As he sat in a remote field station in Madagascar, surrounded by dense rainforests, Mark Krasnow realized that his journey halfway around the world was worth it. The handful of biologists gathered around him agreed that the mouse lemur could be the animal he was looking for.
The HHMI investigator from Stanford University School of Medicine was on a quest for a better animal model for human disease. The fruit flies and mice he’d been studying couldn’t help him answer many basic research questions on lung diseases, and he knew that scientists studying other disorders had similar experiences. He wanted to find a better disease model.
After a year of research into species worldwide, Krasnow had brought an unlikely team of high school students, molecular biologists, mouse lemur experts, and a veterinarian to the East African country to search for an animal that might be a closer match to people than mice, the perennial lab favorite. Madagascar’s early separation from the continental land masses, some 80–90 million years ago, created an evolutionarily eccentric collection of plants and animals, including lemurs. “It’s like a biologist’s dreamland,” says team member Sarah Zohdy, a doctoral student at the University of Helsinki and one of a small number of scientists studying mouse lemurs.
The group spent several nights in the summer of 2010 scanning the tall trees for all types of lemurs, but they were most interested in the grey mouse lemur, Microcebus murinus (see Web extra sidebar, “Meet Microcebus murinus”). The big-eyed, bug-eating lemur from Madagascar’s west coast is one of the world’s smallest primates. And, more importantly for Krasnow’s group, mouse lemurs’ DNA has diverged from humans only half as much as the DNA of mice.
At the field station, in Ranomafana National Park, Krasnow talked with Malagasy biologists about the potential of mouse lemurs as a model for human disease. “They had grown up with lemurs but had never thought about model organisms,” Krasnow says. They loved the idea that mouse lemurs could help cure diseases, he says, but they were concerned that the lemurs—and the country—not be exploited in the process.
Moving Beyond the Mouse
During the past half century, biomedical research has focused on a handful of model organisms, as research communities have developed tools that make in-depth studies possible. The most widely used models include the mouse, the roundworm, the fruit fly, and, more recently, the zebrafish. For disease research, mice have been the focus; introducing genetic changes, scientists have made great leaps in understanding disease and basic biology (see Web extra sidebar, “Model Redefined”).
A model organism doesn’t just mean a mouse or fruit fly anymore.
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But mice can’t do it all. A 2008 analysis by University of Michigan scientists showed that in 40 percent of genetic defects known to cause human disease, researchers either do not see symptoms in mice or cannot identify an equivalent gene. “The mouse has revolutionized medical research, but it is necessarily limited by its biology,” Krasnow says.
Physician-scientist Michael Welsh had been studying cystic fibrosis (CF) for many years when it became clear that the field needed a new way to understand the disease. In humans, the single gene mutation that causes CF induces problems throughout the body, especially the lungs and gastrointestinal system. In mice, the mutations fail to produce typical CF disease.
“To understand the pathogenesis of a human disease, a model can be critical. If the model does not reproduce features seen in human disease, making progress can be a challenge. And if you want to develop new therapies, and the model does not manifest those key defects, you have nothing to correct,” explains Welsh, an HHMI investigator at the University of Iowa. “It was frustration and the lack of an ability to make sufficient progress that led us to develop another model of cystic fibrosis.”
Welsh’s team settled on the pig, and their new CF model develops disease like that of humans. “It is a very exciting time,” Welsh says. “We are able to answer questions and approach persistent problems that have been plaguing the field.”
Failure to replicate human disease isn’t the only problem with mouse models of disease. “There have been some very expensive long-term clinical trials based on mouse models that just didn’t turn out the way they did in mice,” says immunologist Mark Davis, an HHMI investigator at Stanford University. “The real test of a model is whether there is any predictive ability, and I think there is often a disconnect between mouse data and human disease.”
Davis says scientists should make a more systematic attempt to understand disease in people, which is the direction he has taken his own research. For many diseases, he says, “We don’t know enough about the human disease to know whether it is a good model or not.” But he is enthusiastic about Krasnow’s attempt to identify a better model. “We should rationally choose other models that are closer to humans and therefore more likely to translate.”
