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The Scientist January 2016 Issue Features Cover Story

Viral Soldiers
Phage therapy to combat bacterial infections is garnering attention for the second time in 100
years, but solid clinical support for its widespread use is still lacking.

By Jyoti Madhusoodanan | January 1, 2016

Popular

RICHARD BIZLEY/SCIENCE SOURCE

I
n July 2011, a 43-year-old woman walked out of the National Institutes of Health (NIH) Clinical Center
in Bethesda, Maryland, after a month of battling a serious bacterial infection. Three weeks later, two
more patients tested positive for the same bacterial strain after checking into the clinic. Over the next four
months, the pathogen, a multidrug-resistant form of Klebsiella pneumoniae, continued to spread;
approximately one clinic patient acquired the infection every week.

Clinicians threw up wallsboth physical and chemicalto contain the pathogen. All patients were kept
isolated and under surveillance; after the fourth case, infected patients were placed in a separate section of
the center and tended to by a dedicated staff using dedicated instruments. Visitors wore caps, gowns, and
gloves, surfaces were routinely washed with bleach, and the intensive care unit was regularly gassed with
hydrogen peroxide to decontaminate the rooms. Still, patients in the hospital continued to become
infected. At the end of the months-long outbreak, 18 patients had suffered Klebsiella infections; 11 had
died. As the researchers reported later, bacteria isolated from many of these patients were resistant to
most known antibiotics, leaving no effective therapeutic options for some patients. 1

In the last decade, antibiotic resistance has grown from a concern to a crisis. In addition to the deadly
incident at the NIH, a multidrug-resistant form of methicillin-resistant Staphylococcus aureus (MRSA) in a

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UK neonatal unit infected 12 babies in 2011. And just last year, carbapenem-resistant enterobacteria
infected seven people and killed two at a Los Angeles, California, hospital. Even when antibiotics do work,
theyre not always the best option, as they wipe out beneficial bacteria as well as pathogenic ones, with
potentially long-lasting health consequences. Stay Con
Scientist
Researchers on the hunt for more-effective therapies that preserve a healthy microbiome are taking a
closer look at the many different viruses that attack bacteria. Bacteriophages (literally, bacteria eaters) The Scie
punch holes through the microbes outer covering and inject their own genetic material, hijacking the The Scie
hosts cellular machinery to make viral copies, then burst open the cell with proteins known as lysins, Neurosc
releasing dozens or hundreds of new phages. The cycle continues until there are no bacteria left to slay.
Genetics
Phages are picky eaters that only attack specific types of bacteria, so theyre unlikely to harm the normal
microbiome or any human cells. And because phages have coevolved with their bacterial victims for Biology
millennia, its unlikely that an arms race will lead to resistance. This simple biology has led to renewed Biochem
interest in the surprisingly long-standing practice of phage therapy: infecting patients with viruses to kill Bench to
their bacterial foes.
Cell Biol

While most research is still in the preclinical phase, a handful of trials are underway, and a growing number Microbio
of companies are investing in the treatment strategy. Phage therapy is receiving as much attention now as Cancer R
it did in the pre-antibiotic era, when it flourished in spite of the dearth of clinical tests or regulatory Stem Ce
oversight at the time. Bacteriophage therapy will have its day again, pathologist Catherine Loc-Carrillo of
the University of Utah told The Scientist last year. It sort of had one, before antibiotics came along, but it
wasnt well understood then.
Current
But with lingering questions about phages, which are often dubbed viral dark matter because so little is
known about their biology, their use in mainstream medicine still faces many hurdles. And the
consequences of moving phage therapies forward without more concrete evidence could be devastating,
adds phage biologist Ryland Young of Texas A&M University. If we have more poor data like we did in the
1920s, itll really set applications back in the long term.

A century of cures
The roots of phage therapy stretch back more than 100 years, even before the discovery of
bacteriophages. In 1896, British bacteriologist Ernest Hankin tested water from two Indian rivers, the
Ganges and its tributary the Yamunalocally believed to have curative propertiesand found evidence of
antibacterial activity. He used porcelain filters to strain the river water, removing bacteria and larger
organisms while retaining a suspension that could kill Vibrio cholerae. He suspected some unknown
substance or agent in the water played a part in limiting the spread of cholera epidemics in the area. Over
the next few years, reports of natural waters with similar antibacterial properties trickled in from Russia
and other parts of the world.

