The New Microbiology. Pascale Cossart

These live on our skin and in different places in our bodies, such as the intestine, the mouth, and the nose, or they participate in various processes, such as the making of cheese, yogurt, and other foods, or water treatment and environment decontamination. They play a key role in maintaining the stability of our environment and the biodiversity of the flora and fauna of our planet.

      Thanks to the studies of Louis Pasteur and Robert Koch at the end of the 19th century, it is well established that microbes do not spontaneously generate, that each microbe is born from another microbe, and that the smallest living organisms capable of autonomous life are called bacteria (from the Greek bakteria, meaning a stick or rod, named for the rod-like shape of the first observed bacteria). These bacteria, observable with simple microscopes, are single-celled organisms that can generate thousands of similar unicellular daughter cells.

Louis Pasteur and Robert Koch importantly discovered that bacteria were responsible for numerous diseases that have devastated humanity for thousands of years, such as the plague, cholera, and tuberculosis. Their studies paved the way for powerful methods of diagnosis of, and treatment for, bacterial infections, and for the development of vaccines, some of which are still being used today. Pasteur and Koch also introduced the concept of the study of bacteria in general, whatever their nature—i.e., either pathogenic, illness-generating bacteria or nonpathogenic bacteria that carry out other functions. In fact, the discoveries of Pasteur, Koch, and their collaborators were so revolutionary and so important that by the early 20th century they triggered an immense interest, first among medical doctors and then among biologists of all sorts attracted to this new discipline: microbiology, the study of various microorganisms invisible to the naked eye, and more specifically, bacteriology, the study of bacteria.

      During this flourishing period and the entire century that has followed, the field has advanced by leaps and bounds in many directions. At first, shortly after Pasteur and Koch, microbiology developed rather slowly, with the meticulous identification of all kinds of bacteria, the establishment of various collections, and diverse classifications and precise descriptions. Then things really sped up. In the early 1950s, the discovery of DNA as the basis of the genetic material of all living organisms, combined with the previous research on bacteria, quickly led to the development of concepts that applied, as Nobel laureate Jacques Monod put it, to the bacterium as much as to the elephant. These concepts included DNA replication, DNA transcription, protein translation, and protein synthesis. This in turn led to the development of molecular biology and genetic engineering: the art of manipulating genes and species.

      By the end of the 20th century, technologies in DNA sequencing—the determination of the structure of genes and, soon, of complete bacterial genomes—sparked a totally unexpected acceleration in the study of bacteria, both pathogenic and not. Our understanding of infectious diseases was completely redefined by these approaches that, in association with cellular biology techniques such as imaging, started to shed light on the multiple mechanisms used by microorganisms to establish infection by interacting in various ways with the infected host and by harnessing many of the host’s essential functions and fundamental mechanisms.

      In parall el with this new vision on infectious diseases, research on the behavior of bacteria has shown that all bacteria without exception have a social life. They can live in small groups and diverse communities known as biofilms present on all kinds of surfaces. They can live in harmony with their fellow bacteria in heterogeneous, but stable, groups. When these groups grow in size and associate with other microorganisms, including parasites or viruses, they are called microbiomes. What was once known as the “intestinal flora” is now termed the intestinal microbiome. The intestinal microbiome is not the only type of microbiome; other parts of the body, and other organisms, feature their own. We now know that these microbiomes evolve and that they are unique to the individual they inhabit, based on their host’s specific eating habits, genetic heritage, underlying illnesses, and even personal behavior.

Even if bacteria seem to live independently in nature, many exist in symbiotic relationships not only with humans but also with all animals, including insects, and even plants. This cohabitation sometimes produces stunning effects on the host, such as sterility and even the eradication of males in insects. Bacteria present on plant roots can help them capture the soil nitrogen essential for the plant’s growth.

      Bacteria have very elaborate social lives. In addition to their ability to live in groups, and in order to do so, they can communicate using a chemical language that allows them to recognize and distinguish one another by species or family. Bacteria use these chemical languages to cooperate against a common enemy. For example, some pathogenic bacteria will not deploy their attack mechanisms unless they are numerous enough to succeed. Some bacteria can also regulate the times when they become luminescent, lighting up only once their numbers reach a certain threshold.

      In order to adapt to various situations and to decide when to use their special capabilities, bacteria employ very sophisticated regulatory mechanisms. Each bacterial component, from proteins to small molecules, including vitamins and metals, participates in multiple adaptation mechanisms that bacteria put into action at various points in their lives. The molecules that participate in the controlled expression of genomes, and on which researchers have made the most progress recently, are RNA molecules. François Jacob and Jacques Monod hypothesized that RNAs could regulate gene expression, but they never imagined that RNAs could regulate gene expression in so many different ways. Bacterial RNA, considered as recently as the end of the last century to be mostly a production intermediary between DNA and proteins (hence the term messenger RNA), plays various and sometimes surprising roles. One of the most important recent advances in biology is the discovery that bacteria have extremely effective RNA-dependent defense strategies in place, known as CRISPR (pronounced crisper) for clustered regularly interspaced palindromic repeats, which they use to prolect themselves from the bacteria-infecting viruses known as bacteriophages, or just phages. Specifically, bacteria remember their first encounter with a given phage and are able to put in place a kind of immunity, “vaccinating” themselves against this phage.

      These bacterial systems work so well and are so adaptable that they are now the basis for a revolutionary technique, the CRISPR/Cas9 technology, that allows genome editing in all organisms that have been tested so far. This method makes genome modification quick and easy, and the mutations created allow for sophisticated studies of gene function or for the replacement of defective genes, paving the way for gene therapies. The CRISPR/Cas9 technology was recognized by a Breakthrough Prize in Life Sciences in 2015 in the United States and by numerous other prestigious international prizes that honor great scientific advances.

Bacteria defend themselves not only from viruses but also from their fellow bacteria, which are sometimes very aggressive. To do this, they produce many kinds of toxins and antibacterial poisons for which they themselves have one or more immunity proteins. In the bacterial world, the struggle for life is continually taking place on an infinitesimal scale. But could these antibacterial poisons also be used on a much larger scale, to fight and gain better control over pathogenic bacteria? They certainly constitute a foreseeable strategy for replacing antibiotics that have become ineffective.

      In fact, antibiotics have been, for decades, the most used antibacterial agents. Unfortunately, bacteria have adapted accordingly, developing resistances that have dramatic medical consequences, as in the case of the bacterium responsible for tuberculosis (Mycobacterium tuberculosis, or the Koch bacillus). We are no longer able to treat certain serious illnesses, and, as a result, they are coming back with a vengeance. The alarm has been sounded. The public is aware that this is a worldwide concern. Nevertheless, there are now reasons for optimism, or at least hope. Based on our recent knowledge, we are discovering new, alternative ways of fighting pathogens, raising new hopes for more effective treatments. For example, we can use our knowledge of bacterial genomes to identify inhibitors of chemical reactions or metabolic pathways that exist only in bacteria, not in humans.

      Nevertheless, the threat of returning to a “preantibiotic” era is real and must be taken into account. We must therefore maintain constant vigilance when putting in place new therapies or when halting formerly obligatory vaccinations. Would it be reasonable, for example, to continue the policy in France