Cardiac Surgery: Living, growing heart valves made in the lab
Endocrinology: A gene for height?
Infants and children who receive artificial replacements for missing or malformed heart valves face several more heart operations as they grow, since the replacements become too small and must be traded for bigger ones. Virna Sales, MD, John Mayer, MD, and colleagues in the Department of Cardiac Surgery have developed a solution: living, growing valves created through tissue engineering.
In a special issue of Circulation published September 11, they describe making pulmonary valves in the laboratory. These valves, which provide one-way blood flow from the heart's right ventricle into the pulmonary artery, are often
malformed in congenital heart disease, putting an extra burden on the heart. The researchers first isolated endothelial progenitor cells (precursors of the cells that line blood vessel walls) from the blood of laboratory animals. They then "seeded" the cells onto tiny, valve-shaped biodegradable molds pre-coated with proteins found in the natural "matrix" that surrounds and supports cells. Experimenting with different matrix proteins and growth factors, they were able to make pulmonary valve leaflets that had the right mechanical properties—sturdy yet pliable.
Sales is now refining the lab-grown valves by exposing them to mechanical stress in a bioreactor and using a "cardiac jelly," rich in growth factors and matrix proteins, to mimic natural valve formation in the embryo. Her next step will be to implant the living valves into animals. She and former surgical research fellow Bret Mettler, MD, have already used tiny tissue-engineered patches in sheep to rebuild a portion of the pulmonary artery, an area that often needs augmentation in patients with congenital heart disease. The patches grew over time and functioned well for up to six weeks.
It's long been obvious that height is an inherited trait, but so many genes probably contribute to stature that no one's been able to pinpoint a single one. Now, a collaboration co-directed by Joel Hirschhorn, MD, PhD, of Children's Hospital Boston and the Broad Institute has done just that. The findings appear in Nature Genetics.
In the most thorough search ever done for genes that regulate height, Hirschhorn and colleagues from Peninsula Medical School/Exeter University, the University of Oxford and other institutions scanned the complete genomes of nearly 5,000 people—some 30,000 genes each. They then validated their findings in samples from more than 22,000 adults and nearly 7,000 children. Many genes they'd expected to be players didn't show any special association with height. But one gene, called HMGA2, did: having a "C" rather than a "T" at a certain spot on the gene added a small gain in height.
Hirschhorn speculates that HMGA2 may have something to do with early cell
proliferation, possibly in the pituitary gland, which makes growth hormone. Interestingly, increased HMGA2 activity is also associated with certain types of cancer, perhaps triggering a similar but unwanted cell proliferation.
Although this HMGA2 variant explains less than half a percent of a population's height variation, its discovery is the first clue that researchers may be able to find many other genes that regulate height and learn how they work together, Hirschhorn says. "To find more height genes, we will need to look at hundreds of thousands of samples, and we'll soon be able to do this."
Knowing the responsible genes will give insights into the biology of growth, which is poorly understood. And in the clinic, genetic testing might eventually help reassure parents that their child's short stature is simply an inherited trait, not part of a nutritional problem or underlying disease.
More immediately, Hirschhorn hopes that understanding how genes influence height may help illuminate the genetics of common, genetically complex diseases like diabetes and cancer. "Since height can be accurately measured in hundreds of thousands of people, it may be a path to understanding very subtle gene effects," he says.