TRAFFIC: Carl Zimmer and Timothy Lu

May 20, 2011

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Welcome back to TRAFFIC, a Chicago Blog series featuring leading figures from across the humanities and sciences, whose prescient views on current events help us to interpret contemporary culture. We’re delighted to continue this month’s Friday TRAFFIC features, led by popular science writer Carl Zimmer. This week Zimmer welcomes MIT scientist Timothy Lu to talk about the quest to use viruses to cure infectious diseases.
Timothy Lu is assistant professor of electrical engineering at MIT, where he heads the Synthetic Biology Group. Carl wrote a profile of Lu last year in Technology Review.

All About Phage Therapy

Dear Carl:
Bacteriophages are the most abundant biological particles on earth, but due to their size, and perhaps ubiquity, most of us don’t think of them very often. Phages are essentially just bacterial viruses. When it comes to viruses, the popular notion is that they are bad entities that are responsible for disease and suffering. The truth is, however, that phages are very different from human viruses. Phages do not infect human cells and are not responsible for the viral diseases that plague mankind, such as AIDS, herpes, cervical cancer, and the common cold. Furthermore, phages have had a tremendous impact on modern biology and biotechnology.
Much of our early scientific efforts to understand genetic regulation were carried out in the humble phage. Phage proteins called recombinases are an integral component for the construction of “knockout animals,” which cannot express particular genes—an indispensable tool in modern biological research. Phage display, a technique for sticking a library of peptides on phage surfaces and panning for targets to which these peptides will bind, has been used to make nanowires for batteries, identify new antibodies to treat human diseases, and understand the basic science which underlie protein-protein interactions.
Despite their importance as major research tools in the biomedical community, however, research into the use of phages as human therapeutics has garnered a mixed reputation in the Western world. Soon after their discovery in the early twentieth century, phages were tried as novel antimicrobial agents. Indeed, one can imagine the excitement that the early phage researchers must have experienced when observing the lysis—or clearing of bacterial cultures—by the addition of a newly discovered biological agent!

a bacteriophage

However, early reports claiming impressive successes at treating bacterial infections with phages were later tempered by failures in other settings and repeated trials.
Looking back, it is likely that a lack of detailed understanding of phage biology was responsible for much of these failures. Unlike antibiotics, which act like broad-spectrum bombs that blast all bacteria, good or bad, in their paths, phages are targeted warriors, the biological equivalent of a sniper or laser-guided missile. This targeted behavior is beneficial because it avoids killing bacteria which are good for us, as opposed to antibiotics which cause collateral damage. However, this targeted behavior also has its flaws because to effectively treat a specific bacterial contamination with phages, one must understand the bacterial compositions in detail and know what mixture of phages to use against them. Such capabilities were not available or known during the early days of phage therapy.
Thus, the subsequent discovery of antibiotics, along with their simplicity and miracle successes, largely displaced phages from antimicrobial research in Western medicine in the latter half of the twentieth century. As a result, the notion of phage therapy often elicits justifiable skepticism when discussed as an alternative to antibiotics today, even though the antibiotics pipeline has dried up and we are in desperate need of new strategies to combat the rising tide of antibiotic-resistant superbugs.
Fortunately, in the past few decades, there has been a renaissance brewing in the phage world. Commercial, government, and academic labs have begun to tackle the fundamental issues that have held back phage therapy using rigorous molecular tools. To use phages to effectively treat bacterial contaminations, these labs have been developing technologies for classifying bacterial populations, identifying the right combination of phages to use, and optimizing phage properties using evolutionary or engineering approaches.
Instead of tackling the high hurdles that need to be crossed for direct human use, many labs and companies have chosen to apply phages to other applications in industrial, environmental, and diagnostic settings. For example, Intralytix makes phages to treat listeria contaminations of food, Omnilytix makes phages that control bacterial infections on tomatoes and peppers, and Microphage makes phages that can detect and report on the presence of harmful antibiotic-resistant superbugs, such as MRSA. A company called Novophage is advancing the use of phages for industrial applications, where they have the potential to enhance energy inefficiency and decrease biofouling (for full disclosure, I am a founder of this startup). Major advantages of phages compared with chemical biocides and pesticides include greater biocompatibility and decreased environmental toxicity. Using natural biological particles to combat biological problems is consistent with our society’s continuous drive to reduce the use of harmful chemicals and is, I believe, a great application for phages in the modern era of biotechnology.
The hurdle that has yet to be overcome is the use of phages for human therapeutics, the original application area for phage therapy. Nonetheless, given the great need for new antimicrobial therapies and the inroads that these laboratories have been making into optimizing phages for practical applications, the prospect of effective phage therapy being applied to human infectious diseases in Western medicine seems to be growing!

