Build and run hospitals that don't kill their patients – F Nightingale

 kw: book reviews, nonfiction, history, bacteriology, public health, epidemiology, antibiotic resistance

The title of this review is not quite a quote, but is the conclusion Florence Nightingale drew from her work in Istanbul during the Crimean War in the middle 1850's. The following diagram tells its own tale in the text block; please read it all:

Then pay attention to the blue wedges. Their areas, measured from the center, represent Preventable deaths, deaths of soldiers who died of infections that occurred in the hospital. The modern adjective for "doctor caused" is iatrogenic, and a near-synonym for "hospital sourced" is nosocomial. The appallingly filthy conditions in the hospital at Scutari, and the gore-drenched hands of the doctors going from patient to patient without washing, are summed up in those two adjectives. Thus it was when Florence Nightingale and her team of nurses arrived at the Scutari hospital in November 1854.

The rose diagram (Nightingale called it a "cobweb diagram") on the right shows the horrific toll from seven months before her arrival until five months afterward. Its last two months plus the other rose diagram also show the gradual reduction in overall deaths and particularly preventable deaths as her recommendations, and then demands, were instituted. The risk of dying because one had entered the hospital was reduced, month after month, and was almost eliminated after January 1856.

This and other "cobweb diagrams" proved to most medicos that there was a physical Something that carried contagion from patient to patient in unsanitary conditions, and from doctor to patient on soiled hands. In the 1850's, "germs" were unknown as agents of disease. Also in the mid-1850's, John Snow in England used black dots on street maps to demonstrate a similar fact: that a physical Something had gotten into water and spread disease. One of Dr. Snow's maps motivated the city council to disable a certain contaminated water pump, the famous Broad Street pump.

Facsimiles of that map and the rose diagrams are found in So Very Small: How Humans Discovered the Microcosmos, Defeated Germs—and May Still Lose the War Against Infectious Diseases, by Thomas Levenson. The book is a rather detailed history of the strains of knowledge that led up to the discovery by Dr. Robert Koch that specific microbes cause specific diseases, in the 1880's. This was two centuries after Leeuwenhoek first saw, and drew, and wrote about bacteria he found in scrapings from his teeth.

The author makes much, repeatedly, of the blindness of those with a theory to any evidence that overturns it. Thus "miasmas" were thought to cause diseases during those two centuries, and early-Enlightenment "cancel culture" was waged against anyone who advocated anything different. An abridged quote by Max Planck states, "Science progresses one funeral at a time." My father said it this way, "It's the Moses Method: spend forty years in the wilderness and let them all die out."

The Postulates of Robert Koch were originally developed as criteria for contagion based on studies of anthrax, cholera and tuberculosis. These and many other diseases are caused by bacteria that are visible with a microscope. That is, they are larger than about 1/5th of a micron. The common gut bacterium E. coli, for example, is in the form of rods about 3/4 micron in diameter and 2-3 microns long. Later the Koch Postulates were expanded to other organisms (including fungi) and near-organisms (such as viruses), as technology developed methods of detecting and visualizing them.

The first vaccine was developed in the 1790's by Edward Jenner. The first antibacterial drugs, primarily Salversan and the Sulfa drugs, were developed after 1910, and antibiotics were developed starting in 1929 with Penicillin. We are now about a century into the "age of antibiotics", laid on a foundation of vaccination. Public health measures such as clean (later chlorinated) water and sanitary sewers, followed by vaccinations and antibacterial drugs, have reduced infant and childhood mortality to almost negligible levels in Western countries, such that life expectancy for a newborn is now about 80 years. In a cemetery I visited when researching family history of the 1800's, half the graves were for infants and children under the age of five. Think about that.

The last section of the book deals with antibiotic resistance. Here, the author declares we are at risk of losing the war, after having won so many battles for the past century. He relates the case of a woman, diagnosed with a formerly "easy" microbe, but the strain that has infected her is fully resistant to every antibiotic the hospital has available. The doctor appeals to the CDC, which has twice as many kinds of antibiotic on hand. None of them is effective. The woman dies.

At the moment, our only defense against such "superbugs" is to continue to improve public health measures, and to more fully educate the public about risk mitigation. Alongside this there is a diatribe against the political confusion that surrounded SARS-Cov-2, the agent of the COVID-19 pandemic. The author is fully in the Fauci camp. That is unfortunate, because to my knowledge, Dr. Fauci lied so frequently and so self-contradictorily that a large proportion of "COVID" deaths must instead be attributed to governmental overreach and misapplication of treatment measures. An example is the push to provide millions of ventilators to help patients that developed pneumonia. About half died. The real misinformation was the incredible outcry against the use of Hydroxychloroquine and Ivermectin. The most damaging misinformation was, on the one side, that either of these was antiviral (they aren't), and on the other side, that they were "totally" ineffective. 

Both medicines are immune system modulators. Taken early, Hydroxychloroquine tamps down cytokine reactions, reducing or preventing pneumonia. After pneumonia begins, Ivermectin tamps down a different immune reaction, reducing the pneumonia so the body can recover. In any case, the body eventually eliminates the virus on its own, if the patient can be kept alive long enough. Ventilators all too frequently made things worse. OK, enough of that.

Where I truly fault with the author is that he never mentions phage therapy. Bacteriophages, bacterium-destroying viruses, were used before antibiotics were known, and before the viruses themselves had been seen with electron microscopes. They are agent-specific, meaning that a phage that is "tuned" to a certain strain of strep will not affect other bacteria. That is in great contrast to antibiotics that kill off most of a patient's gut microbiota, which requires some time to recover after the patient recovers from the disease. Many doctors I have read claim that more research into phage therapy can make most antibiotics unnecessary, even as they are already obsolete.

To end on a side note (not in the book): The title So Very Small got me thinking. I suspect not many folks really appreciate how small microbes are. This illustration from The Visual Capitalist will help:

Human hair diameter depends on hair color. Blond hair is the thinnest, 50-70 microns, and black hair like that of my Asian wife is the thickest, 150-180 microns. A micron is a 25,000th of an inch. The first thing you could call a microbe in this illustration is the "bacterium", the little blue comma near lower left. The comma shape indicates that the organism is probably the Cholera bacterium. It is the largest item shown that is larger than one micron. Viruses of COVID-19 and of most strains of influenza are about two tenths of a micron in diameter, or about one-tenth the size of the bacterium shown; the illustration shows the virus as much too large. Other viruses of other shapes range widely in size, but are almost all smaller—usually a lot smaller—than one micron. A bacteriophage is shown, appearing 2-4 times as large as it should, compared to the illustration of the bacterium it attacks.

Small things don't always have small effects. In the case of disease-causing bacteria and viruses, they really can have effects bigger than we may know what to do about!

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.