The gene detective

For decades, scientists have searched our DNA for clues about the origins of disease, seeking to find the culprit genes and the key changes within those genes that can disrupt normal biology. In the early days of gene sleuthing, long before the Human Genome Project and the advent of high-throughput tools for DNA sequencing and analysis, this work was slow and somewhat hit-or-miss. It also tended to focus on single-gene diseases like cystic fibrosis or Huntington’s disease. Although such conditions are rare, they stem from just one aberrant gene, and are therefore more readily deciphered.

Fast forward about thirty years, and now, researchers at The Jackson Laboratory (JAX) and across the world are able to set their sights on a range of devastating maladies, including diseases that are not only more common but also more genetically complex. These so-called “complex diseases,” including type 2 diabetes, cancer, Alzheimer’s disease, and many others, are the work of multiple genes — tens or even hundreds — that collude to increase a person’s risk of illness.

This increased complexity brings new challenges, and requires robust methods to sift through ever-increasing quantities of data— encompassing not just individual genes but entire genomes — to reveal telltale patterns and connections that point to the genes involved in disease. For the past twenty-five years, JAX Professor Carol J. Bult has been at the forefront of these data-mining efforts. A computational biologist who joined JAX in 1997, Bult is wielding the powers of quantitative science to crack open big biological problems.

“It is very much like detective work,” Bult says. “If you are trying to solve a crime, you look at some of the usual suspects, but you don’t just focus on one individual — you look at whom they associate with as well. You follow those associations, and you start building a picture not about an individual, but about a network of individuals that might be in collusion.”

Bult is deeply passionate about these pursuits, but what drives her is not one particular disease per se, but rather the desire to apply her expertise in meaningful ways. “[As a scientific community], we’ve invested all of these resources in generating large data sets, and you generate the data, you publish one paper, and then you move on to the next [problem]. I think it’s a lost opportunity not to take advantage of all the information that is out there, that has been published from different data sets, and to get new information out of it.”

Over the course of her career, Bult has worked on a variety of questions in human biology. One that looms large these days involves a common and often deadly birth defect. Known as congenital diaphragmatic hernia (CDH), the disorder is characterized by a hole in the diaphragm, the muscular sheet that separates the abdominal and chest cavities. Because of this hole, the liver and even the stomach can move up into the chest and impinge on the lungs, restricting their growth and compromising function. Although the condition can be surgically repaired, the mortality rate remains quite high, around 50 percent. Those who do survive have long-term health problems.

Although scientists have recognized that CDH has genetic roots, the disorder involves a multitude of genes. Together with collaborators at the Massachusetts General Hospital in Boston, Mass., Bult and her team have been scouring databases filled with genome-scale data sets, spanning both human and mice, to reconstruct the intricate networks of genes that conspire to cause CDH.

“We’re using this kind of detective work approach to identify as many of the genes contributing to this defect as we can,” explains Bult. “We identify a suspect, and then we look in human populations to see if any of the affected individuals have a variation in the gene, and then we go to the mouse and re-create that variation in the mouse, and then ask, in the mouse, does this cause the disease or not?”

If the suspect indeed causes disease, then it becomes perpetrator number one, forming the first link in a vast genetic “crime ring” that underlies CDH. Then, Bult and her colleagues begin again — using guilt by association to identify other genes and gene variations that track along with the first, and then exploring how those work in the mouse. Through this iterative process, Bult and her team can reveal the entire network that underlies CDH. In fact, they have already identified a surprising new suspect gene, called PBX-1.

This find, together with the other suspects Bult is collecting, forms a critical knowledge base that sheds a bright light on the biology of CDH. Indeed, great power flows from this genome-based view of human disease. It is the foundation for a new era of medicine, known as genomic or precision medicine.

“When we say genomic medicine, we mean in every single case the possibility of knowing every single component contributing to that disease,” says JAX President and CEO, Edison Liu.

By assembling a comprehensive genomic picture of CDH, Bult and her colleagues are not only improving the biological understanding of the disorder, but also accelerating efforts aimed at finding more effective methods for diagnosis, treatment, and prevention.

“For 90 years, JAX has been the premier institution for using the mouse as a model for human diseases, and it’s allowed us to delve deeply into the biology of specific genes, and how those genes interact with one another,” says Charles Lee, scientific director of JAX Genomic Medicine. “Now, we can take the technologies that we have, the knowledge that we’re building, the research that we’re doing, and directly bring it back to the patient.”

For Bult, this is the opportunity of a lifetime. “The fact that I’m getting to work at a place that is setting the stage for the future of precision medicine, the application of those basic concepts into patient care, that’s not something I could have anticipated,” she says. “It’s an extraordinarily rewarding and exciting time.”

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