For evolutionary molecular biologist Eugene V. Koonin, science is not just a job or even a career—it is intrinsic to how he experiences the world. “It’s a way of living and thinking,” he says. “It’s effectively a devotion or dedication to creative but rational thinking. These are things that can apply to everything and anything in the world.”
Koonin (seated, third from left) and his research group at the NCBI. Seated to the right of Koonin is Staff Scientist Kira Makarova, with whom Koonin identified the genetic region known as CRISPR-Cas. Image courtesy of Yuri I. Wolf (photographer).
Koonin, of the National Center for Biotechnology Information (NCBI), National Institutes of Health, and a recently elected member of the National Academy of Sciences, pursues his devotion in the field of evolution, investigating what functions genes perform and how organisms gain and lose genes over time. Koonin hopes to weave together clues in genome sequences into a story on the origin and progression of life on Earth.
Koonin was born in 1956 and raised in Moscow, then the capital of the Union of Soviet Socialist Republics (USSR). His closest family connection to science came through his maternal grandparents, who both worked in the medical field.
“As long as I remember myself, I wanted to be a biologist,” he says. During his elementary school years, the structure of DNA came to the public attention, and Koonin remembers feeling fascination with the helical structure and the concept of a genetic code. In middle school, Koonin participated in magnet groups, akin to clubs, to pursue science. Through these groups, he attended lectures and laboratory courses taught by eminent researchers from the USSR Academy of Sciences.
When enrolling at Moscow State University, Koonin initially planned to study molecular biology, but felt entranced by a relatively new department: virology. The department felt fresh and interesting, he says, filled with young researchers. Koonin and a group of friends decided to try virology together. “I learned how interesting and unusual viruses could be, and that was very intriguing,” he says. “I made my choice, which I do not regret to this day.”
Koonin found a Soviet scientific enterprise affected by a closed country and a general lack of resources. Although many scientists in the USSR conducted work that served to replicate previous research or confirm their hypotheses, Koonin’s mentors, particularly virologist Vadim Agol, set his sights on conducting meaningful research, teaching him to search for data and observations that would falsify hypotheses rather than confirm them.
After earning his PhD degree in 1983 with a dissertation on replication of viral RNA, Koonin returned to his fascination with molecular evolution in his position as a research scientist at the USSR Academy of Medical Sciences. Five years before, in 1977, biochemist Fred Sanger and colleagues had published an efficient method for DNA sequencing. At the time, sequencing a contiguous piece of 10,000 DNA bases was around the upper limit of possibility. Conveniently, small virus genomes are about that size. “It’s difficult to imagine our view of genomes in 1983,” he says. “The genomes at the time were streams of unintelligible As, Gs, Cs, and Ts. It was terra incognita.”
Koonin and colleague Alexander Gorbalenya dived into the emerging genomic data, looking for, in Koonin’s words, “tiny islands of understanding.” The two proceeded on the evolutionary hypothesis that sequences conserved by evolution in various organisms likely carried out important functions. One of his guiding principles was the title of Theodosius Dobzhansky’s 1973 essay “Nothing in biology makes sense except in the light of evolution” (1).
By 1988, Koonin and Gorbalenya’s efforts, using simple computer algorithms, began to yield results. “It was possible at that time in the late 1980s to reveal a lot of novelty with relatively simple effort,” he says. “It was all happy serendipity.” In particular, their work described the diversity of helicases, enzymes that unwind double-stranded DNA or RNA (2).
Around 1989, sweeping social and economic changes in the USSR aimed to end decades of economic stagnation. Openness initiatives brought a scientific revolution. Koonin left the Soviet Union for the first time in 1989 to attend a conference in what was then Czechoslovakia.
At another meeting in Berlin in 1990, Koonin met plant virologist James Carrington. Koonin commented on the likely function of a protein Carrington was studying, and Carrington later invited Koonin and his close collaborator Valerian Dolja to visit Texas A&M University to continue virus evolution research and contribute to the tests of the protein function. Koonin and Dolja arrived in Texas in early 1991.
While there, Koonin read about the recent formation of a new center for computational biology at the National Institutes of Health known as the NCBI (National Center for Biotechnology Information). The NCBI is a bioinformatics nexus, a repository for large databases, such as GenBank. Intrigued, Koonin inquired about the possibility of a visit, a conversation that evolved into a temporary appointment offer. In November 1991, six weeks before the Soviet Union dissolved, Koonin and his family left the USSR and moved to Bethesda, Maryland, where he resides today.
Twenty-five years later, Koonin asserts that the NCBI is a great environment in which to conduct fundamental research. Over the past quarter-century, his research program has evolved dramatically. Initially, he and his colleagues continued his line of computational observational research, comparing sequences of protein domains and protein structures to elucidate gene and protein functions. Their work helped uncover evolutionary relationships between cellular and viral genomes, and led to further generalizations on evolution of viruses (3).
“And then things changed,” Koonin says. In 1995, the first bacterial genome was sequenced using shotgun sequencing, in which short snippets of DNA are sequenced individually and then compiled together using overlapping sequences as guides (4).
