The Tangled Tree: A Radical New History of Life

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The two authors gave their kingdom a tentative name: archaebacteria. Archae- seemed apt, suggesting archaic, because the methanogens appeared so ancient, and their metabolism might have been well suited to early environments on Earth, about four billion years ago, before the onset of an oxygen-rich atmosphere. Woese had made that very point in an interview with the Washington Post. “These organisms love an atmosphere of hydrogen (#litres_trial_promo) and carbon dioxide,” he said (or at least, so he was quoted). “Just like the primitive earth was thought to be,” he said, adding, “No oxygen and very warm.” But the other half of that compound label, archaebacteria, tended to blur the central point of the discovery: that, as Woese had announced to Wolfe, these things aren’t even bacterial forms of life. They’re quite different. Wolfe himself told Woese that archaebacteria was a terrible choice. If they’re not bacteria, why retain that word at all? The provisional name stuck for about a dozen years, before being emended to something better, something that stood by itself: the archaea.

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George Fox was no longer a rangy young man when I sat with him in a nondescript pizza parlor near the campus in Urbana, after the opening session of a Carl Woese memorial symposium, and watched him eat a nondescript little pizza. Fox is a man who prefers simple, plain food, and he had cringed when I ordered pepperoni and mushrooms on my own. At age sixty-nine, he carried the full body and slight jowls of a lifetime spent in laboratories and classrooms; wire-rim spectacles had replaced the dark horn-rimmed glasses he had worn in the 1970s photos, and his brown hair was graying at the temples, but his eyes still shined brightly blue as he recalled the days and years with Woese. Now a professor at the University of Houston, Fox had flown up for the Woese meeting, which was hosted by the Carl R. Woese Institute for Genomic Biology (its name reflecting the fact that Woese has become a venerated brand at the University of Illinois). Fox would give one of the invited talks.

He had spent his academic career at three institutions: Houston, for almost three decades; preceded by Illinois, as a postdoc with Woese; and before that it was Syracuse University, as an undergraduate and PhD student. The circumstances of Fox’s arrival in Urbana were haphazard, beginning from a coincidence in Syracuse, where Woese himself grew up. There at the university, Fox belonged to a professional engineering fraternity, Theta Tau, of which Carl Woese’s father—also named Carl Woese—was a founder, and so Fox was required to know the name. As he shifted interest from chemical engineering to theoretical biology, he noticed and became fascinated by some of the early work of Carl Woese the son. In particular, there was a paper on what Woese called a “ratchet” mechanism (#litres_trial_promo) of protein production by ribosomes—a risky proposal, a wild and interesting idea (later proven wrong in its details), published in 1970. So Fox wrote to this ratchet guy asking for a postdoc fellowship, and Woese seemed to see the Syracuse connection as karma. He had a position to fill, yes, with the departure of Mitch Sogin, the ultimate handyman grad student, and he offered that to Fox.

“We did not discuss salary,” Fox said over his pizza and Coke. “He never sent me a letter offering the position. It was all completely verbal.” On such assurance, Fox got married and showed up in Urbana that autumn with his wife. Arriving unannounced, he encountered a man at the lab door, an unprepossessing figure in jeans and a drab shirt, with a chain holding a huge bunch of keys. “He looked like the goddamn janitor.” Fox gave his name and prepared to talk his way in. “No!? Welcome!” It was Woese.

“He sat me down in his office and …” Fox hesitated. “You got a piece of paper?” On a yellow sheet from my legal pad, he began sketching the layout of the lab. He drew a long rectangle and subdivided it. There were three major rooms, he explained, and the middle room, here, held the light table, where Carl usually worked. Linda Magrum and Ken Luehrsen were here, in the left room. Over here on the right side of the center room was Carl’s little personal office and the electrophoresis room. The radiation room and the darkroom were across the hall, and then storage, three more spaces barely bigger than closets. Woese gave Fox a table in his office, Fox said, with a door that stayed open, “so he could see me.” Like the young Luehrsen, only more so, as a postdoc, Fox was on probation.

