scientist using pipette microscope

New stem cell projects will examine how gene variants cause disease

Nine studies focus on heart, lung, and blood diseases

The National Institutes of Health has funded nine new studies that will develop induced pluripotent stem cells, or iPS cells, from patients with genetic variations that have been associated with coronary artery disease, pulmonary hypertension, clotting disorders, diabetes, and other conditions. Building upon previous genome-wide association study (GWAS) findings, these studies will seek to illuminate how gene variants lead to the physical manifestations of disease.

"These studies will illuminate how specific genes behave in different tissues and should clarify the mechanisms by which a gene associated with a disease affects the biology of different tissues," said Susan B. Shurin, M.D., acting director of the NIH's National Heart, Lung, and Blood Institute, which is funding most of the studies. "Understanding the cellular and tissue biology will allow us to develop and test new therapies and prevention methods. These approaches using iPS cells on a large scale could improve the predictive value of preclinical testing, benefit regenerative medicine, and reduce the need for animal models of disease."

The nine cooperative agreements total $85 million over five years. The NHLBI is contributing $76 million and the NIH's National Human Genome Research Institute (NHGRI) is contributing $9 million of the total.


Why conduct these studies?

Sampling internal organs such as the liver, kidney, heart, lung, or bone marrow requires invasive procedures that entail discomfort and some risk to the patient. The samples obtained are often quite small. Many genetic, molecular, and biologic tests are done on tissue samples taken from the blood, urine, saliva, skin, or hair of living patients to avoid such risks. Studying those samples often doesn't give researchers a useful picture of a disease, because each type of tissue has a different set of functions determined by the expression of a different combination of genes. Transforming easily harvested samples into iPS cells and then differentiating them into heart, lung, or other types of cells should provide a noninvasive way to more completely model and understand disease.

The newly funded projects will develop improved technologies and techniques for creating and differentiating iPS cells more efficiently. Effective tools will be scaled up so that iPS cells can be created from hundreds or thousands of patients and healthy volunteers and applied to large populations of people.

Once the iPS cells are developed and transformed into various tissues, the researchers will be able to conduct tests on their "diseases in a dish." The researchers will be able to assess how the tissues react to a drug or to environmental changes such as low oxygen levels. The results should provide information about the molecular and cellular effects of genetic variation, the mechanisms of disease development and progression, and the way tissues with genetic variants respond differently at a cellular level to medical therapies and environmental factors.

"We have an opportunity here to study tissue-specific cells on a large scale, including how gene variants are expressed and alter a tissue's behavior," said Cashell Jaquish, Ph.D., a program officer in the NHLBI's Division of Cardiovascular Sciences. "That is something we haven't been able to get near before" because the technology was not available. The opportunities are great because genome-wide association studies have identified multiple potentially important genetic variants, she added.


What are the nine studies?

  • Eric Topol, M.D., at the Scripps Translational Science Institute, La Jolla, Calif., will investigate a genetic variant associated with coronary artery disease, heart attack, and aneurysms.
  • Marlene Rabinovitch, M.D., at Stanford University, Calif., will study rare genetic variants and other genetic and epigenetic changes related to pulmonary hypertension, which could in turn improve the understanding and treatment of other blood vessel diseases.
  • Thomas Quertermous, M.D., at Stanford University, Calif., will develop and study iPS cells from several hundred people with insulin sensitivity to gain further insight into type 2 diabetes, insulin resistance, and susceptibility to other cardiovascular disease.
  • Ulrich Broeckel, M.D., at the Medical College of Wisconsin, Milwaukee, will investigate the molecular mechanisms that underlie the genetic basis of left ventricular hypertrophy (enlargement of the left side of the heart).
  • Daniel Rader, M.D., at the University of Pennsylvania, Philadelphia, will develop iPS cells and iPS-derived liver cells to learn more about the fat that leads to coronary artery disease and metabolic disorders.
  • Kelly Frazer, Ph.D., at the University of California, San Diego, will turn iPS cells into heart muscle cells to study how human genetic variation influences cardiac biology and disease, potentially including new insight and treatments for irregular heartbeats such as ventricular arrhythmia and atrial fibrillation.
  • Lewis Becker, M.D. at the Johns Hopkins University, Baltimore, will use iPS cells to study platelets and blood clotting with the goal of better understanding the genetic basis of thrombotic disease and differences in how aspirin works in people. The work could provide insight into other diseases as well as personalized medicine (pharmacogenetics).
  • Martin Steinberg, M.D., at the Boston University School of Medicine will develop technology to mass-produce sickle cell anemia-specific iPS cells. By studying these cells and their offspring, he hopes to better understand how genes are involved in sickle cell disease.
  • Chad Cowan, Ph.D., at Massachusetts General Hospital, Boston, will build on the association between LDL or "bad" cholesterol and gene variants associated with heart attack. He will derive liver and fat cells from blood cells and study them to learn more about gene expression and metabolism.