Two decades later, another British bacteriologist,

Frederick Twort, found a bacteria-killing agent
while working with Micrococcus cultures, although
The roots of phage therapy View the Ju
he hesitated to hypothesize that it was a virus.2 In
the 1910s, French-Canadian microbiologist Felix
stretch back more than 100
dHerelle was testing fecal filtrates from soldiers years, before the discovery Subscrib
infected with Shigella, a causative agent of
dysentery, when he uncovered evidence to support of bacteriophages. All
Tworts discoveries. After a few days of applying the The Nuts
fecal samples to Shigella cultures, dHerelle saw kill News &
zones on the culture plates where something had
Careers
decimated the pathogen. Conjecturing more boldly than Twort, dHerelle suspected he was observing the
work of viruses that infect bacteria, and he coined the term bacteriophage, from the Greek word for to
eat, to describe the disease-fighting agents.3 In a flash I had understood: what caused my clear spots
was, in fact, an invisible microbe, a filterable virus, but a virus parasitic on bacteria, dHerelle recalled in a
1948 article.4

DHerelle conjectured that the sick soldier whose fecal sample had killed the bacteria in culture would
probably also recover, thanks to the same microbe-killing virusand he was right.5 Four years later, in
1919, dHerelle used these same phages, isolated from the fecal samples of dysentery patients whod
recovered, to successfully treat children suffering the same infection.

No one had actually seen a phage; it would be another 20 years before scientists captured the earliest
electron micrographs of bacteria-infecting viruses.6 But phage therapy began to be used around the world
to treat a dizzying array of infections. Belgian researchers reported injecting phages isolated from various

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sources to cure staphylococcal skin infections; intravenous phage therapy was used to treat cholera in
India and streptococcal infections in France; studies in the U.S. reported treating septicemia and
meningitis.

The rapid growth of the field was characterized by an early, enthusiastic period during which claims were
excessive and often unrealistic, while at the same time little was understood of the viral nature of phages
or their strengths and limitations, Elizabeth Kutter of Evergreen State College in Washington and
colleagues wrote in a 2011 review of phage therapys history.7 Despite the fact that some pharmaceutical
companies began standardizing and marketing the therapies as early as the 1920s, the US Food and Drug
Administration was not overseeing their development, and few were subjected to controlled clinical testing.

In 1934, a three-part JAMA report provided the first objective evaluation of phage therapy. The authors
assessed more than 100 studies and concluded that the treatment was only reliable for some
staphylococcal infections. Without double-blind trials and clinical research to test its effectiveness and
safety, phage therapy fell out of favor in the West. Attention turned to antibiotics, which had been
discovered in 1928 and were easier to manufacture and standardize.8 But phage therapy stuck around in
many parts of the world, particularly in Eastern Europe, where modern drugs are expensive and often hard
to come by.

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1910: Wellcome Images; 1915: Obituary Notices of Fellows of the Royal Society; 1917: Pasteur Institute; 1928: The University of Edinburgh Library; 1940:
Hans-Wolfgang Ackermann; 1977: Protein Data Bank/2BPA; 2015: Dr. Graham Beards

These days, centers like the Eliava Institute of Bacteriophages, Microbiology and Virology in the Republic of
Georgia offer commercial phage preparations for specific indications, such as MRSA and gastrointestinal
infections caused by E. coli and Shigella species. Researchers at the Eliava Institute also mix phages into
custom cocktails for many infections. Phages for these mixtures are isolated from some of the same
sources that yielded them a century ago: sewage, hospitals, rivers and lakes, and other places where
pathogens thrive. Purified isolates from these sources are grown on bacterial cultures in the lab to identify
phages that target the pathogen of interest. Years of research at the Eliava Institute have led to a carefully
curated library with hundreds of vials of such isolates, from which the scientists prepare their custom
combination therapies.

Mzia Kutateladze, the institutes current director, says she receives a growing number of requests for
treatment, including from patients in the U.S. and Western Europe. They send us clinical materials, either
cultures or swabs, before they arrive, she says. We first test our commercial products. If they dont work,
we identify phages in the library, prepare and test a final customized product before its used in the
patients. Patients can then travel to the clinic for treatment, or the Eliava Institute will send the phages
to patients to use on their own.

