Dr. Michael Dean, Principal Investigator,
Laboratory of Genomic Diversity

Spotlight Archive

Part of the mission of the National Cancer Institute at Frederick has long been translational research: moving research out of the laboratory and into practical applications. That certainly has held true for Dr. Michael Dean, Principal Investigator, Laboratory of Genomic Diversity, NCI-Frederick.

Cystic Fibrosis Gene Identified

As a postdoctoral fellow in Dr. George Vande Woude’s laboratory, NCI-Frederick, in the 1980s, Dr. Dean developed genetic markers in the MET oncogene and collaborated with researchers in Dr. Ray White’s laboratory at the University of Utah to map the MET oncogene to chromosome 7. When other published work showed that the cystic fibrosis (CF) gene was on chromosome 7, they found that Dr. Dean’s marker “was essentially right on top of the gene,” Dr. Dean said in a recent interview.

Since this exciting discovery, Dr. Dean and his colleagues have focused on learning how the CF gene functions. Moving research out of the laboratory has meant helping people with CF and “has led to some new therapies, but not a cure. When cystic fibrosis was first described, those children died at age 2 or 3; now they live to about 30,” Dr. Dean said. Today, “If a family has one child with CF, the family can be tested prenatally to determine if subsequent children will be affected. It’s even possible now to test in vitro fertilized embryos. The American College of Medical Genetics recommends that all couples planning to have children get tested,” Dr. Dean added.

The name, cystic fibrosis gene, can confuse the layman because the gene carries the name of its disease, which occurs due to a defect or loss of function of the gene. However, Dr. Dean pointed out, the “gene actually has a normal function.”

CF develops when each parent has one defective and one normal copy of the gene. The resulting child has two defective copies and thus lacks control over bodily secretions “Everything from sweat to mucus in the lungs and intestine, and secretions of the pancreas that digest food—all secretions that the body makes are controlled by this gene,” Dr. Dean explained.

Thanks to research, the digestive enzymes can be replaced orally, essentially as drugs. “Through nutritional therapy (high-calorie diets and high amounts of fat-soluble vitamins to counteract problems with digestion and absorption) and the digestive enzymes, you can treat the digestive problems,” Dr. Dean commented.

However, he added, the critical problem—“insufficient mucus in the lungs which makes it difficult to clear bacteria”—hasn’t been resolved. “CF patients die of lung infections” and resulting complications. A heart and lung transplant is an alternative treatment, although, infections may recur, he said.

Dr. Dean said that research continues to find drugs to reactivate the defective protein and to determine how to circumvent CF, possibly by triggering another protein to compensate for the defect or through gene therapy. “Until something like that is accomplished, there is plenty more to do,” he said, adding that not many genetic diseases have effective treatments.

ATP Binding Cassette Transporters

Dr. Dean’s research into CF has led him to further discoveries. “The gene that causes cystic fibrosis is part of a large group of genes, ATP binding cassette transporters, which transport things into and out of the cell,” he said.

ATP binding cassette (ABC) transporters are pumps that use energy from an ATP molecule, the fuel of cells. “We started studying other genes in the ABC gene family, initially to find a version of the CF gene in a simple organism, like yeast, or fruit flies, or a worm” to perform genetic or functional studies. However, they discovered that the CF gene is only present in vertebrates and above, Dr. Dean noted.

“We now know that there are 48 of these genes in humans; each of these codes for a protein which is a different pump. This is important for cancer because three of those pumps can get turned on in tumor cells and the tumor cell pumps out the chemotherapy drug faster than it comes in, and essentially chemotherapy fails. Most resistance to chemotherapy is caused by one of these pumps being activated,” Dr. Dean explained.

As an outgrowth of his research, Dr. Dean now focuses on related genes and ways to prevent the proteins from pumping out the drug. Working with researchers Tito Fojo and Susan Bates at the Clinical Center, NCI-Bethesda, he developed inhibitors to the pump and discovered the third most important of these pumps, ABCG2 or MXR. Now, they plan to work with the drug screening program at NCI-Frederick to identify useful drug inhibitors.

As Dr. Dean began to concentrate on other genes in the CF family, cataloging the transporter genes, he realized that his group’s discoveries had implications for other diseases, such as “retinal degeneration disorders and some rare disorders of either too much cholesterol in tissues or too much being absorbed out of the intestines,” he said.

Now that Dr. Dean and his group have catalogued the ABC gene family, they are developing tools to analyze gene expression “in different cells or tissues. In other cases, we are focusing on the function of specific members. We would like to have an antibody that recognizes all of them, and inhibitors that would block these pumps and prevent tumor cells from developing drug resistance.”

