Genes that we share with fungi may hold the key to cancer and other diseases. Biology Prof. Steve James ’80 focuses on a common bread mold. His collaborative research style has propelled a generation of alumni into grad school, just as his Gettysburg mentor, Prof. Emeritus Ralph Cavaliere, inspired him.
Passing on the research gene
Prof. Steve James ’80 is a central link in Gettysburg’s intellectual lineage. His mentor, Prof. Ralph Cavaliere, introduced him to his area of research and inspired him to go to grad school. James has transmitted that inspiration to his own students.
Since James returned to Gettysburg in 1992, more than 90 students have completed for-credit independent research under his tutelage. Among the approximately 20 who have collaborated closely with him since 2005, nine have undertaken Ph.D. studies. Others are in medical, dental, or veterinary school, or seeking master's degrees, or in research or teaching careers.
“I’d like to think I’ve inspired some of my students as much as Ralph inspired me,” James said. “It would be the ultimate compliment if that were true. Ralphie is inimitable and unmatched, and, yes, I strive to follow him as that role model.”
Alumni agree that James is succeeding: “If I hadn’t met Steve James, it is highly likely that I never would have gotten into a career in research,” said Dr. Greg Crawford ’95, a pediatrics professor at Duke University’s Institute for Genome Sciences and Policy. “My lab does genomic research to understand how all our 20,000 genes are switched on or off in different parts of our body, and in certain diseases like cancer. The skills and thought processes I learned from Steve continue to be relevant every day. I try to mentor my students similar to how Steve mentored me.”
While Kalin Vasilev ’06 was completing his Ph.D. at Carnegie Mellon University, he helped develop new technology that he is taking with him to a leading research lab at Cambridge University in England. Vasilev’s novel biosensor monitors when cells touch and move apart, as when nerve cells communicate by forming synapses. “The implications are endless — memory, diseases, brain development and operation, etc.,” he said. “Dr. James and Gettysburg College were my foundation. He was the first one to see the connection between my character and following the biotechnology research path. This would have never happened in a larger university, since usually the interactions between students and professors are quite limited. He combined an easy-going and relaxed lab setting with unlimited insightful one-on-one time, everything culminating in a creative environment.” James proudly attended Vasilev’s dissertation defense last year.
Matt Denholtz ’05 is completing his Ph.D. at UCLA, where he and his colleagues are probing how embryonic stem cells bring related genes together in three-dimensional space even when they are millions of DNA base-pairs apart. He said that James “was my bridge from the classroom, where we learn what facts are known, to the lab, where we focus on what is not known by learning what questions to ask and how to ask them. A liberal arts education forces you to become comfortable thinking deeply in a broad range of subjects. This breadth naturally leads to the out-of-the-box thinking that is so necessary for scientific problem solving.”
Kristy Bialas ’08 is completing her Ph.D. in virology at the University of Rochester Medical School. She has been working on H1N1 flu virus genetics. “Nothing could have prepared me better for a successful career in graduate school than my years spent in Dr. James’ lab. Aside from learning how to design my own experiments, keep a good notebook, train incoming students, have meaningful discussions, and suffer through draft after draft in order to become a better scientific writer, it was in his lab that I really discovered my passion for science. His unwavering enthusiasm about his and everyone else’s projects in the lab had us racing to work each morning to be the first to see the results of yesterday’s experiments,” she said. “Being a student at a liberal arts college was very meaningful to me as a person. I got to take classes on psychology, gender identity, Roman civilization, and other fields that I hadn’t yet been exposed to. It was a great opportunity to try new things and become a more well-rounded person.”
Kristin Shingler ’11 is studying viral structure in the microbiology and immunology Ph.D. program at Penn State’s College of Medicine in Hershey. Four years of research with James provided crucial preparation for grad school, she said. “Being able to think about problems in a laboratory setting from multiple angles is a great advantage, and I believe the diverse training I received at Gettysburg helps.”
“Joining Dr. James’ lab has been the most important and rewarding decision of my scientific career thus far,” said Tina Kelliher ’11, who is pursuing a Ph.D. at Duke University. “He taught me how to think and communicate my ideas like a scientist in an interactive and personal way. My lab works on modeling a gene regulatory network of the eukaryotic cell cycle, using budding yeast as a model, in collaboration with mathematicians, statisticians, and computer scientists. The systems biology field is driven by people who have developed a variety of skills and can speak multiple scientific ‘languages.’ I believe that my training in the James lab and at Gettysburg College in general has prepared me for the experiments, research talks, and grants that I am presently working on.”
What could the genes of a common bread mold like Aspergillus nidulans have to do with human cancer? Well, it’s all in the family.