Kutter suspects that success stories from the Eliava Institute and others will ease acceptance of phage
therapy into the modern pharmacopeia. Indeed, retrospective analyses of phage therapies published by
these groups are helping researchers understand which particular infections are likely to respond to the
treatments. Fueled by these data and a prominent mention in a 2014 National Institute of Allergy and
Infectious Diseases (NIAID) report on the agencys antibacterial resistance program, companies around the
world are preparing for a second coming of phage therapy.

But many questions remain. Laboratory studies of phages have typically relied on well-understood model
systems, such as E. coli and its viruses; the myriad phages used in cocktails to treat human infections are
grossly understudied. And while phages are typically thought to be harmless to human cells, in part
because they are ubiquitous in the environment and in the human body, little is known about how phages
interact with human cells such as those of the immune system. One recent study, for example, reports
that phages may be able to use mucosal surfaces in tissues to enhance their predatory activity.9

Almost all bacteriophage biology has focused on the paradigm of E. coli phages lambda, T4, and so on,
says Texas A&Ms Young. Bacteriophages of most major pathogens have not been studied very well. The
basic science [of phage therapy] is still way behind where it needs to be.

Probing dark matter

Evaluating a phages bacteria-killing activity in the lab is easy: simply apply a known amount of purified
phage to a lush lawn of microbes in a petri dish and measure the resulting kill zones. But an infection of
human tissue looks nothing like a monoculture of well-fed bacteria smeared across a plate. In diseased
tissue, pathogens produce a slew of different proteins and small molecules, often form 3-D biofilms, and
exist within complex microbial communities. How phages interact with pathogens in such situations
remains unclear.

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This lack of understanding has posed obvious

hurdles for those interested in developing phage
therapies. One issue is whether phages are
uniquely suited to treat certain infections. For
example, phages may work better than antibiotics
when a deep, localized lesion, such as a bone
infection, is difficult to access via the bloodstream.
Even when bacteria are inherently sensitive to an
antibiotic, the drug often cant reach the site of
infection [in sufficient concentrations], says
Kutter. Phages, on the other hand, can multiply
within pathogens once they reach the site, quickly
rising to the level of a therapeutic dose.

Another open question is how therapeutic viruses

interact with the human immune system, and
whether they might cause side effects. At the
Ludwik Hirszfeld Institute of Immunology and
Experimental Therapy at the Polish Academy of
Scienceswhere patients receive phage therapy on
CLEARING GUT INFECTIONS: Treating infections of
compassionate-use grounds after theyve failed to
the gastrointestinal tract has been one of the most
respond to other treatmentsresearcher Andrzej successful uses of phage therapy since its inception.
Grski is sifting through years of clinical data to find Although antibiotics are the go-to treatment today,
answers. In a retrospective analysis of immune concerns about increasing drug resistance and
responses in 153 people treated with phages disrupting the microbiome have led researchers to
between 2008 and 2010, Grski and his colleagues reconsider using bacteria-killing viruses instead.
reported that the therapies were well-tolerated in See full infographic: WEB | PDF
ANDREW SWIFT, ISO-FORM
80 percent of patients.10 Only a small number had
to stop treatment because they experienced
adverse reactions such as nausea or pain in response to gut treatments, or local reactions to topical phage
applications, Grski said at a first-of-its-kind NIAID workshop on phage therapies that convened in
Rockville, Maryland, last July.

Grskis group has also assessed inflammatory markers such as C-reactive protein and white blood cell
counts in 37 patients treated with phage for S. aureus bone infections and found that phage therapy
lowered the levels of these markers.11 It appeared that the phages dampened the bacteria-triggered
inflammation, a modulation that was associated with a positive clinical response in almost half the
patients.

Looking more carefully at the immune responses triggered by phage therapy, Grski and his colleagues
found that repeated exposure to the same strain of phage could trigger an adaptive immune response,
resulting in anti-phage antibodies. At the NIAID workshop he reported that such antibody responses may
be higher when using cocktails of phage than when dosing with a single viral strain. But whether such
antibodies help or hinder phage therapy is still unclear. In 122 patients and healthy volunteers who
received phage orally or in local applications, Grski and his colleagues found that, while several patients
produced anti-phage antibodies, the presence of antibodies had little correlation to whether or not the
therapy was successful.12 When you have anti-phage serum activity against phages, that doesnt
necessarily mean the phage isnt working, Grski said at the meeting.

