T H E   N I H    C A T A L Y S T     N O V E M B E R   – D E C E M B E R  2003

>the Sum of the Parts



text and photo
by Peter Kozel


Neal Copeland and Nancy Jenkins backlit by their famous map of the mouse genome

It’s hard to say what the NIH scientific directors were honoring when they picked husband-and- wife cancer genetics investigators Neal Copeland and Nancy Jenkins to present this year’s Mider Lecture.

Was it their legacy—almost 700 papers and the reference mouse genome map? Was it their astonishing record of training successful scientists? Was it their innovative "recombineering" technique that’s revolutionizing the manipulation of DNA?

Or was it their almost unparalleled, highly productive collaboration, now in its third decade?

The NIH Catalyst spoke with Copeland and Jenkins—chief and senior investigator, respectively, of the NCI-Frederick Mouse Cancer Genetics Program—shortly before they taught a short course on mouse genetics at the Jackson Laboratory in Bar Harbor, Maine, this past summer.

Jenkins and Copeland met in 1977 as postdoctoral fellows in Geoffrey Cooper’s retrovirus laboratory at the Dana Farber Cancer Institute in Boston. At the time, retroviruses were at the "very forefront of molecular biology," according to Jenkins. "Molecular biology was just flourishing," Copeland continues. "They lifted the cloning ban shortly after we arrived in Boston and Boston became a hotbed of molecular research. I think we probably did the first Southern blot at Harvard Medical School, with David Livingston’s help," he recalls.

By 1980, Jenkins and Copeland had decided to marry and began to look for institutions that would hire them both. One offer, from the Jackson Laboratory, was an intriguing, albeit curious, choice.

"We didn’t know mouse biology at all," Copeland recounts. The pair quickly realized that "JAX" and its mouse mutants were a gold mine—"models for human cancer and a lot of developmental disorders in people. We could apply molecular biology to mouse genetics and the combination of the two would hopefully be better than each of the parts," Copeland says.

"It was a very unique time at JAX," Jenkins continues. "There were no other molecular biologists. We were the first [at JAX], and they were very excited about learning molecular biology, and they reciprocated by teaching us formal genetics."

"A lot of the projects we worked on for the last 20 years, and what we work on today, got their start when we were at The Jackson Lab," Copeland reminisces. "It was a magical time to be there. It set the tone for our whole career."

After three years of learning, teaching, and groundbreaking publications, Jenkins and Copeland were getting restless. As much as they loved the research environment, "we were just going stir crazy," says Copeland. Jenkins found Bar Harbor "a little too isolated" by 1983, and the pair moved to the University of Cincinnati, the only place to which they applied.

It wasn’t long before they started to be recruited by, and interested in, other programs. Jenkins remembers, "We weren’t looking for jobs, but the draw of having a really large animal colony that we could devote to our numerous interests—we think the whole genome is interesting—was just too strong to let go."

George Vande Woude offered the couple the chance to pursue their interests as he was setting up the NCI-Frederick Applied BioSciences Laboratories–Basic Research Program in 1985. They saw it as a unique opportunity to conduct mouse genetic research on an unprecedented scale. "We really wanted to fuse molecular biology and developmental biology on a large scale in mice . . . . this was the only place we could really do it," says Copeland.

The Royal Beginnings of Mouse Genetics

"The first geneticists were the Japanese emperors," Jenkins notes. "They collected the unusually colored mice and the neurological mutants, the waltzers. When trade finally opened between Europe and Japan, the mice were given as pets or presents to Europeans.

When Mendel’s laws were rediscovered at the beginning of the 20th century, all they had for reagents were these funny colored mice and ones that had neurological phenotypes."

Copeland says the mouse fanciers bred coat color mutants such as "dilute," "brown," and "nonagouti." These mutations were incorporated into early inbred strains, such as "DBA," which had all three traits.

"Dilute" has a special significance for the lab, Copeland says. "The first paper we ever published together at JAX was a 1981 article in Nature that showed that dilute was caused by the integration of a retrovirus into the mouse genome that happened hundreds of years ago. That was the first insertional mutation ever described in mammals." This mutation could be traced back to a mouse fancier in the 1700s, and from there to the Japanese emperors. "We’ve been studying that mutation ever since."

Dilute was just the beginning. In the ensuing years, Jenkins says, "there’s almost no area of biology that we haven’t touched on." The overall theme has remained constant, however. Copeland says, "We specifically tried to work on mutations that were models of human disease."

The translational emphasis has permeated Jenkins’ and Copeland’s work in both development and cancer biology and the intergrading and interacting zones of these fields. Copeland notes that the coat color mutations, for example, led to a deeper understanding of deafness disorders, such as Waardenburg syndrome type 2A.

Jenkins says the goal of their work "has always been to manipulate genes and understand their biology, their physiology, [and] their interaction pathways in mouse and [to] try to translate that back into human."

Copeland & Jenkins To Deliver Mider Lecture

Neal Copeland and Nancy Jenkins are this year’s Mider Lecture honorees, a recognition of their significant contributions to the biomedical research eminence of NIH.

They will deliver their lecture— "Retroviral insertional mutagenesis provides a road map for navigating the cancer genome"—on Wednesday, January 14, 2004, at 3:00 p.m., in Masur Auditorium, Building 10.

She sees the mouse as an excellent model for human diseases—about 80 percent of human genes have mouse orthologs.

