When a recipient of an NIH Research Career Development Award fails to win tenure, something strange is going on. Or someone. In this case, that someone is Marcie McClure.

McClure, a pioneer in bioinformatics and still a leader in the field, claims to be an odd person. There's no point in arguing. This is a researcher in a microbiology department who hasn't touched a pipette in 20 years. This is a researcher who once accepted a university position for $1 a year. And, most famously, this is a researcher who was denied tenure at the University of Nevada, Las Vegas (UNLV), because of her supposed lack of "collegiality"--a criterion that hadn't even existed until she came along.

McClure says she's as offbeat today as she was 10 or 20 years ago. She just happens to be much more content. After losing her long tenure battle at the UNLV--a battle that went all the way to the state supreme court--she put together a string of victories. She landed a job at Montana State University, Bozeman, and easily won tenure. She now gives invited lectures across the country, including a recent appearance for Stanford University's Luminary Series. Most importantly, she continues to produce the kind of stunning scientific results that caught NIH's attention years ago. McClure's realm of research--bioinformatics, the computer analysis of amino acid sequences--may isolate her from the pipette and petri dish crowd, but it has also opened the doors to discovery.

Sitting at her desk on a recent spring afternoon, McClure took time to reflect on her unusual career. Her office is barely large enough for visitors, but it connects to a spacious lab equipped with a suite of computers and a million-dollar view of the Bridger Mountains. (Her second lab is down the hall.) On that particular day, she had the look of someone running a pottery booth at a folk festival: paisley velvet pants, red boots, large earrings, and curly auburn hair. She describes herself as "eccentric" and "flamboyant," and, once again, there's no point in arguing.

Hidden Messages

From her earliest days as a biologist, nobody knew what to make of her. As a doctoral student at Washington University School of Medicine in St. Louis, Missouri, she baffled her peers by deciding to conduct much of her research on computers--"in silico"--a highly unusual aspiration in the early 1980s. By the time she earned her Ph.D. in 1984, she was ready to abandon the bench altogether. For perspective, this was the same year that Apple released its first Macintosh, complete with an 8 MHz processor. Even way back in the computing dark ages, McClure knew that computers had the potential to unravel some of biology's thorniest problems.

Throughout her career, McClure has been fascinated with one problem in particular: decoding the strange patterns and hidden messages written in the genes of RNA-based life forms. Much of her work has centered on HIV, hepatitis B, and other viruses that use the enzyme reverse transcriptase to copy their RNA into DNA and then back into RNA. In recent years, she has also turned her attention to Ebola, rabies, and other "true RNA" viruses that never go through a DNA stage.

McClure's obsession with RNA and reverse transcriptase isn't limited to viruses. It just so happens that humans have more in common with Ebola and HIV than we might like to think. A large part of our genome--indeed, of any eukaryotic genome--consists of "retroid agents," chunks of genes with a decidedly viral lifestyle. Just like RNA-based viruses, these agents contain a code for reverse transcriptase. The enzyme allows the genes to make DNA copies of themselves through an RNA intermediate. The new copies then jump to different locations in the genome. Retroid agents found in humans and other eukaryotes come in two basic forms: retroviruses that have inserted themselves into the host genome, and "host" genes that may have actually been viruses in the distant evolutionary past.

Retroid agents were once considered junk DNA, nothing more than white noise in the real genetic message. In reality, the genes are major players--in sickness and in health. Over the last decade, McClure and other researchers have discovered many important functions for the so-called junk. As a dramatic example, one type of endogenous retrovirus produces syncytin, an adhesion protein that is crucial to placental development. Other retroid agents have been linked to diseases ranging from breast cancer to type I diabetes.

Whether she's studying the genes of HIV or humans, McClure has a gift for spotting patterns. An abstract painter in her younger days, she still sees meaning where other people see randomness. Show her a string of 300 or 500 amino acids from distantly related proteins, and she can find similarities that the untrained eye--and even the untrained computer--would miss. "My secret is, I can read in both directions," she says. Once she identifies certain patterns, she works with programmers to develop software that can search for the same motifs elsewhere.

