If you had to pick one organism with which to tell the story of the modern science of biology, you couldn't do better than to pick the tiny gut bacterium Escherichia coli, commonly called just E. coli. In his latest book Microcosm: E. coli and The New Science of Life, Carl Zimmer, uses E. coli as a decoder ring to open up the dense and diverse world of biological research, taking us on a panoramic tour of some of the most important conceptual advances and outstanding scientific questions in this important realm of science.
Biology, in contrast to a science like physics, is a science of particulars. In physics, if you understand one electron, you understand them all, but in biology every organism is unique. In biology it is more challenging to find universals, to pick an object of study that let's you ask big questions with the hope of finding general answers.
With E. coli we can come quite close: this tiny bacterium is the hydrogen atom of biology, a model simple enough to be experimentally tractable, but representative of general principles that apply to all life. As the pioneering molecular biologist Jacques Monod put it, "What is true for E. coli is true for the elephant," and also true for us. In Microcosm, we follow E. coli through a survey of some of the deep foundations and controversies of biology.
For such a slender book, Microcosm covers a wide-ranging selection of science. Zimmer begins by recapping the key events in the history of molecular biology, events in which E. coli was frequently a central player. Once scientists realized that E. coli had genes just like animals and plants, this gut bacterium gradually became one of the favorite model research systems in the then hot, new science of molecular biology. Experiments in E. coli revealed how genes are structured, how DNA is replicated, and how genes are controlled. Marshall Nirenberg and his colleagues cracked the essentially universal genetic code using cellular components from E. coli. Joshua Lederberg used bacterial 'sex' to bring the formidable tools of genetics to bacterial studies. Today, E. coli is the most well-mapped organism on the planet.
Explaining Systems Biology with E. coli
E. coli has continued to be a major research workhorse in biology. Classical molecular biology is now old news in E. coli, but scientists working on this organism have branched out into new areas of scientific inquiry. Zimmer focuses on two fields where E. coli continues to be an important model: systems biology and molecular evolution. Because the molecular map of E. coli is now known in great detail, scientists in the developing field of systems biology are using it to probe the design principles of a cell's information processing circuits. How does a single cell, wihout a central nervous system, respond to changes in temperature and oxygen, control its swimming pattern to find food, or coordinate the hundreds of chemical reactions to maintain a coherent metabolism? Zimmer introduces us to the work of some of the researchers who are using a combination of mathematical modeling and simple experiments in E. coli to understand how patterns of feedback loops and other network structures enable a one-celled organism to coherently respond to its environment. Systems biology is currently one of the most active fields in molecular biology, and E. coli is right at the heart of it.
Two aspects of systems biology make it a difficult field to describe, and these difficulties come through in the book. First, systems biology relies much more on mathematical theory than the more intuitive subject of molecular biology; consequently, it is more difficult to explain to general readers. Microcosm highlights some important and interesting research in systems biology, but this work often gets only a brief treatment in this slim book, probably not enough for readers to really have learned anything concrete about the subject.
A second difficulty is that systems biology in its current incarnation is a young, untamed field. There hasn't been enough time to sort the wheat from the chaff; there is a lot of research published under the label 'systems biology' which has not yet been verified to the level we expect in other fields of biology.
One common approach in systems biology is to computationally predict gene regulatory networks - that is, networks of regulators and the genes they control. You take a well-known organism like E. coli, in which the gene regulatory networks have been mapped out experimentally, and compare its genome with those of other uncharacterized organisms to predict gene regulatory networks in these uncharacterized organisms. Predictions like this are getting more and more sophisticated, but they are rarely followed up with experiments. Most scientists in the field would agree that our predictions, while they are getting better, have not yet reached the point where we have enough confidence in them to render experiments superfluous.
Zimmer discusses the interesting work of Madan Babu, who has done many of these computational reconstructions of gene regulatory networks. Babu has computationally predicted the gene regulatory networks in 175 different prokaryotes, based on comparisons with the well-mapped E. coli gene regulatory network. He has used these reconstructed networks to draw conclusions about how regulatory networks have evolved in the different environments inhabited by these different bacteria. Babu's ideas are fascinating, but without more physical experiments to test them, they have to be considered hypotheses about network evolution. This is a general difficulty in systems biology: our ability to perform computational studies, aided by thousands of available genome sequences, has far outpaced experimental work in this field; as a result, I think the field has grown a little too complacent about how far we can get without doing some hard experiments. I am worried that readers of Microcosm will be unaware that many of the fascinating ideas about network evolution that Zimmer describes are still considered predictions by most scientists.
The problem of matter-of-fact treatment of controversial science comes up again later in the book. We read that Neanderthals interbred with humans, and that scientists have detetced one such Neanderthal gene, micocephalin, in the human genome. This claim is still extremely controversial, and accepted by only a small number of scientists. Of course that doesn't mean that the claim is false; it means the jury is still out, and readers should be aware of that.
Evolution Examined and Defended With Bacteria
Molecular evolution is another field that has seen spectacular growth in the era of genome sciences, and Zimmer uses E. coli as an entry point to tell us about some important developments in our understanding of evolution. He discusses paradigm-changing work on the biochemical versatility of RNA, work which gave rise to the idea that before the evolution of DNA and proteins, RNA was the molecule that did it all. We learn about direct gene-swapping among bacteria, which has forced scientists to revise some of their thinking about bacterial evolution, and we learn about the evolution of antibiotic resistance and virulence.
