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Nature Nurtured

Plant biologist Virginia Walbot broke new ground for women in the sciences and sowed the seeds of the corn genome project.

Linda A. Cicero

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By Krisin Sainani

Just after dawn on a chilly September morning, Virginia Walbot strolls among the rows in a cornfield near the western edge of campus. She peels the husks off purple-spotted ears—the result of a genetic cross—and drops them into labeled bags. All at once, the field awakens with life, as birds suddenly blanket the plants. When the air hits a certain temperature, Walbot explains, tiny bugs called aphids start moving; they draw the ladybugs, which in turn draw the birds. "There's lots of life on life out here."

A geneticist, Walbot, '67, has been conducting research and teaching at Stanford since 1981. In the 1980s, many of her peers switched their focus from corn—which dominated research due to its importance in agriculture—to Arabidopsis, a genus of flowering plant related to mustard, which flourishes in the laboratory. But Walbot remained in the field. She spends much of her time at the Stock Farm plant facility, which is tucked away behind a mature stand of trees near the site of Leland Stanford's early experiments applying science to the breeding and training of horses. "Most of my colleagues at other universities have to commute to farms," Walbot says. "We're lucky to have this facility so close to our labs."

She points out the dahlias, which she breeds as a teaching tool, the roses, and the old wooden house where Nobel Prize-winning geneticist George Beadle (a Stanford professor from 1937 to 1945) lived in the summers to be close to his research. Walbot says she often reads the newspaper in one of the greenhouses in the mornings. It's warm and humid inside; and the lights are so bright—mimicking summer sun—it's instantly uplifting. Walbot's demeanor is as calm as her surroundings. "She has to be one of the most patient people I know," says Timothy Kelliher, PhD '13. But in her science, she is remarkably bold.

Walbot began her career in what she describes as a "dark" era for women in science. After studying biology at Stanford, she attended Yale for her doctorate. At the time, Yale was still an all-male college at the undergraduate level. Walbot remembers women being prohibited from the main library, for fear they would disturb the men. On her first day, the department head proudly announced that about half of the incoming class of biology graduate students was female, adding, "There is no better combination than a male professor with a PhD-wife to run his lab."

"We were in shock, especially those of us who came from co-ed schools," Walbot recalls. "But it was an inkling of what the next 10 years would be like for women in science like me."

At the time, universities did not widely advertise faculty openings; rather, department chairs exchanged phone calls and hand-selected the "best" candidates. "It was a job placement service that was just a worst-case scenario for diversity," Walbot notes. So, she organized female graduate students and postdocs from the American Society of Cell Biology to make regular inquiries of their department secretaries regarding any job openings, which she and two Yale colleagues printed and circulated in a monthly newsletter. "We completely broke the system open, at least in this area of science."

Despite repeated warnings that they were jeopardizing their careers, Walbot and her co-conspirators kept the newsletter going for several years. "It was thought that that activity was beyond the pale. The threats were very intimidating," Walbot recalls. Nevertheless, all three went on to highly successful careers and their actions helped instigate a sea change for women in science by the late 1970s and early 1980s.

By the time Walbot came to Stanford, the dean's office was offering incentives for science departments to hire women. (She became the second tenured female faculty member in biology in the post World War II era.) Although women in scientific disciplines continued to face subtle discrimination through the 1980s and 1990s, Walbot says, even these biases have now largely disappeared. "It was like darkness to dawn to bright sunlight."

In the mid-'90s, while preparing a grant application to lead a massive, multisite effort to sequence corn genes, Walbot says she drew inspiration from Undaunted Courage, a history of the Lewis and Clark expedition. "Their mission was to make a map from the East Coast to the Pacific and describe what there was along the way. The Maize Gene Discovery Project was to make a map and discover the genes that allow you to build a corn plant. So the themes in that book—entering the unknown, getting scared, seeing your first grizzly bear—these had analogies to our project."

In 1998, Walbot was awarded a $12.54 million grant from the National Science Foundation—an extraordinary amount for the time. The NSF also funded several other plant gene projects at the same time, including cotton, tomato and soybean. While other teams bought gel-based gene sequencers, the standard at the time, and immediately began sequencing genes, Walbot took a calculated risk. She had seen demos of a new gene-sequencing technology utilizing a capillary mechanism that was "much more efficient and much more thrifty of materials." So she decided to hold off on sequencing until her team could obtain an early capillary machine. Six months into the project, researchers working on other plants had surged way ahead in terms of numbers of genes sequenced.

But Walbot's gamble paid off. "We got our machines in April, and by June we had twice as many sequences as anyone else—and they were better quality." The project ultimately accomplished two to three times more than its original goals. The genes identified in this project, as well as a subsequent project Walbot led, laid the foundations for the sequencing of the complete corn genome in 2009.

Using a combination of modern genetic tools and simple, elegant experiments, Walbot has helped to unravel many of corn's developmental secrets. One long-standing mystery concerned how sex cells form in the plants.

Animals make sex cells in the early embryo; but plants form these cells late in development, and the mechanisms aren't well understood. An individual corn plant makes both male and female parts. The tassels—the fringy tufts at the tips of corn stalks—contain male organs, called anthers, which produce the pollen. The ears contain the egg cells, which will be fertilized by pollen from the same or neighboring plants.

