Using a virus to kill what antibiotics can’t
arstechnica.com
arstechnica.com
https://archive.org/details/BBCHorizonS1997e13TheVirusThatCu...
A post on this from a day or so ago, my usual take on phage, from the standpoint of someone who works in healthcare epidemiology and has always been fond of phage therapy:
1) Even with resistance on the rise, we still have antibiotics that work. Phage therapy is a "someday we're going to need this...we think" type treatment.
2) There's no such thing as a "broad spectrum" phage. They're organism specific, and that means not only would you need to keep a phage library on hand, but you'd have to do a lot of diagnostic tests. That's going to be both expensive and tricky.
3) Phages are living things. Not only is that a weird regulatory framework to be in for a drug, but it also means that you need to be able to keep phage alive. In contrast, antibiotics are inert.
4) Phage therapy is also relatively new in the West, which means there's just less of a R&D infrastructure behind it.
There have been people working on commercializing phage therapy since I was in undergrad (I'm now a tenure-track professor). The problem is it's hard, and antibiotics are so much better as a treatment that there's kind of a ceiling on the excitement that they can generate.
Re 2) I don't think that would be a problem considering together with 1 there will simply be a need to develop a quick but reliable method to test for which collection of phages work, probably even develop cocktails of phages for a more broad application. Reducing the amount of antibiotics used would also help reduce the risk of the broad spectrum antibiotic failing because of resistant bacteria.
3) Phages are living things depending on who you ask. Phages are rather simple and will to my knowledge remain viable for a good and long time. Antibiotics may be inert but also have an expiration date, you can't just use an 60yo antibiotic and hope that works. At some point the contents of the antibiotic will have broken down and oxidized.
4)Fair but apparently people have been using it in the Eastern Block for a while with some success. There are some shoulders to stand on and continue R&D.
4) USSR jumped onto antibiotics as soon as they were available, and hasn't really looked back.
Successfully regulating antibiotics is a worldwide effort. I'm not confident we'll ever be more than moderately successful at that.
Proper antibiotics circulation is a policy problem; phage therapy is scientific, technological and policy problem.
2) "There will simply be a need to develop a quick but reliable method to test..." is a really big ask. We don't have quick but reliable tests for some common human pathogens. You can't simply posit that a great test will work. You're right about antibiotic stewardship, which is something I work on, but that's orthogonal to how good phage are as a clinical treatment.
3) While yes, in some particularly strict senses they're not alive, the actual point of that is there's currently no phage preparation technique that is not extremely lab intensive at the site of treatment.
4) Agreed - and the Russians and Georgians have some really cool work, but even there, it's for what are, clinically, extremely difficult edge cases, rather than the kinds of things antibiotics are routinely used for.
No they're not. Virus particles are totally inert on their own. They incorporate themselves into and modify other living systems. But that's no different from drugs.
And while there's no rule that prevents that, I don't know of a single drug - or even the suggestion of a drug - that's capable of integrating with a bacterial host genome, producing the needed compounds, and then exporting them out of the cell.
It's not impossible, no, but it's not a thing presently happening.
Viruses are more like a delicate molecule than like a living thing, because they don't have a metabolism. Kept in the proper conditions they last indefinitely.
"more like" in this context. "Are viruses alive" is the most popular thread in bio-ontology, locked by the moderator after 12,493 pages of heated debate.
But there's a few major concerns:
1. Most preparations are bespoke. The FDA has made some headway with this because of fecal transplants, but it's still a problem.
2. Phages evolve. That's one of the benefits of them. Generally speaking, self-adaptive medications are not something we have a good regulatory context for.
3. They need culturing, isolation, identification, etc. and those are "wet lab" things.
5) phages are viruses and our bodies are very efficient at not letting them in, so you can't just pop a pill, you need them injected into the bloodstream
6) you need a lot of phages (and/or a steady supply of them) because they don't replicate in our bodies (they don't infect us), but our immune system is very good at clearing them out so their blood concentration drops really fast
7) because phages are viruses and we need them injected into bloodstream in copious amounts, our own immune response to them may become a problem. Potentially-fatal-cytokine-storm kind of a problem.
We have antibiotics that work for most infections. For people with antibiotic-resistant infections (especially hospital-borne ones) they are already not an option. A childhood acquaintance of mine with CF recently died of an antibiotic-resistant infection in her newly-transplanted lungs. Lack of awareness and research into phage therapy was fatal in her case, as it meant they started the process late and it took longer than it needed to.
Said process is: take samples of the infectious agent, culture them, and send the cultured bacteria to "phage banks" so they can test their existing phages against it. There's a lead time both because of the initial setup required per-patient, and because of the scarcity of comprehensive phage banks and the lack of good coordination between them.
And yes, highly resistant infections are a problem - and one I work on - but from a "market forces" perspective they're still relatively rare. Even for most highly resistant infections we still have some antibiotics that work - not well, and not without side effects, etc.
In this particular case, they found a phage for the particular infection, but at too late of a stage - most of the development I've heard of has been less about basic research and more about building institutional processes for quickly finding existing predators of a given bacterium. (Which, I agree, is a lot more expensive and risky than an antibiotic if you can find one that works.)
