When a true genius appears in this world, you may know him by this sign, that the dunces are all in confederacy against him. – Jonathan Swift

(excerpted–and updated–from Every Living Thing in honor of Carl Woese who died on 12/30/2012. Thank you Carl Woese. Thank you  for rearranging the evolutionary tree, that we might see, even if we just as quickly forget, our place in things.)

One day in Illinois, Carl Woese decided that he would like to understand how all of the organisms around him, the birds, trees, bugs, humans and most importantly, the microbes, were related. He had no good reason to believe he could do such a thing and little hope of much support in the endeavor. It was, at the time, impossible. As R. Y. Stanier said in 1970, speculation about evolutionary history was, “a relatively harmless habit, like eating peanuts, unless it assumes the form of an obsession; then it becomes a vice.lxxx” To many, such evolutionary “speculation” was both unwarranted and intellectually dangerous, but, as would soon become clear, not to Carl Woese.

Carl Woese did not want to speculate. He would instead try to invent a method of seeing evolutionary history, a kind of microscope through which to visualize relationships among species. Carl Woese thought that with this new method he might delve into the history of life and understand  the broadest patterns of evolutionary change. Mark Twain said that a man with a new idea is a crank until he succeeds. Twain does not need to state the related assertion, that a man with a new idea who never succeeds is forever a crank.

Carl Woese was serious about science from an early age. For him “there was no other way to cope with (his) world.” For Woese, even as a young boy, there seemed to be “two worlds, that of nature and that of people. The first was vast, wonderful, inscrutable, frightening, exciting, enticing, always moving, but nevertheless with an immutable consistency—it was a never failing touchstone of truth. The world of people was the opposite; inconsistent, ever arbitrary, full of contradiction, anthropomorphizing, untrustworthy—almost devoid of truth.lxxxi54” Woese was called to a quiet life of science and inquiry. He chose microbiology, but could have been an astronomer or a physicist. What was important was the search for truths.

Like Linnaeus, Leeuwenhoek and many others, Carl Woese started his career at the periphery of his scientific field. Trained as a physicist for his undergraduate degree at Amherst College and then as a biophysicist for his doctorate at Yale University, he studied the physics of the cell, the bump and grind of microscopic machinery. He worked at General Electric and then the Pasteur Institute before being hired as a Professor at the University of Illinois in 1964. At Illinois, he studied ribosomal RNA. Watson and Crick had decoded the language of DNA, but Woese was interested in translation, the process in the ribosome by which a specific RNA is converted into protein and hence function. Woese perceived that at that moment, with DNA deciphered, it “was the time to start thinking about the evolution of the cell55 and its macromolecular componentry.lxxxii” It was time to start thinking about the deep evolution of life. Woese felt that “a slight diversion” was in order from his main research, in order to address these questions. That diversion occupied his days.

To make an evolutionary tree of all life, including microbial life, one would need to study an attribute of that life that changed slowly and hence allow the differences between very old lineages to be compared. The building blocks that make up the ribosome, your ribosome, my ribosome, every ribosome, seemed to Woese like a good candidate. The ribosome is composed of protein and then also, and this is the key, a special kind of RNA, ribosomal RNA (rRNA). The rRNA in the ribosome interacts with the messenger RNA to convert it to protein. In every living cell, rRNA performs nearly exactly the same task. rRNA aids in the translation of rRNA to protein, and Woese hoped to translate the history of life as recorded in rRNA.

Ribosomal RNA is a foundation upon which evolution’s building stands. Change it a little and the building begins to creak. Change it a lot, and it will fall. In the same way that all wheels are round and those that are not function poorly, there is but one good way to be an rRNA molecule, one good way to keep the machinery of life rolling. And so, unlike many genes, the genes of ribosomal RNA cannot change much, through time or species, over millions or even billions of years. As DNA is copied by cells’ tiny chemical monks, the DNA that codes for ribosomal RNA must be copied near perfectly, and so too the rRNA itself. Consequently, the differences in the ribosomal ll. Your ribosomal RNAs are like mine. Mine are like a squirrel’s. A squirrel’s ribosomal RNAs are very similar to a tree’s. The monks in cells make mistakes in copying the genes for ribosomal RNA, but they make few. Such mistakes accumulate very slowly through time.

