PNAS CLASSIC PROFILE Woese and Fox: Life, rearranged n April 2011 an international team led by researchers at the European Mo- Ilecular Biology Laboratory in Hei- delberg, Germany announced in Nature that the mind-boggling mix of mi- crobes in the human gut could be neatly grouped into categories called enterotypes (1). Hailed as a finding that might some- day help researchers address the long-in- tractable problem of antibiotic resistance, the discovery of gut microbial signatures in people raised the possibility that in- dividuals might have a defined enterotype, like a blood type, regardless of age, sex, or ethnicity (1). The study, which garnered attention in scientific and journalistic circles, follows a long-running initiative funded by the Fig. 1. (A) Carl Woese examining film on which ribosomal signatures are displayed (2003). (Photo by Jason Lindley; used with permission of the College of Liberal Arts and Sciences, University of Illinois at National Institutes of Health called The – B Human Microbiome Project, whose goal is Urbana Champaign.) ( ) George Fox (1999). (Used with permission of the Department of Biology and Biochemistry at the University of Houston.) to catalog the genetic diversity of the tril- lions-strong microbial communities that inhabit our bodies. The hope is to deter- organization on microbial diversity,” says In the next 5 years, Woese documented mine how changes in the microbiome—the University of Colorado, Boulder molecu- the formation of parts of the bacterial genetic endowment of our microbial lar biologist Norman Pace, a self-avowed protein-synthesizing machinery—the selves—might influence health. follower of Woese. ribosome—as the slumbering bacteria The microbiome project turns on emerged from the spores, and studied researchers’ ability to compare evolution- Biology, by Way of Physics how radiation could be used to inactivate arily conserved gene sequences in human- A child of the 1930s Depression era, the spores (3). At the end of his post- associated microbes. Such a comparison Woese was born in Syracuse, New York, doctoral stint, in the fall of 1960, Woese might yield signatures that can help fore- where he was raised under straitened set up his own laboratory at General tell how our bodies might respond to diets, circumstances. Ever in search of com- Electric’s Knowles Laboratory in Sche- diseases, and drugs. “With the recognition forting, objective truths, he was drawn to nectady, New York, where he continued that the human body is an ecosystem that the reassuring consistency of mathematics’ to explore the molecular biology of spore is host to ten times as many microbial cells often-categorical laws. That is partly why germination. While waiting for his labo- as human cells, the prospects of the pro- Woese graduated with a bachelor’s de- ratory equipment to arrive, Woese read ject for personalized medicine become gree in physics from Amherst College, voraciously on a challenge that in- clear,” says Nigel Goldenfeld, a professor Massachusetts in 1950. There, he was in- creasingly preoccupied the decade’s of physics at the University of Illinois at spired to pursue science as a career by leading molecular biologists in the wake Urbana–Champaign who has worked on physicist William Fairbank. Later, Woese of the discovery of DNA structure: the evolution of biological complexity. began doctoral studies in biophysics un- cracking the genetic code. Recent advances in DNA sequencing der the guidance of Yale University On the eve of the molecular biology technology have no doubt accelerated the physicist Ernest Pollard, whose con- revolution, the question of how cells effort, but the microbiome project, like tributions to the use of radar in World made proteins began to intrigue many others aimed at documenting biological War II earned him a permanent place in researchers. Of particular interest was the diversity, has its roots in a once-contro- the history of radiation physics. “Pollard process by which the assemblage of the four versial discovery now enshrined in the came from a respectable lineage of nucleotide bases that make up DNA was annals of evolutionary biology. physicists,” Woese says, referring to an interpreted by the cell into the sequence of Memorialized in a 1977 PNAS article by academic pedigree replete with physics amino acids that make up proteins. Al- biologists Carl Woese and George Fox heavyweights like J. J. Thomson, Ernest though RNA’s role as a messenger in the (pictured in Fig. 1), the discovery Rutherford, and James Chadwick. For his protein-making process was suspected at helped reclassify cellular life into three dis- doctoral thesis, Woese studied how radi- the time, the mechanics of protein syn- tinct domains, upending conventional views ation and heat could inactivate viruses thesis was a mystery. Before long, the ex- on biological classification and offering like Newcastle disease virus, which af- istence of transfer RNA, a molecule that deep insights into the origin of life