Last year I had a nasty, infected cut on my big toe. The doctor suggested I might want to have it amputated. I told her, OK, if you think a new one will grow back, let's go ahead and amputate it, but if you don't, let's see if we can't do something about the infection.
Saving my toe, however, cost me and my insurance company, mostly my insurance company, over $300 thousand dollars. People who don't have really good health insurance, or a few hundred thousand dollars lying around, often have to have amputations.
It would be nice if humans, like salamanders, could grow amputated limbs back. Maybe by studying salamanders and similar creatures researchers will find a way to do that.
Zeroing In on the Zebrafish to Understand Regeneration
Fruit flies have genes that enable them to regenerate lost limbs. Salamanders and lizards and zebrafish have genes that enable them to regenerate lost limbs. Even mice and, surprisingly, human have analogous genes that don't perform the obvious task. How could the regeneration genes in humans somehow be activated?
To answer this question, scientists have taken a closer look at the zebrafish. Researchers love to study zebrafish, because their females lay eggs with transparent shells. They can easily watch the prenatal development of the babies without destroying the egg, observing the sequence of steps through which the zebrafish "recapitulates" its evolutionary development (as it is understood by biology).
Specific enzymes help the embryonic zebrafish organize cells into organs. Some of these enzymes continue to work even after the fish has hatched. If a zebrafish escapes a predator but swims away with an injured fin, the injury activated a gene for fibroblast growth factors that help it regrow the injured fin. It also has active genes for a protein called leptin b that can repair damage to its heart.
Genetic Enhancers That Make Repair Genes Superactive
The researchers also observed that some zebrafish regrow missing fins faster and more completely than others. To find out why this happens, they did a detailed study of the base pairs of DNA around the genes that enable regeneration. They discovered "tissue regeneration enhancer elements" that can (but don't always) turn on the regeneration genes at the site of an injury, or "turn up" the production of the proteins that start the process that restores the tissues.
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The next step in the research was to genetically modify zebrafish so that enhancer elements were "welded" to the DNA coding the genes for regeneration. The result was super-regenerating zebrafish with superior abilities to restore damaged tissues. Next the researchers transferred the enhancer elements to the DNA of mice to see if the genetic modification would help mice recover from injuries to their paws and hearts.
Obviously, it doesn't do a mouse (or a human) a lot of good to acquire the ability to grow a new zebrafish fin. These enhancer elements don't dictate the exact proteins that the recipient body will make. But they do generate a diffusible signal that stimulates existing genes to do the task.
What the Latest Regeneration Research Doesn't Tell Us
Headlines are easy. Science is hard. Writers who just scan headlines of articles and papers written by others can generate some fanciful, unrealistic, and just plain wrong headlines of their own:
- Map of Lizard DNA Reveals Secrets of Regeneration: Why We Can Never Defeat the Reptilians
- DNA Regeneration Discovery Explains Why Godzilla Can Not Really Beat the Rhedosaurus
- NSA Using Zebrafish DNA to Clone Body Parts of Espionage Suspects
These kinds of headlines of ridiculous, but more importantly, they obscure the process through which real people may someday soon benefit from this kind of technology. Here's what is important to know.
- Regeneration of human limbs through this technology does not require splicing genes from zebrafish, lizards, salamanders, fruit flies, or mice into human DNA. The objective is to enhance existing DNA, not to replace it with the DNA of other creatures.
- It's much more likely that this kind of technology will be used to regenerate heart tissues before it is used to regenerate lost limbs. There is already experience with regeneration of cardiovascular tissue. Without any medical intervention at all, some people grow collateral blood vessels that take over when original arteries are blocked by atherosclerosis. This kind of gene therapy wouldn't enable recipients to grow an entirely new heart. It would allow them, possibly, to repair a heart damaged by heart attack or some other kind of cardiomyopathy. Regenerating missing limbs would be an even more complex process.
- Gene therapy is usually accomplished by genetically modifying a virus to carry the gene into the cells that need it. That's what viruses do. They carry their own DNA or RNA into cells to replicate themselves. Gene therapy uses the infective principle to carry desirable DNA into a group of cells that can benefit from genetic repair. Retroviruses, like HIV (which is not used in gene therapy), are very effective at carrying target DNA into the cells being treated, but the problem is that they may also splice DNA where it can interfere with the function of the cell. That's why one of the side effects of gene therapy with Retroviruses has often been leukemia.
- Another method of genetic modification for treating disease is out-of-body DNA modification. Doctors take a sample of bone marrow, blood, or fat and separate out stem cells. The stem cells are cultured in the laboratory to produce a large number. Then the stem cells are treated in specific ways to turn into the desired cells that can repair tissues.
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Turning a mass of stem cells into a functioning arm or leg so amputees would not have to use prosthetic arms or legs, however, would require a huge number of intermediate steps. Such a limb would have to include bone and blood vessels and muscles and connective tissues and skin, all of which develop differentially. For this reason, growing a human limb will probably not be accomplished in the lab. Somehow stem cell researchers will have to learn how to stimulate just enough of the human body's dormant regenerative processes to restore desirable limbs without dangerous, cancerous tissues.
Sources & Links
- Kang J, Hu J, Karra R, Dickson AL, Tornini VA, Nachtrab G, Gemberling M, Goldman JA, Black BL, Poss KD. Modulation of tissue repair by regeneration enhancer elements. Nature. 2016 Apr 14. 532(7598):201-6. doi: 10.1038/nature17644. Epub 2016 Apr 6.L PMID: 27049946
- Photo courtesy of zimpenfish: www.flickr.com/photos/zimpenfish/6957807090/
- Photo courtesy of dougbeckers: www.flickr.com/photos/dougbeckers/3490105228/
- Photo courtesy of zimpenfish: www.flickr.com/photos/zimpenfish/6957807090/