At the beginning, Woese assigned him to assembling sequences from 5S rRNA, the shortest and least informative of the ribosomal RNA molecules, as a way of getting up to speed on what the lab was doing. That project yielded some unexpected results, impelling Woese to try to make Fox an experimentalist. But it wasn’t his forte, and he knew that. He wanted to do the sort of “theoretical stuff,” the deep evolutionary analysis of molecular data—what would now be called bioinformatics—that Woese himself did. Reading the code, drawing conclusions that went back three billion years and more. Woese, on the other hand, wanted him to generate data. “I was under a lot of pressure,” Fox recalled—the pressure of Woese’s expectations versus his own interests and skills. “What I had to do was, every other day, come up with a novel insight, so that he would continue to allow me to work on the sequence comparison project.” Failing that impossible standard, he was banished back to the lab, set to the tasks of growing hot cells and extracting their ribosomal RNA. But Fox continued, in flashes, to show his value to Woese as a thinker. Gradually he proved himself, not just sufficiently to work on sequence comparisons but well enough to become Woese’s trusted partner, as well as the sole coauthor on the culminating paper in 1977, with its announcement of a third kingdom of life.

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Wondering how that announcement was greeted by the scientific community at the time, I had put the question to Ralph Wolfe, several months before the pizza with George Fox.

“It was a disaster,” Wolfe said mildly. Then he explained, with the sympathy of friendship, why Woese’s declaration of a third kingdom—the substance of the claim, and the manner in which Woese made it—had sounded discordantly to many of their peers. The crux of the problem was a press release.

Woese’s lab had been supported by the National Science Foundation and the National Aeronautics and Space Administration, the latter under its exobiology program (devoted to extraterrestrial biology, in case there is any), presumably because grant administrators felt that his research on early evolution might help illuminate the question of life on other planets. As the first PNAS paper in the methanogens-aren’t-bacteria series moved toward publication, Woese acceded to a suggestion from the federal agencies and allowed a public announcement of his findings from Washington, rather than just letting the article drop in the journal’s November issue and speak for itself—which was how science, in those days, was customarily done. Ralph Wolfe knew nothing about this, despite his close connection with the work, until one day when a mutual acquaintance let slip that the press release would appear tomorrow. “What press release?” Wolfe asked.

The cat was out. It was an indelicate situation. “A few minutes later,” Wolfe told me, “Carl was in my office, explaining.”

Wolfe showed no dudgeon as he recounted this. The human comedy is various, not always funny; Woese’s lapse was just a miscommunication between friends, a misstep by a colleague he held in high regard. To understand what went wrong, you had to consider an insult Woese had suffered years earlier, a hurt he had carried long afterward. “He presented a paper in Paris,” Wolfe said. It was on the ratchet model, the same clever but incorrect idea that later caught George Fox’s interest. Woese had conceived this brainstorm—a conceptual construct for how ribosomes work in manufacturing proteins—and called it a Reciprocating Ratchet Mechanism, by which RNA cranks through the ribosome structure, adding amino acids to the protein chain, a notch forward, and then a reload, and then another notch forward, but never a notch back.

“He didn’t present any evidence for it,” Wolfe said. “He just presented this as a concept.” The audience at the Paris meeting may have included luminaries such as Jacques Monod, François Jacob, and Francis Crick, whom he knew a bit better than the others. “It was the last paper before lunch,” Wolfe said, “and nobody asked any questions. They all got up, and left, and went to lunch. And this hurt Carl. It was almost a mortal wound. He was just so offended by the behavior of these scientists. He told me that ‘I resolve next time they will not ignore me.’ And so this was the rationale behind his press release.”

The press release went out from Washington, presumably with an embargo to the date of journal publication. On November 2, 1977, the third kingdom became an open topic for all comers. The following day, based on that alert and three hours with Woese in his office, a reporter for the Times told the story on page 1, beneath the photo I’ve already mentioned—of Woese with his Adidas on a messy desk—and a headline emphasizing the ancientness theme: “Scientists Discover a Form of Life That Predates Higher Organisms.” The article, by a veteran Times man named Richard D. Lyons, began:

Scientists studying the evolution of primitive organisms (#litres_trial_promo) reported today the existence of a separate form of life that is hard to find in nature. They described it as a “third kingdom” of living material, composed of ancestral cells that abhor oxygen, digest carbon dioxide and produce methane.

