improved our understanding of the infected host’s immune response to viral infection. The Nobel Prizes since the 1980s often acknowledge the importance of new technologies and concepts, and include awards for the establishment of transgenic animals, gene targeting methods, and immune cell recognition of virus-infected cells.
Figure 1.3 Consequences of the 1918 influenza pandemic. (A) The 1918–19 influenza pandemic infected a staggering number of people, resulting in the hasty establishment of cavernous quarantines in college gymnasia and large halls, filled with rows and rows of infected patients. Photo courtesy of the Naval History and Heritage Command (Catalog # NH 2654). (B) Of particular concern, this epidemic had a high death rate among young, otherwise healthy individuals compared to deaths in previous flu seasons, in which deaths occurred mostly among the very young and very old (representative data from Massachusetts shown). Based on data from Dauer CC, Serfling RE. 1961. Am Rev RespirDis 83:15–28.
The emergence of molecular biology and cell biology as distinct fields marked a transition from a descriptive era to one that focused on the mechanisms underlying viral reproduction, transmission, and disease. Genomes were isolated, proteins were identified, functions were deduced by application of genetic and biochemical methods, and new animal models of disease were developed. These approaches also ushered in practical applications, including the development of diagnostic tests, antiviral drugs, and vaccines. As the 20th century came to a close, another paradigm shift was occurring in virology, as many scientists realized the power of large-scale, unbiased screens to study virus-host relationships. These scientists embraced the notion that all the molecules or reactions that govern a biological process could be identified and monitored during an infection, allowing discovery of new molecules and mechanisms that would be overlooked by more reductionist, gene-specific approaches. Large data sets were acquired, initially using microarray technology, which enabled a global and unbiased snapshot of both host and viral RNAs under defined conditions. Today, next-generation strategies, including high-throughput RNA sequencing (RNA-Seq) and nanopore sequencing, are used to reveal the type and quantity of nucleic acid in a biological sample at a given moment (Box 1.3).
New tools continue to expand our capabilities, and methods once considered cutting-edge are eclipsed by more-powerful, faster, or cheaper alternatives. Parallel developments in information technology and computer analyses (often called “data mining”) have been critical to draw conclusions from the massive data sets, requiring in-depth expertise in bioinformatics and biostatistics. Computer-aided approaches have enabled scientists to define cellular pathways that are triggered during viral infection, to identify common features among seemingly diverse viruses, and to make structural predictions about small-molecule inhibitors that could prevent infection. While these new tools are exciting and powerful, it is likely that traditional approaches will still be required to validate and advance the hypotheses that are emerging from these more global analyses.
Although the methods that virologists employ may be ever-changing, one fundamental question asked by early pioneers remains with us: how do viruses cause disease? The remainder of this chapter focuses on how outbreaks and epidemics begin, and the impact of viral infections in large populations.
Viral Epidemics in History
In the apocalyptic movies I Am Legend (2007), Contagion (2011), and World War Z (2013), fictional epidemics are depicted following introduction of a virus into a naïve human population. (In some of these films, the virus turned the infected victims into zombies; although viruses cause many diverse outcomes, zombification is not among them.) Some of these doomsday films include a scene in which an epidemiologist ominously describes the devastating consequences of uncontrolled, exponential viral spread through a population. These movies were certainly frightening, but ultimately comforting, as humans, with improbable speed, developed strategies to limit viral spread. But how realistic is this Hollywood vision? One could argue that proof of our triumph over viral pathogens can be found in the eradication of smallpox and the development of vaccines to prevent infection by many viruses that historically resulted in much sickness and loss of life. However, there is a risk in becoming self-congratulatory. Doing so makes us ignorant of how quickly a virus can spread in a susceptible population, as the recent SARS-CoV-2 pandemic has taught us. When epidemics and pandemics occur in real life, there is a pervasive feeling of helplessness, and often interventions are not developed in time to mitigate substantial clinical impact. The stories that follow highlight the financial toll, loss of life, and historical ramifications of viral outbreaks, and underscore a new reality: the increased mobility of human and animal populations on the planet has almost certainly accelerated the emergence of epidemics.
METHODS
Nanopore sequencing
A new approach for determining the sequence of a nucleic acid has been developed, referred to as “nanopore sequencing.” This method relies on the use of biological nanopores, such as the bacterial hemolysin, which forms extremely small holes, or pores, in a membrane. These pores have a diameter wide enough to allow only a single strand of RNA or DNA to pass through. When an ionic current is applied to the membrane, each of the four nucleotides passing through the pore alters the current in a characteristic manner, which can be interpreted by a sensor (yellow starburst in panel A in the figure) and de coded to provide the sequence. This approach obviates the need for PCR amplification, greatly reducing experimental error that can accompany other sequencing techniques that rely on such amplification. Moreover, this approach is portable to remote locations, accelerating pathogen identification at sites of outbreaks.
Kafetzopoulou LE, et al. 2019. Metagenomic sequencing at the epicenter of the Nigeria 2018 Lassa fever outbreak. Science 363:74–77.
Simplified overview of the process of nanopore sequencing.
Epidemics Shaped History: the 1793 Yellow Fever Epidemic in Philadelphia
One powerful example of a deadly viral epidemic that influenced American history and changed how cities are managed is the yellow fever outbreak that occurred in Philadelphia, Pennsylvania. In 1793, when this epidemic occurred (and a full century before Walter Reed’s commission), nothing was known about yellow fever virus, the disease, or how it was spread. Worse, no one at the time knew that viruses existed, so the seemingly random way that individuals became sick com pounded the confusion and sense of helplessness. Further-more, this epidemic struck at a pivotal time for the fledgling Union. At that time, Philadelphia was the new nation’s temporary capital and a city of active commerce and trade. One can easily imagine the panic in Philadelphia when scores of individuals became ill and died of this mysterious disease within a very short time. In the 101 days between August 1 and November 9, some 5,000 people perished in a city of about 45,000, making this one of the most severe epidemics in the history of the United States (Fig. 1.4). There were few families that did not lose a relative to this disease, and many entire families were lost. Those who could flee the city did so, including the new president, George Washington, and his cabinet. Others stayed behind to aid the sick, including men of the Free African Society, who volunteered on the basis of the incorrect notion of Benjamin Rush, a prominent Philadelphia
