Genome technology wizard

Mardis stays on top of technology to help pinpoint causes of disease

Those of us who are bewildered by the furious pace of changing technology wouldn’t want to walk in the shoes of Elaine R. Mardis, Ph.D., co-director of the Genome Sequencing Center (GSC).

Her domain is not cell phones, laptop computers or other such conveniences of the modern age. Rather, Mardis specializes in half-million-dollar genome sequencers and the technological accoutrements that have enabled scientists to decode whole genomes at lightning speed and probe human DNA for variations linked to diseases such as cancer.

Elaine R. Mardis, Ph.D. (right), co-director of the Genome Sequencing Center (GSC), works with Lisa Cook, research lab manager, at a next-generation genome sequencing machine. “Elaine’s task is to figure out what technology is the real deal, what is hype and what is worth taking a closer look at, and then to make the decision about whether we should devote time and resources to take a new technology to the next level,” says Richard K. Wilson, Ph.D., director of the GSC.

She is charged with researching and evaluating all new technologies considered by the GSC. It’s a huge job; genome technology is evolving faster than ever, and companies consistently claim their technology is better than anyone’s.

“Elaine’s task is to figure out what technology is the real deal, what is hype, and what is worth taking a closer look at, and then to make the decision about whether we should devote time and resources to take a new technology to the next level,” says Richard K. Wilson, Ph.D., director of the GSC. “She’s very good at this. Elaine screens out a lot of stuff before she finds something to really get excited about.”

A budding scientist

Mardis’ passion for science began as a child.

“I’m one of those really weird people who knew since I was very young that I wanted to be a doctor or a scientist,” she says. Her enthusiasm was nurtured by her father, who taught chemistry at a junior college in North Platte, Neb., for more than 30 years.

But it was a college biochemistry class taught by Bruce Roe, Ph.D., the George Lynn Cross Research Professor at the University of Oklahoma, that opened Mardis’ eyes to the awe-inspiring molecules of life: DNA and its chemical cousin, RNA. “It was like, ‘Oh, this is it!’ You always hope for a eureka moment, and that was mine,” she says.

Mardis stayed at Oklahoma and earned a doctorate in chemistry and biochemistry under Roe’s tutelage. It was there that she first crossed paths with Wilson, who was working on a doctorate in the same laboratory.

When Mardis began her graduate work in the mid-1980s, Roe was one of the few U.S. scientists proficient at sequencing, or reading, the precise order of chemical bases that make up DNA. It was a slow, laborious task.

Mardis mastered the technique and found herself on the receiving end of efforts by others to automate DNA sequencing: Roe’s was the first academic laboratory in the country to possess a fluorescent DNA sequencer, the machine that later made large-scale sequencing possible.

The machine attached different colors of fluorescent dyes to the four different chemical units in the genetic code, allowing the sequence to be read by machine. About that same time, simple robotic arms were introduced to further automate the process. They were designed to push down on pipette tips, which could then move to another workspace and pick up set volumes of samples containing DNA for sequencing.

Like the rest of the technology being developed at the time, the robotic apparatus was clunky and slow. Rather than get frustrated, Mardis became a technological pioneer. She was part of the first generation of scientists who used ingenuity and resourcefulness to pull together the technology necessary to make the automated DNA sequencing feasible.

She was also ahead of her time.When she finished a doctorate in 1989, no federal research funds existed for DNA sequencing projects. Instead, the focus was on first developing physical maps of the locations of genes within a genome.

“I wasn’t interested in that kind of work or trained in it,” Mardis says. Instead, she took a position at Bio-Rad Laboratories, a California-based company, to help develop the technological components to make DNA sequencing easier.

A technological innovator

But the landscape for genomics changed dramatically in 1993. The University’s GSC had just received a multimillion dollar grant to sequence the C. elegans roundworm, a prelude to the Human Genome Project. To do the work, the GSC had to ramp up its DNA sequencing capabilities to handle bigger chunks of genetic material.

Elaine R. Mardis (left) with her daughter, on vacation in France.