Phages may also elicit different immune responses depending on how they are administeredtopically,
orally, intravenously, or rectallyand on what tissues or organs they target. Lumping every treatment
together as phage therapy undermines efforts to understand such nuances, says Young. Phages are
treated like theyre all the same, but they can be more different from each other than ants and elephants.

Going mainstream
Despite the challenges still facing phage therapy, numerous companies are now looking to bring the
treatments to mainstream clinics. (See table below.) In September 2015, researchers in France launched
the first multicenter study and clinical trial to evaluate phage therapy. Known as Phagoburn, the project
began in 2013 with preclinical work to produce two phage cocktails using methods that met European
Medicines Agency (EMA) manufacturing standards. Now, the two treatmentswhich target burn-wound
infections caused by E. coli or Pseudomonas aeruginosawill be administered to 220 patients and the
therapeutic results compared with those in patients treated with silver sulfadiazine, the current go-to drug
for such infections.

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Like the phage cocktails used by the Eliava

Institute, the Phagoburn therapies are a mixture of
naturally occurring viruses selected for their ability
to target specific bacterial species. The P.
aeruginosa cocktail is a mix of 13 phages, according
to Patrick Jault, a Phagoburn investigator and chief
of the burn treatment center at Percy Military
Hospital outside of Paris; the E. coli cocktail
contains 12 phages.

A handful of US companies also aim to bring phage

preparations to clinical trials. In 2009, the
Maryland-based firm Intralytix published the results
of its Phase 1 trial for a phage therapy that targets
venous leg ulcers in diabetic patients. None of the
40 or so patients who received the phage cocktail
had any adverse reactions to the treatment, but
the company has not said whether a Phase 2 trial
is planned.13 Meanwhile, Richmond, Virginiabased
AmpliPhi Biosciences announced in November it
was enrolling nine patients to test the safety of a
natural phage cocktail intended to treat chronic
sinus infections caused by S. aureus.

These and more trials are needed to determine

which phage therapies will work best for which TELL-TALE TAILS: Tailed bacteriophages
indications, and how to scale up the production of (Caudovirales), which make up the vast majority of
those that are successful. Weve yet to see how known phages, fall into three families: Myoviridae (T4
shown at top), characterized by straight contractile
this plays out both in the clinic and when we try to
tails; Siphoviridae ( shown at bottom left), known for
manufacture these at large scales, says AmpliPhi flexible non-contractile tails, and Podoviridae (T7
CEO Scott Salka. shown at bottom right), which have very short non-
contractile tails. Some companies are exploring the
With these hurdles in mind, San Diegobased use of purified tail proteins as antibacterial agents.
Synthetic Genomics, founded by synthetic biologist R. DUDA/ UNIVERSITY OF PITTSBURGH; P. SERWER/THE UNIVERSITY OF
TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO
J. Craig Venter, is taking a different approach.
Rather than mixing natural phages together,
company researchers are attempting to engineer a synthetic virus that combines the properties of multiple
phages into a single genome. Such engineered phages are simpler to manufacture than cocktails with
dozens of different phages, says Bolyn Hubby, vice president of research and development at Synthetic
Genomics. Not having very large complex cocktails makes these products compatible with current GMP
[good manufacturing process] standards.

The company is currently applying bioinformatics

and viral engineering methods to understand the
natural host ranges of various phages, and then
If we have more poor data
inserting genes from other viruses to expand those
ranges to include other subtypes of the targeted
like we did in the 1920s, itll
bacterium. By iteratively doing this, we can
expand a phages host range while maintaining
really set applications back
specificity so commensal bacteria are unaffected, in the long term. TexasRyland Young,
A&M University
says Hubby. Eventually, the researchers plan to
layer on additional ammunition, such as potency
against biofilms or synergistic interactions with
antibiotics.

In addition to phage cocktails and engineered viruses, researchers are also putting phage components to
work. New Yorkbased Contrafect and Netherlands-based Micreos, for example, use isolated lysins, the
phage enzymes that rip through a bacterial envelope when a virus injects its DNA into a cell or when viral
progeny burst out. Others are experimenting with just the phage tail proteins, called tailocins. (See image
here.) These parts lack the ability to multiply within a host, so they avoid risks inherent to phages that
carry DNA, making such protein therapies potentially much easier to manufacture and bring to market,
says Rockefeller Universitys Vincent Fischetti, who is a scientific advisor to Contrafect.