The human-murine genetic similarity has led to some amazing genetic feats. Shyam Sharan, an investigator in the Mouse Cancer Genetics Program, has "rescued the embryonic lethality of the loss of a mouse BRCA gene with a human ortholog." Copeland notes that this is even more astonishing because "the regulatory sequences are not conserved at all" between the two species.

Copeland says his more than 20 years of experience has forged his impression that, as a model of human disease, the mouse is "much better than we expected." Noting that it’s not perfect, Jenkins says, "the mouse has three very strong advantages: it’s a mammal; you can manipulate its germline . . . and you have very good genetics." As if tossing down a latex glove, Copeland adds, "I challenge you to find a better one."

One way that Jenkins and Copeland linked their mouse mutants to human disease was by mapping and cloning the genes responsible for the spontaneous mutations in JAX mice. The pair learned about interspecific backcrossing needed for this linkage at a conference shortly after arriving in Frederick.

Realizing its potential, Copeland recalls, "when we came back, we announced to the postdocs, ‘we’ve decided to make a map of the mouse genome. Would you like to participate?’"

The project quickly took on a life of its own. Copeland and Jenkins spoke about their map at meetings, and it quickly attracted the appreciation and contributions of other scientists. Copeland recalls, "People would say, this is really cool! And so we had more and more people contacting us, and pretty soon we were overwhelmed."

Although other groups also made maps of the mouse genome, it was the Jenkins-Copeland map that was the standard in the field for several years. They note that there are several reasons for this success. Their map was gene-based, and human gene-hunters could use their mouse map to predict locations—and proximity to disease genes—on human chromosomes. As new genes were mapped, the resolution of the map improved.

Another key advantage of the pair’s map was that it focused on the markers and repeated questionable results until they "disappeared." Finally, all the mapping experiments were carried out inhouse—making for "extremely high quality," according to Copeland.

The map eventually became an international resource that Jenkins, Copeland, and their collaborators used to localize and clone entire families of new and important genes.

Technology for the Future: Recombineering

With the mouse genome nearly complete, Jenkins and Copeland have moved beyond mapping. "Technology has always been a real interest," says Jenkins. In 2001, they described a groundbreaking new method for precisely manipulating cloned DNA by homologous recombination, alleviating the need for restriction enzymes and DNA ligases.

Dubbed "recombineering," this technology sprang from the brainstorm of an excited postdoc returning from a meeting. Developed in collaboration with Donald Court’s bacterial genetics lab across the hall, recombineering "has widespread implications for mouse functional genomics," according to Copeland. "Everybody’s using it," he adds. "As far as I can tell, it’s not limited to any species, prokaryotic or eukaryotic."

Recombineering takes advantage of enzymes from bacteriophage l to precisely manipulate DNA cloned in plasmids, BACs, or PACs, or even the Escherichia coli chromosome.

For example, Copeland explains that they use recombineering to "make conditional targeting vectors in less than two weeks," a process that takes months using conventional cloning techniques.

Epitope tags can also be introduced "to the nucleotide, anyplace you want in cloned DNA, and it does not depend on the location of convenient restriction enzyme sites," Jenkins adds. "It’s almost like PCR was in its infancy," Copeland continues. "There are so many uses. The more we give it out, the more people think about what you can do with it."

The method is extremely popular—"most every system that has a BAC library at some stage of development has requested this," Jenkins notes.

In addition to the conditional targeting vectors they are making for their own mouse research, Copeland and Jenkins are setting up a recombineering core to make targeting vectors for NCI’s Mouse Models of Human Cancer Consortium.

Even before developing the revolutionary recombineering technique, the Copeland-Jenkins lab had generated such powerful new tools, data, and strategies that in 1999 it was given an expanded mission and renamed the Mouse Cancer Genetics Program.

The team could now offer to other early-career investigators the lure that had brought them to Frederick. In addition to tenure-track investigators Sharan, in breast cancer, and Lino Tessarollo, a neurogeneticist, Jenkins and Copeland have successfully recruited another two "spectacular" tenure-track investigators: Karlyne Reilly, who works on brain cancer modifier genes, and angiogenesis researcher Brad St. Croix. "They were our top two candidates," remembers Copeland. They are now about to begin a search for the program’s next recruits.

While Copeland and Jenkins recognize it would be impossible to support their research program at a university, they still "really like training and teaching." Speaking like a proud parent, Jenkins credits much of the success of their lab to their "incredibly talented postdocs." She says they try to encourage creativity and then send the postdocs on their way only when "their creativity is fully in bloom."

The postdocs usually don’t leave empty-handed, but take with them the research projects and mutant mice they’ve developed. "We’ve trained, frankly, some of the best people in mouse genetics," Copeland says. "They’ve been successful because they have projects that are great for grants, and they didn’t have to compete with us."

Copeland and Jenkins also avoid competing with one another. Although administratively separate, their labs function as a single entity, as they have since they began work at JAX, where they shared an office, research projects, and publications. "It was never clear to us what you gain by splitting everything up," Jenkins says.

"A lot of fairly well known scientists have looked at our careers and have said that we’re better working together than we would be on our own," Copeland says.

After more than 20 years and nearly 700 co-authored papers, the couple often finishes each other’s sentences, but can’t precisely explain how the symbiosis of their careers evolved.

"It just happened that way," Jenkins reflects. "Each one of us has strengths and weaknesses that the other one complements. People who know us say that the sum is better than the parts."



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