Microbes as Menaces, Mates & Marvels Bonnie L. Bassler Abstract: The conventional understanding of microbes as causative agents of disease has led us to fear them and to consider them our deadly enemies. Much less appreciated are the central roles microbes play in shaping the environment and in maintaining plant, animal, and human health. All metazoan organ- isms–organisms that we can see with the naked eye–exist in lifelong partnerships with vast microbial communities. These “microbiomes” supply metazoans with essential life processes that are not encoded in nonmicrobial genomes. Recent work in microbiology has revealed that microbes, like metazoans, have speci½c body plans and sensory systems, that they can communicate with each other, and that they orches- trate collective behaviors. Investigations of these ancient yet enduring processes are uncovering the fun- damental design principles of life. Microbes are also storehouses of new molecules, biochemical pathways, and materials with medical, industrial, and agricultural relevance. Scientists are harnessing these micro- bial products in efforts to confront humanity’s most pressing problems. This essay explores the wonder, complexity, power, and utility of microbes in the twenty-½rst century. You may think you’ve seen everything, but in fact, most of the world is invisible to us. It is composed of, and was constructed by, microbial organisms. Microbes are single-celled organisms too small to see with the naked eye. They include archaea, fungi, and protists, but overwhelmingly, they are bacte- ria. For billions of years these invisible critters, our forefathers, have been shaping the Earth and mak- ing it a suitable place for us to live. Higher organ- BONNIE L BASSLER . , a Fellow of isms–all plants, invertebrates (including insects), the American Academy since 2007, and vertebrates (including humans)–occupy only is the Squibb Professor of Molecu- lar Biology at Princeton University a sliver of the world. We live exclusively within and a Howard Hughes Medical In- narrow ranges of temperature, air pressure, atmos- stitute Investigator. Her research phere, pH, and nutrient sources. Microbes, by con- focuses on the molecular mecha- trast, have adapted to, inhabited, exploited, and nisms that bacteria use for inter- tamed every niche on Earth. They thrive under cellular communication. Her work extreme pressure and at high temperatures miles has appeared in such journals as below the ocean surface, enveloped in the sulfu- Molecular Microbiology, Genes & De- velopment, and Cell. She edited the rous smoke spewing from thermal vents. They live volume Chemical Communication encrusted in the sediments of lakes beneath ice caps among Bacteria (with Stephen C. that have not thawed in more than ten thousand Winans, 2008). years. There, they exist in a world that has not seen © 2012 by the American Academy of Arts & Sciences 67 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/DAED_a_00162 by guest on 01 October 2021 Microbes as the light of day or taken a breath from the great promise for medical, agricultural, Menaces, atmosphere for millennia. Microbes flour- industrial, and technological applications. Mates & Marvels ish at the pH of battery acid, and in this This exciting research has coincided with hostile environment, they produce the the alarming rise of antibiotic-resistant stunning, gemstone-colored pools found microbial pathogens across the planet. in Yellowstone National Park. Unlike the New research directions, coupled with the human diet, which is narrow and invariant, recurrence of the microbial threat, have microbes consume, well, everything. They propelled microbiology once again to the eat the regular stuff–proteins and car- forefront of science. This essay explores the bohydrates–but also radioactivity, rocks, wonder, complexity, power, and utility of crude oil, rust, paint, dirt, and wood. Every microbes in the twenty-½rst century. plant, animal, and human requires a vast community of commensal microbes work- We divide all life into two categories: ing 24/7 to keep it alive and healthy. prokaryotes and eukaryotes. Every eukary- As the foundation of nineteenth- and otic cell has a nucleus; prokaryotic cells twentieth-century biological science, do not. Prokaryotes are further divided microbes enabled scientists to dismiss the into archaea and bacteria.1 We suspect that possibility of spontaneous generation. Earth’s ½rst organisms were archaea be- They inspired Robert Koch’s postulates, cause they thrive in habitats mirroring revealing disease causation for the ½rst those of early Earth: hot, salty, anoxic, and time. Microbes gave scientists a way to de- metal-rich. Bacteria live in more tem- duce the famous dna double helix; they perate places. Eukaryotes include fungi, showed that heritable information is en- protists, plants, invertebrates, and ver- coded in units of genes and that the essen- tebrates. Eukaryotic species are also pre- tial parts of life are dna, rna, proteins, dominantly microbial, which means that and