Another interesting and quite old example of a defense mechanism is the toxin-antitoxin system. Briefly, a gene on a plasmid might encode for a protein that is highly toxic unless neutralized by an antidote, known as an antitoxin.19 Instructions for producing an antitoxin in turn may be embedded on the bacterial chromosome. Thus, when conjugating with a “friend” (which can produce the antitoxin), the toxin will be countermanded by the production of the antitoxin. However, a close embrace with an “enemy” could be lethal if one lacks the instructions to produce the antitoxin. Such tricks are often deployed by bacteria, who, like modern-day street gangs, seek to dominate the neighborhood and eliminate the competition.
An even more elaborate set of defensive measures has evolved to protect bacteria from viruses. As we will soon see, viruses are at least as obnoxious and problematic to bacteria as they are to people—perhaps even more so.20 One feature that renders some viruses particularly problematic is their ability to insert their genetic material into the host chromosome. Like a monster from science fiction, the instructions to construct viruses can be snuck into a host chromosome and lurk unseen until some signals trigger the virus to reemerge and resume its rampage. To combat this menace, bacteria have evolved extraordinary mechanisms to identify and eliminate viral genetic materials. One set of evolutionary defenses, known as restriction enzymes, can slice the viral DNA into small pieces. As described in my book A Prescription for Change, recognition and reproduction of these gene-modifying events gave rise to the modern field of biotechnology, which followed upon the discovery of these enzymes and their potential use to cut up and modify human genes.21
Another defense mechanism that has gained considerable notoriety within the past few years is known as clustered regularly interspaced short palindromic repeats (or CRISPR), which also evolved to eliminate embedded viruses.22 As a brief interlude, some bacteria have evolved a system whereby DNA sequences that are unique to viruses are captured and organized into repetitions of DNA that are stored by the bacterium as a means to recall viruses that they (or their ancestors) have encountered. These sequences provide an early-warning mechanism the bacteria can use to identify invading viruses. By utilizing these unique sequences as a guidance strategy for enzymes, known as a DNases (the most famous of which is known as Cas9), the CRISPR system can seek out and obliterate the unique signatures of viral DNA (thereby killing the virus as well). Over generations, the CRISPR-based immunity allows bacteria to recall previous encounters with viruses and to develop a defensive strategy to minimize harm from future attacks. In the hands of contemporary molecular biologists, CRISPR holds promise likewise to identify the unique signature of diseased DNA to correct these defects, thereby leading to opportunities to prevent or reverse established diseases in humans.23 As such, the technology has recently gained great acclaim (and substantial investment dollars) for start-up biotechnology companies seeking to modify everything from inborn genetic diseases to cancer and/or eliminate certain infectious diseases.24 A more detailed overview of CRISPR-Cas9 is beyond the more limited scope of this book but it nonetheless suffices to state that this system holds the potential for a future revolution in medicine.
From Eating to Fighting
For a billion years after life arose, the single-cell organisms—bacteria, archaea, and the viruses that infest them—continued their relentless warfare. Excluding viruses, all single-cell organisms derived their nutrition (and energy) from either eating bits of proteins, lipids, and carbohydrate (e.g., detritus from organic life) or synthesizing their own materials using solar (photosynthetic) or chemical (chemosynthetic) power. All the while, life was evolving sundry ways to improve its offensive and defensive capabilities. One example was a modification of an engulfment technique that single-celled organisms used to ingest foodstuffs. Analogous to how the largest forms of life (blue whales) ingest and filter some of the smallest (plankton), single-cell organisms evolved to filter their immediate environment to capture nutrients. Given the efficiency gains from targeting larger prey, this system was improved to capture and kill entire microorganisms (rather than individual molecules). The prey in turn developed ways to defend themselves using specialized techniques such as the aforementioned toxin-antitoxin approach.
