No dead ends on these detours
In the intriguing world of science, even the most straightforward research path sometimes leads to unexpected places. A researcher sets out to solve one scientific puzzle and, like a traveler passing through towns that weren’t on the map, ends up finding answers to other questions that hadn’t even been posed when the work began.
That’s the way Phil King’s scientific journey has unfolded. His initial quest to understand how immune system components called T cells develop and function has yielded insights about immunity that may be helpful in treating allergies, cancer and autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis. But the work also has led to findings, unrelated to T cells, that may someday alleviate lymphedema—the troublesome and uncomfortable swelling of extremities that results when lymph nodes and vessels are removed or damaged, as in cancer surgery or radiation treatments.
All of this is possible because King uses powerful techniques that reveal the functions of specific genes in various types of cells, both within and outside the immune system.
In the T cell work, he’s exploring the biochemical signals that occur inside T cells when they’ve been recruited to defend the body against foreign invaders. His lab uses a variety of methods to home in on the specific molecules involved. Once the researchers have a likely candidate, they explore its role directly using “knockout” mice, in which the gene responsible for producing the molecule of interest has been deleted (knocked out). After knocking out a particular gene, King and coworkers determine whether T cells still develop and function normally. If not, that’s a hint that the deleted gene and the molecule it encodes are somehow essential to T cell activation.
In addition to knocking out genes in the whole mouse, King’s group is able to focus more finely, excising a particular gene from only one cell lineage—T cells for instance, or any other cell type they choose. This allows the researchers not only to see how a specific molecule affects T cell activation, but also to systematically explore other roles that molecule may play.
“Often, we stumble upon functions that are not directly related to immunity, but are no less significant,” says King.
One recent finding involves a molecule that King’s group learned is essential for T cells to develop and function properly. The researchers then went on to discover that the same molecule plays a key role in maintaining the integrity of the lymphatic system—a network of vessels and nodules (lymph nodes) that transport white blood cells and lipids throughout the body and help maintain fluid balance. Without this molecule, the lymphatic system “goes crazy” and grows out of control, King’s experiments have shown.
“Now that we have identified the molecule that plays such a critical role in regulating lymphatic growth, we could potentially manipulate it to promote lymphatic vessel growth and improve drainage of accumulated fluid in lymphedema patients,” King says. Such an advance could alleviate suffering not only in developed countries, where breast cancer surgery is the leading cause of lymphedema, but also in other parts of the world, where the condition results from parasitic infections such as filariasis and elephantiasis.
And because the lymphatic system also is the thoroughfare that cancer cells travel to spread through the body, getting a handle on the system’s regulation could lead to new ways of controlling that deadly disease.
