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Illinois IGB

Remembering Carl Woese

February 5, 2013

Professor of microbiology and a founding member of the University’s Institute for Genomic Biology, Carl Woese was a giant among scientists. Best known for his discovery of Archaea, a third domain of life, his wider work and theories have transformed scientific thinking about the very origins of life and the nature of evolution.

“Carl was truly a man of vision, creativity and passion, with a deep love of this university,” said Gene Robinson, director of the IGB. “Carl demonstrated that DNA provides the common threads that unite all forms of life on this planet and also began to show how they are related to each other. He rewrote the textbook on evolutionary biology. In addition, without Carl’s discoveries, we would not have the tools today to study the human microbiome, the incredibly diverse and complex assemblages of microorganisms in our bodies that contribute so much to both health and disease, in ways that we’re only beginning to understand. Carl Woese was one of the most significant biologists of the 20th century.”

In the mid-1950s the discovery of the structure of DNA triggered extensive research into deciphering the genetic code, which has yielded much insight. But Woese, whose research career spanned more than 60 years, believed the more fundamental question was, how did the code get here in the first place?

Perhaps understanding the origin of the translation mechanism of the genetic code could lead to an understanding of how the cell evolved, which could lead to understanding the very origins of life itself. Woese’s curiosity about this problem animated his entire career.

“In the popular imagination Darwin figured it all out in his On the Origin of Species,” says Nigel Goldenfeld, professor of physics and longtime collaborator. “Well, what was evolution like before there were species? What was evolution like before there were genes? Carl Woese was already thinking of these questions in the 1970s.”

For Woese the origin of species, Darwin’s claim to fame, was an epiphenomenon of the evolutionary process; the more important question was how cells first emerged and how they became organized into organisms.

“Woese did more for biology than Darwin,” says Norman Pace, professor of molecular, cellular and developmental biology at the University of Colorado, Boulder. “What Woese did was wholly original. Darwin did not have the originality of Woese.”

Woese thought the first step to understanding the origins of life would be to find a way to determine a phylogenetic tree for all of life. Since at that time biologists divided the living world into eukaryotes (can be multi-celled, and have a nucleus) and prokaryotes (single-celled organisms with no nucleus) he thought he might be able to find the organism that existed before the two branches split.

In order to pursue this very speculative, risky research, Woese, a brilliant, iconoclastic thinker, needed institutional support. The University of Illinois provided it. When Woese was hired, in 1964, the head of his department simply offered him a tenured position at the same salary he had in his previous job at GE.

It was the beginning of a beautiful relationship.

It is no accident that Woese’s work took place at the University of Illinois, says Goldenfeld. “People here have the time to be a bit more contemplative.  When you are on one of the coasts, in the thick of things, there is more social pressure to get on with things.”

But how to actually conduct this research? One challenge was how to classify microbes, considering that, unlike toucans and tigers, they can’t be compared using morphological differences. Another challenge was what part of the cell would provide the best “fossil” record?

Woese managed to solve both of these challenges with highly creative scientific thinking. He determined that if there’s going to be one place to look, it should be part of the machinery essential to making proteins. The ribosome, he reasoned, forms part of the protein-making machinery at the heart of all cells and every organism has them. Changes that occur in the ribosome can’t be so frequent that they are hard to follow and they can’t be so rare as to be uninformative.

In order to choose the ribosome Woese had to have a deep understanding of its biochemistry, which he did. Many of Woese’s earliest papers concern the biochemistry of the ribosome.

“He chose the ‘Goldilocks’ spot,” says Goldenfeld. “Nobody since then has come up with a better idea for a molecule to look at as the proxy for the history of evolution. There are other molecules one could use, but this is the best one because it varies so slowly. He really thought it through. If it was going to be anything it was going to be the ribosome.”

Serendipitously, Frederick Sanger had just developed an early sequencing technique known as olignonucleotide cataloguing. Woese thought he’d try to adapt it and use it to create his phylogeny. And so, in the late 1960s he began to classify life by sequencing the 16S rRNA (ribosomal RNA) gene of as many organisms as he could get his hands on. It took him a year to create his first catalog.

“What Carl invented in a sense was a microscope that goes back in time,” says Goldenfeld. “It works by reading molecular sequences in a smart way so that we can work back and see what must have been the changes that happened at a molecular level as organisms evolved.”

Adapting Sanger’s method to study the RNA of the ribosome (which, he reasoned, pre-dated DNA) gave Woese both a way to categorize microbes and to study the deep evolution of cells.

So while the majority of the scientific community was trying to understand how the code worked, Woese spent more than a decade working in obscurity to figure out where the code came from in the first place.

In those early days sequencing was mind-numbing, repetitive, solitary, and tedious work. By 1976 he had sequenced the 16S rRNA of about 30 different kinds of bacteria. Today, with computers and automated sequencers, the work that took him thousands of hours would take less than a week. It took 10 years of this work before he began to publish his findings.

But Woese never gave up.