Constant warfare among single-cell organisms reigned supreme until 2.7 billion years ago, when a nano-sized but groundbreaking peace treaty was achieved by only two of the countless cells on the planet. At the time, the event went largely unnoticed, but the implications were profound. Like the events of any other day, this one began when one single-cell organism ingested another. Rather than the victor feasting upon the various proteins, fats, and carbohydrates of its victim, the two organisms arrived at a mutually beneficial arrangement. The ingesting organism, which we will call the host cell, gained a specialized function that was provided by keeping the prey alive (rather than killing and digesting it). The cohabiting organism, which we will call a hitchhiker, in return provided ongoing benefit to its host and gained from the encounter not only by not being killed but also by being protected by the host from attack by other pathogens—namely, protection from the harsh outside world, where the next host cell might not be so benign. Indeed, the hitchhiker might have gained the better part of the deal because it could itself proliferate within this new protective cocoon provided by the host.
As this new companionship continued, it was inevitable that there would be a split. Specifically, the host cell eventually needed to divide. For its progeny to survive, the hitchhikers needed to be divided up as well. Thus, both the host and hitchhiker evolved a means such that when cell division occurred, the hitchhikers would be equally dispersed between the two daughter cells. Variations on a theme continued as changes in the local availability of nutrients required the number or function of both the hosts and/or hitchhikers to change. Over time, a system evolved to assure a proper balance of hitchhikers.
The process described above is an example of endosymbiosis, a theory substantiated by the American scientist Lynn Margulis.25 The evidence for at least one endosymbiotic event resides in each cell in our body and powers all aspects of human life. Indeed, all animals and plants are the direct progeny of that first peace treaty. The combined structure is known as a eukaryotic cell, a name derived from a Greek term meaning ‘true nut.’ Eukaryotic cells have a nucleus, a specialized structure that evolved as a centralized storehouse for DNA storage. In contrast, the DNA in bacteria and archaea float around the cell interior. These cells are known as prokaryotes (meaning ‘before nuclei’).
The hitchhikers in our story are more commonly known as mitochondria. Mitochondria are a component of virtually every cell in our body, and the specialty they provided to their host cells was the production of energy. Like their independent ancestors, mitochondria encode for their own DNA and replicate themselves independent of, but in coordination with, the host cell. Mitochondria are thus in constant communication with the larger cell. Sometimes they will increase in number or become degraded to recycle their key building blocks, as fits the continued survival and propagation of the overall cell, in response to changes such as lean times or old age. While all known species of eukaryotes contain mitochondria derived from that initial pairing, a subset of eukaryotic cells underwent additional endosymbiosis events. The most prominent example arose when a eukaryotic cell engulfed a bacterium that had the capacity to generate its own food (or more specifically sugar) in response to sunlight. The resultant cell gained a photosynthetic element known as a chloroplast and was the progenitor of all plants.
These two small accommodations went almost unnoticed within the internecine fray that persisted all around the planet as microorganisms fought to secure a future for themselves and their progeny. As we will see in a future chapter, some cooperative events involved bacteria and eukaryotes. Other benefits were derived by partnering with one’s own progeny. For most of evolution, cell division was followed by the two daughter cells going their own way. Eventually, some daughter cells d
ecided to remain attached and work together. As these collections of eukaryotic cells organized and evolved into what we now refer to as multicellular organisms, specialization became possible. Like the well-known transition in human civilization that facilitated specialization of work when some individuals remained in place to farm the land (rather than constantly chase wild game), the idea of remaining attached to the collective could allow some cells to hone certain specialties. Amidst the chaotic need for defense, some of these cells were specialized to defend against outside aggression.
