Study of Rare Disease helps unravel key question of human biology

by Rob Levy, Dana Farber Cancer Institute, Boston, Massachusetts

One of the oldest puzzles in biology is being solved by research into one of the world’s rarest diseases.

The disorder is known as von Hippel-Lindau (VHL) disease and occurs when blood vessels grow uncontrollably and form tight knots that can damage surrounding tissue. Caused by an error in a single gene, the disease is known to affect one in 35,000 people worldwide, or just over 6,000, total, in the United States.

Investigators led by William Kaelin, M.D., of Adult Oncology at the Dana Farber Cancer Institute (DFCI) are using their understanding of VHL disease to answer a question that has intrigued biologists for generations: 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 in the blood?

The question is 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 enough oxygen. It may also shed new light on cells’ ability to attract additional blood vessels – an important avenue of cancer research.

"Our work is an example of how research into rare hereditary disorders can provide important insights into the normal functioning of genes and cells," Kaelin says. "It offers a window into a broad array of cell processes."

Following a Lead

Kaelin first learned about VHL disease as a medical student. He began studying it in hopes that the unusual features of the disease might provide insights into how cells control the growth of blood vessels and utilize oxygen.

Though it is far from complete, the emerging picture of cells’ "dialogue" with oxygen is already complex, involving the creation and destruction of proteins, the switching on and off of genes, and use of protein parts as signaling devices. The purpose of this activity is to keep cells attuned to the amount of oxygen in their vicinity, so they can burn it when it is plentiful and use other energy sources when it is not.

Biologists have long known that when oxygen levels drop, cells respond by switching on a gene called HIF. HIF activates other genes that help cells compensate for the loss of oxygen. 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 a greater flow of oxygen to cells.

Several years ago, Kaelin’s lab and others found that when the protein for VHL disease is normal – as in more than 99 percent of the population – it is part of the cell’s machinery for turning HIF on and off. "We showed that when the VHL protein [called pVHL] is defective, HIF is poorly controlled, preventing the cell from adapting to changes in oxygen levels," Kaelin remarks.

Last year, several labs including Kaelin’s demonstrated how one aspect of that machinery works. It turns out that pVHL helps destroy the HIF protein when oxygen levels rise. The result is that cells burn less sugar, cut back on their building of blood vessels, and begin burning more oxygen.

Still, there were gaps in scientists’ understanding of how the system operates. A key one: what is the precise link between oxygen and pVHL? How does pVHL "know" whether oxygen levels are increasing, decreasing, or holding steady?

In a study in the April 20, 2001, issue of Science, Kaelin and his colleagues provide an answer.

The focus of the study is a small residue on the surface of the HIF protein. The residue is composed of an amino acid called proline. When oxygen is present, the proline residue becomes covered with hydrogen-oxygen pairs known as hydroxyl groups, the researchers report. The hydroxyl groups are the "Oxygen is Here!" sign that pVHL looks for.

"The hydroxyl groups play a key role in cells’ ability to sense oxygen in their environment," Kaelin explains. "If they signal that oxygen is present, pVHL begins destroying the HIF protein, and the cell shifts from burning sugar to burning oxygen."

Broader Applications

Intricate as this system is – and research is under way to draw out even more details – understanding it will help scientists develop new treatments for a variety of conditions.

For example, many people suffer from conditions in which their muscles or other tissue don’t receive enough blood as a result of clogged blood vessels. It may be possible, Kaelin’s research suggests, to stimulate the growth of new blood vessels to these areas by preventing pVHL from destroying the HIF protein.

"Our work is also shedding light on the system that governs angiogenesis," Kaelin observes. A promising area of cancer research involves attempts to short-circuit angiogenesis so that tumors are starved of blood.

"This research illustrates just how much world has changed since the VHL syndrome was first identified more than 100 years ago," Kaelin says. "A convergence of technologies including gene cloning, techniques to analyze gene function, and the Internet, has made it possible to understand the basic mechanics of the disease and brought closer the day when we can develop new treatments for it."

For VHL patients and their families, 
support is vital medicine

When Joyce Graff began reading up on von Hippel-Lindau (VHL) disease – which claimed her husband’s life in 1977 and afflicts her son – she felt like a one-member support group. Through 30 years of coping with her husband and son’s condition, she had never met anyone with the disease or a family member of a VHL patient. Few doctors were familiar with the disorder and fewer still had expertise in treating it.

"I remember sitting one day in the Harvard Medical School library reading a research article on VHL, and I sat back and thought, ‘I’m doing what a doctor would have to do to learn about VHL, and no doctor is going to be able to spend as much time reading up on it as I have,’" recalls Graff, of Brookline.

One of the particular cruelties of rare diseases is the isolation experienced by many patients and their families. "I felt like no one else could understand what I was going through," Graff says. "I wound up repressing a great deal of pain."

Today, though her son, now 30, continues to battle the disease, Graff doesn’t feel alone. In 1993, she and the mothers of two other VHL patients – one in Maryland, one in Michigan – founded the VHL Family Alliance. Now encompassing 10,000 members in 67 countries, the association serves as a crucial link for VHL families.

To let people know about the organization’s existence, Graff and her co-founders wrote to every physician who had published an article on VHL disease in the previous 20 years and asked them to let their patients know about the organization. They started a newsletter and asked doctors to distribute it to patients. "Little by little, we formed a very strong group."

The biggest boost to membership, as might be expected, was the advent of the Internet. The alliance’s Web site – one of the first established by a disease-related organization – went live in 1994.

Today, the organization maintains a toll-free number for information and support (1-800-767-4VHL). "The average first call from a family lasts between 45 minutes and an hour," she says. "People are often reluctant to make that first call – they may never have reached out this way before – but once they call and discover they’re talking with someone who has VHL, it’s magic."

Because they are so widely dispersed, alliance members tend to stay in touch by e-mail, Internet chats, and phone calls. The organization sponsors an annual meeting in the United States and, every two years, holds a symposium for physicians and researchers studying the disease. "The symposium gives doctors a chance to share their findings and network with each other," Graff remarks. The alliance also raises money to support scientists in the field of VHL research, including Dana-Farber’s William Kaelin, M.D. (See above)

Because VHL can affect different organs, treatment can involve physicians from a variety of specialties. "We convey to patients and families that treatments are available, but it’s a complex disorder, and finding the right doctors is hard work," Graff says. "When people call asking, ‘Where is there a specialist for VHL?’ we tell them, ‘You’re going to get to train one.’"

Graff emphasizes that with the proper treatment, VHL disease can usually be managed. The alliance has identified a set of clinical-care centers around the country that have experience treating the disorder. "The key is to stay on top of it and pay attention to symptoms," she says. "We tell people that, even though no cure exists, there’s a lot they can do avoid the worst consequences of the disease. Through the efforts of people like Dr. Kaelin, more treatments are becoming available to manage this condition and keep it at bay."

Graff currently serves as the Alliance’s Chairman of the Board and Editor of the organization’s newsletter. "The group is a vital link for people affected by this disease," she remarks. "To have a support group of people who understand what you’re going through has been – for me and many others – an incredibly healing experience."

mystory

As printed in the VHL Family Forum  9:2, June 2001.  For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.