“He knew what he was asking and why,” says Goldenfeld. “It’s that kind of very open-minded scientific investigation, it’s very rare that people would do that. You have to really convince yourself that this is the right thing to do and be very determined.”

Woese’s method worked perfectly; it showed a clear difference in the 16S rRNA between eukaryotes and prokaryotes. One of the most revolutionary results of this work is that, for the first time ever, microbes could be objectively catalogued. Bacteriologists had long since given up being able to do anything of the sort. This achievement opened up the world of microbes to further study and analysis.

Meanwhile his work led Woese to an unexpected discovery the day he analyzed a methanogen. Methanogens, it was thought, are prokaryotes that live in very hot, oxygen-free environments and produce methane gas. They are difficult to grow in the lab, but Woese’s colleague Ralph Wolfe had succeeded and offered his methanogen to Woese for his project.

“The big surprise was when we finally did do one of these methanogens . . . uh-oh, it didn’t fit into the prokaryote signature,” Woese once said.

The methanogen didn’t fit with the eukaryotic signature, either. In fact, methanogens share some characteristics with both eukaryotes and prokaryotes, Woese determined that these organisms, which he termed Archaea, are a third form of life that arose separately from prokaryotes and eukaryotes.

Woese did not set out to discover the Archaea. They were as much a surprise to him as to the rest of the scientific community. The finding, announced in 1977 in the journal Proceedings of the National Academy of Sciences and trumpeted in newspapers and magazines around the world, rocked the scientific community. This was no new species of butterfly or frog, but a whole new branch of life. Granted, it had been hiding in plain sight; researchers had thought Archaea were bacteria because they looked like bacteria. Thanks to Woese we learned they were not.

This discovery absolutely transformed taxonomy, phylogeny and evolution into experimental sciences rather than subjective pursuits. Woese’s work also unveiled the great diversity in microbes. We know now that on the tree of life plants and animals are the tiniest twigs, and microbes occupy 90 percent of the branches. Today, researchers investigate everything from the role of microbial communities in the human gut to microbes in the environment. Their work would not be possible without Woese’s fundamental research.

“He was very clever, he understood so much and yet so much was intuitive for him,” says Goldenfeld. “There are other, highly technical things that he did that were just brilliant. Some of them I would ask him, ‘why did you do this? And how did you have this stroke of insight?’ and he’d say, ‘I don’t know, actually.’”

Woese’s groundbreaking approach and paradigm-shifting research findings should have made the University of Illinois the center of this new field of research. But there was strong resistance within the scientific community. He was not invited to speak at conferences; graduate students did not flock to his lab; funding was sparse.

There were many hard years, but gradually the magnitude of this discovery began to be recognized.

Woese received a MacArthur Fellowship (1984); election to the National Academy of Sciences (1988); the Dutch Royal Academy of Science’s Leeuwenhoek Medal, the highest honor in microbiology (1992); and the U.S. National Medal of Science (2000). Probably the most important recognition for Woese was the $500,000 Crafoord Prize in Biosciences in 2003 in recognition of his discovery of the Archaea. The Crafoord Prize is the equivalent of the Nobel Prize for his field, for which there is no such prize. He was elected to the Royal Society in 2006.

When asked about this major contribution, Woese shrugged it off.

“I'm just an average guy,” he told one magazine. “I just happen to have a pretty good intuition regarding biology. I may have brought the complete phylogenetic tree into being, but all I am is a midwife. I'm just glad I was there to help bring it in. Do I feel proud about it? Yes, sometimes. But I don't sit around thinking how great I am.

“I come in here every day because I love this stuff, that's all. To be able to study the past, and to look back down the road into what was happening three or four billion years ago—what a privilege!”

Meanwhile, Woese did not rest on his laurels.

Having studied untold numbers of microbes, he began to appreciate that they swap genes constantly between organisms, not just between a single species. This so-called “horizontal gene transfer,” or HGT, is an entirely different model than vertical gene transfer, which occurs when genes are passed from parents or ancestors. Woese posited a connection between the origin of the genetic code, the translation mechanism and the emergence of cells and their organization.

2003 not only marked his receipt of the Crafoord Prize, but also the launching of the IGB at the University. Woese’s involvement with, first the W. M. Keck Center for Comparative and Functional Genomics, and then the IGB was critical for both Woese and the University. In the late 1990s, Woese was instrumental in getting a major grant to create the Keck Center. There were already four or five major NIH-funded centers for genomic research in the country focused on sequencing the human genome, but that suggested to Harris Lewin, then head of the University’s Carver Biotechnology Center, later founding director of the IGB, and now vice chancellor for research at University of California, Davis, that Illinois could conduct genomics research on a great many biologically interesting organisms, not just humans or the traditional animal models, such as mice and flies. Analyzing the genomes of organisms based on their location in the tree of life fit with Woese’s continued interest in evolutionary questions. Woese was extremely supportive of the “phylogenomics” concept and made a convincing presentation to the Keck Foundation representatives at the site visit prior to the $1.25 million award being made. 

