"A" is for axolotl, a funky looking salamander regarded by the Aztecs as a delicacy and by cell biologists who believe it could hold the key for unlocking regeneration. The axolotl (Ambystoma mexicanum) is not new to science. It's been used in the lab for over 150 years and like many lab animal systems, the axototl has had peaks and valleys of popularity. But David Gardiner, professor at University of California, Irvine (UCI) and an ASCB member, has been working on regeneration with axolotls for over 30 years. It was his wife, Sue Bryant, who is also a UCI professor and fellow ASCB member, who first introduced Gardiner to this nontraditional animal model.
Gardiner recalled, "Sue and I have been working together (on this) for 30 something years." Bryant is from the UK and was an undergraduate with Lewis Wolpert in London. It was Wolpert who got her hooked on the idea of pattern formation and that led her to the study of regeneration. Gardiner said, "She wrote a big essay on everything that was known about regeneration, and Wolpert said, 'That's fine, but how does it work?' He said 'why don't you go find out?'" Bryant came to the US to do a postdoc, working on regeneration in lizard tails and, as Gardiner says, "She never made it back to England." She also discovered the axolotl as a possible experimental system for regeneration studies.
"The point of the nontraditional organism is they allow us to see what is possible," Gardiner said. "We know a lot about a very select group of model organisms that share certain features, like they are really good for doing genetics, they're rapid developing, and you can do mutant screens. What's happening now is that we're taking that information and starting to work on organisms that have interesting biological properties, like regeneration," Gardiner explained. "We're learning how the fundamental biological properties work and somebody else can use that information in a model organism that's more translatable," he said.
Gardiner's lab is focused on how developmental signaling pathways are used in regeneration. They're also interested in how the extracellular matrix is involved in recruiting cells for regeneration. Putting pluripotent cells into patients could lead to problems, he explained, but by manipulating the matrix you could recruit the patient's own cells to incorporate into that matrix and restore some function. "The people who are interested in what we do are tissue engineers or biomaterials engineers," he explained. "They're trying to engineer bioactive stuff, scaffolding or something that you can put into a patient and take advantage of this endogenous regenerative response, recruit cells, control cell fate, restore structure."
Axolotls made their way to research from the Valley of Mexico's Lake Xochimilco and Lake Chalco during the French occupation of Mexico in the 1860s, when live specimens were shipped to Auguste Dumeril, a French zoologist. The wild axolotl may be extinct in its native habitat due to competition and predation from non-native carp and tilapia.
Ironically, axolotls are easy to breed in the lab unlike other salamanders or newts. However, there are obstacles for lab use. It takes a full nine months for axolotls to reach sexual maturity, making it difficult to manipulate their genes. Nor is the axolotl genome is completely sequenced. "It's 10 times the size of the human genome and people have been reluctant to sequence it. But Randal Voss at University of Kentucky has been working on it and his lab is ready to publish the sequence of the first chromosome, which is the size of one human genome. A lot of the extra DNA is not junk DNA, it's in really giant introns. It's pretty fascinating," Gardiner said.
It's also difficult to work with a nontraditional organism but uncommon lab creatures like the axolotl offer new perspectives, according to Gardiner. "This stuff is hard. But flies were hard and worms were hard. It's just you had thousands of people in hundreds of labs around the world working on them," Gardiner said. "But we're beginning to see the next generation of young scientists looking for problems to work on and ways to do it. The resources are there." Gardiner says that there is funding available for axolotl regeneration through the National Science Foundation and the Department of Defense.
For all their problems, the axolotls in his lab have given Gardiner a system for tackling the very difficult question of limb regeneration. Don't pick a scientific problem just because it seems doable, Gardiner urges young scientists, "If you're going to set your sights on some long-term research goals, you need to pick something big. Regeneration is a really good one. The idea is that we have these abilities to heal ourselves, we just need to enhance that ability or provide some scaffolding or something." Gardiner continued, "I have to believe what we learn from this research will have relevance to humans."