The Humble Axolotl and the Quest for Human Organ Regeneration

The popular science article I'll point out today takes a look at research into axolotl biochemistry. The scientists involved are searching for ways in which they might be able to improve upon mammalian regeneration; the axolotl is one of the few higher species capable of perfect, repeated regeneration of lost limbs and severe damage to other organs. There are limits, of course, and the axolotl is just as mortal as any mammal, but mammals, ourselves included, have in comparison a very poor capacity for regeneration. We can barely grow back a fingertip, and even that only when very young, and not at all reliably. There are tantalizing hints that the capacity for far greater feats of regeneration still lurks within mammals, but disabled, or overridden. Mammals can regenerate during later embryonic development. The MRL mouse lineage can regenerate small injuries without scarring. African spiny mice have evolved to regenerate whole sections of skin perfectly, and don't appear all that different from other rodents in other aspects.

In addition to axolotls, researchers work with zebrafish, newts, and other highly regenerative species. It is an exercise in comparative biology, an effort to reverse engineer the important differences between these species and mammals. Some interesting advances have emerged in recent years. For example the human tumor suppressor ARF shuts down the exceptional regeneration of zebrafish when introduced into that species. This strongly suggests that the majority of higher species that have poor regenerative capacity do so because of evolved defenses against cancer. After all, the controlled cell growth of regeneration versus the uncontrolled cell growth of cancer are two sides of the same coin. Another important discovery centers around the role of macrophages and transient senescent cells in regeneration. The details of the intricate interactions between these and other cell types in injured tissue seems at the center of the choice between scarring or regrowth. Mammals scar, axolotls regrow.

Despite being a focus of attention for the popular science media, the prize here is not really a way to regrow lost limbs. That is a minor benefit. The real prize is a way to repair damage to internal organs, including important aspects of the slow-moving loss of function that arises with age, such as the internal scarring of fibrosis. Enabling axolotl-like proficient regeneration will be a form of therapy that partners well with the restoration of stem cell function in the old. Both lines of research may come to fruition in the clinic on a similar timescale in the years ahead.

Salamander's Genome Guards Secrets of Limb Regrowth

In a loudly bubbling laboratory, about 2,800 of the salamanders called axolotls drift in tanks and cups, filling floor-to-ceiling shelves. Salamanders are champions at regenerating lost body parts. A flatworm called a planarian can grow back its entire body from a speck of tissue, but it is a very small, simple creature. Zebrafish can regrow their tails throughout their lives. Humans, along with other mammals, can regenerate lost limb buds as embryos. As young children, we can regrow our fingertips; mice can still do this as adults. But salamanders stand out as the only vertebrates that can replace complex body parts that are lost at any age, which is why researchers seeking answers about regeneration have so often turned to them.

While researchers studying animals like mice and flies progressed into the genomic age, however, those working on axolotls were left behind. One obstacle was that axolotls live longer and mature more slowly than most lab animals, which makes them cumbersome subjects for genetics experiments. Worse, the axolotl's enormous and repetitive genome stubbornly resisted sequencing. Then a European research team overcame the hurdles and finally published a full genetic sequence for the laboratory axolotl earlier this year. That accomplishment could change everything.

After an amputation, a salamander bleeds very little and seals off the wound within hours. Cells then migrate to the wound site and form a blob called a blastema. Most of these recruits seem to be cells from nearby that have turned back their own internal clocks to an unspecialized or "dedifferentiated" state more like that seen in embryos. But it's unclear whether and to what extent the animal also calls on reserves of stem cells, the class of undifferentiated cells that organisms maintain to help with healing. Whatever their origin, the blastema cells redifferentiate into new bone, muscle and other tissues. A perfect new limb forms in miniature, then enlarges to the exact right size for its owner.

Arms, legs, and tails aren't the only body parts that laboratory axolotls can regrow. They also recover from crushing injuries to their spinal cords. They can regenerate a millimeter-by-2-millimeter square of their forebrain. Scientists don't know whether axolotls use the same mechanisms to regenerate their internal organs as their limbs. They also don't know why an axolotl can grow back an arm many times in a row but not indefinitely - after being amputated five times, most axolotl limbs stop coming back. Another mystery is how a limb knows to stop growing when it reaches the right size. But these may not be mysteries for much longer.

Comments

"This strongly suggests that the majority of higher species that have poor regenerative capacity do so because of evolved defenses against cancer."

Yet - many of these species including the axolotl, are extremely robust / resilient when it comes to cancer - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706275/

Posted by: Ira S. Pastor at July 7th, 2018 2:01 AM

This is complete speculation but (in response to Ira's counterpoint above) perhaps Axolotl is resilient to cancer due to its salamander associated neoteric state and therefore doesn't require tumor suppressor mechanisms the way mammals do?

Posted by: Anon at July 7th, 2018 8:56 PM

Perhaps it might be why it has good regenerative capabilities - if you've got really good anti-cancer mechanisms in place already, then you can afford to increase the cancer risk a bit by having better regeneration.

Posted by: Arcanyn at July 8th, 2018 2:15 AM

@Ira S. Pastor: In Norwegian pastor means higher priest.

Posted by: Norse at July 8th, 2018 8:21 AM

AgeX is pursuing this path for some time now.

Look at the work of Dr. Michael West @ AgeX:

"Induced Tissue Regeneration (iTR)

Some naturally-occurring animals such as the Mexican salamander can profoundly regenerate damaged tissues. Humans also have this potential, but only in the first weeks of development. Using advanced molecular and artificial intelligence technologies, we have identified pathways we believe may provide means of unlocking this profound biology in human medicine. The pathways suggest that they may also be integral to the biology of aging and cancer as well. Patents relating to this emerging technology called induced Tissue Regeneration (iTR), have been filed and animal studies are currently underway. iTR was the subject of a recent conference presentation from AgeX CEO Dr. Michael West."

http://www.agexinc.com/product-development-reverse-aging-tissue-regeneration/

Posted by: Adrian Crisan at July 8th, 2018 4:17 PM

Thanks for pointing this out Adrian, that's exciting !

Posted by: Spede at July 8th, 2018 5:46 PM

" ... that's exciting !" - there are lots of groups working on the same "regeneration path".

This is one of the most elegant solutions, not being cumbersome and prone to mistakes like Sens' "remove damage" approach. There are lots of question marks with their approach, just them and their followers doesn't seem to see those issues.

As an another example, just look at Frequency Therapeutics:

http://www.frequencytx.com/index.php

http://www.frequencytx.com/our-company/about-us.php

I keep an eye on Frequency TX for a while.

"The search started by looking to nature. Certain species can regenerate and heal specific cells and tissues, whereas that capability remains biologically elusive to humans and other mammals. For example, some amphibians can regrow limbs and amphibians and birds can regrow hair cells in the inner ear if they've been damaged. Mammals have underlying progenitor cells in multiple areas of the body, but their regenerative capacity is dormant after development."

Posted by: Adrian Crisan at July 8th, 2018 8:08 PM

Life expectancy of 5 to 15 years. Why isn't it longer?

Posted by: Tom Schaefer at July 9th, 2018 8:11 AM

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