“We were eagerly anticipating that,” he says. “This was expected and we were extremely eager to get our hands on these genomes.” The importance of complete genomes, he adds, is partially to see what genes are not present, to understand how genes are acquired and lost through evolution.
The next year, in 1996, Koonin and postdoctoral scholar Arcady Mushegian used their understanding of comparative genomics and functional pathways to posit a minimal genome for cellular life (5). “It turned out to be a rather good model, a reasonable reconstruction based on very simple premises,” he says.
By 1997, genomes of seven organisms had been fully sequenced. To facilitate comparative studies between genomes, Koonin and NCBI director David Lipman came up with the idea to construct a collection of clusters of orthologous genes (COGs) to help organize the comparative genomic effort. Simple algorithms allowed them to identify genes with similar predicted functions that were either inherited by different organisms from a common ancestor gene or developed through gene duplication and divergence within a single organism (6). “It was an important effort that became one of the foundations of comparative and evolutionary genomics,” Koonin says.
Entering the 2000s, Koonin and his colleagues used COGs and comparison of the order of genes in a genome to identify gene neighborhoods of interest and reconstruct conserved neighborhoods in various species. One of the neighborhoods Koonin and his colleague Kira Makarova identified (7) is now known as the CRISPR-Cas system, which is at the heart of current gene editing research (8). “Very regrettably, we did not quite correctly predict the biological function,” he says. At the time, in 2002, he and his colleagues hypothesized that the Cas genes were involved in a DNA repair system. “In a sense, not quite wrong,” he says, “And yet, off the mark.”
Three years later, work by other groups reported additional discoveries about the Cas genes that helped Koonin, Makarova, and other colleagues put the pieces of the system together: CRISPR-Cas is a genetic defense system, they wrote in 2006, analogous to RNA interference in eukaryotic cells (9). The system serves to protect cells from foreign genetic elements, such as viral DNA, by remembering the elements and using them as guides to destroy invading DNA or RNA. Other groups have since adapted CRISPR-Cas into a tool for precisely removing and replacing genes, effectively editing a cell’s genome (10). “The whole field of CRISPR became very dynamic and exciting,” Koonin says.
Today, Koonin’s group continues to work on microbial defense systems, while additionally returning to virology, his “first love.” Recent discoveries of giant viruses and of the virophages that parasitize on them have “extended the imagination” of virology and have prompted Koonin to revisit viral evolution, particularly the process of host/parasite coevolution, a key driver of evolutionary complexity in both hosts and parasites (11).
Another research focus is constructing and testing computational models of general evolutionary processes. In his Inaugural Article, Koonin describes the contributions of one of these models (12). “Microbial genomes are extremely streamlined,” he says. Previous theories of prokaryotic genome evolution held that the genome’s small size was due to loss of any nonessential genes to reduce the energy burden associated with genome replication (13). However, that model alone was not sufficient to explain genome sizes. Koonin and colleagues found a better fit to the data with a model that included gene acquisition as well as deletion. “These genes are, on average, useful,” he says. “The genes that are acquired are adaptive. They are not all strongly advantageous, but by and large, it is not neutral material.” Gene deletion occurs slightly more often than acquisition in Koonin’s model, in agreement with observations of many organisms.
Koonin is now collaborating with physicists to link the fields of biology and physics through principles of emergence that, he hopes, can be shown to govern both condensed matter behavior and genome evolution (14). He and his group are also actively pursuing the research opportunities provided by metagenomics, the study of populations of microorganisms present in various environments. “Until very recently, [if] you needed to culture something, you had to be able to grow the organism in the lab,” Koonin says. “Now it’s not really essential. You can go out and sequence the sea or the soil or the contents of the human gut. There are many important discoveries on that path.”
He also continues to work with the researchers who are advancing CRISPR-Cas gene editing technology, particularly Feng Zhang of the Broad Institute at Massachusetts Institute of Technology and Harvard. Koonin’s computational observations are being translated into application and experimentation by his collaborators (15⇓–17). “This is one of the greatest beauties of science,” he says, “that when you are studying life, you cannot get away from touching on problems of biomedical and biotechnological relevance. I notice that, to my greater satisfaction than I would have thought a few years ago, the pipeline is getting shorter and shorter. We can see things that are absolutely fundamental being applied.”
As Koonin advises aspiring scientists, his advice reflects his unqualified enthusiasm for science but also the realities of limited funding in the biomedical field. Accordingly, he tells students that they should follow the career path that best suits their interests and aptitudes, whether that leads them to academia, industry, or journalism.
He has never had any question about his own career path, however. “I simply do not have a good way of thinking of a different mode of existence,” he says, and his interest in science encompasses the entire search for fundamental truth, the general laws of evolution, whether in biology or cosmology. Science, he says, is an intrinsic mode of experiencing the world. “That is the way of living that is infinitely more interesting than anything else I can think of.”
This is a Profile of a recently elected member of the National Academy of Sciences to accompany the member’s Inaugural Article on page 11399 in issue 41 of volume 113.
