When antibiotics failed a severely ill patient, a virus saved him
nautil.us
nautil.us
The really interesting thing is that there are phages that have a broad host range (multi-species or even multi-genera), but due to the nature of how phages are typically isolated they are not often found by researchers. Phages, like other living organisms, show differences in ecological adaption with some being specialists (leopards) while others are generalists (rats). The specialists grow faster in their specific hosts than the generalists do so in the normal isolation process which uses a single host bacteria strain (plaque plate assay) and so they appear first. The generalists grow slightly slower and so are typically missed by the scientists.
In my lab we developed a different assay that favoured the isolation of generalist phages and we were really successful in finding broad host range phages (many were multi-genera in host range). I no longer work in this area and it is something I miss as it is such an interesting topic :(
Did your group publish anything on this approach? If so, could you share a link to one or some of the papers?
The basic idea is pretty straightforward. Rather than plating a filtered sample directly onto a overlay plate of a single bacterial strain, we pre-enriched for phages in a mixed culture of multiple bacterial strains (we would sometime use up to 50 different strains/species in the one enrichment flask). What this does is give the broad host range phages a competitive advantage since they can reproduce in multiple hosts and outgrow the narrow host range phages. When you plate out onto a specific strain for isolation of the phages you end up with mostly broad host range phages.
The idea is so obvious I am surprised it is not more widely used in the field. It seems to be the norm to just use a single bacterial strain for the phage isolation. I think most people just assume all phages are narrow host range.
I find myself wondering what I would want to do if I were in a similar situation: long-term, treatment-resistant illness, pain and inevitable death. At this point in my life, I think I would be okay saying "okay nothing is working. I volunteer to be an experimental subject - and if I die, please absolve anyone working to cure me from punishment."
There are restrictions, of course. First, if a doctor start prescribing opiates to every patient s/he'll probably get a call from the DEA :). Second, insurance companies may refuse to pay for experimental treatments. And third is potential malpractice liability, but making sure the patient has informed consent can limit that. And this all only applies to drugs that are already FDA approved, just not for your specific use case.
I should point out the only reason I know this is from an article about some drug companies that have been accused of encouraging doctors to use their drugs for non-FDA approved purposes to boost sales. So I may be missing some key details here.
The FDA drug approval process was basically designed for things like antibiotics: Single molecular compound, high purity, standardized dosage and application, and run trials with many many patients.
Treatments that don't fall under that umbrella (like phages) are very difficult to develop and bring to market, even if they work very well, just because of the impedance mismatch.
Phages are basically individually tailored to the patient, require a lot of work in administering, and difficult to test under the FDA's guidelines. Many people have unnecessarily died because treatments that could be are lifesaving aren't brought to market due to too much rigidity in the system.
To be fair, the FDA has been active in coming up with ways for things like phages to be brought to market safely, but it's a very slow, uphill battle.
“We should reform FDA so there is approving drugs after their sponsors have demonstrated safety -- and let people start using them, at their own risk, but not much risk of safety,” O’Neill said in a speech at an August 2014 conference called Rejuvenation Biotechnology. “Let’s prove efficacy after they’ve been legalized.”
http://www.bloomberg.com/politics/articles/2016-12-07/trump-...
If we're getting lots of political change, this sounds like something that could benefit.
So we'd need to see other mechanisms, regulatory or otherwise[1], that would counter that effect. FDA approval is a powerful motivator for 1) companies to find actually effective therapies and 2) as an extremely efficient signaling mechanism to the market regarding efficacy. But it's sub-optimal for many reasons, including erring too heavily on the side of safety. It's just not obvious what would replace it.
Don't forget, snake oil thrives in the free market.
[1] Medicare reimbursements predicated on FDA efficacy approval? I'm not sure insurance companies can be expected to do the right[2] thing. It might be cheaper to reimburse a snake oil treatment that allows the patient to die than to pay a premium for an effective treatment. And while presumably a good doctor would insist on the effective treatment, at the margins the insurance company could expect to profit from allowing their patients to choose the snake oil.
[2] Where "right" means a course of action that maximizes long-term social wealth (i.e. preferring effective treatment and therefore subsidizing research), rather than simply maximizing the short-term utility of patients and profits (i.e. allowing the patients the salve of snake oil, with reimbursements, in lieu of effective treatment).
[1]http://www.fiercepharma.com/pharma/anthem-declines-coverage-...
> zero other options
Those patients literally had zero other options than just dying.
