Profile of Daniel E. Gottschling

Geneticist Daniel E. Gottschling is driven by discovery. From doctoral projects involving the identification of the first self-splicing RNAs and telomere-binding proteins to recent work at the forefront of the cellular aging field, the Fred Hutchinson Cancer Research Center researcher’s career has leap-frogged from one area to another in the pursuit of discovery. In his Inaugural Article, Gottschling, elected to the National Academy of Sciences in 2011, identified 135 age-associated proteins retained by the yeast mother cell throughout multiple asexual replications (1). These long-lived proteins provide Gottschling with more questions about their role in aging than answers, a challenge in which he revels.

Daniel Gottschling. Image courtesy of Bo Jungmayer, Fred Hutchinson Cancer Research Center.

Microcolony of yeast (red) formed from a single mother cell (green) after approximately seven divisions. Image courtesy of Dan Gottschling, Fred Hutchinson Cancer Research Center.

Midwest to Mountains

Gottschling was born in Gary, Indiana and grew up surrounded by extended family. His mother worked at US Steel as a draftswoman, and his father advanced from “climbing poles and installing phones” to middle management at Bell System. “While they started out as blue collar, they were both ambitious,” says Gottschling. Throughout school, “the thing that got me the most excited was math,” he says, but Gottschling also enjoyed sports and music. Disheartened when a hernia prevented him from joining the swim team, Gottschling tried theater and ended up performing extensively through high school. “I began to get the perspective that if you gave up one thing, it gave you the opportunity to go ahead and do something else you weren’t expecting,” he says. “It’s been a theme of my scientific life.” As a result, Gottschling doesn’t hesitate to let postdoctoral fellows take projects with them, knowing the temporary void opens new research avenues.

In 1973, Gottschling entered Augustana College, a small liberal arts school that appealed to his broad interests. In the beginning, Gottschling, whose only scientific role model was the family’s doctor, aimed for medicine. “After one quarter I realized that I did not want to be a doctor.” Instead, he weighed a major in chemistry or philosophy, but “science won out.” One summer, Gottschling earned a National Science Foundation undergraduate research fellowship and worked with Ohio State University physical chemist C. Weldon Matthews. “Because of the math and also the kind of logic used in it, I got really entwined in physical chemistry,” Gottschling says.

Gottschling returned for his senior year intent on graduate school and applied to programs across the Midwest. After arriving for his interview at the University of Colorado, Boulder, in the dark of night, it was the view of the surrounding mountains the next morning that charmed Gottschling. He matriculated in 1977, intending to join a physical chemistry program, but switched to biochemistry. None of the existing professors would take a student who had only one quarter of biochemistry experience, though, and Gottschling found himself referred to incoming faculty member Tom Cech. “He got me sort of by default,” says Gottschling. “It turned out to be an amazing bit of good fortune, at least on my part.”

Stepping Back from the Crowd

Gottschling began by studying the ribosomal RNA gene in Tetrahymena, a single-celled organism. At the same time, others in Cech’s laboratory were investigating a newly discovered intron in the same gene. Determined that the apparently self-splicing intron must be an error in isolation technique, Gottschling decided to clone the intron’s DNA and express it in Escherichia coli, but to everyone’s surprise the intron got spliced in bacteria, too. This work helped confirm that RNA can function not only as genetic information but also as an enzyme called a ribozyme, able to splice itself (2). “At the time, I was questioning if I wanted to be in graduate school.” When he learned of a last minute sabbatical opening at Western State College in Gunnison, Colorado, Gottschling took a year off to teach undergraduates. The experience “opened my eyes that I could be a pretty good teacher,” says Gottschling, but “I discovered that I really missed doing primary research.”

Gottschling returned to Cech’s laboratory but not to the RNA work, which was moving apace. “I was in a state of not wanting to do what everyone else was doing, though without appreciating that this was the only place in the world where this research was happening.” Instead, Gottschling started a collaboration with molecular biologist David Prescott to work on telomere binding in Oxytricha, another ciliated protozoan with DNA that exists as ∼24 million gene-sized pieces. Telomeres are conserved repeating sequences of noncoding DNA. Located on the ends of chromosomes, they act as caps, buffering the coding portions of DNA. Gottschling found that Oxytricha’s plethora of ends contained a specific DNA–protein complex (3). Subsequent work characterized the proteins as some of the first specific to telomeres, requiring not only the characteristic sequence repeats but the structure of the terminus to bind (4).

In Cech’s laboratory, Gottschling watched discovery in action. “It made me realize I was someone who was happiest discovering things in a broad sense, rather than delving into mechanistic details.” Gottschling begins to feel claustrophobic when his area of current focus gets too crowded, a measure he evaluates by asking himself, “If you aren’t here for a few years, will the field still discover it?” If the answer is yes, his interests shift.

