William Kaelin, MD, first learned about VHL disease in medical school and has followed its trail for two decades.
Seeking a cellular switch
Medical students know von Hippel-Lindau (VHL) disease as a textbook disorder — one they read about but are unlikely to encounter during their training. Hospital interns and residents are apt to be quizzed about it during rounds, on the (remote) chance that a patient is afflicted with it.
It's an elusive condition because it's a diverse one. It is characterized by the formation of small knots of blood vessels, called angiomas, that can rupture and bleed or press dangerously into vital organs. But because angiomas can grow nearly anywhere in the body — with the eyes and nervous system the most common sites — the condition appears in many different guises. The angiomas are often accompanied by cysts or blood-rich tumors in the kidneys, pancreas, liver, or adrenal glands. As a result, VHL disease can be an especially tricky condition to diagnose.
"There's a saying that when you hear hoofbeats, you should think of horses, not zebras," says Dana-Farber's William Kaelin, MD. "But it's important to be aware that it could be zebras."
Kaelin first learned about VHL disease in medical school, where it was presented as something of a clinical curiosity. Only one in 32,000 people worldwide develops the disease — a total of about 8,000 in the United States — and it's known to be caused by a mutation in a single gene. Symptoms of the condition can appear at any age, but the most common time is early adulthood.
"Our research into von Hippel-Lindau disease will not only help diagnose and treat this rare condition, but gain a better picture of how cells normally work."
— William Kaelin, MD
The abnormal gene responsible for VHL disease was identified, and cloned for research, in 1993 by scientists at the National Cancer Institute and in Cambridge, England. When Kaelin learned of the discovery, he sensed a field wide open for investigation.
He had been probing retinoblastoma, a childhood eye tumor that was the first type of cancer to be linked to a specific genetic mutation. "Like the retinoblastoma gene, the gene for VHL was a blank slate," Kaelin says. "We had to develop models for studying it, to understand its role and why a mutation in it leads to the formation of angiomas."
Even more, Kaelin thought, studying VHL disease could pierce one of the oldest mysteries in biology: how do animal cells sense the presence of oxygen — a major source of their energy — and how do they respond to rises and falls in oxygen levels? The fact that a defective VHL gene causes blood vessels to grow like kudzu — thereby increasing oxygen flow — suggested the gene normally helps cells control their oxygen diet. But how?
Biologists have long known that when oxygen levels drop, cells respond by switching on genes that help compensate for the decline. Some of these genes enable cells to burn glucose (a sugar) in place of oxygen. Others trigger the growth of new blood vessels — a process called angiogenesis — that bring more oxygen to cells.
In 1996, Kaelin and his colleagues found that when normal VHL protein (called pVHL) is absent, cells behave as if they're being starved of oxygen, even if they aren't. "We showed that if pVHL is missing, cells lose some of their ability to adapt to changes in oxygen levels," Kaelin says. "This proved a connection between pVHL and oxygen use, but we didn't know how many steps it involved."
Studying VHL disease could pierce one of the oldest mysteries in biology: how do animal cells sense the presence of oxygen — a major source of their energy?
Subsequent research by Kaelin and others has found it to be a highly complicated connection, a micro-drama of protein production and destruction, of gene activation and deactivation, of signals and sensors. Most recently, Kaelin has discovered a modified protein "flag" that alerts pVHL to the presence of oxygen.
The findings are of more than theoretical interest. Understanding how cells detect oxygen in their neighborhood, and how they switch to alternate fuels when oxygen supplies are low, may one day lead to new therapies for conditions in which tissue is deprived of oxygen. It may also shed new light on cells' ability to attract additional blood vessels — an important avenue of cancer research.
Already, the findings are generating novel ideas for treating VHL patients. By understanding in detail the processes that go awry in VHL disease, researchers are zeroing in on new targets for therapies.
"Our research will not only help us diagnose and treat this rare condition, but gain a better picture of how cells normally work," Kaelin comments. "That will be applicable to understanding a wide variety of disorders."
