A Report on Limb Regeneration and The History of Its Research

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Imagine this: A baseball pitcher loses his pitching hand when crushed between two closing elevator doors. Instead of reattaching the partially crushed hand, which would end his pitching days, he simply goes to the hospital, gets a few treatments, and in a few months or so is back, pitching on the mound again. How is this possible? His hand has grown back identically and is just as successful at throwing in the strike zone as his previous one.

Sounds impossible? I don’t blame you for thinking that. But according to current limb regeneration scientists, such as Dr. Susan Bryant, Dean of Biological Sciences at UCI, this fiction may soon be reality.

I personally became interested in this topic when I learned that young children commonly regenerate their fingernails if severed at the nailbed. In fact, my baby cousin Rachel had recently had her fingernail tip severed in an accident with a drawer, and she underwent plastic surgery to cover up the wound. The question arose: was it worth it to get the plastic surgery when the fingertip might have regenerated itself after a short period of time? I decided to find out.

Limb regeneration is the ability to grow back lost limbs . Unlike wound healing, regeneration leaves no scars and generates a perfectly similar copy of the original limb or organ, as the case may be. Many animals, such as sea stars, frogs, newts and especially axolotl salamanders have this ability. In this report, the process of limb regeneration, a timeline of its research, and how it might be possible to trigger in the human body in the future will all be explored.

Limb regeneration is possible in the above-mentioned species thanks to a process called dedifferentiation. This is a process in which cells around a wound lose their identity, transforming themselves into a cluster of stem cells called a blastema. These blastema cells then respecialize, transforming into the types of cells required for limb replacement, and begin to undergo mitosis as the new cells.

For instance, when the limb of an axolotl salamander was amputated, it was able to regenerate a cone-shaped partial-limb (still in blastema form) within nine days. Within thirty days, the new limb will be complete and all the blastema cells will differentiate into nerves, muscle, cartilage etc. Interestingly enough, the axolotl salamander does not following the standard regeneration pattern, and is therefore often studied in labs. This salamander actually turns the process around. At the wound site, the cells lose their specialization and turn back into stem cells. They then work to regenerate the new limb, redifferentiating as needed.

Looking at the molecular level is one way to better understand regeneration. The ever-popular Dr. Susan Bryant, of the University of California Irvine and her staff have been working on getting a profile of genes expressed during axolotl regeneration. They have discovered that part of the hox genes, crucial to species development, get triggered as a result of the wound. They have also shown that the hox 8 gene, usually triggered during embryogenesis, is also found to be a trigger and expressed during axolotl regeneration .

This field of research was first brought to public attention by none other than the well-known philosopher Aristotle (384 BC-322 BC), who first observed lizards regenerating their tails. Keep in mind that this was the man who postulated incorrectly the theory of spontaneous generation that turned the science of life on its ear. Unfortunately, Aristotle hypothesized over several theories, like that of spontaneous generation, which were eventually proven false. Aristotle went on to write two books on the subject of limb regeneration . Here is some of what he had to say: “Some affirm that this phenomenon [limb regeneration] is observable with serpents, as with swallow chicks; in other words, they say that if you prick out a serpent’s eyes, they will grow again. [wrong!] And further, if the tails of serpents are cut off, they will grow again [right!]” This is from Historia Animalia, Book II, by Aristotle. A perfect example of learning in process.

In 77 AD, Pliny the Elder (AD 23-AD 79), a Roman scientist who wrote Naturalis Historia, marveled that lizards could grow back their chopped-off tails (obviously not reading Aristotle’s earlier observations) and found some lizards had two . Around 1240, Saint Albertus Magnus
(~ 1200-1280), a teacher and bishop who promoted the study of nature as a legitimate science, noted the same thing (obviously reading neither Pliny nor Aristotle). In 1712, the French physicist René Réaumur (1683-1757) observed that a crayfish’s severed claw could grow back . Thusfar, not much progress can be noted in the actual science of this research, but the concept at least appears to have fascinated many individuals across the globe and across the ages.

But it was really the lesser-known Dutch scientist and philosopher, one Abraham Trembley (1710-1784), working in Britain, who took regeneration to the next step. He reported that the two halves of a bisected hydra (a type of plant/animal hybrid that lassoes its prey with its tentacles) could become two new animals (he also believed the hydra was the missing link between animal and vegetable). The Italian scientist Lazaro Spallanzani (1729-1799) then discovered the presence of the Spallanzani’s cone, also called the blastema (see above).

In modern days, this science continues to fascinate the minds of such scientists as Dr. Kerby C. Oberg, professor of human anatomy and plastic reconstructive surgery at Loma Linda University in California ; and, once again, Dr. Susan Bryant, professor and Dean of biological sciences at the University of California Irvine and her partner David Gardner, a research biologist.