There and Back Again

When it came time to find a postdoctoral position in 1984, Gottschling applied for a diversity of research areas that reflected the myriad interests he had developed over the previous seven years. He chose to take a position with Virginia Zakian, who studied yeast telomeres at the Fred Hutchinson Cancer Research Center on the advice of Cech. The deal was sealed when Gottschling, who had developed a passion for backcountry skiing, saw Mt. Rainier.

Gottschling brought Oxytricha with him to Zakian’s laboratory, but working with Oxytricha “was like tending an animal,” he says, noting that 50-gallon water changes were required just to keep the organism alive. “I developed yeast envy.” Gottschling began tinkering with yeast, attempting to monitor chromosome loss while disrupting telomere function with a marker gene inserted near a telomere. To his surprise, chromosome loss in the controls with normal telomere function appeared to be greater than expected. A perplexed Gottschling wasn’t prepared to analyze these strange results. “I put it in the freezer and said, ‘That was my yeast experiment. Yeast isn’t as good a system as advertised.’”

As he traveled to faculty interviews across the country, Gottschling pondered, “Why didn't my experiment work?” Eventually, Gottschling connected his results with classic studies he had heard about variegated gene expression in Drosophila, an effect that reversibly silences genes near heterochromatin, a kind of structural organization of DNA. Further experiments showed the same effect at telomeres in Saccharomyces (5). Gottschling took the work with him to the University of Chicago for his first faculty position.

During his time in Chicago, Gottschling continued to explore biochemical and genetic approaches to epigenetics and discovered a critical component of telomerase, the enzyme responsible for adding length to telomeres. His first yeast screen identified telomerase template RNA, the scaffolding that the enzyme uses to gain a foothold (6). In 1996, Gottschling received an unanticipated offer to return to the Fred Hutchinson Cancer Research Center as a full member. “There was a lot of excitement about modern genetics here,” he says. Although he loved Chicago, says Gottschling, “I missed being in the mountains.”

Aging Questions

Gottschling continued his work on telomerase RNA in yeast, but it proved short-lived. “Once we started to get into the nitty gritty, I started to lose interest.” Once again, Gottschling jumped ahead. He began to explore histones, proteins that wind DNA into tightly packaged cores forming the basis of chromatin, and purified a yeast histone acetyltransferase, HAT1 (7), and the first histone methyltransferase that antagonizes silencing (8).

When the histone field became too populated, Gottschling says, “I started thinking about the problem of cellular aging.” He first wanted to use yeast to determine “age-associated phenotypes other than death.” Yeast can replicate asexually via budding about 35 times before the mother cell enters senescence. Gottschling started crafting assays to monitor chromosome damage. A novel approach “allows us the time in a new field to discover and reflect,” he says.

A new approach turned out to be time-consuming. For several days in a row, student Michael McMurray would check the colonies under a microscope, separating the mother and daughter cells every 90 minutes so that the lineages could be tracked. They discovered that after 25 replicative cycles, subsequent daughter cells showed a 100-fold increase in genome instability, a phenomenon that illuminated potential mechanistic links between aging and cancer (9). The result “encouraged us to go deeper and further, but the nature of the experimental assay turned off a lot of potential students and postdocs.” This aspect prompted Gottschling to develop, with postdoctoral fellow Derek Lindstrom, yet another tool, a technique for isolating only aged cells, called the mother enrichment program (MEP) (10). Normally, because of exponential growth, an aged cell represents only one in every 10 million cells of a colony, a needle in the haystack of daughter cells. MEP circumvents the problem by preventing daughter cells from reproducing via an inducible genetic system. “That has busted things open for us,” says Gottschling. “We can apply biochemistry, genetics, and cell biology to cells that are replicatively aged.”

In his Inaugural Article, Gottschling uses MEP to look for proteins associated with aging. Some extracellular proteins, like knee cartilage proteins, are present in their original form throughout the life of an organism, and Gottschling wants to determine whether similar kinds of proteins exist in dividing cells. Using mass-spectrometry pulse chase technology, Gottschling identified 135 mother cell proteins that are retained through repeated replications (1). Identifying these “long-lived asymmetrically retained proteins” opens numerous intriguing questions about the biological consequences of retained proteins, their potential role in aging, and the mechanisms involved. “Here again it basically widened our vision,” says Gottschling. “At least for now, we have something new to think about.”

With the work in the Inaugural Article, Gottschling says, “We have cleared a little space for ourselves,” and he anticipates several years of fruitful exploration. The question of how genetics and environment affect aging, with multiple intertwined effects, is “a tough nut,” he says. “In conceptualizing how to approach the problem, yeast offers hope.”