Katherine D. Rouse (KD)Bibliography AssignmentDr. Carmichael 11/2010

The Amazing Phage: A Non-Scientist’s Peek at the Smallest Biological Entity on Earth

Scope

The bacteriophage is a virus that infects bacteria. Far smaller than a cell, it was the catalyst for great leaps made in molecular biology, biotechnology, and genetics, playing a crucial part in the discovery of DNA. Known to be successful in the treatment of disease since the early 20 th century, and used in Russia in lieu of antibiotics, phage therapy is being reconsidered in the West due to increasing bacterial resistance to antibiotics. In addition to treatment of bacterial disease, the phage is proving useful in cancer and Alzheimer’s research. It is being used in innovative ways in industry and by the military.

The bacteriophage, half protein, half nucleic acid, and the ability to replicate itself, is a model of the human gene. As much as it has been studied, and used the bacteriophage still holds mysteries, enough to inspire a t-shirt that pictures a phage and asks ‘Do you know God?’ This is not a comprehensive study, therefore, but a mere introduction to the amazing phage.

Introduction

No one knows how many 19th century bacteriologists stared at their agar dishes of carefully grown bacteria in dismay, finding their cultures ruined by inexplicable clear spots. What these early bacteriologists did not realize was that these round, clear spots were evidence, the only possible evidence at the time, of one of the smallest, most abundant biological entities on earth: the bacteriophage, or phage.

“Agar Dish with Clear Spots.”

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F.W. Twort’s ‘Glassy Transformations’

As banal an experience as seeing clear spots on cultures of bacteria, it sparked the curiosity of two scientists in the 1910’s. They were strangers, working independently in different parts of the world, yet both sought to explain the phenomena.

F.W. Twort, an English pathologist, was the superintendent of the Brown Institute in London, a place “dedicated to the study of animals and birds useful to humans”. While he experimented with colonies of the bacterium, micrococcus, Twort noticed that some of the colonies had taken on what he referred to as a “glassy transformation,” instead of the normal opaque creamy-white appearance expected. When Twort transferred a minute speck of the “glassy” colony to a normal colony, the normal colony soon became glassy.

Twort was able to do this indefinitely, with each normal colony taking on the same glass-like appearance when exposed to even a minute sample from a glassy colony. As no bacteria was detected in the new glassy colonies, Twort surmised that the bacterial cells must have lysed or dissolved, a phenomena he termed ‘transmissible lysis.’ He discovered too, that only colonies of living bacteria could be lysed, and during lysis, the lytic substance increased dramatically. Twort published a paper describing the phenomena that went virtually unnoticed for the next five years.

Frederick William Twort

Twort became a professor of bacteriology at the University of London. He researched into Johne's disease, a chronic intestinal infection of cattle, and also discovered that vitamin K is needed by growing leprosy bacteria.

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Felix d’Herelle, Locusts, And Clear Spots

The other scientist in question, French Canadian bacteriologist, Felix d’Herelle, was busy collecting sick and dying locusts in Mexico, starting in 1910. Isolating the bacteria deadly to the locust, coccobacilli, in locust diarrhea, D’Herelle dusted coccobacilli on plants ahead of advancing columns of locusts in Argentina and North Africa, causing the locusts to infect themselves as they devoured the plants.

In cultivating the coccobacilli bacteria that he needed, d’Herelle witnessed what he described as “clear spots, quite circular, two or three millimeters in diameter, speckling the cultures grown on agar.” D’Herelle again noticed the phenomena when working with soldiers suffering from dysentery in Paris, 1915. Using rabbits and guinea pigs, d’Herelle found that filtered emulsions made from the clear spots in dysentery cultures did not give the disease to test animals.

At the hospital of the ‘Institut de Pasteur’, in Paris, 1916, d’Herelle hoped to understand the infection process of dysentery, using methods learned in his days of global pest-control. He followed the progress of a dysentery patient from the onset of his disease, testing daily fecal cultures of the ill man in his laboratory located in the basement mortuary of the Institut de Pasteur.

For the first three days d’Herelle’s agar garden of active dysentery bacteria flourished without a blemish. According to d’Herelle, the fourth day was one of the most exciting days of his scientific life. There were clear spots on the cultures of dysentery, spots devoid of the disease. He was certain that this meant his patient should be showing vast signs of improvement. Rushing to the hospital, d’Herelle was deeply gratified to find that his patient’s symptoms had improved dramatically.

D’Herelle was certain that the clear spots appearing on his cultures of bacteria were caused by a virus infecting bacteria, which he named the bacteriophage, or “bacteria-eater” from bacteria and the Greek word phagein, meaning “eater.” According to his own account, d’Herelle had remarkable success curing difficult diseases with phage therapy. He envisioned the phage as a way to cure mankind of bacterial disease.

Unlike Twort, d’Herelle’s publication in 1917 succeeded in arousing worldwide interest in bacteriophage research.

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A Scientific Duel Decides Who Discovered the Phage

In 1921, famous immunologist and Nobel prize winner, Jules Bordet, objected to d’Herelle being credited with discovery of the bacterial virus. Not only had Twort’s paper been published two years before d’Herelle’s, argued Bordet, but the two scientists hadn’t witnessed the same phenomena at all. At Bordet’s insistence, a scientific duel was fought, with prominent, independent scientists carefully scrutinizing the steps and methods used by Twort and d’Herelle as they individually repeated the experiments that revealed Twort’s “glassy transformation,” and d’Herelle’s “clear spots,” this time in the same laboratory at the same time.

It was concluded that Twort and d’Herelle’s discoveries were identical. They had both observed spots of lysis (or glassy spots) on beds of bacteria, an occurrence officially named the ‘Twort-d’Herelle Phenomenon.’ It was decided that both scientists found the bacteriophage independently of each other. Though some sources vary, most give credit to both Twort and d’Herelle.

The ‘Twort-d’Herelle Phenomenon’’ did not disappear, but its official name was soon dropped from scientists’ working vocabulary. Clear spots that appear on cultures of bacteria are now called plaques.

Felix d’Herelle

Host Specific “Dancing Points of Light”

In the 1940’s, it was discovered that instead of one type of bacteriophage able to attack all bacteria, there were many different phages, each having one particular strain of bacteria that it could infect. At that time, phages were only able to be

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observed as “dancing points of light,” using high powered, dark-field microscopes, unable to be seen at all through traditional light microscopes.

Inexplicable clear spots on cultures of bacteria, and elusive “dancing points of light” revealed the existence of the phage, yet it was much too small to be seen.

By counting the plaques that arose from a known volume of phage suspension, scientists could accurately estimate the number of phage particles in it, a process called the ‘plaque assay technique’. By filtering with smaller and smaller filters, they even had an accurate measurement of the size of the phage.

