A Look at AIDS In Brazil

http://query.nytimes.com/gst/health/article-printpage.html?res=9D05E5DB113CF93BA15752C0A9679C8B63

Phage Therapy Pt. 3

When we propose the bacteriophage as an alternative to antibiotic antimicrobial treatments, we cannot ignore the possible resistance issues with phage therapy. As many readers know, bacteria are becoming more and more resistant to traditional antibiotic treatments. Phage therapy is often celebrated as the antibiotic resistance miracle cure however it is important to remember that bacteria can and will develop resistance to any form of therapy including phage because of their ability to transfer genes horizontally. Because phage are subject to the same nary a of selection that cause antibiotic resistance, the phage that successfully kill bacteria will be those that can infect bacteria and will release their progeny. This back and forth battle between bacteria and bacteriophage has been likened to an "evolutionary arms race"- an apt analogy. The outcome of this arms race is, even theoretically, largely unstudied. Bruce Levin of Emory University and James Bull of the University of Texas at Austin published an article in 2004 on many of these issues of resistance and evolution. The article puts forth the idea that bacterial resistance could proceed so that the mechanisms of virulence are simultaneously disabled along with the bacterium's susceptibility to bacteriophage infection. In other words, the cell receptors that allow bacteriophage to attach to the exterior of a bacterial cell could be eliminated so that the bacteria could resist phage attack. Mutants who lose these receptors might also lose their ability to attach to tissues in humans (the exterior cell receptors are responsible for host pathogenesis). This hypothesis merits further study. 

Phage Therapy Pt. 2

So what have we learned about bacteriophages? While early phage therapy proved inconsistent because phages were expelled from the host's immune system before they could properly eliminate microbial infection. In fact, it was shown by Carl Merril at the NIH in the 70s that the bacteriophage were cleared from the systems of mice without even using antibodies. By 1996, Merrill published a paper stating that certain mutants of lambda phage could circulate long enough to have therapeutic potential. Longer circulation periods in hosts meant that the mutant phage could evade the hosts immune system which in the case of bacteriophage, is a great thing.

In addition, it was shown that when bacteriophage lyse gram-negative bacteria there is a release of endotoxin that is so damaging to the host organism that it negates the benefit of the page action against the bacteria. In 2003, Steven Hagens and Udo Blasi at the Vienna Biocenter were able to build a phage that could kill the gram-negative bacteria with negligible release of endotoxin through the use of a restriction endonuclease. There was no compromise in killing efficiency. 

Phage Therapy Pt. 1

Phage therapy, the method of treating infection by Bacteriophage (bacteria eating virus) has been around since the beginning of the 20th century. In 1896, Ernest Hanbury Hankin found that the waters of the river Ganges had some mysterious healing power upon the causative agent of cholera, Vibrio cholerae. Bacteriophage are known to inhabit sewer waters frequently so it is thought that this must have been the origin of the anti-cholera effect. Further progress was made when Frederick W. Twort noted the existence of "ultramicroscopic viruses" that could kill bacteria in solution. However, the credit for the discovery of phage and their potential for treatments is given to Felix d'Herelle, a Canadian scientist who, while working at the Pasteur Institute, applied the phage to the treatment of dysentery by isolating the dysentery pathogen and inoculating it with bacteriophage. The result was profound. Bacteriophage were naturally occurring elements that could kill bacteria.

A Georgian scientist, George Eliava, showed great interest in d'Herelle's work and in 1926 invited d'Herelle to his laboratory in Tbilisi. By the mid-1930s, d'Herelle agreed and began further work with bacteriophage in Georgia. The work of d'Herelle gained Stalin's attention which afforded d'Herelle a great amount of support for his work in the years to come. The 1925 publication of Arrowsmith by Sinclair Lewis, a novel about a scientist/physician had further proliferated the methods of phage therapy in its passages on an outbreak of the bubonic plague in the West Indies. The notoriety of phage therapy grew in spite of inconsistent trials. Pharmaceutical companies began investing, most notably Eli Lilly. However, back in Georgia, the ties with Stalin were less fortuitous for d'Herelle's partner George Eliava as he fell in love with the same woman Lavrenti Beria, head of the NKVD (Soviet secret police) had. This was a death sentence for Eliava. After Eliava was shot, d'Herelle left Georgia and never returned.

After a brief honeymoon of investment and promise, 1928 would be the year marking the downfall of phage therapy. While the accidental discovery of penicillin did not reach public markets until 1940 when Ernst Chain, Norman Heatley and Howard Florey were able to isolate, concentrate and produce the antibiotic for further testing. The reliable success of penicillin (especially its use in World War II) and later streptomycin by Albert Schatz pushed phage therapy to the side while antibiotics enjoyed integration into clinical practices around the world.

In reality science and medicine were not ready for phage therapy in the early twentieth- century. Knowledge of bacteriophage was not nearly advanced enough until molecular biology arrived in the late 1940s. The "Phage Group" founded in 1940 by Max Delbruck was a network of scientists dedicated to studying bacterial genetics. Delbruck was originally a member of the T.H. Morgan Caltech fly lab but decided to study bacteriophage instead of Drosophila. The Phage Group marks the return of bacteriophage study and its new connections with molecular biology. The Hershey-Chase experiment of 1944 that earned its leaders a Nobel Prize and suggested that DNA was the central hereditary material of living organisms, was facilitated by bacteriophage study.
Although bacteriophage were used in many important biological experiments, their medical importance was overlooked until the 1970s. Until then, the mechanisms of phage therapy and its inherent inconsistency were unknown.


to be continued...