Woese’s idea of understanding the evolution of a group of organisms based on some feature of their physical structure (such as their RNA structure) was not novel. Other biologists were doing similar work with proteins. The longer two proteins were separated in evolutionary time, the more different they would be. Such  work rested on the work that had been done for centuries–nearly since Linnaeus–comparing external features of plants and animals. If the sex organs are more different, Linnaeus almost but didn’t say, two species had been diverging for more time. By looking at differences and similarities, it was becoming clear, one might assemble life’s  evolutionary tree, or at least parts of the tree.

When most biologists imagined an evolutionary tree, however, they thought about big species—tigers and tiger lilies. Woese imagined that microbes could be mapped onto a tree, put on their right branch. He wanted to “move the evolutionary discussion away from animals and plants and onto the molecular level, where it belonged in the 20th century.lxxxiii” and he thought it could be done with rRNA in which he saw grand possibilities. Differences in rRNA, Woese posited, meant evolutionary differences in time. The more different two species were in their rRNA, the longer they had been separate. Leave two monks in two different dimly lit rooms to copy a text. Let them make each subsequent copy based on the copy before it. With time, the mistakes they make will accumulate. The two sets of copies will diverge. If one knew the rate at which the monks made mistakes, he could look at the final products, the newest copies, and by comparing their differences estimate how long the two monks had been separately working.

Woese wanted to know, when different types of organisms diverged, how long different lineages had been separated in their proverbial rooms copying the text. He also wanted to know what that first text looked like, to look into the recesses of time and find the first life. He began to compare the ribosomal RNA of different species in order to construct a microbial evolutionary tree. Woese began optimistically, believing that “only technological problems seemed to stand in (the) way: growing the various organisms and doing so in a low phosphate, radioactive medium; tweaking the … method to fit needs; finding needed help; and so on.” Those technological challenges would be formidable. He was, as a side project, initiating an entirely new field of inquiry using a method no one else had used (and that no one else would use for years). If he were right, his method would, like the microscope or the telescope, make visible what had long been unseen. It as far wmore likely that he would be wrong. These are also the basic components of DNA, except Uracil is replaced by Thymine. The differences between you and a microbe are nearly entirely due simply to the arrangement of those nucleotides. Each three letter stretch of DNA codes for a particular amino acid, such that if one knows where to start reading on a stretch of DNA, one can read out the amino acids that will be produced. 58 An rRNA with the code AGCUAAACG would be fragmented into two pieces, AG and then CUAAACG. If the rRNA was then split at its Adenines it would be divided into more pieces, A and G from the AG and then CUA, A, A, and then CG from the remaining section. And so on.

At the outset, several things separated Woese’s work from everybody else’s. First, the rRNA analyses took far, far, more time than the existing protein analyses and required unique skills, such that only Woese could do them. Second, no one, including Woese’s peers and department head, knew why on Earth he would do them.lxxxiv Further, the questions Woese wanted to get at, the evolutionary tree of microbial life or even of life more generally were viewed, as Woese’s colleagues were to make clear, as unanswerable. Woese’s colleagues wondered what he was trying to do. He needed to focus on work that would yield something. He seemed obsessed, even bothered. His willingness to participate in the niceties of daily society was dissolving. Biologists can, in focusing on a narrow piece of the world, focus so intensely that everything else seems irrelevant. The talk at the coffee pot is ridiculous banter, informal greetings a waste of time. Departmental meetings, advising students, emptying one’s garbage all become things left to someone else, someone not so involved. This is the kind of intensity that biologists and scientists, more generally, both fear and love. Scientists obsessed like this, if right, can be vindicated royally. Imagine, they might say, how much less he would have done had he brushed his hair more often. But scientists obsessed like this on a research question that does not lead to discovery are running very quickly into oblivion, very quickly into drink, spirituality, madness or all of the above.

