I think.
https://m.youtube.com/watch?v=SbvAaDN1bpE
Are we also eliminating transposons? We would not survive that.
https://en.m.wikipedia.org/wiki/Transposable_element
Viruses are part of other biological processes as well as keeping things in check. For example, there is a bunch of viral activity involved in human pregnancy. A quick web search found this:
https://pmc.ncbi.nlm.nih.gov/articles/PMC6177113/
I would be worried about:
* An increase in autoimmune diseases (related to the hygiene hypothesis).
* Decreased resistance to future viral pandemics, since the body wouldn't have practice since childhood in fighting viral disease.
On the other hand viral infections themselves can instigate autoimmunity. After all, your body now has to fight your own cells (in contrast to other foreign infection)
Yep, hard to know for sure which way it would go.
Population control.
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Not really. Races don't exist biologically. There are certainly traits within populations but that's a bit like my cousins tend to be fatter than my family. It's not something that can be accurately targeted.
You'd be surprised. There is quite a bit of polymorphism within the human species that is very much distinguishable per population. E.g. haplogroup analysis or microsatellite analysis is remarkably accurate in this regard due to a lack of interaction between far flung populations until quite recently in human history. Now, does this imply all the bullshit eugenicists and other racists tend to preach about with race? Hell no, social factors are responsible for most of that variance, but to suggest there would be no biomarker for "race" in its colloquial definition as proxy for population of origin is inaccurate.
This is also why there is a big focus now to seek out underrepresented populations in genetic analysis, because there may be population specific biomarkers that are relevant in disease that you miss if you limit yourself to the handful of widely sequenced homogeneous populations (e.g. there are Utah and Iceland datasets that are popular to use for this).
Not an expert but I don't think that still qualifies as biological differences in races. I mean, obviously we are all biological different and it seems obvious as well that if a group of people stays isolated enough it will develop and reinforce differences to other groups.
For example the Basque population has clear genetic differences to the rest of the Iberian and Westerner population [1] but that doesn't make them a different race.
Race is just a social construct, mostly based on visual traits.
[1] https://www.ibe.upf-csic.es/news/-/asset_publisher/PXTgqZXxl...
What there isn't is a small number of distinct subgroups that are more related to each other than to the other subgroups.
Sure there are. An easy example is Australian aboriginals. They were geographically isolated for tens of thousands of years. Their subgroups are more related to each other than to other subgroups.
There is, due to the way humans migrated and geographically isolated themselves over human history where founder effect, genetic drift, and evidence for introgression (both within our species and from hybridization with other species of hominids) is easily appreciated among populations even today.
http://www.stat.yale.edu/~jtc5/papers/CommonAncestors/Nature...
Strong statistical signals but no sharp lines between groups - we as a species like travel and sex.
Depends on the group. Oldie but goodie (1). Salient quote: "The Mormon gene frequencies are similar to those of their northern European ancestors. This is explained by the large founding size of the Mormon population and high rates of gene flow. In contrast, the religious isolates (Amish, Hutterites, and Mennonites) show marked divergence from their ancestral populations and each other, due to isolation and random genetic drift. "
1. https://pmc.ncbi.nlm.nih.gov/articles/PMC1684477/
"Races don't exist biologically"
This being your first sentence doesn't warrant continued reading.
The historical conception of race doesn't translate simply to human genetics.
There is more genetic variation within a what we might call a race than between them. And it's interesting to note that the genetic diversity of Eurasian populations is in large part contained within the much greater diversity of Africa. In some sense we're all Africans. On top of that there has been a good amount of mixing, both historically and in the present day.
To think in terms of "races" might lead one to hold a mental model of impermeable boundaries between populations that in many cases were never present, and certainly aren't today. Geneticists tend to use the word "population" instead, since it doesn't connote any unhelpful assumptions about uniform or fixed phenotypes within a well-defined species subgroup.
Of course there are certain obvious environmental adaptations that have been selected for in different geographies/climates, as well random genetic drift between distant populations. Sometimes those difference might have medical relevance, and you can make statistical generalisations about the prevalence and distribution of genetic markers within any group you like. But for most medical and public policy applications it is likely most useful to focus on populations within an administrative area, and increasingly, individualised medicine.