That was relatively accurate compared with coverage in some other news outlets. The Washington Post did less well than the Times, reporting that Woese claimed to have found the “first form of life on earth,” which suggested that a dawn organism, the very earliest living creature, self-assembled somehow about four billion years ago, had survived to occupy sewage in twentieth-century Urbana. Wrong. The Chicago Tribune was worse still, proposing that Methanobacterium thermoautotrophicum (misspelled) had left no fossil record because it “evolved and went into hiding” at a time before rocks had yet formed. Which rocks? “Utter nonsense,” Wolfe said. The Tribune story even carried a dizzy headline asserting “Martianlike Bugs May Be Oldest Life.” And from there the coverage spooled outward, via United Press International and other echo chambers, to small-town papers such as the Lebanon Daily News in Pennsylvania, under similar headlines tooting about “Oldest Life Form” rather than the distinctness between methanogens and all (“typical”) bacteria. At very least, the stories bruiting “Oldest Life Form” were missing an essential point presented by Woese and Fox. A headline about “Weirdest Life Form” might have captured that better.

The problem, according to Ralph Wolfe, was not just announcing scientific results by press release but also that Carl Woese himself lacked facility as a verbal explainer. He had never developed the skills to give a good lecture. He stood before audiences—when he did so at all, which wasn’t often—and thought deeply, groped for words, and started and stopped, generally failing to inspire or persuade. Then suddenly that November of 1977, for a very few days, he had the world’s attention.

“When reporters called him up and tried to find out what this was all about,” Wolfe told me, “he couldn’t communicate with them. Because they didn’t understand his vocabulary. Finally, he said, ‘This is a third form of life.’ Well, wow! Rockets took off, and they wrote the most unscientific nonsense you can imagine.” The press-release approach backfired, the popular news accounts overshadowed the careful PNAS paper, and many scientists who didn’t know Woese concluded, according to Wolfe, that “he was a nut.”

Wolfe himself heard from colleagues immediately. Among his phone calls on the morning of November 3, 1977, “the most civil and free of four-letter words” was from Salvador Luria, one of the early giants of molecular biology, a Nobel Prize winner in 1969 and a professor there at Illinois during Wolfe’s earlier years, who called now from the Massachusetts Institute of Technology (MIT), saying: “Ralph, you must dissociate yourself from this nonsense (#litres_trial_promo), or you’re going to ruin your career.” Luria had seen the newspaper coverage but not yet read the PNAS article, with the supporting data, to which Wolfe referred him. He never called back. But the broader damage was done. After Luria’s call and others, Wolfe recollected in his memoir, “I wanted to crawl under something and hide (#litres_trial_promo).”

To me, he added: “We had a whole bunch of calls, all negative, people outraged at this nonsense. The scientific community just totally rejected the thing. As a result, this whole concept was set back by at least a decade or fifteen years.” Wolfe himself felt badly burned by the events, his professional reputation in peril. There arose a wall of resistance—cast up by visceral objection to science by press release—against recognizing the archaea as a separate form of life. “Of course, Carl was very bitter all through the eighties and well into the nineties,” Wolfe said. “He was bitter that the scientific community rejected his third form. His phylogeny and taxonomy.” As it had been for Stanier and van Niel, and still earlier for Ferdinand Cohn, bacterial taxonomy was a hot issue again. This time the evidence was molecular, and the deeper story was of evolution on its broadest scale.

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It’s hard to know in retrospect, and perhaps tempting to overestimate, just how severely Carl Woese was doubted, dismissed, and ridiculed during the decade following 1977. Certainly there was some of that, especially in America. But the resistance to his big claim softened somewhat after still another article, coauthored again with Ralph Wolfe and Bill Balch, offered many kinds of evidence (in addition to the 16S rRNA data) for considering methanogens a separate form of life. And in Germany, on the other hand, his idea of the newfound kingdom met a warm reception.

Researchers there—three in particular—had been developing some parallel observations. The first was Otto Kandler, a botanist and microbiologist from Munich, with an interest in cell walls, who happened to visit Urbana earlier in 1977, before the papers were published, and met Woese through Ralph Wolfe. “Ralph marched him into my office (#litres_trial_promo) to hear the official word from George and myself,” according to Woese’s later memory of encountering Kandler. “I think he smiled.” With a smile or not, Otto Kandler easily accepted the premise that methanogens were profoundly unique, because he had suspected it himself. His own work had shown him something even Woese and Wolfe didn’t know: that the cell walls of at least one methanogen were starkly anomalous. They contained no peptidoglycan. Remember that stuff, peptidoglycan—the latticework molecule, a strengthener of cell walls, that Stanier and van Niel had cited as one of the defining characters of all prokaryotes? It didn’t exist, zero, in the cell walls of a certain methanogen Kandler was studying. Furthermore, he told Woese, it seemed absent also from some other untypical bacteria, which lived amid high concentrations of salt. They were known, for that affinity, as halophiles. Salt lovers.