But regardless of whether a product is naturally derived or engineered, or a whole virus or just pieces, the
bar for success is the sameand its a high one. Trials will have to demonstrate that phage therapy, either
alone or in conjunction with other drugs, is superior to current standard treatments. You cant just show
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the two arms of a trial are equivalent and convince people to change, says infectious disease specialist
Brad Spellberg of the University of Southern California.

What the field needs now is solid clinical research, says Spellberg, who compared the promise of phage
therapy to the elusive Sasquatch. After 90 years of talking about it, all we have are these grainy videos of
some dude in a costume walking through the woods; at this point you want someone to catch Bigfoot and
take him to the zoo, he said. Its time for someone to pony up the product and the dough to do the
clinical trial.

INVESTING IN PHAGE THERAPY

A sampling of firms in the U.S. and Europe that are conducting research on viral treatments for bacterial
infections

COMPANY LOCATION PRODUCTS APPLICATIONS IN

TRIALS?

AmpliPhi Richmond, Natural phage P. aeruginosa lung infections in cystic Phase 1

Virginia cocktails fibrosis; S. aureus wound and skin approved
infections; C. difficile gastrointestinal November
infections 2015

ContraFect Yonkers, Bacteriophage S. aureus bacteremia Phase 1

Corporation New York lysins launched
April 2015

EnBiotix Cambridge, Engineered Staphylococcal infections of prosthetic Preclinical

Massachusetts phages joints

EpiBiome San Francisco, Natural phage E. coli and Shigella dysenteriae Preclinical
California cocktails diarrheal infections in children

Fixed-Phage Glasgow, Natural MRSA wound infections Preclinical

U.K. phages fixed
to solid
surfaces

Intralytix Baltimore, Natural phage S. aureus, P. aeruginosa, E. coli Preclinical

Maryland cocktails wound infections; irritable bowel
disease

Micreos Wageningen, Bacteriophage S. aureus and MRSA skin infections Preclinical

Netherlands lysins

Novolytics Warrington, Natural phage MRSA skin infections Preclinical

U.K. cocktails

Pherecydes Romainville, Natural phage E. coli and P. aeruginosa burn and Phase 1
France cocktails skin infections; P. aeruginosa launched
respiratory infections; S. aureus September
bone/joint/prosthetic infections 2015

Synthetic San Diego, Engineered Infections in burn wounds, skin, and Preclinical
Genomics California phages cystic fibrosis

TechnoPhage Lisbon, Natural phage Chronic ulcers, respiratory and skin Preclinical
Portugal cocktails infections

Jyoti Madhusoodanan is a freelance science writer living in San Jose, California.

References

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03/08/2017 Viral Soldiers | The Scientist Magazine

1. E.S. Snitkin et al., Tracking a hospital outbreak of carbapenem-resistant Klebsiella pneumoniae with
whole-genome sequencing, Sci Transl Med, 4:148ra116, 2012.
2. A. Sulakvelidze et al., Bacteriophage therapy, Antimicrob Agents Chemother, 45:649-59, 2001.
3. F. dHrelle, Sur un microbe invisible antagoniste des bacilles dysentrique, CR Acad Sci Paris,
165:373-75, 1917.
4. F. dHerelle, Le bactriophage, Atomes, 3:399-403, 1948. (Translated in Sci News, 14:44-59,
1949.)
5. D.H. Duckworth, Who discovered bacteriophage? Bacteriol Rev, 40:793802, 1976.
6. H.-W. Ackermann, The first phage electron micrographs, Bacteriophage, 1:225-27, 2011.
7. S.T. Abedon et al., Phage treatment of human infections, Bacteriophage, 1:66-85, 2011.
8. M.D. Eaton, S. Bayne-Jones, Bacteriophage therapy, JAMA, 103:1769-76, 1847-53, 1934-39,
1934.
9. J.J. Barr et al., Subdiffusive motion of bacteriophage in mucosal surfaces increases the frequency of
bacterial encounters, PNAS, 112:13675-80, 2015.
10. R. Mi?dzybrodzki et al., Clinical aspects of phage therapy, Adv Virus Res, 83:73-121, 2012.
11. R. Mi?dzybrodzki et al., A retrospective analysis of changes in inflammatory markers in patients
treated with bacterial viruses, Clin Exp Med, 9:303-12, 2009.
12. M. ?usiak-Szelachowska et al., Phage neutralization by sera of patients receiving phage therapy,
Viral Immunol, 27:295-304, 2014.
13. D.D. Rhoads et al., Bacteriophage therapy of venous leg ulcers in humans: Results of a Phase I
safety trial, J Wound Care, 18:237-38, 240-43, 2009.