Humans are animals, adaptable animals. We have seen how pigment faded when people moved out of Africa and the energy cost of melanin was saved as men lost melanin to allow Vitamin D internal synthesis, and as they went to Asia they regained melanin in the South-East and even changed to another pigment in China etc - might be dual pigments. Hot climates often had ample food = over-population and competition for food = war and internecine conflict for resources and people optimised for combat. As you went North food became seasonal and people starved at time = crops/storage = less fighting = Eskimos are non combative against people, but their enemy was the climate = they learned to combat that quite intelligently with tooth/bone/sinew - also animals are high calory food, but deficiencies can lead to 'rabbit starvation' can occur, but in Eskimos was abated by fat from seals etc. https://en.wiktionary.org/wiki/rabbit_starvation So we are like cats/dogs/hamsters and the same for birds = hundreds of chicken variants. We are just meat in varied shapes/minds I recall an SF book by Jack Vance called 'Dragon Masters' where there were 2 habitable planets, one with Earth men and one with smart lizards and every few thousand years they would pass nearby and the higher tech lizards with space ships would raid the 'Earth' for slaves/plunder and would also lose some lizards to Earth capture. In the long period between orbital intersections, each side would breed their captured slaves into combat beasts of varied types. The lizards bred variants from massive Gorilla types to medium and smaller warrior variants, much like we bred cats/etc. The lizards also bred Juggers, Fiend, Blue Horror, and Murderers - all optimised for combat role against the other race. Vance created many highly creative novels, many with race variants as well as species on various planets. Often they had devolved from fallen interplanetary societies, near savagery, in a complex web of interspecies trade/conflict after the ancient fall when space travel was lost. SF in those days differed a lot from now. Even so, I found Vance's novels fascinating as a teenager. He is long gone, but not forgotten but his novels live on as e-books/audio books and are worth reading.
If there was ever a race targeting disease they will exist by definition. Those it inaccurately targets are just not pure-blooded enough.
Wont viruses just adapt and now we've got worse viruses as a result? Isn't this kind of why doctors don't like to prescribe antibiotics too often, because they become ineffective in the long run.
I'm genuinely asking, I'm a simple software dev not a doctor.
Maybe, maybe not. Antibiotic resistance develops because antibiotics are only somewhat deadly to bacteria, so natural selection can occur and bacteria develop resistance over time. There are some antibiotic/bacteria combinations where this doesn't happen, because the respective antibiotic is so deadly to that special kind of bacteria, that no survivors can pass on their slightly increased resistance.
And bacteria self-replicate, whereas a virus needs to infect a cell and be reproduced by that cell. Some antiviral mechanisms attack the reproduction proteins that the human cells use, which the virus cannot do without. And the human cells don't have reproductive pressure to replicate viruses, quite the contrary.
Is a fair analogy, antibiotics kill, whereas antivirals use birth control? So viruses would have to find a way to circumvent the replication inhibitors or potentially find a noval way to replicate.
Some classes of antibiotics use birth control - rather than killing bacteria directly, they inhibit reproduction.
I think the biggest difference is that bacteria can react to a treatment, while viruses don't have the capacity to react. If you've stopped a virus from replicating, it's essentially dead. A bacterium may have defensive measures it can take. It could form an endospore and try to wait things out. If you've stopped it from reproducing, as it ages it might start accumulating free radicals that increase DNA damage, leading to a higher chance of it mutating to resist the antibiotic. Etc.
> I think the biggest difference is that bacteria can react to a treatment, while viruses don't have the capacity to react.
Bacteria also swap genes between themselves [0], whereas two viral particles sitting on the same Petri dish are too inert/simple for that. That represents an additional way for adaptive tricks to spread.
https://en.wikipedia.org/wiki/Horizontal_gene_transfer
Antibiotic resistance costs bacteria dearly. The proteins they lose (typically related to cell membrane building) are honed by millions of years of evolution. The resistance mutations end up being inferior, slowing down growth and perhaps other capabilities.