Until the invention of the electron microscope in 1942, however, the phage had never been seen.

The Electron Microscope

Even the scientists studying the phage were surprised upon seeing the bacteriophage for the first time. One was heard to exclaim, “It has a tail!”

Bacteriophage—Some “heads” dissolving

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“It Has A Tail!” The phage is composed of half protein and half nucleic acid. It has a head, a collar, a tail, an end plate, and six tail fibers that look like spidery legs. It is non-mobile, but when swept near its type-specific bacterial host, it attaches itself with its tail fibers, in a state of reversible attachment, while the tail fibers then probe the cell surface for an optimum point of entry.

Once the tail fibers have positioned the phage, they anchor themselves firmly to the cell surface and irreversible attachment begins. The hexagonal base plate of the phage, composed of at least 16 proteins, changes to a star shape, making an opening through which the tail tube protrudes. The tail sheath then contracts, driving the tail tube into the bacterial cell, where the phage deposits its DNA.

The phage multiplies within the host cell, either killing the host by replicating itself until lysis occurs, or lying dormant inside the cell, sharing its life support systems without apparent harm to the cell. The host is safe from lysis as long as the phage remains in a latent state.

T-7 phage penetrating E. Coli

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The phage hovers It lands

It attaches It injects its DNA into its Host.

Virulent or Temperate? Sperm or Phage? Questions Abound

Phage that replicate inside their host until lysis occurs are called virulent. Temperate phages live inside their host without killing them, lysis sometimes occurring in the future. External stimuli, such as x-rays or exposure to ultra-violet lights, have sometimes triggered temperate phages into lysing, thus making them virulent.

A bacteria cell is roughly one micron or one/thousandth of a millimeter, while the phage measures as small as twenty-five/thousandths of a micron. Early photographs of the magnified phage attaching to bacterial cell walls looked much like sperm fertilizing an egg, so much so that scientists were accused of perpetrating a hoax on the public, passing off sperm as the mysterious phage.

Living or Non-Living?

Whether the phage is ‘living’ or ‘non-living,’ also remains a mystery. Twentieth century scientists argued definitions of life as the phage floated at the crossroads of life and non-life. Even today, there is no definitive answer as to how the phage should be classified.

The phage is unique too, that it is the only biological entity on earth known to undergo an event known as the phage eclipse. Phage eclipse occurs right after

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the phage injects its DNA into a bacterial cell. During its eclipse, which lasts for roughly 20 minutes, the phage disappears. It cannot be seen, even with an electron microscope or detected with known testing. It vanishes until it reappears with a sudden burst, as lysis occurs, releasing all the new phages.

Where Are Phages Found?

Phages are everywhere, found in food, soil, fresh water, seawater, domestic sewage, and human and animal excrement. The highest concentration of phage is found in seawater. While there may be healing power in phage-rich waters, high phage levels in a community’s water supply can also indicate fecal contamination.

Where Is the West With Phages?

Research into the healing powers of the phage was virtually abandoned in the Western Hemisphere with the discovery of antibiotics in the early 1940’s. Russia was not aware of Western advances in antibiotics, however, due to the scientific barriers of the Cold War, and used phage to successfully treat WWII soldiers in field hospitals, for dysentery, gangrene, and other bacterial infections.

While phage therapy has been used as an alternative to antibiotics in Russia and Eastern Europe for over 90 years, Western scientists are only now re-examining the phage for use in treatment of bacterial infections in humans and animals. This change of attitude is a response to the emergence of antibiotic-resistant strains of bacteria.

The Phage Group

Excited by the potential of the phage as a means to study the basic properties of living organisms, a group of scientists, including Max Delbruck, Salvador Luria, and Alfred Hershey, formed ‘The Phage Group’ in the late 1930’s. In 1945, Delbruck organized an annual summer phage course at Cold Spring Harbor Laboratory in New York, attracting more scientists to ‘The Phage Group.’ Delbruck, Luria, and Hershey were given the Nobel Prize in Physiology and Medicine in 1969, "for their discoveries concerning the replication mechanism and the genetic structure of viruses."

Max Delbruck, Salvador Luria

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Using the phage, they showed that while a reproducing cell specializes, and replicates exponentially, the phage completes its replication in one step. This made the phage the ideal subject for genetic studies. A scientist could study virtually millions of phage on a single tabletop, splicing DNA into phages, to better understand the mechanics of genetics. These studies led to important discoveries about the nature of living organisms, including, eventually, the discovery of DNA by Francis Crick and James D. Watson in the early 1950’s.

Alfred Hershey/Cold Springs Harbor Laboratory

The Phage Treaty

Delbruck helped standardize phage research with ‘The Phage Treaty,’ a call for phage researchers to focus on a limited number of phage and bacterial strains, with standardized experimental conditions. This helped to make research from different laboratories more easily comparable and replicable, helping to unify the field of bacterial genetics.

Foe or Friend? Wineries and Living Libraries

While the phage has many uses, they are destructive to certain industries that rely on fermentation of bacteria to make products, such as wine, beer, and cheese. While these industries have to guard their operations from phage contamination, the cattle industry is using phage concoctions, sprayed on the

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hides of animals to reduce bacteria. Phages are also used to store genetic information in living libraries called combination libraries for future study and use.

To use phages as information receptacles starts with isolating a gene, a theoretical “Z” gene, for example, and introducing the “Z “ gene into the phage. The “Z”-phage is then grown in a culture until it is introduced to new bacteria. The “Z”-phage infects the bacteria. The bacteria, then, produces “Z”-phage. Genetic material of any kind is stored in the phage.

The Phage: More to Learn

As much as is known about the phage, there is still more to learn, especially related to the cure of illness. Research into the phage for medical use in the United States was never thorough. Tests seemed to be designed for failure, low doses being used to treat patients rather the high doses Felix D’Herelle had found successful in his cures in the 1920’s. Some literature indicated that this might have had something to do with the public’s fear of “taking a virus.” Phage as a way to treat bacterial disease was entirely abandoned with the discovery of antibiotics in the early 1940’s.

Drug companies, of course, favored antibiotics that they could patent. The phage can be made into pill form, but obtaining a patent presented some difficulties. The question was ‘How does one patent a biological entity?’ That the FDA has just approved a topical phage spray to treat acne indicates that this issue has been resolved.

The use of medical phage therapy is being reconsidered for use in the United States because of the “superbugs,” bacterial infections ever more resistant to treatment with antibiotics. Topical treatments and sprays have been very successful in curing diseases of the skin, and in clearing areas of bacteria, such as in hospital operating rooms. Inoculation of phage is not effective because the body goes into defense mode if phage is introduced into the blood stream, rendering phage treatment useless in the future.

