To accelerate genome sequencing applications for patient care, the National Human Genome Research Institute today, Tuesday, Dec. 6, announced the establishment of two major programs at the University of Washington.
Center for Mendelian Genomics: The UW will be home to one of three new centers nationwide that will search for the genes underlying Mendelian disorders. These are inborn diseases and birth defects caused mainly by single-gene mutations. Conditions like cystic fibrosis, sickle cell anemia, and muscular dystrophy are called Mendelian disorders because they are inherited in families in a pattern similar to those discovered by Gregor Mendel, a 19th century friar. There are more than 6,000 of these Mendelian disorders. While most are rare, in conglomerate inherited diseases affect millions of Americans. Importantly, the causative gene has been found for less than half of these conditions, and of these, only a fraction have treatments. Understanding these disorders also sheds light on human biology that can help in treatment of more common disorders.
The new UW Center for Mendelian Genomics, along with the Center for Mendelian Disorders at Yale University and the Baylor-Johns Hopkins Center for Mendelian Genetics, will use the latest advances in rapid genome sequencing to aid in the discovery of the genetic changes responsible for these illnesses. They will collaborate with each other and with a global network of rare disease experts to sequence the genomes from patients and their families to identify genetic variants and their possible link to disease. The UW group will also serve as the coordinating center for this large-scale effort.
The principal investigators for the center are Drs. Deborah Nickerson, Michael Bamshad, Mark Rieder, and Jay Shendure, all of the UW Department of Genome Sciences. Bamshad is the chief of genetic medicine in the UW Department of Pediatrics. Funding for the UW Center of Mendelian Genomics will be $5.2 million a year for four years.
Clinical Sequencing Exploratory Research Project: The second new National Institutes of Health initiative announced today will fund Clinical Exploratory Research Projects. The UW will conduct one of the five projects, all designed to speed the application of genomic science to medical care. Other projects will be at the Baylor College of Medicine in Houston, Brigham and Women’s Hospital in Boston, the Childrens Hospital of Philadelphia, and the University of North Carolina Chapel Hill.
These projects will explore the ways health care clinicians might use genome sequencing information in caring for patients. Health care professionals, genome scientists, ethicists, patients and patient families will work together to learn important lessons from actually applying genome sequencing information in a medical setting. From these findings they will develop methods to improve the future use of patient and family genome sequencing data in clinical practice.
“The research teams will try to reveal barriers and cover all of the issues that need to be addressed in order for genome sequencing to become a routine component of medical care,” said Dr. Eric D. Green, director of the National Human Genome Research Institute.
At the UW, researchers will work with people diagnosed with colon cancer to discover new approaches — as well as pitfalls — of incorporating the data gleaned from sequencing the entire protein-coding regions of the genome, the exome, into patient care. Using this specific type of cancer as an example, the researchers hope to find the commonalities that can be applied more generally to the medical, personal, family, social, ethical, legal and economic issues raised by clinical genomic sequencing.
The UW will receive $2.3 million a year from the National Human Genome Institute and the National Cancer Institute. Pilot studies leading to the successful proposal were funded by the State of Washington through the Life Sciences Discovery fund.
Dr. Gail Jarvik, professor of medicine and head of the Division of Medical Genetics in the UW School of Medicine will lead the project, including a diverse team of experts. Dr. David Veenstra, professor of pharmacy, will oversee the outcomes aspect. Drs. S. Malia Fullerton and Wylie Burke from Bioethics will explore the social, legal and ethical realms of genome sequencing in health care, and Mark Rieder and Deborah Nickerson from Genome Sciences will manage the technological and basic science components.
Jarvik and Nickerson said that the new Mendelian Genomics Center and the Exploratory Clinical Sequencing Project build on the long-standing strengths of the UW in the fields of genomic sciences and medical genetics. Through ongoing collaboration between basic science and clinical faculty, the UW is well-prepared to move genome sequencing advances into patient care settings.
The UW’s Northwest Genomics Center, which Nickerson heads with Rieder and Shendure, and the UW’s National Heart, Lung and Blood Institute-funded exome center under Bamshad, have made major strides in reducing the costs and increasing the accuracy of new sequencing technologies. The Northwest Institute of Genetic Medicine, directed by Jarvik and funded by the Washington State Life Sciences Discovery fund, works to make these technologies broadly accessible to medical scientists in our state.
