Salamander Science and Regenerative Medicine

Painting by Gary Lyons

Until man duplicates a blade of grass, nature can laugh at his so-called scientific knowledge.

Thomas Edison

Salamanders are a biological marvel: they are the only larger vertebrates that can regenerate entire limbs, a capacity for healing unmatched in the animal kingdom. Lizards can grow new tails, and human children can regrow the tips of their fingers, but only the salamander can cook up perfect shoulders, elbows, wrists and hands from scratch. (For bonus points, they are also photosynthetic — no, seriously.1)

And it’s a mystery how they do it. If we only understood how their cells do this wonderful thing, what else would we know about biology and healing? How would it change health care? Our ignorance and our potential are dizzying.

And yet progress has been made. In 2010, researchers were able to trigger impressive regrowth of joint surfaces in rabbits.2 We’ve also found a mammalian gene that suppresses regenerative function. When the gene is turned off, presto: animals that couldn’t regenerate suddenly can!3

Forget jetpacks: I want the future to bring us regeneration powers! I could use at least three regenerated body parts: an acromioclavicular joint that got ripped up a decade ago and has given me hassles ever since, a cervical intervertebral joint that’s menacing my spinal cord a bit, and flaming Achilles tendons that have been through so many bouts of tendinitis now that it’s frankly amazing neither of them has ruptured.

The salamander’s talent is an ideal example of and symbol for healing, and for what health care professionals do — for how much there is to learn, and for learning itself, the regeneration of our minds if not our limbs!

On the other hand, the actual “regenerative medicine” of today is almost a cruel joke of empty, premature promises.

Every therapy in the rehab business thinks it’s “regenerative”

When I first started writing about musculoskeletal and pain medicine in the early 2000s, I never expected my interest in salamanders and regenerative medicine to be anything more than symbolically relevant, just a quirky source of inspiration. Now I take it for granted that regenerative therapies are widely prescribed and sold to patients struggling with pain and injury recovery — but none of them even remotely resembles the miracle that salamanders routinely perform.

Dozens of common rehab treatments are billed as “regenerative” in some sense, mostly stretching the idea to the breaking point. Most of these claims are based on extremely vague claims of “stimulating cellular repair,” and are firmly in the category of pseudo-quackery: snake oils that masquerade as mainstream/advanced. Really anything at all that can be considered stimulating in any way get a shiny “regenerative” sticker. Even doing damage with intense treatments like shockwave therapy or brutal scraping massage has been reframed as regenerative because they “kickstart healing.”

In other words, nearly all of them have more to do with marketing than biology.

However, there are some more serious attempts to imitate salamanders …

Cells as medicine: the use of regenerative medicine for injuries and chronic pain

There are three major types of therapy in the physical/pain medicine domain that have somewhat stronger claims to being “regenerative” in principle. “Stronger” is still not necessarily “good,” and there are a lot of asterisks, but these are at least more substantive and interesting:

• Autologous chondrocyte implantation (ACI) is implanting a “patch” of your own cartilage cells to treat arthritis. This is the most legitimately promising of the regenerative therapies, although it is still far from well-established as good evidence-based medicine.
• The blood therapies. You can inject your own blood into an injury to “increase circulation” in an almost brutal way, delivering everything that blood has to offer at high concentrations right where healing needs to happen. This is the injection of “autologous whole blood” (AWB), or the parts of blood: for platelet-rich plasma (PRP) the blood is processed to make a concentrated mixture dominated by platelets, a blood ingredient that releases more growth factors. Either way, the hope is that a bloody injection will stimulate healing where it is otherwise failing — one of the simplest kinds of “regenerative” medicine, especially for stubborn, slow-motion injuries like tendinitis. PRP is popular and profitable, but the evidence for its efficacy is simply abysmal.
• Stem cell therapies are based on “generic” cells or their biochemistry. Stem cells are as biologically fascinating as salamanders, no doubt about it, and they could have unusual properties and might well be a healing stimulant. But in terms of understanding and translating that biology into useful medicine, it’s an extreme case of caveat emptor: stem cell therapy clinics have sprung up everywhere and they are way ahead of the science. This medical tech is just not safe and proven yet, and many of the clinics selling it are just cashing in on hype and hope. Regulation (American) of stem cell clinics is “something of a dumpster fire,” writes Jann Bellamy, a medical law expert.4 There are serious risks of wasting your money at the least, and serious medical risks from shoddy practices as well.5 It is barely studied, and what little science exists is either inadequate or negative.6