I'm very sorry for your loss.
How is that any different from probiotics or yeast? Those are also "living" but my understanding is that they are dormant and inactive until reactivated.
(Lots of good points raised in your comment, though.)
- Viruses aren't particularly stable. They're fussy little things - it's easy to deactivate them.
- How you get phage preparations is to find them where the bacteria you want to target are growing, then culture them, filter out the bacterial endotoxins (because that'll kill someone), and then use that purified preparation. That needs a lab, and one that's reasonably good at what it does, vs. a random pharmacist at Walmart.
bacteriocidal antibiotics tend to be cytotoxic with aminoglycosides causing hearing loss, fluoroquinolones causing heart problems tendon problems psychiatric problems and even more. Cdiff colitis is a deadly risk and also toxic epidermal necrolysis. These effects are noted to be happening more often than previously thought in clinical trials, in some cases because they can develop overtime rather than immediately.
Also, what other exciting front in biotech should I know about?
This is the equivalent of "roll your own encryption" in the computer security world.
The number of real world cases where people have no or little immune system is likely minuscule (real numbers?) compared to the number of people that destroy their immune system through poor life and health choices. (obviously high number)
Eat better, exercise some (any?) and let your immune system take care of this stuff. That is what it's there for. Introducing _another_ foreign substance that will need to be fought off later is a recipe for disaster.[2]
[0] https://en.wikipedia.org/wiki/White_blood_cell
[1] https://en.wikipedia.org/wiki/T_cell
[2] https://www.amazon.com/King-Mice-Cheese-Nancy-Gurney/dp/0394...
https://www.cdc.gov/drugresistance/protecting_yourself_famil...
You source simple concepts and then use a children's book to back up your final claim?
Oh please...
Yes, your immune system is a wonderful defense that you can damage or improve based on lifestyle but medical advances are often necessary to assist the immune system.
Yes, because the concepts of healthcare in the US are absurd, and it's easily illustrated through a children's story book. In the US diabetes (1 version of it) has no known cause or cure, but in other countries (where there is free health care) it has a known cause and cure.
>...medical advances are often necessary...
Again, in countries with government supported healthcare they recognize that lifestyle choices are the number 1 cause of preventable disease. Number 1. What is "often necessary" in the US is in reality a rare exception.
Consider smoking, alcohol and drug abuse, junk food diets, no exercise, etc... these all are widely _known_ to deplete the immune system. So the only argument left for hacked viruses is for people with auto-immune diseases or other serious compromised systems, which is in fact rare.
"The only"
You start off making good points then you take this giant leap to absurdity. It's beyond hyperbole.
Any foreign substance added to the body (even if it's fighting an infection) still needs to be cleaned out by the immune system. So adding viruses that attack bacteria isn't a zero sum game.
Please explain how you'll handle infection by a resistant strain.
One kind is caused by alcohol abuse, tobacco use and diabetes, (or frostbite, trauma, etc..) all treatable with life style changes (according to healthcare in other countries, not in necessarily in the US)
The other kind is "caused by infection", so you seem to be misunderstanding what gangrene is. It's a symptom/end result from something else.
It seems once it's gets to gangrene the flesh is already dead, so removal is the only option, not antibiotics. It's too late for that.
You've been infected with an antibiotic resistant strain - of tuberculosis for example. Please explain how you'll resolve the situation.
Note that I'm not arguing lifestyle changes aren't important; I agree with parts of your other comments on that issue. I just don't understand why you think that pursuing other research avenues into defeating antibiotic resistant bacteria, that can cause a resurgence in plagues that were previously under control, is a bad or unimportant thing.
I'd very much like to not go back to the days when people died from Consumption left and right.
"Tuberculosis (TB) is an infectious disease usually caused by the bacterium Mycobacterium tuberculosis (MTB)."
"Treatment of TB uses antibiotics to kill the bacteria."
You also evade the point that many people used to die from infections that can now be cured by antibiotics and for which we have no backup plan once the bacteria have evolved resistance.
For example, tuberculosis was on the decline for a very, very long time before any medical solution was found, and it was nearly irradiated before there was a vaccine. [0] The vaccine had almost no effect on TB's decline in society.
This graph is nearly identical to all diseases that I looked up. Good housing, nutrition, cleanliness are the biggest cures for disease.
[0] https://en.wikipedia.org/wiki/File:Tuberculosis_in_the_USA_1...
> Gangrene is caused by a critically insufficient blood supply (e.g., peripheral vascular disease) or infection.
https://en.wikipedia.org/wiki/Tuberculosis#Management
Please read it. And also:
https://en.wikipedia.org/wiki/Extensively_drug-resistant_tub...
Lastly, TB is caused by a bacteria, not a virus. Again, it's right there in the wikipedia page you linked.
Could you please answer the question then? How do you go about treating an antibiotic resistant TB infection you've acquired?
>"How do you go about treating an antibiotic resistant TB infection you've acquired?"
