Thursday, November 24, 2016

Microbes, Microbial Consortia, Antibiotics, and Our Future

The danger from antibiotic resistant strains of microbes has been well publicized as the occurrence of difficult-to-control infections has grown.  As this resistance is developed it appears to spread quickly to other species of microbes.  The response has been to seek new and more powerful chemicals, but the prospects appear dim.  What is less well publicized is the fact that most of our current antibiotics were obtained by extracting chemicals that are produced by microbes.  One difficulty in finding new antibiotics is that 99% of the world’s microbes seem to refuse to allow themselves to be grown in a laboratory where their products can be assessed and harvested if appropriate.  To obtain an understanding of why this is the case and why microbes can mutate so quickly, we will turn to Paul G. Falkowski and his book Life's Engines: How Microbes Made Earth Habitable

Single celled microbes have been around for billions of years.  Falkowski details the relatively small number of chemical “engines” that evolved to provide the basis of life for these creatures.  He then illustrates how these simple structures could have evolved into more complex multicellular forms and, in so doing, remade the earth into a platform that would support the huge array of large life forms that inhabit the planet today.  Of interest relative to the search for new antibiotics is the symbiotic existence developed by most forms of microbes.

Microbes learned early on that survival is easier if they form cooperative groups.

“Microbes do not live in isolation; most of them are symbionts, that is, they live together and depend on each other for resources.  More specifically, microbes use each other’s waste products for sustenance.  The use of waste products—also known as the recycling of elements—is one of the basic concepts in ecology, and it has strongly influenced the evolution of microbial nanomachines.”

Microbes also have a very flexible and efficient mechanism for evolution.  Rather than evolving via some random genetic variation that is passed on to offspring, microbial evolution is dominated by horizontal (or lateral) transfer of genetic information via mechanisms that are not well understood.  The most direct means is for a microbe to simply absorb genetic material from its environment.  A fraction of the time the material will be incorporated and passed on to subsequent generations.  Genetic material can also be incorporated via interaction with the numerous viruses which inhabit the environment.  Also, similar types of microbes can form a bond together and exchange DNA.

“Horizontal gene transfer is not a biological curiosity; it is a major mode of evolution in microbes.  Simply put, genes that were preadapted by selection in one organism can somehow be transferred to another, completely unrelated organism without sexual recombination.  In effect, this is quantum evolution—an organism that did not have the capability of fixing nitrogen can acquire genes for nitrogen fixation from the environment, and voilĂ , it instantly can fix nitrogen.”

This method of evolution is important because it can happen so quickly.

“Indeed, the process is frighteningly rapid.  One of the very first examples of horizontal gene transfer was discovered in Japan when it was realized that resistance to antibiotics was acquired by pathogenic bacteria much faster than could be explained by classical vertical inheritance.  When the era of gene sequencing came into its own, it was quickly shown that genes for resistance to many common antibiotics were spread all across the microbial world.”

The collections of interacting microbes that form stable communities are labeled by Falkowski as “consortia.”  Given a large number of members made up of a significant number of species, one arrives at a highly adaptable entity that can respond to dramatic changes in environment.  The microbes of a consortia share their products, and they are also capable of internal communication.

“Microbial communities, or consortia, are microscopic jungles in which tens or even hundreds of species of microbes live in a mutual habitat.  It should be noted that it is often difficult to strictly define what a microbial ‘species’ is.  The traditional definition of the word—that the offspring from sexual recombination is viable—which is testable in animals and plants does not readily apply to microbes….horizontal gene transfer makes defining ‘species’ somewhat specious.”

“On a microscopic scale, the organisms within a consortium are living within very close proximity.  Under such circumstances, the opportunity for successful horizontal gene transfer is greatly enhanced.  Hence, within consortia, gene transfers often allow a distribution of metabolic nanomachines across many groups of microbes, thereby allowing the flows of elements between organisms to be tightly controlled.”

“Controls are imbedded in the chemical signals that are sent from microbe to microbe within the community and that provide information about who is doing what and how many are where.  The system of intercellular signaling, called quorum sensing, resulted from the evolution of specific molecules that are made and used by microbes to assess their own population density, as well as to signal other microbes about who and where they are.  This mode of intercellular communication remains pretty remote to us, although we do know that there are specific molecules sent out be some cells that float around until they attach to specific receptor sites on another microbe’s membrane.”

“Once attached, the molecules work by altering the expression of genes in a cell.  Quorum sensing allows consortia to establish a spatial pattern of microbial metabolism that further increases the efficiency of recycling nutrients.  But it can also alter behavior.”

Given that most of our antibiotics are produced by microbes, Falkowski believes that these forms of molecules are used as a defense mechanism against dangerous microbes.  If true, that would be a rather sophisticated response to a threat by one of these consortia.

Falkowski also reminds us that we carry around our own private consortia of microbes.  We evolved within a microbial bath, and the microbes evolved with us.  We and they are one.  The most important consortia are those that exist within our digestive systems.  They are essential to life, yet we damage them every time we take an antibiotic.  After an individual course of an antibiotic it takes time for the consortia to recover.  Multiple courses taken over a lifetime can result in permanent changes in our individual consortia and produce effects on our health.  Species of microbes can be eliminated entirely if they are not available to be passed on to our offspring.  The medical community is currently struggling to understand how bodily function is dependent on the specifics of our digestive consortia.

