From the moment of birth, a child is bathed in an environment crowded with microbial pathogens, any of which could be fatal. Therefore, humans are born with a fully functioning immune system that is prepared for such assaults from the moment of birth. This capacity requires that the work of the thymus in educating the immune system begins in earnest prior to birth. Hence the thymus is one of the most metabolically active of all organs during gestation and shortly after a child first enters the world. As an understandable means to conserve energy and not have to constantly repeat the process, evolution allows T cells to survive for decades (unlike most cells). Consequently, the education overseen by the thymus is concluded prior to puberty. Like many teenagers, the immune cells seem to know everything by the beginning of high school. Having completed its mission, the thymus withers away.
As is well understood by anyone who has experienced an immune system gone astray, the power of host defenses has the potential to wreak havoc. Specifically, the same mechanisms that can mobilize the body to fight infections can cause extensive damage to the host itself when the system malfunctions. The outcomes range from relatively mild effects of seasonal allergies to extreme and sudden death in reaction to a bee sting or the chronic, debilitating, and sometimes fatal array of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and lupus, to name but a few. Indeed, in looking at the raw power that the immune system can impart (think of how quickly a temperature can spike during a fever), it is rather remarkable that autoimmune misfiring is not more common. This fortunate feature is attributable to a series of safeguards that have co-evolved to mitigate the harmful effects as the firepower of the immune system has increased over the eons.
Dual Key Systems
Those who have viewed or read any of the genre of popular culture tropes focused on the use of nuclear weapons is at least generally familiar with the “dual key” or “two person” system. The idea is that no nuclear weapon can be launched by any single individual, since two keys (and locks) that are separated by a large distance (at least wider than a person’s outstretched arms) must be turned in exact synchrony. If one key is turned before the other, the system is disabled. This safeguard generally works quite well in Hollywood films (and we must have faith in the real world as well) and is quite like the safeguards regulating the immune system.
An analysis of how T cells are activated in response to a perceived foreign attack reveals a surprisingly similar set of safeguards as those portrayed in the Matthew Broderick film War Games or any number of Tom Clancy novels. As we have seen, the T cell receptor is the primary signal that alerts a T cell to the presence of an infectious assault. This single key alone is insufficient to trigger the vigorous and energy-consuming activation of an immune response. As often occurs during a frenzied state of mind, decision making is often compromised by a need for action, any action. In the case of the immune system, this means killing something, and fast. The considerable power exerted by activated immune cells could thus wreak havoc upon innocent bystanders if left unchecked.
The immune system has evolved a series of “co-stimulatory” signals that must be relayed at the same time, for the exact same rationale behind the dual-key system: to prevent unwanted attacks. Although we discussed the exquisite ballet that governs how the T cell receptor dynamically interacts with the MHC molecule and the peptide therein, the dangers of an unintentional misfiring of the T cell receptors are so potentially catastrophic that a co-stimulatory interaction of another pair of molecular partners—one on the T cell and the other on the antigen presenting cells—must also engage within a predetermined time and location on the surface of the T cell. Absent this second set of activation signals, the T cell is irreversibly shut down through a process known as anergy.61 Likewise, other series of precautions have evolved over time, including the use of certain processes known as checkpoints, which can actively prevent a frenzied T cell from activating and killing innocent bystanders during an attack meant to target foreign invaders.
Life is a complex process. At any given moment the body is multitasking in an infinitely complex manner. Energy and focus are constantly demanded by many of the trillions of cells in the body. With this in mind, it is important to understand that the evolution of a complex immune system is not arbitrary. It earnestly produced a defense against many disease-causing events. These diseases represent the wide array of pathogens that threaten not only individuals but can and do convey existential threats to entire species. As one example, while the world remained transfixed upon the terrible and highly publicized Ebola virus outbreak that began in 2013, considerably less attention was paid to the fact that the same virus had already killed more than 90 percent of mountain gorillas and is hurriedly pushing that species towards extinction.62 Indeed, the only way to avoid the catastrophic loss of this noble ape may be active intervention in the form of a vaccine originally developed to manage the outbreak in people.63 Before returning to the subjects of vaccines in detail, however, it is necessary to better understand adversaries such as Ebola virus and the myriad of other viral and bacterial pathogens confronting our species and others. Thus, we now turn our focus for the next two chapters to some of the many challenges presented by the microbial world.
