Stuck on Giardia

Heidi Elmendorf's passion for parasitology is matched only by her passion for teaching.

Karen Hopkin
Nov 30, 2007
<figcaption> Credit: © Jason Varney | Varneyphoto.com</figcaption>
Credit: © Jason Varney | Varneyphoto.com

Heidi Elmendorf grew up wanting to be a veterinarian. As a teenager in upstate New York, she worked with a small-animal veterinarian on weekends and after school. And as an undergraduate at Princeton University in the late 1980s, Elmendorf spent a summer as an elephant caretaker at a zoo in Stuttgart, Germany, where she "learned how to feed elephants, bathe them, and shovel up after them," she says.

To be accepted into Cornell's College of Veterinary Medicine, Elmendorf needed to take a course in microbiology, a course that Princeton didn't offer. "So I asked a guy who I thought was a microbiologist if he would do a tutorial with me," she says. Every week, Elmendorf would meet with that guy - who happened to be John T. Bonner, a scientist who she says "more or less invented research on Dictyostelium" - and the two...

MITOCHONDRIA AND OTHER MISSING BITS

Elmendorf was drawn to parasites because, she says, they "generally don't behave by the rules." Giardia, for example, has two nuclei and no mitochondria. For her doctoral work, Elmendorf explored how the malaria parasite generates a series of membranes inside a red blood cell, which is little more than a sack of hemoglobin, to help traffic the proteins it secretes. "Heidi did a lot of really nice work describing those membranes, how they connect to one another, and how they emerge in the first place," says Stanford's John Boothroyd, who was on her thesis committee. "It's a testimonial to the work that I can discuss it at all, because I haven't looked at it in 15 years."

But for Elmendorf, something was missing. "By the end of grad school, I really loved parasites, but I felt I'd lost a lot of perspective about biology. So I started looking for teaching positions." It was 1993, and Elmendorf's then-husband Steve Singer was starting a postdoc at the Harvard School of Medicine. (They've since divorced.) She "drew a 30-mile radius around Boston" and wound up at the Philips Academy in Andover, where she lived in an old Victorian dormitory with 10 teenage girls and taught 9th to 12th grade biology.

"That was a fabulous experience," says Elmendorf. "I think I'm still in biology because I took off time to teach. Graduate students become jaded," she says. But during her first month teaching, Elmendorf watched a 14-year-old boy look through the microscope for the first time and yell, "Oh my god, look at that! Damn, that is cool." Seeing such excitement, she says, "helps you rediscover your own, when you can see it through their eyes."

"Heidi has a really good sense of the teaching mission and the research mission and how they go hand in hand. You don't have to choose between being a good researcher or a good teacher. You can be both." --Scott Dawson

The excitement of looking at cells under a microscope ultimately led Elmendorf back to the bench. She recognized that her teaching benefited from her recent experience in research, and she feared that the more time she spent away from the lab, the more stale her lectures might grow. Plus, Elmendorf had fallen in love - with Giardia. "Giardia is absolutely beautiful," she says. "It's shaped like half a pear, with eight flagella and two nuclei. It looks a little like Mona Lisa with quirky smile." Being attracted to Giardia by its looks "is not very scientific," she admits. But she found the bug "captivating." So in 1996 she moved to Bethesda where she joined the lab of Ted Nash at the National Institutes of Health; Nash was one of the few people working on Giardia.

GIARDIA'S MYSTERIOUS GENETIC REGULATION

At the start or her postdoc, Elmendorf chose to focus on Giardia's cytoskeleton. The actin cytoskeleton helps the parasite maintain its pear shape, but more importantly it allows the organism to cling tenaciously to the intestinal wall, so it can avoid being swept away by peristalsis. That makes the cytoskeleton an attractive target for drugs to treat a Giardia infection. "If you disrupt the cytoskeleton with drugs, Giardia can't attach, and if it can't attach, it can't cause disease."

So she started screening a cDNA library for cytoskeletal genes. In the process, however, she stumbled across something quite odd. Giardia, it seems, produces prodigious amounts of antisense RNA; about 20% of its transcripts don't code for anything. "The first few I tossed off as being something wrong with my sequencing reaction or a mistake in the library." However, of the first 50 clones she sequenced, 10 appeared to be nonsense. "Everyone thought they were garbage and that I should ignore them and get back to the meaningful cytoskeletal genes I was working on." Elmendorf persisted, and by 2001 she and Singer, who had also been a postdoc in the Nash lab, published the observations regarding this abundance of antisense in Nucleic Acids Research.

