It was 1980, and Styx was playing at the Cow Palace in Oakland. We took the BART from San Jose (or rather Fremont, near where we lived) and anticipated little bathroom access at the arena so the tampons offered a big “convenience” to her instead of waiting in the predictably long lines at the women’s restroom. It was the first time she had used Rely, and the tampon worked amazingly well. But, she said, “I remember removing that Rely tampon after getting home late at night and wondering whether I had lost my virginity, that thing had gotten so huge. I stopped using them after that because of being too grossed out.”67
Shortly thereafter, epidemiologists throughout the United States noted increased occurrence of women with high fever, hypotension, and extreme fatigue. Other odd symptoms included the loss of skin on the palms of the hands and the soles of the feet. These symptoms rapidly progressed into coma, organ failure, and death within days.
In the closing days of 1979, CDC investigators were inundated with cases of a new disease, later named toxic shock syndrome, whose victims were primarily women. The cases could be tied to one another by the presence of a common bacterium, Staphylococcus aureus.68 This particular bacterium is broadly found in the environment and resident on the body, as experienced by anyone who has had acne or minor food poisoning. Most Americans suffer minor food poisoning at least once a year, usually manifesting itself as a queasy stomach or light diarrhea. However, the extent and severity of Staph-based toxic shock in the late 1970s outbreak initially stymied CDC investigators. Within three months, strong detective work revealed a link with the use of tampons in general and the Rely brand in particular. Working backwards, we now know the powerful moisture absorbency of carboxymethylcellulose had unintentionally dried the normally moist environment of the vaginal cavity. The sudden drying of these tissues created small ulcerations in the normal microflora and thereby provided a foothold for foreign pathogens such as Staph. aureus to take hold. Compounding the problem, the increased viscosity of the fluids remaining in the parched environment conveyed advantageous growth conditions for the invading microorganisms. As the degree of infection increased, the woman’s body sensed the foreign interlopers, and endotoxins present within the Staph bacterial membranes triggered host defenses to perceive a massive infection with bacteria. In response, these immune cells overreacted and caused blood vessels to leak, decreasing blood pressure and the ability to succor vital organs. In this complex but fundamentally primitive manner, the seemingly innovative and innocent idea of creating a more absorbent tampon unintentionally caused a devastating response.
Friend and Foe
The examples of Staphylococcal and botulinum infections may seem to portray bacteria as dire threats. However, this would unintentionally convey an oversimplified view of human interactions with bacteria. A more nuanced exposition must convey that our species, like many others, has developed an intricate relationship with microorganisms that conveys extraordinary benefits. A failure to recognize the complexity of these interactions could be shortsighted and disastrous. The recognition that humans, animals, plants, and even microorganisms work together in a larger ecosystem parallels the discovery of the microbial world itself.
An early pioneer in the field was the French microbiologist and ecologist Rene Dubos, who has been given credit by some for the well-known saying “Think globally, act locally.”69 (This saying was attributed to Dubos during a 1972 United Nations Conference on the Environment but has also been credited to the American ecologist David Ross Brower, who might have used it as a 1969 slogan for the Friends of the Earth, a nonprofit he founded.70 Additionally, it has been attributed to the architect and designer R. Buckminster Fuller.71 All these contenders might have been eclipsed a half century earlier by the Scottish biologist Patrick Geddes, who alluded to its use in 1915.72 Regardless of its unclear parentage, this statement is quite prescient not only in reference to the environment (think water pollution or climate change) but also in reference to the microenvironment that exists everywhere we look. This sentiment was championed by Rene Dubos, whose range of thinking spanned from the very small (he was trained as a microbiologist) to the very large (he championed the causes of global environmentalism). Dubos trained in microbiology with the Canadian-American scientist Oswald Avery, who would later discover DNA and is widely regarded as the most deserving scientist never to receive the Nobel Prize. While studying the myriad bacteria and fungi in dirt, Dubos discovered a set of compounds that could kill other bacteria.73 Some of this research led to the discovery of the antibiotic streptomycin. Dubos and Selman Abraham Waksman were awarded the 1948 Lasker Prize, the highest American scientific honor for the discovery of this key antibiotic (Waksman later received the 1952 Nobel Prize for the work).