Phage Cocktails

To effectively treat a bacterial infection with phage, the patient must be tested to find out the particular type of bacteria causing the illness. The phage is as varied as its bacterial host, with one particular type of phage able to inject itself into its one particular strain of bacteria. Unless each patient is tested, and the specific bacteria causing

illness identified, a single phage type would be too “hit or miss” to be effective for treatment. A phage “cocktail,” containing many types of phage would need to be used, something the FDA does not easily approve.

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The Phage is All the Rage

The Phage is versatile, useful in a variety of fields, in a variety of ways. It is being used in animal nutrition:

“Lallemand Animal Nutrition and Gangagen, a Canadian biotechnology company will collaborate to exploit the potential of phages to selectively destroy pathogens within the animal’s digestive tract.” “Phage venture.” Feedstuffs: 6 September 2005. Tittering phages

As a cure for acne:

“Scientists have identified a naturally occurring bacteriophage that reduces the density of Propriobacterium acnes, the bacteria responsible for acne. A topical formulation containing the phage would be more specific than benzoyl peroxide and not have the antimicrobial resistance problems associated with long-term antibiotic use,” said Professor Keith Holland of the Skin Research Centre at Leeds University. "Future acne gel free of side effects." Chemist & Druggist: 4 April 2004.

For treatment of disease in humans:

“GangaGen (gangagen.com) is focused on the discovery and development of proprietary bacteriophage preparations for the prevention and treatment of multiple bacterial diseases in humans.” Monari, Gina-Louise. "GangaGen Inc." R & D Directions: 7 June 2004.

To Produce Human Insulin:

“Phage have proved to be valuable molecular tools for biotechnology, as they can be used as vehicles to move genetic material from one organism into another organism. It is through this revolutionary use of phages to introduce foreign DNA into new cells that human insulin was first safely and cheaply produced.” Science News: 5 October 2009.

To Keep Swine Salmonella-Free:

"While we do not suggest that we have a complete solution for salmonella, our data indicates that the concept of using phage to reduce salmonella in swine is valid and feasible," says Researcher Todd R. Callaway of Texas at Southern Plains Agricultural Research Center at College Station, Texas.

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A scanning electron micrograph of T4 cells, a virulent phage in E. coli.

The phage has been approved by the FDA to treat ready-to-eat meat:

“In the USA, the FDA approved the use of bacteriophage-cocktails against Listeria monocytogenes in ready-to-eat meat and poultry. The FDA classified these bacteriophages under the generally recognized as safe (GRAS) product regulation.” FDA: April 2006.

The phage is even being used as a power source for soldiers on the field.

“Soldiers have to carry heavy loads of battery to keep their gizmos high on power every time. This besides exhausting the soldiers can also act as a hindrance in their efficiency and safety during conflicts. To make things simpler for soldiers, scientists at MIT have developed M13 bacteriophage, common virus, enabled wearable lithium-ion batteries, which can be woven into fabrics such as a soldier's uniform or into a ballistic vest. Featuring cathodes made from iron-fluoride material, for minimal loss of performance.” Instablogs.com 24 Aug. 2010.

Experiments on rodents show promising results using the phage as a treatment of Alzheimer's Disease :

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“Phages, which are viruses that infect bacteria, cut through plaques in the brains of mice engineered to develop a disease similar to Alzheimer's. That action helped the rodents recover. Phages dissolve plaque," says Beka Solomon of Tel Aviv University in Israel. "We saw improvements in memory and smell tests" of the mice. Vastag, B. "Phages break up plaques." Science News 9 June: 2007.

The phage is even playing a part in disarming bioterrorism:

“Scientists at Rockefeller University in New York City have made the grade in the subject of defense against anthrax. An anthrax-specific bacteriophage produces a protein--a lysin--that kills anthrax bacteria by destroying their cell walls from the outside, the researchers said. Better yet, the anthrax bacteria seem unable to develop resistance to this external attack.” Pediatric News: 16 October 2002.

The Amazing Phage

While phage research in the West lay dormant for nearly 30 years after its discovery, the efforts of such scientists such as Max Delbrück, Salvador E. Luria, and Alfred D. Hershey revived interest in the phage in the 1940’s. Using the phage, scientists made the many important discoveries that led to the secret of DNA, advancing molecular biology, genetics, and a host of other fields.

The existence of the phage was discovered by two independent scientists in the 1910’s, both curious about innocuous clear spots on their bacteria cultures, that most likely had been seen many times before, in many laboratories, by many others before them. No one could guess that taking note of this small anomaly could lead to such leaps, and potential leaps for mankind.

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Search WordsBacteriophagePhage LysogenyPhage LambdaElectron MicroscopeDNA and PhagePhage and Molecular BiologyPhage EcologyTwort, Frederick, W.d'Herelle, FelixDelbrück, MaxLuria, Salvador E.Hershey, Alfred D. Cairns, John,Stent, GutherWatson, James D. Crick, FrancisBacteriophages--Research—FloridaMicrobiologists--Canada--Biography.Molecular biology--History--20th century.Corals--Diseases--Alternative treatment.Corals--Diseases--Florida.Biotechnology--history.Neoplasms--therapy.Biotechnology--Popular works.Medical genetics--Popular works.Genetic engineering--Popular works.

Using the Jackson Library Catalog, these were the results of various searches: phage: 54 useful matchesbacteriophage: 38 useful matchesdna and phage: 25 useful matches phage and molecular biology: 14 useful matchesphage lambda: 11 useful titlesgenetics phage: 7 useful matches lysogeny : 5 useful matches phage and biotechnology: 5 matches pertinentbiotechnology: 1322 matchesViruses: 726 matchesbacterial viruses: 44 matches, primarily useless

Search words must be specific to the phage. WorldCat Database of Libraries Worldwide offers a dizzying 68,593 matches for ‘phage,’ and requires even more specificity.

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Related Subjects

Molecular BiologyMicrobial BiologyApplied BiologyBiotechnology Gene transfer

Lateral gene transferGeneticsViral GeneticsMolecular Genetics Food ScienceCombination or Antibody Libraries Cal TechCold Springs Harbor Laboratory

FDAFood and beverage industriesBusiness and industriesNobel Prize

CLASSIFICATION

Library of Congress

Some information on the bacteriophage can be found under class Q, most, however, is found in the subclasses of Q. Information can also be found in the subclasses of T.

