Research into the burrowing habits of the lowly deer mouse may lead to the unlocking of one of biology’s most elusive secrets
CAMBRIDGE, Mass. — Hopi Hoekstra is standing in the attic of Harvard’s Museum of Comparative Zoology among horns and pelts, an elephant skin under a table here, giraffe parts over there.
She is handling lumpy pieces of something that looks like molded Styrofoam and that seem entirely out of place. One has a long handle, like a cudgel. Another is shorter.
“It looks like a little sock," she says, holding it up for a reporter to inspect.
The sock and cudgel do belong in the museum, however, every bit as much as the antlers and skins. They are key parts of a research program that is helping unlock one of biology’s elusive secrets — how genes control complicated behavior.
Each is a cast of a deer mouse burrow, and since each species has its own characteristic burrow, these lumpy molds embody inherited behaviors. Length, volume and shape are easily measured.
And that data, partly drawn from the field and partly from the lab, once combined with crossbreeding and advanced DNA analysis, may allow Hoekstra, an evolutionary geneticist, and her colleagues to trace the architecture of a mouse burrow right back to the genes.
Two weeks ago, in the journal Nature, Hoekstra and two colleagues — Jesse Weber, now a postdoctoral researcher at the University of Texas at Austin, and Brant Peterson, a postdoctoral researcher in Hoekstra’s lab — reported on a major step toward that goal. They identified four regions of DNA that help control burrow design: three for length and one for the presence or absence of an escape tunnel.
Just a single step
Their report was hailed by other scientists as an elegant and inventive piece of research. Cori Bargmann, at Rockefeller University, who studies the neurobiology and genetics of behavior in nematodes, said, “I think it’s a really exciting paper." She added, “The genetics are beautiful." But it is only the beginning.
Now comes the hunt for the genes themselves, and perhaps even the biochemical pathways that show, step by step, how a DNA blueprint is transmitted to the scrabbling paws of a tiny mouse and translated into a hideout from foxes, hawks and other predators.
The investigation of the genetics of behavior is a huge scientific enterprise, with great progress being made in a variety of species — roundworms, fruit flies, lab mice, sticklebacks. Hoekstra’s work is unusual in that it deals with a naturally occurring, complicated behavior in mammals that is important for survival. And it is significant that she has been able to separate that behavior into two modules controlled by separate and independent DNA regions — burrow length, and escape tunnels.
Bargmann said she was impressed at Hoekstra’s success in unpacking the behavior into modules, a result that adds to the likelihood of one day finding simple genetic controls underlying the mystifying diversity of natural behavior patterns. The extraordinary variety of animal body shapes, after all, has been found to grow out of a relatively few master control genes.
“I really believe that there are rules for behavior that go all the way back," Bargmann said.
One component of Hoekstra’s success has been oddly low-tech: the kind of fast-hardening foam that can be purchased in a hardware store for home repair. It quickly produces an easily measured mold — behavior solidified.
Another important factor is as high-tech as tech gets. Decades ago, evolutionary biologist Richard Dawkins suggested that one could study the evolution and genetics of behavior just the way one studies the evolution of body shape: concentrate on what animals build — birds’ nests, beaver dams, termite mounds — and treat them like beak length or coat color. Writing before the development of enormously powerful technology for analyzing DNA, he regretted that his proposals were hypothetical.
They are hypothetical no longer.
From volleyball to research
Hoekstra spends a lot of time explaining that her first name has nothing to do with the Native American Hopi tribe. It comes from a Dutch term of endearment, meaning a little bundle, that her grandmother called her when she was a baby.
“And it stuck," she said.
Both her parents grew up in the Netherlands before coming to the United States, but Hoekstra is a true child of California. She went to high school near Palo Alto and college at the University of California, Berkeley.
“I had some scholarships to other places, but I went to Berkeley because I wanted to play Pac-10 volleyball," she said. “I got lucky because they also had a great biology department."
She did play for Berkeley for a couple of years and started out studying political science.
“I wanted to be the ambassador to Holland," she said. But things happen in college and she got distracted — by biology.
It was a class on biomechanics taught by professor Robert Full that hooked her, and she ended up doing work in his lab. “I was working on cockroach locomotion, running little cockroaches on treadmills," she said. “He taught me to love research, but I didn’t have a passion for cockroaches or biomechanics."
She did, however, have a passion for field work, and for mice, although she did take a detour to work on bears after graduation. “I think I’m one of the few people," she said, “who have taken the rectal temperature of a grizzly bear."
Her scientific path led her to the University of Washington, where she received a doctorate in zoology, and to stints at the University of Arizona as a postdoctoral researcher and the University of California, San Diego, as an assistant professor before arriving at Harvard in 2007. She received tenure in 2010, at age 37.
Although she still considers California home, she says, one part of Cambridge that appeals to her is the high concentration of other academics and researchers. And she not only has a thriving lab there, she and her husband, James Mallet, also an evolutionary biologist at Harvard, have a 10-month-old son.
In the lab or at a meeting, Hoekstra’s enthusiasm is contagious. Weber, who worked with her for eight years, starting in San Diego, said, “She gives one of the best seminars of anyone I’ve ever seen," and added that everyone wants to talk to her afterward.
A team player
In a basement room at Harvard, where the mice she studies are kept, Hoekstra encourages graduate students and postdoctoral researchers, and praises her experimental subjects as well, deer mice of two species: oldfield mice (Peromyscus polionotus), which dig a long entrance tunnel to a nest as well as an escape tunnel, and P. maniculatus, which dig a short simple tunnel to a nest.
She began by studying the genetics of coat color and its significance as an evolutionary adaptation, but moved quickly to the genetics of burrowing behavior. Crossbreeding these two species and comparing their genetics led to the recently published report. But a number of projects continue in her lab.
In one, mice are dropped into enclosures that look like giant ant farms and serve the same purpose. Drop a mouse in and it will tunnel as you observe it through the glass, digging away in what one of her researchers called its “2-inch-wide world." The behavior is videotaped and sorted by software to track how much time the mice dig and when they dig. The hope is that these details will help get at what motivates them to stop and start.
Other researchers are working on neurobiology, trying to learn whether reward systems in the brain (involving dopamine, for example) may play a role in both the urge to dig, and the signals that allow a mouse to stop. If such reward systems are involved, then the behavior may have some connection to human behaviors, including addiction.
One of the unusual aspects of Hoekstra’s management style is that she emphasizes teamwork and the personal interactions among people on her team. The current members of the lab have a veto over any new member, if they think the new person won’t fit in.
“That’s one of Hopi’s gifts and one of the reasons that the lab is so great to work in," Weber said. “She is really a master at being able to put together a team."
The search for specific genes that control behavior is a new challenge, but she is confident that her group will be able to handle it.
Other scientists who have watched her career are hopeful, but aware of the pitfalls. Gene E. Robinson at the University of Illinois at Urbana-Champaign, who has used honeybees to study social behavior, praised her “exciting, pathbreaking work" and said, “It will be hard to get to the genes, but not impossible. She has established a powerful experimental system."
Bargmann at Rockefeller said “genetics and genomics tools developed over the past five years" are making it easier to get from a region of DNA down to one of the hundreds or more genes in that region.
But she added, “The hardest thing about studying natural traits is that endgame."