“We live in a dancing matrix of viruses; they dart, rather like bees, from organism to organism, from plant to insect to mammal to me and back again, and into the sea, tugging along pieces of this genome, strings of genes from that, transplanting grafts of DNA, passing around heredity as though at a great party.” Lewis Thomas
Anyone who knows me will tell you, I tend to think in terms of lists—lists along alphabetical lines. This week, I’ve been thinking a lot about “a” words. And I’ve also been ruminating about viruses, but not our enemies like SARS-CoV-2, the cause of COVID-19 and so much anguish, but, rather, about the vast majority of viruses that are either harmless or beneficial. This post is devoted to this latter group of viruses that I find astronomical, astounding, and amazing. And that quite frankly we can’t live without.
Astronomical and Astounding. Evolutionary biologists think that bacteria were the first life form to emerge, an estimated 3.6 billion years ago. Viruses appeared at about the same time. And the two have been co-evolving ever since.
Viruses are, however, the tiniest creatures on Earth. There are more than a quadrillion quadrillion viruses, or 10 to the 31st power—that’s 10 with 31 zeroes (32 nonillion). That is more than the stars in our universe. And viruses are found everywhere that you find bacteria.
At a species level, viruses outnumber bacteria 10 to 1 (100 million species of viruses versus 10 million species of bacteria on our planet). (Compare that with the paltry number of mammalian species—5,416, of which Homo sapiens is one.) And, approximately 8% of the human genome is comprised of endogenous retroviruses, which are viral gene sequences that have become a permanent part of the human lineage after they infected our ancient ancestors. Yet, it is estimated that only a trivial number of viral species (128) are human pathogens, ones that make us sick.
Most viruses are called bacteriophages—or bacteria eaters (derived from “bacterio” and the ancient Greek word “phagein”, meaning “to eat”). Bacteriophages don’t actually eat bacteria, but like all viruses they commandeer cells of the host, in this case bacterial cells, where they multiply, are released into the environment, and taken up by other bacterial cells. In the process they kill their host. They were discovered and named by the French microbiologist Felix d’Herelle in 1917. But, these viruses, also referred to simply as phages, have been busy culling out bacteria and archaea (members of another domain of life called Archaea) since time immemorial. They are enormously helpful to human beings as they wreak havoc on bacterial pathogens, and hence are the enemies of our enemies.
Bacteriophages are particularly abundant in seawater, where they far outnumber every other biological entity. For example, a liter of seawater collected from marine surface waters typically contains at least ten billion bacteria and one hundred billion viruses—the vast majority of which remain uncharacterized. According to some estimates, phages destroy up to 40 percent of the bacteria in Earth’s oceans each day. In doing so, bacteriophages may influence the oceans’, and perhaps the entire world’s food supply by limiting the number of bacteria available for other organisms to eat.
These bacteriophages are also considered drivers of global biogeochemical cycles of carbon, nitrogen, sulfur, and oxygen. Along with unicellular eukaryotes—plankton and algae—they play an enormous role in shaping the Earth’s atmosphere and in sustaining marine food webs. Bacteriophages are also indirectly responsible for limiting global warming. They reduce the amount of carbon dioxide in the atmosphere by about three billion tons per year.
Amazing—Phage therapy. Any one type of phage infects only very specific bacteria. This phenomenal precision makes phages highly attractive as therapeutic agents because they take down certain bacterial enemies while leaving our bacterial friends intact. In contrast, antibiotics inhibit or kill trillions of bacteria of all types—our enemies, as well as our friends.
In the 1920s and 1930s, physicians were using phages to treat a variety of bacterial infections. But once antibiotics hit the market—sulfonamide in 1935, penicillin in 1942—interest in phages as antibacterial agents almost disappeared, the exceptions being the then Soviet Union and Eastern Europe. (The Eliava Institute in Tbilsi, Georgia founded by George Eliava in 1923, remains the epicenter of phage therapy today.) Because of massive overuse of antibiotics, many bacteria are now resistant to their effects, and alternative treatments are in growing demand worldwide.
In fact, many infectious disease experts believe that the single biggest microbial threat to humans are infections caused by bacteria that have become resistant to most, if not all, currently available antibiotics. In a recent report from the United Nations Interagency Coordination Group, a panel of global experts formed to provide guidance and ensure sustained global action on antimicrobial resistance, it was estimated that global deaths from drug-resistant bacterial infections could rise from the current estimate of 700,000 a year to 10 million a year by 2050, and that the economic impact could be similar to the 2008 global financial crisis.
But the good news is that many bacteria that cannot be killed by antibiotics are vulnerable to attack from phages. (To avert the problem of bacteria becoming resistant to phages during treatment, cocktails of multiple types of phages are often formulated. This strategy is reminiscent of the administration of a combination of antibiotics to treat bacterial infections, such as tuberculosis.)
The first studies of phage therapy in humans that met United States Food and Drug Administration (FDA) standards have now been completed. So far, the results have been promising. Phages have successfully treated: diarrhea; infected ulcers associated with leg veins; and chronic otitis externa, a bacterial ear infection that is notoriously difficult to cure. Properly controlled clinical trials have also been carried out, or are in the planning stage, for the treatment of burn wounds and diabetic foot infections.
In 2015, the European Medicines Agency and the National Institutes of Health (NIH) hosted workshops on the therapeutic use of bacteriophages. That same year, the NIH’s National Institute of Allergy and Infectious Diseases announced that phage therapy was one of seven prongs in its plans to combat antibiotic resistance.
Anecdotal reports continue to surface of what appear to be miraculous cures of patients with life-threating infections caused by antibiotic-resistant bacteria. One such recent case, published in 2017 in the journal Antimicrobial Agents and Chemotherapy, describes a 68-year-old diabetic patient with an overwhelming infection caused by Acinetobacter baumannii, which was resistant to all antibiotics. Out of desperation, Dr. Robert Schooley, head of the Infectious Diseases Division at the University of California San Diego (UCSD), enlisted the help of bacteriophage experts, who tailored a cocktail of phages that were active against this bacterium. The phages were administered intravenously—a first. And they saved the patient’s life. This remarkable anecdotal case, coupled with a number of similar cases seen elsewhere, spurred UCSD to launch a clinical center in 2018 to refine phage treatments and help companies bring them to market.
Perhaps the most promising role of phages in human health involves the things we eat. In 2006, the FDA and US Department of Agriculture approved several phage products for the treatment of foods. Intralytix is a company that markets two products for the prevention of foodborne infections: ListShield, a phage cocktail that is sprayed on food to kill Listeria monocytogenes; and EcoShield, phages that are sprayed on red meat before grinding it into hamburger, to kill E. coli. A third product, SalmoFresh, targets Salmonella in poultry and other foods; it is currently awaiting FDA approval.
Given the monumental problem of the emergence of antibiotic resistance, it isn’t surprising to see that phage therapy is undergoing a renaissance. With appropriate support from the pharmaceutical industry, this strategy—fighting fire (bacteria) with fire (viruses)—is one promising solution to the challenge. And it serves as a reminder for us to thank our lucky stars for the great ingenuity not only of members of our species but also of the tiniest creatures in the microbial world—viruses.