"Most advanced eukaryotes don't waste their time and energy synthesizing useless antisense RNAs," notes Wang. So if Elmendorf can determine what these transcripts are doing for Giardia, which is one of the earliest nucleated cells, "she will be able to make a major contribution toward showing how gene regulation evolved in eukaryotes," he says.

Elmendorf continues to pursue the antisense story, but she has also returned to her quest to understand the cytoskeleton. In the paper describing the Giardia genome that was published in Science at the end of September, Elmendorf and her collaborators, Cande and Scott Dawson of UC, Davis, describe Giardia's unexpected lack of actin-binding proteins: no myosin, no profilin, no cofilin, and none of the standard actin-associated proteins found in other eukaryotes. "It's possible that they're so divergent that it'll be impossible to find them," says Dawson. "But based on the things we've done, and that other people have tried, I would say they're not there."

Still, the nondiscovery is an active area of debate. "Giardia is tricky because it's so divergent, so I don't really trust it," says Andrew McArthur, a bioinformaticist who worked on the Giardia genome. "When I do a search in Giardia and I don't find a particular protein group, I'm pretty skeptical. I think Heidi's work on the cytoskeleton will hold up, but I'd like to see more experimental work to be absolutely certain they're not there."

STUCK ON GIARDIA - AND TEACHING

In the meantime, Elmendorf is collaborating with Georgetown physicist Jeff Urbach to probe the mechanics of attachment. The researchers have built a flow cell to measure how much force it takes to dislodge Giardia. After seeing how the parasites behave when subjected to a current - they slide around on the cover slip to which they're anchored, even pivoting when the researchers change the direction of the flow - Elmendorf hypothesizes that Giardia attach like a suction cup, with their ventral sides flat on the surface and the cytoskeleton that shapes their rounded dorsal side providing the pressure that sticks them down.

That paper is now ready for publication, but it's taken awhile, in part because so many of Elmendorf's students are undergraduates. "That's hard for continuity," says Cande. "You train them, then they split." The student on the flow-cell project made significant progress, says Urbach, "but just when we were getting ready to crank through a lot of data, she graduated."

Working with undergraduates does have its rewards, though. "You get to help bright kids appreciate the pleasure of creating new knowledge," says Urbach. And that's something that Elmendorf cares deeply about. "Heidi has a really good sense of the teaching mission and the research mission and how they go hand in hand," says Dawson. "You don't have to choose between being a good researcher or a good teacher. You can be both."

That makes Elmendorf unique. "She knows her science. She knows her teaching. And she loves both of them," says Joseph Neale, who was chair of the biology department when Elmendorf was hired in 1999. At a place like Georgetown - a Jesuit university that prides itself on being a student-centered research institution - "someone like Heidi is absolutely invaluable," says Neale.

In addition to teaching the majors' microbiology course, Elmendorf engages nonmajors in a course that asks "Shall microbes inherit the Earth?" When avian flu hit the news in 2003, Neale says, "Heidi had the whole syllabus lined up, but she turned on a dime. She said, 'you want to study this?' and she restructured the course. The students loved it." Elmendorf also initiated and manages a program that allows Georgetown students to teach science in the Washington, DC-area public schools, because one of the best ways to learn something is to teach it. "The students come away amazed by the experience," says Georgetown colleague Ellen Henderson. "Heidi is passionate about improving science teaching and about understanding how students learn."

To that end, Elmendorf also studies her students, doing research for which she has IRB approval. In her nonmajors course, for example, Elmendorf set out to explore how students could learn about science from one another; she says she hopes they'll be doing that around water coolers and at dinner parties for the rest of their lives. She set up an online chat room where the students could post queries and discuss material being reviewed in class. At first, she says, students used the discussion board to let Elmendorf know they'd done the required reading. Soon they were using it to flesh out their communal understanding of ideas, together building what Elmendorf says were "nice, intellectually rich, quite accurate scientific answers."

The experience left the students less intimidated by science. "A lot of these nonmajors are afraid of science, sometimes even hostile toward it," says Henderson. "But Heidi turns them around. She's simply one of the most outstanding teachers I've encountered in 30 years on the faculty."

In a way, Elmendorf is just listening to the data. "Maxine Singer talked about the act of teaching as being an experiment," says Elmendorf. "And if you don't look carefully at how students learn, it's like doing an experiment without looking at the data that comes out."