The University of Arizona Alumnus / Fall 2008
iPlant — Facing Challenges in Biology and Cyberinfrastructure
by Ford BurkhartIn Richard Jorgensen’s lab south of Old Main, little green petunias poke their heads out of layers of white agar in square plastic cups, ready to strut their genetically-tweaked stuff. Hardly seems like anything earthshaking is afoot. But it is.
Jorgensen’s discovery of the mechanism that will alter their floral pigments also has altered his own career in ways no one could have predicted.
Two decades ago, Jorgensen made genetics history with an experiment involving petunias that didn’t go as expected. The blooms should have been deep purple, but turned out white instead. The results led to an explanation of how a newly introduced gene can interfere with parts of an original recipe carried by the RNA of any plant or animal, and thus its name, RNAi (the small i is for interference). That principle helps explain things like how our cells ward off disease.
Jorgensen’s reputation grew through the 1990s for his discoveries in plant sciences. Now the scope of his academic life is about to change, fast. He has been chosen to lead iPlant (a name he invented), a project to enhance the ability of researchers to collaborate through a global cyberinfrastructure of computers, software, and design expertise. As its director, Jorgensen lives two lives: sparkplug of a remarkable science team and researcher still studying those petunias.
Although Jorgensen came upon RNAi by happenstance, it has become a standard chapter in textbooks on molecular biology, and the theory may one day have implications for how plant scientists respond to challenges like global food shortages and climate change.
Explaining RNAi is still central to his research, amid the tall plant incubators and other machines and microscopes on the eighth floor of the Marley Building. There he looks carefully at the flowers that emerge after a few weeks incubated at exactly 26.6 degrees centigrade. His crew will freeze plant tissue in liquid nitrogen, grind it up into fine dust, and place it in a watery solution in order to examine the DNA for mutations.
That work falls into a new science called epigenetics, studying how genes are turned on and off. Epigenetic changes persist over generations without affecting the underlying DNA. Jorgensen was portrayed in a Nova television special two years ago. (Here’s the link: www.pbs.org/wgbh/nova/sciencenow/3210/02.html.) It compared the RNA role to that of a smart policeman who nabs any harmful recipes that float by. That’s what happened in the petunia experiment.
RNA, for decades the lesser known cousin of DNA, is now seen as central to things like cell differentiation, production of chemicals like insulin, and the spread of cancer. All creatures are the expression of the recipe in their DNA, in the double helix of chromosomes. But it’s RNA that translates the DNA’s recipe into the creation and operation of an actual living creature.
On a tour of his lab, Jorgensen ties together the petunias and the big questions that iPlant will investigate, like how one little plant can manufacture as many as 5,000 chemical compounds. “How little we know,” he says.
Meanwhile, east of Speedway, Jorgensen works part of each day in the gleaming metal and red brick Thomas W. Keating Building, which houses the BIO5 Institute, a collaboration factory. As the lead iPlant investigator and director, he is assembling a blue-ribbon staff of experts in science and cybernetics. Then they will set up Grand Challenge teams to frame big questions to be asked, and will oversee design of a computer network to ask the questions, share data, analyze it, and collaborate in yet-unimagined ways.
A few years ago, the National Science Foundation set out to create this futuristic framework. The University of Arizona won the competition to run the project, and the NSF awarded the first of two $50-million grants to the UA-led team. It can be renewed for a total of $100 million.
The dawn of iPlant recognizes several factors. “It responds to the growing capabilities of computers, urgent global problems to be solved, the power of e-mail to link scientists, and new Web tools for research collaboration,” Jorgensen says. Creating that framework will occupy much of this year.
Last year, Jorgensen received the Martin Gibbs Medal from the American Society of Plant Biologists for his work on RNAi. This year, he was named to a new UA professorship — the Bud Antle Endowed Chair for Excellence in Agriculture and Life Sciences. The Bud Antle Corporation is the largest grower of lettuce, and is a subsidiary of Dole, the world’s largest producer of fruits and vegetables.
From here on, the iPlant effort will stretch out into the rest of the century, he says, unfolding unlike anything else in the 10,000 years since humans began cultivating and studying plants.
“We only know 1 percent of what there is to know about plants,” he muses. “There’s so much we have to learn.”
He looks ahead and offers a mental snapshot.
“Picture someone standing in a field in China, Japan, the Philippines,” he says. “Imagine they have a hand-held device that lets them run a computer model right there in the field. They can ask about different conditions, wet, dry, various elevations. And on a wire overhead is a camera that can monitor each plant. Take its temperature. Check the color spectrum. Sense whether stomates (pores) are closed or open. Now that’s systems biology.”
That researcher will be able to zoom in or out, from the level of molecules to organisms to ecosystems, asking about effects on carbon, oxygen and water use, and in turn, air quality and climate. With the new framework, that scientist will be able to engage in a global conversation about genes, proteins, hormones, ions. About global warming and CO2 fixation.
Picture that happening in southern Mexico or on the Gaspé Peninsula in Canada, with data on corn (called maize in most places), beans, potatoes, tomatoes, peppers, and soybeans.
That, says Jorgensen, may be the story of the century, what he calls Biology Century.
Bending the Rules of Inheritance: the New Take on HeredityNot long after sunrise, Vicki Chandler was hard at work in her off-campus corn field in Tucson when her name came up far away, at a New York Botanical Garden show called Darwin’s Garden. Someone was wondering about a slice of evolutionary theory called paramutation. “Vicki Chandler is the world expert on paramutation,” one expert said. “Ask her.”