Antibiotics are related to bacteria, which have different mutation mechanisms than viruses. I'm also a tech guy, so someone may correct me. Also, this seems to influence the human end to make protective material, not act on the viruses directly.
Viruses can acquire resistance by mutation. This has been well established for decades.
FWIW, I was trained as a bacterial geneticist and routinely used bacteriophage (viruses that infect bacteria) with various resistance mutations.
Viral mutations are not restricted to viruses that infect bacteria.
edit: in fact, fundamental aspects of the genetic code were determined by analyzing and exploiting viral mutations.
https://en.wikipedia.org/wiki/Crick,_Brenner_et_al._experime...
OT: Just replying to myself to ramble a little bit more.
The Crick, Brenner et al. paper that I cited above
* studied mutations in a viral gene called "rIIB"
* the authors used those rIIB mutations to determine that the genetic code was a non-overlapping triplet (now called codons) -- a pretty fundamental discovery.
* What's amazing to me is that they still have NO IDEA what the rIIB gene actually _does_, mechanistically.
It's like learning a little bit about God using an enigma machine (sorry, shitty simile).
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What's the purpose of annual flu vaccination programs if "viruses do not mutate!"?
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I'm honestly confused about what the OP could be getting out of a drive by comment so obviously and verifiably wrong. Seems like a poor use for even cheap AI inference tokens. It doesn't even have trolling value.
Is it so wrong of me to demand competence of my spammers?
My understanding is that there's often at tradeoff between fitness and antiviral resistance. The virus starts on a fitness local maximum, and it has to pay a fitness cost as it evolves resistance to the antiviral (due to stepping off the local maximum). If the antiviral is ineffective, and the virus continues reproducing, over time it will evolve "compensatory mutations" which allow it to regain some or all of the lost fitness.
Based on my recollections of this paper https://pmc.ncbi.nlm.nih.gov/articles/PMC5499642/
So yeah, I wouldn't be super worried about the virus evolving to become worse in absolute terms as a result of antiviral exposure. Virii are evolving all the time anyways. Antivirals can also reduce evolution speed by fighting an infection: A more severe infection means more virions means greater evolution speed. I believe some new COVID variants were thought to have evolved in the body of someone who was severely infected. (However: Note that it's not necessarily beneficial for fitness for the virus to evolve greater infection severity, especially if that interferes with transmission.)
Same deal with vaccination, right? We saw this with covid; as new variants evolved to evade the vaccines, they tended to result in less severe infections (even to the unvaccinated) than the original.
Citation?
I think (also without a citation) that this was never properly demonstrated.
And there is nearly nobody left who has no immunity from either infection or injection. We are definitely still seeing quite a few deaths from COVID.
After some reading, it appears it's more of a mixed bag. Evolutionary pressure from vaccines can have that effect, as appears to have been the case with Omicron, but it's not guaranteed, and some variants appear to have been more virulent than the original virus. See the "Relative Severity of Variants" section of this paper: https://www.nature.com/articles/s41579-022-00841-7?utm_sourc...
1) Viruses don't adapt instantly nor perfectly - that's why viruses can be animal-specific. Influenza (or recently SARS-CoV) are famous because they are malleable enough to adapt to new hosts, human or animal, within a few months or years, but not all viruses have this ability.
2) To further illustrate, some viruses have been nearly eliminated with a single vaccine. Polio didn't manage to adapt before going almost extinct. And a good reason why is:
3) Viruses can only evolve inside contaminated hosts. If you find a cure that stops quickly the virus from multiplying and contaminating, you are also curtailing its ability to adapt. A contaminated host is a giant casino machine, allowing the virus to mutate until it hits a new evolutionary step. A strong enough vaccine or treatment is like throwing out the virus before it has time to play much.
Two viruses have been entirely eliminated in the wild, one (Smallpox) still exists in government research facilities the other (Rinderpest) I believe is just gone because it wasn't useful as a direct weapon (humans aren't affected) and nobody actually wants Rinderpest, it was just killing cattle and while poor farmers need their cattle or they'll starve the rich want to drink milk and eat steak so they weren't keen on this virus either and helped fund its eradication.