Woese toiled. There is no other word for it. Ribosomal RNA like all RNA is made up of a simple alphabet of nucleotides, Adenines, Guanines, Cytosines and Uracils57. Woese had to decode tiny sections of rRNA at a time. He had to do it through a method that ultimately converted the rRNA code into black smudges on photo paper. He would fragment segments of rRNA at each Guanine nucleotide.58 Each of the resulting fragments was then fragmented again at each of the other types of nucleotides, systematically, monotonously. Woese could then photograph the distribution resulting fragments and, like a code breaker, work backward, letter by letter, to what t have been. As he split the rRNA into its bits, there was a sense of discovery every day in the lab. The photographs of the dissected bits of rRNA were beautiful, like abstract paintings, each one different and each one representative of some part of the evolutionary tree. Yet the tedium was overwhelming, something like trying to read a copy of Shakespeare left on the moon using a telescope. The beauty of the text, the book of life, could be missed in the difficulty of the process at hand. Woese’s lab and office piled thick with photo sheets for RNA comparisons. His shelves were soon covered with yellow Kodak boxes to hold the film. Light boxes were brought in from who knows where and each one always had a film on it. His chairs were taken over and then his desk and then the floor. This went on for weeks, months and then years, without an answer, without a revolution, without a natural order. It just went on. He went home some days saying to himself, “Woese, you have destroyed your mind again today.lxxxv” He spent every day in front of the film sheets, brooding over patterns. After ten years of toil, he had catalogued just sixty bacterial species, sixty of the hundreds of thousands of species thought to exist.59 He was forty seven. He had written essentially no papers on his results. He had told few about what he was doing. He had taught no one his methods. He was the only one in the world who could decode rRNA and in doing so, he hoped, reveal life’s story. Like Leeuwenhoek with his microscope, he was alone.

It was then that one of Woese’s colleagues threw him a rope, albeit one that neither appreciated the importance of at that moment. Woese’s colleague Ralph Wolfe wondered if Woese would work with him on a separate project. Wolfe thought, contrary to the public opinion, that Woese was making exciting progress, that the two of them together might make more progress on one particular group of organisms. Wolfe was the much better known of the two scientists and might have felt himself something of a mentor. Wolfe asked Woese if he would “run the rRNA” of a group of methane producing bacteria he was working on, a group of life forms found in sewer sludge and related environments. Woese had, several years earlier, talked with Wolfe about looking at some of these methanogens.lxxxvi Wolfe had not yet been able to grow them in the lab, a necessity for the quantity of material Woese needed, but by the beginning of 1976, he could.lxxxvii Wolfe could by then “grow a kilogram of methanogens” in bottles pressurized with CO2.lxxxviii These methanogens, Wolfe told Woese, were united by their chemistry (they all produce methane as a byproduct of their metabolism) and unique enzymes and seemed very different from other bacteria.60 No one knew quite what kind of bacteria they were related to. One possibility was that the methanogens were not really related to each other at all, but had simply evolved convergent traits to deal with their particular lifestyle (For many of the initial samples, that lifestyle was living in sewage. One of the first species sequenced was Methanobacterium ruminatum, named for the cow guts it calls home.). The other possibility was that they were a unique evolutionary group. It was a perfect challenge for Woese.