An even more impactful outcome of these studies was the recognition that bacteria such as Streptomyces (from which the antibiotic was discovered) produce antibiotics to thwart the growth of other organisms in the environment. Dubos realized that the same dynamics that occurred in soil samples also occur throughout the body’s surfaces, including the skin, mouth, nose, throat, and lining of the gastrointestinal system. Another prescient view was that the study of individual bacteria was insufficient to model the extraordinary dynamics among the different species. Consistent with this, surprisingly few bacteria within any given specimen (be it a soil sample or cheek swab) can be cultured and studied in the laboratory due in part to the fact that biology unforgivably defaults to a complexity that is largely beyond our ability to grasp. For example, some organisms may become so reliant upon interactions with others that their isolation disrupts their normal functioning or is irreversibly lethal.
Virtually every square micrometer of our body that interacts with the external world is host to a teeming scaffold of diverse species. Although the numbers can vary, the latest estimates from investigators at the Weizmann Institute indicate that an average 150-pound person is composed of forty trillion bacterial cells and thirty trillion human cells.74 The complexity of the cohabitation is evidenced by the fact that the mouth alone serves as host to hundreds, if not thousands, of different bacterial species but the different parts of the mouth (e.g., the tongue, tonsils, soft palate, and saliva) each plays host to a different density and identity of microorganisms. Altogether, the combination of humans and their microbiome brethren has elicited a new category called “superorganism.”75
These bacteria are not just passengers along for a ride. As we learn more about these coinhabitants, we appreciate their necessary contributions to an ever-increasing number of key functions needed for everyday human life. For starters, the act of recruiting benign microorganisms, particularly those that bring along their own defensive strategies as described above, provides a first line of defense against some of their more nefarious toxin-wielding or flesh-eating cousins. Alterations in the microbiome have been associated with a variety of diseases.76 For example, a strong course of antibiotics can devastate the normal flora of the gut, rendering a person susceptible to particularly aggressive and deadly bacteria such as Clostridium difficile. Beyond this, the bacteria lining our gut, of which more than one thousand different species have been identified, contribute to our ability to digest certain sugars, synthesize essential vitamins, and regulate the metabolism.77 Unsurprisingly, a poorly functioning microbiome is also associated with a variety of diseases of the digestive tract, ranging from malnutrition to obesity, as well as autoimmune and inflammatory diseases of the bowel.78 A particularly interesting study from the laboratory of my colleague at Washington University in St. Louis, Dr. Jeffrey Gordon, shed light upon the interplay between the microbiome and obesity.79 The gut bacteria from normal or overweight mice were isolated and transplanted into germ-free mice. Remarkably, the simple transfer of the bacteria from fat mice was sufficient to cause the germ-free mice to gain weight—despite the fact that their caloric intake was tightly regulated and unchanged. Stated another way, weight gain was dictated by the bacterial component of the “superorganism” and was un
linked from the number of calories consumed. Expanding the study further, the Gordon laboratory isolated fecal bacteria from sets of identical twins, where one was lean and the other obese. Much as was seen before, the mice receiving the bacteria from the obese twin became fatter even though the calories were strictly monitored.