> A contaminated host is a giant casino machine, allowing the virus to mutate until it hits a new evolutionary step.
And even worse, some viruses can swap genes if a host has multiple infections at a given time. Bats in particular are known as "hot pots".
Probably, currently it's just 15 people that have it, but if you started giving it to more people there would be incredible advantages to any virus that could adapt and viruses mutate fast.
Of course. Given unlimited time, viruses will develop resistance. Resistance = evolution = descent + modification + selection. You can quibble about whether viruses are alive, but they definitely evolve.
But so what? Anti-pathogen drugs are useful in the period during which resistance hasn't become universal, and if and when it comes a problem, we'll have other drugs.
Besides: sometimes you get lucky and the virus goes extinct before it can develop resistance (e.g. smallpox)
That's not really true. Evolution is constrained by physics, so while bacteria can evolve to live in 100C water, they can't evolve to live in molten magma, or the surface of the sun. Similarly, they can evolve to live off of isopropyl alcohol, but they can't evolve resistance to sufficiently concentrated bleach (sodium hypochlorite).
I'm not sure what you consider "sufficiently concentrated" but some existing viruses (which form spores) can already survive a 1% sodium hypochlorite solution cleaning, which is pretty crazy-high. At that point you're risking damage to surfaces/skin. Doesn't seem impossible it could go higher if bleach exposure was consistently selected for.
Surviving in 1% bleach doesn't demonstrate the supremacy of evolution over physical constraints, and it's important to keep the eye on the ball of what this whole point was about. There are circumstances such as the temperature of the Sun, where DNA, or any molecular structure, or even atoms, can't hold together, and so there's no evolutionary pathways that can iterate toward survival. You can't have molecular biology without molecules.
It's an extreme example, but it demonstrates a fundamental constraint that can't be evolved around. Ideally vaccines can find an equivalent in the space of mechanistic interactions that cut off any evolutionary pathway a virus could reach, either exterminating the virus before it has enough time to complete the search, or by genuinely leaving no pathway even with infinite searching.
Contrary to what you may have heard from Jeff Goldblum life does not always find a way.
Yeah, wasn't disagreeing with fundamental premise, just picking on the bleach bit.
My sentence construction was a little ornate but the antecedent was "bacteria", not "viruses and bacteria and anything else you can imagine"
Correct.
And the really, really bad part about abusing natural parts if the immune system to provoke pathogen resistance against them is that the resistance will target part of natural immunity.
See also https://news.ycombinator.com/item?id=35700881
Don't viruses evolve to evade the immune system anyways though?
Normally they don't get to try that with a strong selection pressure for a handling a particular monoculture.
Admittedly the method in the present article is probably better than the idiocy of extracting antibacterial peptides from context for use as drug products, since at least this will always be used in the context of a full immune system and they trigger a number of genes which probably regulate a whole subcomponent of measures rather than just one or two mechanisms.
Even so, it lifts up a particular part from the diffuse field of defenses as salient and particularly worthwhile to defeat.
Also, keep in mind that many species of virus have so small genomes they have to overload the readings of parts of the nucleic acid sequences to get a full set of proteins.
Evolve to evade the immune system, certainly. But if you're implying that it will happen in the same ways, at anything like the same rate and to the same extent regardless of what we do, no that's not right.
Interesting. Not sure I buy it though.
By your logic, we'd be better off if we gave patients a cocktail containing small amounts of many different antibiotics. By giving a single antibiotic in a large dose, we are "lifting up a particular part of our field of defenses as salient and particularly worthwhile to defeat". Sounds bad.
Willing to bite the bullet and sign on to this kitchen-sink approach, of offering patients a cocktail containing small amounts of many antibiotics?
The problem I see with the cocktail approach is that a pathogen can gradually evolve defenses against everything simultaneously, in parallel. With a cocktail, every element of the cocktail provides a distinct glide path for a virus to increase its contextual fitness. That also sounds bad! The main way I see this situation improving is if two elements of the cocktail happen to act as a sort of clamp, where any virus which begins to defeat one ends up increasing the effectiveness of the other.
