“The Martians—dead! . . . slain, after all man’s devices had failed, by the humblest things that God, in his wisdom, has put upon this earth.”

—The War of the Worlds, H. G. Wells, 1897

Just about everywhere you look an invisible (and humble) presence lurks, a horde of single-cellular organisms that is found on every surface of the planet, in the depths of our deepest oceans, and even floating high up in the atmosphere mixing with the very air we breathe. These organisms belong to life’s two super domains of organismal classification: prokaryota (organisms without a nucleus, including bacteria and archaea) and eukaryota (those with a nucleus).

The planet’s microbiome is the entire collection of bacterium, archaea, viruses, various fungi and yeasts, protists, amoebas, and other single-celled eukaryotes. There are more bacteria living on Earth than there are stars in the known universe, and it is currently thought that there are approximately as many microbes in and on our bodies as there are human cells, perhaps more. Not bad for something so small. In fact, it’s estimated that our breathing expels nearly forty milligrams of microbial matter into the air every hour, roughly the same amount of matter as half a typical baby aspirin.

Microbes have long captured our imagination since the veil was lifted on their presence in the 1670s by Dutchman Antony van Leeuwenhoek and others (several philosophers centuries before also suspected the presence of infinitesimally small organisms). Bacterial pathogens have also been major plot points in some of the most famous works in science fiction, including their unassuming role in defeating our alien invaders in The War of the Worlds.

In reality, we have an intimate connection with our unicellular cohabitants. Our gut and skin harbor millions of bacteria, fungi, and viruses that interact with our own cells and even provide us with essential metabolites that our bodies cannot produce. An excellent overview about this interaction can be found in Clarkesworld #117, written by Matthew Simmons, and we’ll touch on some of the most recent discoveries here.

Scientists have found that the food we eat profoundly influences our gut flora. Analysis of the bacteria found in the digestive tracts of individuals eating high-fat, high-protein diets showed higher production of metabolites that cause inflammation in the colon. Switching an individual’s diet to an agrarian, high-fiber diet caused the microbiome of the gut to shift in response. This resulted in lower amounts of inflammatory metabolites produced by the newly introduced microbes within the colon, including a significant reduction in secondary bile acids like deoxycholic acid, which can increase colon inflammation and has been found to be carcinogenic by causing DNA damage.

Food isn’t the only source of our own microbes. We interact daily with the microbiomes living on the surfaces of our homes and offices. In return, these little ecosystems are also heavily influenced by us and shift in their makeup depending on who passes through and with what they are carrying. Additionally, it has recently been shown that our skin and gut microbiomes are seeded by our mothers during birth. Important strains of bacteria that stimulate the activation of the immune system early in life are found in babies who have gone through vaginal birth as opposed to Caesarian sections. Researchers are now looking at ways to grow these bacteria and supplement babies born via C-section to provide their immune systems with a boost. 

We have seen that the profile of the human microbiome can change over the course of our lifetime. As we grow into old age, we lose quantities of an interesting bacteria called Akkermansia muciniphila, found commonly within our digestive tract. It’s believed the presence of this bacteria can reduce inflammation in the gastrointestinal (GI) tract, particularly by creating short-chain fatty acids used as fuel by our own cells in the gut and stimulating the production of additional compounds required for the growth of additional beneficial bacterium.

Lower levels of A. muciniphila are associated with diabetes, age-related insulin resistance, and in some cases, resistance to chemotherapy in cancer patients. For the last few years most of these associations did not have a fully elucidated mechanism on how this relationship occurs on the molecular level. A study published in November 2018 in Science Translational Medicine has established a firm link between A. muciniphila and its protective effects against inflammation in the immune system. It was observed that the presence of A. muciniphila protects against gut leakage, preventing other bacterial toxins from getting into the bloodstream and activating our immune cells and downstream inflammatory response. Dietary intervention and supplementation of aging mice and macaques with A. muciniphila restored age-related insulin sensitivity and reduced overall inflammation in these animals.

