It's not often that leading PIs in genomics can trace their current area of focus all the way back to the days before the term was even coined, but such is the case for Ross Hardison. Currently the T. Ming Chu Professor of Biochemistry and Molecular Biology at Pennsylvania State University, Ross and his lab take a comparative genomics approach to predict gene regulatory modules, test them for function in the laboratory, and work to pull all this together into a more thorough understanding of global regulation of erythroid genes.
It all started during his days as a postdoc at Caltech in the late 1970s under the watchful eye of his advisor, molecular and cellular biology pioneer Tom Maniatis. "A lot of great stuff was happening then," Hardison says. "We were trying to isolate eukaryotic genes — that was the big deal in the 1970s — and the techniques that were developed there I think led to the ability to do genomes of complex organisms, like humans."
While Hardison's contributions to genomics are many, worth mentioning is his participation with David Haussler in key human-mouse alignment studies of the International Mouse Genome Sequencing Consortium. Their collaboration demonstrated that the rates of evolution vary markedly along chromosomes and the amount of the human DNA under selection is at least three times the amount of the coding capacity.
In his own career, Hardison has undoubtedly influenced scores of graduate students and postdocs over the years — and he says that that's a result of all the people he was fortunate enough to work with. In particular, though, he points to his graduate advisor, Roger Chalkley, a senior associate dean at Vanderbilt University, and Maniatis as shaping influences. "The thing then with both Roger and Tom was that they were so motivated by the excitement of discovery," Hardison says. "They both had a huge amount of energy and worked real long hours, but there was a lot of excitement which always overrode the frustrations of things that didn't work. When we did discovery stuff it was just great [and] Roger had a really fun lab to work in. … I hope people find my lab fun to work in as well, but it depends upon the personalities of the people in the lab at the time."
Hardison's approach to being a mentor is not unlike that of a sports coach pushing to get top performance out of each player. "You have a group of people in your lab or team and you've got goals to accomplish, and you try your best to make sure people have the necessary skill sets and they're using them in an optimal way," he says. "Every project in my lab, someone is in charge of it — but I'm always saying, 'Oh, you should talk to this other student or check with my research associate because I think this would help.' … Trying to move the projects along as best you can, but everybody has to be engaged and working as a team."
While issues vary from person to person, Hardison says that in general, getting timid students to have self-confidence in the lab is a major challenge. Oftentimes, it requires a steady hand and a willingness on the part of the students to embrace the research process, which typically includes failure. "There's some people who just walk in and for good reason are very confident, and occasionally you get someone who's awfully self-confident where it isn't necessarily justified," he says. "But much more frequently I get people who are smart and are curious and want to accomplish stuff, but they're just not sure they're doing it right, so you [have] to get them into this mentality of: you just do a plan and execute the experiments well."
He always reminds his students that they have to accept the data as the truth, and that just because an experiment might not yield the desired result, that doesn't make it a waste of time. "There are still some folks who think that the purpose of science is to prove certain ideas and to test hypotheses. … Often people will say, 'I did that experiment [and] the results are bad,' and I say, 'What do you mean by bad?'" Hardison says. "There's no such thing as a bad experiment if you design it well and execute it well, and frequently what they mean is that what we thought was going to happen didn't, but that's fine. The sooner we find it out the better," he adds.
He encourages students to embrace these unexpected or disappointing results and use them as a springboard for future paths of investigation. "Don't fear ruling out an idea because another will come, you should always have multiple models anyway," he says. "Ideas are easy; experiments can be very difficult." Keeping his students energized is a constant priority for Hardison, who says that in good conditions "usually sooner rather than later [students] turn on to this excitement thing."
After spending time under his tutelage, Hardison wants his postdocs and grad students to go out into the world with this as their number one priority: to focus on what is exciting to them — not just what is considered important or what might put them on the map in the research community — without losing sight of the big picture. "That's the advice I give most often, but that's a challenge for some people to do," he says. "I do think we're incredibly blessed that we have money from hard-working taxpayers to do this research and we have a tremendous obligation to society to use these resources well. … But the way you stay engaged is to work on questions that really motivate you and you have a fair bit of control over what you're doing. That's the key to having a happy and exciting career."
The list of folks who have passed through Hardison's lab is a mile long. Here are just a few names you might recognize.
After complete his undergraduate degree in Hardison's lab, Callaghan went on to get a PhD in microbiology from Case Western Reserve University. He was a DNA examiner for the Penn State police, where he was the lead implementer of Pennsylvania's CODIS program. He's been a DNA examiner with the FBI for five years.
After earning her PhD in molecular and cellular biology with Hardison, Elnitski went on to pursue a bioinformatics postdoc with Webb Miller. Elnitski is currently an investigator at the National Human Genome Research Institute, where she focuses on noncoding functional genomic elements.
After finishing his PhD in biochemistry with Hardison, Rohrbaugh conducted molecular and cell biology research in academic and industrial laboratories. He is currently director of the Office of Technology Transfer at the National Institutes of Health, where he oversees the patenting and licensing of NIH inventions and contributes to intramural and extramural technology transfer policy at NIH and in the US Department of Health and Human Services.
After assisting Hardison with several gene expression studies during his graduate studies, Schewchuk went on to take a position as assistant professor of biochemistry and molecular biology at East Carolina University, where he concentrates his research efforts on chromatin structure modification and epigenetic processes in tumorigenesis.
Taylor worked closely with Hardison on several projects, including participating in the Penn State group that provided one of the three major sets of mammalian genome alignments and analysis of patterns of conservation and constraint in several functional classes for the ENCODE consortium. Taylor is now an assistant professor at Emory University.
During his time in Hardison's lab, Vandenbergh made major contributions to several comparative analysis studies of rabbit genes. He is currently an associate professor of biobehavioral health at Penn State, where he focuses on the control of neuronal gene expression by drugs of abuse and QTL identification of behaviorally relevant genes.