By the time that Wolfe offered Woese his specimens (first a species with the Linnaean name of Methanobacterium thermoautotrophicum, which, if you read Latin, says it all and then some), Woese had already constructed, species by species, a tree of life. It was his private tree based, at that time, on tens of microbial species. He had shown few others, or maybe he had shown no one at all. It was there, in his office, in yellow Kodak boxes, arranged in a way clear only to him. Woese would turn on his record player, put on an old jazz record and marvel at what he had revealed. He was close to seeing the history of early life. He began, again letter by letter, to analyze Wolfe’s samples. He looked at the negatives in an upright light box, with the lights in the room off. He would look at the signs of the nucleotides, his own face by lit by the light passing through the photos of rRNA nucleotides. He arranged the negatives and organized them and then translated. Almost immediately, what he saw was surprising. After the first step, the “signatures were remarkably distinct” from those of any bacteria he had yet looked at. Each of the first nucleotide signatures he was accustomed to seeing in all bacteria, was missing. When he did the more detailed work, to actually decode, nucleotide by nucleotide, the sequence of the RNA, the results continued to be surprising. Now he saw some RNA sequences that he associated with bacteria, but others were missing. It was as if the RNA were from something that was half bacteria, half eukaryote. As Woese would later say in an interview, “by this point one stops wondering what they have done wrong and begins to ask what this all means.” He had an idea, but before he said anything he repeated the whole process from scratch, a second, and then a third, and then even more times.lxxxix The results were the same. The samples were not, Woese thought, bacteria, nor were they eukaryotes,xc but instead something else entirely, some new form of life. Now here was the kind of discovery Woese had worked for all those years. Woese has never been prone to outbursts, but if he ever did yell with joy and dance in his office of rRNA and jazz, these were the days. Woese rushed to find his postdoctoral fellow, George Fox, to “share (his) out‐of‐biology experience” with someone. Fox was skeptical so Woese ran to tell Wolfe, saying, as Wolfe remembers, “Wolfe, these methanogens are not bacteria.” Wolfe told Woese they had to be. “Of course they are bacteria ; they look like bacteria, he would later remember saying, “Now, calm down; come out of orbit.xci”

The next step was to examine other methanogens and other species that were morphologically similar to the methanogens. By the end of the year, the team, led by Woese, had decoded the gene sequences of the RNA of five other methanogens. More were in the works, but the result was getting more and more clear. The methanogens were very different. Once “a second methanogen was characterized and showed itself to be related to the first, there was no doubt” that they had found a new form of life, Woese would later say. This form of life had been different from the others, bacteria and Eukaryotes, a very long time. Understanding how these methanogens related to other kinds of life was, it seemed to Woese, a big discovery. Woese later wrote of the moment, “Darwin had long ago said that there would come a day when there would be very fairly true genealogical trees of each great kingdom of nature. Perhaps that day was at hand!”

Woese would immediately write two papers about his new finds. One paper was written sed on the new kind of microbe.61 The other paper, however, written with George Fox, Wolfe’s postdoc, was the one that would prove more controversial xcii. The first place that anyone saw the results of the paper with Fox was in the newspapers. Woese was 49. He had worked without recognition for decades, but that was to change this day. The news media saw an advance copy of the edition of the Proceedings of the National Academy of Sciences in which the Woese and Fox article was to appear. The media found the result tantalizing. The New York Times ran the headline, “Scientists Discover a Form of Life That Predates Higher Organisms,” on page 1, November 2, 1977. The first lines of the article summed up the outrageousness of what the scientific article was about to claim, that scientists had described a “third kingdom of living material composed of ancestral cells that abhor oxygen, digest carbon dioxide and produce methane.” Woese was thrilled with the popular attention for the find, but his mood would change. Woese had discovered, or he so argued, an entirely new domain of life. The monks in these single cells, however faithful to the ancient text, had long, long, been separate from those of all others. Woese and Fox went on to argue that there are three major divisions of life: one is bacteria, one is the lump of flesh and plant that includes all eukaryotes. The third is Archaea,62 the group that Woese, Wolfe and their labs had just discovered, essentially, in specimen jars in their office In Woese’s scheme, not only are humans a tiny branch on the tree of life, but so are mammals, so are vertebrates, so are all other animals. Most of life, from an evolutionary perspective, is microbial‐everything else a minor branch, a fit of evolutionary whimsy. This is what Woese has gone on to contend to this date. To the extent that he changed his opinion, it was only to become even bolder in his statements, to argue, through new results, that he could see even further back in time.

