You wouldn't know by looking at Escherichia coli that it's kind of a big deal.
The non-descript, pill-shaped cell is why we understand fundamental life processes (think DNA replication and transcription). With its speedy growth and adaptability, E. coli has spent many years at the top of the "model organism" list, with no signs of slipping.
But E. coli is a blip in a rich microbial world; in an age of rapidly advancing technology, scientists are routinely uncovering a plethora of bacteria in, on and around us. With a siloed focus on E. coli and other go-to model microbes, what are we missing? How much of what we know about E. coli really applies to the countless bacteria inhabiting our planet? Such questions have prompted researchers to rethink our infatuation with microbiology's superstar and consider what can-and should-constitute a model going forward.
E. coli: Microbiology's First Top Model
Nearly 150 years ago, a physician scientist named Theodor Eserchich isolated a rod-shaped bacterium from the gut of an infant. That bacterium was E. coli, and it would go on to revolutionize science.
E. coli is a hardy microbe with a short generation time, flexible growth requirements and genetic malleability, all of which prompted its early adoption by laboratories and underlie its continued use today. The microbe shares these traits-i.e., quick growth and relatively easy manipulability-with other model organisms, like fruit flies and mice. Scientists study such organisms to generate knowledge that can be extrapolated to other species. "The real world is vast," said Brett Baker, Ph.D., an associate professor of integrative biology and marine science at The University of Texas Austin. To narrow things down, he noted, scientists often focus on a subset of key organisms and apply the findings to the greater world.
In this regard, E. coli has served researchers well. It has had a storied career as the vessel for seminal discoveries like elucidation of the genetic code, gene regulation, the stochasticity of mutations and horizontal gene transfer, among others. The bacterium has also proven invaluable in genetic engineering and biotechnology.
The more E. coli has been studied, the more tools and resources have been created to study it, leading to new insights that inform development of additional tools and resources. This self-perpetuating cycle is common among model organisms-researchers use them because it has become easy and approachable to do so; the more they use them, the easier and more approachable they get.
When asked how E. coli became the giant it is, Paul Jensen, Ph.D., an assistant professor of biomedical engineering at the University of Michigan, pointed to inertia. "Things that we know a lot about are the things we have good tools for," he said. "Everything in science leads to more follow-up questions, [and] it just branches out."
Dominant in Research, Not in Life
But there's a catch: "Basically all model organisms, the ones that are most studied and most published on, are rarely that abundant in the environment," Baker said. Indeed, despite its bigwig status in research, E. coli is not usually a primary member of environmental communities and generally exists at low abundances in the human microbiome, with exceptions-infants, for instance, have higher gut populations of E. coli than adults, and the concentration can wax and wane throughout life.
Omics and sequencing technologies have shone a light into the dark corners of the microbial world. The result is an expanding roster of organisms with largely underexplored or unknown roles in the machinations of life. But these organisms tend to get little attention. Researchers know a lot about E. coli-what is unclear is how much of that knowledge applies to uncultured and/or understudied bacteria living in diverse landscapes and communities.
Jensen crunched the numbers to reveal just how skewed research is toward a favored few bacterial species. He counted how many articles in the PubMed database refer to 1 of the over 43,000 known bacterial species in their title or abstract. The results, published in a recent pre-print, show that nearly 74% of species have never been the subject of a publication. For those that have been studied, 50% of all articles refer to only 10 bacterial species. Unsurprisingly, E. coli holds the top spot, with 21% (over 300,000) of all articles. Staphylococcus aureus and Pseudomonas aeruginosa are next, with 8.8% and 4.9% of published papers, respectively. The bacteria on the list also lean heavily in the direction of human health, with less representation of environmental organisms.
"I think the surprising finding is that we're going in the wrong direction. It's getting worse," Jensen said. Scientists are uncovering so many new microbes that it will take years to compile a decent knowledge base for even a handful of them-especially if E. coli and its 9 closest friends continue to dominate. By persistently homing in on tried-and-true organisms, countless bacterial processes, functions and ways of existing in the world remain a mystery.
"We're missing a lot of cool microbiology," Jensen noted. "There are all sorts of new bacteria that have interesting chemistry and live in in ridiculous environments that we're just never going to see, because E. coli doesn't behave that way." Even well-studied bacteria diverge from E. coli in basic processes (e.g., the ins and outs of the TCA cycle), and there are also variations between and among countless laboratory and natural E. coli strains, highlighting the nuance underlying the humdrum of existence.
This is a known limitation of model systems; they are, after all, models, not the end all be all of biology. But probing bacteria existing in the shadows could unearth processes and functions that are valuable not just for advancing the field, but with potential applications for advancing human and planetary health.
Rethinking Model Organisms: Looking Toward Unstudied Microbes and Communities
It is also worth reconsidering what a model even is. It may be an individual organism, like E. coli, but it could also be a mixture of organisms that interact and rely on each other in their natural habitat. This is admittedly more complex, but perhaps more biologically relevant.
When it comes to all the unstudied microbes out there, scientists may have to look beyond models entirely. Jensen proposes harkening back to the days before scientists could interrogate the molecular nitty gritty of how a bacterium functions. "We had to do these very phenomenological studies where we would just grow things and see what they did and try and observe them before we could manipulate them," he said. "Maybe we need to give ourselves a break and say it's okay to go back to that kind of science, even though we have tools to do more advanced science in these [model] organisms."
One hiccup with this plan: most bacteria in the world are hard to cultivate or have never been cultivated. Baker, who uses culture-independent techniques to understand microbial communities, such as those associated with deep sea hydrothermal vents, highlighted that the reason that people work on models is because they're easy to grow in a lab. But, he explained, metagenomics, coupled with other analytical tools like metabolomics, transcriptomics and proteomics, means scientists can learn a lot about microbes without growing them up. It is even possible to do genetics from uncultured microbes. It's not that culturing isn't important, just that it doesn't have to be an insurmountable roadblock for gaining insights about organisms-especially if the goal is to study them directly from environmental samples (i.e., not in the artificial conditions of a lab, which can alter how bacteria behave and respond).
Furthermore, there are also ways to leverage technology to examine never-before-seen bacteria. For instance, Align to Innovate, a science non-profit Jensen is involved in, kickstarted a project using an iterative automated phenotyping platform to culture 1,000 diverse microbial strains across 1,000 culture conditions. Jensen thinks this type of automation will go the way of genomics and become broadly accessible to laboratories. Such advancements could streamline the time-consuming steps of traversing new microbial terrain, allowing scientists to dive into how novel bacteria go about this thing called life. "[Someday], we'll just put the microbe in and have it be phenotyped by a robot," he said. "I think that's going to be the future."
The more that future becomes reality, the more researchers will uncover about the unique, mysterious and potentially useful microbes inhabiting our world. Will any of these microbes become the next E. coli? Maybe not. But perhaps that is exactly the point.
Scientists are looking toward unusual and (once) unculturable microbes to address some of our biggest challenges, including antimicrobial resistance. Check out this next article for the full story.
