Search Magazine February 16, 2016

From rockets to genomes

For a young boy coming of age in south central Pennsylvania, few things seem more majestic than space exploration. The planets, their moons, the stars — they have an otherworldly beauty that beckons to those standing light years away with feet set on terra firma, eyes gazing toward the heavens. But sometimes, the urgency of life on our own planet can pale the celestial glow. As a child, Michael Stitzel felt this strong pull back to Earth as the first HIV/AIDS epidemic unfolded during the 1980s.

“I remember following the news, and there was no cure,” says Stitzel, an assistant professor at The Jackson Laboratory for Genomic Medicine. “Then I heard about different researchers who were trying to understand what the virus did and why it was so deadly, and I thought, ‘I want to find a cure for AIDS.’”

Although HIV/AIDS would not become his calling, another important human disease would: diabetes. For almost a decade, Stitzel has been unraveling the complex biology of type 2 diabetes, using an ever-growing assortment of genomic tools. Since joining The Jackson Laboratory more than two years ago, he and his budding laboratory are revealing how variations in our genome impact the work of a special group of cells in the pancreas that are thought to be among the biological underpinnings of type 2 diabetes.

Driving forces

For Stitzel, the imprint left by the HIV/AIDS crisis symbolized the power of basic science to unlock the biology of disease. In high school, his interest in human disease was cemented by a deep fascination with genetics. “Mendel’s peas are cool, but it was really realizing, ‘Whoa, there is a change in the DNA that leads to Huntington’s disease, there is a change in the DNA that leads to cystic fibrosis,’” he recalls.

Shortly after Stitzel headed off to Penn State in 1996 to pursue his bachelor’s degree, his mother made a bold move. An article about a trail-blazing, motorcycle-riding scientist who was pushing the frontiers of human genetics caught her eye, and reminded her of her own son’s interests. She wrote the scientist a letter, asking if he would kindly meet with her son.

That extraordinary letter was addressed to Francis S. Collins, now the Director of the National Institutes of Health. At the time, he was leading the National Human Genome Research Institute (NHGRI) and overseeing the Human Genome Project (HGP), a decade-long, international effort to decode our full genetic blueprint. Collins agreed to meet with Stitzel, and the two convened that winter over the holiday break. That meeting helped shape Stitzel’s initial forays in science. He went on to work in a lab as an undergraduate and also spent three summers interning in labs at the NIH, giving him early, valuable lessons in biomedical research.

Seduced by worms

After spending a year abroad as a Fulbright fellow, Stitzel began graduate studies at Johns Hopkins University in 2001. There, he joined the lab of an up-and-coming developmental biologist, Geraldine Seydoux. Her group seeks to decipher the earliest decisions cells make, using the roundworm, Caenorhabditis elegans, as a model system.   

“It is a very seductive system,” says Stitzel. “You can tether cellular proteins to a fluorescent marker and then watch, in real-time, as the chromosomes condense, align, and separate in the developing embryo. Truly amazing.”

Together with Seydoux, Stitzel helped shed light on the earliest steps in embryonic development — the moment when two germ cells, an egg and a sperm, unite to form an embryo. At the time, conventional wisdom held that the molecular processes in the early embryo were focused on building new things — like a molecular version of a sprawling construction site. But Stitzel’s work showed that demolition is important, too, particularly in the egg, helping to clear the way for the developmental programs of the young embryo.

Despite the worms’ inherent beauty, he longed for a more direct impact on human health. “My graduate work wasn’t directly linked to disease genetics,” he says. “I struggled with that.”

Convergence

A revolution in human genetics and genomics was quietly unfolding as Stitzel completed his Ph.D. Following on the heels of the HGP, researchers across the world had set their sights on another big goal: to define how genomes vary from one person to another and to pinpoint genetic variants linked with disease.

