“I was always interested in science, and specifically in science as it applies to medicine,” says Se-Jin Lee, a professor in the Department of Molecular Biology and Genetics at Johns Hopkins University School of Medicine in Baltimore.
In 1981, after having graduated with high honors from Harvard with a degree in biochemistry, he went to Johns Hopkins University School of Medicine, earning an M.D. as well as a Ph.D. in molecular biology and genetics in 1989. “Medical school for me was learning about human disease — what we know, what we don’t know and what the big problems are that need to be solved,” he says.
His next step was an appointment as a staff associate at a private research institute then called the Carnegie Institution of Washington. Now known as the Carnegie Institution for Science, this nonprofit enterprise was created by philanthropist Andrew Carnegie in 1902 as a place where exceptional scientists could be given free rein to pursue their interests.
“They brought people in, gave them some lab space and some money, and basically let them do whatever they felt like for three to five years,” says Lee, who started at Carnegie at age 31 and describes the experience as “exhilarating.”
Lee soon became interested in the role of secreted proteins in regulating how cells interact with one another, particularly a group of proteins called the TGF-beta family that are known to be potent regulators of cell growth and cell differentiation (maturation).
TGF stands for “transforming growth factor,” a protein family that was beginning to receive a lot of attention in the 1980s. In 1989, Lee says, “there were about a dozen members of the TGF-beta family that were known. They had really remarkable biological properties. One subtype could cause bone to form wherever they were implanted. I was interested in doing things that might have some clinical relevance, and the TGF-beta proteins looked really intriguing. I figured there had to be a lot more of them that hadn’t yet been identified, so I started to look for new ones.”
Lee began the work at Carnegie and then continued it after moving back to Hopkins as a faculty member in 1991.
“We didn’t really know anything about these new proteins,” he says. “We tried to figure out what they were doing, and one of the approaches we took was to knock out the genes for them in mice and see what happened.”
Lee numbered each new suspected TGF-beta family member. One of them, number 8, looked like it might have a role in muscle tissue. “When we knocked out the gene for number 8, the mice developed muscles that were huge,” Lee recalls. “Once we realized that growth and differentiation factor (GDF) 8 functioned to limit muscle mass, we decided to rename it ‘myostatin.’” (Myo is a prefix meaning “muscle,” and statin means “at rest.”)
In 1997, Lee and his colleagues published a paper describing the myostatin discovery and mouse findings in the prestigious journal Nature. Later that same year, he co-authored another paper, showing that cattle bred to have especially large muscles had natural myostatin mutations.
Lee started focusing more and more effort on myostatin — how it worked and how its activity might be changed to treat muscular dystrophy.
For instance, most secreted proteins land on docking sites called receptors, and Lee wanted to identify the receptor for myostatin. In 2001, he and his colleague Alexandra McPherron at Hopkins published a landmark paper describing how myostatin is maintained in an inactive, latent state, how it interacts with an inhibiting protein called follistatin, and how it binds to a receptor on the muscle-fiber surface called activin receptor type IIB, through which it signals the fiber.
In 2002, with Kathryn Wagner (see Creating a Hospitable Environment for Muscle Regeneration) and others, Lee showed how mdx mice (a model of human Duchenne muscular dystrophy) were stronger and more muscular than expected when they were genetically engineered to lack myostatin.
It was about this time that Lee received a phone call from Markus Schuelke, a neurologist in Berlin who had been called to the delivery room in 1999 to see a newborn baby boy who had unusually large muscles.
“He immediately was struck by the amount of muscle,” Lee says. Schuelke remembered having read about myostatin and wondered if he was looking at a child with a myostatin mutation.
“Schuelke was so convinced this was possible that he looked for the mutation,” Lee says. “The child’s appearance must have been pretty dramatic for him to have gone to all this trouble.”
His trouble was well-rewarded. The German baby had two mutated myostatin genes, one from each of his parents, and he was producing almost no myostatin.
When Schuelke asked Lee for help in analyzing the effects of the mutated genes, Lee got involved, and along with many other researchers, Schuelke foremost, published a paper in 2004 that announced to the world that myostatin’s role in human muscle was similar to its role in mice and cattle. It also suggested that drastically reducing its level in a child could increase muscle mass without any apparent harm. (According to Schuelke, as of early 2011, the child continues to do well.)
Lee is now a member of MDA’s Medical Advisory Committee and has received two MDA research grants since 2004, both focused on understanding how myostatin normally behaves and identifying ways of changing its activity as a potential treatment for muscle diseases. All the myostatin-associated pathways that Lee’s group has identified have the potential to become targets for therapeutic development.
“The mouse studies look good,” says Lee, who is also encouraged by the health of the myostatin-deficient cattle and the myostatin-deficient child. But, he cautions that humans are not mice or cows and also that there are differences between genetic mutations that exist from birth and later manipulations of proteins or genes.
“I really hope it works,” he says of the myostatin-inhibiting strategy now being tested by Acceleron Pharma (see Diverting an Unwanted Protein). “But I think there are lots of issues that still have to be resolved. The good news is that the field is moving forward quickly, so we should have at least some answers soon.”