I am not a doctor, but I found out 20 years ago the University of Oregon had done research on bacteria and showed that anti-bacterial soap did no better than regular soap at killing bacteria.
What this tells me is there is some logical problems with our general perspective on health and bacteria. There was a time when the medical industry believed "bad air" (miasma) was the cause of disease. And before that some other explanation.
There was a time when doctors recommended certain brands of cigarettes and leaded gasoline additives was considered safe enough to eat. To believe that we understand everything about disease today (even in face of the fact that we are losing the battle against it) is the height of hubris.
Do I have my own experience and beliefs about fighting sickness and disease? Yes, but I am learning to not bother discussing it online, the attacks for daring to question the established authorities is exhausting.
I was sick constantly as a child, ear aches, migraines, severe athletes foot, pink eye, sore throats, flu, diarrhoea, intolerable gas pains, delusional sleep episodes, pnuemonia (sick 3 months one summer), colds every winter, tooth decay. When I got older, all I did was change my diet. And I haven't been sick in twenty years. (to be accurate I was sick a few times when I didn't sleep for days and lived off coffee, but this was my choice)
My kids are almost never sick. They get a runny nose when they don't dress properly, or don't get enough sleep. All my friends kids are out of school every winter with flu and colds, vomiting and horrible coughs.
One simple rule I live by, don't put crap in my body, or my kids' bodies. (or at least as much as I can manage) No magic there. I've only taken one child to the emergency room for being sick, she had a fever and since I so rarely dealt with sickness, I didn't know what it was. The nurse recognized it while we were in the waiting room, I could have just gone home right then.
What would I do if I got TB? I'd remove every single obstacle in my body's immune system to fight it off.In fact, that is pretty much what all medicine does anyways (look up how vaccines work, they don't kill anything, and if antibiotics don't work, what choice do you have?), and try and provide my body with anything that is missing that it needs (nutrition perhaps? don't know...). No doctor would argue about these basic concepts. In fact the doctor told me I could have just put my daughter in a cold bath to deal with fever, would have been just as effective as bringing her into the hospital. All they gave her was tylenol and advil. (rotating doses) Fever broke in minutes.
Look up recent "discoveries" about effective hand washing, even soap isn't effective, but scrubbing with water is. Just water and scrubbing kills bacteria better than antibiotic hand soap, and antibiotics are failing. There's some missing knowledge, and maybe some old knowledge that's been lost that needs to be found again.
Edit: Most people who die from TB (quick look on google) seem to have auto-immune disease (ie, immune system doesn't work), I think with modern nutrition and cleanliness in society TB isn't even an issue anymore. If your immune system doesn't work, then my very first comment applies, create your own custom immune system is maybe your last resort. (ie, hacked viruses) But I am a total ignoramus, all I have are google searches to base my opinion on. I am not a doctor, nor a scientist to prove anything.
Why not consider "stop weakening the immune system" first?
No one supports giving a lung transplant to a persistent smoker. This extreme example demonstrates that damaging life choices _need_ to be addressed to actually help people heal.
One of the nasty ones is that accidentally teaching the immune system to attack the wrong thing is catastrophic, and we don't really have good general ways to undo learned response once present. (Exposure/desensitization therapy works for some things, but is still relatively early in its refinement.) Just look at the fun with the lone star tick and induced red meat allergies, and that's apparently a purely incidental outcome (e.g. it's not obviously a beneficial part of the tick's outcomes from biting things, just a quirk of primate biology not possessing a protein that every other mammal does, and getting upset when it finds it in the bloodstream).
Another example that comes to mind of when this doesn't "just work" is culturing uninfected immune cells from HIV+ patients, teaching them to kill HIV, and then putting them back.
AIUI, this works for a little while, but then it just shows back up again, like it never left. As it turns out, T cells happily share information between each other by making a happy little bridge between the two cells, and HIV is perfectly capable of spreading that way. Womp womp.
If you want to see a really strange immune outcome, go read the recent experiments about graft-versus-host disease potentially wiping out HIV in patients. (It didn't work for two patients in one experiment, so not extremely hopeful about the outcome, but it's a fascinating complex interaction. [1] [2]
[1] - https://www.nature.com/news/hopes-of-hiv-cure-in-boston-pati...
[2] - https://www.newscientist.com/article/mg23431244-400-immune-w...
If they make something that helps you, I think that would be great.
It isn't flashy. It doesn't make headlines. Doctors and scientists can't get rich off it.
It's also incredibly hard to explain the point of view you have.
I'm actually very sympathetic to your position, having pursued diet and lifestyle changes to manage a dread disease. But I will say that your comments here read as rather snarky, not good faith efforts to explain.
Edit: Having read through more of the article, it is (at least in part) research into helping patients with cystic fibrosis, who actually have a seriously impaired immune system.
It's actually what I have. And I'm quite sure you are wholly unqualified to tell people with CF what they need to eat to restore the functioning of their immune system in spite of a defective cell channel permanently impairing their functioning at the cellular level in all systems, but especially so in epithelial tissues, which includes both the lungs and gut.
If they make something that helps you, I think that would be great.
Note: I accidentally posted this comment further down. More proof of fallibility.