Whereas the impact of the gut microbiome on physiological processes such as weight gain might be expected, given the known location and function of bacteria in digestion, much less obvious is evidence linking the microbiome with susceptibility to a variety of human diseases ranging from depression and schizophrenia to diabetes and rheumatoid arthritis. In a 2016 study from investigators at the Mayo Clinic, a link between the microbiome found on the patient’s breast (skin) or in her mouth related to a diagnosis of breast cancer.80
Such emerging findings are consistent with a thesis advocated by Dr. Martin J. Blaser of the NYU School of Medicine. Blaser maintains that the widespread use of antibiotics has critically altered the composition of the microbiome in a manner that has increased susceptibility to obesity and a variety of diseases.81 The livestock industry is well known for supplementing animal feed with antibiotics to increase the growth rate and weight gain of livestock. Such findings may not be unique to livestock as antibiotics alter the microbiome of virtually all human and non-human animals. Blaser’s studies link one organism, Heliobacter pylori, whose absence in both mouse and man can cause greater susceptibility to obesity, gastrointestinal reflux disease (GERD), and esophageal cancer, as well as the incidence of a variety of inflammatory and even neurological disorders such as autism. Although this field of research remains quite preliminary, a May 2016 report at the International Meeting for Autism Research by investigators from the Texas Children’s Microbiome Center revealed a potential link between the intestinal flora and autism, though the causality, if any, remains questionable as of press time.82
Such findings are consistent with the idea that the health and well-being of the human component of the exquisitely complex superorganism is highly dependent upon our constitutive microorganisms. Such understanding underlines the need not to regard the bacteria in our environment as implacable enemies to be destroyed. Rather, keeping our superorganisms healthy requires us to properly distinguish between friend and foe. With this in mind, we turn to another set of organisms that has traditionally and rightfully been viewed as man’s deadliest enemy: viruses.
5
Spreading Like Viruses
Many children ask, Who is the king of the mountain and master of the planet? An alien looking at Earth from a distance (or at least at our social media) might conclude the dominant species is canine or feline in origin. After all, humans often work long hours to provide food, shelter, and healthcare for their pets, while the pets partake in constant leisure. From this our alien might conclude that companion animals are the dominant species. Other observers might maintain the dominant species is either a cockroach or bacterium, based on sheer numbers. An occasional bigot might instead nominate our own species. The current ecological epoch is known by many as the Anthropocene, due to the impact of humans on the planet (though it’s not necessarily a positive attribution).1
If our alien were to analyze the planet with higher-resolution optics, a more defensible answer would be viruses. Even the most inaccessible bacteria, such as those found in volcanic trenches in the lowest depths of the Earth’s oceans, find themselves infected by, and providing sustenance for, a multitude of viruses. By the time such a question is asked by a young child, the youngster has already been feasted upon by at least a few viral pathogens.
In order to evaluate the public health danger of an infectious agent, public health officials gauge its deadliness (i.e., what fraction of infected individuals succumb) and contagiousness (the number of additional people an infected person is likely to infect). A pathogen with high scores in both could truly be species-ending, but, fortunately, such infections are rare. It is nonetheless striking that infections caused by viruses are seven of the ten most contagious (rotavirus, measles, mumps, chicken pox, rhinovirus, smallpox, polio) and four of the five most deadly (rabies, HIV, Ebola, pandemic influenza). Compounding the dangers posed by viral pathogens, these infections are notoriously difficult to treat for reasons we will soon address. Before addressing such complexities, it will be useful to recount the history of viruses and how we have come to fear and respect these deadly pathogens.
A simplistic view of a virus is to consider it a highly evolved and still rapidly changing organism. A never-ending controversy surrounds the question of whether viruses are alive.2 For example, I maintain they are, though my scientist spouse (and undoubtedly others) believes me a fool for believing such notions. Regardless of your position on the subject, viruses have evolved in such a way that they remain at the top of the food chain. One can argue convincingly that virtually any living cell on the planet serves as the sustenance for at least one (and often many) viruses. This dominant position has arisen as viruses have over time evolved to take advantage of the machinery of the hosts they infect. Indeed, the most sophisticated viruses are often those with the fewest number of genes, as they leave the heavy lifting to the unfortunate victims they infect. Furthermore, viruses have been actively participating in the evolution of all living structures. A landmark paper by the Australian biologist Philip John Livingstone Bell suggested that the nucleus, a subcellular structure that contains the DNA of all eukaryotic cells, represents an example of a mutually beneficial partnership, known as an endosymbiotic event. It can be viewed as a viral variation of one bacterium engulfing another, which led to the appearance of mitochondria.3
Through the Filter
The last time we encountered the 19th-century microbiologist Charles Chamberland, he had forgotten to perform a study on anthrax for his boss. After returning from vacation, he had injected chickens with old bacterial culture and unintentionally found that exposure to dead bacteria protected the chickens from future infection (and thus acted as a vaccine). Rather than sacking Chamberland for the oversight, the appreciative Louis Pasteur kept him on, particularly because it seems that Chamberland had quite the touch for inventing devices to simplify laboratory research. For example, one year before the fateful chicken experiment, Chamberland had championed a project that led to the modern autoclave, a device used by virtually every biologist and clinician to sterilize their tools. This innovative aptitude also led Chamberland to unintentionally facilitate the discovery of viruses.