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Is it really true that we have “worse” viruses, or that they are adapting to our modern antibiotic regime & reverting to the status quo?
Antibiotics have never killed any viruses ever. They are exclusively for treating bacterial infections (which are generally worse by a lot).
Azithromycin (rhinovirus, influenza A, Zika), clarithromycin (influenza A, rhinovirus), doxycycline (dengue, Zika), minocycline (West Nile), teicoplanin/dalbavancin (Ebola, MERS/SARS-CoV and SARS-CoV-2), rifampin/rifamycins (orthopoxviruses), aminoglycosides (HSV-2, influenza A, Zika), salinomycin/monensin (influenza A/B, coronaviruses incl. SARS-CoV-2), nanchangmycin (Zika, West Nile, dengue, chikungunya), nitroxoline (mpox), and some fluoroquinolones have all shown antiviral properties.
And no, strep throat is not worse than ebola.
Citations?
The examples that you gave that I checked were not supportive of your assertions.
I think they used “generally” on purpose, to make a general observation. Of course, there exist viral infections that are worse than the most common bacterial ones.
There’s some ambiguity in their comment because it isn’t obvious what we’re sort of… averaging over, but I think they clearly don’t mean that there no serious viral infections exist.
It was already invented [0], but the patents were bought by a small company in New Zealand (some kind of big pharma shell company?) who isn't seriously developing it and now appears to be defunct.
[0] https://en.wikipedia.org/wiki/DRACO
Both are broad spectrum antivirals, but completely different mechanism.
DRACO "is a chimeric protein with one domain that binds to viral double stranded RNA (dsRNA) and a second domain that induces apoptosis when two or more DRACOs crosslink on the same dsRNA." (Ridder et al 2011). This article is about packaging mRNA for a set of 10 interferon-stimulated genes that express multiple proteins that target various stages of viral replication.
Doesn't sound all the bad from the linked wiki:
""" In March 2024 Kimer Med announced it has signed a contract valued at up to USD$750,000 (NZD$1.3 million) with Battelle Memorial Institute (Battelle), the world’s largest independent, nonprofit research and development organization. The contract is focused on the discovery and development of new antiviral drug candidates for the treatment of alphaviruses. """
The cynical part of me wonders: if this has been a promising approach for 10+ years, why weren't they able to secure VC funding years ago (or nonprofit biomedical research funding from places like the Gates Foundation that care a lot about infectious disease)?
This. Claims of a universal antiviral are as old as western medicine itself. Literally the only reason anyone knows what the Hippocratic oath is is because Hippocrates was already famous at the time for promoting elderberry as the universal antiviral.
My understanding is that the _concept_ of a virus wasn't even established until the late 19th century, because we first needed the germ theory, and then we needed to understand bacteria well enough to have a filter whose pores were known to be smaller than bacteria could pass through, but which some _other_ infection agent could still pass through.
https://en.wikipedia.org/wiki/History_of_virology#Discovery
Hippocrates could recommend elderberry for a bunch of ailments, but he didn't have the concept of a "universal antiviral".
Did Hippocrates know the difference between viral and bacterial infections?
Definitely! However, the parent made it sound like the pharma industry put it in a giant warehouse next to the arch of the covenant
There’s alot of promising approaches and investments made.
The miracle of the mRNA covid vaccine and the use of that framework to treat cancer is a good example.
As we wind down research in the US, there will be lots of churn as the market finds new approaches to development.
Because curing profits isn't really on their priority list at all, it's all virtue posturing.
And the part where he says people with this mutation are more prone to bacterial infections is not worrying, because…? In a world of more and more antibiotic resistant bacteria, that does not seem like a good trade-off…
This is researched as a potential treatment to an acute viral infection. For the duration of the treatment, you can accept the increased risk of bacterial infections.
Just like you accept the risk of increased yeast infections while treating bacterial infections with antibiotics, or the risk of any infection while treating a cancer with chemotherapy.
One of the effects of ISG15 deficiency is a disease called "Type I interferonopathy".
