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Neal Copeland is a man used to looking at things a bit differently. With a Ph.D. in biochemistry, this gourmet cook and world traveler began his career doing postdoctoral work in retrovirology at the Dana Farber Cancer Center, Harvard Medical School, and also learned molecular biology along the way. “Boston was one of the places in the country where molecular biology was at the forefront,” Dr. Copeland said in an interview for Spotlight.

At Boston, Dr. Copeland also met his future wife, Senior Investigator Dr. Nancy Jenkins, who joined the same laboratory a year after Dr. Copeland.

It’s difficult to write just about Dr. Copeland, because he and his wife seem to share everything, whether it’s household chores, an office, or running a laboratory. For example, the two knew from the start that they wanted to run a lab together and to co-author every paper. And in the past 25 years, they have coauthored nearly 700 publications. “We switch around who’s going to be last author, to make it equitable,” he said with a chuckle. Currently, Dr. Copeland heads the Molecular Genetics of Oncogenesis Section of the Mouse Cancer Genetics Program (MCGP), while Dr. Jenkins heads the Molecular Genetics of Development Section.

Married in 1980 when they completed their post-docs, Dr. Copeland and Dr. Jenkins were invited to join one of the biggest mouse genetics laboratories in the world: The Jackson Laboratory, Bar Harbor, Maine. “We were the first molecular biologists to go to the Jackson Laboratory. We taught them molecular biology and they taught us mouse genetics, the foundation for our whole research,” Dr. Copeland noted.

Although they only stayed at Jackson three years, Dr. Copeland said that he and his wife still count some of the staff there among their best friends and return to Jackson each summer to teach in a mouse genetics course for graduate students and post-docs. “We love going up there and teaching because it’s August, a great time to be there,” he said.

In 1985 the two were recruited to do large-scale mouse genetics at NCI-Frederick. Dr. Copeland’s Mouse Genetics Laboratory (now MCGP), studied various disease models, both cancer- and technology-related. The main focus of the MCGP is cancer, but staff continues developmental biology projects. Besides Drs. Copeland and Jenkins, who are tenured, the MCGP includes a third tenured investigator, Lino Tessarollo, and four tenure-track investigators, Shyam Sharan, Karlyne Reilly, Brad St. Croix and Philipp Kaldis.

And the work has paid off with numerous discoveries that have an enormous positive impact on cancer research. Dr. Copeland shook his head and grinned with delight as he reminisced about the past 25 years of discoveries. “If you had asked me in 1980 if we could make designer knock-outs, transgenic mice, and know the sequence of the whole mouse genome, I’d tell you that was pure science fiction. One thing that I’ve learned is, never underestimate the field, because technologies will be invented at any time that you can’t even dream about. It’s those revolutionizing technologies that really drive the field forward, I think. And you just can’t predict what will happen.”

Gene-based Linkage Map

As one of its first NCI-Frederick projects, Dr. Copeland’s laboratory developed a gene-based linkage map of the mouse genome. Other researchers, soon realizing the map’s value, requested that MGL map certain genes. MGL staff were able “to identify and clone genes mutated in several mouse models of human disease, including models for neurological, learning and memory, cancer, ear, eye, skeletal, hematopoietic, fertility, autoimmune and vesicle transport diseases,” according to the MCGP Web site .

“We eventually had the densest gene-based map of the mouse genome in existence. It generated lots of important findings,” leading to hundreds of collaborations and papers, Dr. Copeland said. The whole mouse genome is interesting. The ‘theme’ of our lab is mouse models of human disease. Everything we are doing is mouse-focused but disease-related in many different areas,” he added.

Retroviral Insertional Mutagenesis

Another project, still an important focus of the lab, is a very powerful technique called retroviral insertional mutagenesis. Using inbred strains of mice with a high incidence of leukemias and lymphomas, MCGP researchers have used retroviral insertional mutagenesis as a tool to identify many new hematopoietic cancer genes and in the process developed several mouse cancer models that may be useful for testing new human therapeutics before clinical application.

