Of Mice and Medicine Men
Dr. Se-Jin Lee, MD., PhD. has increased muscling on mice in research laboratory trials showing promising potential The work of an unassuming and somewhat humble Johns Hopkins researcher holds the potential to revolutionize the treatment of diseases sappin
The work of an unassuming and somewhat humble Johns Hopkins researcher holds the potential to revolutionize the treatment of diseases sapping away muscle strength, as well as to mitigate some of the muscle-draining effects of aging.
Dr. Se-Jin Lee, M.D., Ph.D., who is the Michael and Ann Hankin and Partners of Brown Advisory Professor in Scientific Innovation and Professor of Molecular Biology and Genetics at Johns Hopkins University School of Medicine in Baltimore. Lee was interviewed regarding the current status of his research into the effects of a protein he discovered in 1995 and named myostatin. Naturally occurring in mammals, this protein plays a crucial role in regulating muscle growth by preventing muscles from growing too large for the skeletal frame upon which they function.
Lee’s research demonstrated that the myostatin protein signals other dormant or non-active muscle-building cells to activate when muscle building or repair becomes necessary. This discovery led to a number of questions, the most important of which revolved around what effects the removal of myostatin would have on muscular development. The pharmaceutical industry responded with interest in how people suffering from muscle depletion could be helped, and the sports industry was also interested, hoping that mastery
of myostatin could lead to enhanced performance, possibly proving to be an alternative to controversial steroids.
Interestingly enough, Lee – an avid sports fan himself, to say the least – is much more interested in the potential that medical regulation of the myostatin protein presents for an aging America losing its muscle strength and for patients whose illnesses leave them fighting muscle deterioration, than he is in myostatin’s application to sports figures, including any accompanying financial windfalls that might result.
In 2008, he told David Epstein from Sports Illustrated that he would do an interview on the condition that Epstein make it eminently clear to readers that Lee’s work was not now – and would not be – directed toward enhancing athletic performance. Epstein complied, and the sports world learned first-hand from Lee about the medical applications of his research at a time when national attention focused on anabolic steroid abuse as the Roger Clemens scandal unfolded in professional baseball.
Fast-forward to 2014, and Lee’s insistence that his muscle-regulating protein discovery be limited to medical uses appears to be holding firm. The list of current research trials he provided to The Suit Magazine addresses medical issues such as muscle wasting after hip fracture surgery, muscle atrophy post hip replacement, muscle weakness after a fall and myostatin’s role in treating various types of cancer. Each of these trials represents common geriatric health issues that Lee has regularly insisted his research needs to address.
After attending Johns Hopkins, Lee graduated from the
Medical Scientist Training Program, a federally-funded MD/PhD program, spending time as a staff associate at the Carnegie Institution of Washington’s Department of Embryology in Baltimore. Then Lee received an offer from the Johns Hopkins Molecular Biology and Genetics Department – one of the best departments in biological sciences anywhere in the world. “The department has had three sitting members receive the Nobel Prize in Medicine or Physiology, including our current chair, Carol Greider, who received the prize for her work on telomerase,” Lee said.
Believing that he was in an excellent position to make a difference scientifically, little did he know that the discovery by his team would trigger such a firestorm of interest in slow-paced, repetitive scientific research.
Lee spent a number of years focusing on genetically engineered mice, either to delete individual genes or to produce too much of an individual protein. It was in 1995, while working with laboratory mice in an attempt to understand the role signaling mole- cules played in regulating embryonic development and adult tissue homeostasis, that Lee and his team discovered the myostatin protein.
Lee and his research staff genetically altered some of the mice by limiting the amount of myostatin in their systems. “We found that deleting the myostatin gene in mice led to mice with about twice the normal muscle mass throughout the body, demonstrating that myostatin normally acts to limit muscle mass,” Lee said. This lack of myostatin produced mice with significantly larger muscle mass, quickly earning them the name “knockout mice” within the scientific community.
The publication of his initial research results in a standard research paper outlining their findings opened a floodgate of questions from within the medical pharmaceutical industry regarding practical applications. In relatively short order, the somewhat unwanted media spotlight zeroed in on Lee.
His efforts currently focus on two general areas. The first is in continuing to understand how myostatin works at the molecular and cellular level. There are still many unanswered key questions regarding the protein, and Lee believes that a greater understanding of the mechanisms by which it acts will have important implications for the development of therapeutics targeting this pathway. The second area his research impacts is a potential understanding regarding the role of myostatin in diseases having mus- cle-wasting symptoms, along with the consequences of manipulating this pathway in various disease states.
Although Lee’s current work focuses almost entirely on mice, his research has shown that naturally occurring mutations in the myostatin gene also lead to increased muscle mass in other species, including cattle, dogs and sheep. In addition, there are some interesting studies showing that variants of myostatin can increase racing performance in horses, according to Lee.
Currently, Lee and his research team continue to focus on a group of proteins referred to as the transforming growth factor-ß superfamily. “This group of proteins function as signaling
molecules that act to regulate the state of growth and/or differentiation of target cells and tissues,” Lee explains. “Because these normally act from outside the cell, manipulating the activities of these molecules, it is more straightforward than those that act intra-cellularly.”
The body-building industry is wildly interested in the effects it perceives the regulation of myostatin could have on muscle enhancement. The 2008 Sports Illustrated article highlighted current speculation that myostatin regulation could lead to gene therapy aimed at altering DNA. In theory, this type of muscle enhancement might be able to circumvent drug testing. The body-building community, by envisioning yet another way to manipulate muscle mass, has been controversial, to say the least. Lee remains adamant, however, that the goal of his work is not to improve the odds of athletes, but to help aging America trade in their canes and wheelchairs for more active golden years. For now, he has been able to limit myostatin research to valid medical purposes only. Yet, he knows that once a myostatin regulator hits the market, it’s highly likely that some people will get their hands on the drug and use it for enhancing athletic performance in humans and animals, bodybuilding, bulking up food sources and other, as yet unidentified non-medical uses.
Despite lamenting these possibilities, Lee believes that the medical ramifications warrant continued research.
“People who suffer from a disease can develop a severe wasting pro- cess, which is called cachexia,” Lee explains, “Cachexia is also known as a wasting syndrome – meaning loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite in someone who is not actively trying to lose weight. The formal definition of cachexia is the loss of body mass that cannot be reversed nutritionally. Even if the affected patient eats more calories, lean body mass will be lost, indicating a primary pathology is in place.”
Ten different clinical trials are in the second phase of research aimed at developing myostatin inhibitors to treat patients with muscle loss. “For now, we are focused on myostatin – but this type of research always ends up moving in directions that may be unexpected, so it is difficult to predict where we will be in the future,” said Lee. “My work on myostatin has certainly been interesting. It is too early to say how important this will be one day, but I am anxiously awaiting the results of the clinical trials to see whether this is going to work.”
This last statement came with the kind of knowing chuckle that only a research scientist could fully appreciate. Lee cautions that any medical usage of myostation regulation is not years, but most likely decades in the future. Yet, the possibility that his work has more than laid the foundation for advancements in muscular support to aid coming generations as they age, seems to be an unusually bankable one. In our opinion, savvy biomedical investors might wisely evaluate pharmaceutical companies currently running clinical trials based on the potential changes that mastery of this protein represents for the medical community.