Oxygen & Cell Fate
B. Stauch/Science
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Using 3D confocal microscopy and gene expression studies, Walbot's team set out to understand how the baby tassel emerges, including the emergence of the male sex cells. Each developing anther forms four lobes around a central vein—which in cross-section looks like a butterfly. When the anther is still small, the innermost cells stop dividing normally and start dividing into sex cells (which contain only half the genetic material). The cause of this shift had long been debated, but the predominant theory was one of lineage: Certain cells are genetically predestined for the job.

Walbot and Kelliher suspected otherwise. Their observations suggested that a cell's position in the tissue mattered more than who its parents were. But they couldn't prove it definitively. Then Walbot had a flash of insight: "It just flew into my mind that what might characterize the area where the germ cells arise would be hypoxia, the absence of oxygen."

Several clues pointed to the idea: a tight whirl of baby leaves surrounds the growing anther, which could block out air—particularly from the innermost cells; rapidly growing cells consume tons of oxygen, which could deplete it locally; and corn cannot form male sex cells without the protein MSCA1, which regulates oxygen status. Hypoxia plays key roles in animal biology—such as in stem cells and cancer—so the idea that it could play a fundamental role in plant biology seemed plausible. Still, it was a radical hypothesis.

Walbot's team tested the idea in one weekend. They threaded hoses through the leaves that surround the baby tassel and pumped in either oxygen or nitrogen (which lowers oxygen levels). When Kelliher harvested the anthers a few days later and viewed them under the microscope, the changes were dramatic—the nitrogen-treated plants had eight times the normal number of sex cells and the oxygen-treated plants had many fewer than normal.

The initial experiments were simple and inexpensive—involving just a few tanks of gas, some needles, a hose and a microscope. "This is one of my favorite things," Walbot says. "If the concept is great, you often don't need a huge amount of equipment and money." Typically, graduate students in biology are not encouraged to try older, cheaper experimental techniques, which is a huge loss for the field, Kelliher says. "Too often we're just answering the same old questions with fancier and more expensive equipment rather than answering new questions."

Other proofs came soon after. They showed that any cells in the developing anther, regardless of origin, could become sex cells if deprived of oxygen. They also showed that they could reverse male infertility in MSCA1 mutants—which normally cannot make male sex cells due to a defect in the MSCA1 gene—by lowering the oxygen to ultra-low levels (using nitrogen).

Walbot and Kelliher published the results last fall in Science. "This is one of the first studies to give us a sense of what determines germ-line fate in plants," says Clinton Whipple, assistant professor of biology at Brigham Young University who wrote an accompanying commentary. Although it's still possible that an internal genetic program sets up the oxygen gradient, it looks like the driving factor is an external, environmental cue, he says.

If this holds up, it would strike at the heart of the nature versus nurture debate. "Some biologists think that there are no emergent properties in life. They assume that all life is preprogrammed," Kelliher says. "That's what is so beautiful about this to me. It's something that arises simply from the structure and the growth pattern. And you don't need any sort of intelligent programming in these cells."

The finding also has important practical applications, which Stanford is seeking to patent. Corn farmers plant hybrid corn because hybrid strains are more robust than inbred ones. To make hybrids, seed companies grow two strains of corn in close proximity; one strain (the seed-producing corn) must have the tassels removed to prevent self-fertilization. Teenagers in Midwestern corn-producing states perform much of this detasseling by hand, on about a million acres—billions of plants—each year. The enterprise is expensive (about 10 percent of the cost of seed, Walbot estimates) and sometimes dangerous. In 2011, two 14-year old girls in Illinois died after being electrocuted while detasseling near an irrigation system.

Walbot's research suggests a low-cost alternative: Seed makers could sterilize plants with oxygen. For example, they could drop bleach pellets, which contain oxidizing agents, into the flowering plants. This low-cost solution might be especially beneficial in the developing world, she says.

Besides corn, Walbot's other passion is dahlias. These easy-to-grow flowers can be coaxed into an amazing array of colors and patterns. In her plant genetics course, students design experiments to tease out whether pigment decisions are under genetic or environmental control. Walbot gives them a box of tin foil, plastic wrap, scissors and hole punches ("kind of like a kindergarten teacher") and they have to figure out the rest.

For example, they may start by covering a budding plant with tinfoil to test the effect of darkness on color patterning; then they realize that they need a control, so they punch holes in the foil. "You can see the lightbulb of discovery," Walbot says. "A lot of students have taken plenty of biology and chemistry, but they've never had to plan everything from scratch before."

Many undergraduates end up working for Walbot. "The big attraction is that they want to work outdoors or not at a desk," she says. ("It's a great quality of life in the job," Kelliher agrees.) Walbot identifies with this need to be outdoors, working the fields. She finds something therapeutic in the labor: filling pots, germinating, transplanting and harvesting. Plus, it keeps her connected to the big questions in biology—not just how one gene functions, but how multiple genes and the environment work together to define a life.

Kristin Sainani, MS '99, PhD '02, is a freelance writer and clinical assistant professor in the department of health research and policy.

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