Evolutionary Lessons From Superbugs

The genetics and genomics of bacterial antibiotic resistance and virulence teach us some fundamentally important lessons about evolution. They also pose some significant challenges to scientific explanation.
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Virulent drug-resistant "superbugs" are back in the news. We have a lot to learn from these small but smart creatures. To the dismay of many in the pubic health field, the FDA just dropped plans to enforce a 1977(!) decision to limit the use of antibiotics in animal feed, which facilitates the emergence of antibiotic-resistant pathogens. A December 23, 2011 article in Wired by Maryn McKenna ("FDA Won't Act Against Ag Antibiotic Use") and a December 27, 2011 New York Times blog by Mark Bittman ("Bacteria 1, F.D.A. 0") tell the story. I'll leave it to others to discuss the political ramifications of this disastrous (in)action. Here, we'll look at it as another reflection on public misunderstanding of modern evolutionary science.

How do bacteria acquire antibiotic resistance? How do they become pathogens? We currently know a great deal about the genetic basis of these critically important bacterial properties. We also know how resistance and virulence are acquired and spread to new species. The story of how we came to this knowledge is a fascinating and instructive chapter in the history of science -- it illuminates the insight that scientific "fact" consists of more than experimentally confirming hypothetical predictions.

In the early days of molecular biology, bacterial geneticists applied conventional evolutionary concepts from the pre-DNA period to explain the evolution of antibiotic resistance. The theory was that mutations could alter the structure of cell components and either block entry of the drugs into the bacteria or prevent their action on cellular targets, such as the enzymes essential to cell wall synthesis. Even if the initial mutation did not confer a high degree of resistance, accumulation of several sequential changes would result in resistance to the antibiotic levels used in clinical medicine. Indeed, a wide variety of laboratory experiments confirmed this theory, and bacterial geneticists isolated the predicted mutant strains. In virtually all cases, the resistant mutants grew less well than the parental sensitive bacteria, leading to the comforting conclusion that resistant bacteria would not significantly accumulate in nature. The degree of confidence was so great that the U.S. Surgeon General in 1967 declared that "the war against infectious diseases has been won" (Fauci 2001).

There were problems both with the science and the new public health policy based on it. The Surgeon General "misunderestimated" the bacteria, which followed their own evolutionary rules and did not listen to what the scientists said they should do. Although experimentally confirmed, the mutation theory of antibiotic resistance failed to account for most cases in the real world. Resistance continued to spread among bacteria isolated in clinics around the globe. Even more ominously, different strains of pathogenic bacteria increasingly displayed resistance to more than one antibiotic at a time. Research pioneered in Japan found that multiple antibiotic resistances could be transferred simultaneously from one bacterial species to another (Watanabe 1967). The DNA agents responsible for this transfer are circular molecules that are called multidrug resistance plasmids, which can move from one cell to another (Clowes 1973; Novick 1980). Moreover, the resultant multiply resistant bacteria were not altered in their cellular structures or inhibited in their growth properties. Rather, they had acquired new biochemical activities that could destroy or inactivate the antibiotics, chemically alter their targets, or remove them from the bacterial cell (Davies 1979; Levy 1998).

Multiple antibiotic resistance clearly represented genome change and evolution of a type unimagined in the pre-DNA period. DNA molecules could be transferred "horizontally" between unrelated cells rather than inherited from ancestral cells. Moreover, horizontally transferred DNA could carry complex sets of genetic information encoding multiple distinct biochemical activities. Evolutionary leaps involving several characteristics at once could occur through horizontal DNA transfer.

Over time, it became increasingly clear that bacteria and other microorganisms engage in a great deal of horizontal DNA swapping. In addition, these small cells have an ample toolbox of natural genetic engineering mechanisms to incorporate and rearrange this horizontally acquired DNA (Miller 1998; Shapiro 2011). In the early 1980s, two obscure French-Canadian microbiologists published a book called A New Bacteriology, postulating a radically different approach to thinking about bacterial evolution (Sonea and Panisset 1983). Sonea and Paniset argued that bacteria have a huge collective genome distributed throughout nature in different kinds of cells, in viruses and latent in the environment. When a new ecological niche appears, bacteria can assemble the genomic assets they need to exploit the opportunity.