In fact, Prof. Steve James said, fungi and humans could literally swap some genes without harm to either organism, like trading sparkplugs between a Volkswagen and a Ferrari. The fungal and human genes match because basic mechanisms of cell division and DNA repair evolved early on, and proved so effective in promoting survival that they’ve been conserved with little or no change in increasingly complex creatures — including us.
Two genetic widgets under particular scrutiny by James and his students are nimO and snoA, genes crucial to sensing and repairing DNA damage and to facilitating the necessary flow of genetic information during meiosis, when cells divide to produce gametes (sperm and eggs, for example). Understanding the functions of such genes, James said, could help unravel the mystery of “why normal cells get it right every time they divide, and why cancer cells get it wrong every time. A worst-case double-whammy plays out again and again in cancer. The first ‘whammy’ is when cells forget how to stop dividing and begin to proliferate incessantly, but that is not enough by itself to drive cancer. A second whammy comes after gene-altering mutations shut down surveillance and repair. Cells literally become blind to the steady onslaught of DNA damage to which all cells are prone. Absent the means to detect and repair this DNA damage, mutations accumulate more rapidly, propelling cells that are already practicing unfettered division to evolve more rapidly to full malignancy.”
Over the years, James and his students have deleted more than 80 different genes from A. nidulans, creating transgenic organisms whose DNA damage-sensing and repair functions are compromised. nimO and snoA are of special interest because they also have roles during the early stages of meiosis, when a cell deliberately breaks its own chromosomes (coils of DNA containing many genes) in order to promote “crossing over,” or genetic exchange between cells. James’s discoveries suggest that the two genes collaborate to control both the breakage and subsequent repair of chromosomes. James and his students discovered snoA in his lab through collaborative research in 1998-2000.
“I’m not a cancer researcher per se,” James said. “I am a basic researcher working on questions that are intimately connected to understanding the way a cancer cell works.”
His research would have been impossible in the pre-digital age. Since James joined the faculty in 1992, the evolution of digital technology has birthed a revolution in biology. We know that DNA encodes genetic information via precise sequences of four nucleotides referred to as A, C, G, and T. But without today’s number-crunching capabilities, there would be no way to make practical use of that knowledge.
Here’s why humans need digital help to sequence whole genomes. Imagine a tall stack of identical dictionaries — fat unabridged ones. Each is a copy of a genome, the entirety of an organism’s genetic information. Now, run all the books through a shredder, and from that mountain of confetti reassemble one absolutely perfect copy. The shredding is unavoidable because the best automated DNA sequencers can “read” only about 400 consecutive letters in a strand of DNA. But there are 30 million letters in the genome of the fungus that James studies, and 3 billion in Homo sapiens. Without brilliant software, there would be no way to reassemble myriad 400-letter fragments into flawless prose. The words and sentences are genes, each of which controls a particular aspect or activity of a cell. In humans, some 23,000 genes are scattered widely through the genome, intermixed with non-gene material that only a computer can sort out.
Once you have a computer-generated genetic vocabulary, you can add, delete, or change genes to create transgenic organisms and see what happens to them, which is exactly what James and his students have been doing since 2005, when the genome of A. nidulans became available in usable form.
From fascinated kid to genetic engineer: The journey of Prof Steve James ’80
A fascination with living things spawned early for Steve James ’80. As a kid, he captured salamanders until 146 of them inhabited a basement window well of his family’s home near Minneapolis.
But a different creature coiled at the heart of the “watershed moment” that he recalls from around age 6, when, on a rock wall in the garden, he encountered a garter snake. “It might as well have been a pot of gold,” he said, grinning like a kid at the memory. Thrilled, he snatched up the serpent and sped into the house, terrifying his unsuspecting mom, who immediately exiled both beast and boy and phoned his father: “You have got to do something with this boy.” Waiting for his dad to come home was probably less comfortable for James than for the snake, now safely ensconced in a coffee can on a bed of grass. When James’ dad finally arrived, he gave the boy exactly what he deserved — an aquarium and a book about snakes.
“I was a real outdoorsy kid,” James said. By high school, he was a veteran birdwatcher and cataloguer of wildflowers, a field-guide always in hand. In Ontario, the future Eagle Scout caught the fishing bug from his grandpa: “I could’ve spent my entire life in a boat with him.” James got a taste of that imagined existence during his college years, spending summers as a guide at the Boy Scouts’ national Wilderness Canoe Base in northern Minnesota.