The tip from Kandler about anomalous cell walls triggered a memory in George Fox. He had once been taught, in a microbiology course, that all bacteria have peptidoglycan walls—all except the extreme halophiles. Reminded of that by the German, Fox went to the library to verify it, and, in the process, he found another clue to the defining characters for inclusion in this third kingdom. Here we get technical again, but I’ll keep it simple: weird lipids.

Lipids are a group of molecules that includes fats, fatty acids, waxes, some vitamins, cholesterol, and other substances useful in living creatures for purposes such as energy storage, biochemical signaling, and as the structural basis of membranes. Fox, rummaging in his library, learned that halophiles contain lipids unlike those in other bacteria. They were structured differently, with radically different chemical bonds. Carl Woese now had another omigod moment: Omigod, these salt lovers are full of weird lipids, just like our methanogen. The fact of such weird lipids in halophiles had been reported by other researchers a dozen years earlier—as Fox found in the library—but no one had drawn any conclusions. It was merely a little anomaly. But for Woese, in his ferment of discovery, it clicked into the larger pattern. “In my whole career I had never paid attention to lipids (#litres_trial_promo), and here we were with lipids on the brain!”

And not just the lipids he found in halophiles. Fox also turned up the fact that two other kinds of extremity-loving bugs, known by their genus names as Thermoplasma and Sulfolobus, also had weird lipids of the same sort. Those two groups preferred environments that were very hot and very acidic, such as hot springs in areas of volcanic activity. In the technical lingo, they were thermophilic and acidophilic. Perverse little beasts, by our standards. Both had recently been isolated—one from a coal refuse pile, the other from a hot spring in Yellowstone—and characterized in the lab of Thomas Brock, the codiscoverer of Thermus aquaticus. Alerted to the weird-lipids connection by Fox, Woese got hold of samples and began trying to grow them and catalog them.

The three domains of life: Bacteria, Archaea, Eukaryotes.

In light of all this, Woese suddenly became very keen to fingerprint some salt lovers. He reckoned that “if unusual cell walls meant anything (#litres_trial_promo), perhaps the extreme halophiles would turn out to be members of our new ‘far out’ group.” George Fox, by this time, had left for the University of Houston. With Fox gone and his other lab people already busy, Woese couldn’t wait for another student or collaborator to come along, so he started the wet work himself. Fortunately for him, growing halophiles is relatively easy. “I donned my acid-eaten lab coat (which had hung on the back of my office door for over a decade) and went back to the bench.” He grew the cultures in quantity from samples sent by a colleague, tagged them with P-32, and turned them over to Ken Luehrsen for the dicier next step: extracting and purifying radioactive RNA. Then from Luehrsen the stuff went to Linda Magrum—“our trusty Linda,” Woese called her—for separation by electrophoresis and burning the films. Within a few months, they had their first catalog from a halophile. “It didn’t disappoint,” Woese wrote. It was another strange thing: not a bacterium after all, but a member of the archaea.

So much for the halophiles. He turned back to the thermophilic acidophiles. When his team finished fingerprinting the coal-refuse creature, Woese sent a manuscript to the journal Nature, presenting the new ribosomal RNA catalog and making a case that this creature too belonged among the archaea. Nature rejected the paper, with a return letter that essentially said: “Who cares?”

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The three Germans cared—not just Otto Kandler, who became a great pal to Woese, but also Wolfram Zillig, an eminent biologist who directed the Max Planck Institute for Biochemistry, in Munich, and his younger associate, Karl Stetter, formerly a student of Kandler’s. After meeting Woese and hearing firsthand about his evidence and his radical idea, Kandler carried the news back to Munich, where he shared it with Stetter, then still a junior researcher. Stetter was straddling two roles—teaching in Kandler’s institute at the University of Munich, running a lab within Zillig’s operation, commuting between them daily—and he brought Kandler’s news from America across town. When he delivered his thirdhand account in a Friday seminar at the Max Planck Institute, Wolfram Zillig’s initial reaction was cold. Zillig, born in 1925, was just old enough to remember Nazism and the war from the perspective of a soldier-aged young man. As the story comes from Karl Stetter, recounted to Jan Sapp decades later, Zillig in 1977 reacted sourly to Kandler’s scuttlebutt about Woese’s third kingdom of life. “A Third Reich?” he snapped (#litres_trial_promo). “We had enough of the Third Reich!”