CLASS Q Science (General)

Subclass QD ChemistrySubclass QH Natural history - BiologySubclass QL ZoologySubclass QP PhysiologySubclass QR Microbiology

CLASS R--Medicine

Subclass RM Therapeutics. Pharmacology

CLASS T Technology (General)

Subclass TP Chemical technology

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Dewey Decimal

000 – Computer science, information & general works

010 Bibliographies, 030 Encyclopedias & books of facts, 050 Magazines, journals & serials 060 Associations, organizations & museums, 070 News media, journalism & publishing

300 – Social sciences

341 International law342 Constitutional & administrative law

500 – Science

570 Life sciences 572 Biochemistry 576 Genetics and evolution 577 Ecology 578 Natural history of organisms 579 Microorganisms, fungi, algae

600 – Technology/Applied Science

600 Technology 601 Philosophy & theory664 Food technology

900 – History, geography, and biography

903 Dictionaries & encyclopedias904 Collected accounts of events

Library and Research Centers

Cold Springs Harbor Laboratory: Cold Springs Harbor, New York.

CalTech: Pasadena, California.

Institut de Pasteur: Paris, France.

Eliava Institute: Tbilisi, Georgia.

Félix d'Hérelle Reference Center for Bacterial Viruses: Quebec, Canada.

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Companies Developing Products With Phage

GangaGen Biotechnologies is a biotechnology company focused on the development of bacteriophage-based products for prevention and treatment of bacterial infections. Gangagen has received two US patents for its proprietary bacteriophage technologies "Lysin-Deficient Bacteriophages with Reduced Immunogenicity" and "Incapacitated Whole-Cell Immunogenic Compositions." http://www.gangagen.com.

Lallemand Animal Nutrition is a feed and food industry pioneer, offering a wide range of natural products that improve animal performance and health.http://www.lallemandanimalnutrition.com.

Intralytix, Inc. is a biotechnology company focused on the production and marketing of bacteriophage-based products to control bacterial pathogens in environmental, food processing, and medical settings. http://www.intralytix.com.

Camelyn Ltd. Tbilisi, Georgia has developed a process for removing the sugar from honey. The remaining ingredients, called Camelyn "M" provide the basis for a number of products including food additives, food supplements and drugs. http://www.camelyn-usa.com.

Eliava Biopreparations, Tbilisi, Georgia. The Eliava Institute is a world renowned institution working in the field of applied microbiology, virology and infectious immunology. The main direction of the Institute since its establishment in the early 20’s of 20th century remains study of bacteriophages. http://eliavaphageny.com.

JSC Biochimpharm. JSC has massive collection of several classic phage preparations, rennovating the bacterial strain and phage collections, and enhanced these products to address newly emerging antibiotic resistant strains. http://www.biochimpharm.ge.

Phage International is a multi-national corporation that is engaged in discovery and rediscovery of effective health care technologies developed in Eurasia. Their businesses are engaged in technology transfer, clinical research, manufacture and distribution. http://www.phageinternational.com.

MicroPhage Inc. uses bacteriophage amplification technology, which detects proteins produced by viruses.

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Encyclopedias

Lerner, Lee K., and Brenda W. Lerner, eds. The Gale Encyclopedia of Science. 3rd ed. Detroit: 2004. For a brief, basic overview of the bacteriophage, this encyclopedia is a good source. While scientists of the phage have a complex system of naming phages and their replicates with names such as phage lambda, and the T-phages, it is interesting to note that officially phages are named according to the bacteria they infect. The staphyolococcal is host to the staphylophage. The coliform bacteria is prey to coliphages. Potential medical use of the phage is not stressed, but the phage is called both a model of viral infectious mechanisms, and a valuable research tool in biotechnology and other sciences. The Gale Encyclopedia of Science includes charts, photographs, illustrations, graphs, references and index.

Heldman, Dennis, ed. Encyclopedia of Agricultural, Food, and Biological Engineering. New York: Marcel Dekker, 2003.

Engineering processes that create agricultural materials or make food and nonfood products from these materials is examined in this encyclopedia. Nearly 240 entries broadly cover agricultural and food engineering with topics such as biomass engineering, biomedical biomaterials, enzyme kinetics, fossil fuel energy, and microbial genetics. The number of articles, and the broad range they cover within a focused study provides an intensive view of agriculture and technology. The phage has a very interesting part, and is considered a very innovative approach to the problem of bacteria resistant strains, and food contamination. This volume includes charts, photographs, illustrations, graphs, chemical reactions, and equations, as well as references and an index.

Brenner, Sydney, Jeffrey H. Miller, and William Broughton, eds. Encyclopedia of Genetics. San Diego: Academic Press, 2002.

More than 700 expert authors contributed articles that range from glossary items, definitions, and short articles to full articles of five pages or longer, many with further reading lists. Many entries are accessible to non-specialists, while others are written for expert researchers. Cross-references and liberal inclusion of figures and tables enhance the text. A thorough table of contents provides an overview of the set's coverage, while a more detailed index is also available. The information on the bacteriophage is interesting, and is found throughout this four-volume set.

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Bains, William, ed. Biotechnology from A to Z. New York: Oxford University Press, 2004.

This 413-page volume is a readable mini-encyclopedia with 300 one- or two-page entries relevant to biotechnology. It contains a brief but informative view of the bacteriophage, and contains illustrations, charts, tables, and an index. This is a volume recommended for non-specialists, who want to know the simple facts (as they stood in 2004).

Lerner, Lee K., and Brenda W. Lerner, eds. World of Microbiology and Immunology. Detroit: Gale, 2003.

The most intensively studied bacteriophage, phage lambda, is the focus of this volume. Lamda is an important model system for the latent infection of mammalian cells by retroviruses, and it has been widely used for cloning purposes. Bacteriophages are useful in the study of how genes function. The attributes of bacteriophages include their small size and simplicity of genetic organization. Interesting and well organized, this work is illustrated and indexed.

Calendar, Richard, ed. The Bacteriophages. New York : Plenum Press, 1988.

Volume Two in the Series: The Viruses, The Bacteriophages, is not for the beginning phage student. While the subject matter is very detailed, there are some informative illustrations. Table of contents is in outline form, and index is included. Early black and white photos of the bacteriophage are included.

Bacteriophage Bacteriophage(small, light circles) Attacking Bacteria

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Textbooks

Sulakvelidze, Kutter E., ed. Bacteriophages Biology and Applications. Boca Raton: CRC Press, 2005.

A well-written and documented textbook, Bacteriophages, Biology and Applications includes interesting history on the bacteriophage, as well as on the actual ways that the phage can be used. Illustrations, graphs, charts, cross-referenced index are included.

Mcgrath, S., and Van D. Sinceren, eds. Bacteriophage : Genetic and Molecular Biology. UK: Horizon Scientific Press, 2007.

