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.
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.