In 1884, Chamberland crafted a rectangular porcelain box to filter water.4 The rationale for this invention was based on increasing evidence from the Pasteur team that some bacteria secrete toxins into their environment—the very toxins that are responsible for their deadliness (as we observed with botulism). Chamberland and Pasteur realized a filtering mechanism would allow them to separate the relatively large bacteria from the much smaller toxin proteins. The resultant Chamberland-Pasteur filter (as it is still known today) was a hit among microbiologists endeavoring to understand how toxins functioned, but its real value was even more transformative.
At about the same time Chamberland was tinkering with the development of the autoclave, the German agricultural chemist Adolf Mayer was leading the Agricultural Experiment Station at Wageningen in the Netherlands.5 Mayer’s interest in chemistry might have come naturally, as he was the grandson of the great chemist Leopold Gmelin. Though this name hardly resonates today, among Gmelin’s contributions to science was the discovery of potassium ferricyanide, whose distinctive hue is familiar to anyone who has seen architectural blueprints.6
While serving his duties at the Wageningen agricultural station, Adolf Mayer was approached by tobacco farmers complaining of a new disease that was affecting their crops. This strange new disease revealed itself through a patterned and not entirely unattractive mottling of tobacco leaves in a manner reminiscent of a mosaic. Early studies on the tobacco mosaic disease had revealed it could be transmitted via the sap, suggesting it was i
nfectious in nature. Mayer presumed this to be the result of an undiscovered bacterium. Eager to make his name by discovering a new microorganism, Mayer subjected the samples to microscopic analysis, as most bacteria can readily be seen by eye with the assistance of these optical magnifiers. However, Mayer failed to see any bacteria in the infectious cultures. A second possibility was that the disease was being transmitted by a toxin in the sap rather than the bacteria itself. By the summer of 1886, Mayer published this speculation and began using Chamberland’s filters to identify the responsible toxin.7 Consistent with his hypothesis, Mayer was excited to see that something in the filtered fluid could cause the disease. However, excitement turned to confusion with additional investigation. Specifically, the plants infected with the toxin could themselves transmit the disease to other plants. This did not make sense, since the toxins could not replicate themselves and thus the infectious capacity of a toxin would be self-limiting. Yet Mayer’s findings revealed that the pathogenic agent could propagate itself indefinitely. After eliminating the possibility that such a bizarre finding was not simply a reflection of some sort of contamination, Mayer appreciated that he was confronting something never seen (or, more accurately, unseen).
By the time Mayer was performing his follow-up studies, concerns about the rapidly spreading tobacco disease had captured the attention of scientists around the world. In 1892, the Russian botanist Dmitri Iosifovich Ivanovsky was studying a tobacco disease in the Crimea and likewise described the cause to be an infectious agent capable of passing through Chamberland-Pasteur filters.8 Unlike Mayer, Ivanovsky remained convinced until his death that the cause of the tobacco mosaic disease was a bacterium that was simply too small to be captured by the filter. Such small thinking was refuted by the Dutch microbiologist Martinus Beijerinck, who experienced the same experimental outcome in 1896 but was convinced it was caused by a new form of life.9 Beijerinck named this causative agent a virus (the Latin term for ‘poison’) to distinguish this activity from both bacteria and their toxins. These new viral beings remained a matter of blind faith, as they were far too tiny to observe with the eye or even the most powerful microscopes of the age. In 1934, the American Wendell Meredith Stanley utilized the new technology of electron microscopy, which affords far greater resolution than conventional microscopy. In his life’s work, Stanley described the isolation and purification of a virus. It consisted of a hollow tubelike protein structure, known as a capsid, loaded with an RNA-based genetic material (which is closely related to but distinct from the more familiar DNA-based material that controls heritability in people).10
Between Hope and Fear Page 16