Recent chapters were added to an already new textbook, chapters including new advances in phage research and genetics. Also included are questions of ethics, and the regulation of phage therapy. Illustrations, graphs, charts, cross-referenced index are included.

Monographs

Cairns, John, Guther S. Stent, and James D. Watson, eds. Phage and the Origins of Molecular Biology. New York: Cold Spring Harbor Laboratory Press, 1992.

Written in honor of scientist Max Delbruck’s 60th birthday, authors were hand-chosen by editors Cairns, Stent, and Watson, all famous scientists themselves. (Watson is of “Watson and Crick”, co-discoverer of DNA.) Each scientist author wrote about a particular aspect of the phage, with subjects such as phage eclipse, the lysogenic cycle, one-step growth, and electron microscopy. Although many of the essays are quickly inaccessible to the non-scientist, there is an undeniable enthusiasm coursing through each scientist’s account, as moments of discovery are relived without the constraints of academic writing.

A fascinating story is conveyed in the introduction, “Waiting for the Paradox,” by Gunther S. Stent. Famed Austrian physicist, Erwin Schrodinger wrote a book called “What Is Life?” before the end of WW II, which drew wide interest in biological research. Schrodinger wondered if there might be new laws of physics to discover in order to answer the question of life. While biologists found Schrodinger’s short volume to be out-dated, and of little interest, it caused many physicists to turn to molecular biology.

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Later, Max Delbruck wrote and delivered a speech called “A Physicist Looks At Biology,” which is included in this volume, and was the only essay not written solely for the book. Despite the work it entailed, editors and authors were able to keep the book a secret until it was presented to him on his 60 th birthday. Diagrams and graphs are included. Each article ends with its own bibliography. While the glossary includes descriptive chapter titles, there is no main index. This book also includes priceless photographs of scientists at Cold Spring Harbor Laboratory in New York.

Goyal, Sagar M., Charles P. Gerba, and Gabriel Bitton, eds. Phage Ecology. New York: John Wiley and Sons, 1987.

An enjoyable read despite what the title may sound like to the non-scientist, Phage Ecology gives accounts of the phage in many environments: phages in seawater, phages in freshwater, soil, and waste water treatment plants. A colorful account of the history of the phage is included in this collection of essays, as well as a discussion of phage contamination in fermentation industries. Detailed bibliographies, graphs, and charts are included. An index is not.

McGarth, Stephen, and Douwe Sinderen, eds. Genetics and Molecular Biology. New York: Caister Academic Press, 2007.

Scientists in a wide range of medical and biological disciplines, from universities and companies around the world, review the understanding of bacterial viruses, or bacteriophages. Genetics, food fermentations, medicine, Western perspective, and the transfer of DNA from phage to host is presented.

BOOKS

Walker, Sharon, PHD. Biotechnology Demystified: A Self-TeachingGuide, New York: McGraw-Hill, 2007.

For those needing definitions and explanations pertaining to biotechnology, this self-teaching guide provides the answers in a clear easy-to-read manner. There is a fascinating section on the phage used in Living Libraries to store genetic information. These are also referred to as Combination Libraries.

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Stephenson, Frank H., DNA : How the Biotech Revolution is Changing the Way We Fight Disease. New York: Prometheus Books, 2007.

Stephenson examines bacteriophage therapy to combat resistant bacteria. He also discusses gene therapy, cloning, stem cell research, and the use of the bacteriophage to treat cancer, Alzheimer’s, aging and bioterrorism. A very interesting “cutting-edge” read about the changes occurring in treatment of disease, which includes bibliographical references and an index.

Sneppen, Kim, and Giovanni Zocchi. Physics in Molecular Biology New York: Cambridge University Press, 2005.

Physics in Molecular Biology examines physical properties in molecular biology, such as the protein structure of DNA, how protein acts molecularly, and molecular networks. A large section is devoted to the physics of genetic regulation with the lambda phage in E. Coli. This interesting book includes bibliographical references, illustrations and an index.

Stahl, F.W. We Can Sleep Later: Alfred D. Hershey and the Origins of Molecular Biology. New York: Cold Spring Harbor Press, 2000.

Nobel Prize winning bacteriologist and geneticist, Alfred Day Hershey, was a powerhouse in the field of Molecular Biology. One of the original members of the informal ‘Phage Group,’ he worked with Max Delbruck and Salvadore Luria. In 1952, Hershey performed the famous Hershey-Chase “blender experiment” with Martha Chase providing additional evidence that DNA, not protein, was the material of genetic transfer.

Summers, W.C. Felix d'Herelle and the Origins of Molecular Biology. New Haven: Yale University Press, 2000.

Felix d'Herelle, one of the two independent scientists credited with the discovery the bacteriophage, is an extremely interesting subject brought to life by W.C. Summers. D’Herelle traveled around the world, ridding Mexico, Argentina, and Algeria of locusts in the early 1900’s, using his biological experimentation with bacteria to rid the world of pests. After discovering evidence of the phage, d’Herelle thought immediately of a virus that kills bacteria, He continued to research, later fighting cholera and plague in India with phage therapy. D’Herelle had high hopes of using phage to fight infection in humans and animals, but saw his dreams dashed by the discovery of antiobiotics. This book includes illustrations, a map, and an appendix of Felix d’Herelle’s original publication in 1917, called "On an Invisible Microbe Antagonistic to the Dysentery Bacillus."

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Watson, James D. A Passion for DNA : Genes, Genomes, and Society. New York: Cold Springs Laboratory Press, 2000.

James D. Watson, famed geneticist who unraveled the secret of DNA with Francis Crick, is the author of this book, which has an introduction, afterword, and annotations by Walter B. Gratzer. Watson discusses both the moral and ethical aspects in genetic research, and reasons why genetic engineering must continue. Watson includes a chapter called ‘Growing Up in the Phage Group,’ and ‘Rules of Thumb’ for succeeding in science in this readable book.

Ward, P. Life As We Do Not Know It. New York: Viking Penguin, 2005.

A well written book for a non-virologist or non-fundamental biologist audience, summarizing the latest ideas of 'what life is.’ and especially, ‘what life could be'. Life As We Do Not Know It is an interesting read into the status of viruses.

Holmes, Frederic L., and William C. Summers. Between MolecularBiology and the Classical Gene: The Pathway of Seymour Benzer into the rII Region.

Between 1954 and 1961, biologist Seymour Benzer mapped the fine structure of the rII region of the genome of the bacterial virus known as phage T4. Drawing on Benzer's record of his experiments, this book reconstructs how the former physicist initiated his work in phage biology, and how he accomplished his investigation. Benzer’s studies have helped define the field of the history of science and medicine.

Stent, Gunther S. Bacteriophages. Boston: Little Brown, 1965.

