From Alzheimer’s to Zebrafish: Eclectic Science and Regulatory Stories 64
Long before there were antibiotics, researchers envisioned using viruses to seek out and
destroy bacteria. Now, as organisms continue to develop resistance to existing antibiot-
ics, these viruses, called “bacteriophages,” are finding new advocates. According to the
US Food and Drug Administration (FDA), bacteriophages (phages) are defined as RNA
or DNA viruses that infect bacteria without infecting mammalian or plant cells. Phages
are ubiquitous in the environment, and humans are routinely exposed to them at high
levels through food and water without adverse effects. FDA has approved one product, a
Listeria-specific bacteriophage preparation made from six individually purified phages to
be used on ready-to-eat meat and dairy products, as an antimicrobial agent.1 The product,
a food additive, is reported to be effective against 170 strains of L. monocytogenes. Other
phages have been approved in the US as pesticides.
Although not currently permitted here, phages are used in other countries (e.g.,
Eastern Europe, the former Soviet Union) as antibiotic therapy. Phages may eventually
become the treatment of choice in the US for cases where antibiotics fail, but there are
a host of problems to be solved before that happens. This article will review the history
of phage discovery, biology, medical uses, advantages and disadvantages and the likely
future of phage therapy.
History
A paper written by Frederick Twort and published in 1915 is generally considered the
beginning of phage research, although there are earlier reports that suggest their pres-
ence.2 Twort was attempting to grow vaccinia virus on agar media in the absence of living
cells when he noted that some colonies of contaminating micrococci appeared mucoid,
watery or glassy. This glassy transformation could be induced in other colonies by inocu-
lation of the fresh colony with material from the watery colony. When he examined the
glassy colonies under a microscope, he noted that the bacteria had degenerated into small
granules. His interpretation of glassy transformation was tentative, but he concluded
that the agent responsible might almost be considered as an acute infectious disease of
micrococci.3
Although he may not have been first to publish, Felix d’Herelle is generally credited
as the scientist most intimately involved in phage research and its medical application.4
The discovery or rediscovery of phages by d’Herelle is associated with an outbreak of
severe hemorrhagic dysentery among French troops stationed on the outskirts of Paris
in 1915. Several soldiers were hospitalized and d’Herelle was assigned to conduct an
investigation of the outbreak. During these studies, he made bacterium-free filtrates of
the patients’ fecal samples and mixed and incubated them with Shigella strains isolated
from the patients. A portion of the mixtures was inoculated into experimental animals
and a portion was spread on agar medium to observe the growth of the bacteria. It was on
these agar cultures that d’Herelle observed the appearance of small, clear areas, which he
initially called taches, and later plaques.5 His findings were presented during the September
1917 meeting of the Academy of Sciences, and they were subsequently published in the
meeting’s proceedings.6 D’Herelle had little doubt about the nature of the phenomenon,
and he proposed that it was caused by a virus capable of parasitizing bacteria. He also
proposed the name “bacteriophage” on 18 October 1916.7 The name was formed from
“bacteria” and “phagein” (“to eat or devour” in Greek) to imply that phages consume or
destroy bacteria.
Biology
As mentioned earlier, phages are DNA or RNA viruses that infect only specific bacteria.
They have colorful names such as T4, Mu, Qß, P1 or CTXØ. Bacterial phages come in
many shapes and sizes (e.g., tailed or nontailed, icosahedral, filamentous and enveloped
or nonenveloped). The tailed, double-stranded DNA phages began evolving over three
Long before there were antibiotics, researchers envisioned using viruses to seek out and
destroy bacteria. Now, as organisms continue to develop resistance to existing antibiot-
ics, these viruses, called “bacteriophages,” are finding new advocates. According to the
US Food and Drug Administration (FDA), bacteriophages (phages) are defined as RNA
or DNA viruses that infect bacteria without infecting mammalian or plant cells. Phages
are ubiquitous in the environment, and humans are routinely exposed to them at high
levels through food and water without adverse effects. FDA has approved one product, a
Listeria-specific bacteriophage preparation made from six individually purified phages to
be used on ready-to-eat meat and dairy products, as an antimicrobial agent.1 The product,
a food additive, is reported to be effective against 170 strains of L. monocytogenes. Other
phages have been approved in the US as pesticides.
Although not currently permitted here, phages are used in other countries (e.g.,
Eastern Europe, the former Soviet Union) as antibiotic therapy. Phages may eventually
become the treatment of choice in the US for cases where antibiotics fail, but there are
a host of problems to be solved before that happens. This article will review the history
of phage discovery, biology, medical uses, advantages and disadvantages and the likely
future of phage therapy.
History
A paper written by Frederick Twort and published in 1915 is generally considered the
beginning of phage research, although there are earlier reports that suggest their pres-
ence.2 Twort was attempting to grow vaccinia virus on agar media in the absence of living
cells when he noted that some colonies of contaminating micrococci appeared mucoid,
watery or glassy. This glassy transformation could be induced in other colonies by inocu-
lation of the fresh colony with material from the watery colony. When he examined the
glassy colonies under a microscope, he noted that the bacteria had degenerated into small
granules. His interpretation of glassy transformation was tentative, but he concluded
that the agent responsible might almost be considered as an acute infectious disease of
micrococci.3
Although he may not have been first to publish, Felix d’Herelle is generally credited
as the scientist most intimately involved in phage research and its medical application.4
The discovery or rediscovery of phages by d’Herelle is associated with an outbreak of
severe hemorrhagic dysentery among French troops stationed on the outskirts of Paris
in 1915. Several soldiers were hospitalized and d’Herelle was assigned to conduct an
investigation of the outbreak. During these studies, he made bacterium-free filtrates of
the patients’ fecal samples and mixed and incubated them with Shigella strains isolated
from the patients. A portion of the mixtures was inoculated into experimental animals
and a portion was spread on agar medium to observe the growth of the bacteria. It was on
these agar cultures that d’Herelle observed the appearance of small, clear areas, which he
initially called taches, and later plaques.5 His findings were presented during the September
1917 meeting of the Academy of Sciences, and they were subsequently published in the
meeting’s proceedings.6 D’Herelle had little doubt about the nature of the phenomenon,
and he proposed that it was caused by a virus capable of parasitizing bacteria. He also
proposed the name “bacteriophage” on 18 October 1916.7 The name was formed from
“bacteria” and “phagein” (“to eat or devour” in Greek) to imply that phages consume or
destroy bacteria.
Biology
As mentioned earlier, phages are DNA or RNA viruses that infect only specific bacteria.
They have colorful names such as T4, Mu, Qß, P1 or CTXØ. Bacterial phages come in
many shapes and sizes (e.g., tailed or nontailed, icosahedral, filamentous and enveloped
or nonenveloped). The tailed, double-stranded DNA phages began evolving over three