But Zillig’s resistance fell and his interest rose when he heard, a few months later, that Woese possessed data on the uniqueness of halophiles that nicely paralleled his data on the uniqueness of the methanogens. Zillig and Stetter then reset their own research efforts, which involved something called RNA polymerase (the enzyme that helps turn DNA code into messenger RNA), to see whether anomalies in that molecule among salt-loving “bacteria,” among heat-loving and acid-loving “bacteria,” and among methane-producing “bacteria”—anomalies that might set them apart from typical bacteria—matched the drastic anomalies Woese was finding by his own method. They did match. So maybe these microbes weren’t bacteria after all.

Derided in the United States, controversial at best, Woese was becoming a scientific lion in Germany, at least in those erudite circles where researchers studied the molecular biology of microbes. In 1978 Kandler invited him to a major congress of microbiologists in Munich. Woese declined. In a polite but cranky letter, he groused that the National Science Foundation and NASA were being stingy with him on grant funds while enjoying the considerable publicity from his work, and also that, quite apart from the costs, travel interrupted his research. Interruptions he found annoying. He was a driven man—toward results, not companionship. But the following year, Kandler tried again, and this time Woese accepted. His hosts paid the way. They treated him well. They asked only that he deliver a keynote lecture at another microbiology conference and then a seminar at Zillig’s institute. On the night of a festive dinner, in a great hall at the University of Munich, Kandler laid on a brass section from a local choir. They gave Woese a fanfare of trumpets. Not many molecular phylogeneticists ever get that level of jazzy appreciation. It melted his frosty rime.

Two years later, his German friends organized another meeting in Munich, this time an international conference—though they called it a workshop, suggesting informality and collaboration—devoted entirely to the archaea. It was the first such conference ever, giving the third kingdom a new measure of recognition. The attendance was relatively small, about sixty people, but included researchers from Japan, the United States, Canada, Great Britain, the Netherlands, and Switzerland, as well as the Federal Republic of Germany (West Germany), where the archaea were now big; and its program encompassed a wide range of topics and approaches. Ralph Wolfe came. So did Ford Doolittle, George Fox, and Bill Balch. Woese not only traveled to Munich again but also delivered the welcoming address—and he made that a substantive lecture, rich with ideas and provocations, not just a ceremonial greeting.

“We are about to embark on a scientific meeting (#litres_trial_promo) of historic significance,” he told the group (as reported later in the proceedings, edited by Otto Kandler). What they shared, this assemblage of scientists, was their concept of the archaea, which “did not exist four years ago.” They had been working, in their respective labs, with “organisms that intuitively felt peculiar”: methanogens, halophiles, thermoacidophiles. These things had seemed idiosyncratic and unrelated. We had been slow to recognize their connectedness, their unity, Woese said, because the existing framework of bacterial taxonomy was so misleading in its overview and so wrong in its details.

“Generations of failure had discouraged the microbiologist (#litres_trial_promo) about ever uncovering the natural relationships among the bacteria.” Here he was talking about the generations that had included Ferdinand Cohn, C. B. van Niel, and Roger Stanier. “With a few important exceptions, microbiologists were content to classify bacteria determinatively,” he added, alluding pointedly to Bergey’s Manual of Determinative Bacteriology, the authoritative handbook, and the cautious experts who had produced it for sixty years. The problem with that approach, Woese complained, was that it tried to understand bacteria only as static entities—items to be placed into categories of convenience. “Matters of their evolution became reserved for enjoyable but idle after-dinner speculation.” That’s what was missing from both microbiology and now molecular biology, he said: evolution.

Woese was casting down a gauntlet: telling some of the most brilliant and influential figures of late-twentieth-century biology—his friend Francis Crick, Crick’s colleague James Watson, the Nobel winners François Jacob and Jacques Monod and Max Delbrück and Salvador Luria, who had counseled Ralph Wolfe to stay away from Woese for the sake of his good reputation—that they were shallow, mechanistic thinkers with no curiosity about life’s history. That they were nothing but code breakers, riddle solvers, and engineers. The questions and answers offered now by the recognition of the archaea, he said, should go far to revivify evolutionary thinking, and “hopefully divert biology to some extent (#litres_trial_promo) from its present course of technological adventurism.” By that odd phrase, “technological adventurism,” he seems to have meant not just high-tech molecular biology for its own sake, without regard for evolutionary questions, but also perhaps gambits in genetic manipulation. It was a condemnation so damning and prescient, this whole 1981 rant, that you might imagine he had foreseen gene patenting, the growth of the biotech industry, gene-editing therapies, preimplantation screening of human embryos, and full-on human germline engineering. He set this “technological adventurism” against “molecular evolutionary biology,” his ideal, but an unspoken phrase, which at that time would have seemed oxymoronic.