Using reprints of research papers from various scientific journals, famed microbiologist Gunther Stent examines the history of the bacteriophage from discovery to 1965 through the original sources. The index is a Who’s Who of molecular biology. The prolific Stent also wrote other works with intriguing names such as Nazis, Women, and Molecular Biology: Memoirs of a Lucky Self-Hater, and Neurobiology of the Leech.

Douglas, John. Bacteriophages. London: Chapman and Hall, 1975.

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In his preface, Douglas promises a volume for “young readers,” and hopes his “mature readers” will “excuse the omission of cherished specialties.” While most of this short volume is not as readable as Douglas intends, his introduction is informative and interesting. His explanation of lysis is also very clear. The unique feature of this book lies in the Appendices, where Douglas gives recipes to make “media for bacteriophage studies.”

Schrödinger, Erwin. What Is Life? Cambridge: Cambridge University Press, 1944.

‘What Is Life?’ is an extremely influential book by Austrian physicist Erwin Schrödinger, published in 1944. The book was based on a course of public lectures delivered by Schrödinger in February 1943 at the Dublin Institute for Advanced Studies at Trinity College, Dublin. Francis Crick, co-discoverer of the structure of DNA, credited Schrödinger's book with presenting an early theoretical description of how the storage of genetic information would work, and acknowledged the book as a source of inspiration for his initial research.

Lewis, Sinclair. Arrowsmith. Boston: Harcourt Brace & Company, 1925.

Arrowsmith is arguably the earliest major novel to deal with the culture of science. The fictional Dr. Martin Arrowsmith, who happens to share biographical elements with bacteriologist, Félix d'Herelle, discovers the bacteriophage that destroys bacteria just as he faces an outbreak of bubonic plague on a fictional Caribbean island. Félix d'Herelle, the actual co-discoverer of the phage, is identified in the novel as having beaten Dr. Arrowsmith into publication with his results.

Arrowsmith contains considerable social comment on the state and prospects of medicine in the United States in the 1920s. Lewis was greatly assisted in its preparation by science writer Dr. Paul de Kruif, who received 25% of the royalties on sales, but Lewis is listed as sole author. Sinclair Lewis turned down the 1926 Nobel Prize for Arrowsmith,

In a letter to the Nobel Prize committee, Lewis wrote:

"I wish to acknowledge your choice of my novel Arrowsmith for the Pulitzer Prize. That prize I must refuse, and my refusal would be meaningless unless I explained the reasons. All prizes, like all titles, are dangerous. The seekers for prizes tend to labor not for inherent excellence but for alien rewards; they tend to write this, or timorously to avoid writing that, in

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order to tickle the prejudices of a haphazard committee. And the Pulitzer Prize for Novels is peculiarly objectionable because the terms of it have been constantly and grievously misrepresented.

Those terms are that the prize shall be given "for the American novel published during the year which shall best present the wholesome atmosphere of American life, and the highest standard of American manners and manhood." This phrase, if it means anything whatsoever, would appear to mean that the appraisal of the novels shall be made not according to their actual literary merit but in obedience to whatever code of Good Form may chance to be popular at the moment."

Popular Magazines and Newspapers

Smith, Deborah, and Stephen Smith. “The Enemy of My Enemy is My Friend,” The Boston Globe, 26 July 2007.

As resistance to antibiotics grows, scientists are turning to natural predators to fight infection. "It's a very old area that has been rediscovered, and what has prompted it is the rise in antibiotic resistance, for which, unfortunately, there is very little cure,” said a great-grandson of Felix d'Herelle. D’Herelle works for Special Phage Services, a Sydney company which hopes to begin testing some of its phages in people next year. Clinical trials of phages to treat different infections in patients have started in the United States, Britain, Germany and Poland. Approval was given recently in the US to use phages in food processing to kill harmful bacteria including listeria and salmonella.

Koerner, Brendan. “Return of a Killer, U.S. News & World Report, 02 November 1998.

Drug resistance in microorganisms is causing another look at the bacteriophage for use in medical treatment. This article introduces the phage, current as well as projected future use for the treatment of bacterial disease.

Technical Journals and Magazines

Rousseau, Genevieve. “Evolution of Lactococcus Lactis: Phages within a Cheese Factory.” Microbiology, 24 August 2009.

Six lactococcal phages (SL4, CR13, CB14, CR19, CB2O, and GR7) were isolated over a 9-year period from whey samples obtained from a Canadian cheese factory. Through experimentation and testing, it was found that phage

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could survive for over a year in a cheese factory. While phages are in use in many industries, phages are unwelcome in cheese factories or any other factory producing foods relying on the fermentation of bacteria process.

Tucker, Miriam E. "Rapid test flags Staph. aureus and methicillin susceptibility." Skin & Allergy News, 12 December 2008.

A single-use bacteriophage amplification test kit was able to both accurately identify Staphylococcus aureus and determine whether it was methicillin sensitive or resistant within 5 hours in a study of clinical bacteria isolates.

The findings suggest that it is possible not only to slash the diagnostic time for bacteremia--from 2-3 days to 5 hours--but also to obtain rapid results that will guide treatment and prevent overuse of broad-spectrum antibiotics. The test, made by MicroPhage Inc., uses bacteriophage amplification technology, which detects proteins produced by viruses.

"Bacteriophage from OmniLytics Approved for Use on Animal Hides as Defense Against E.coli." In Defense, 3 January 2007.

A bacteriophage to fight E.coli O157:H7 contamination manufactured by OmniLytics Inc. has received approval for use as a mist, spray or wash on live animals prior to slaughter from the USDA's Food Safety and Inspection Service (FSIS).

Research has demonstrated the need to reduce the presence of E.coli on the hide as it has been shown that a high occurrence of E.coli on the animal greatly increases the risk of occurrence on the carcass. OmniLytics also believes the bacteriophage could be used to treat holding areas, transportation vehicles, containers and living quarters.

Higgins, Kevin T. “Antimicrobial Tools: Name Your Poison: Want to Get Tough on Mold and Bacteria? An Impressive Arsenal of Microbe Killers Exists.” Food Engineering, 4 April 2008.

From “exotic newcomers” like bacteriophage to cheap and effective standbys like chlorine, food and beverage manufacturers have a growing number of arrows in their antimicrobial quivers. Bacteria and mold killers are being swabbed on surfaces, coated inside packages and sprayed on products from the time food enters the supply chain until it's plucked from a retail shelf

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Jancin, Bruce. "New Bacteriophage-Laden Cleaners Lethal to MRSA." Skin & Allergy News, 12 September 2006.