4
The Wurst Way to Die
The germ theory of disease relates that organisms too small to be seen by the unaided eye can cause disease. This idea is not particularly new, yet it needed to be rediscovered on different occasions. Early evidence of this fact can be found in Roman writings. Marcus Tarentius Varro was a high-ranking equestrian soldier, farmer, and scholar who rose through the ranks to become a tribune of the Roman Republic. Despite being a supporter of Pompey in the Roman civil war, Varro was pardoned by none other than Julius Caesar himself (although later banished by Mark Antony and, later still, reinstated by Augustus). Casting aside his militant days, the older and wiser Varro settled into a life’s work focused on scholarly pursuits. His noteworthy achievements included the first encyclopedia and comprehensive (albeit inaccurate) listing of all Roman consuls from Lucius Junius Brutus (who is credited with ending the monarchy and transitioning Rome to a republic) through the end of the Roman Republic with the rise of Augustus (during Varro’s lifetime).
Like many early authors, his reputation if not the works themselves remain largely incomplete, with one exception. Varro’s Rerum Rusticarum Libri Tres conveyed an encyclopedic overview of conventional Roman views on agriculture and farming.1 Within this volume Varro expresses a word of caution for readers contemplating work in or around swamps, which have a long-understood link with diseases such as malaria. Varro counseled precaution in working near swamps, “because there are bred certain minute creatures which cannot be seen by the eyes, but which float in the air and enter the body through the mouth and nose and cause serious diseases.”2 It is presumed that Varro did not necessarily originate this idea but rather passed along a concept from others.
Sadly, this advice and understanding of the tiny microbial world would mirror the rise and fall of the Roman Empire, being lost for at least a millennium until being rediscovered in the 16th century by the Italian scholar Girolamo Fracastoro. Fracastoro’s contributions to science include astronomy (for which he was honored by putting his name on a prominent crater on the moon), geography, and biology. Regarding disease, Girolamo proposed that there were small particles, which he termed as “seeds” or “spores,” that could convey infection between and among people, even when there was not direct contact between them.3 Although this is quite close to the modern definition of infectious disease, Fracastoro did not specify whether these spores were of a biological or chemical nature. In a more specific reference that rings truer to a 21st-century audience, he used a word translatable by the English tinder to describe the disease today know as syphilis (which coincidentally reflects the fact that the modern mobile phone application Tinder promotes “hook-ups” that can increase susceptibility to the same venereal disease).
/> Seeing is Believing
It is perhaps a bit glib and overly obvious to state that the definitive discovery of the microscopic world awaited the invention of the microscope. The key breakthrough in this regard arose from a most unusual source. Antoni van Leeuwenhoek was a drapery maker in mid-17th-century Delft, in the Dutch Republic. As a scion of an upper-middle-class family, Antoni combined an education with considerable curiosity and a variety of professional experiences and personal hobbies, which eventually ranged from accountancy to land surveying and glass blowing.
As a creator and purveyor of fine linen products, van Leeuwenhoek sought means to better observe the threads in his work, a need sated by experiences gained during his glassblowing hobby.4 While melting a glass rod and pulling out a long string of glass, Van Leeuwenhoek realized that when he did it in just the right manner, the surface tension of the glass could create spherical glass beads. Moreover, Antoni realized smaller spheres of glass could magnify objects near it, acting as what we now refer to as a simple microscope. The draper proceeded to make more than two dozen such devices, improving his technique with every new version. These tools proved quite useful for observing very small objects such as a fraying thread, but Van Leeuwenhoek was not satisfied with the vocational applications of his invention. Instead, he began to look at many everyday objects in a different way.