“I came to Gettysburg knowing that I was interested in biology,” James said, but Gettysburg wasn’t the first college he looked at. Luckily, it was the last. In March of his senior year in high school, he told his parents he didn’t like any of the campuses they’d visited. So, dad and son lit out from the Philly suburbs, where James spent most of his childhood, to scout nearby schools. Unsurprisingly for a Saturday morning, both Franklin & Marshall and Dickinson seemed deserted. “We got to Gettysburg about 2 p.m.,” James said, “and what looked like a thousand students were on Stine Lake, throwing Frisbees and footballs around. Which campus do you think a high school kid would like best?” A tour from biology Prof. Jan Mikesell helped seal the deal. It didn’t hurt that James looked up to a recent Gettysburg grad who lived in his neighborhood, lacrosse standout John Myers ’75.
James soon came to look up to another Gettysburg standout, though in a different field: biology Prof. Ralph Cavaliere. “Ralphie turned me on to mycology” in an intro course, James said in an interview this past September. “I’d never been around microscopes much, and fungi are fascinating on both the micro and macro levels. I was primed by always trying to ID wild plants and animals, and challenging myself to learn details like the difference between an eastern ribbon snake and a garter snake. I had that penchant as a budding biologist, but it was Ralph who taught us to key out different fungi using scientific principles. Ralph and his enthusiasm — and the organisms themselves — drew me in and hooked me. After that I took every course he offered,” including a between-semesters field trip to study marine biology at a Duke University facility in Bermuda, plus lots of research time both in and out of the lab. “I love libraries as much as I love the outdoors,” James said. “I could spend hours in some corner of the library researching the physiology and growth habits of a plant. Ralph gave us a lot of assignments to write about plants, which was unusual then — and great training in the art of scholarship.” It’s also not so different from James sending today’s students to an online resource to learn what genes do.
Cavaliere, now a professor emeritus, not only introduced James to fungi, but also helped him transform his fascination into a career. In the fall of James’ senior year, Cavaliere took him aside. “He didn’t say hello or say what he wanted to talk about. There was no lead-in. He looked me in the eye and said ‘Steve, where are you going to grad school?’ In that utterly surprising and transformative moment, I said to myself ‘Oh, it looks like I’m going to grad school.’ He knew I needed a push.” But, James said, Cavaliere also knew when not to push. He could have advised James to head to Duke, where Cavaliere had long-standing ties to marine biology researchers. But James also had his eye on the University of Minnesota, which offered more opportunities in his area of interest and was near the northern wilderness he loves.
“Ralph said ‘You’re more of a freshwater guy than a saltwater guy.’ He gave me permission. He had the wisdom to know what I needed and who I was. He helped me all along. You can see that he shaped my thinking at critical moments.” (James has done the same for his students. See page 16.) With Cavaliere’s encouragement, James went to Minnesota and earned a master’s in botany and a Ph.D. in cell and developmental biology. He worked alongside fungal researchers with whom he remains connected. “I learned what research really is,” said James, who also discovered that some of the wild samples he collected were delicious sautéed in butter.
Crucially, James also discovered that the world of genetics was about to break wide open with the advent of genetic engineering. DNA sequencing had been invented in 1977, while he was still an undergraduate, and the field remained in its infancy in the early 1980s. “But it was clear that that these new methods, with their unprecedented power to reveal the underpinnings of life, would be mandatory in the scientist’s toolkit,” James said. So, he began applying to institutions with labs where “the next level” was beginning to become real. “I wanted to learn the hottest tech techniques, and it took five years at that time — essentially what I do now with undergraduates in 14 weeks in my Molecular Genetics course.” It wasn’t long before he became a postdoctoral fellow at the University of Medicine and Dentistry of New Jersey, probing the Aspergillus nidulans fungus at one of the foremost labs in the field of cell division research. For three years there, he helped advance understanding of the genetic mechanisms controlling cell proliferation.
But, by now, he and his wife — fellow Gettysburgian Laura Mendelman James ’80, who earned a master’s in social work at Minnesota — had two young sons. It was time to evolve again. While applying to institutions large and small, and being invited to interviews, he happened across an ad for a certain liberal arts college in Pennsylvania. Gettysburg was not only looking for a molecular biologist, but it had just received a grant from the Howard Hughes Medical Institute to set up a genetic engineering lab. “I had never imagined it would be possible to return to Gettysburg,” James said, but when the opportunity came “it was an easy decision.” (Learning to teach was a bit more challenging. See story below.)
“Gettysburg shaped my life,” James said in an oral history interview conducted this past March by Alexandra Milano ’14. “I really grew up here and found out who I was here, learned who I was as a person, and discovered that I could become a scientist. I met my wife here. I guess you could say Gettysburg has given me the whole package.”