Despite a modest range of credibility, for practical purposes all three of these types of regenerative therapies more or less the same with regards to safety, efficacy, and the concerns of skeptical consumers and regulators. They are all biologically intriguing treatments that might still amount to something someday — after all, we know regeneration is possible, thanks to salamanders! — but for now it’s still a depressing mess, instead of being inspiring and promising. These treatments are all being rushed to market in the same way, all sold as high-tech medicine to desperate consumers long before the science is done.

This is the “salamander” that lives on my desk. Got this li’l guy many years ago in Playa del Carmen. Technically a gecko, not a salamander—heresy! But he is so blue (and fun) that I decided he was close enough to the PainScience.com salamander for mascot duty.

Wounds that do not heal

Most of the time it’s hard not to heal. You couldn’t stop it if you tried. The body is going to bounce back from most kinds of injuries, almost no matter what — it’s just a matter of time, with or without tricks like icing or soaking in an Epsom salts bath. It’s infamously impossible to rush healing.

Or is it?

But stubborn pain problems, the subject of this website, are different by definition. Or healing itself fails, or pain persists even when the tissues seem to be fine (like common muscle aches), or a bit of both. Repetitive strain injuries, which usually afflict connective tissues like the it band, plantar fascia, or the wrapping around your shin bones, are slow-motion traumas that often seem immune to recovery — this is what makes them both terrible and fascinating. They usually don’t heal because they need more rest than most people will give them, but sometimes healing just doesn’t work. Sometimes bone fractures and lesions will not close (a problem every surgeon dreads). Sometimes pain persists because of a known glitch in biology!

The regenerative healing powers of the salamander are amazing and bizarre … but they are also darkly reflected in the human wounds that do not heal. It doesn’t seem fair: salamanders can regenerate entire limbs, but we often can’t recover from a little overuse!

Other kinds of critter regeneration

Mickey Samuni-Blank, CC BY-SA 3.0

The African spiny mouse

The only mammal with some impressive regenerative powers.

Many tiny organisms are masters of regeneration. But it’s rare in animals larger than a speck, and particularly rare in mammals. If regeneration is possible in any mammal, then there’s hope for us.

And it is possible. This neat 2012 science story is promising: “Biologist discovers mammal with salamander-like regenerative abilities.”7 The African spiny mouse does a far better job at regenerating any part of itself than any other known mammal to date. Salamanders are much better at regeneration, in every way, but at least we know mammals aren’t completely left out of the regeneration game.

And there are many other examples of limited critter regeneration of specific body tissues and parts.

• Another mouse may deserve even more attention than the African spiny: the MRL mouse is a strain of mouse that exhibits diverse regenerative abilities. While they fall short of the salamander, they heal from all kinds of wounds far better than we do.
• The ogre-faced spider has better vision that we do, and it never gets old — its eyes specifically, literally, never get old, because the O-F spider replaces its retinas every night.8
• Many species can shed limbs and tails parts as a defense and then regrow them (automy).
• The annelids (flatworms) are unusually good at regeneration. For instance, a planarian split lengthwise or crosswise will regenerate into two separate individuals. Quite a party trick.

The mole rat’s superpower

This isn’t about salamanders or regeneration, but I think I’m going to start turning this page into a general collection of cool biology of pain and healing throughout the animal kingdom.

