When viruses help us

 kw: book reviews, nonfiction, science, virology, bacteriophages, antibiotic resistance, medicine

These barely-living creatures look to me like a balloon attached to a hypodermic syringe. They are T2 bacteriophages injecting DNA into E. coli bacteria. The common term for a bacteriophage, a virus that infects bacteria, is "phage", which means "eater". They eat bacteria.

The phage's DNA is packed into the "balloon", a protein capsule, so tightly that the pressure inside is more than 300 psi. No wonder that, once the "syringe" pierces the cell wall of the bacterium, the DNA erupts into the cellular interior. There, "shepherd" proteins that accompany it help it integrate with the cell's DNA and begin to make great numbers of copies of the phage. Once all supplies within the cell are exhausted, lytic enzymes cause the cell to rupture, releasing thousands of new phages.

To learn of phages and the breadth of their usefulness, I read The Good Virus: The Amazing Story and Forgotten Promise of the Phage by Tom Ireland. The book has two strong themes: that phages save lives in an almost miraculous way; and that political and scientific blindness have hindered the study of phages in the "free world", primarily because they were primarily developed as a therapeutic tool in the Georgian SSR and Soviet Russia. By the time scientists in the West learned of their antibacterial use, the cultural trend was "Better dead than Red."

The first viruses discovered were phages. Doctors noticed that sometimes the bacterial "lawn" growing in a Petri dish would develop "plaques"—clear, circular holes—but that nothing could be seen under the microscope, just bits of broken bacteria. Later, by filtering the liquid mix from the clear spots through a very fine porcelain filter, a "something" could be produced that killed bacteria. The term "filterable virus" was coined. Only later, when the electron microscope was invented, were phages seen and given their name.

Bacterial cells are so different from the cells of animals that phages cannot infect us. While there are 600 or so human pathogenic viruses, there are tens to hundreds of thousands of known phages (so far), many millions of phages known only from DNA screening of water and soil, and from billions to perhaps more than a trillion varieties of phages in existence worldwide. I way "varieties" because the biological understanding of "species" doesn't really fit the way viruses, and phages in particular, evolve and reproduce.

Step a little closer to home. It is rather tricky to count the cells in a human body. About 80% of "our" cells are red blood cells, so when you hear a number like 30 trillion, realize that about 24 trillion are RBC's, and the other six trillion are nucleated cells (RBC's don't have a nucleus). We have a microbiome, mainly in our gut but also across our skin, that numbers 60-100 trillion bacterial cells. Bacteria are so small that this amazing number of cells weighs, in total, a few pounds, or a kilogram or two. How about viruses? They are in the air we breathe so of course we contain some. Just counting the phages that have been found preying on bacteria within and on us, the number is about ten phage particles per bacterial cell, or roughly a quadrillion. Phages are so tiny that a quadrillion of them totals about 1/30th of a gram.

After phages were discovered more than a century ago, they were found to have antibacterial properties that could be used to cure infections. Before the discovery of effective and economical antibiotics such as Penicillin, phages were the only cure.

Side note: no medicine is perfect. Whether antibiotic or phage therapy, the dose doesn't destroy 100% of the invading bacteria. Rather, bacterial numbers are reduced to the point that our immune system has time to kill every single bacterium that remains, and then we are fully well. We need at least a minimally functioning immune system to overcome an infection, no matter what medicines we may use.

An early practitioner and proponent of phage therapy, Felix D'Herelle, called phages a "third arm of the immune system". The classical arms of the immune system ("arm" in this case meaning "weapon system") are innate immunity and adaptive immunity. The first is immediate, the second requires cellular learning, but also confers longer-lasting immunity. More recently I have read that our microbiome can be considered a preventive arm of immunity, because the good bacteria in us prevent pathogens from getting a foothold and causing disease. Thus I would call phages either a part of this third arm, or a fourth arm, destroying many pathogens once they "land".

A long section of the book tells of the Eliava Institute in Georgia (European Georgia), in Tblisi, a focus of "medical vacations" by people with multi-drug-resistant bacterial infections. For decades Eliava was the only place where a patient could have a sample taken, a phage therapy either found in the "archives" at Eliava or developed from searching in dirty water (!), and, hopefully before dying, being treated and their life saved.

Later chapters tell us of an increasing number of phage therapy centers arising. Parallel to them, recent excitement about the possibilities of phages has led to some businesses developing ways to create custom phages from scratch. This is based on work done with the ΦX174 phage: This virus was the first organism to have its DNA completely sequenced, in 1977; and a slightly simplified phage based upon it was synthesized in 2012. It was first isolated in 1935 from sewer water in Paris. That makes sense, because it infects E. coli, the famous "poop germ".

ΦX174 is one of the smallest viruses. It doesn't have the syringe like the "T" phages and some others. It is just a tiny balloon containing the DNA for 11 genes. The capsule has 12 spikes that allow it to attach to a bacterial cell.

Phages, with their simplified genomes, were first-line tools in the early days of the genetic revolution, even before the structure of DNA was discovered in 1951 by Crick and Watson. They remain useful for genetic studies.

One reason for producing synthetic phages is that the capsules of certain ones, without the DNA content, can penetrate the brain-blood barrier. If the content of such a capsule is a chemotherapy drug, and the spikes are created to attach to cancer cells, extremely targeted therapy becomes possible, in the brain or elsewhere.

That is just one use for phages that we find in the last couple of chapters of The Good Virus. The author also discusses fears of "gray goo", because viruses are actually nanotechnological machines. If a nanotech machine has the directive, "reproduce at all costs", can it spread throughout the biosphere, turning all plants, animals, and everything into a mass of nothing but themselves? Considering that nature has already developed exactly such machines, but that they are engaged in an eternal "arms race" with bacteria—which quickly learn to fight back—we realize that no gray goo scenario is imminent.

One more note: not all phages are wholly beneficial to us. This lovely image from Science Photo Library shows A45 phages attacking Streptococcus pyogenes cells. These phages carry genes that induce the cells to release fever-inducing chemicals, which cause strep throat. If the Strep that naturally exists in you is healthy, there's no problem. When the bacteria get sick, though, so do you!

An even worse case of "sick bacteria causing sick people" results when this filamentous phage known as CTXφ infects Vibrio cholerae: the deadly waterborne disease cholera. No doubt, other such cases abound.

Nonetheless, the usefulness of the great majority of bacteriophages is so great that the author optimistically hopes that they will provide a very beneficial path toward treating infections that our antibiotics are increasingly unable to cope with.

By the way, images and articles regarding phages and E. coli seem to outnumber the rest, not because that's the most common, but because E. coli are used for so many kinds of genetic studies that they dominate the literature.