Woese did not think personality was part of science, that scientists themselves are an important part of how science should be recorded. As a consequence, we have few direct views into what Woese would think in those years in which he was buried, religiously, in his office, working. Those views  we do have, though, tell miles. The day the announcement of Woese and Wolfe’s finding came out in the newspaper, November 3rd, 1977, Woese was thrilled. He thought the revolution had begun. He asked a woman at a fast food restaurant if she knew who he was. She looked at him, thought for a while and struggled for the answer. He prompted her by mentioning his discovery. She then realized, oh yeah, “You’re Bob’s dad.xciii” He was, of course, but Woese had thought deeply, without whimsy or humour, that his discovery would be big enough that the woman at the checkout line in fast‐food counter would know who he was. He was wrong. It was, in many other ways, not Woese’s day. What followed was angry; hate mail, promises of academic oblivion. Both Woese and the relative innocent in this enterprise, Wolfe, would be attacked. Ralph Wolfe recalled that: “One Nobel Prize winner, Salvador Luria, called me and said, ‘Ralph, you’re going to ruin your career. You’ve got to disassociate yourself from this nonsense!xciv’ Wolfe “wanted to crawl under something and hide.xcv” He did not disassociate himself (though he did take a vacation) but nearly everyone else did. The criticism of Woese was never very public. It was, the “talk of corridors.” Woese was “itching for (his critics) to come after (him) in print. But none of them would!” So Woese kept working, knowing that many of his colleagues quietly doubted him. Woese thought the “matter would resolve scientifically.” There were reasons to be skeptical. The question Woese proposed to address, the relatedness of the deepest lineages of life, was still seen as too deep in the early time to answer. If Leeuwenhoek looked up God’s dress, Woese was trying something bolder, more inappropriate. He was trying to do so with a new ribosomal RNA method that no one else was using. No one else was familiar with it. No one else had confidence in it. In short, Woese had proposed to have answered an unanswerable question with an unlikely and unknown method. Even for those who knew his method, it seemed, well, insufficient. Woese had proposed a new domain of life and a reordering of life’s tree to put man, all animals and plants, as minor players circling a microbial Earth. He had, late at night, with charcoal on the cave walls of science, sketched a tree. At its base was a microbe, perhaps something like an Archaean. From that microbe would descend three great lineages, the Archaea, the Bacteria and the Eukaryotes. Within the eukaryote branch, the most recent of the tree, were all the fungi, all the plants, all the protists and all the animals. All vertebrates were a twig 135 branch on the small, recent, branch of the animals. We were in this big tree, not worth drawing, too mall a twig to make it into the big story, which was, in nearly its entirety, about microbes. Woese went back to science, back to work on Archaea, for thirty years. He had made an extraordinary claim and despite everything, he still believed in his work. He went back to his light table and went through sequences one by one. He added other microbial lineages to his analyses. He studied, along with a growing number of other scientists, other unique features of the Archaea. They had different lipids (fats). They had different metabolisms. If people thought him a bit of a crank before, this would not help things. He buried himself in his discovery. Since Leeuwenhoek, there were the microscopic things and the big things. The big things were the more important, the main story, and then the microbes, the back‐story. Woese was trying to turn the back‐story into the plot.

Woese was like Leeuwenhoek. He could see something others had not seen. He could see it because of his method. Like Leeuwenhoek, he was confident. What remained to be seen was, if, like e was right.

***

Vindication for big speculative ideas comes slowly. It must trickle in on the back of new results. It comes, paper after paper, until at some undefined point, what was once heretical has become the status quo. Copernicus published, posthumously or nearly so, his treatise suggesting that the Earth and other planets circle the sun. It would take generations for this idea to become fully accepted. A few believed easily, but one of those, Galileo, went on trial for that belief and another, Bruno, was burned at the stake. Yet, it was not long before average citizens looked up and imagined the sun as stationary, the Earth as moving, to the extent that they looked up at all. If you now open an introductory college biology book, you will, more likely than not, find that Carl Woese is mentioned alongside the idea that there are three main divisions of life, the Archaea, the Bacteria and the Eukaryotes. We now accept as near law Woese’s new divisions of life. It is now presented in introductory biology class by tired professors who flash the information up on the board early in the morning, read through it, as they gaze into groups of somnambulant students, less worried about their place relative to the Archaea than about what they will do that evening, who the girl with the long hair is in front of them, or why their professor has now worn the same shirt three lectures in a row. But don’t be confused. Woese’s result was both right and revolutionary. It’s just that we quickly grow used to revolutions once they happen; the idea that the Earth circles the sun is now, on most days, unremarkable, so too Woese’s revolutionary change, one that altered  our place in the living world, permanently.

(story continued in Every Living Thing)

Image provided courtesy of of University of Illinois Archives.