In doing so, van Leeuwenhoek discovered a strange and fascinating microscopic universe all around him. Among his discoveries were muscle fibers (in meat), spermatozoa (within male ejaculate), and small animalcules (small animals) residing everywhere, including drinking water, raindrops, and saliva. We now know these animalcules to be the earliest representations of the microbial world, extending to the smallest of the observable species, the bacteria. His remarkable observations (and drawings based on his findings) were shared with his friend Reinier de Graff, a Delft anatomist, who touted van Leeuwenhoek’s work to the Royal Society of London.5 At first, the hobbyist van Leeuwenhoek demurred from the considerable interest conveyed by the Royal Society, but eventually he penned almost two hundred different reports on the microscopic world.
Unfortunately for the field, van Leeuwenhoek was not as forthcoming in detailing how he could generate such superb microscopes with high magnification and resolution. This reticence encouraged the indignation of the irascible Robert Hooke, an English polymath and serial provocateur, who is better known today for his contributions to physics, including the laws surrounding elasticity, advances in understanding the phenomena of gravity, and the introduction of the pendulum and watch spring. Based on reports from van Leeuwenhoek, Hooke became enraptured by the microscopic world. In January 1665 he published a treatise, Micrographia, which popularized the emerging field of microscopy.6, 7 Despite the critical and widespread success of this book, Hooke remained frustrated that his microscopic observations could not surpass those of the comparatively pedestrian Dutch draper. Even in the face of haranguing from Hooke and others, Van Leeuwenhoek remained taciturn about his techniques, and the field of bacteriology nearly succumbed with Van Leeuwenhoek’s death in 1723.
Progress in understanding the tiny world of bacteria was to remain largely dormant for more than a century until it was rejuvenated by German naturalist Christian Gottfried Ehrenberg.8 Ehrenberg completed a doctoral dissertation on the subject of fungi in 1818. Only two years later, he agreed to embark on an expedition with his friend Wilhelm Hemprich to survey the Libyan desert to identify novel plant and animal specimens.9 This campaign on Minutoli, which was underwritten by the Egyptian government, was to be led by the legendary Prussian explorer and former military general Heinrich Menu. The Nile Valley–based dynasty of Muhammad Ali was still evolving as an independent nation under nominal control of the dying Ottoman Empire. Ali had taken over Egypt after the withdrawal of the French, who had captured and occupied his homeland since an invasion by Napoleon Bonaparte. Looking to establish its sources of opportunity and avoid taking sides with either England or France, Ali looked to the seemingly disinterested Prussians to lead a scientific survey of his newly independent territories. This was the first in a series of events that would, and not for the last time, allow a bacterium to delineate Ehrenberg’s career. The first defining event of the expedition began with an outbreak of typhus in Alexandria, which caused the team to divert to a study of the Upper Nile basin rather than the Sahara.
Typhus is a louse-borne bacterial pathogen that has quite a history of changing history. One of the first written descriptions of typhus was recorded during the Spanish siege of Granada in 1489. The delirium and rotting sores characteristic of the disease hastened the downfall of the Moorish civilization in Iberia in 1492. These victories heartened Spanish King Ferdinand and Queen Isabella to open their purses and sponsor an expedition by an Italian navigator from Genoa by the name of Christopher Columbus.10
Though the fall of Granada meant later funds could be redirected from the siege to exploration, the victory came at a high human cost, with roughly five sacrifices to typhus for each battlefield death. Three centuries later, typhus would again sway human history by decimating the ranks of Napoleon Bonaparte’s army (a decade after leaving Egypt) during its retreat from Moscow in the winter of 1812, again claiming more French soldiers than the Russians had.11, 12 The utter breakdown of public health in times of war allowed typhus repetitively to claim thousands of victims in virtually every conflict from the English civil war through the Second World War, including the young lives of Anne Frank and her sister Margot, who were held under pestilential conditions at the notorious Bergen-Belsen concentration camp.13 The spread of typhus has only been managed with the 20th-century advent of dichlorodiphenyltrichloroethane (DDT), an insecticidal chemical developed by the Rockefeller Foundation, which, as we will see throughout the book, has waged a long war against insects.14
