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Introduction

A SCANDALOUSLY SHORT HISTORY

Microbiome! Who, these days, hasn't heard about "the microbiome"? From TV pitches to "support gut health" to complex explanations in high-end magazines about new understanding of the myriad human-microbe interactions, some apparently essential for our existence as living, breathing organisms. For those of us of a certain age, microbes, aka "germs" were mainly to be casually washed away a few times a day from our grubby little hands before meals and after using the bathroom. How did "microbes" become a central concern in modern life, and what is the history of this recent interest? This question is the theme of this book.

Microbes (a name coined by a French surgeon in the latter part of the nineteenth century) by their nature are not visible to the naked eye, so they were unknown until the mid-seventeenth century when high-powered glass lenses were employed to magnify these tiny objects. The microscope was simply a handy magnifying glass arranged to look at things up-close (1). An amateur scientist from Delft, in the Dutch Republic (at that time science was done by amateurs with regular day jobs because there was no such career path as "scientist.") became very skilled at making lenses and microscopes and recorded his many observations over a period of a half-century (1676-1723). The various objects that Antonie van Leeuwenhoek (1632-1723) observed, he called "little animals" (animalcules) because he viewed them as simply tiny versions of the known animals of common experience.

Leeuwenhoek's work became widely known and appreciated, but it took over a century for others to understand just where these animalcules fit into the schemes of life that were being formulated, and what they might be doing in the many environments where they were found. The 19th century was a time of intense expansion in scientific knowledge in many fields; new theories of chemistry, new technologies, new philosophies of nature, and new questions fueled this expansion. The stories of the germ theories of disease and the debates over the living nature of microbes as the agents of fermentation and related everyday processes are by now almost folk tales.

The heroic figures of Louis Pasteur (1822-1895) and Robert Koch (1843-1910) as discoverers of microbes as the causes of many here-to-fore mysterious diseases of both humans and other animals paved the way for the "microbe hunters" of the twentieth century. In the early years of that century, medical scientists (by now "scientist" had become a legitimate job description) sought microbial causes for every known malady, from cancer to mental disorders to heart disease and strokes. These hunters of microbes were remarkably successful. Many serious diseases of humankind turned out to be caused by microbes: tuberculosis, pneumonia, typhoid, cholera, polio, influenza. the list goes on and on (2).

Not only were microbes important in causing diseases, it was found that the animal body had a mechanism to deal with these invading microbes: the immune system. For many diseases, the body could react, over time, and develop powerful defenses against a later infection with the same or a related microbe. In a way, the body learned from its first encounter. The way this immunological learning works has taken nearly a century to unravel. But even before this process was completely understood, the phenomenon of immunity was quickly exploited to devise preventative measures. A deliberate infection (under mild conditions, it was hoped) could be used to induce this immunological protection against later, more dangerous, natural infections. Historically, smallpox was the human scourge most widely prevented by this inoculation procedure. Later, in 1796 Edward Jenner (1749-1823) introduced a novel variation on smallpox inoculation when he recognized that a related but benign infection with material from animals with cowpox induced immunity to smallpox just as well as a mild case of smallpox itself. This kind of immunization became known as "vaccination," a name derived from vacca, Latin for a cow.

In addition to the development of immunizations against many microbes, from the early years of the twentieth century the pharmaceutical chemists were developing drugs to suppress microbial diseases. Some of these drugs were quite successful. One such drug made from arsenic and called Salvarsan became the first really useful treatment for the dreaded syphilis. The real "breakthrough" and the real start of this account came in the mid-decades of the twentieth century with the discovery of several drugs with broad use against many different microbes, drugs such as the sulfa drugs. These drugs were based on the known metabolic reactions shared by many microbes but not their animal hosts. But the main event turned out to be the recognition that various microbes compete with each other in the environment and have evolved toxins to destroy their competitors. In 1928, famously, Alexander Fleming (1881-1955) in London observed a case of this microbial antagonism on some of his accidentally contaminated culture plates of bacteria that had been invaded by a mold. The mold, Penicillium notatum (now called P. chrysogenum), a common bread mold, produced a soluble substance, a chemical that Fleming partially isolated and showed would inhibit the growth of certain disease-causing bacteria. He named this substance penicillin. Because it was from a biological source, the mold, and because it was useful to inhibit other organisms, penicillin became known as an "antibiotic" to be distinguished from the antimicrobial agents produced in the lab by chemists (3). For various technical reasons, it took nearly15 years to produce and purify enough penicillin to show that it was clinically useful to treat microbial infections. Fleming's discovery, expanded on by others, about microbial antagonism led the former microbe hunters to become antibiotic hunters. Many new and useful antibiotics were discovered, tested, and brought into routine clinical use. There was hardly an infection known to medicine for which a useful antibiotic could not be found. Thus begins our story.

MICROBIAL HUBRIS

What microbes do we know about, and, how do we know them? Two problems confronted the early microbe hunters: what methods are available to hunt microbes, and how should we classify, describe, and catalog our quarry. The first question is primarily one of laboratory technology, the second is practical as well as philosophical.

The microbiologists of the nineteenth century employed several basic techniques: inoculation of suspect material into various experimental animals, usually guinea pigs or mice and the watch for changes in health, appearance, or behavior. The affected animal was then dissected to look for both macroscopic and microscopic traces of the suspect microbes. A more focused method was to smear suspect material on a surface of some substance that was both free of known microbes, i.e., was "sterile" and was believed to support the growth of a microbe if it was present. These sterile culture surfaces were sometimes gelatin or agar surfaces that had been sterilized in an oven, or sometimes just the cut surface of a potato. The gelatin or agar was supplemented with sugars, meat broth, or other "nutrients" that the microbe hunter believed (or guessed) was needed by the microbe to grow and flourish on the surface. If the conditions were right, a microbe that landed on the surface and started to grow would eventually form a visible "colony" of all the millions progeny of the original microbe, a colony of identical descendants, a so-called pure culture. Some of these microbes could then be observed under the microscope, tested in other ways, and eventually characterized and identified as either a known type or as a new, unknown, isolate. For a long time, basically up until the molecular revolutions of the 1970s, the main way microbes were described and characterized was by their size, shape, and appearance of their colonies, as well as their chemical properties as identified by their staining with various dyes, their growth or non-growth on culture media of varying nutritional composition, or by their reaction with known antibodies (the molecules of the immune system that had been stimulated by specific known microbes to produce these identifying tools). With these rather simple and universally available technologies, the microbe hunters could be reasonably confident that microbes found in nature in one part of the world or by one laboratory could be compared with microbes found elsewhere.

With descriptions and characterizations of microbes in hand, the microbe hunters had to decide how to organize their collection. In the very early days in the nineteenth century, they relied on microscopic size and shape plus visible appearances of the colonies on various culture setups. As chemical and cultural technologies advanced and the relationship between the conventional classifications of Carl Linnaeus (1707-1778) and the evolutionary principles of Charles Darwin (1809-1882) were recognized, new microbial taxonomic systems developed. By about 1920, consensus was developing around certain principles, and several groups of microbiologists came together to produce what very soon became the standard authority on bacterial classification (viruses and...