There was a deep interest in so-called complex diseases. Unlike disorders that stem from mutations in just one gene (such as cystic fibrosis or Huntington’s disease), complex diseases are influenced by changes in tens or even hundreds of genes and include common conditions, such as diabetes, heart disease, and psychiatric disease. Scientists had been working for years to unearth these genes, but with limited success. Now, the tools and information at hand were significantly more advanced.

The time was ripe for science and it was ripe for Stitzel, too. His long-time mentor, Collins, had an opening in his lab for a postdoctoral fellow. Stitzel applied and more than a decade after their first meeting, he and Collins embarked on a scientific journey to probe the genetics of type 2 diabetes.

As they began, a flurry of papers, including one led by Collins, reported the results of three landmark studies of type 2 diabetes — among the earliest efforts to scan the entire genome for genetic variations associated with disease. Using the projects’ findings as a launching point, Stitzel set out to further explore the genomic regions and the genes within them that were implicated in diabetes.

He soon found himself in the genome’s equivalent of no man’s land — large stretches of the genomes that are completely devoid of genes. This dark matter of the genome, also referred to as the “non-coding regions” — non-coding in that they do not code for proteins, as most typical genes do — were repeatedly turning up in genome-wide hunts for disease genes, but their functional significance was, and in many cases still is, unclear.

Stitzel thought these non-coding elements might be playing regulatory roles, orchestrating which genes are made active and which are kept silent. That idea led him to probe the epigenome, the collection of chemical tags and modifications that are layered on top of the genome and serve to regulate gene activity. Like a vast network of light switches, the epigenome determines when and where genes are turned on or off.

By searching the epigenomes of pancreatic islet cells, Stitzel and his colleagues zeroed in on uncommon stretches of activating epigenetic marks, called “stretch enhancers,” which are unusually long and seem to be playing important biological roles. In particular, these stretch enhancers appear to be linked with diabetes as well as other common diseases.

Of mice and humans

As he builds his laboratory at JAX, Stitzel hopes to further dissect the roles of the stretch enhancers that he helped uncover. But that is just one small piece within a larger, three-pronged research strategy.

First and foremost, he and his growing, four-person team seek to develop a better understanding of the genetic variants implicated in type 2 diabetes — what are the variants doing, what genes are affected, and how can these effects be modeled, either in cells or in mice.

They also want to assemble a clearer biological picture of islets cells. In the pancreas, islets consist of at least five distinct cell types — alpha, beta, delta, gamma/PP, and epsilon cells. Typically, when scientists study islets, they treat these cells as a homogeneous group, collecting and studying them together. But this approach likely misses some key cell-specific differences that could help explain what goes wrong in diabetes. By taking advantage of recent advances in single-cell technologies, Stitzel hopes to bring clarity in this important area.

Finally, Stitzel and his lab members want to look at diabetes in a longitudinal sense — what events happen first and contribute to the diabetic state? What events are more downstream and likely consequences of disease? These efforts are ideally suited to the various mouse models of diabetes are JAX cornerstones. Stitzel and his colleagues plan to look for the key changes that arise early in the mouse and then extend those studies to understand which events also transpire in humans.

“Here at JAX, we can really leverage the genetic diversity in the mouse, and we can also ‘humanize’ regions of the genomic dark matter in the mouse,” says Stitzel. “That is the only way we are really going to be able to look at longitudinal effects and distinguish causality versus correlation.”

Although he is not realizing his childhood dream of blasting off into space to survey the far reaches of the solar system, Stitzel is nevertheless exploring a vast, unknown realm. He is probing a universe, exceedingly small and unseen, that is tucked away inside our cells. “In this world, you never have a firm ending. You never have a guaranteed outcome,” he says. “You are just digging into the unknown and seeing what comes out.”


Nicole Davis, Ph.D., is a freelance writer and communications consultant specializing in biomedicine and biotechnology. She has worked as a science communications professional for nearly a decade and earned her Ph.D. studying genetics at Harvard University.