With the mouse genome completely sequenced and the development of very high-throughput techniques for cloning these bits of DNA, identifying cancer genes has dramatically increased in both speed and number, from a previous average of one cancer gene a year to possibly a hundred cancer genes in a year. In just the past two years, at least 250 candidate cancer genes have been identified, although Dr. Copeland cautioned that not all of these 250 genes have been validated. “That’s really an impressive number, but there could be a lot more. Nobody knows, since other genes appear to function in pathways not yet associated with human hematopoietic disease,” Dr. Copeland said.

Recombineering

Still another, more recent technology is recombineering; Dr. Copeland’s MCGP developed this technology in collaboration with E. coli geneticist Dr. Don Court. With this technology researchers can modify cloned DNA in E. coli by homologous recombination rather than by restriction enzymes and DNA ligases.

“Normally, you manipulate DNA by cutting with the restriction enzyme and then ligating pieces back together. Recombineering allows you to take a piece of DNA and make an exact deletion or insert something in it exactly where you want it to the nucleotide, because you don’t cut it with the restriction enzyme, you put it in exactly the same spot in the gene by homology. It allows you to manipulate DNA in a way and on a scale that you couldn’t do before,” Dr. Copeland explained with enthusiasm, his delight in the science obvious.

Recombineering has applications for many fields, from mouse genetics to E. coli and zebra fish genetics—they’re all using it. Dr. Copeland’s laboratory has shared this technology with more than 1,500 laboratories throughout the world. Because the technique speeds up the analysis of sequenced genes, it has “made it possible to analyze genes functionally on a scale that was either very difficult or not even possible to do before. So it’s really revolutionizing functional genomics,” Dr. Copeland said.

When researchers know what a gene does, Dr. Copeland explained, they can use that knowledge to help develop cures for the disease. Already, translational applications are occurring: some of the genes thus identified are being used as targets for drugs. “The recombineering technology that we’ve developed is helping people make better mouse cancer models, and make knock-out mice and mutations in tumor suppressor genes faster and more easily. And then you can use these cancer models to test drugs before you put them in people,” he said. NCI has filed for a patent on recombineering technology.

Dr. Copeland is very proud of the staff at MCGP. “Some of the best mouse geneticists in the country have come through our lab.” He also takes delight in the fact that since NCI groups aren’t in competition, researchers are often able to “take their projects with them when they leave, and they have all the reagents, the mice, or whatever, so that’s helped them get established. Of course,” he adds, that also means “we continually re-invent ourselves, because we’re always giving away things.”

Frederick is a long way from Bar Harbor, Maine, in more ways than one, but Dr. Copeland and Dr. Jenkins have been here for 21 years, and he said, “We love the area.”

One of the things they especially like is Frederick’s proximity to Washington, DC. “We like big-city life,” Dr. Copeland said. “We have all of the advantages of living in a small town; yet, we’re close to DC, so we can go there on the weekends; the commute to work is nothing, takes us 15 or 20 minutes, and we’re going against the traffic.”

Physical fitness is also important to Dr. Copeland and his wife. Since they live on a golf course, he has taken up golf, a sport he enjoyed as a teen-ager. And, as if that weren’t enough, they exercise each morning for an hour and a half in their home gym before coming to work.

They share household chores, and Dr. Copeland enjoys gourmet cooking. “We tend to eat really good, fresh stuff—simple things but good.” They also enjoy eating in fine restaurants, especially when they travel.

A world traveler, Dr. Copeland has experienced many exotic vacations, such as an elephant safari in Nepal and a cruise on the Nile. He has been invited to give many distinguished lectures and was selected as the National Institutes of Health G. Burroughs Mider lecturer for 2005; has served on numerous scientific advisory boards; acted as a consultant for several biotechnology and pharmaceutical companies. He also serves on several editorial boards and has been an associate editor of Cell since 1996.

For further information on mouse cancer genetics, contact Dr. Copeland, Building 539, Room 229, at 301-846-1260, or by e-mail at copeland@ncifcrf.gov. You can also visit the MCGP Web site for detailed information at http://ccr.cancer.gov/Labs/Lab.asp?LabID=61.

Maritta Grau, Writer,
Senior Technical Editor
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Photography Department
Scientific Publications, Graphics & Media
SAIC-Frederick, Inc.
National Cancer Institute at Frederick

Jim Miller,
Web Graphics & Development
Computer & Statistical Services
Data Management Services, Inc.
National Cancer Institute at Frederick