MDI Biological Laboratory
Regeneration

Limb Regeneration: Fitting the Pieces of the Puzzle Together

  • June 4, 2020

The phenomenon of regeneration has fascinated scientists for hundreds of years. But until the last decade, scientists haven’t had the molecular and genetic tools to unravel its mysteries. These advances have changed the landscape of regenerative biology – particularly so at the MDI Biological Laboratory.

Though limb regeneration has been studied at the laboratory since the mid-20th century, these new tools, along with the addition to the faculty of regenerative biologists James Godwin, Ph.D., in 2016, and now, of Prayag Murawala, Ph.D., are establishing the MDI Biological Laboratory as global hub of research in this area.

Godwin and Murawala are studying limb regeneration in the axolotl, a Mexican salamander that can regenerate virtually any body part, including limbs, brain and heart. The aim of Godwin’s and Murawala’s research is to determine why adult mammals form a scar at the site of a wound or injury instead of regenerating the missing part as axolotls do. Ultimately, they want to be able to identify molecular targets for pharmaceutical therapies to enhance regenerative ability in humans.

As a result of advances in regenerative biology, scientists like Godwin and Murawala are identifying the elements involved in the cascade of molecular events required for the formation of a new digit or limb. But they have yet to figure out how these elements fit together and how they communicate with one another. 

“I think of the former state of the field as a puzzle in which the pieces have no pictures. Now, with the molecular and genetic tools in place, it can be thought of as a puzzle with pictures on the pieces, which means that the real work of fitting the pieces together can begin.”

Prayag Murawala, Ph.D., MDI Biological Laboratory faculty

If regeneration is a puzzle, Godwin and Murawala are working on two of the major sections. Godwin’s focus is on the role of the immune system, while Murawala’s is on the blastema, the bud of tissue that is transformed into the muscle, cartilage, skin, nerve and bone of a new limb that is properly positioned and organized. “Our work is complementary,” says Godwin. “Though it’s unusual for two research groups to be working with the axolotl at the same institution, in this case it will help us both in terms of sharing resources and opening up new funding opportunities.”

Godwin has discovered that the innate immune system, or the system an organism is born with, promotes regeneration and that the adaptive immune system, which develops in response to exposure to pathogens, is a barrier to it. Thus, it is easier for an axolotl, which lacks a complex adaptive immune system, to regenerate than it is for a mammal. “We believe this is an evolutionary trade-off,” Godwin explains. “As mammals evolved, they developed highly specialized adaptive immune systems to protect against bacteria and other pathogens, for instance by sealing a wound with a scar. But this response is a barrier to scar-free repair, which is a prerequisite for regeneration.”

Murawala’s section of the puzzle involves specialized cells called fibroblasts that are recruited to form the blastema. These cells, which encode positional information from the remaining part of the limb, interact with one another to program the transformation of the blastema into a new limb structure with a normal pattern. Murawala brings to his new position the extensive expertise he acquired as a post-doctoral fellow at the Research Institute of Molecular Pathology in Vienna, Austria, where he worked with Elly Tanaka, Ph.D., who is considered the world’s foremost investigator of limb and spinal cord regeneration.

 

Though the axolotl is ideal for the study of regeneration, it isn’t a common model due to the fact that the tools to work with it have been limited until now. For example, its genome, which is 10 times longer than the human genome – perhaps because of the complex instructions required for regeneration – was only recently sequenced. And it’s perhaps serendipitous that many of the laboratories studying limb regeneration in the axolotl are located in the Northeast. Outside of Tanaka’s laboratory and a few others, Boston and now Maine are home to most of the world’s axolotl laboratories, making New England a powerhouse of axolotl research.

“The concentration of the current generation of investigators in limb regeneration in the Northeast presents a great opportunity for the MDI Biological Laboratory,” Haller says. “We look forward to building on our traditional role as a meeting place for scientists by becoming a regional center for research in this area.”

The implications of solving this complex puzzle are far-reaching. Limb loss is more common than most people realize, with causes including combat, accidents and diseases such as diabetes. More than 2 million people live without a limb in the U.S. – a number that is expected to double by 2050 due to the increased prevalence of diabetes. An increased understanding of limb regeneration could also lead to regenerative therapies for tissues and organs, including the heart and brain, as well as to other clinical applications. Murawala notes, for instance, that the ability to simply mitigate scarring would have an enormous impact on millions of people.


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