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The secrets of symbiosis

Science

Nancy Moran on a rooftop with boxes of her research

Nancy Moran keeps honey bees on a university building rooftop so she can study their microbiomes.

Julia Robinson

A love of insects and their microbial partners helped this biologist reveal secrets of symbiosis

Nancy Moran has found clues to evolution in some unlikely places. Some 20 years ago, living in Arizona, she would frequent a Mexican restaurant in Tucson for more than its food. She regularly climbed the fire escape behind it to visit the upper branches of a hackberry tree—along with all the insects lurking there. One night, she reached into the foliage and scooped up a nondescript bug that helped change the way she and other biologists think about the evolution of complex life.

The sesame seed–size bug she nabbed—a psyllid, which causes the plant stems or leaves it feeds on to form hard nodules called galls around the insect—harbored symbiotic bacteria that appear to capture a key stage in the evolution of the cell. Their genomes are so shrunken, Moran found when she returned to her lab and analyzed the bug’s microbial cargo, that they seem to be losing their ability to live on their own. They may be on their way to turning into organelles, like mitochondria and chloroplasts, which originated as symbiotic microbes early in the history of life but ultimately became dependent wards of the cell.

Moran, an evolutionary biologist now at the University of Texas (UT) in Austin, has built a career from groundbreaking findings made in plant-dwelling insects. Her work on psyllids, aphids, and other sap-sucking insects has uncovered intricate, intertwined relationships with internal bacteria, which help them survive on a meager diet of plant juices. Moran is “one of the people who pioneered symbiosis as a field and did so with rigorous work and creativity,” says John McCutcheon, a former postdoc and now an evolutionary biologist at the University of Montana in Missoula.

Today, such symbioses are widely recognized for creating life as we know it. Energy-producing mitochondria power all complex cells; chloroplasts, where photosynthesis takes place, make plant life possible. The cementing of other host-microbial alliances enabled animals to expand what they could eat, diversify into new species, and conquer almost all parts of the planet. We humans are increasingly aware that communities of microbes in our guts, on our skin, and elsewhere—our microbiome—shape our physical and perhaps even mental well-being.

Moran, who received a MacArthur “genius grant” early in her career and was elected to the National Academy of Sciences in 2004, has developed her own vital partnership. She has teamed up with Howard Ochman, another UT biologist, for more than 20 years, both personally—they married in 1998—and professionally. She has dedicated her career to symbiosis; he has ranged more widely but has contributed fundamental principles about how microbes evolve. “This is quite the power couple,” says biotechnologist Andrew Ellington, a UT colleague.

After decades uncovering the evolutionary roots of symbiosis, Moran now looks to microbial communities for ways to address today’s challenges. She’s studying the gut bacteria in bees, which depend on microbial guests to thrive. That new system, she hopes, will suggest ways to stop the decline of the bees and other pollinators and perhaps yield a simple model for exploring the roles of gut microbes in people.

Honey bees need their gut bacteria to thrive and keep their hives healthy.

Julia Robinson

While playing outside with her seven siblings or hanging out at the Dallas, Texas, drive-in theater her father ran, the young Moran would collect bugs, leaves, and flowers wherever she could. “I was known as the kid who liked plants and insects,” she recalls. Her favorites were the tarantulas. (Yes, the entomology Ph.D. knows they are spiders, not insects.) She kept them in jars and fed them crickets. Her family accepted her hobbies, fretting only when, at age 9, she convinced a friend they should test whether the poison ivy next to the school playground really could cause a rash. “That was a horrible disaster,” Moran recalls.

Yet she was slow to realize that she could make a career of biology. At UT, she majored first in art and then in philosophy. But an introductory biology class, a university requirement, had an enduring impact. “Once I learned about evolution and natural selection, I decided this was the most interesting thing to spend time on,” Moran says.

As a graduate student at the University of Michigan in Ann Arbor, Moran trained with the famous 20th century theoretical evolutionary biologist W. D. Hamilton, and they became close friends. “We talked about everything … big ideas and what kinds of science make a difference in understanding the evolution of life,” Moran says. Entomology remained her first love, however. Every free moment she wriggled into bushes, looked under leaves, and peered into flowers to see what new insect species she could find.

After she took a faculty job at the University of Arizona in Tucson in 1986, a phone call from Paul Baumann, a microbiologist at the University of California (UC), Davis, helped her link her two scientific passions. Baumann was studying Buchnera, a once free-living bacterium now found solely inside aphids. In the 1960s, a German biologist named Paul Buchner had cataloged these endosymbionts and written a tome with intricate illustrations of where they lived in the aphids, as well as in lice, beetles, and other insects. Buchner suggested those symbioses were essential, life-long relationships that had existed for millions of years.