“These new technologies, combined with new analytical methods in statistical genomics, have enabled UW researchers to identify the underlying genes in several rare diseases, including Kabuki syndrome and Miller syndrome,” Nickerson said.
“These technologies have also allowed us to find a lipid gene that may influence heart disease,” Jarvik added.
“We look forward to this new opportunity to work with colleagues at the other two new Mendelian disorders genome centers, and rare disease experts around the world, to uncover the mechanisms underlying many rare disorders, ” Nickerson said.
She and co-principal investigator Jay Shendure explained that identifying such genes opens up avenues to understanding the biochemical mechanisms behind the symptoms of inherited diseases. Knowing which proteins or biological pathways are changed due to a rare variation in a human gene may suggest possible treatments.
Nickerson and Shendure also pointed out that understanding the nature and activities of single gene rare disorders also can provide insights to more common disorders in which similar mechanisms are disrupted.
Nickerson gave as an example genetic studies for rare, inherited disorder in which several family members had unusually high lipid (blood fat) levels leading to early on-set heart attacks. This research helped elucidate a more general understanding of cholesterol metabolism and the problems faced by many people with more common forms of high cholesterol.
In the Clinical Sequencing Exploratory Project, researchers from a wide variety of disciplines will enter some uncharted territories.
“This project is at the forefront of genomic medicine. We need to explore the needs of patients and referring physicians, the economic and social implications, as well as the genomic technology and interpretation. One exciting challenge is to determine which genomic information is useful to patients. In sequencing all of the protein-coding region of the genome for our patients who come to us with early onset (before age 50) colon cancer, we might find other mutations that might affect their health or the health of their families,”
Jarvik said. An example might be seeing a genetic change that would cause resistance or sensitivity to a drug.
“We plan to return the information we gather to the patients,” Jarvik said. Clinicians in the age of genomic medicine will need to learn how to interpret the results for their patients, not just from a bio-medical perspective but also with a sense of how the knowledge will affect them psychologically and socially.
In carving the path to clinical genomics, the researchers in Clinical Sequencing Exploratory Project will examine the integration of genomic data into clinical care from a variety of perspectives. By comparing a group of patients receiving best standard care with those who have exome testing incorporated into their care, the researchers will look not only medical outcomes, but also at efficiency, cost effectiveness and the patients own reports.
They will also measure the patients and physician needs and goals, and touch upon some of the ethical, social and legal issues in using genomic data in health care. Bioinformatics experts will propose ways to include extensive genomic data in a patients records and software tools helpful to physicians . The researchers also hope the study will help identify as yet unknown genetic mutations for colon cancer, thereby improving knowledge about this common cancer.
“Because of the amazing advances in genomic technologies,” said Veenstra, “this project will provide wide-ranging information about disease diagnosis, the risk of future diseases, and other estimates, such as how well a patient with a particular mutation responds to certain drugs. This information could affect a patient and his or her family in terms of their health, quality of life, and decisions about healthcare.”
Veenstra explained, “Our multidisciplinary team will ask patients about their experiences, and measure their quality of life using surveys. We will also ask them about their healthcare decisions and expenditures.”
Veenstra said the project results might help healthcare professionals better explain to patients considering genomic sequencing what they might experience.
Jarvik mentioned some of the other goals the project would like to achieve.
“We hope the findings from this project will provide guidance for the implementation of genomic medicine and data for public policy decisions.” Jarvik said. “We will begin to learn if clinical exoming will improve health care outcomes and reduce health care costs, and whether it will help us as health care professionals personalize prevention and treatment for our patients.”
All of the researchers interviewed agree that genome science has arrived at an exciting point when the much heralded possibilities of human genome science are closer to becoming more widely applied in patient care.
A briefing from the National Institutes of Health on the nationwide effort to accelerate the application of genomic sciences to medical practice and understand the issues this poses will be available to the public at www.nih.gov before 2 p.m. PST, Tuesday, Dec. 6.