Cells of Resistance: All life forms fight to survive

The struggle for life is a trait shared by all living organisms, not just humans; from the biggest to the smallest, from bears to bacteria. A corollary to our shared struggle for life is a built-in resistance to death: when any form of life is threatened by an enemy, a serious injury, or disease, it fights back. The interesting thing is that regardless of which kind of life is under threat, the fight back — the resistance response — is remarkably similar. You can see this in 3 cases: bacteria’s resistance to antibiotics; cancer’s resistance to chemotherapy; and the French Resistance to the Nazi German occupation during the Second World War. There are dissimilarities too, certainly moral ones, but the value of the comparison is that it offers a crucial lesson about bacteria: the harm that they cause is probably more our doing than theirs.

French Resistance 2We begin with the heroic French Resistance because it offers a helpful perspective, one that is too seldom taken into account in health circles: looking at resistance from the point of view of the “organism” under threat, in this case the French citizenry.

The Nazi German invasion and occupation of France during the Second World War constituted an existential threat to French nationhood. In response, resistance cells of small groups of armed men and women sprang up and fought back. They were few in number at first, but their numbers grew as the Occupation became increasingly unbearable. For instance, due to collective punishment — the taking of thousands of hostages from the general population and the shooting deaths of an estimated 30,000 of them — the number of resistance fighters grew to over 400,000 by the last year of the war. And as we know, the Resistance prevailed, the Occupier defeated.

Looking at antibiotic resistance through the same lens, the organism under threat is bacteria. Let’s remember, we live in a bacterial world and the vast majority of them either help us, with things like digestion and immune function, or are harmless. The invader/occupier in this case is the antibiotic; the word means, literally, ‘anti-life’ (bios, from Ancient Greece, means ‘life’). As the NEJM reminds us, antibiotics en masse constitute a huge assault: In 2009, more than 3 million tons of antibiotics were administered to human patients in the United States alone; in 2010, a staggering 13 million tons were administered to animals.

weaponry

When you’re hit hard like this, you fight back, and so the “bacterial resistance” evolved against all major antibiotics pretty much from the get-go. For example, staphylococcus bacteria developed resistance to penicillin when it was first used in the 1940s; staph then developed resistance to the penicillin-derived methicillin about a year after it was first used in 1960; hence the origin of methicillin-resistant Staphylococcus aureus (MRSA).

However, unlike the French Resistance, the bacterial resistance was slow moving for a quite a number of years. For example, the US death toll from MRSA as recent as 1999 may have been as low as 4 (children). But just over a decade later and commensurate with the antibiotic onslaught mentioned above, the Centers for Disease Control tells us that the bacterial resistance spread across the country and so MRSA now kills more than 11,000 Americans every year and seriously wounds more than 80,000. If you add in other resistant bacteria and cases where “the use of antibiotics was a major contributing factor leading to the illness,” the annual American death toll is close to 40,000 people.

Cancer cells, too, develop resistance to the “assault” from chemotherapy drugs. (There’s certainly nothing beneficial about cancer cells, as there is with bacteria, let alone something heroic about them, as with the French Resistance, but we include them because they also illustrate the principle that all living organisms respond to serious threats by developing resistance to overcome them.)

With cancer cells, as with bacterial cells, drug therapy — chemotherapy and antibiotic therapy, respectively — kills the drug-sensitive cells, but leaves behind a higher proportion of drug-resistant cancer cells. As the tumor begins to grow again, chemotherapy may fail and the patient relapses because the remaining tumor cells are now resistant. In fact, one way cancer cells resist chemotherapy is similar to how bacterial cells resist antibiotic therapy: molecular “pumps” actively expel drugs from the interior of the cell.

The lesson in all of this is explained by infectious disease specialist Brad Spellberg, MD, chief medical officer of the Los Angeles County and University of Southern California Medical Center. His point is that we have to change how we think about the bacterial world. We need to shift our approach from one based on confrontation to one based on co-existence. Thus, for example, the language of war metaphors of invasion, defense, destroying the enemy, and so on, should be abandoned because those words fundamentally misdiagnose what bacteria are about. Instead, Dr. Spellberg suggests this approach:

I like to go back to first principles before I tackle complex problems. This whole thing about winning the war against microbes … nah!

We’re not going to win a war against organisms that outnumber us by a factor of 1022 , outweigh us by a hundred million-fold, replicate 500,000 times faster than we do, and have been doing this for 10,000 times longer than our species has existed!

So what we need to do is flip it around. We’re not at war with them. What we need to do is, in the immortal words of Dave Gilbert, achieve peaceful coexistence. The question is, what strategy do we deploy to achieve peaceful coexistence?

I think we need to start thinking of infections, by and large, in most cases, as accidents. There is no advantage for bacteria in most cases to infect us. They are much better off being non-infectious commensals in our gut.

In this sense, then, our massive overuse of antibiotics is simply fertilizing disease, death, and pain. So much so that the figure mentioned above of 40,000 American deaths a year caused by the “bacterial resistance,” rivals the annual death rate of any war the US has ever been in with the exception of their Civil War.

At the end of the day, says Dr. Spellberg, it comes down to “our wits versus their genes,” and the job of our collective wits is simply to come to grips with one fundamental truth about resistance:

This is what bacteria do. They’re just being bacteria. They become resistant to stuff, they adapt. We have to accept that’s never going to stop. No matter how perfect our stewardship is, no matter how prefect our infection control is, they’re always going to adapt. So, yes, we are never going to win in the end. But … we know steps that we can [adopt] to get back ahead in the race.