But my personal favourite is a scientist named Dr. Paul Peitsch, a.k.a. Dr. Asa Zook, a fictional scientist-philosopher who occasionally serves as a resource person for an imaginary popular science writer (with a great web site) . The real man behind the science studies is a professor emeritus at Indiana University, formerly of optometry. He used to teach human anatomy, and now researches in developmental biology (especially regeneration) and neurosciences. Dr. Peitsch currently is the producer of Shufflebrain (see footnote nine) and is also interested in how the human brain is like a hologram. He also enjoys using fiction (and humour) for exploring and explaining scientific concepts and ideas. Speaking of media…

Limb regeneration has also fascinated those in the world of media, especially film and graphic literature. It has been the focal subject of several films (e.g. The Alligator People; Severed Ties; Swamp Thing; Return of Swamp Thing and The Limb Salesman [recently screened at the Toronto International Film Festival] ), comic books (e.g. Man-Thing & the Lizard, both villains in the Spiderman series and, you guessed it, the actual critter Swamp Thing in the comic of the same name). Even some of the monsters in the obsequious Yu-Gi-Oh! card game have limb regenerative abilities.

Back to the world of science, experiments and research. The most notable major experiment on limb regeneration was performed on… mice. A salamander’s blastula (pre-embryo stage) was implanted onto a mouse’s amputated arm. The cells around the wound showed signs of dedifferentiation. Something in the genome of the salamander was likely responsible for the mouse’s regeneration ability! However, Dr. Susan Bryant scornfully says that “some researchers try to work with mice to stimulate regeneration. But I always say, why not look at what can already regenerate [like the axolotl salamander] and find out how that animal is doing it.”

So what is happening in the science labs of today regarding human limb regeneration of tomorrow? Scientists can now grow muscle cells, nerve cells, etc., even muscle cells covered by layers of epithelial cells, which is wonderful progress. However, the secret to limb growth is still locked in the DNA of our genes. To show how challenging this is, consider this: there are between 30,000 and 40,000 human genes to explore , and they must also be turned on or off in a particular combination in order to trigger regeneration. Another exciting development involves microCT’s, which are hi-tech, digital X-ray microtomography devices. These microCT’s have allowed scientists to closely observe the microscopic changes in process inside regenerating limbs without ever dissecting anything. One interesting finding contradicted the common belief that limbs regenerate from the amputation area up to the fingertips in order. In fact, bone formation, when watched under the microCT, showed a different order: the bone area near the wound site had a gap where bone didn’t form yet, even though the rest of the limb was already regenerated. This gap resembled normal wound healing rather than regeneration. From Hans-Georg Simon, researcher at Northwestern University in Chicago: “With this microCT method, we can see things other people have missed in previous years…e.g. the process of rebuilding a limb over time…what the genes are doing and how they instruct the growth of new structures, such as cartilage and bone.” No doubt technology will play a major role in future limb regeneration research.

So, let’s return to one of my previous points, which may raise some eyebrows: …cells around a wound lose their identity, transforming themselves into stem cells. Hmmm…I’ll say it again: transforming into stem cells. Why don’t the researchers who are trying to get stem cells genetically engineered to create new organs, try and get them to dedifferentiate instead? The mice’ bodies didn’t reject the blastula of the salamander, so perhaps our stem cells could be triggered to do the same thing? Could that truly mean that human stem cells (the tremendously versatile cells found in human placenta) could cause a limb (or organ) to regenerate?

However, using stem cells by harvesting from the placenta or growing them from aborted fetuses is of ethical concern (to some). With the recent American re-election of George W. Bush and Stephen Harper’s Conservative Party at Canada’s opposition, the attitude toward abortion is being controlled by the religious and conservative right wing. These religious and political fanatics are so opposed to abortion that they won’t even consider using fetal tissue from LEGAL abortions or medical miscarriages for treatment of Parkinson’s disease (which attacks the brain cells, and leads to slow and agonizing death via deterioration). Would they possibly consider it for something as “minor” as limb regeneration? I fear that in the next decade or two, fetal tissue may be extremely hard to come by, even for valid scientific purposes.

However, what if there was no need to harvest the stem cells from a third-party source?

How about this? After all, as Dr. Susan Bryant (once again!) states, “if we could harness the axolotl’s ability, any ethical debate about [harvesting] stem cells would be eliminated. All you would have to do is give a shot of the stimulus agent at the site [where] you want it to regenerate, and the person’s body would create [his or her own] stem cells.”

Even if we are able to deal with the ethical issues, we must also ask ourselves about the economic costs of the research for limb regeneration possibilities, not to mention the actual costs if we were to perform limb regeneration on everyone who needed it. I was unable to find any real statistical data on the costs of this procedure in humans. However, I did find some award-winning student research, a science paper entitled “Costs of Limb Regeneration in Walking-Sticks”, written by Tara Prestholdt from the University of Manitoba, but unfortunately there was no direct link to the paper itself. However, spoilsports may say we could be spending our money on research for cures for cancer, Parkinson’s, AIDS, and tuberculosis, to name a few illnesses.

Limb regeneration is still a relatively new discovery. What lies ahead in the future? If you are of the energetic and demanding type, you could build a time machine and see for yourself, or you could just wait it out. Either way, the human race will go on…even if out on a limb.

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