Tags
phage therapy, phage, drug development, disease/medicine, Bacteriophages, bacteriophage, antibiotics and
antibiotic resistance

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Comments
January 1, 2016

I believe the real question we need to discuss is, how much evidence do we
bsguyx
need to at least use phage ttherapy when all other treatments fail? Most
Posts: 4
countries have legal compassinate use provisions - what are the moral,
legal and ethical questions of knowingly withholding phage therapy when
"approved' drugs fail"?

Here are 6 references everyone should read - specifically note the thoughts
of Ian Humphery-Smith :

1. Lisa Jutras, (2014) Viral Agent - A forgotten weapon for the post-
antibiotic era, The Walrus, July/Aug. 21 - http://thewalrus.ca/viral-
agent/

2. Koren Wetmore, (2015) A Cure Exists For Antibiotic-Resistant

Infections. So Why Are Thousands Of Americans Still Dying? (Deadly
antibiotic-resistant infections have American doctors trembling. Thanks
to a therapy long forgotten here, one country in Eastern Europe is
having no such crisis. So why isn't the US on board?) PREVENTION -
http://www.prevention.com/health/health-concerns/cure-antibiotic-
resistance

http://www.the-scientist.com/?articles.view/articleNo/44785/title/Viral-Soldiers/ 8/12
03/08/2017 Viral Soldiers | The Scientist Magazine

3. William C. Summers (2012) The strange history of phage therapy,

Bacteriophage vol. 2:2, p.130 -
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442826/

4. Ian Humphery-Smith (2014) Importance of Bacteriophage in Combating

Hospital-Acquired Infection (HIA), Pharmacology & Pharmacy, 5, 1192 -
http://www.scirp.org/journal/PaperInformation.aspx?
paperID=52867#.VSqj7fnF-Ck

5. Kropinski, Andrew M. (2006)Phage Therapy Everything Old is New

Again, Can J Infect Dis Med Micrbiol 2006 Sep-Oct. 17(5)297-306. Kropinski
was at the Public Health Agency of Canada, Guelph Ontario.

6. Elizabeth Martin Kutter, Sarah J. Kuhl, Stephen T. Abedon - Re-

establishing a place for phage therapy in western medicine, Future
Microbiology, vol. 10, No.5, pp. 685-688
http://www.futuremedicine.com/doi/full/10.2217/fmb.15.28

Sign in to Report

January 4, 2016

1 - I think it has been learned that in many cases the bacteriophage

Monodb
actually causes the coding of highly toxic protiens that promote the growth
Posts: 9
of its bacterial target, e.g. cholera, by breaking down the tissue of the
bacteria's target necrotically. Thus, it has been concluded by many that any
such phage would not be suitable for use as treatment. For example, I
think I have read that in the case of cholera, deceased victims have been
found to be completely cholera bacteria free (but nontheless dead),
apparently killed due to the necrotic protiens encoded by the phage.

2 - CRISPR-C* provides a revolutionary prospect. The phage genome can

be edited so that it no longer produces this necrotic effect and might be
fine-tuned to be even more effective against the invading bacteria. AI think
a new era is upon us.

Sign in to Report

January 4, 2016

1 - I think it has been learned that in many cases the bacteriophage

Monodb
actually causes the coding of highly toxic protiens that promote the growth
Posts: 9
of its bacterial target, e.g. cholera, by breaking down the tissue of the
bacteria's target necrotically. Thus, it has been concluded by many that any
such phage would not be suitable for use as treatment. For example, I
think I have read that in the case of cholera, deceased victims have been
found to be completely cholera bacteria free (but nontheless dead),
apparently killed due to the necrotic protiens encoded by the phage.

2 - CRISPR-C* provides a revolutionary prospect. The phage genome can

be edited so that it no longer produces this necrotic effect and might be
fine-tuned to be even more effective against the invading bacteria. I think
a new era is upon us.