If so, the microbes and the insects must have evolved together—and their DNA should tell the tale. To test the idea, Baumann needed Moran’s aphid expertise. By sequencing the genomes of various aphid species and their Buchnera, Baumann and Moran built family trees for both organisms, and found that the microbes had diversified in step with the insects. Using various aphid fossils to date the trees, they found that the partnership began some 200 million years ago. Since then, Buchnera has passed from one aphid generation to the next, coevolving with its host.

Can’t live without you

Aphids dine on sap they suck from a plant’s phloem, or circulatory system, but that diet lacks key nutrients. The insects rely on internal bacteria called Buchnera to convert amino acids in sap, such as glutamate, into ones they are missing. The bacteria, in turn, benefit from other nutrients and shelter provided by the aphid.

For the next 15 years, Baumann, Moran, and their colleagues used similar DNA analyses to document equally long-term relationships between bacteria and white flies, spittlebugs, cicadas, leafhoppers, and psyllids. Some partnerships dated as far back as 270 million years, they concluded. The work “established that symbiosis is a central part of evolution that goes way back,” Moran says. She and other biologists propose the microbes helped the insects exploit new food sources and habitats, resulting in a rapid diversification that paralleled the diversification of flowering plants.

“Having her as an organismal biologist and him as a microbiologist was really helpful for the field,” McCutcheon says.

The sequencing also suggested why such partnerships have persisted for so long. Buchnera, for example, has genes that enable it to make amino acids not available from sap or from the aphid’s own metabolism, compensating for the insect’s poor diet. Meanwhile, living in the protected environment of the aphid’s specialized bacteria-carrying cells, Buchnera has lost essential genes, so it has to rely on the aphid to make up for those losses. In the late 1990s, this interdependence seemed remarkable, and it helped reshape how symbiosis was viewed.

Moran’s genomic approaches to symbiosis have since inspired many researchers, says Angela Douglas, who studies insect-microbe interactions at Cornell University. Twenty-five years ago, “We were the crazy people” for thinking symbiosis was so important, she recalls. Today, such close connections have proved to be the rule for many host-microbe partnerships.

Moran’s later work in insects confirmed the power of symbiosis. She, McCutcheon, and others found that some insects can’t survive without multiple symbionts. In the glassy-winged sharpshooter and the cicada—both also sap-sucking insects—one symbiont supplies eight of the 10 essential amino acids missing in their diet, and another symbiont supplies the other two. In other sap-sucking insects, symbionts serve additional functions, Moran and her colleagues discovered. In aphids, a symbiont makes the insect less susceptible to parasitic wasps by carrying a virus that’s toxic to the wasp’s young. Other symbionts improve the aphid host’s tolerance for high temperatures, enabling it to thrive in new environments. That work illustrated the complexity of microbial partnerships and hinted at the spectrum of advantages that microbial guests confer, a theme increasingly evident in studies of the human microbiome.

A room full of plants teeming with aphids keeps Nancy Moran and her team well-supplied for experiments.

Julia Robinson

Moran also unexpectedly discovered that deleterious mutations are often common in the hosted microbes, suggesting symbiosis isn’t always a win-win for both partners. The microbial genomes were naturally decaying through time for two reasons: The bacteria lacked a sexual phase of reproduction, which could recombine DNA and replace bad genes, and only a few of the bacteria trapped inside an aphid pass along to the next generation, a winnowing that further restricts recombination between microbes. The buildup of mutations steadily erodes the number of working genes in the bacteria—Buchnera has just 600 genes compared with the 5000 or so powering Escherichia coli—and make those that remain less functional. “The insect is basically relying on a symbiont that’s falling apart,” Moran says.

She and Japanese colleagues later identified one way aphid endosymbionts cope with the decay: by making a lot of heat shock proteins, which can help stabilize faulty proteins produced from the mutated genes. Another bulwark against decay, Moran suggests, is what’s known as horizontal gene transfer, in which essential genes from the partner microbe or outside microbes migrate to the host genome—as genes from mitochondria did. That way they can benefit from the host’s sexual reproduction, which enables intact copies to replace mutated ones.

Moran’s groundbreaking paper on gene decay came out in 1996. Her lab in Arizona was thriving, but her associate professor’s salary barely covered her bills. “I was broke,” she recalls, and nearly overwhelmed being a single mom. Divorced for the second time in early 1997, with a 5-year-old daughter and a 14-year-old stepdaughter, she struggled to balance work and family life. “If you have kids, you are not allowed to fall apart,” she says. Yet she couldn’t travel to scientific meetings—key to any young professor’s career.

The MacArthur grant she received in 1997, which paid more than $50,000 annually for the next 5 years, lifted those burdens. She immediately hired a housekeeper and reduced her teaching load.

At the time, Ochman was studying bacterial genomes. Curious to meet this newcomer to microbial evolution, he prodded organizers of one of the exclusive Gordon Research Conferences to invite Moran. So few women were present that Ochman knew exactly who she was. With characteristic directness, he walked up and asked what she was doing with the MacArthur money. Moran, who tends to be reserved, was charmed. They married 14 months later, and he followed her to the University of Arizona. In 2010, Yale University recruited them to set up a center on microbial diversity. In 2013, the couple moved back to Moran’s home state.

