Disease is the disorder or abnormal condition of a structure or function. Nearly one in every 100 babies are born annually with a congenital heart defect — a large portion of such defects found in the heart valve, responsible for unidirectional blood flow. The continued misunderstanding of heart formation despite advances in the human genome library makes us rethink whether we are thinking about development and disease wrong.
Cornell researchers have found that a focus on the signaling microenvironment rather than the genome may lead us closer to understanding disease.
As the genome provide instructions for developing into an embryo, how exactly does the body sculpt its own tissues such as the heart, and can understanding of these mechanisms heal malformations and eventually disease?
Prof. Jonathan Butcher, biomedical engineering, associate professor at Cornell University Nancy E. and Peter C. Meinig School of Biomedical Engineering, said yes.
“Most scientists look for molecular signatures that precede formation of a defect—the genetic inducers that will lead to disease,” Butcher said. “But the cell is like a social being that interacts with its neighbors in the environment, and these interactions provide cues for what it should become.”
The heart is the first organ to form in the embryo. During development a human heart is morphing dynamically and rapidly, all while pumping nutrients and keeping the body alive. A single tube is able to transform into four chambers and eventually develop valves to maintain unidirectional blood flow.
The presence of a heart valve is an advanced structure that only two phylum have: vertebrates and mollusks. Considering how phylogenetically distant they are, it is a fascinating feature to consider. Different organisms vary in size and need to perform certain actions with a certain amount of energy. Humans are large and need a heart with lots of energy, and therefore need valves.
“When the heart beats, tissue is exposed to cyclic periodic stretch which actively switches between signaling programs. With no switch, no valves will form,” Butcher said. “The heart assumes a continuum of bringing about its own maturation and is well-tuned to doing this.”
Cornell researchers pursue this approach by looking at the signaling mechanical microenvironment surrounding heart formation. By modulating the mechanical environment, researchers can see how the heart controls signaling programs in that environment to bring about proper structure or malformed structure — looking backward rather than forward.
A recent discovery in the Butcher Lab identified the signaling mechanism that coordinates this cyclic stretch by activating enzymes called RhoA and Rac1 — specific proteins known as GTPases that translate and amplify signals within the cell. A cyclic stretch deactivates RhoA and activates Rac1, which then switches back to activating RhoA and inactivating Rac1 in a cyclic rhythm with each beat.
“We initially were interested in how mechanical forces were translated into a biological response in the developing heart,” said Russell Gould, postdoctoral researcher at Johns Hopkins University and formerly a part of Butcher’s lab.
“A valve needs to get stronger and condense into a strong, fibrous leaflet. While early cushion formation requires RhoA signaling, the transition to remodeling the heart form requires Rac1 signaling,” Butcher said. “It is this maturation process that is likely the source of these heart malformations.”
Using chick embryos, the lab sutured off different sides of the heart to shunt blood flow. In doing so, the heart valves were either over-developed or under-developed. This discovery led to the hypothesis that blood flow and pressure was capable of shaping the heart valve structure.
Butcher’s focus on the signaling microenvironment rather than the genetic predisposition led to a successful foundation for “hemodynamically informed surgical interventions that potentially retard valve malformations, or to restore it,” said Gould.
Another example of this kind of reverse-disease thinking is a current Cornell study on heart calcification. A good model is considered able to test therapeutic cases in which the calcium disease state is present and clinically accurate. Scientists used to study culture systems that develop calcification in order to stop and reverse when present.
Lara Estroff, associate professor in Materials Science and Engineering, has successfully synthesized nanoparticles that mimic native calcification. Taking these particles into a 3D culture system, researchers have been able to begin with a model already in the disease state. Using these particles in a culture environment, cells start in the disease state instead of being healthy which is clinically relevant because patients come into have already began calcification.
Programs may be already turned off to disease process and patients are already past the point in which development of disease is irrelevant. Studying the process of signaling and reversing disease using a signaling approach this way we are taking rugs to prevent what happens in the future.
Scientists of different expertise from across department and institutions are working together and continuing to contribute their individual assets and skills to further develop this idea. Translating such findings directly to medicine has evolved into an incredible example of scientific collaboration — on Cornell University campus to the Weill Medical College and beyond.