The ability to regrow limbs lost through accident or the action of their nemesis is a power usually thought of as belonging only to comic-book heroes, but in nature the ability to regenerate tissues and even whole limbs is surprisingly widespread across the plant and animal kingdoms. While in the womb mammals such as humans have a powerful ability to repair and regenerate tissues, but this ability has only been observed to a limited extent in young children, who partially grow back the tips of fingers that have been lost in accidents, and is rarely seen in adults. The ability of mammals, including humans, to repair damaged tissues is rather paltry* when compared to the ability of the axolotl, a species of salamander, which can regrow an entire limb if the limb is amputated anywhere between the shoulder and hand (1). Since the axolotl, an amphibian, shares much of the basic wound healing machinery with mammals scientists study it to gain a better understanding of how wound healing and tissue regeneration take place, and through understanding why wounds heal differently in mammals and they hope to develop new treatment that improve healing and decrease scarring in patients who have suffered serious injuries. Ultimately it is hoped that this knowledge will help scientists to engineer tissues and organs for transplant, and perhaps someday to replace limbs list in automobile accidents and conflict.
This week the science journal Nature reports that a team of scientists working in Dresden and Florida have made a significant discovery concerning the limb regeneration process in the axolotl (2). Very early in the regeneration process a clump of cells known as the blastema forms at the site of injury, and this clump of apparently identical cells gives rise to all parts of the regenerated limb such as cartilage, muscle, nerves and skin. Until now it has generally been assumed that the blastema is composed of uniform pluripotent cells that can develop into a wide range of tissues. To examine if this was indeed the case Martin Kragl and colleagues used transgenic technology to label specific tissues in the axolotl with Green Fluorescent Protein (GFP). They found that when they transplanted GFP-labeled cells from a particular tissue at the injury site they could watch these cells became blastema cells and later develop into new tissue in the regrown limb. The interesting finding was that cells could only produce cells of the original tissue type, muscle cells became blastema cells and then developed into new muscle, and nerve cells became blastema cells and then developed into new nerve tissue. The one exception was cells from a layer of skin known as the dermis, which contributed to both the dermal layer of the new skin and to new bone. This basic research discovery that the cells of the blastema are not in fact pluripotent despite taking on many of the characteristics of stem cells, and the implication that the blastema needs to include cells from a range of tissues for proper regeneration to occur, is of critical importance to scientists who are seeking to reproduce blastema conditions in mammals.
Meanwhile a technique that might once have seemed like science fiction, the use of high-energy ultrasound beams to heat and destroy tumors, has been in the news after a successful clinical trial for the treatment of prostate cancer in the UK. While the use of ultrasound in medicine is something most of us are familiar with, being frequently used to produce images of the developing fetus during pregnancy, high intensity focused ultrasound (HIFU) is less well known, despite being under development for more than fifty years. The earliest research on the use of HIFU was performed by ultrasound pioneer William Fry who used it to produce lesions deep in the brains of cats and monkeys (3), technique that was subsequently used in the treatment of Parkinson’s disease. Technological limitations however impeded the development of the technique, and it was not until the development of technologies such as magnetic resonance imaging (MRI) , used to identify the targets for the beams and monitor their destruction, that HIFU became a practical technique.
From the late 1970’s until the early 1990’s a series of experiments (3,4) in rodent models of cancer showed that HIFU could be used to safely kill tumor cells, and in the early 1990s studies undertaken by Dr. Albert Gelet and colleagues in Lyon and Prof. Francis J. Fry at the Indiana University Medical Center demonstrated that it was possible to precisely destroy small regions within the dog prostate without harming the surrounding tissue using a probe inserted in the rectum and guided by MRI (5,6). These studies led directly to successful clinical trials of this technique in humans, and to the introduction of a treatment that is now gaining acceptance as a safe and effective alternative to invasive surgery or radiation in the treatment of prostate cancer. Animal research was crucial to the development and evaluation of HIFU over the past decades and continues to play a key role in ongoing work to adapt HIFU to treat other types of cancer, including cancers of the kidney and liver.
* An exception to this rule is deer, which regularly regrow antlers containing skin, bone and blood vessels.
1) Gurtner G.C. et al. “Wound repair and regeneration” Nature, Volume 453, Pages 314-321 (2008) DOI: 10.1038/nature07039
2) Kragl M. et al. “Cells keep a memory of their tissue origin during axolotl limb regeneration” Nature, Volume 460, Pages 60-65 (2009) DOI:10.1038/naure08152
3) Kennedy J.E. et al. “High intensity focused ultrasound: surgery of the future?” The British Journal of Radiology, Volume 76, Pages 590-599 (2003) DOI:10.1259/bjr/17150274
4) Acher P.L. “High-intensity focused ultrasound for treating prostate cancer” BJU International, Volume 99(1), Pages 28-32 (2007) DOI: 10.1111/j.1464-410X.2006.06523.x
5) Gelet A. et al. “Prostatic tissue destruction by high-intensity focused ultrasound: experimentation on canine prostate” Journal of endourology, Volume 7(3), Pages 249-253 (1993) PubMed: 8358423
6) Foster R.S. “Production of prostatic lesions in canines using transrectally administered high-intensity focused ultrasound.” European urology, Volume 23(2), Pages 330-336 (1993) PubMed: 7683997