“To deal with their miserable lives” naked mole rats evolved to feel no pain:

And yet in this harsh environment, under extremely crowded conditions, the naked mole rat has evolved to be virtually indestructible: these small mammals almost never get cancer, live to be over 30 (much longer than other rat species), and they are insensitive to acid burns. A study in Cell Reports reveals one secret behind these rats’ abilities. Evolutionary tweaks to the amino acids in their pain receptors make naked mole rats extremely insensitive to pain after they are born.

I think it’s surprising and fascinating that immunity to pain isn’t a more common adaptation in biology. Clearly pain has potent survival benefits — the ultimate double-edged sword.

This salamander is skeptical

The PainScience.com salamander is more of a mascot than a logo. He’s a character. He has represented this website with a bit of flair since the very beginning (since before it was even called PainScience9).

The PainScience.com salamander does not believe everything he hears. The salamander is no sucker. The salamander watches MythBusters, and applies the same attitude here: let’s just check that. Sometimes the salamander squints at stupid ideas in health care and says, “Meh, not even worth testing.”

When something seems too good to be true, the salamander rolls his beady little eyes, heaves a sigh, and gets ready to do brain battle with the forces of the evil Lord Gullible. The salamander is especially irritated by big promises. He is just not that impressed by a lot of expensive therapies and products, like acupuncture, Traumeel, or platelet-rich plasma injection (a therapy that actually claims to regenerate tissue).

The salamander is living, breathing proof that there are miracles enough in biology without inventing new ones.

Sometimes you just need to hear sense from a salamander.

Fine, dash my hopes with all your crazy logic and science. Be that way.

funny reader

Related

• What does electricity have to do with salamanders? Read all about it! The body electric: electromagnetism and the foundation of life (book), by Robert O Becker and Gary Selden. Amazon.com ❐
• Don’t Believe Everything You Hear about Stem Cells, by Deepak Srivastava, president of the International Society for Stem Cell Research. “The science is progressing rapidly, but bad actors have co-opted stem cells’ hope and promise by preying on unsuspecting patients and their families.”
• Cold Laser Therapy Reviewed — A critical analysis of treating pain and injury with frickin’ laser beams How can you get some regeneration for yourself? From lasers, supposedly: laser therapy is the main representative of regenerative medicine in the world of aches, pains, and injury rehab. But there are other contenders …
• Does Cartilage Regeneration Work? — A review of knee cartilage “patching” with autologous chondrocyte implantation (ACI), one of the only examples of true regeneration produced by high-tech medicine. To a point.
• Zapped! Do TENS and friends work for pain? — The peculiar popularity of being gently zapped with various kinds of electrical stimulation therapy
• Does Ultrasound or Shockwave Therapy Work? — They seem like mainstream physical therapies, but warming and vibrating tissues with sound/pressure waves has never been supported by good evidence
• Does Platelet-Rich Plasma Injection Work? — An interesting treatment idea for arthritis, tendinopathy, muscle strain and more

• A thorough discussion of the state of human regeneration science on The Science Show (Australian Broadcasting Corporation, June 9, 2018):

  Bespoke bodies. No we do not mean making human bodies fit for the cover of vogue. We mean bespoke in its literal sense meaning ‘made for purpose’ and the proposal that human regeneration is a necessary scientific pursuit, to make our bodies work better for longer, as human longevity continues to increase. Indeed, what is the point of living until to 90 or 100 if all our bits start to give out decades before that? So what are some of the current possibilities in the realms of human regeneration? What can we do right now to make our bodies last a bit longer?

Notes

1. Kerney R, Kim E, Hangarter RP, et al. Intracellular invasion of green algae in a salamander host. Proceedings of the National Academy of Sciences. 2011. PainSci Bibliography 53091 ❐

   It’s not enough that salamanders have seemingly miraculous regenerative powers, without equal in vertebrates. Oh no, salamanders have to be more amazing still, by being the only vertebrates that are effectively photosynthetic, thanks to a deep symbiotic relationship with an algae, a proper endosymbiote. That is, the algae don’t just hang out around the salamander cells, but actually in them — and you can even see the algae, the only endosymbiote visible to the naked eye (you can see it in their eggs). Incredible.