That’s the notable takeaway from his 1981 Munich talk: it reflects Carl Woese’s compulsion to dig ever deeper into the narrative of life. He was a man possessed by the most deep-diving curiosity. This work he was doing, this door he had opened, this journey he was on—it wasn’t just about the Archaea, a third kingdom. It was about the origins and history of the other two kingdoms also. How did they arise? How did they diverge from one another? How were each of the three related to the two others? Which came first? Why did just one of the three lineages lead onward to all visible, multicellular organisms—all animals, all plants, all fungi, ourselves—while the other two remained unicellular and microscopic, though still vastly abundant, diverse, and consequential? And what kind of creature, or process, or circumstance preceded them all? Where was the tree of life rooted?

Woese wasn’t interested just in this separate form of life he had chanced upon. He was interested in the whole story.

Immediately after the workshop, which had gone well and given its participants a sense of momentum for the archaea concept, Kandler and his wife took Woese and Wolfe on a larkish field trip. They drove south from Munich into the Bavarian Alps and climbed a modest but picturesque mountain, the Hohe Hiss, along a graded path. “Woese and especially Wolfe were not in top physical shape (#litres_trial_promo), but with some huffing and puffing, they reached the top,” according to Ralph Wolfe’s own self-mocking account. At the summit, Kandler’s wife took a photo of the three men, all of them sunlit and contented on a clear day. Wolfe and Kandler appear as what they are: middle-aged scientists, balding, amiable, savoring a day outdoors. To their right sits Woese, with a full beard, leonine hair, a sweater tied jauntily over his neck, a cup of champagne in his left hand, smiling an easy, full smile of triumph. He was fifty-two years old, at the height of his powers and fame, and looked like a man on his way to a Nobel Prize.

PART

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The entrance of Lynn Margulis into this story occurred abruptly, with some fanfare, at a time when Carl Woese still labored in obscurity. Margulis was a forceful young woman from Chicago. Her role proved important because it brought new attention and credibility to a very strange old idea: the idea that living ghosts of other life-forms exist and perform functions inside our very own cells. Margulis, adopting an earlier term, called that idea endosymbiosis. It was the first recognized version of horizontal gene transfer. In these cases, rare but consequential, whole genomes of living organisms—not just individual genes or small clusters—had gone sideways and been captured within other organisms.

Margulis made her debut in March 1967 with a long paper in the Journal of Theoretical Biology, the same journal that had carried Zuckerkandl and Pauling’s influential 1965 article on the molecular clock. This paper was much different. Its author was no canonized scientist like Pauling, and its assertions were peculiar, to say the least. Put more bluntly: it was radical, startling, and ambitious, proposing to rewrite two billion years of evolutionary history. It included some cartoonish illustrative figures, funny little pencil-line drawings of cellular shapes, and virtually no quantitative data. According to one account, it had been rejected by “fifteen or so” other journals (#litres_trial_promo) before a daring editor at JTB accepted it. Once published, though, the Margulis paper provoked a robust response. Requests for reprints (a measure of interest, back in those slow-moving days before online access to journals, when scientists mailed one another their articles) poured in. It was titled “On the Origin of Mitosing Cells (#litres_trial_promo).”

That was a quiet phrase for a huge subject, though the title’s echoes of Darwin’s On the Origin of Species suggest the loud aspirations of the paper’s author. Never short of confidence, she was twenty-nine years old at that time, an adjunct assistant professor at Boston University, and a single mother raising two boys. She had been married as a teenager to a flashy young astronomer and, for the moment, was still keeping his surname. Her authorship on the paper read: Lynn Sagan. Later, she would be famous—venerated by some, dismissed and disparaged by others, including Carl Woese—under the surname of her second husband, Thomas N. Margulis. But to many of those who knew her, she was always and informally: Lynn.

