Unearthing Cell Mysteries
Last fall, biology major Natalie Miller was flattered to be invited by Greg Hermann to join the popular assistant professor’s cell biology lab. As she saw it, the only drawback was the lab animals.
Not mice. Not fruit flies. Worms.
“Initially, I thought they were pretty gross,” says Miller, a senior from Orange, Texas. “All I could picture when I looked at that first plate was worms crawling all over me.”
Peering through a microscope at hundreds of slithering nematodes might not sound appealing. But, as Miller quickly learned, the millimeter-long worm known as Caenorhabditis elegans, or C. elegans for short, is considered by many one of the best models for studying how a single fertilized egg develops into a complex multicellular animal.
Molecular biologists are drawn to C. elegans because of its anatomical simplicity and visibility. When observed under a microscope, the worm’s transparent skin and organs reveal the inner workings of each of its 959 cells. Even though that number is exponentially fewer than the number of cells in your pinky finger, it’s still enough to produce a nervous system, muscles, an intestine, and even a rudimentary heart and brain. Plus, approximately half of C. elegans genes have similar counterparts in humans.
Combine these characteristics with an astounding growth rate–from a single cell to a fully formed adult in 36 hours–and it’s easy to grasp why researchers consider C. elegans an ideal specimen. Studying its insides could lead to new treatments for cancer, cardiovascular disease, amyotrophic lateral sclerosis, and other ailments.
Hermann, a lanky Portland native in his mid-30s, has infected dozens of Lewis & Clark students since 2001 with his buoyant enthusiasm for this microscopic soil roundworm. He’s the kind of wide-eyed scientist who sees the world brimming with mysteries waiting to be solved. And the mysteries that intrigue him most have to do with the formation of cells, the basic structural unit of all living organisms.
“You can crack open any histology textbook,” he says, leaping out of his office chair to grab a thick text about minute animal and plant anatomy from his bookshelf, “look at any cell, and ask, ‘How does it get to be that way?’ And 99 percent of the time, you’re asking a question that no one knows the answer to.”
Hermann has no qualms about unleashing even first-year students on unanswered questions in cell biology, trusting them to help him identify the genes responsible for producing a critical organelle in the worm’s gut. In other words, his method of getting students to “think like scientists” doesn’t include a lot of hand-holding.
“He’ll give you some information, but he relies on you to press further,” explains Lena Schroeder ’04, who got hooked on worms as a junior and now keeps Hermann’s lab stocked and operating smoothly as its full-time technician.
Schroeder’s first experiment involved writing down what she observed while watching a worm embryo grow. More recently, one of her experiments factored into an article on a newly described gene, coauthored with Hermann and three other Lewis & Clark students, in the July 2005 issue of Molecular Biology of the Cell, an influential academic journal.
Schroeder isn’t the only alumna making a name for herself. Hermann has mentored several students now working in prestigious worm-research labs, including the one run by 2002 Nobel Prize winner H. Robert Horvitz of MIT (see related article). “I want to build a community of Lewis & Clark student scholars who love the worm,” Hermann says.
That community currently numbers seven: Erin Currie ’07, Max Kramer ’07, Susan Kremer ’07, Marcela Kokes ’08, Natalie Miller ’06, Beverley Rabbitts ’06, and Dyea Summers ’06. And that’s not counting the 20 or so students who pursue unanswered questions about C. elegans biology in Hermann’s fall-semester cell biology course. All are conducting experiments in genetics, cell biology, and molecular biology: locating certain genes on the worm’s chromosome, visually observing the formation of gut cells, injecting genetic material into a worm’s reproductive system, and so on.
Each is trying to find and decipher one of the 50 or so genes that Hermann speculates are involved in creating the lysosomes in the worm’s gut cells. Lysosomes, which are found in nearly every cell of our bodies, operate like a recycling center, breaking down old cellular material so it can be refashioned into something useful. Lysosomes also play a role in repairing cell membranes, destroying pathogens, and determining body pigmentation.
In a ground-floor lab crowded with microscopes, petri dishes, and bottles of gene-altering chemicals, Beverley Rabbitts ’06 slides a plate under a microscope and peers into the eyepiece. Hundreds of thin-bodied worms slither on and around each other in a sea of tasty bacteria. She’s tampered with one of their genes, the one known as glo-3, and wants to know how its absence affects the worms’ gut lysosomes.