Subsequent research has bolstered Sonea and Paniset's initially outlandish idea. First of all, we know that bacteria have all the abilities they need to acquire DNA from the environment, from viruses and from other cells. Secondly, detailed study of many bacterial characteristics, especially pathogenicity (the ability to cause disease) and virulence, indicate that they are encoded by plasmids or by critical segments of the DNA, so-called "genomic islands" (Hacker and Carniel 2001; Juhas, van der Meer et al. 2009). The sequences of genomic islands show that they have been acquired from unrelated organisms and integrated into the cellular genome by natural genetic engineering methods. (Future blogs will explore these methods in more detail.) Finally, the new field of "metagenomics" (viz. isolating and analyzing mass DNA samples collected directly from the environment) has demonstrated that there are vast ecological reservoirs of viral and other extracellular DNA encoding many properties useful to bacterial cells (Gilbert and Dupont 2011).

The DNA sequences that encode molecules needed for essential virulence processes in pathogenic bacteria are most often found on plasmids and in genomic islands, indicating that they are subject to frequent horizontal transfer (Tseng, Tyler et al. 2009). These virulence molecules almost invariably include several that associate to form complex structures, which span across the membranes and cell wall that comprise the bacterial envelope. These envelope-spanning structures have proven essential to the transport of large biological molecules (so-called "macromolecules") from one cell to another. The pathogens use these molecular transport systems to inject protein and RNA molecules into cells of the host organism (whether animal or plant). In so doing, they subvert host cell regulatory circuits in a way that meets the invading bacterium's needs (Bhavsar, Guttman et al. 2007). Truly, bacteria are the smartest cell biologists on the planet because they control events in cells of higher organisms in a way that mere human scientists can only dream of imitating.

The bacteria also use these or similar macromolecular transport structures to acquire DNA from the environment or transfer DNA between cells (even to cells of plants and, at least in the laboratory, to fungus and animal cells) (Chilton 1983; Sprague 1991). These structures are further used for so-called "twitching" movement across solid surfaces (Mattick 2002) and are related to other envelope-spanning structures involved in synthesis of high-energy storage molecules and rotation of bacterial flagella (literally, "whips") for swimming through fluids (Egelman 2010; Filloux 2011). Thus, there has been a wide-ranging use and reuse of these elaborate systems in the course of bacterial evolution. Since the Intelligent Design (ID) advocates point to the bacterial flagellum as an example of an "irreducibly complex" structure that could not have evolved by Darwinian evolutionary processes (Behe 1996), they need to address how such intricate and clearly related biological inventions have come to be diversified for so many different uses. Certainly, the ID argument is greatly undermined if it has to invoke supernatural intervention for the origin of each modified adaptive structure. At the same time, it is fair to recognize that the evolutionary science community is also challenged to come up with detailed explanations for the origin and diversification of a basic complex functional design.

The genetics and genomics of bacterial antibiotic resistance and virulence teach us some fundamentally important lessons about evolution. They also pose some significant challenges to scientific explanation. The main evolutionary lessons are:

(1) Living cells are not solely dependent upon vertical inheritance for acquiring DNA encoding new traits; they can definitely acquire DNA by horizontal transfer from other cells, often of different species or even different kingdoms.

(2) Multiple genomically encoded functions can be acquired at once in a single DNA transfer event; in other words, evolutionary change can be sudden and does not have to proceed one trait or one small change at a time.

(3) Once a complex invention has arisen in evolution, it is subject to modification and adaptation to a variety of different uses, sometimes related functionally (as in macromolecular transport) but sometimes of quite different function (as in twitching and flagellar motility).

In addition to these three important lessons, the bacteria pose at least two great challenges to evolutionary science:

(I) How did the first functional envelope-spanning complex originally arise in evolution? Although we can easily reject the supernatural solution ID advocates propose in response to this question, we also have to acknowledge that we still have no clear scientific answer to it.

(II) How did the bacteria come to be such sophisticated cell biologists and evolve the capacity to produce molecules that subvert the cell control regimes of higher organisms to their own (i.e. the bacteria's) benefit? To my mind, this is a far deeper and, ultimately, far more rewarding question to pose.

Let us conclude this blog in the head-scratching mode, which is the right place for scientists to be. I am in the habit of telling students, "If you're not confused, you're not doing science" -- by which I mean: if we already know the answer, there is nothing new to learn from asking the question. Even when we think we know the answer, as in the case of bacteria evolving antibiotic resistance, nature may well have another solution we never considered. It is salutary to remember that this last point proves more often to be the rule than the exception.


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