The phrase “mitosing cells” is another way of saying eukaryotic cells, the ones with nuclei and other complex internal structures, the ones that compose all animals and plants and fungi (as well as some other intricate life-forms, less familiar because they’re microscopic). “Mitosing” refers to mitosis, of course, the phase in eukaryotic cell replication at which the chromosomes of the nucleus duplicate, then split apart into two bundles within two new nuclei, as a prelude to the cell fissioning into two complete new cells, each with an identical set of chromosomes. You learned about it in high school biology, not long before you dissected the poor frog. Mitosis is taught along with meiosis, the yang to its yin. Mitosis occurs during ordinary cell division, whereas meiosis constitutes “reduction division,” yielding the specialized sex cells known as gametes (eggs and sperm in an animal, eggs and pollen in a flowering plant). Meiosis in an animal yields four new cells, not two, after two divisions, not one, each resulting cell reduced to a half share of chromosomes. Later, sperm will meet egg, and, bingo, the full measure will be restored. It’s a little hard to remember which of those terms is which, I concede, but here’s my mnemonic: meiosis is reduction division because its spelling is reduced by the loss of the t in mitosis. Helpful? Granted, that leaves the inconvenient fact of meiosis containing the addition, not reduction, of an e. So, okay, never mind. But it works for me.

Mitosis defines all the cell divisions by which a single fertilized egg grows into a multicellular embryo and then an adult, and also by which worn-out cells are replaced with new cells. Your skin cells, for instance. The cells of a scar when a wound heals. The cells that replace your worn-out colon lining. Mitosis occurs everywhere in a body. Meiosis, by contrast, occurs only in the gonads. Lynn Sagan’s paper, though, wasn’t focused on mitosis as an ongoing process. The key word in her title was origin.

Her interest was the deep history, to the beginning, of eukaryotic cells. She quoted the statement from Roger Stanier and his textbook coauthors, declaring that the prokaryote-eukaryote distinction “probably represents the greatest single evolutionary discontinuity (#litres_trial_promo) to be found in the present-day living world.” It was the biggest leap in the history of life—an Olympic long jump, a high jump, a backward slam dunk—forever reflected in the differences between bacteria and more complex organisms. She proposed to explain how that leap happened.

“This paper presents a theory (#litres_trial_promo),” Sagan wrote—a theory proposing that “the eukaryotic cell is the result of the evolution of ancient symbioses.” Symbiosis: the living together of two dissimilar organisms. She gave her theory the more specific name endosymbiosis, connoting one organism resident inside the cells of another and having become, over generations, a requisite part of the larger whole. Single-celled creatures had entered into other single-celled creatures, like food within stomachs, or like infections within hosts, and by happenstance and overlapping interests, at least a few such pairings had achieved lasting compatibility. So she proposed, anyway. The nested partners had grown to be mutually dependent, staying together as compound individuals and supplying each other with certain necessities. They had replicated—independently but still conjoined—passing that compoundment down as a hereditary condition. Eventually they were more than partners. They were a single new being. A new kind of cell.

No one could say, not in 1967, how many times such a fateful combining had occurred during the early eras of life, but it must have been very rare that the resultant amalgams survived for the long term. Later, there would be ways of addressing that question. Sagan left it open. Microscopy, which was her primary observational mode of research, couldn’t answer it.

The little entities on the inside of such cells had begun as bacteria, she argued. They had become organelles—working components of a new, composite whole, like the liver or spleen inside a human—with fancy names and distinct functions: mitochondria, chloroplasts, centrioles. Mitochondria are tiny bodies, of various shapes and sizes but found in all complex cells, that use oxygen and nutrients to produce the energy packets (molecules known as adenosine triphosphate, or ATP) for fueling metabolism. ATP molecules are carriers of usable energy, like rechargeable AA batteries; when the ATP breaks into smaller pieces, that energy is released for use. Mitochondria are factories that build (or recharge) ATP molecules. To drive the production, mitochondria respire, like aerobic bacteria. Chloroplasts are little particles—green, brown, or red—found in plant cells and some algae, that absorb solar energy and package it as sugars. They photosynthesize, like cyanobacteria. Centrioles are crucial too, but for now, I’ll skip the matter of how. All these components, Sagan wrote, resemble bacteria by no coincidence but rather for a very good reason: because they evolved from bacteria.

The bigger cells, within which the littler cells were subsumed, had been bacteria too (or possibly archaea, though that distinction didn’t exist at the time). They were the hosts for these endosymbioses. They had done the swallowing, the getting infected, the encompassing, and had offered their innards as habitat. The littler cells, instead of being digested or disgorged, took up residence and made themselves useful. The resulting compound individuals were eukaryotic cells.