Among the symptoms of this disease includes things like necrotic lesions and severe multi-systemic damages.
From what I gather the fact that these people are not more susceptible to viral infections was a surprise. Which probably relates to why the doctors in the parent article were investigating its possible anti-viral properties.
Probably the issue is microphages being wiped out which allows bacteria to thrive. But you wouldn't take this _all the time_, only when you had a specific viral infection to get rid of.
Persisting inflammation is not kind to bodies. All kinds of things could go wrong, and longterm consequences are easy to hypothesise.
Not saying this isn't worth researching but I'd expect big question marks around risk/reward.
It seems to me that the point is to induce the inflammation only when someone is exposed to a virus or developed a viral infection, not to have a persisting one. Just like you take antibiotics if you get a bacterial infection, but only for the time needed to treat the infection. You don't take antibiotics every day "just in case".
Exactly my thought. There must be a reason that evolution didn't auto-optin us to these proteins. Everything is a trade-off. It's possible with the prevalancy of viruses in the modern world that we would, on balance, benefit from a more vigilant immune system.
I'm guessing the deployment ends up being less mass-population and more "oops, this guy with a viral disease just coughed on me." Though I can easily see long-term, preemptive use being worth the risk for people dealing with, say, ebola patients.
Sounds like the first few scenes of every Zombie movie and TV show ever...
Indeed. Or an Utopia. But sentencing on that is still open
I like the turn of phrase "sentencing" here. The jury gave its verdict, guilty as all hell, and now we're ready for the sentencing hearing, Your Honor.
There are things that are wrong and there are things that are crimes and it is up to those on the bench to appreciate the difference.
Interesting, and potentially very good. But I can't help but wonder, like at least one other commenter, that this might have unexpected effects if applied at a larger scale. I know some viruses kill bacteria for instance. I don't know, something about universal applicability makes me a little uneasy.
Bacteriophages don't infect things which aren't bacteria.
In fact they're so absurdly specific that while you could bathe in a solution of them and not get sick, they also frequently fail to infect slightly different members of the same species, which is why ultimately they never become antibiotic alternatives: having the right one on hand ranges from difficult to impossible.
Yes, some phages are very specific - but not all of them! And we're slowly getting better at this: https://www.nature.com/articles/s41564-024-01832-5
Yep, in cheese making, we regularly rotate between very similar strains of starter culture for phage resistance. The company we buy from even lists what cultures to use for anti-phage rotation.
Are you saying that this antiviral would not kill bacteriophages? Or are you saying you think the effect would be small because the population in our bodies is small?
There are not bacteriophages in your body, except where bacteria are. And since they don't infect human cells, they're being constantly destroyed already by the primary immune system even if they get there.
Viral infections only successfully persist by replicating faster then the human body destroys them, and by hiding in human cells.
This isn't a system which is some sort of toxic to viruses, it's an immune booster.
Got it, thank you for explaining. That was unclear to me from the article.
It is well established vaccines are totally safe and have zero to neglected side effects!
Paper appears to be paywalled. It is however an update to this preprint which is available on Biorxiv: "Broad-spectrum RNA antiviral inspired by ISG15-/- deficiency" https://www.biorxiv.org/content/10.1101/2024.06.24.600468v1
My summary for programmers:
When you get a viral infection, immune cells make a signalling protein called a IFN-1 (Type I Interferon) cytokine, and this flips a boolean flag to True on a bunch of genes (interferon-stimulated genes or ISGs) that produce a bunch of proteins (hundreds) that control the infection. ISG15 is one of them and its role appears to be to downregulate and to limit the inflammation.
The paper title refers to a ISG15 deficiency, meaning if you are dificient in ISG15 that inflamation limitation goes away. But the paper is actually about how in people that naturally have a ISG15 deficiency, there is an always-on low level expression of some of these pro-inflamation genes. So they take that as a safe level.
The did RNA sequencing on experimental ISG15 deficient cells and from heatlhy individuals, identified the mutations, narrowed down to 10 genes (antiviral ones not inhibitors) that in combination significantly inhibited viral replication. They stuck the RNA for such genes in lipid nanoparticles such that they enter host cells, whose ribosomes happily read the RNA like a turing head reads a tape in base 20 and produce proteins encoded by these genes, similar to how the mRNA vaccine works.
