Fast-Forwarding Mendel

Codevelopers of enhanced genome sequencing technique Eric Johnson and Michael Miller, along with Floragenex CEO Nathan Lillegard. Photograph by John Bauguess

Nineteenth-century monk Gregor Mendel spent eight years painstakingly planting and crossbreeding more than 30,000 pea plants in the garden of his Austrian abbey. Along the way, he rather unknowingly founded the science of genetics. For many decades after his death, anyone interested in Mendel’s science used a relatively similar technique: mate, wait, and analyze. But with advances in our understanding of DNA and the advent of computers, the pace of discovery increased dramatically, opening the door for sequencing the entire genetic makeup of an organism.

Once mapped, the bases of DNA—the fundamental A, T, C, and G—reveal the blueprint of an organism, from what diseases it can resist to how environment influences development. Even with the power of computers, however, accessing that information required a slow, complicated, and expensive process. That is until RAD, a technology created at the University of Oregon that unlocks the code of life at unprecedented speed.

In a process akin to speed-reading, RAD (restriction-site associated DNA) offers volumes of genomic information using a fraction of the resources required by older methods, says RAD cocreator Eric Johnson, associate professor of biology at Oregon. A genome sequence, he explains, is much like a book. “When people talk about sequencing a genome, they want to read all the words in the book,” he adds. “The RAD method takes the shortcut of reading only the first sentence of each ‘chapter,’ so it takes a lot less effort to read just that much.” Comparing “first sentences” allows researchers to figure out where certain genes are. The result is a streamlined method of decoding anywhere from ten to fifty times faster than traditional techniques.

Such speed was unthinkable in 1990 when scientists around the world focused their energies on the historic Human Genome Project. The international effort involved twenty academic institutions, hundreds of scientists, and billions of dollars. In all, the venture to map the human genome spanned thirteen years. Now, thanks to RAD, a similar task took UO graduate student Michael Miller ’06 less than six months.

As an undergraduate, Miller cocreated RAD in Johnson’s lab, developing the technology with input from Johnson and others in the biology department. Now a graduate student, Miller recently used RAD to sequence his first genome: the steelhead salmon.

“To think that now some graduate student like me could scrape together some money and do that is just unbelievable,” Miller says. “These are really the first cases where single people are starting to sequence genomes from really important, interesting species.”

Miller and Johnson invented RAD with help from UO associate professor of biology William Cresko. Cresko’s research animal of choice, the stickleback fish, was one of the first sequenced using RAD. Initially, Miller says, he didn’t fully grasp the significance of the group’s work.

“The thing that sort of woke me up, that made me realize this is the real deal, was Science,” he says. As is tradition for the prestigious research journal, every December the editors publish a list of the year’s most significant breakthroughs. In 2010, RAD made the list alongside a pair of heavy-hitters, the first plug-in electric hybrid car and the malaria vaccine. “Just thinking of RAD on the same level as the malaria vaccine, it’s pretty phenomenal,” Miller says.

Long before RAD reached Science, however, it had already caused a stir on campus. When MBA student Nathan Lillegard ’98, MBA ’06, first heard of the technology in summer 2005 he knew he’d discovered the idea that could put his degree to good use. Johnson agreed, and in 2006, a year after Johnson and Miller filed a patent with the UO’s Office of Technology Transfer, RAD became a business: Floragenex, with Johnson as chief technology officer and Lillegard as president and CEO.

The company, which operates out of the UO’s Riverfront Research Park with labs in Portland, has six full-time employees—all Ducks—and has worked with companies and organizations around the world, including the USDA.

By genetically altering seeds, Monsanto and other Floragenex customers attempt to breed new varieties of plants with marketable qualities, like stronger disease resistance. Prior to RAD, clients had to take Mendel’s route to figure out which seeds did what.

“If you were a soybean company in the old days of five years ago, you would take two soybeans you liked, cross them, plant hundreds of thousands of seedlings, and check them out to see what happened,” Johnson says.

RAD allows breeders to skip the seedling step by showing which sequences equal which traits. That means more food grown more quickly, the type of output needed to feed a world bustling along to an estimated nine billion people by 2050.

Despite its name, Floragenex doesn’t deal only with plants. That’s where Biota comes in. Founded by Jason Boone, PhD ’08, the Floragenex subsidiary works with animal DNA. One project involved the cousins of beloved Oregon Zoo resident Chendra the pygmy elephant.

Chendra’s fellow pygmy pachyderms live in the jungles of Borneo, where an estimated 1,500 fend off extinction as humans encroach on habitat. Figuring out where these elephants live is the first step toward saving them, but the traditional method of using tagging darts led to unfortunate consequences. The darts’ anesthesia inhibited the elephant’s sex life for an extended period, a potential death sentence for an endangered species. Because RAD quickly reads genomes, Biota offers a solution: collect dung for its DNA, match the poo to the elephant, and track the animal as it roams. 

It’s impossible to know the full reach of a technology that quickly shares DNA’s secrets. The possibilities even astonish the cocreator.

“DNA—it’s the book of life,” says Miller. “There are so many applications that RAD can be used for. How do you even begin?”

One way, as Johnson and Cresko have found, is to sequence individual human genomes and apply that information to medicine.

“Some drugs will work on you that don’t work on me or vice versa. To some extent that has to be due to our genetic makeup,” says Cresko. “At some point you’ll go to the doctor and have your whole genome sequenced so drugs can be tailored to you.”

Cresko and Johnson are also investigating the genetics of a person’s microbe communities, which can cause illness when not functioning correctly. “I wouldn’t be surprised if a few years down the road you go to the doctor and samples are taken not only for sequencing your genome but also for all the microbes you have in your teeth or your gut or on the scalp of your head,” Cresko says.

But RAD—and what it promises for the future and has already delivered—may never have existed if not for a bit of serendipity, a lecture Cresko gave to fellow UO faculty members in summer 2005. After hearing Cresko’s plan to map the stickleback fish genome using traditional methods, audience member Johnson mentioned a new project he’d just begun.

“If I hadn’t given this research talk and Eric hadn’t talked to me and we didn’t have our students in our labs working together, maybe the RAD technology wouldn’t have worked,” Cresko says.

But it did. Now much of the UO’s newest scientific research uses the technology. 

Down the hall from Cresko’s lab, assistant professor Hui Zong seeks out genetic mutations in worms that could someday lead to earlier detection tests for cancer. One building over, fellow professor John Postlethwait decodes the Antarctic icefish, whose unique genes for bone density could lead to breakthroughs in studying osteoporosis. Even Miller continues to use the technology. Due to RAD’s game-changing nature, any topic the grad student explores is likely to be influenced by the very work he cocreated.     

“We’re really at a revolutionary time in biology right now,” he says. “RAD empowered us to study whatever we want.”

For Miller, that means more salmon DNA. Next up, Chinook.

By Elisabeth Kramer