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President Shirley Tilghman in Freshman Seminar

Exploring Epigenetics

President Shirley Tilghman in the Classroom

by Kitta MacPherson

As a light rain swept across campus one October evening, 15 freshmen were tucked around a seminar table immersed in a discussion about nature in another form.

With their eyes riveted on their class instructor, Princeton University president and molecular biology professor Shirley M. Tilghman, they grappled with one of the deepest questions in the natural world: What is at the root of the intricate process that makes us all so different?

In her freshman seminar titled "How the Tabby Cat Got Her Stripes or The Silence of the Genes," Tilghman, one of the world's foremost authorities on genetics, is introducing the students to a newer aspect of her subject known as epigenetics. The topic is vast, touching upon any factor not already predetermined in specific genes that affects the behavior of a living being's collection of chromosomes. Influences as simple as the parent from which the gene was inherited, the chromosomal neighborhood in which a gene resides and even chance, scientists are learning, influence whether the gene will be expressed. Epigenetics bears upon the question of the extent to which the expression of genes is "hardwired" or preprogrammed, or shaped by circumstance.

"The big idea we start with is: 'How is the genome interpreted, and how are stable decisions that affect gene expression inherited from one cell to the next?'" Tilghman said about the content of the class. "This is one of the most competitive areas of molecular biology at the moment, and the students are reading papers that in some instances were published this past year. As a consequence, one of the most common answers I have to give to their questions is, 'We just don't know.'"

In the weekly course, which is designed to be accessible to anyone who has taken high school biology classes, Tilghman assigns readings of science papers published in leading journals. She walks the students through the questions at the base of the studies, the evidence presented and the legitimacy of the conclusions. The freshmen respond freely to the dynamic mix of ideas.

"We all get a chance to speak, ask questions and have open-ended discussions about various topics that arise each week," said freshman Michael Moses. "I think that this seminar will definitely leave a lasting impression on all its members."

In fast-paced, three-hour sessions, Tilghman packs in lessons on the formidable lexicon of molecular biology. She treats lab experiments as though they are logic puzzles, creating opportunities for students to think out loud. She frequently says, "OK, let's talk this through," and checks in to ensure that students are retaining details.

For example, during a class when she started to launch into a description of an experiment, Tilghman stopped to ask: "What is it called when genes jump from one chromosome to another?" The class chimed instantly: "Translocation."

As the class progressed, the students posed Tilghman with a series of their own questions, including why Dalmatians are spotted (not because of epigenetics -- they lack a gene that controls pigmentation) and whether Alzheimer's disease may be caused by an epigenetic change to a neuron (probably not). In response, Tilghman probed their thinking, creating a give-and-take environment similar to a collaborative lab meeting.

"I absolutely enjoy the class: I'm learning a tremendous amount, but it doesn't feel like work," said freshman Gitanjali Gnanadesikan. "In fact it's a lot of fun. Not only is the subject interesting, Professor Tilghman has done a wonderful job in constructing the course so that we discuss not only the mechanics of epigenetics, but the ideas behind important scientific papers in the field, how the discoveries were made and what might come next."

The focus of a recent class was on two milestone papers in epigenetics published three decades apart. Tilghman pointed to the first, a 1961 Nature paper written by the British scientist Mary Lyon displayed on a screen at the front of the room. The study explains how X chromosomes can sometimes be inactive in mammals. Tilghman, seated at the table's head, scanned the students' faces and asked, "If women have two X chromosomes and men have an X and a Y, what does it tell you?"

The room fell silent. After a pause a student ventured: "That you don't really need a Y to survive?" Tilghman's face brightened. "Exactly," she said.

Lyon's classic study was based on observing a certain strain of female mice carrying a mutation in one of the two copies of a gene on the X chromosome that is responsible for pigmentation in the coat. Based on the striped pattern of the fur, she proposed that only one of the two X chromosomes was active in any given cell; the other X chromosome must be silent. The stripes, she argued, arose because the decision as to which X to inactivate was a random one and occurred early in development. Thus only some of the cells produced pigment because they had inactivated the X chromosome that contained the mutation, while the cells that had inactivated the X chromosome that had a normal gene could not produce the black pigment. Lyon noted a similar pattern seen in the coats of some cats.

Tilghman uses success stories like these to make a point about progress in research. One must work hard, she says, and be willing to accept the fact that most papers represent incremental advances. The payoffs do come, though. "Every once in a while, in science, the sky opens up," Tilghman said, smiling. "You get a breakthrough."

She displayed an image on the screen showing large messy splotches of ribonucleic acid captured in a lab technique known as gel electrophoresis. These are experimental results from the second paper she assigned, a 1991 Nature report on work led by Carolyn Brown of Stanford University.

"What would you do if you got these results?" Tilghman asked.

One student replied: "I would think I screwed up!"

"Ah," Tilghman responded with a smile. "Always be skeptical. Very good."

Brown's paper, which goes on to show that the RNA blobs are not lab accidents but real, is of great interest to epigenetics researchers. As the class talked it through, they learned that Brown was able to show that the gene Brown had discovered was highly unusual because it only was expressed from the inactive X chromosome -- a completely unexpected and counterintuitive result that opened up a new avenue of study on X chromosome inactivation.

Through such studies, Tilghman emphasizes that epigenetics is both fascinating and complicated.

It is a message reinforced at the end of the class when Tilghman asked one last question, too involved, however, to be answered at that time, despite the students' expectant looks.

"We'll see," Tilghman said. "That's for our next class!"