JAX Notes July 01, 2008

Ed Leiter, Ph.D. —over 35 years devoted to diabetes research

Contributions to diabetes research by Jackson Laboratory scientist Ed Leiter, Ph.D., are universally recognized. Below, Leiter offered us a glimpse of his research career.

Early influences

Dr. Leiter's interest in diabetes research was set in motion very early in his career. "Diabetes has always been my focus. My grandfather had type 2 diabetes and one of my uncles on my grandpa's side has been a type 1 diabetic since 1942. So I had a personal 'stake' in this complex set of diseases. I began training for diabetes research when I learned how to culture pancreatic beta cells in Jackson Laboratory scientist Charity Waymouth's lab; she was a pioneer in the growth of mammalian cells in chemically-defined media. My arrival at the Laboratory coincided with the publication by Laboratory staff of the 'diabetes' mouse (subsequently found to become obese because of a mutation in its leptin receptor and diabetic because of additional genes in the inbred strain background on which the mutation occurred). In my first few years at The Jackson Laboratory, I was fortunate to be able to study diabetes pathogenesis of this intriguing new mouse model with Douglas Coleman, Ph.D., senior author of a well-recognized diabetes mouse paper."

Unanswered questions

When Leiter began his career, little was known about the nature of insulin, how it was produced, and the genetic and environmental factors that influenced diabetes susceptibility. "In the early 60's, when I was a graduate student, the chemistry of insulin and the biochemistry of insulin production in pancreatic beta cells were just beginning to be understood." Leiter explains that investigation into what causes beta cell failure in both type 1 and type 2 diabetes was only in its infancy.

"Researchers were beginning to ask if there were different sets of genes associated with each major diabetes form. In the case of type 2 diabetes, were the 'diabetes' genes really common variants, which, earlier in evolution, when food sources were limited, conferred a more efficient metabolism? If so, such 'thrifty' genes would be deleterious in our modern 'Coke and bun' environment by promoting obesity-induced diabetes (diabesity). In the case of type 1 diabetes, why was the major genetic risk factor, the major histocompatibility complex (MHC) linked to diabetes, so common in Caucasians? Why would one identical twin develop the disease and the other not? What was the role of the environment?" These questions are still being debated today.

Critical breakthroughs

Looking back over his more than 35 years in the field, Leiter comments, "There have been many technological 'breakthroughs' since I entered diabetes research, not the least of which was gene cloning (with insulin being the first gene cloned, resulting in recombinant human insulin becoming available for treating type 1 diabetic patients). However, the most notable breakthroughs have been in our understanding that most cases of type 1 diabetes represent an immune-mediated disease."

Leiter also feels that scientists are making significant inroads in understanding the genetics of diabetes: "Because of the genetic heterogeneity and outbred nature of human populations, diabetes was previously referred to as a 'geneticist's nightmare'. Now, with the advent of the human genome sequence and the ability to do high-throughput screening at many thousands of genetic variants marked by single nucleotide polymorphisms, this complex disease is more of a 'headache' than a 'nightmare'. Nevertheless, understanding the complex interaction between genes in multiple combinations and the physical environment in which they express has remained a major challenge."

Persistent challenges

Despite all the progress made in diabetes research, Leiter feels that preventing diabetes is of utmost importance: "Given the high prevalence of type 2 diabetes worldwide, and the relatively high prevalence of type 1 diabetes in Caucasians, disease prevention remains a most pressing problem. The most prevalent 'garden variety' forms of type 2 diabetes can be prevented by lifestyle modifications, but this is not the case for type 1 diabetes. The big challenge for type 1 diabetes patients is the development of a 'cure'. Current efforts focus on disease reversal if treatment begins shortly after onset. For both forms of diabetes, prevention of diabetic complications like heart disease, nephropathy, neuropathy and retinopathy remains a major challenge. Some diabetic individuals are more likely to develop these life-shortening complications than others. We need to understand the genetic basis for the increased risk of development of complications. The Jackson Laboratory is working with the Animal Models of Diabetic Complications Consortium to assist in this discovery effort."

