Bernard Dixon

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Progeny of the Phage School

Frederick Twort, the eccentric polymath who discovered bacterial viruses, would have robustly welcomed the applications of bacteriophages now emerging, from therapeutics to environmental protection

Bernard Dixon

Nearing 70 but determined not to retire, the discoverer of bacteriophage, Frederick Twort, applied for eight different scientific posts. His potential employers ranged from the London Water Board to a company developing new treatments for bacterial infections. All rejected the distinguished but testy man whose work on phages was to prove pivotal in the development of molecular biology.

Just over half a century later, Twort would have been delighted to know that his bacterial viruses are beginning to find uses ranging from the treatment of disease to the tracing of water pollution. At least two such applications are based on genetic modification and thus stem directly from the work of the "phage school"—Max Delbrück and other pioneer molecular biologists in the 1940s.

The first of these innovations, developed at the Medical College of South Carolina in Charleston, has the potential to become a peculiarly potent weapon to attack pathogens. The second, engineered at the University of Lancaster in Britain, promises to be a much more discriminating tool for identifying sources of pollution than those used hitherto.

There's an odd disparity about the recent and otherwise excellent biographies of Frederick Twort and Felix d'Herelle, the French-Canadian whose 1917 "discovery" of bacteriophage two years after Twort helped to rescue the Englishman from obscurity. Antony Twort's In Focus, Out of Step (Alan Sutton, 1993) is a lovely portrait of an eccentric polymath who made violins, was a highly skilled amateur radio constructor, designed a more efficient internal combustion engine, and tried to breed the biggest sweet pea in England for a newspaper competition. Despite being an experienced microbiologist, he threw meat and vegetables each day into a large cooking pot of stew which he kept continually on the hob.

Twort's biography of his father surprisingly neglects the part played by phages in the emergence of molecular biology. It does not even mention the classic experiment in which Alfred Hershey and Martha Chase labelled phage protein and nucleic acid and showed that it was the latter which entered bacteria when they were infected.

Frederick Twort was a brilliant but eccentric man, who for much of his career, engaged in splenetic and often unreasonable conflicts with Britain's Medical Research Council (MRC). His grievances were perhaps heightened by his relative isolation as superintendent of the Brown Institution in London. Founded on the legacy of a rich Dubliner, the purpose of this unique center was to look after sick animals at little or no cost and to conduct research into animal diseases. In the 70 years between its foundation and World War II, when one of Hitler's bombs brought its work to an end, at least a quarter of a million dogs, cats, horses, and other animals were treated there.

But as superintendent, Twort never had sufficient money or staff to work as he wished. Although the MRC helped over many years, Twort's gratitude was eclipsed by the anger he felt when those funds were later reduced following less than satisfactory reports on his research.

Much of this work—not only the discovery of bacteriophages but also the first cultivation of Johne's bacillus and the discovery of the accessory food factor later known as vitamin K—had been of undoubted practical importance. But there was little enthusiasm for his speculations on viruses as the most primitive forms in evolution, and his suggestions that he had cultivated them in the absence of living cells.

Although he made no steps in developing the therapeutic potential of phages, Twort would be pleased today to see that this approach is now firmly on the agenda. This follows many decades when the idea was strangely neglected, though with two notable exceptions during the 1980s.

The first was work conducted by Wille Smith and colleagues at the Houghton Poultry Research Station in Britain. They demonstrated that bacteriophages could control diarrhea caused by enteropathogenic Escherichia coli in calves, piglets, and lambs.

The second exception was clinical work in Wroclaw, Poland. There, phage therapy proved successful in dealing with severe, suppurative wound infections that had failed to respond to any other therapy. Perhaps because these findings were published in peripheral journals, they failed to attract much interest in the West. Recent years, however, have seen a minor explosion in therapeutic phage studies, reflecting the pressing need to develop alternatives to antibiotics because of the burgeoning problem of resistance. A major landmark was the paper by Carl Merril and colleagues at the U.S. National Institutes of Health and Exponential Biotherapies in New York, in the Proceedings of the National Academy of Sciences (93:3189, 1996).

They used bacteriophages selected by serial passage for their capacity to avoid elimination from the body for a much longer period of time than wild-type viruses—an important advance in overcoming a previous obstacle to effective phage therapy. Used to treat potentially fatal infections in mice, the phages were highly effective against both enteropathogenic E. coli and Salmonella typhimurium.

ASM's 2000 Annual Meeting marked further advances. One was made by Paul Gulig and coworkers at the University of Florida, Gainesville. They used a particular phage to combat infection with Vibrio vulnificus, which can cause a devastating human infection, in vulnerable mice. This development illustrated another likely advantage of phage therapy—its specificity, and thus freedom from the dangers that can arise when antibiotics knock out the body's natural flora.

That potential was underlined in a presentation at this year's ASM General Meeting by David Schofield and a team from the Medical College of South Carolina. They have genetically modified a phage to code for a bactericidal protein which will then be produced by the target bacterium—a Trojan horse containing the instructions for mass suicide.

Recombinant phages may also prove to be exceptionally valuable as biotracers to introduce into suspected sources of water pollution in order to monitor their spread. Richard Smith and colleagues at Lancaster University have created a library in which each M13mp18 phage genome contains a unique identification sequence (J. Appl. Microbiol.88:860, 2000). Restriction site polymorphism and other methods are used to identify the phages in water.

This strategy overcomes the two limitations of the small number of phages currently used for this purpose. These are the difficulty of distinguishing them from organisms present naturally (ammunition for defense lawyers in legal cases) and the impossibility of testing several possible pollution sources simultaneously. The Lancaster technique, field tested at an abandoned oil refinery, appears to be a major advance.

The only query regarding the timely exploitation of this new tool for environmental protection is not technical but social. In a world that has recently seen vigorous though irrational opposition towards genetic modification, is the deliberate introduction of recombinant phages into rivers and other water systems likely to be publicly acceptable? The same question might be asked regarding therapeutic applications of modified phages.

There's little doubt what Frederick Twort's answer would have been. A believer in "science and efficiency," he demanded that research be unfettered and directed solely by scientists, and insisted that "experts in each branch must teach, advise, control and appoint." Even in mid-20th century, such sentiments appeared somewhat reactionary. Have we now gone too far in the opposite direction?