
When antibiotics failed a severely ill patient, a virus saved him - sergeant3
http://nautil.us/issue/43/heroes/will-viruses-save-us-from-superbugs
======
danieltillett
I used to work in the phage field and apart from regulation (phages are near
impossible to get approved by the FDA), the big problem is the phages people
have isolated have a very narrow specificity - most target only individual
strains of a specific bacterial species (i.e. they have a very narrow host
range). This means you need to have hundred or thousands of different phages
to treat even a single bacterial species.

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 :(

~~~
falsestprophet
_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)._

Did your group publish anything on this approach? If so, could you share a
link to one or some of the papers?

~~~
danieltillett
Yes we did, but we didn’t make a huge deal about it in the papers (it is just
in the methods sections). If you want to find my phage papers just have a look
at my profile on ResearchGate [1].

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.

1\.
[https://www.researchgate.net/profile/Daniel_Tillett2](https://www.researchgate.net/profile/Daniel_Tillett2)

------
mentalpiracy
Do you think it is feasible to allow some kind of voluntary FDA opt-out for
individuals, in extremely limited cases?

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."

~~~
maxerickson
It exists:

[http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194958.ht...](http://www.fda.gov/AboutFDA/Transparency/Basics/ucm194958.htm)

~~~
mentalpiracy
Thank you for teaching me something new today.

~~~
ceejayoz
There's a bunch more info at
[http://www.fda.gov/ExpandedAccess](http://www.fda.gov/ExpandedAccess).

------
smallnamespace
This is a good example of a downside of regulation: regulations embed
assumptions that favor certain outcomes. Those assumptions might have made
sense when the regulations were written, but are very slow to adapt to changes
in the industry.

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.

~~~
HillaryBriss
FWIW, Silicon Valley investor Jim O'Neill, who might well be the next head of
the FDA, said this in 2014 about that:

“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-...](http://www.bloomberg.com/politics/articles/2016-12-07/trump-
team-is-said-to-consider-thiel-associate-o-neill-for-fda)

~~~
wahern
That makes a ton sense, except that one wonders if any manufacturer will ever
bother proving efficacy. Worse, they may instead double-down on marketing
campaigns. Doctors and other professionals, working scientists or not, are
susceptible to marketing like anybody else.

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).

------
carbocation
Fun fact about the T4 bacteriophage: the dissection of its protein structure
led to important refinements of SDS-PAGE, which is a protein analysis method
that is still in wide use today. For that, the article that describes its
analysis is one of the most widely cited in history[1]. (Also, yes, this is
shamelessly a link to a tool I've developed to examine the importance of
biomedical research papers.)

1 =
[https://pubrank.carbocation.com/article](https://pubrank.carbocation.com/article)

------
jobu
_One of the major critiques of phage therapy is that it will fail the same way
antibiotics have failed: Bacteria can evolve phage resistance._

That's interesting. Previously I've read that evolution was one of the
benefits of phage therapy because phages could evolve alongside the bacteria.

~~~
tgb
My impression is that virus evolution is much slower than bacterial evolution.
They can't reproduce sexually, so there is no gene recombination to spread
beneficial mutations. This difference is partly why vaccines are done for
viruses and not so much for bacteria.

~~~
maxerickson
The flu vaccine is seasonal because it evolves so quickly.

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...](https://books.google.com/books?id=BYsW6qTP0pMC&lpg=PP1&pg=PA105#v=onepage&q=mutate&f=false)

 _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._

~~~
tgb
This is very interesting, however, is it answering the right question? HIV and
flu vaccine are specifically called out as having unusually high mutation
rates. Apparently the difference is between RNA viruses and DNA viruses - the
RNA ones have no "double checking" to repair errors, so have much higher
mutation rates. The rates quoted here [1] put DNA viruses as similar to
humans. I don't know if these phages are RNA or DNA ones (Wikipedia says there
are phages of both types and while the T4 virus they have a picture of in the
article appears to be DNA-based, they probably just chose it for its striking
appearance).

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...](http://www.nature.com/nrmicro/journal/v11/n5/box/nrmicro3003_BX1.html)
[2]
[https://en.wikipedia.org/wiki/Horizontal_gene_transfer](https://en.wikipedia.org/wiki/Horizontal_gene_transfer)
[3]
[http://cid.oxfordjournals.org/content/48/8/1096.full](http://cid.oxfordjournals.org/content/48/8/1096.full)
[4]
[http://rspb.royalsocietypublishing.org/content/royprsb/269/1...](http://rspb.royalsocietypublishing.org/content/royprsb/269/1494/931.full.pdf)

~~~
maxerickson
_More importantly - is mutation rate what we want to consider?_

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.

------
notadoc
Phage therapy is very promising but it's labor intensive and specific to each
particular infection. That also poses a monetization problem for
pharmaceutical companies who prefer to create a pill that can be universally
applied to many patients, which is perhaps why it is not more widespread.

But, it is currently practiced in Poland and Russia.

[https://en.wikipedia.org/wiki/Phage_therapy](https://en.wikipedia.org/wiki/Phage_therapy)

------
ARothfusz
Is this part significant?

> 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?

~~~
tstactplsignore
The short answer is no. Bacteria like pseudomonas don't really have
geographical ranges because they are not just human pathogens- they are
prolific in temperate soils throughout the world. The same species can be
found throughout the world and spread from place to place with great ease, and
there will be hundreds of pseudomonas phages capable of infecting any given
strain. I am fairly confident that you could isolate an infectious phage for
this pseudomonas strain from many temperate soils or mucky ponds anywhere in
the world. This is not universally true for all bacteria, but is mostly true
for bacteria like pseudomonas.

------
rdtsc
> Tbilisi draws patients from around the world who are suffering from
> untreatable UTIs, acne, cystic fibrosis, and intestinal infections.

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...

------
mrfusion
Funny, I actually came across this the other day in my endless quest to cure
my worsening gum disease:
[http://aem.asm.org/content/76/21/7243.full.pdf](http://aem.asm.org/content/76/21/7243.full.pdf)

I wonder why they never pursued it further. Their results sounded promising.

------
danielmorozoff
There was a bunch of work done on bacteriophages by the soviets in the pre
antibiotic era and then later as part of the bio weapons programs.

[https://en.m.wikipedia.org/wiki/Phage_therapy](https://en.m.wikipedia.org/wiki/Phage_therapy)

------
norea-armozel
I wonder if the study of these phages can give us better treatments than just
gambling with cocktails of the phages themselves. Like understanding their
point of infection and how we can exploit that to deliver some chemical to
kill the hostile bacteria more effectively.

------
chadcmulligan
I remember when i was young whenever we had a cut that had got a bit red my
grandmothers solution was to go for a swim in the ocean, maybe we were phage
hunting.

------
rubicon33
What I found slightly disturbing from this article was that the cure for the
bacterial infection, was to drink pond water.

~~~
tim333
Well, spray it in your chest cavity more than drink it.

------
mrfusion
I never understood how they produce these phages. You can't just make them in
a factory.

~~~
marcosdumay
They probably reproduce the phages inside bacteria.

~~~
mrfusion
Wouldn't that kill the bacteria though?

~~~
arrosenberg
Yes, but bacteria reproduce quickly enough that it's not really an issue.