Moving out of the lab, Zimmer takes us on a field tour of E. coli in the wild, an opportunity for us to learn lessons about the evolution of cooperation. In nature, E. coli needs to carve out its niche in a crowded ecosystem filled with other bacteria, which in some cases is done by forming biofilms for gathering nutrients, or, inside of our guts, by taking part in a metabolic bucket brigade, scavening the waste products that are passed down by other gut bacteria. Researchers can use these examples of coorperation to answer questions about how cooperative behaviors evolve generally, at least on a cellular level. E. coli also goes to war, and Zimmer describes the chemical warfare attacks mounted by E. coli against other bacteria, including other E. coli strains.
And of course E. coli, while usually innocuous, can attack us. Shigella, a bacterial strain responsible for a form of dysentery is actually one form of E. coli. There is also the infamous O157:H7 strain, which is responsible for the high-profile and sometimes fatal E. coli outbreaks initiated by contaminated spinach or hamburgers. In their effects, Shigella and O157:H7 are very different from the more common harmless E. coli strains that spend their innocuous lives in our guts, or in the lab, and yet their DNA unambiguously tells us that they are all a single bacterial species. There is a lesson about variation here, Zimmer tells us: "We tend to assume that a species is made up of individuals that all share the same essence... [but] there are no fixed essences in life. One of the most important rules of life is that it changes." Malleability under evolutionary forces has been a primary feature of life on this planet since its beginning, and E. coli demonstrates this well.
This engrossing science is frequently described with well-chosen analogies. To explain how E. coli balances the amount of defensive heat shock proteins it keeps on hand, Zimmer tells us that "Making heat-shock proteins in ordinary times would be like paying the local fire company to park all its trucks in your driveway just in case your house catches fire." To convey how researchers search genomes for information about the past, he compares the E. coli genome to a palmipset - an ancient book that has been scrubbed and written over multiple times over hundreds of years, but if you examine it carefully enough, you can still see the original ancient text beneath the newer layers. Popular science writing should be both clear (if you can't effectively convey great scientific ideas, you're missing the best part) and not boring - it's easy to get bogged down in tiresome details that most readers won't care about. Zimmer generally is both clear, and very entertaining.
Any complete discussion of E. coli and evolution has to include the social controversy over intelligent design, for which the bacterial flagellum has become the poster child. Zimmer shows us how research in E. coli has led scientists to an even more detailed, experiment-based undertsanding of how complex machines like the flagellum evolve. This science has landed E. coli in court, where both sides invoked this tiny bacterium in the Intelligent Design case Kitzmiller vs. Dover.
The Ethics of Genetic Engineering
Microcosm closes with an extended discussion of the ethical arguments over genetic engineering, an area where again E. coli has been in the spotlight. In the early 1970's when scientists were first developing the technology to cut and paste genes, producing "recombinant DNA" (an awful misnomer denoting pieces of DNA that have been artificailly spliced together into new combinations in the lab), there were worries about out-of-control, genetically engineered bacteria, designer babies, or biological weapons much worse than anything cooked up so far in US and Soviet labs. The worries were significant enough to cause the scientists involved in recombinant DNA work to enact a temporary moratorium on genetic engineering until the risks could be further evaluated.
None of those initial fears about genetic engineering has come true, and in the mean time, the technologies involved have revolutionized biology, and few major discoveries in molecular biology in the last 30 years would have happened without recombinant DNA technology. In fact, we don't have a single confirmed instance of a genetically engineered bacteria inadvertently causing harm, either within or outside the lab. While we have fretted about genetic engineering, Zimmer points out, naturally engineered bacteria like the O157:H7 strain have done the real killing.
Genetic engineering hasn't necessarily lived up to some of the early hype, such as claims that most major diseases would succumb to the power of biotechnology by the year 2000. Zimmer cautions us, as we confront the next generation of biotechnology, best exemplified by the field called "synthetic biology", to avoid "empty fear and empty hype." Excessively grandiose claims are unfortunate, because they mislead the public, and they are not actually believed by the vast majority of scientists. Ask a molecular biologist today if genetic engineering is a failure because it has not cured more diseases, and you're likely to get a long list of the spectacular successes we have seen, if not in medical practice, then certainly within science. Genetic engineering has revolutionized biology, and it has catalyzed phenomenal leaps in our understanding of how disease develops. Any future success in the clinic, (and many are coming) will owe a huge debt to genetic engineering.
What about moral repugnance? Isn't it just wrong to mix genes among species, especially among humans and non-humans? By splicing genes, are we crossing bounds that we were never meant to cross? One New York Times ad, cited in Microcosm, claimed that "Whether you give credit to God or to Nature, there is a boundary between life forms that gives each its integrity and identity." Yet a major message of Zimmer's book, and of evolution in general, is that there is no such boundary: it's largely a contruct of our intuitive biology, our habit, quickly gained in childhood, of classifying different types of living things. "It does not," Zimmer says, "arise from an objective perception of some deep, incontrovertible fact of life." Species are mutable, and interspecies gene-swapping played a critical role in the development of the more complex eukaryotic cells that eventually led to multicellular life. Today, few of us have any qualms about using pig heart valves to extend the life of someone's grandfather, so why should it be unethical to use (hypothetically for now) a transplanted bacterial gene to stave off Huntington's Disease? The argument of moral repugnance is never so much refuted as simply rendered irrelevant. "As we see the world not coming to a Pandora's-box end, our sense of disgust fades," Zimmer writes. And so we can expect genetic engineering to continue on for the forseeable future.
Microcosm packs a lot of depth into less than 200 pages. If you are looking for a peephole into today's world of modern biology, how it has developed, what are its triumphs, where are the controversies, there is probably no better place to start than Zimmer's marvelous examination of the world of E. coli