Building a more human mouse

Jackson Laboratory scientists bridging gap between mouse genetics and human disease

Imagine a day when a patient diagnosed with cancer has a sample of his tumor transplanted into a “humanized” mouse genetically engineered to mimic that patient’s immune system. Such an individualized in vivo model could be used to more accurately predict which drug or other treatment will work best for a patient based on the patient’s own genetic profile.

That’s the vision that geneticist Carol Bult, PhD, a professor at The Jackson Laboratory, shared recently with faculty, staff and students attending the USF Health’s 21st Annual Research Day.

“It’s a vision we’re driving for,” said Dr. Bult, who delivered the Roy H. Behnke Distinguished Lectureship entitled Mouse models of human disease: Where we are, where we are going. “Hopefully, together, we’ll make inroads into bridging the divide between mouse genetics and human biology and disease.”

Mice genetics and personalized treatment solutions are central to the growth strategy of USF partner Jackson Laboratory.

Dr. Bult is the principal investigator of Jackson Lab’s Mouse Genome Informatics database consortium, the most comprehensive, publicly available database of integrated functional genetic and genomic data for the laboratory mouse. The primary mission of the project is to build information systems to facilitate use of the mouse as a model for understanding normal human biology and disease processes in humans.

Jackson Laboratory maintains more than 400 inbred lines of mice, all used to study the genetic basis of susceptibility to diseases ranging from cancers and neurological disorders to diabetes and cardiovascular diseases.

Laboratory mice are by far the most popular model system for studying diseases and their treatments, Bult said. They are small, easy to breed, and live only one to three years, allowing researchers to follow disease processes from start to end in a relatively short time. In addition, many genes of mice are remarkably similar to those of humans.

Improvements in mouse models of human disease

Advances continue to lead to improvements in these mouse models, offering new insights into how genes function, regulate, and go about promoting health and disease in humans.

Transgenic, or genetically altered, mice contain foreign DNA in every cell that produces specific biochemical, physical or behavioral characteristics the mice would not otherwise have – for example the manifestation of obesity or memory loss. In some cases, that means a new protein is produced or an existing protein is overexpressed.

Researchers can also inactivate, or “knock out” an existing gene by replacing or disrupting it with an artificial piece of DNA. It’s now possible to produce knockout mice carrying specifically defined mutations by targeting genes of interest in mouse embryonic stem cells. Newer technology even lets researchers dictate the place and time that a gene is switched on or off, so that mutations can be targeted to any cells or tissue or any particular stage in development.

Phillip Marty, PhD, USF Health associate vice president for research, presented a plaque to Jackson Laboratory geneticist Carol Bult, PhD, recognizing her partcipation in Research Day 2011.

Jackson Laboratory has been a pioneer in developing mouse models capable of simulating the human condition. These “humanized” or immunodeficient mice either express human genes or can be transplanted with human tissue or cells. The work has wide implications for translational research on cancer, infectious diseases, human immunity and autoimmune diseases.

“The mice don’t mount an immune response,” Dr. Bult said. “So this in vivo system theoretically lets you transplant any human tissue type, preserve the stromal environment and move forward… The genetic modifications required to build such a model are complex.”

System genetics approach

Dr. Bult’s work emphasizes a comprehensive system approach to genetics, which recognizes that disease is caused by disruptions to entire networks of genes and their pathways, not a single gene defect.

“Illness is a system gone wrong, and treatment tries to correct the system,” she said. “If we focus only on individual genes we’re going to miss the bigger picture.”

So how do mice genetics fit into the emerging era of personalized medicine?

“So many exciting things are happening in this field,” Dr. Bult said. “The combination of being able to discern (human) gene function and model gene systems using mice will help tremendously in the rational design of new drugs and identification of drug targets that have the individual properties we want… The humanized mice and in vivo modeling will advance our ability to test effectiveness and toxicity of compounds in mice in a human context.”

Jackson and USF have proposed to build a biomedical research facility in Florida that would combine Jackson’s expertise in cutting-edge genomics techniques with USF’s extensive capabilities in clinical medicine to explore new approaches to preventing, diagnosing, and treating the diseases.

During her visit to USF Health, Dr. Bult met with several faculty members and browsed the Research Day poster presentations to chat with students. She was enthusiastic about potential biomedical research collaborations between scientists here and at Jackson Laboratory, mentioning in particular the areas of engineering, medicinal chemistry, protein structure and function, and clinical medicine.

Partnership built on common interests in personalized medicine

“At Jackson, we bring tremendous resources to bear on understanding the genetic basis of disease, possible targets and how pathways respond to treatment,” Dr. Bult said. “But translating that information into something directly relevant to human health requires partners like USF, with access to patients and expertise in clinical care.”

USF Health’s Dr. Leslie Miller sees great opportunity for partnering with Jackson Lab on innovative cardiology research that would work toward tailoring health care to each individual patient.

Leslie Miller, MD, chair of the Department of Cardiovascular Sciences at USF Health, said that one of the other important advances from genomic research is that the genes identified as important markers or steps in the pathogenesis of a disease also serve as targets for drug, cell, or gene therapy.

Understanding the interaction between genetics and epidemiological and environmental factors, or epigenetics, will be vital in understanding some of the challenges in identifying genes linked to a specific disease, Dr. Miller said. “Twins share the same genome, but one can develop diabetes while the other doesn’t. It’s not purely genetics.”

Dr. Miller sees great opportunity for partnering with Jackson Lab on innovative cardiology research that will work toward tailoring personalized health care to each individual patient.

“For instance, if they (Jackson) identified a panel of candidate genes that increases the likelihood of developing arthrosclerosis, we could identify at-risk people earlier when tailored intervention may prevent or delay disease,” Dr. Miller said.

Story by Anne DeLotto Baier, and photos by Eric Younghans, USF Health Communications