She says their shared passion for evolutionary biology and Ochman’s encyclopedic knowledge of the field have aided her immeasurably. He “has had a huge positive impact on my science.”

Nancy Moran met her husband Howard Ochman, who studies microbial evolution, at a scientific conference and their professional and personal lives have become deeply intertwined.

Julia Robinson

Early on, Ochman had been puzzling over two microbial mysteries: why genomes of E. coli strains can vary in size by as much as 50%, and how other bacteria abruptly change from benign to pathogenic. By scrutinizing the microbes’ genomes, he found that they readily gain and lose genes by swapping them with other bacteria or with their hosts. Such horizontal gene transfer could help explain the genome size variation, how bacteria pick up genes for toxins or other weapons—and also how a symbiont such as the ones Moran studies might shift essential genes to its host.

Moran and Ochman have offices less than 100 meters from each other. He often pops in on her, whether to discuss a possible grant proposal, go over the latest data, or just have lunch. “We spend 18 hours a day together,” Ochman says. Yet their personalities are a world apart. Boisterous and impulsive, Ochman jumps quickly into new topics (ape microbiomes recently). Steadfastly loyal, Moran picks a question—or a partnership—and works on it thoroughly. “She is more logical and takes a more long-term view,” Ochman says.

Moran’s continued insect collecting led her to examples of bacterial symbionts with such tiny genomes that they are inextricably tied to host cells. One was Carsonella ruddii, from that psyllid from the Mexican restaurant, which proved to have just 160,000 bases compared with E. coli‘s 5 million bases and Buchnera‘s 640,000. Other genomes were even smaller. The findings have convinced her that no clear dividing line separates organelles and endosymbionts. “My view is that these words are just labels,” she says.

Honey bees have become one of Moran’s enduring interests, prompted by her hypothesis that gut bacteria might play a role in the well-documented decline in the bee population. Her team’s early work showed the honey bee gut contains eight species of bacteria—a manageable number compared with the hundreds typical of the mammalian gut—and that every honey bee around the world has the same set. A student in her lab at Yale figured out how to grow each of the eight kinds in the lab; in contrast, Buchnera continues to be unculturable.

Nancy Moran’s molecular and microscopy studies of aphids (in dish) have uncovered key principles of symbiosis.

Julia Robinson

By isolating pupae before they emerge, Moran’s team can keep worker bees from inoculating the young bees with the bacteria. The resulting “microbiome-free” bees, the group found, vividly demonstrate the importance of these microbial guests. Lacking their usual microbiomes, the bees gain less weight, are more susceptible to pathogens, and die sooner. Hives decline.

Recently, Moran’s graduate student Erick Motta showed that bees with an intact microbiome become more susceptible to pathogens when exposed to glyphosate, the herbicide marketed as Roundup. Glyphosate has been considered harmless to insects and other animals because it affects an enzyme that only plants and microbes use. But through its effects on microbial guests, the compound may harm insects as well, the work suggested. (When this work was published last year, Roundup’s maker issued a statement saying: “No large-scale study has ever found a link between glyphosate and honey bee health issues.”)

To Moran, the honey bee microbiome is complex enough to stand in for the human microbiome but simple enough to be dissected in a way the human counterpart cannot be. Moran’s work on bees “has been some of the most reliable, clearly articulated work” on gut microbes, says Jon Sanders of UC San Diego, who studies human microbiomes. He expects the honey bee studies will yield insights into how gut microbial communities in general function.

The bee work led to other payoffs after Moran started to work with the Defense Advanced Research Projects Agency (DARPA). which sought proposals to harness microbial systems. At first she hesitated: “The purpose was to engineer something, rather than simply to understand something, as had been true for all my work up until then,” she explains. But she, UT bioengineer Jeffrey Barrick, and Ellington got DARPA funding to devise methods to alter the bee microbiome in ways that would change the insect’s traits. Such tinkering might make bees more resistant to stresses, for example, which could help preserve the vital pollinators. To show a proof of principle, UT graduate student Sean Leonard recently engineered a bacterium from the bee gut to produce RNA that increases production of dopamine, a key neurotransmitter. Preliminary results suggest those bees are better learners as a result.

Colleagues are curious to see what Moran learns next from honey bees or any of the insects whose inner lives she probes. “She’s not just a one-hit wonder,” says Ute Hentschel, a marine biologist at GEOMAR-Helmholtz Centre for Ocean Research Kiel in Germany who studies sponge-microbe symbioses. “She has an amazing capacity to focus things so that [new insights] precipitate out.”

Moran believes that, like most complex partnerships, the unions between insects and microbes will take a lifetime to unravel. “The host and the symbiont communicate in ways we don’t understand,” she says. “We’re working to figure that out.”

 

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