“Immobilized bacteriophages offer a novel solution to the growing problem of hospital-acquired infection with methicillin-resistant Staphylococcus aureus”, said Michael Mattey, Ph.D., at the 12th International Congress on Infectious Diseases. Bacteriophages are highly effective bacteria killers. Until recently, however, their use in medical settings has been impractical because in nature these viruses are effective only in water.

The hurdle has been overcome by a British biotech company, Blaze Venture Technologies, that has developed a stabilized bacteriophage to withstand dehydration.

"GangaGen Gains Patent for Therapeutic Bacteriophages.” Biopharm International, 19 November 2006.

GangaGen (Ottawa, Ontario, Canada, www.gangagen.com), a firm developing bacteriophage technology for treating antibiotic-resistant bacterial infections, has received a new US patent. It is for the invention of "Lysin-deficient bacteriophages having reduced immunogenicity," to be used to destroy pathenogenic bacteria. The patent is a major step in developing phages for use as systemic therapeutics in human and veterinary medicine.

Ackerman, H. “5500 Phages Examined In the Electron Microscope.” Archives of Virology, 5 February 2007.

Phages include viruses of eubacteria and archaea. At least 5568 phages have been examined in the electron microscope since the introduction of negative staining in 1959. Most virions (96%) are tailed. Only 208 phages (3.7%) are polyhedral, filamentous, or pleomorphic. Phages belong to one order, 17 families, and three “floating” groups. Of the tailed phages, 61% have long, noncontractile tails and belong to the family Siphoviridae. Convergent evolution is visible in the morphology of certain phage groups.

Vastag, B. "Phages Break Up Plaques." Science News, 9 June 2007.

Phages cut through plaques in the brains of mice engineered to develop a disease similar to Alzheimer's. That action helped the rodents recover. "Phages dissolve plaque," says Beka Solomon of Tel Aviv University in Israel. "We saw improvements in memory and smell tests of the mice.”

Solomon worked with a phage that infects Escherichia coli bacteria. It's long and thin and is naturally attracted to the flat proteins that form plaques in the brains of Alzheimer's patients. Scientists generally agree that these plaques cause the disease.

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Papers

Martinez, J.L., and F. Baquero. “Interactions Among Strategies Associated with Bacterial Infection: Pthogenicity, Epidemicity and Antibiotic Resistance.” Clinical Microbiology, 12 January 2002.

Martinez and Baquero offer a well-reasoned global and clinical view of strategies in treating bacterial infections. They include options, such as phage therapy, for the increased antibiotic resistance of many strains of bacteria.

Bamford, D.H. “Do Viruses Form Lineages Across Different Domains of Life?” Microbiology, 14 June 2003.

This is a very interesting paper discussing the viral world based on recent new sequence data and fundamental aspects, such as the idea that there is supporting evidence for a redefinition of 'life' from a cell-centered description toward a viro-centered one.

Forterre, P. “ The Origin of Viruses and Their Possible Roles in Major Evolutionary Transitions.” Virus Research, 15 May 2006.

Thoughtfully written, this paper concentrates on the different origins of viruses and their role in the emergence and evolution of life. It also examines their role in major evolutionary transitions.

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Government Resources

Kellogg, C.A., “Phage Therapy for Florida Corals?” U.S. Geological Survey Fact Sheet, 2007.

Coral disease is a major cause of reef decline in the Florida Keys. Bacterium has been defined as the most common pathogen (disease-causing organism). Although much is being done to catalog coral diseases, map their locations, determine the causes of disease, or measure the rates of coral demise, very little research has been directed toward

actually preventing or eliminating the diseases affecting coral and coral reef decline.

GenBank.

www.ncbi.nlm.nih.gov/GenbankNational Center for Biotechnology Information, Bethesda, Md.: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, United States Department. of Health and Human Services.Genetic sequence database, an annotated collection of all publicly available nucleotide (DNA and RNA) sequences and their protein translations. Laboratories around the world contribute sequence data to GenBank, and more than 100,000 organisms are represented. The overview gives current status of number of records and nucleic acid bases in the database and also instructions for submitting, revising, or updating sequence data. Maintained by NCBI, GenBank joins the DNA Databank of Japan (DDBJ) and the European Molecular Biology Laboratory (EMBL) in forming the International Nucleotide Sequence Database Collaboration (www.insdc.org), based on continual exchange of data among these organizations.

National Center for Biotechnology Information.www.ncbi.nlm.nih.govNational Center for Biotechnology Information: Rockville, Maryland.:The National Center for Biotechnology Information (NCBI) "disseminates biomedical information—all for the better understanding of molecular processes affecting human health and disease.” Its main page provides links to NCBI's molecular databases, genomic resources, and tools for data mining as well as information about the work of the NCBI that provide direct links to resources.

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The NCBI Handbook.www.ncbi.nlm.nih.gov/books

National Center for Biotechnology Information, Bethesda, Maryland. 2002. In-depth guide to NCBI bioinformatics resources, including a variety of databases and search engines. Describes both well-known (e.g., GenBank, PubMed, OMIM, and others) and also less well-known NCBI databases (e.g., the macromolecular structure databases, GEO, and many others) and gives details on how they work. Intended for biomedical researchers, health professionals, and students.

PubMed.

http://www.ncbi.nlm.nih.gov/sites

U.S. National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health: Bethesda, Mayland.

PubMed, developed and maintained by the National Center for Biotechnology Information at the National Library of Medicine, is available via the NCBI Entrez retrieval system. PubMed also provides access to the other Entrez molecular biology resources.

Audio Files

Podcast

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Scientists Engineer Viruses To Battle Bacteria.(14:00-15:00 PM)(Broadcast transcript)(Audio file)

Talk of the Nation: Science Friday (March 6, 2009)

Podcast Using 'Phage' Viruses to Help Fight Infection.(14:00-15:00 PM)(Broadcast transcript)(Audio file)(Report)

Talk of the Nation: Science Friday (April 4, 2008)

Film

“Identifying the Genetic Material,” Molecular Basis of Heredity Series. Cambridge: Ealing Corporation, 1970.

An animated film showing the Avery-McLeod experiment, which gave an early indication that DNA was the material of genetic transfer.

“Identifying the Genetic Material Part 2: Phage Experiment,” Molecular Basis of Heredity Series. Cambridge: Ealing Corporation, 1970.

Part 2 is also animated and demonstrates the famous Hersey-Chase “blender” experiment that gave further indication that DNA was the genetic material.

“Tracing the Spread of Infection.” C.O.I. Publishing, 1949.

A twenty six minute black and white film, “Tracing the Spread of Infection,” contains the only known film records of the phage typing test and the coagulose test. It demonstrates how these tests can be used to trace a strain of staphylococcus back to the source in a human carrier. The film is16 mm.