At roughly the same time discussions began on campus about an inter-disciplinary institute (which eventually became the IGB) that could probe questions of biology using genomics as the enabling technology. Lewin spent many hours discussing these ideas with Woese, who was excited about the prospect and threw his weight behind the initiative. In addition, discussions with people like Goldenfeld, who could translate his concepts into mathematical models, were very exciting to him.

“Carl had been searching for the answers to big questions in evolution. That’s what drove him, and the IGB represented new thinking on the topic,” says Lewin.

Ultimately, the IGB, specifically the Biocomplexity theme, became Woese’s new intellectual home, says Lewin.

And meanwhile, Woese’s insights and conversations helped Lewin develop his own thinking.

“He became a mentor to me,” says Lewin. “I changed my thinking and even my research direction based on our discussions.”

Woese’s influence will be felt for many years to come. His work of the last 40 years played a pivotal role in a recent project proposal to mine genomic data to determine universal aspects of the evolution of life and will characterize the fundamental principles governing the origin and evolution of life elsewhere in the universe. NASA’s Astrobiology Institute recently funded this project with a five-year, $8-million grant to IGB’s biocomplexity research theme.

In a 2006 paper, Woese theorized that Darwinian natural selection (and vertical gene transfer) did not become a factor in evolution until more complex life forms evolved. He suggested that in the early stages of the development of life, all organisms engaged in HGT and were not in competition. It is possible, Woese thought, that HGT was the norm for billions of years; far longer than natural selection and vertical gene transfer. Woese also proposed that instead of all life evolving from a single cell or pre-cell, that various forms of life evolved independently from as many as several dozen ancestral pre-cells. The three forms of life, archaea, bacteria and eukaryotes may have emerged independently from this soup of pre-cells.

Woese is regularly hailed as an intellectual genius, slaving virtually alone for years upon years, wearing his trademark red-plaid flannel shirts and worn out sneakers, doggedly pursuing his research. But what is missing from this narrative is the enormous influence Woese had as a teacher and mentor.

Over and over again his former students talk about Woese being an outstanding teacher because he was learning and questioning things all the time. Larry Gold, who first met Woese when they were both working at General Electric, says one of his most common expressions was “Huh, I didn’t know that.”

“He taught me how to think,” says Gold, now a professor at the University of Colorado, Boulder. “That’s his gift. He never ever cared that I was just a kid. He talked to me, to all of us, the same way.

“I’m always carrying that guy on my shoulder,” he says. “People like Carl don’t come around too often. It’s kind of magical.”

Woese modeled, for students and colleagues, how to think about things, to step back and wonder about the big picture. Woese’s behavior reminded others that they can also always be learning, says Gold.

“I wouldn’t call Woese a teacher,” says Pace. “I’d call him a guru. He showed the way.”

“Carl knew how to think about things,” says Dan Wolf, (PhD. ’76), CEO of Videobotics, a technology development company.

As a graduate student in zoology, Wolf took a class in molecular genetics taught by Woese as an elective. “This class was more than the facts, it was how to think about things,” he says. “I’d never come across anything like this. Up until now my classes had been cut and dried: chemistry, physics, math, etc., all discrete and focused. Carl talked about the philosophy of how living systems work and the problems with how we think about them. We talked about what is not known.”

From that time on, Wolf  “got permanently stuck in the Carl Woese field of gravitational attraction. And I never left. I moved away, but every time I returned to town, I always came by to visit Carl.”

Dan Oerther, who earned his PhD from Illinois in 2002, also took a graduate-level class with Woese when he was at Illinois. He got so much out of it he participated three more times.

“Carl's course was something unique,” he said.  “You would attend a 90-minute lecture, twice per week, for fifteen weeks.  Each lecture was interesting, and most of the time Carl would talk about whatever was on his mind — his scientific thought of the day, as it were. “

Chatting with and listening to the ideas of such a tremendous teacher twice a week was a highlight of Oerther’s time at Illinois, he says. Another of Oerther’s favorite memories was the class period when students brought a cake to celebrate Woese’s teaching.  Oerther, now a professor of environmental engineering at the Missouri University of Science and Technology, still remembers Woese’s smile, covered in blue icing.

“It was incredible to have so much fun with someone of such scientific stature,” said Oerther.  “The ability to interact with him was amazing!”

Woese was a deep, deep thinker and intensely private, yet enormously generous with his students and his friends, and stoutly loyal. He really enjoyed interacting with students and would talk with them about science at every opportunity. He was also quite shy, with a mischievous sense of humor; it wasn’t all work and no play with Woese.

For five years in the 1980s, for example, microbiology students in Woese’s and Wolfe’s labs organized an annual putt-putt golf tournament, the Archaea Masters (“putt-putt belongs to the archaea”). There was a desire for a famous sponsor and Woese, the “Archaeaköening,” was the clear choice. Following the tournament each year the group retired to Woese’s house, aka the Phylogenanda Ashram, for a cookout. Jorge Escalante, now a professor at the University of Georgia, remembers those cookouts fondly.

“As students, we saw the side of Carl that few others saw,” he says, of that time. “A real friend, unassuming and genuine.”

February 5, 2013
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