“We really needed someone who had been thinking about the technology 100 percent of the time,” Wilson says. “I had followed Elaine’s work in grad school and at Bio-Rad, and I thought she was clearly the only person in the genome community who could get it right.”

With Mardis on board, the GSC became the first large-scale sequencing center with a dedicated technology group. Its mission was to develop technology and find out about technology being developed elsewhere — either by companies or academic laboratories — and determine whether it would be a good fit for the GSC.

To understand the technology and the way it works, Mardis had to learn components of engineering, molecular biology, enzymology, optical engineering, computer science and nanotechnology, among others.

“I think most of modern genomics involves a certain amount of appreciation for the interplay between these different disciplines,” Mardis says. “When you start to think about all the different components that go into the technology and that actually have to talk to each other in a systematic way to reliably produce data, well, it’s a minor miracle that it all works.”

A consummate collaborator

As an extension to her work heading the technology development core, Mardis also plays key roles in many of the GSC’s sequencing projects.

The GSC is involved in several projects to sequence the genomes of nonhuman primates, such as chimpanzees and orangutans, which are some of human’s closest living relatives. “These animals need to be understood at a genetic level and at a genomic level because they provide essential information about the course of human diseases, such as diabetes, hypertension and HIV,” she says.

Mardis also is heavily involved in studies to find the numerous genetic alterations in cancer as part of the federally funded Cancer Genome Atlas project. The research initially focuses on ovarian and lung cancer and glioblastoma, an aggressive brain tumor.

Genetic errors, or mutations, are known to accumulate in normal cells, ushering in a transformation that can lead to cancer. An estimated 300 genes involved in cancer are already known, and a more in-depth search could identify numerous others that determine, among other things, how aggressive a particular tumor is or which drugs might work best to treat it.

Elaine R. Mardis

Position: Co-director, Genome Sequencing Center; associate professor of genetics and of molecular microbiology

Education: B.S., zoology, University of Oklahoma; Ph.D., chemistry and biochemistry, University of Oklahoma

Family: Husband, Larry, an airplane pilot; daughter, Lauren, 17

Sport: Tae kwon do. Mardis holds a first-degree black belt.

Hobbies: Mardis is an avid reader and novice golfer. She is now reading “Einstein’s Dreams” by MIT professor Alan Lightman, Ph.D., “Night” by Nobel Prize winner Elie Wiesel and “The Last Lecture” by the late Carnegie Mellon professor Randy Pausch, Ph.D. She has recently taken up golf and finds it far more challenging than DNA sequencing technology.

Throughout the medical school, Mardis has garnered a reputation for going out of her way to help physicians, scientists and medical students understand how genomics can advance their own research studies.

“Elaine is a vital link between the Genome Sequencing Center and the investigators in molecular medicine at the Siteman Cancer Center,” says Matthew J. Ellis, M.D., Ph.D., the Anheuser-Busch Endowed Professor in Medical Oncology. “We explain to Elaine our clinical issues and what we’re trying to accomplish. She plays the role of interpreter to explain how the technology at the genome center can help us.”

Together, Ellis and Mardis are developing a breast cancer genome atlas to document all the genetic changes associated with breast tumors. The project provides the framework for physicians to understand which genetic changes drive poor outcomes, such as early recurrence or a lack of response to treatment.

Cancer databases like those being developed at the GSC could help usher in a new era of personalized medicine, where disease treatments are based on a person’s genetic makeup.

The GSC’s next-generation genome sequencers — all 20 of them — are churning out genome sequence data exponentially faster than earlier machines, thereby speeding scientists’ ability to pore over the genome in search of disease genes.

The machines first used to sequence the human genome allowed 96 discrete sequencing reactions to occur at a time, but the newer sequencers permit anywhere from 800,000 to 80 million simultaneous reactions.

“This has a big pay-off in speed, efficiency and ultimately cost and puts us closer to realizing possibilities of personalized medicine,” Mardis says.

While acknowledging the challenges of staying on top of the rapid changes in technology, Mardis says she enjoys the fast pace of her work.

“It is ever-changing, so there is never a dull moment,” she says. “You never stand still. It is very, very exciting to see these new instruments and imagine how ultimately they will transform medical practice.”