These faint hints of similarity between distant proteins often prove to have significant biological meaning. McClure's discoveries have helped predict the function of genes and have shed light on the evolutionary relationships of RNA-based viruses. She recently published the first paper to demonstrate that organisms in all three realms of life (eukaryotes, eubacteria, and archeae) have transferred genes to viruses multiple times. McClure now has the modest goal of identifying the structure and function of all retroid agents in all sequenced genomes, starting with humans. She recently helped develop powerful software--The Genome Parsing Suite--in pursuit of that goal.

One Dollar per Year--Before Taxes

McClure's brand of research would come to be known as bioinformatics. Although the field is booming now, it was a foreign concept in the mid-1980s. After completing a postdoctoral fellowship under Russell Doolittle at the University of California, San Diego (UCSD), McClure applied for positions in many different departments--virology, molecular biology, evolutionary biology--but nobody had a full-time position for a biologist/computer jockey.

Desperate for a place to call home, she took a research scientist position at UCSD that paid $1 a year. Her mother gave her money for rent and groceries, and Doug Smith, one of her former undergraduate professors, loaned her an office and a computer. From this humble position, she applied for--and won--a 5-year grant from NIH.

Her early struggles put a sharp edge on an already strong personality. McClure saw science as her entire life, even her religion, and she wouldn't let anyone slow her down. She became more driven, more assertive, and more willing to fight for what she needed to conduct her research. "I had to become defensive about my work," she says. "Nobody knew what I was talking about."

Miss Uncollegiality?

After years of searching, she finally landed a tenure-track position at UNLV in 1993. Instead of keeping a low profile and blending into her surroundings--a standard approach for new faculty--McClure immediately launched simultaneous battles to win lab space from the university and respect from her colleagues.

Neither came easily. In her view, the university failed to give her even the most basic support. She needed a small workplace with a fast, functional computer, a seemingly minor request that turned into a major ordeal. Similarly, all she wanted from her co-workers was freedom to pursue her research. Instead, she says, she met with hostility almost from the beginning.

Most of the bad vibes came from three women researchers who, in McClure's mind, took issue with her ambitions, her style, and, ultimately, her success. "They didn't think a woman should be doing this sort of work," she says. "I was even told that I needed to start dressing like a secretary."

Even in this poisoned atmosphere, McClure's research steamed ahead. In 1996, she won a prestigious Research Career Development Award from NIH, a first for a researcher at UNLV. At about the same time, she also landed a second 5-year grant from NIH. The university trumpeted the two grants with a glowing press release. The awards should have sealed her career at the university, but, according to McClure, they only spawned more jealously and resentment. One colleague immediately told her "this is not going to help you get your tenure," a comment that proved prescient.

When McClure became eligible for tenure in 1997, a small group of researchers launched a campaign against her. Among other things, they gathered letters from faculty and staff--including secretaries--that presumably documented all of her shortcomings. McClure can only guess what those letters said; to this day, she has never been allowed to see them.

Armed with this secret testimony, the review board denied McClure's bid for tenure. They faulted the quality of her research, an odd claim against someone who had raked in millions of dollars of grants. They also cited her lack of collegiality, a standard that the university had never before applied. McClure appealed the decision to the state supreme court, but the court ruled that college faculty have no constitutional right to tenure.

Some people close to McClure couldn't understand why she would sue to stay close to her enemies. For that matter, they couldn't understand why she didn't leave the university years ago. Looking back, McClure says she had few options. "There were still very few jobs in bioinformatics," she says. "Besides, someone had to stand up to those people."

Out of the Desert

Sitting in her office in Bozeman, McClure sees that defeat as a blessing. She's now at a place where research and scholarship matter more than social skills. "We have differences of opinion, but it's not me against them," she says. "They like me here." She says she's toned down her act in recent years, but only slightly. She still speaks up at every staff meeting. She still asks hard questions of students and deans alike. And she still talks at a volume and pace reminiscent of small arms fire.

Now that she has tenure--a process that went without a hitch the second time around--she has more time to relax. Science is still her life, but she takes a few breaks to practice yoga and work in the garden. She's even thinking about writing a science fiction novel--about RNA-based life forms, naturally. The creatures would adapt to hostile conditions by morphing into completely new beings, something we DNA-based creatures just can't do. We're just too slow to change. And, in some cases, just too stubborn.

Marcie McClure's Lab Webpage can be found at http://shiva.msu.montana.edu/.