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 voilà, 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.
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