Profs. Susan Braunhut and Kenneth Marx have teamed up to pursue a “mind-blowing” innovation—to cause a limb to re-grow in an adult mammal.

The UMass Lowell research group has joined groups from five other institutions and secured funding from the Defense Advanced Research Projects Agency (DARPA). The UMass Lowell portion of the DARPA grant is $1.2 million for the first two years, with an anticipated continuation of $1.4 million for the next two years.

The research groups expect that by working together they will gain a more complete understanding of the cellular and molecular processes that allow certain creatures, such as salamanders, to completely regenerate lost limbs, and be able to harness this capacity in mammals.

“As a consortium, we’re putting together our knowledge of stem cells, tissue development and healing, extracellular matrix, growth factors and the regulation of gene expression,” says Braunhut. “We’re encouraged by research results and recent discoveries and we believe this goal is attainable.”

The implications of such research are especially evident considering the wounded soldiers returning from Afghanistan and Iraq include twice the number of amputees of previous conflicts and wars.

Braunhut and Marx had already taken great strides in understanding the role of the cell scaffolding, or extracellular matrix, in healing—work that has been spun off into a commercial wound-healing application, the Smart Bandage™. Now they will be working on understanding how the matrix derived factors can compel mammalian cells to express the genes promoting limb regeneration, at the right time and in the right order.

Coordinating the consortium’s effort is Stephen Badylak, D.V.M., M.D., Ph.D., research professor of surgery at the University of Pittsburgh School of Medicine and director of the Center for Pre-clinical Tissue Engineering. The consortium includes other senior investigators with diverse, yet complementary, research interests. They include two leading salamander researchers, Dr. Hans-Georg Simon from Northwestern University and Dr. Shannon Odelberg from the University of Utah, a specialist in  stem cells and retinoids from Cornell Medical School, Dr. Lorraine Gudas, and an immunologist from The Wistar Institute, Dr. Ellen Heber-Katz, who has studied a ‘super-healer’ mouse called MRL.

Some cells in adult humans, such as liver cells, are capable of self-renewal; and embryonic stem cells can form many diverse tissues, if provided with the right signals. But humans usually respond to injury with scar tissue, while salamanders instead form a blastema, containing a large pool of progenitor cells that will specialize and grow to form the bone, muscle, cartilage, nerves and skin of the regenerated limb.

The team will begin with intense study of salamanders and the super-healer mouse, MRL, to develop a comprehensive understanding of the mechanisms and processes—to obtain a blueprint—for regenerative growth. The team will then attempt to orchestrate the formation of a blastema in a non-healing mouse, where scar tissue would normally form.

DARPA demands high levels of accountability and an aggressive schedule—continued funding is contingent on six-month milestones, a fact the UML group appreciates.

Marx says, “It’s exciting to be involved with research that moves beyond the cautious, incremental approach.” Marx will analyze all the data from the consortium researchers to identify the molecular signature of regeneration. “Thousands of genes are expressed simultaneously; we’ll be looking for markers and their temporal order of expression. We have unique software to work with—a tribute to our bioinformatics expertise and Marx’s prior work with Professor Georges Grinstein (UML professor of computer science and director of the Bioinformatics Program).”

“Our goal is to discover what’s really required to change the molecular path from developing scar tissue (in response to injury) to developing a functional limb,” says Braunhut. “For example, we’ll be looking at how cells are affected by the extracellular matrix and investigate how cells make the matrix. Then, using mouse embryonic stem cells or adult progenitor cells, we’ll investigate how the matrix guides these stem cells to construct the appropriate three-dimensional limb structure. Once that is understood, we’ll see how to stimulate adult circulating progenitor cells to form a blastema.”

The UML researchers are particularly grateful to Rep. Marty Meehan and his efforts to help Louise Griffin, vice chancellor for administration and finance, to bring DARPA Director Dr. Anthony Tether to campus a few years ago. His visit led to other DARPA-funded research for the UML team and the opportunity to interact with leading researchers in all specialties concerned with wound healing.

The interdisciplinary consortium is one of only two funded for the project, out of more than 100 applications. Much of the work here on campus will be in Braunhut’s new lab, outfitted with three cell culture rooms, new equipment and laminar flow hoods and a clean room. The working group includes three staff people and nine students, including one graduate student and four undergraduate biology majors, three from the honors program on campus.