Phages should be another weapon in our arsenal. You're right that they might not end up working out, but right now there is chronic underinvestment in research to find out whether work, because nobody is going to heavily fund research for therapies that will never pass the regulatory hurdle. It seems like bad risk management to back ourselves into a corner -- the whole point of research is to find out whether other things work. Defense in depth isn't just for software security.
I mean we have plenty of ridiculously expensive treatments out there already. It's not clear creating such things are a good investment vs. reducing traffic fatalities etc.
Phage therapies are actually used regularly in Georgia, Russia, and other parts of the former Soviet Union, in part because they couldn't get access to antibiotics during WW2 and right afterwards.
You can do the math as to whether we've passed the point of diminishing marginal returns on antibiotics.
[1] https://en.wikipedia.org/wiki/Phage_therapy
[2] https://www.phagetherapycenter.com/pii/PatientServlet?comman...
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3365524/
A few facilities in the USA are currently treating with fecal transplants, like John Hopkins.
http://www.hopkinsmedicine.org/gastroenterology_hepatology/c...
That's interesting. Previously I've read that evolution was one of the benefits of phage therapy because phages could evolve alongside the bacteria.
If you just handed out phage freely, as you do abx, bacteria will "eventually" evolve resistance to phage....at a 2-3 orders slower rate, but it will eventually happen.
Of course, the solution is easy, you don't develop a phage therapy like you would an antibiotic, but rather like a constantly updating flu vaccine.
This was how phage therapy was originally developed, and it's still being done that in some surprising places like Georgia [1]. They have phage 'banks' for common bacterial species, and it's not effective, they end up taking bacterial samples from each patient and isolating more phages.
[1] https://www.phagetherapycenter.com/pii/PatientServlet?comman...
Same with HIV, a high mutation rate complicates making a vaccine.
I was really struck by this part of The Great Influenza:
https://books.google.com/books?id=BYsW6qTP0pMC&lpg=PP1&pg=PA...
Influenza is an RNA virus. So is HIV and the coronavirus. And of all RNA viruses, influenza and HIV are among those that mutate the fastest. The influenza virus mutates so fast that 99 percent of the 100,000 to 1 million new viruses that burst out of a cell in the reproduction process are too defective to infect another cell and reproduce again. But that still leaves between 1,000 and 10,000 viruses that can infect another cell.
More importantly - is mutation rate what we want to consider? Bacteria exchange DNA with each other through horizontal gene transfer and Wikipedia quotes that as the main means of transmitting antibacterial resistance, for example [2], even across species (to the extent that bacterial species are even well-defined). I'm not sure how to make the comparison with that to viral mutation rates. This [3] source gives the following interesting, but imprecise, quote:
> This antagonistic coevolution results from the constant emergence of countermeasures by which bacteria resist phages, while phages, mutating at a more rapid rate than their prey, find means to overcome this resistance.
The paper it cites [4], definitely shows phage evolution alongside bacteria evolving counter-measures. So I think that's enough to answer the original question posed, though the question of "which is evolving faster" is harder to answer and probably isn't very well-posed.
That all said, I know nothing about this field and would be happy for some better insight.
[1] http://www.nature.com/nrmicro/journal/v11/n5/box/nrmicro3003... [2] https://en.wikipedia.org/wiki/Horizontal_gene_transfer [3] http://cid.oxfordjournals.org/content/48/8/1096.full [4] http://rspb.royalsocietypublishing.org/content/royprsb/269/1...
I think it is quite important when considering this particular interaction. Horizontal gene transfer will help a population of bacteria share a successful strategy, rampant mutation will help the virus try more strategies.
The article mentions that the particular infection reached a balance with the phage overnight, so it is likely to be a quite an issue. But the population of bacteria resistant to the phage had become susceptible to an antibiotic (for reasons related to the resistance). So it can still be a valuable tool, even if resistance happens quickly.
But, it is currently practiced in Poland and Russia.
> A virus from a pond just 40 miles from his house apparently gave him a new lease on life—and gave a new meaning to the term “local medicine.”
That is, are phages for a specific bacterium more likely to be found local to the person infected? Would they have been even more likely to find the right phage if they had collected samples from the patient's neighborhood, family and friends? Nearby people who weren't infected?
I've heard of a case where someone with a horrible Staph leg infection was desperate so flew to Tbilisi, apparently it worked for them.
Wonder if they can monetize that better. Say set up something in Mexico right across the border, so people don't have to fly half way across the world...
I wonder why they never pursued it further. Their results sounded promising.