lipids. Ironically, these paradigm- you haven’t seen most of them, either. changing discoveries also made the micro- The Earth is about 4.5 billion years old.2 bial sciences passé. By the mid-twentieth At present, the oldest known prokaryotic century, microbes were generally thought fossil dates back 3.5 billion years. The old- to have been picked clean. Science instead est known eukaryotic fossil, a microbe, is focused on more “complex” problems: about 1.7 billion years old. By contrast, the namely, embryonic development, neuro- most ancient macroscopic fossil is only circuitry, and cancer. about 650 million years old.3 Thus, the However, much more remains to be better part of the world’s living history is gleaned from examining the lives and exclusively microbial, and it is predomi- personalities of microbes. Microbiolo- nantly prokaryotic. Archaea had their day gists recently demonstrated that microbes back when the Earth was in chaos. They possess the features of metazoans: they have trouble living in the presence of oxy- have precise body plans and sophisticated gen, so when the planet became oxygen- sensory mechanisms; they communicate ated roughly 2.5 billion years ago, archaea with each other; and they amass their num- were relegated to the most hostile loca- bers in order to act collectively. Investiga- tions remaining on the planet. Bacteria, tions of life’s oldest organisms are teach- on the other hand, flourished because they ing us how these processes operate in meta- adapted to both oxygenated and anoxic zoans. Further, microbiologists are mining environments. They prevailed and made microbes for new genes, molecules, and the world we know. Indeed, the vast ma- biochemical pathways–work that holds jority of biological change and diversi½ca- 68 Dædalus, the Journal ofthe American Academy of Arts & Sciences Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/DAED_a_00162 by guest on 01 October 2021 tion has occurred and continues to occur trum. Because of these qualities, only in- Bonnie L. in the unseen bacterial world. cremental improvements to existing drugs Bassler have been made in the past forty years. The Gates Foundation, the National During this same time frame, pathogenic Academy of Engineering, the Plant Sci- bacteria emerged across the globe, and ences and Environmental Sciences divi- many of them are resistant to convention- sions of the National Research Council, al antibiotics. This predicament has been and other groups spanning diverse sci- fueled by the widespread use of bacterici- enti½c disciplines have proposed sets dal drugs. Multidrug-resistant bacteria are of “grand challenges” facing humanity. now prevalent around the world, and they Strikingly, the clear consensus among lead- contribute greatly to the increasing micro- ing scientists is that the microbial sciences bial threat to human health. are key to confronting the majority of these Microbes are Mates. Every plant and an- challenges.4 In the recent National Acad- imal (including insects and humans) emies report A New Biology for the 21st Cen- depends on microbial partners for life tury, for example, all four of the suggested because they provide essential functions grand challenges have signi½cant micro- that are not encoded in metazoan ge- biological components.5 The overarching nomes.7 Consider the human-microbe scienti½c imperative is to ensure that mi- relationship: there are ten times more crobes’ potential contributions to a healthy microbial cells than human cells and one planet are fully realized. There are three hundred times more microbial genes main reasons why the science world is than human genes in and on every per- directing its focus toward microbes. son. These metrics suggest that, at best, Microbes are Menaces. The top killers of you are 10 percent human (in terms of humans are microbes. Chief among these cells), and more realistically, you are only are hiv (a virus), malaria (a eukaryotic 1 percent human (in terms of genes).8 microbe), and tuberculosis (a bacterium), The remainder of “you” is microbial. Not which collectively claim more than ½ve only do you inherit your human genome million lives every year. The next biggest from your parents, you also inherit, during killers are microbes that cause diarrheal the ½rst few months of life, your micro- diseases and pneumonias, which lead to flora. These vast communities of microbes another two million human deaths per –your “microbiome”–have effects on year.6 At present, these microbial scourges metabolism, immunity, and behavior9; are restricted to underdeveloped regions. and properly balanced, invisible inter- If you live in a developed country, there is actions with your microbes are essential little chance (at least for now) that you to your well-being. Microbes cover you will die of an infectious disease unless you in a thin bio½lm that serves as invisi- are elderly and frail. Residents of devel- ble body armor protecting you from envi- oped countries will overwhelmingly die ronmental insults. Microbes help digest from heart disease or cancer.