Dear Tim:
In all my work as a science writer, I can’t think of a story as strange as the history of phage therapy. It’s been nearly a century since the Canadian physician Felix d’Herelle discovered viruses that infect bacteria. And yet, despite great promise, phage therapy has yet to become a mainstay of medicine.
What makes the story even stranger is that Herelle could see the promise of phage therapy as soon as he discovered the viruses. He was soon using them to treat dysentery and cholera. When four passengers on a French ship in the Suez Canal came down with bubonic plague, Herelle gave them phages. All four victims recovered. He went on to conduct large-scale public health campaigns for the British government in colonial India. Phage therapy became so well-known that Herelle inspired the central character in Sinclair Lewis’s 1925 best-selling novel Arrowsmith. Phage therapy became big business: Herelle developed commercial drugs that were sold by the company that’s now known as L’Oreal, which were used to treat skin wounds and to cure intestinal infections.

Felix d’Herelle

But by the time he died in 1949, Herelle had sunk into obscurity. Doctors had abandoned phage therapy for antibiotics. His dream did not vanish entirely, however. On his travels, Herelle met Soviet scientists who wanted to set up an entire institute for research on phage therapy. In 1923 Herelle helped establish the Eliava Institute of Bacteriophage, Microbiology, and Virology in Tbilisi, which is now the capital of the Republic of Georgia. At its peak, the institute employed 1200 people to produce tons of phages. In World War II, the Soviet Union shipped phage powders and pills to the front lines, where they were dispensed to infected soldiers.
Soviet scientists continued to investigate phage therapy after World War II. They conducted the best trial of the viruses in 1963. They enrolled 30,769 children in Tbilisi. Once a week, about half the children swallowed a pill that contained phages against dysentery. The other half of the children got a pill made of sugar. To minimize the influence of the environment as much as possible, the Eliava scientists gave the phage pill only to children who lived on one side of each street, and the sugar pill to the children who lived on the other side. The Eliava scientists followed the children for 109 days. Among the children who took the sugar pill, 6.7 out of every 1,000 got dysentery. Among the children who took the phage pill, that figure dropped to 1.8 per 1,000. In other words, taking phages caused a 3.8-fold decrease in a child’s chance of getting dysentery.
Phage therapy only began to attract interest in the West after the fall of the Soviet Union, when Soviet scientists could communicate more freely with the rest of the world. And yet, as you point out, the U.S. government has been leery of approving viruses for medical treatments. Gone are the days when a physician like Herelle could pretty much do as he pleased. As a result, many companies and investors are reluctant to embrace his phages.
If phage therapy can leap over these hurdles, I think that there are a vast number of potential applications. Treating a skin infection is just the start. Phages, after all, are part and parcel of every person’s inner ecology. Our bodies are home to 100 trillion bacteria and other microbes. Recent surveys estimate that these microbes play host to about four trillion phages, which come in about 1,500 different species. In some cases, our phages kill their hosts, and thus maintain an ecological balance in our mouths, noses, guts, and other nooks and crannies. In other cases, phages insert genes into their microbial hosts, giving them new powers.
The human microbiome is not merely an infestation we tolerate. It plays many different roles in our bodies. Microbes synthesize vitamins for us, regulate how much energy we get from our food, fight off invading pathogens, nurture our immune system, and potentially even influence our behavior. It may be possible to manipulate the microbiome through the phages that have coevolved with it for millions of years.

Stay tuned for next Friday’s installment of TRAFFIC, featuring a conversation between Zimmer and Sallie Chisholm on the nature of ocean viruses. And for more info on A Planet of Viruses, please visit the book’s UCP page here.
This blog and the book A Planet of Viruses are part of the World of Viruses project, funded by the National Center for Research Resources at the National Institutes of Health through the Science Education Partnership Award (SEPA), Grant No. R25 RR024267. Additional materials, including those directed at a K-12 audience, can be found on the World of Viruses website.

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