The mouse and diabetes research

Leiter comments: "The availability of diverse models has shown us the incredible genetic diversity that can underlie a complex disease. The MHC requirement underlying susceptibility to type 1 diabetes is common to both the rat model and the NOD mouse, but the non-MHC genes required for a diabetogenic interaction are different in both. Yet, these divergent non-MHC genes in both rodent genera work in common immune networks to control T cell tolerance. The differences are fascinating: the NOD mouse is the 'poster mouse' for the hygiene hypothesis, positing that immune tolerance is not learned if individuals are not sufficiently exposed to natural enteric microbial challenges when juveniles. The NOD mouse develops a high incidence of type 1 diabetes if raised in high barrier specific pathogen-free (SPF) environments. By contrast, there is a genetically-predisposed rat model which remains type 1 diabetes-free unless one either uses a virus to trigger disease, or simulates a virus infection by injecting double stranded RNA."

Leiter readily admits that animal models cannot answer all our diabetes questions: “There are critical differences among the genera (mice, rats, humans) at multiple levels. For example, rodent beta cells are much more sensitive to killing by certain toxic insults than are human beta cells, and further differ in terms of the sets of protein antigens expressed in beta cells. Given such differences, when a diabetes prevention therapy works well in an inbred mouse model (where genetic homogeneity is assured and treatments can be initiated in early, prodromal stages), it is important that the protocol be tested in another animal genus before assuming that it will be efficacious in the human clinical setting. Jackson Laboratory researchers have been at the forefront of attempts to 'humanize' the NOD mouse model of type 1 diabetes. Researchers Lenny Shultz, Ph.D., and Dave Serreze, Ph.D., have been developing severely immunodeficient NOD stocks to both allow constitution with a human immune system and express key beta cell components not expressed in mouse pancreatic islets."

The Jackson Laboratory difference

Having spent his career at The Jackson Laboratory, Dr. Leiter is clear about what differentiates the facility from other world-class biomedical institutions: "The Jackson Laboratory's most important resources are the community spirit of the research staff and its support team at JAX® Mice & Services. The Type 1 Diabetes Resource (T1DR) is but one manifestation of this, as is the Animal Models of Diabetes Complications Consortium. The Jackson Laboratory maintains a phenome database which, along with bioinformatics resources and an incredible collection of induced mutant stocks of critical importance to diabetes research, collectively makes the mouse the pre-eminent mammalian resource for diabetes research."

Sharing knowledge — a top priority

Throughout his career, Leiter has never forgotten that people come first and that knowledge must be shared. "My most important contributions have been generating both human and mouse resources for diabetes research. The human resources are the students who have come through my laboratory and now are making important contributions to diabetes research. One, David Serreze, is now a JAX staff member advancing understanding of autoimmune diabetes in the NOD mouse model. The NOD/ShiLtJ mouse is one of many useful mouse resources for diabetes research that I have helped to bring to the Laboratory.

One of the attributes that I learned from my mentor, Doug Coleman, and passed on to my students, is that an animal model of any disease or a reagent derived from it gains value when it is openly shared and not kept 'private' or unduly saddled with intellectual property issues. The story behind the NOD mouse emphasizes this point. Originally, in the 1980s, the NOD mouse was distributed primarily to Japan. Its promise was realized only after the international research community gained access. Today, the Type 1 Diabetes Resource at The Jackson Laboratory serves as an international repository for over 150 genetically manipulated stocks of NOD mice important to advance type 1 diabetes prevention, treatment, and cures."

Although Leiter is in the process of closing his active research career, he continues to be involved with diabetes resources development and management at the Laboratory under the aegis of the Type 1 Diabetes Resource (T1DR). Through this resource, Leiter will undoubtedly inspire future diabetes researchers to continue the quest he began long ago — the search for a cure.