The Resistance Movement: Bacteria Want to Live Too

Team BT 1The vast majority of bacteria, as it turns out, are our little buddies: They help us digest food, for example milk sugars and fiber; and they help assemble nutrients, such as amino acids, the building blocks of proteins, and vitamin K, which we need to clot blood. The surprising part, however, is they actually help us fight disease, says NYU infectious disease expert, Martin Blaser, MD, in his book, Missing Microbes: How the Overuse of Antibiotics is Fueling Our Modern Plagues. They do this, for example, by sending chemical signals to our immune system to keep it on high alert; they help to metabolize needed pharmaceuticals such as the heart drug digoxin; and they even secrete substances, including their own antibiotics, which are poisonous to foreign invaders. But they can’t do this work single-handedly; instead, bacteria have to work together in huge numbers to get the job done. For example, just one milliliter of our colon — where bacteria metabolize fiber — contains more bacteria than there are people on Earth, says Martin Blaser.

And in return for all the help they give us, how do we treat these guys? Apparently, we’re slaughtering them in droves with our indiscriminate use of antibiotics. Margaret Riley, PhD, and professor of biology at the University of Massachusetts, Amherst, analogizes the taking of antibiotics to the ingestion of a hydrogen bomb on the basis that it kills all of our body’s bacteria, not just the kind that’s causing a problem.

The extent of this antibiotic “bombing” is massive: Health care providers prescribed 258.0 million courses of antibiotics in 2010, or 833 prescriptions per 1000 persons. And according to the US Centers for Disease Control, 30-50% of antibiotics prescribed in hospitals are unnecessary or inappropriate. But there’s a bigger issue: 70 – 80% of all antibiotics sold in the US are used for the single purpose of fattening up industrial farm animals. In 2011, animal producers bought nearly 30 million pounds of antibiotics for the purpose of fattening up their livestock, a practice banned in Europe.

One has survival advantage: Light- and dark- colored moths against a dark background

One has survival advantage: Light- and dark- colored moths against a dark background

So when we drop over 15 tons of antibiotics a year on our bacterial population — in the US alone — we can expect a response. And just like any other living organism being bombed, bacteria don’t want to die either, and so they fight back by developing resistance to the antibiotic bombs. This development of resistance is simply evolution at work, meaning that developing resistance is inevitable. Evolution, however, much like bacteria, is often misunderstood, so it’s worth taking a closer look at it because it shows us how we’re not going to win a “war” against disease if our strategy is based on fighting nature. So here’s the classic example of evolution in action, which is defined as the change in a characteristic (color, in our example), of a population (moths), over time, i.e. generations, in response to an environmental event (the Industrial Revolution and soot production). OK, it involves the Industrial Revolution, but nonetheless it’s a rather cool example:

Nineteenth century England spawned heavy industry and with it came chimney smoke: dark sooty pollution that covered trees and buildings. Which just happened to be where the peppered moth like to hang out. There are 2 kinds of peppered moths, one is dark-colored, the other light-colored. At the time of the IR most were light-colored. But, as the bark of trees and the sides of buildings took on black soot, the light-colored moths began to stand out thus becoming more noticeable to birds, their natural predator. As a result, their population declined and the dark-colored moth population rose, as they were now camouflaged by the darkened trees.

This is evolution by means of natural selection: the environment changes, and that change ‘selects’ for some fraction of the population — dark-colored moths, in this case — and giving that population a survival advantage and thus a reproductive advantage.

Back to our bacteria. The analogue to the IR and soot is the antibiotic. The analogue to the light-colored moth that the changed environment selected against is all our bacteria that aren’t resistant to antibiotics: i.e. the vast majority that help us live healthier lives or are at least harmless. And the analogue to the dark-colored moth that the changed environment selected for, thus giving it a survival and reproductive advantage, is the bacteria that are resistant to antibiotics.

Bacteria GT3

There is one important difference with (resistant) bacteria. They have a trick up their sleeve: the ability to transfer their genes that confer resistance to antibiotics, to other (susceptible) bacteria, in real time — nicely illustrated in the above cartoon. Think of genes, Dr. Blaser says, as a deck of cards, and the transfer of genes as swapping out of one of the cards. It would be as if the dark-colored moth could hand their genes that code for their dark color to the light-colored moth sitting sitting beside it on the tree.

The upshot of our “drug abuse” — the overuse and misuse of antibiotics on our resident bacteria — is the proliferation of bacteria that are resistant to those very same antibiotics. So much so that the US Centers for Disease Control reported that:

Antibiotic resistance is a worldwide problem. New forms of antibiotic resistance can cross international boundaries and spread between continents with ease. Many forms of resistance spread with remarkable speed. World health leaders have described antibiotic resistant microorganisms as “nightmare bacteria” that “pose a catastrophic threat” to people in every country in the world.

The same CDC report said that MRSA poses a serious public health threat. The agency conservatively estimated that it caused 80,461 invasive infections and 11,285 related deaths in 2011, the last year for which statistics were available. The report also said that a much higher number of less severe infections occurred in both the community and in healthcare settings.

So here’s a question. We have two examples of evolution where organisms successfully adapted to environmental pressures: dark-colored moths and bacteria that are resistant to drugs — in each case conferring a survival advantage. But what about humans: can we think of a case where we have evolved, say over the last 50 to 100 years, in a way that has conferred a survival advantage? If so, what is our newly acquired trait that’s analogous to the dark-color in the moths or the drug-resistance in the bacteria, that gives us that advantage?

Put another way, if we can’t specify such a trait, does that mean humans have stopped evolving?

 

 

 

 

 

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