In many cases, the primary defense utilized by our early ancestors simply entailed the creation of a physical barrier such as skin, which prevented unwanted invaders from gaining access to the organism’s interior. Over time, other adaptations in the multicellular organism included further specialization resembling the use of something akin to modern-day firearms, which could project protection at a distance to repel or discourage potential dangers. One example can be seen with the hydra, a relatively simple multicellular organism.26 Complementing a protective outer barrier (i.e., its skin), the hydra evolved a means to produce and secrete a surprisingly complex array of antimicrobial peptides (very small proteins). These defenses comprised some of the first examples of antibiotics, a term that literally translates from its original Greek into ‘anti-life’ and accurately reflects the goal of killing other organisms. This adaptation was crucial, given the fact that the hydra’s environment was swarming with bacterial pathogens. One interesting detail is that the hydra’s defense was selective, targeting some bacteria while encouraging interactions with others.27 This approach is perhaps the most ancient form of a microbiome, the collection of microscopic organisms within the local environment intimately interacts with a macroscopic organism such as you or me. The symbiotic relationship people have with microbes is a relatively new discovery despite increasing evidence the microbiome crucially controls virtually all aspects of life and death and as we will see, will weave intimately throughout the rest of our story.
Chemical Warfare
Further evolution gave rise to more sophisticated defense systems. As multicellular animals became ever more complex, specialization became even more important. Given the hostile nature of the environment, technologies to increase defense continued to improve. A subset of cells called phagocytes, named for a Greek term meaning ‘eating cells,’ appeared. Their primary responsibility was to ingest potential enemies. Whereas in their ancestors such mechanisms had primarily served to gather nutrients, the new adaptations repurposed the activity to kill trespassers.
Further adaptation amidst an ever-changing environment of comparably adapting enemies compelled more sophisticated needs for attack and defense, and thus even greater specialization. Among the phagocytes, some cells were tasked with more efficient ways to kill intruders, while others were tasked with manufacturing and releasing specialized chemicals that could sense or immobilize potential invaders. Rather than remaining as static cells that simply awaited a chance encounter with potential invaders, many phagocytes gained the ability to actively move and thus patrol the entire host in constant search of potential threats. This newfound mobility also allowed multiple defenders to swarm upon the enemy. These adaptations were greatly assisted by the development of a complex set of chemicals collectively known as cytokines.
The name cytokine (a Greek term meaning ‘cell movement’) accurately captures their function. Cytokines can be thought of as early-warning messengers produced by cells threatened with attack from a foreign pathogen. Much as Paul Revere helped mobilize Minutemen to slow the British march on Lexington and Concord, cytokines alert the host defense network to mobilize and localize the forces (including phagocytes) and direct the attack (producing more cytokines as the assault continues or tapering down as the threat diminishes). As the number and types of threats increased (such as different bacteria, fungi, or viruses), the cytokines themselves began to specialize. The discovery of new cytokines or variants of existing molecules continues today. One example of this further specialization is a subset of cytokines known collectively as interferons.
In the mid-1950s, two British scientists, Alick Isaacs and Jean Lindenmann, were studying how influenza virus infects chicken egg embryos (many flu vaccines are grown in eggs). They noted a peculiar finding.28, 29 If the scientists killed the virus with heat and used this material to infect the embryos, the eggs resisted subsequent infection with live virus. This was attributable to a host defense molecule produced by the infected cells. This molecule with the ability to interfere with virus infection gave rise to the name “interferon.” As often happens in science, other laboratories were reporting similar findings at roughly the same time. For example, independent investigation at the University of Tokyo meant to improve smallpox vaccine development reported the same finding, as did a team led by the American polio vaccine researcher John Enders (whom we will encounter again later in our story).30, 31 These seminal observations opened the door to investigation, which revealed that there was indeed not only one interferon but a range of different interferons, many of which shared the same ability to interfere with viruses but each of which had their own ways of doing so. Over time, investigators also realized that the immune-activating functions of interferons were not limited to viral infections but likewise alerted the immune system to the presence of cancer and other diseases.32, 33 Indeed, interferon-based therapeutics are now routinely deployed in the fight against an array of diseases, ranging from infections and cancer to various autoimmune disorders.