On the other hand, he said, “These pumps are also used normally in the body to control the transport of many drugs. For instance, there are some drugs we can’t take orally because our body pumps the drugs out so that we never absorb them. These inhibitors could be used to deliver those drugs orally through the intestine. Some of these drug pumps are expressed in the blood-brain barrier and keep these compounds out of the brain. To treat brain tumors, it may be beneficial to have inhibitors to these pumps so that we could get more drugs into the brain.”

Dr. Dean pointed out that inhibitors are important for cancer chemotherapy because many chemotherapy drugs must be injected over days or weeks. He explained that when a patient begins treatment, the doctor performs an operation to place a big needle into a vein in the patient’s chest to attach a pump for dispensing the drugs. “Some people,” he said, “have no problems, but in others, the vein clogs up. Chemotherapy could be better managed if the doctor could deliver some of these drugs orally.”

He continued, “Perfecting inhibitors will take several years because we have to make sure that they don’t have other bad side effects.” He noted that researchers will re-evaluate dosage concentrations of drugs plus inhibitor. “It will be very difficult research but now we think that we know the major pumps that are the targets.

“Think of a body as like an automobile: If your car broke down and you knew nothing about how the engine worked or the brakes worked, you wouldn’t have a clue as to how to fix it. We are now figuring out how the body works and what goes wrong in disease and we have to know that before we can even begin to rationally figure out how to repair it. Now, with many diseases, we know enough about what’s wrong to know what we would like to fix.”

Frontiers of Research

Dr. Dean said that the most exciting thing about his research “is not knowing what you are going to discover next. Most of the big discoveries are not really planned. But, I also find it very exciting to be working on projects where we can see an outcome that would benefit patients with these diseases.”

Dr. Dean said that one area of research in which he’s interested is discovering why some people have a more efficient immune system and are better able than others to destroy cancer cells. So, Dr. Dean and his group have begun a new project in collaboration with Dr. Berton Zbar to study families that do not have genetic disease but still have two or more cases of kidney cancer—an unusual demographic. “We have worked with Dr. Zbar in the past as well, to help him find mutations in the gene for von Hippel-Lindau disease, which is a kidney cancer and also to find mutations in the MET oncogene which also can cause some types of kidney cancer.”

Dr. Dean explained that determining the reasons for recurrent kidney cancers is difficult because it could be solely environmental, solely genetic, or a combination. “That makes it very difficult to figure out, but challenging and interesting,” he said.

Genetic and Environmental Influences on Cancer

“We believe that virtually all cancers are influenced by a person’s genetic background and some people may be more susceptible to environmental cancers. For example, we know that smoking increases your risk of lung cancer about 20 times but still there are many people who smoke and never get lung cancer. There may be genes that influence that sort of risk; and it’s the same with exposure to chemicals, radiation.

So it is a big challenge now to figure out what genes influence our risk of getting cancer and, hopefully, finding those genes will help us understand more about what those risks mean,” he said.

In a related project, Dr. Dean’s laboratory staff has been developing ways to identify genes involved in other cancers and other complex diseases. “We did a lot of research on genes involved in response to HIV and resistance to AIDS. We have also worked on some inherited cancers, such as basal cell carcinoma, a type of skin cancer. Some people have hundreds to thousands of these tumors starting at quite an early age. These patients also have skeletal abnormalities and other defects. We used genetic analysis to find the gene that causes this disease a number of years ago.”

Founder of the Elementary Outreach Program

In an extension of his life’s vocation, Dr. Dean shares his love of science with elementary school children. In 1989 he led the students in his son’s class at Hillcrest Elementary School in “hands-on” experiments. From an initial visit, he made many, and continued even after his son finished elementary school.

In an article in the SAIC-Frederick, Inc., newsletter, News and Views (5[April]:1, 2001) Dr. Dean commented that the students explore their world with everyday materials, and since volunteers include both scientific and administrative personnel, students learn about “the variety of science-related careers possible.” They talk with “real scientists, not the mad kind they see in the media. I also really enjoy seeing the scientists and other employees experience life in the classroom and the challenge of teaching. I think there is too little appreciation of how hard it is to be a teacher, and how good a job most of them are doing.”

And his enthusiasm is contagious. Eventually, at Dr. Dean’s request, NCI-Frederick became involved, resulting in the signing of an agreement for a formal partnership with the Frederick County Public School System on November 9, 1999. The program has grown from 30 people that first year volunteering more than 800 hours, to 68 volunteers logging more than 2,187 hours last year, to nearly 100 volunteers this year. In addition, some volunteers have been so enthusiastic about the program that they have instituted similar programs in their home counties.

If you’re interested in volunteering for the Elementary Outreach Program, contact Barbara Birnman, 301-846-1956; or register on this Web site.

Article by Maritta Perry Grau
Photography by Jonathan Summers
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