It has been 150 years since Darwin’s “On the Origin of Species,” 140 years since Gregor Mendel’s yellow and green peas taught him about genetics and inheritance, and 25 years since Barbara McClintock won the Nobel Prize for upsetting the applecart of genetic theory. Chandler, the director of the University of Arizona BIO5 Institute and Regents’ professor of plant sciences and molecular and cellular biology, is expanding the frontiers of genetics with her work in paramutation, or how one gene can silence another, for generations. Her experiments with RNA-directed gene silencing are rocking the very foundations of modern biology.
Chandler recently spoke at the UA College of Medicine-Phoenix, at a seminar appropriately called Chicks Rock, on women in science. She spoke of her anything-but-typical path. “I got married very young,” she said, “then started college in my mid-20s as a single mom, as the sole supporter of my kids.” She connected with other moms, a strong child-care system, and a top local campus, Foothills College, in Palo Alto, Calif. Chandler was drawn to music and marine biology, as a scuba diver, but one biology class put her on track. The professor brought in a few Stanford molecular biology whizzes as guests. “I got to hear about the latest, greatest stuff of the mid 1970s — restriction enzymes, the SV40 virus that causes tumors, turning on genes. The molecular side of biology. My goal in life became just to learn more about it.”
Chandler went from being a secretary to a long arc of learning that has put her in charge of the UA BIO5 Institute, one of the world’s leading centers for collaboration in science, since 2004. Chandler joined the UA in 1997 after teaching and research on gene silencing for 12 years at the University of Oregon.
Collaboration seems to be in her DNA. During her first year as an assistant professor at Oregon, a former professor sent her as a replacement to a Banbury Conference, a prestigious science event at the Cold Springs Harbor labs in New York. There Chandler connected with Barbara McClintock, whose Nobel Prize was the first solo award to a woman and who was the third woman to join the National Academy of Sciences. McClintock asked “penetrating, polite questions,” Chandler recalls. “We talked for five hours, about people, science, what I was doing.” McClintock mentored Chandler up to her death in 1991. Chandler was herself named to the National Academy of Science in 2002 and gained her own prominence in genetics and epigenetics — variation not associated with changes in the DNA blueprint.
The BBC suggested a few years ago that paramutation, as reported in mice, might account for why we humans each look so different. Asked about the notion, Chandler laughs heartily. “Well, that’s paramutation, variation not mediated by the DNA sequence,” she says, “so they are on the right track.” Maize, she adds, is just as varied as humans. “Look at Indian corn, its colors, sizes, shapes, the cobs, the leaves. Corn plants don’t look at all the same. But everyone likes to talk about cute, fuzzy mice.”
So how do creatures acquire all these traits? For Chandler, the paramutation explanation blends classical approaches with newer molecular biology and genomics.
In school, biology classes taught us why we have, say, blue or brown eyes. Simple as ABC. The old theory held that any trait came from genes in our personal recipe called DNA, and that RNA worked like an obedient waiter, delivering just what the DNA called for. But there were exceptions that scientists couldn’t quite explain. Chandler has shown that RNA directs changes by itself, determining what new information gets passed on to offspring. Chandler’s newest work, spanning plant and animal gene expression, is funded by a National Institutes of Health Director’s Pioneer Award, a program providing freedom to explore risky, outside-the-box experiments. She recalls, “One of my students said it feels like we are doing the quantum mechanics of genetics.”
In any case, she says, “this research blows the textbook paradigm. We are uncovering the unseen. It was always there but now we are learning how it works.”
At one end of her lab in the BIO5 Building, researchers work on human tissue. At the other end they work on maize and other plants as models of genetic effects.
“You wouldn’t know from the labwork whether they were working on plants or animals,” Chandler says. “The same elements are in play: DNA, RNA, proteins. Very similar genetic and epigenetic pathways operate.”
What ties together her plant and animal studies, Chandler says, is a theme that she calls “misregulation of gene expression.” That phrase explains what happens when cells go off in an odd direction, say, as coat color changes in mammals or when a plant alters its color to adapt to stress.
Discover magazine included Chandler’s RNA experiments with the top-six scientific discoveries in 2006. It said her work was helping solve a perplexing phenomenon in genetics. Specifically, she found that a trait — a light-purple corn stalk instead of a dark-purple corn stalk — was passed on to offspring but the gene sequence remained the same in light-and dark-colored plants. Her work showed that the change is switched on by RNA and passes down through many generations.
She has used maize over the years, Chandler says, because it dramatically displays the RNA influence on the phenotype, the features of an actual organism. Her approach to molecular genetics is the standard one: prevent a gene from expressing itself, then examine the organism and learn what trait it controls. “You silence it,” she says. “Then you observe and deduce the function.”
In nature, it turns out, RNA has done much the same thing for millions of years. That on-and-off function has been critical in adaptation and sometimes in disease, she says. “Cancer can be caused by the on or off state of
particular genes. This has always been going on, but now,
at last, we are beginning to understand the diverse ways that gene expression can be altered, and that alteration is not always associated with a change in the DNA sequence.”
From blue or green eyes to white tails on mice to the shifting colors of corn stalks, the Chandler lab is helping explain what makes us, and all creatures, who we really are.
The story of genetics is far from complete. The chapters on epigenetics and paramutation are being drafted in Chandler’s lab and fields of maize where the latest hue is light purple.
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