About a half billion years ago and deep in the world’s oceans, which were and are brimming with microorganisms, an invertebrate, jawless fish developed an even more complex and efficient means to eliminate potential pathogens.34 By today’s standard, jawless fish are quite primitive. One example is the lamprey eel. Yet by the standards of the day these fish were true trendsetters. Five hundred million years ago, these jawless fish developed the ability to not only eliminate unwanted pathogens but also to remember which organisms were friends and which were foes, and to deploy selective ways to rid themselves of the latter. In short, this new system increased the number and efficiency of how their defenses could recognize and eliminate potential disease-bearing microorganisms. Furthermore, the advance meant that these fish could efficiently keep themselves free of infectious disease, while the new system could remember past infections and use this information to mount a faster and more robust defense against future invasions should the pathogen be encountered again.
These chemical-wielding invertebrates evolved into aquatic and, later, terrestrial organisms with a backbone (known as vertebrates). Even later they evolved into mammals (fur-covered vertebrates that feed babies with milk produced by their mother). As they did so, their defense mechanisms became ever more sophisticated, powerful, and complex. In parallel with improvements in their defensive chemical warfare, comparable changes were improving the efficiency and lethality of the cellular component of the evolving immune system, a subject to which we now turn.
Revolutionary Discoveries
Francois Joseph Victor Broussais was born in 1772 to a physician in the Brittany city of Saint-Malo in northwest France.35 The young Francois learned the basics of medical practice from his father but was drawn to revolution with the storming of the Bastille on July 14, 1789. Inspired by the new revolutionary tricolor flag, Broussais joined the infantry of the French Revolutionary Army, but poor health forced him to temporarily abandon military service. He used this hiatus to finish his medical training in Paris (though he later returned to the army as a practicing surgeon). Ironically, this sojourn by the low-bred Brittan led to a life-changing interaction with a bourgeoisie scion of the establishment.
Marie-Francois Xavier Bichat was also the son of a physician and the mayor of Poncin (a town in east central France near the Swiss border).36 Though only a year older than Broussais, Bichat had already amassed an impressive academic record. His father had sent him to the top schools in N
antua and Lyons, underwriting both his education and his seemingly constant travel to other parts of the country, in part to stay one step ahead of the revolutionary chaos. Ultimately, Marie-Francois was subsumed by the revolutionary wave and indeed went with it, also serving as a surgeon in the army of the republic near his home in the Alps.
After the Reign of Terror, Bichat moved to Paris as a trainee under the famous surgeon Pierre-Joseph Desault in July 1794. Bichat adored Desault and his family. Under his mentor’s tutelage, he quickly rose through the ranks. However, the sudden and unexpected death of Desault in 1795 not only emotionally devastated Bichat but added an additional burden, as Bichat was tasked with even greater responsibilities at work and in his private life, where he helped fill the gaping void in Desault’s family left by the surgeon’s death. The accumulated stresses took a terrible toll, and Bichat later died at the tender age of thirty, being buried in the same crypt as his friend and mentor, Desault.
Despite the prematurity of his demise, Bichat made extraordinary contributions to medicine and our story. For example, he is generally accepted as “the father of histology,” a field he pioneered upon recognizing that each body is comprised of a complex number of different tissues, each of which is tasked with a different function. Together, these disparate pieces collectively work together to provide overall health and well-being and if any one system falters, the overall organism can be in jeopardy.37 Furthermore, Bichat and his work made an indelible impression upon one of his last students, Francois Joseph Victor Broussais, who trained under Bichat from 1799 until his untimely death in 1802.
Building upon Bichat’s idea that the body was composed of different tissues with different functions, Broussais added his own ideas, including the radical concept (at least for early-19th-century Europe) that diseases arose when normal tissue function went awry or failed altogether.38 Although this idea has stood the test of time, Broussais went a bit off course in advocating that “irritations” caused by emotional distress or other stimuli could trigger the digestive system to initiate a sort of domino effect that eventually compromised organs throughout the body. Specifically, Broussais advocated for a “sympathetic” response that was propagated by the blood and tainted blood would cause the organs to fail.39 He further advocated that the best means of countering these “sympathetic” responses was to remove blood via the liberal use of sucking leeches.40
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