From Idea to Madagascar
Krasnow’s path to Madagascar began in 2009 when several Palo Alto High School sophomores—Camille Ezran, Jason Willick, Krasnow’s daughter Maya, and, later, Alex Scholz—pestered him to work in his lab. After fending them off several times, he realized he could apply their growing knowledge of biology to the mouse model problem.
“We spent the entire summer trying to understand what would make a good model, since we had never been exposed to genetic model organisms before,” Ezran says. It had to be small and easy to work with. Its brain, lungs, and other organs had to resemble those in humans. It had to reproduce fairly quickly. And it had to be more closely related to humans than mice were. Spending weeks in the library and on the Internet, the students constructed a spreadsheet of the world’s smallest mammals, which they then narrowed to a dozen to examine in more detail.
The mouse lemur rose to the top. The idea gained traction when Krasnow starting discussing it with other scientists and colleagues. “They agreed with the need for a new genetic model organism and embraced the idea of the mouse lemur,” he says.
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Next, Krasnow turned to Stanford veterinarian and geneticist Megan Albertelli. At first, she thought the idea was farfetched, but then she heard Krasnow describe the biological argument for the mouse lemur as a model organism. After the group learned that several European research centers had decades-old colonies of mouse lemurs, Krasnow decided his team needed to visit one to talk to the scientists.
The grey mouse lemur has many of the same characteristics that make the mouse a good model.
The group went to Europe, where they saw their first live mouse lemurs at a 40-year-old colony housed on the grounds of a small castle. “That convinced me that this was something we could do,” Albertelli recalls. What excited Krasnow was that the scientists had been keeping detailed records and tissue samples for the colony’s history, including the animals’ tendency to get an Alzheimer’s-like disease.
Their next stop was Madagascar, and more research paths emerged as they talked to field biologists there. Those experts could help study genetic links to behavior, the team realized. “Social groupings, behavior, and behavioral diseases, have been very hard to study in mice,” Krasnow explains. “Those studies are already being done in mouse lemurs.”
The visit made clear to Krasnow that, to help local scientists and conservation efforts, as much research as possible should be done in Madagascar. “We would like more researchers coming to Madagascar,” says Benjamin Andriamihaja of the island’s Institute for the Conservation of Tropical Environments, “but at the same time we would like to protect our forest to maintain its value.”
This newfound interest in mouse lemur research offers a great opportunity for training, says lemur biologist Alison Richard, an HHMI Trustee and professor at Yale University who has worked on the island for decades. “Much of the work establishing mouse lemurs as a model organism could involve Malagasy students,” she says.
Creating a Collaborative Landscape
On their return, Krasnow and his team started planning how to move ahead. In June 2011, Krasnow and Albertelli hosted the first ever mouse lemur meeting, at HHMI’s Janelia Farm Research Campus, bringing together field biologists from Madagascar, Europe, and the United States with geneticists, conservation biologists, and model organism experts. “I had not had the opportunity to be in the same workshop with so many other types of researchers,” says Anne Yoder, who runs the Duke Lemur Center at Duke University, a sanctuary that studies lemur behavior and conservation. “It was neat to see what the collaborative landscape might look like.”
The biggest area for immediate impact is genetics and genomics. The June meeting spurred a renewed effort to complete the mouse lemur genome, says Jeff Rogers of the Baylor College of Medicine’s Human Genome Sequencing Center. That could help researchers analyze the thousands of existing tissue samples for genetic connections to disease, including the Alzheimer’s-like syndrome found in these animals, and help to identify what DNA sequences are highly conserved between mouse lemurs and humans.
“It is so beneficial for us to have a community of investigators focused on doing research on mouse lemurs,” Rogers says. “The opportunity to combine years of background information concerning both wild and captive mouse lemurs with new genetic and genomic data is very exciting.”
At Stanford, Krasnow and his group are pushing forward with mouse lemur research, starting with seeking out additional samples and setting up collaborations with Malagasy scientists and other lemur biologists around the world. They think that learning about the genetics and physiology of mouse lemurs could help preserve the endangered animals.
“For decades Madagascar has been seen as a hotspot for biodiversity, and rightly so,” Richard says. “But it is welcome to see that recognition translating into a broader scientific interest in mouse lemurs—primates found nowhere else in the world.”