Sign in to Report

January 4, 2016

1 - In the past, it has been learned that some phages add code to the
Monodb
genome of the targets so that protiens are produced which are very
Posts: 9

http://www.the-scientist.com/?articles.view/articleNo/44785/title/Viral-Soldiers/ 9/12
03/08/2017 Viral Soldiers | The Scientist Magazine

destructive to the flesh of the bacteria's target. This led to the conclusion
that is was very undesireable to use such phage therapies for treatment.

2 - The advent of CRISPR-C* makes it practically possible to edit the

genome of such a phage so that it no longer causes this to happen, and
possibly to be a means of fine-tuning the genome of the phage to be even
more effective against the bacteria. I think we are in a new era.

Sign in to Report

January 4, 2016

Apologies to all for the 2 duplicates; I was super slow in learning how to use
Monodb
this system. - M
Posts: 9

Sign in to Report

January 5, 2016

Surely you can't dismiss all the 100 years of medical evidence that well-
bsguyx
characterized lytic phages can cure infections, including antibiotic-resistant
Posts: 4
infections? The difference between lytic and temperate phages is by now
well understood. I think the issue is really about what role phage therapy
should play - carefully applied by well informed doctors and scientists when
antibiotics fail, it has worked - I was just looking at Anna Kuchment' - The
forgotten cure - the past and future of phage therapy. In the treatment of
Tom Mix in 1931 that was true (page 1) as it is today. I think too many
researchers want phage therapy to compete and/or replace antibiotics. My
point is that if we had continued to use phage therapy along-side of
antibiotics, we would probably have been in a better place today. It is
important to remember that all of us have more phages in us and on us
than bacteria at all times.

Sign in to Report

January 6, 2016

Just want to commend the author for an extremely well-written and useful
bensabio
compilation of history and scientific information. An exceptioinal article. I'm
Posts: 10
sure it will be used widely for instructional purposes by grateful teachers
and professors. Thanks.

Sign in to Report

January 6, 2016

There appears to be some confusion amongst the readership of this article.

Phage.Canada
There are basically two types of phages based upon their interaction with
Posts: 1
the host bacterium. Lytic phages always lyse their host cells, producing the
next generation of phage particles. Temperate phages may lyse their host
upon infection, OR, go dormant in what is know as the lysogenic phase.
Some temperate phages of Escherichia coli, Vibrio cholerae, Staphylococcus,
Streptococcus, Clostridium and Corynebacterium diphtheriae do indeed
carry genes for toxins. This is not the case with lytic phages. Needless to
say, only lytic phages are used as therapeutic agents.

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January 7, 2016

As I am no microbiologist, please treat the following remarks a the purest

hand-waving, whether it is out of date or out of favour (I have no idea).
Like many other biologists I have long been interested in the potential
JonRichfield
value of phages in control of bacterial infections, given that the current
Posts: 125
developments in antibiotic resistance have been predictable since the late
sixties at least, and that phages can co-adapt with pests, whereas
antobiotics are static in their nature.
I also suspect that phage activity has been underestimated in its role in
microbiological ecology in general.

For example, I have no solid evidence to go on, but I suspect that one
major function of the appendix vermiformis is to maintain a culture of
strains of gut bacteria, plus their associated phages. I also suspect that a
major factor in beneficial applications of "faecal transplants" often is the
transplant of phages rather than of bacteria.

FWIW!

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January 7, 2016

As I am no microbiologist, please treat the following remarks as the purest

hand-waving, whether it is out of date or out of favour (I have no idea).

JonRichfield Like many other biologists I have long been interested in the potential
Posts: 125 value of phages in control of bacterial infections, given that the current
developments in antibiotic resistance have been predictable since the late
sixties at least, and that phages can co-adapt with pests, whereas
antobiotics are static in their nature.

I also suspect that phage activity has been underestimated in its role in
microbiological ecology in general.

For example, I have no solid evidence to go on, but I suspect that one
major function of the appendix vermiformis is to maintain a culture of
strains of gut bacteria, plus their associated phages. I also suspect that a
major factor in beneficial applications of "faecal transplants" often is the
transplant of phages rather than of bacteria.

FWIW!

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Replied to a comment from bsguyx made on January 1, 2016

Barry Williams January 11, 2016

Posts: 1
I agree with you. However, I think it is more to the point to discuss the
matter of personal sovereignty. Regardless of individual religious belief, I
think it is safe to say that my life and body were not granted to me by the
state and so the right of the state to dictate to me the substances
introduced into my body for whatever purpose I wish should be my
descision unless such act directly endangers others.

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