So why not dose with the IFN-I directly? Three referenced papers show its "poorly tolerated with significant side effects" and all those downregulators that get expressed limit the inflammation response.
Disclaimer: IANAB (not a biologist) corrections might be due..
This is typical of "why not just one drug/treatment" for something big like viruses, cancer, etc.
I think we'll never have this "one shot," but continue to find tailored treatments for individual conditions. There's no way out of this complexity with "one simple trick," which seems really appealing to the people who determine what gets popular in social media and seemingly politics now. Its just going to be boring and grueling academia and medical trials that are hard for the layperson to understand, hence the important of funding these programs. The recent right-wing election wins and thus a right-wing government cutting all manner of medical grants is supported by the "one weird trick" crowd. Hopefully, the USA will have better leadership in the future to get us back to actual science and to find actual new treatments.
Already, even on HN, the top comments are conspiracy-culture coded, "but, but this one company bought the patent and disappeared with it!" Sigh.
Sounds like they are boosting what body already does in case of a viral infection.
I wonder how different it is from interferon therapy - interferons are used to signal viral infection, so they also activate immunity.
The prospect of being able to use this against viruses like the one causing rabies is pretty exciting!
Don't we already have treatments for the rabies virus but the problem is that it's too late once the virus gets to the central nervous system which is when symptoms show? How would this new antiviral be different?
Rabies anti-virus require very carefully handling and refrigeration and thus can be extremely expensive for hospitals to keep in stock.
And, yes, it needs to be applied before symptoms start to appear. Otherwise death is almost for certain.
I doubt this research will lead directly to a better vaccine, but having a better vaccine could save a lot of lives.
There's a lot of work right now in figuring out ways to reduce the cold chain requirements and make it easier to stock.
Problem are antivaxerz who refuse to treat and test dogs! They prefer random street dogs over children !
Isn't everyone just drinking bleach these days anyway?
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What is the “current” scientifically approved and unbiased understanding about the negative effects of the COVID vaccines?
There seems to be a lot of information, misinformation, conspiracy theories, and information hiding at least in the perception, if not in reality.
I cannot imagine what society at large will have to deal with or what the reaction will be for or against an “everything” therapy, given what happened with Covid.
The current understanding is that you're 15 to 20 times more likely to suffer severe eye damage from taking Viagra than even the highest risk group (young men) is to encounter a serious adverse effect from the COVID vaccine.
The information has not changed dramatically since a few months after its release, and the myocarditis risk was not detected in clinical trials because it is an unbelievably rare event. Detecting it would've required trials orders of magnitude larger than any clinical trial ever.
>about the negative effects of the COVID vaccines?
The biggest negative effect is i've been hearing "you'll be dead in six months from this vaccine" for about 5 years now.
It's been 5 years. have you nothing else going on in your life?
rfk gonna ban hammer this so fast
I don't think this is a good idea.
Broad-based inflammation delivered by lipid nanoparticle chock full of mRNA: what could possibly go wrong? I'll stick with monoclonal antibodies, thanks.
Oh, and here's what the ISG15 deficiency (the condition these mRNAs are there to simulate) does:
> Patients present...with infectious, neurologic or dermatologic features. Basal ganglia calcification is observed in all patients... The basal ganglia calcifications may cause epileptic seizures... The IFN-I inflammation may also manifest early in life as ulcerative skin lesions in the armpit, groin and neck regions. Finally, ISG15-deficiency leads to mendelian susceptibility to mycobacterial disease... [t]hese infections present as fistulizing lymphadenopathies and respiratory symptoms following BCG vaccination.
Yeah, about those antiviral superpowers...
What's wrong with mRNA, or lipid nanoparticles?
For the record, here are the primary researchers qualifications: https://www.pediatrics.columbia.edu/profile/dusan-bogunovic-...
His reputably published, peer reviewed, work can be found here: https://www.science.org/doi/10.1126/scitranslmed.adx5758
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