In more than two years of research, she’s learned a lot about how glo-3 interacts with other genes to affect lysosome production; she’s even cloned the glo-3 gene, an accomplishment for any geneticist. Her thesis work is headier yet: She’s trying to pinpoint what part of the GLO-3 protein is crucial to its function and identify other cellular proteins with which it interacts.
“We’re at the beginning stages of understanding how these lysosomes are made,” says Rabbitts. “We’re not using human cells, we’re not testing pharmaceuticals, but we are doing important work by increasing the fundamental knowledge about what goes on in cells.”
The worm’s entire gene sequence has also been mapped–an important first step in figuring out the role of each gene in the worm’s development–and posted to a searchable Web database.
Hermann was investigating another facet of cell development when he happened upon animals with missing gut lysosomes. As a postdoctoral fellow at Seattle’s Fred Hutchinson Cancer Research Center and the Howard Hughes Medical Institute, he conducted a set of experiments that he hoped would explain how a gut cell grows into a different shape than other cells. Those experiments didn’t pan out. But in his long days at the microscope, he says, “I saw a lot of other things go wrong.”
One cellular malfunction caught his attention. In a mutant worm he created, glowing specks known as “gut granules” were missing from their usual spot in the gut cells. Instead, they showed up in the worm’s intestinal cavity and were then excreted. He labeled these worms glo mutants–both a loose acronym for gut granule loss and a nod to the conspicuous florescence of gut granules–and stashed them in a freezer for later study. (Although the worms have a two-week lifespan, C. elegans can be placed in suspended animation at minus 80 degrees Celsius for years without harm.)
When Hermann arrived at Lewis & Clark in the fall of 2001, he thawed out those mutant strains. He guessed that the gut granules were lysosomes and that the mutants would be perfect research specimens for smart, diligent undergraduates who wanted to discover something new about how cells are put together.
Both hunches proved correct. In the last four years, Rabbitts and 17 other students in Hermann’s lab have identified 14 genes that help create lysosomes–including 3 that, when defective in humans, result in a disease known as Hermansky-Pudlak syndrome, a dangerous form of albinism in which blood does not clot sufficiently and lung function is compromised.
One big advantage of studying C. elegans is that there’s a lot already known about the worm and most of that information is surprisingly accessible. A lifetime’s worth of cell divisions–exactly the same for each worm–has been captured on a flow chart that fits neatly on a sheet of notebook paper. The worm’s entire gene sequence has also been mapped–an important first step in figuring out the role of each gene in the worm’s development–and posted to a searchable Web database. Indeed, the community of worm scholars is so open that students in Hermann’s lab regularly go online to place mail orders for gene-deprived worms stored at other labs.
Hermann regularly immerses students in the worldwide “worm cult” by taking them to scholarly conferences. In June, three current students–along with five Lewis & Clark alumni, including Schroeder–joined the throng of more than 2,000 scientists at the International C. elegans Conference in Los Angeles, thanks in part to funding from Lewis & Clark’s Student Academic Affairs Board. There, Rabbitts and Miller presented a joint poster on their glo-3 discoveries. Both speak enthusiastically about the experience. “I was surrounded by these people who knew so much about the work I was doing,” marvels Miller, “and yet I still had something to add to the conversation.”
Rabbitts enjoyed rubbing shoulders with top scholars–including one who passed on a genetic technique that she quickly incorporated into her thesis work. “What a lot of us get out of the research isn’t necessarily the content we’ve studied but the skills we’ve learned. Our research opens doors for our future.”
Hermann stands ready to open doors for more students. He says his lab is a place where any biology or biochemistry major can discover something of interest. All that’s needed is the dexterity to extricate a single worm from the crowded bacteria soup party using a pencil-sized “worm pick” and an eye for spotting hermaphrodites, the self-fertilizing worms that produce ideal offspring for study.
“Regardless of what aspect of biology you’re into,” says Hermann, “you can learn it through this organism, and with experiments that can be done at any level.”
Opportunities to investigate the glowing gut granules are likely to be available for a long while. Two summers ago, students in the Hermann lab carried out a large screen for mutants with defects in gut granule formation, resulting in the identification of more than a hundred new strains.
“The rest of my career is in the freezer, where those hundred-plus worm families were promptly stashed,” Hermann says. “Lewis & Clark students will be identifying new genes
and learning more things about how those granules are made for years to come.”
Dan Sadowsky is a freelance writer in Portland.
Professor Hermann’s research has been generously supported by the National Science Foundation and the M.J. Murdock Charitable Trust. He has also participated in the Rogers Science Research Program.