on Earth. flicts poultry. In 1953, a standout year bridged messenger RNA and amino acids, To this day, Phylogenetic structure of the in molecular biology’s history that was came to light, and the molecule was prokaryotic domain: The primary kingdoms, marked by the discovery of the double thought to act as an adaptor in accordance which courted controversy and challenged helical structure of DNA, Woese gradu- with the hypothesis advanced by Francis the reigning dogma of its day, remains a ated from Yale. After an inspired but breakthrough—one that emphatically re- unsuccessful foray into medicine that traced the branches on the tree of life to lasted 2 years, he returned to post- fl ’ better re ect its evolutionary roots (2). doctoral research in Pollard s laboratory, See Classic Article “Phylogenetic structure of the prokary- “Without Woese’s 1977 report, today’s focusing on the molecular changes un- otic domain: The primary kingdoms” on page 5088 in issue microbial sequencing efforts would not be derlying the germination of dormant 11 of volume 74. meaningful. Woese put a framework of spores of the bacterium Bacillus subtilis. See Classic Perspective on page 1011. www.pnas.org/cgi/doi/10.1073/pnas.1120749109 PNAS | January 24, 2012 | vol. 109 | no. 4 | 1019–1021 Downloaded by guest on September 27, 2021 Sogin and William Balch, technician Linda Magrum, and others, Woese painstakingly assembled a database of differences in 16S rRNA among a laundry list of microbes that included both eu- karyotes, a group of organisms defined by the presence of a membrane-enclosed nucleus, and prokaryotes, a group defined solely on the basis of its differences from eukaryotes. Meanwhile, the scientific community’s attention was consumed by other developments in molecular biol- ogy’s early days, and Woese’s labors went largely unnoticed. Not for long. By 1976, Woese’s team had developed genetic signatures for dozens of different microbes, including methane producers that thrived in oxygen-starved environments like sewage and cow intestines. “It was a heroic enterprise to develop RNA catalogs for representatives of the different forms of life as we knew it then,” says Fox, now at the University of Houston, Texas. As a picture emerged, Woese realized that the methane producers were not bacteria. In fact, their 16S rRNA signatures suggested that they were fundamentally different from life forms then known as prokaryotes or eukar- yotes. Years later, Woese named the group of extremophiles, which included heat- and salt-loving microbes that occupied extreme Fig. 2. (A) Grand Prismatic Hot Spring, Yellowstone National Park. The red, orange, and green pigments niches like deep sea vents and thermal around the spring are microbial mats fueled by photosynthesis and geochemicals from the hot spring. (B) springs, archaea (see Fig. 2). Other bio- Microbiologists preparing to sample a hot spring in upper Hayden Valley, Yellowstone National Park. chemical signatures of archaea unearthed (Photo courtesy of Norman Pace.) by researchers in Germany and elsewhere lent support to the group’suniqueness. Crick, codiscoverer with James Watson of Ribosomal RNA: Life’s Timekeeper Through calculations of similarities DNA’s double helical structure. By then, Woese had accepted a faculty between the 16S rRNA sequences of Then, molecular biologists banded to- position in microbiology at the University bacteria, eukaryotes, and methane pro- gether to decipher how the 20 amino acids of Illinois at Urbana–Champaign on the ducers, Woese and Fox proposed in the found in cells corresponded to triplet invitation of molecular biologist Sol 1977 PNAS report that the methanogens codes of bases in the messenger RNA. A Spiegelman, whom he had met during represent a separate kingdom of life, “ mechanistic understanding of the genetic a sabbatical at the Pasteur Institute in suggesting that [the living world] is not ’ code became one of molecular biology s Paris. Soon, Woese set out to catalog ri- structured in a bipartite way along the bedeviling challenges, and sure enough, bosomal RNA sequences in a range of lines of the organizationally dissimilar the ensuing years saw a spate of discover- — prokaryote and eukaryote. Rather, it is microbes. One form of rRNA named ” ies that unraveled the molecular mecha- 16S for the rate at which it sediments in (at least) tripartite. nism of protein synthesis. Yet despite the laboratory experiments—turned out to be The report unleashed a minor contro- attention lavished on the code, Woese la- versy among microbiologists even as The the yardstick of choice for evolutionary ments, its evolutionary origin was largely New York Times announced in November comparison, largely because the molecule ignored. “Evolution was dismissed as the same year, “Scientists discover a form a historical accident that didn’tneedto forms a part of the protein-making ma- of life that predates higher organisms” (4). be invoked to explain the code, which chinery at the heart of all cells.