Undergraduates play big role in lab studying atrophy

Some students at Pitt are chasing secrets to space travel, but they’re not working with…

Dom Stokes, a sophomore industrial engineering major, works in the Jacobsen laboratory atop Langley Hall breeding special strains of nematodes

Bobby Mizia, Senior Staff Photographer

Some students at Pitt are chasing secrets to space travel, but they’re not working with rockets or lasers. Instead, they place their scientific bets on a tiny living thing not much bigger than a grain of salt.

The creature’s name is Caenohabditis elegans (C. elegans for short), and it’s a 1 mm-long worm that could — among other uses — one day help astronauts adjust to space flight.

Armed with microscopes, fluorescent dye and the guidance of Lewis Jacobson, a professor in the Department of Biological Science, a squadron of undergraduates are studying C. elegans to better understand and prevent muscle decay. Ensuing insights could be relevant everywhere from the health of space travelers, whose muscles wither and waste in zero-gravity, to medical patients, whose strength is often sapped by cancer, multiple sclerosis or other conditions.

Just as humans can experience muscle atrophy — the physical wearing away of muscle tissue — so can nematodes like C. elegans. In both species, atrophy happens because of a complex, poorly understood interplay between competing forces in muscle cells.

“Your body is always telling certain muscles to degrade and certain muscles to build up,” said senior Amanda Webb, a microbiology major. “We’re trying to figure out the exact means by which muscle atrophy is controlled in the body.”

Piecing together such a “means” isn’t your average afternoon jigsaw puzzle. Together with a sister lab in the United Kingdom, the Jacobson group has identified about 1,000 genes that are somehow involved in the construction, maintenance and breakdown of muscle tissue.

All of these genes have some bearing on the “signal transduction pathway” leading to muscle atrophy. Signal transduction works almost like a multistep relay race, except genes produce each runner and the signal magnifies whenever the baton hands off.

“The first messenger will tell the second messenger, which will tell the third and fourth, all the way down the line until you get to the point where it’s saying, ‘Activate atrophy,’ or, ‘Don’t activate atrophy,’” Webb said.

The problem is, it’s largely unknown how each “messenger” might affect the end result and interact with each other. And converting that unknown into understanding is where students — and the Jacobson group as a whole — come in.

When undergraduates  — you can typically find about seven to eight in the lab in any one semester — enter Jacobson’s lab, they typically pick a step along the “pathway,” and with the support of Jacobson and others, they start chipping away at the unknown.

“Everyone’s got their specific proteins they’re working on, and together we’re trying to compile a library,” Webb said.

Ruth Geller, a sophomore molecular biology major, wants to expand the “autophagy” section in that library. Directly translating to “self-eating,” autophagy involves the breaking down of structures within cells by loading them into spherical compartments filled with “digestive” enzymes.

Autophagy is an important step of the muscle atrophy pathway (think of muscle tissue being broken down by microscopic stomachs), and Geller has investigated a gene, called “unc-51,” critical in the autophagic process. If you mutate the gene, autophagy falls precipitously.

“By treating unc-51 mutant worms with a drug (rapamycin) known to promote autophagy, I am investigating at what point during autophagy the unc-51 protein is involved,” Geller wrote in the opening of her Brackenridge Fellowship talk earlier this summer. The Brackenridge program is an interdisciplinary research fellowship for Pitt undergraduates funded by the University Honors College. Basically, if she finds that the drug compensates for the loss of autophagy in C. elegans, Geller could better localize unc-51’s position in the atrophy pathway, since the drug target’s position is known.

As compelling as the idea sounds on paper, a summer of science taught Geller to appreciate the grueling and often intractable nature of knowledge discovery.

“It’s humbling,” she said. “Sometimes you get your results. Sometimes your results get you.”

A different part of the muscle atrophy pathway fascinates Webb. Specifically, her eyes are set on a protein called a kinase (ribosomal s6 kinase to be specific), which changes the activity of other molecules in the cell that eventually lead to degradation of muscle fibers. No one knows, yet, how important the kinase is in the process, and to find out, Webb wants to mess with worms’ RNA.

Scientists have recently discovered a way to introduce special kinds of RNA, the form of genetic material directly used to build proteins from corresponding genes, into C. elegans cells to temporarily turn off production of any desired protein. It’s a procedure called “RNA interference,” and Webb believes, after a year of research behind her, it could soon deliver her answer.

“You can target which specific protein you’re going for. I’m working to shut [the kinase] down and see how that affects the worms’ development and whether they atrophy more or less and where they atrophy,” she said.

The extensive involvement of Pitt students like Webb and Geller is no accident in the Jacobson group, which has seen upwards of 90 undergraduates in its existence.

“Hierarchy is not a useful thing in science,” Jacobson said. “I think it’s horse sh*t.”

Jacobson, who’s taught in Pitt’s biology department since 1967, contrasts his ways with the archetypal labs, in which undergraduates more or less do graduate students’ bidding.

“It’s a very peculiar thing we do,” he said, referring to his belief that society assigns responsibility to people based on age and academic rank and does so at great cost. “I don’t think anyone grasps how queer it is.”

So he fights that norm by giving students independent projects and investing in mentor-mentee relationships, even though an undergraduate emphasis could cut into short-term measures of research productivity.

“If you were just setting out to do directed research with no educational component, using undergraduates would not be your first choice,” he said, noting split time and focus, growing pains, fluctuating interests and overhead costs for training.

But Jacobson can swiftly brush off such concerns when he thinks of the successful physicians and researchers who populated his lab as undergrads. “I know that they are paying forward with what they learned.”

While Geller and Webb hope to one day go into public health and biology academia, respectively, they have their lives to “pay forward” insight from undergraduate research.

But that doesn’t mean they’re at a loss of insight now. In addition to developing an appreciation for scientific questions with real-life implications, Geller has learned from her time in the Jacobson group how to be critical.

“If you’re presented with a ‘fact,’ you have to ask why and be convinced why,” she said.

As current and future students attempt to apply their insights in their reach from the petri dish to the stars, scientific success will most likely follow out of patience and improvisation, Jacobson said.

“It’s jazz; it’s not Bach.”

[Editor’s Note: This story has been edited to reflect the correct spelling of professor Lewis Jacobson’s name.]