The impact of typhus on Ehrenberg was considerably more personal than the experiences we have noted, but they were defining nonetheless. As their exploration progressed from the Upper Nile to the Sinai Peninsula, Syria, and Lebanon, Ehrenberg and Hemprich collected samples of local flora and fauna until Hemprich was bitten by a lethal viper snake, known by the Latin name Vipera bornmuelleri, while exploring in Lebanon.15 Although the bite was not immediately lethal, Hemprich was still far too weak from his bout with typhus. The snake toxin caused local bleeding, which was exacerbated by a factor that prevents clotting and tissue repair. Despite being severely injured, Hemprich refused to rest, and this decision proved lethal. Hemprich died on June 30, 1825, suffering from a fever on the Red Sea coast of modern-day Eritrea.16
The death of his friend Hemprich created a personal crisis for Ehrenberg, but his career and subsequent remembrance in history would be established by the expedition. Shortly after his return to Prussia, where there was widespread reporting on the expedition’s success (beyond Hemprich’s death), Ehrenberg was approached about a new adventure by Alexander von Humboldt.17 Humboldt was the preeminent explorer of his day and had dreams of exploring Egypt. Two decades before Hemprich and Ehrenberg’s survey, Humboldt had plotted to explore Egypt with Napoleon. However, this adventure had to be abandoned because of a tribal uprising against the French. The timing of this revolt could not have been worse, as Humboldt had been in the process of gathering the personnel and equipment needed for the expedition. All prepared but without finances or a destination, Humboldt had found himself interviewing with the Bourbon Spanish monarchy, which had been seeking a team to explore its possessions in South America. The change in plans had proved fortuitous, as Humboldt had explored the Orinoco River in Venezuela, Cuba, Ecuador, Peru, and Mexico. During this expedition, he’d become arguably the most famous science-based explorer and geographer of his time. No less than Thomas Jefferson invited Humboldt to visit the fledgling United States, toasting him as “the most scientific man of the age.”18
What Humboldt recruited Ehrenberg for in 1829 was an expedition to Russia. The country was massive, but its rulers knew comparati
vely little about their domain.19 The tsar was particularly interested in having Humboldt assemble a team to explore mining opportunities east of the Ural Mountains that might ultimately provide silver and platinum needed for coinage. The tsar’s government provided an escort consisting of a company of Cossacks, who were employed both to ensure the protection of Humboldt and Ehrenberg’s team as well as to prevent them from encountering (and later reporting upon) sensitive subjects such as the social conditions of the country’s many serfs. Although the excursion was intended to venture no further than Tobolsk, a town in south central Russia (and the town where Tsar Nicholas II and his family would later be confined in the days following the Russian revolution), Humboldt and Ehrenberg pushed farther, eventually turning back at the Chinese border. A chance encounter with another bacterium almost cancelled the adventure midway through the expedition. Specifically, a local outbreak of another bacterium, this time anthrax, caused considerable unease within the party and led to discussion about cancelling the expedition. However, the sixty-year-old Humboldt pressed on, stating, “At my age, nothing should be postponed.”20
With a treasure trove of samples obtained from his expeditions to Egypt and Russia, Ehrenberg settled into a domestic life spent staring at the water, rocks, flora, and fauna he had collected with Hemprich and Humboldt. Germany was and remains a dominant innovator in the field of optics and microscopy, and Ehrenberg had access to some of the finest instruments of his era. For the three decades after his return from Russia, Ehrenberg subjected his samples to microscopic analyses and discovered many “animalcules,” including multiple species of bacteria and single-celled eukaryotic life known as protists. His work was widely followed, and it reinvigorated interest in the invisible world of microorganisms. Given the thousands of hours spent behind a microscope, it is quite fitting that Ehrenberg was honored in 1877 as the first recipient of the Van Leeuwenhoek Medal by the Royal Netherlands Academy of Arts and Sciences, a once-a-decade award that recognizes outstanding achievements in microscopy.21
Between Hope and Fear Page 13