It would seem that the reason most microbes refuse to grow in a laboratory is because they are not so much individual species as members of a consortium tuned to and requiring an environment that has not been, and, perhaps, cannot be reproduced in a laboratory.

Raffi Khatchadourian provides a view of the state of antibiotic research with a focus on attempts to gain access to the microbes in the mysterious 99%.  His article appeared in The New Yorker with the title The Unseen.  Khatchadourian uses the efforts of one researcher, Slava Epstein, to access these “unseen” microbes as the theme of his piece.

“Nearly all of microbiology, Epstein eventually learned, was built on the study of a tiny fraction of microbial life, perhaps less than one per cent, because most bacteria could not be grown in a laboratory culture, the primary means of analyzing them. By the time he matured as a scientist, many researchers had given up trying to cultivate new species, writing off the majority as “dark matter”—a term used in astronomy for an inscrutable substance that may make up most of the universe but cannot be seen.”

The available 1% has been tremendously useful to humanity, providing the motivation to access much more of the microbial population.

“The near-universal presence of bacteria in nature—from the deepest layer of the Earth’s crust to the upper atmosphere—is reflected in their protean applications. They can be used to make industrial foods, to engineer perfumes, to produce fuel or to clean it up. More than half the cells in the human body are microbial, and many of them exist as biological dark matter, too; learning how they function could offer countless insights into human longevity. For decades, microbes had been a source of essential pharmaceuticals: chemotherapies, blood thinners, and drugs crucial to organ transplants. From just the one per cent of bacterial life that scientists had been able to cultivate, researchers had derived virtually every antibiotic used in modern medicine.”

The popular notion that microbes produce antibiotics to kill other microbes is dubious, and, in fact, is rather frightening.  One does not wish to envisage a world where microbes are busy producing lethal compounds to kill an enemy.  Humans could one day become the enemy.

“If antibiotics are indeed weapons, then humans are latecomers to an aeons-old arms race, whose rules remain opaque to us. “It is absurd to believe that we could ever claim victory in a war against organisms that outnumber us by a factor of 1022, that outweigh us by a factor of 108, that have existed for a thousand times longer than our species, and that can undergo as many as five hundred thousand generations during one of our generations,” several scientists argued in a recent paper.”

Epstein prefers to assume that what we call antibiotics are used by microbes for cooperative purposes and only become lethal when used at unnaturally high concentrations.

“For one thing, no one has ever measured concentrations of antibiotics in nature which are lethal to bacteria. He is open to the notion that these chemicals might be for signalling, and that they seem like weapons because of how we use them.”

The danger of generating resistant bacteria was apparent as soon as antibiotics were discovered.

“During the Second World War, penicillin was used widely, and it did not take long for resistant bacteria to spread. But many new drugs were being discovered, particularly from easily cultivatable species of actinobacteria. In 1943, there was streptomycin, the first cure for tuberculosis, and on the heels of that came chloramphenicol, chlortetracycline, neomycin, erythromycin. The rush of discovery gave the impression that nature contained an infinitely deep trove of new medicines. In 1962, a Nobel-winning immunologist went so far as to declare “the virtual elimination of the infectious diseases as a significant factor in social life.” Antibiotics became omnipresent. In industrial farming, they were used to hasten animal growth and to shield plants from pests; in medicine they were often overprescribed or incorrectly prescribed. Microbes, meanwhile, kept evolving.”

The 1% could not provide an unending supply of new molecules and progress ground to a near halt.

“As costs rose and results diminished, most of the largest pharmaceutical companies shuttered their antibiotic-discovery programs. The fear now is that the aging war chest will be rendered totally ineffective. Already there are strains of tuberculosis and gonorrhea, among other pathogens, that are resistant to virtually every drug in the medical arsenal. By conservative estimates, there are now seven hundred thousand fatalities from antibiotic-resistant bacteria in the world each year.”

Expressions of unbridled optimism are being replaced with those of despair and of an impending apocalypse.

“In desperation, hospitals have begun to revive old antibiotics that were discarded because they were too toxic. One such drug, colistin, was set aside for decades because its side effects included kidney damage and neurotoxicity. Today, it is a last line of defense against the hardiest of pathogens—though probably not for long. In 2012, the World Health Organization recommended that it be administered under strict regulation, but farmers around the world continued to use the drug liberally, particularly in China, where it was given to livestock by the ton. In 2013, researchers in China discovered colistin-resistant E. coli in the intestine of a pig, and a few weeks ago a similar strain was found in a patient in Pennsylvania—prompting the head of the Centers for Disease Control to declare that ‘the end of the road isn’t very far away for antibiotics’.”

A view of a future with ever-diminishing antibiotic effectiveness is not something one would choose to linger on.

“….a study commissioned by the British government predicts that, if trends continue, annual fatalities from drug-resistant microbes could exceed ten million by 2050, eclipsing those from cancer. Many key advancements in modern medicine could be reversed. As one researcher noted recently, ‘A lot of major surgery would be seriously threatened. I used to show students pictures of people being treated for tuberculosis in London. It was just a row of beds outside a hospital—you lived or you died’.”

Even if people like Epstein are successful at extracting new chemicals from the dark 99%, is that really a solution?  Or does it buy us perhaps another few decades before the ever-adapting microbial armies overwhelm them as well?  Humans like to believe that they rule the earth, but it could be the microbes that are really in charge.

The interested reader might find the following articles informative:

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