Dietary supplementation of bacteria is nothing new. Cheese, yogurt, unpasteurized milk, and many other foods contain beneficial microbes that aid our digestion. Some labs are even trying to develop chocolates that contain supplemental A. muciniphila to provide a boost to the gut flora and benefit the immune system. This may also be the first case in which a human therapeutic intervention is borrowing from fantasy literature, since we all know that eating chocolate will also restore your health after being attacked by the Dementors of Azkaban. Thank you, Madam Pomfrey and Professor Lupin.

But putting our wands aside for a moment, bacteria and other microbes are incredibly powerful organisms that often don’t get the credit they deserve. Bacteria evolved the world’s first rudimentary immune system, known famously today as CRISPR, which is now used for precision genome editing (read more about CRISPR in Clarkesworld #144). Additionally, bacteria are quite sophisticated in communicating with one another using chemical concentration gradients.

Known as quorum sensing, bacteria can release proteins or chemicals, similar to basic hormones, into their surrounding environment and take stock of the concentration of that same chemical released by other nearby bacteria. The greater the concentration of the chemical, the greater the population of bacteria nearby, which can trigger genetic responses that coordinate bacterial growth, metabolite sharing, or the formation of biofilms. Biofilms are three-dimensional scaffolding of bacteria and other microbes that adhere to a surface and provide mutual benefits to each cell involved. These benefits can include protection from changes to the environment, including resistance to antibiotic exposure, and coordinated growth towards new energy sources.

Some bacteria are even being used in batteries. Exoelectrogenic bacteria are capable of transferring electrons to the outside environment in which they live. Scientists have collected these bacteria and used them in fuel cells to create microbial electrochemical systems, which utilize these reactions to build up electric potential. Many of these organisms are extremely difficult to culture in the laboratory. They often grow in the sediments of rivers or the ocean floor and laboratories are looking to scale up these reactions to provide more and more power, including immobilizing bacteria from these sources onto artificial biofilms for a more user-friendly system.

Humans have also borrowed heavily from the capabilities of microbes living in the extreme environments on planet Earth. Archaea extremophiles have evolved and adapted to live in the world’s harshest places, including on extremely hot undersea volcanic vents, in very acidic lakes and caves, and even between the mineral grains of solid rock. Because these organisms still need to exhibit similar metabolic functions as organisms living in less harsh conditions, the proteins they create have evolved to function properly in such environments.

One such protein is called DNA Taq polymerase, first isolated in the 1970s from the bacterium Thermus aquaticus, which thrives in the superheated water of hot springs. DNA polymerases are a group of enzymes that synthesize new strands of DNA, often during mitosis when a cell undergoes division into two daughter cells. These enzymes are so important in maintaining the fidelity of the DNA sequences that they are copying that we have at least 14 different genes coding for these enzymes in our own genome, which all have subtly different functions that are required for DNA replication, maintenance, and damage repair.

But if you plop one of our DNA polymerases into a hot spring, the high temperatures will cause it to denature, meaning it will lose its three-dimensional structure (akin to unfolding a paper airplane back into a flat sheet of paper) and cease to work properly. Bacteria living in high temperatures all the time must still be capable of DNA replication if they are ever to divide and grow. Taq polymerase is a DNA polymerase adapted to such conditions and does not denature at high temperatures.

Clever scientists in the 1980s realized this property of Taq polymerase and used it to their advantage. Today, most laboratories around the world perform a simple reaction called polymerase chain reaction (PCR), which copies strands of DNA into larger quantities for use in the laboratory, similar to a molecular photocopier. PCR is a procedure that requires near-boiling temperatures to work, so scientists decades ago used Taq polymerase isolated from T. aquaticus and other organisms similar to it to perform this reaction. PCR and Taq allow researchers to take very small amounts of input DNA and measure gene expression in cells, identify criminals from a blood sample, and assess and individual’s genetic ancestry and disease risk from saliva.