VHS

Brown, Stephen D. M., “DNA Sequencing Using M13.” The Techniques in Genetic Engineering Video Library, London: IRL Press Video, 1984.

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Partially animated, 30 minutes in length “DNA Sequencing Using M13,” shows sequencing is the key to manipulating and controlling genes, important in both industry and agriculture. Dr. Stephen Brown explains how this can be achieved using phage or plasmid DNA as a vehicle for the selection and analysis of individual fragments of the DNA of interest. The enzymatic method of sequencing is featured and the bacteriophage M13 is used as a cloning vehicle.

“Phage Genetics” Farmington: University of Connecticut, Health Center Department of Biomedical Communications,1958.

Black and white, and seven minutes long, “Phage Genetics” demonstrates experiments with eight phage mutants. It explains the process and results of phage incubation.

DVD’s

Bunting, Judith, “The Virus That Cures,” North Sydney: BBC Education, 1997.

This work explores the successful treatments of illness with phage therapy in the Republic of Georgia, a country at the center of applied phage therapy and technology. Antibiotic resistant bacteria are becoming a threat to human survival, yet mainstream pharmaceutical companies are reluctant to consider phage therapy. The phage is alive, and is, therefore, a naturally evolving medicine. There has been some interest from the West in Georgian methods of treatment, but there was no agreement over patents.

Tracey, Lindalee, Peter Raymont, and Emmanuel Laurent, “Killer Cure.” Canada: White Pine Pictures, 2006.

“Killer Cure,” is 50 minutes, color with some black and white sequences. It reveals the potentially catastrophic consequences of the reckless misuse of antibiotics, and a possible approach to “fix” the problem.

Documenting the personal journey of desperate people in search of medical miracles, this film follows patients as they chase down their last chance for a cure at a dilapidated medical lab in the Georgian capital of Tbilisi. “Killer Cure,” investigates the phage, and the attempts by Western scientists and businessmen to understand and unlock its potential in medicine. There is a commercial motivation for Westerners, contrasted with the more altruistic phage therapy in

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Georgia. Killer Cure has a soundtrack in English and Georgian, with English subtitles.

Websites

Cold Spring Harbor Laboratory: www.cshl.edu/

Cold Spring Harbor Laboratory was the location of the famous phage course given by Max Delbruck every summer, although the current lab has turned its focus to research in cancer treatment, neuroscience, plant biology, quantitative biology, bioinformatics and genetics.

Since 1933, the publication of books and other media by Cold Spring Harbor Laboratory Press has assisted the Laboratory's purpose of furthering the advance and spread of scientific knowledge. Revenue from sales of CSHL Press publications is used solely in support of research at Cold Spring Harbor Laboratory.

American Society of Microbiologists: www.asm.org

The mission of the American Society of Microbiologists is to advance the microbiological sciences and to promote the application of microbiologically related information for the improvement of human health, economic well being, environmental soundness, and national security. The ASM maintains archives from 1899 to the present.

U.S. Food and Drug Administration: www.fda.gov

The FDA has already approved a phage-based acne cream, and a phage spray to reduce bacteria on the hides of animals. What’s next? Watch this website to see.

George Eliava Institute of Bacteriophage, Microbiology and Virology: www.eliava-institute.org

George Eliava Institute of Bacteriophage, Microbiology and Virology is a research institution currently operating under authority of the Ministry of Science and Education of Georgia. The Eliava Institute works in the fields of Applied Microbiology, Virology and Infectious Immunology. The main direction of the Institute since its establishment in the early 20th century remains study of bacteriophages and phage therapy.

Publishers

While not an exclusive list, the following publishers offer many publications about the phage, its history, its many aspects, and applications:

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Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York. CSHL Press publishes monographs, technical manuals, handbooks, review volumes, conference proceedings, scholarly journals and videotapes. These examine important topics in molecular biology, genetics, development, virology, neurobiology, immunology and cancer biology.

Cambridge University Press is the publishing business of the University of Cambridge, one of the world’s leading research institutions. It is the oldest publisher and printer in the world, having been operating continuously since 1584. The University of Cambridge’s own objective of advancing learning, knowledge and research worldwide is furthered through publication and printing.

Academic Press in San Diego, California, has been a leading publisher of scientific books for more than 65 years. For scientific and medical researchers, Academic Press provides high quality scientific reference and academic content. From neuroscience to earth science, Academic Press is committed to publishing a wide variety of superior quality content from today’s leading experts.

Taylor & Francis Group is an international company originating in the United Kingdom which publishes books and academic journals. It is a division of Informa plc, a United Kingdom-based publisher and conference company. The company was founded in 1852 when William Francis joined Richard Taylor in his publishing business. The subjects covered include agriculture, chemistry, education, engineering, geography, law, mathematics, medicine, and social sciences among others. Taylor & Francis publishes more than 1,000 journals, and over 1,800 new books each year, with a backlist of over 20,000 titles.

American Society for Microbiology or ASM Press, in Washington D.C., offers a broad selection of texts, references, monographs, and general interest titles in the microbiological sciences, with archives from 1899 to the present.

Oxford University Press, Inc. (OUP USA) is linked to Oxford University Press in Oxford, England (OUP UK), which is a department of Oxford University and is the oldest and largest continuously operating university press in the world. The main offices of OUP USA are located in New York City and in Cary, North Carolina. OUP USA is a not-for-profit corporation, their mission being to publish works that further Oxford University’s objectives, including its objectives of excellence in research, scholarship, and education.

The Chemical Rubber Company or CRC Press of Boca Raton, Florida, is a publishing group that specializes in producing technical books in a wide range of subjects. While many of their books relate to engineering, science and

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mathematics, their scope also includes books on business and information technology.

Harvard University Press in Cambridge, Massachusetts (HUP) is a publishing house established on January 13, 1913 as a division of Harvard University, and focused on academic excellence in publishing.

Yale University Press, founded in 1908 in New Haven, Connecticut, publishes serious works that contribute to a global understanding of human affairs, further scholarly investigation, and advance interdisciplinary inquiry.

Caister Academic Press is a subsidiary of Horizon Scientific Press located in Norwich. U.K. Caister Academic Press is one of the leading publishers of advanced texts in virology, microbiology and molecular biology. Its publications focus on topical areas and encompass the latest scientific advances and current research. They use specialist editors and authors who are internationally renowned scientists and leaders in their fields of expertise, ensuring that their books are authoritative and up to date. Caister Academic Press books are a major resource for research scientists, graduate students and other specialists.

Bacteriophage

The subjects studied every summer duing the phage course at Cold Spring Harbor Laboratories:

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T-4 Phage and diagram

Phage Art

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The phage is all the rage, even in art:

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