   Just how special are you, salamanders?!

2. Lee CH, Cook JL, Mendelson A, et al. Regeneration of the articular surface of the rabbit synovial joint by cell homing: a proof of concept study. Lancet. 2010 Aug;376(9739):440–8. PubMed 20692530 ❐ PainSci Bibliography 54932 ❐

   Build it and the cells will come. This proof-of-concept study demonstrated what happens if you replace the end of a rabbit’s femur with an empty plastic “scaffolding” of exactly the same shape, and then fertilize it with transforming growth factor beta3. Cells migrate into the framework and start building bone and cartilage! “The entire articular surface of the synovial joint can regenerate without cell transplantation.” Without the growth factor, not much happened: much less than half as many cells moved into the new habitat.

   These findings suggest that “regeneration of complex tissues is probable by homing of endogenous cells.”

3. PopSci.com [Internet]. Humans Could Regenerate Tissue Like Newts By Switching Off a Single Gene; 2010 Mar 16 [cited 15 Aug 5]. PainSci Bibliography 55649 ❐
4. ScienceBasedMedicine.org [Internet]. Bellamy J. FTC settles deceptive advertising claims against amniotic stem cell clinics – Science-Based Medicine; 2018 Oct 25 [cited 19 Jan 5]. PainSci Bibliography 53076 ❐ And here are a couple other older (2015, 2016) critiques of stem cell therapy from my friends at ScienceBasedMedicine.org: FDA Looks At Dubious Stem Cell Clinics (more readable), and Stem cell clinics and unapproved, for-profit human experimentation (more detail).
5. CDC.gov [Internet]. Perkins KM, Spoto S, Rankin DA, et al. Notes from the Field: Infections After Receipt of Bacterially Contaminated Umbilical Cord Blood–Derived Stem Cell Products for Other Than Hematopoietic or Immunologic Reconstitution — United States, 2018; 2018 Dec 21 [cited 20 Nov 12]. PainSci Bibliography 52391 ❐

   A dozen patients became seriously ill after receiving injections that supposedly contained stem cells. See also the New York Times coverage.

6. • In 2017, Pas et al. reported that “no evidence” was found for the therapeutic use of stem cells for tendon disorders. “The use of stem cell therapy for tendon disorders in clinical practice is currently not advised.”
   • In 2020, van den Boom et al. reported that “some studies report improved outcomes, but all are at high risk of bias” — garbage in, garbage out.
   • In 2022, Mirghaderi et al. wrote that “Despite substantial animal evidence, cell therapy in humans remains in its infancy,” and concluded that there was only the weakest possible positive evidence so far.
   • Osteoarthritis is the only moderately well-studied target for stem cells, and the British Journal of Sports Medicine concluded in 2017: “we do not recommend stem cell therapy.” A 2025 Cochrane review was slightly more positive: “very low certainty” about “modest benefits” with additional doubts about whether it’s actually “regenerating” anything even when pain is slightly reduced.
7. Seifert AW, Kiama SG, Seifert MG, et al. Skin shedding and tissue regeneration in African spiny mice (Acomys). Nature. 2012 Sep;489(7417):561–5. PubMed 23018966 ❐ PainSci Bibliography 54267 ❐
8. Citation needed and harder to find than I hoped, but entomologist Gavin Pitts talks it up around the 5:00 mark in the Caustic Soda episode “Web Building Spiders.”
9. PainScience.com was “SaveYourself.ca” for more than a decade, but I never really liked it. I was always uneasy with the connotations of “save”: it smacked of a healing promise I can’t keep, and like Jesus might be involved somehow. I moved everything to PainScience.com in late 2014. For more information, see Why SaveYourself.ca Became PainScience.com: All about the 2014 change from SaveYourself.ca to PainScience.com.