Perhaps the most significant process that bacteria and other single-cellular organisms routinely perform is horizontal gene transfer (HGT). We typically think of inheritance from a generational perspective—our parents had us, passed down their genes to us, and we may have our own children, who will be inheriting our own genetic information. Bacteria, archaea, and eukaryotes all participate in this mode of genetic transfer, but many species within each domain of life are capable of sharing genetic information directly with one another in a routine manner, often even between species of different domains.

Horizontal gene transfer is the direct transfer of genetic information between two individual cells and is a major mechanism of microbial evolution today as well as in our past when it was only unicellular organisms ruling the planet. One such way this occurs is through a process called conjugation, where one bacterial cell will directly transfer genetic information physically to another bacterial cell through a tubelike structure called a pilus.

The pilus generally transfers DNA plasmids. Plasmids are circular pieces of DNA that are smaller than bacterial genomes, but can often carry several genes that encode for different metabolic or physiological functions. Genes that provide bacteria antibiotic resistance can be found on plasmids and their transfer through a given microbiome via HGT is one of the major ways a population of bacteria can rapidly become antibiotic resistant.

There are two other major pathways through which HGT can occur. The first is called transformation, whereby bacteria can simply pick up DNA plasmids or other DNA and RNA found free-floating in the environment. Many times, these random pieces of genetic material have gotten into the environment after other cells have died and burst open, spilling their contents out into the environment for other bacteria to pick up and benefit from.

The last process is called transduction and it requires the aid of bacteriophage viruses. Phage viruses only infect bacterial cells. They’re found in our gut alongside our microbiome, and in every other place that bacteria are found. When a phage infects a bacterial cell, it will hijack the bacteria’s cellular machinery in order to mass-produce copies of itself, and its own genome, before bursting the bacterium open and spreading itself to the next cells. Sometimes during the formation of new virus particles, phages will capture and incorporate part of the genome of the bacterial cell it has infected into the capsid of the newly-constructed phage, where its own genome is stored. This is a random process and when this phage infects a new cell, these captured genes are then transferred to the new bacterium, which will incorporate them back into its own genome if it survives the phage’s attack.

Conjugation, transformation, and transduction have aided the evolution and adaptation of nearly all forms of life on Earth. It’s as important a process as generational inheritance in shaping the course of evolutionary history and it helped give rise to eukaryotic organisms, including our direct single-celled ancestors.

There are many more contributions to our world that we have microbes to thank for, but the last one we will visit here are antibiotics. Sir Alexander Fleming discovered penicillin in 1928, an antimicrobial compound secreted by green molds that was manufactured into the first modern antibiotic for human use during World War II. Soon thereafter, pathogenic bacteria began developing resistance to penicillin and related antibiotic treatment. Today, due to the overuse of antibiotics, many bacteria aided by horizontal gene transfer have resistance to multiple types of drugs. Searching for a new weapon to combat disease, clinicians have looked into our past to find a way to combat MRSA, drug resistant TB, and other types of diseases and infections. Coincidentally, that brought scientists back to World War II.

While the Allied powers benefited from the use of antibiotics on the frontlines, the Russian military did not have access to this technology. Instead, they mass-produced the sworn enemy of the bacterium—the phage virus. Russian medics on the frontlines would carry vials of phage with them to treat infections in their soldiers, acting like an antibiotic to safely treat wounds and other diseases without harming human cells. Today, we have resumed earlier work studying the use of phages as a novel therapeutic to treat drug-resistant bacteria, either alone or in combination with current antibiotics.

This new treatment option faces regulatory hurdles in the United States and will require further examination before drug trials can be begin in earnest, including the safe use of phage in animal models to determine the correct dosage, efficacy, and lasting impact on microbial drug resistance. However, the future looks promising and it only seems like a matter of time before we discover the next big things those small creatures of the world’s microbiome are capable of doing.

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