The Mysterious Mechanics of Morphogenesis

Pitt Bioengineer Lance Davidson Receives $2.2M MERIT Award from NIH to Continue Study of Embryo Organ Development

Tissue engineering – creating a “seed” of tissue that could grow into a functional, life-saving organ – sounds like magic. But it could become technology, thanks in part to the work led by Lance Davidson, William Kepler Whiteford Professor of Bioengineering.

Davidson’s MechMorpho lab works at the interface of physics and biology to understand both biological and physical principles of morphogenesis: the development of embryonic form in the frog embryo. Their research not only lays the groundwork to better understand human cell and tissue development but also has implications for furthering tissue engineering, preventing birth defects, and understanding the effect of tissue mechanics on cancer cell growth and proliferation. The National Institutes of Health awarded Davidson a MERIT (Method to Extend Research in Time) Award of $2.2 million to carry out this work.

“We’re trying to understand, from a physical perspective, how organisms and their organs form,” said Davidson. “Development is commonly viewed as a cascade of biochemical reactions that “magically” generate the body and organs of the embryo. Our group seeks to open that magic black box and understand how physical processes convert those reactions into work and living structures.”

The MERIT award is a highly prestigious award provided by the NIH to only the most outstanding scientists. The five-year grant –with an opportunity to renew for another five years, based on progress made in the first five years – allows recipients to focus more on their research and less on the need to continually seek renewed funding.

“Lance’s research on how cellular biomechanics contributes to the development of organisms at the cellular and tissue levels has wide- ranging implications for human health,” said Mark Redfern, professor and interim chair of bioengineering. “This MERIT award is recognition by NIH of the importance of this work and the potential for new breakthroughs in the future. The very competitive award is well-deserved.”

The MechMorpho Lab’s long-term goal is to reverse-engineer the embryo and organ formation.

“There are a diverse set of chemical and physical pathways that regulate morphogenesis and that interact with the environment. In this project we want to understand how passive mechanics and active forces shape tissues in an early vertebrate embryo,” said Davidson. “We aim to understand the coupling between cell biological and physical mechanisms that drive cell shape changes, control cell behaviors, generate forces, and create tissue properties like stiffness.”

Embryonic Engineering

Convergent extension – the process by which an embryo elongates from a simple clump of cells and begins to take on the shape of its eventual body – is crucial to a vertebrate’s development. If the convergent extension process goes wrong, it often leads to developmental defects in organs and overall anatomy.

Understanding the mechanical basis of this process is a central question in developmental biology. It gives fresh insights into the fundamental principles of organ development and how a tissue assembles itself as it grows and regenerates.

To study this process, Davidson’s lab relies on frog embryos before they are recognizable as tadpoles. Frogs share a surprising amount of DNA with humans but develop much more quickly. In previous work, Davidson and his team were able to characterize the dynamics of key mechanical properties and the proteins involved in morphogenesis. They used confocal microscopy to observe protein complexes within living cells in an embryo on a sub-micron scale, finding that events happening on this microscopic level have a major impact on large-scale events.

Mechanical Memory

Organ growth can follow mechanical clues from their environment, but researchers don’t yet know how those clues are stored or how they dissipate. At the intersection of developmental biology and bioengineering, Davidson is in a unique position to understand these important processes.

In this project, the team will dig deeper and understand how tissues store mechanical information.

“If genes are interacting with mechanics, the mechanics have to be able to hang around in a way that can be sensed by genetic pathways,” explained Davidson. “If mechanical stresses dissipate quickly, it is like a mechanical form of amnesia with cells forgetting their past and possibly resetting their biological processes to an earlier state.”

Reverse engineering organ and tissue development will be a great advance in tissue engineering, but it can also lead to medical interventions to better diagnoses and treatment.

“A great number of human diseases are associated with defects in mechanical signaling pathways,” explained Davidson. “Cardiovascular disease, for example, is thought to be triggered by defects in how cells interact with blood flow.”

The spread of cancer is also clearly dependent on mechanics, Davidson said, as cells are triggered to migrate out of a tumor by the mechanical microenvironment that surrounds them. “If you can modulate the environment around a tumor, and keep it in a softer state, the cells might just stay put,” he said.

This knowledge will give researchers a better basis to understand birth defects and their risk factors. For example, in spina bifida there are genetic risk factors but the mechanisms that cause them to manifest are unknown. If there is a clear mechanical element to the risk, future research could identify ways to offset this risk with medication.

“Our work opens the door for researchers to develop new hypotheses of morphogenesis and bioengineering tools to test them,” said Davidson. “With a better understanding of the role of mechanics in development, we can understand so much more about the human body and how we can overcome some of its most significant ailments.”

Mark Redfern Appointed Interim Chair of Bioengineering

Following the appointment of former Department Chair Sanjeev G. Shroff to Interim U.S. Steel Dean of Engineering, Professor Mark Redfern was named Interim Chair of Bioengineering. Previously Redfern had served as the Swanson School’s Associate Dean for Research (20082012) and Pitt’s Vice Provost for Research (2012-2017).

Redfern, who earned his PhD in bioengineering from the University of Michigan, began his Pitt career in 1988 as Assistant Professor of Otolaryngology in the School of Medicine, with appointments in Physical Therapy, Industrial Engineering, and Rehabilitation Science. He was among the pioneering faculty who helped to establish the Department of Bioengineering at Pitt in 1998, and as its inaugural Undergraduate Coordinator, he helped develop the undergraduate program’s curriculum.

Redfern is nationally and internationally known and respected for his research in the biodynamics of human movement and human factors engineering and leads the Human Movement and Balance Laboratory (HMBL). One of his long-standing research interests is postural control and the rehabilitation of patients with balance disorders. By taking an engineering systems approach to modeling and understanding how various pathologies affect patients, Redfern and his colleagues at HMBL investigate interventions that can improve diagnosis and treatment. The influence of aging on balance control and the prevention of falls is of particular interest, with his longstanding NIH-funded work investigating sensory integration processes that underlie a person’s ability to maintain balance when standing and walking.

Improving Vascular Graft Integration into the Body

A graft can be a life-saving device for coronary heart disease, which remains the leading cause of death for both men and women in the United States. However, at small diameters − such as the coronary artery in the heart – long-term graft failure rates are often higher than 40 percent.

A major cause of graft failure in coronary artery bypass surgery is compliance mismatch between the graft and the native vessel, which can lead to an accumulation of cells and blockages.

A multidisciplinary research team at the Swanson School of Engineering seeks to improve long-term graft functionality through a $2,664,522 award from the National Institutes of Health.

“The goal of this project is not to make a compliance-matched vascular graft; we have already done that,” said Jonathan Vande Geest, professor of bioengineering at Pitt and lead researcher on the project. “We are aiming to make a fully biodegradable small-diameter tissue-engineered vascular graft (TEVG) and keep it compliance-matched as it degrades and remodels.”

Vande Geest uses computational tools to develop TEVGs that are fine-tuned to match the implanted target; however, this development only addresses one of the challenges associated with these devices. TEVGs are often rejected by the body because they do not resemble a native artery, which is the obstacle the research team will tackle.

“The attractive part of a biodegradable graft is that you are allowing the host to direct the remodeling process,” Vande Geest explained. “We will optimize the TEVG before it is implanted, but we want the host to integrate and remodel it and, as such, improve its long-term functional performance.