Banner by Daniel Walsh

Doctor, Who Can Regenerate?

by Reyna Jones

You might not have to be a Time Lord or the Doctor to regenerate! Research in regenerative medicine is a developing and expanding field with endless possibilities. The discipline is primarily focused on the repairing of damaged tissues and organs. Although organ transplants revolutionized regenerative medicine by offering lifesaving procedures for otherwise fatal conditions, scientists are now exploring other methods such as the use of small molecules – known as small molecule regenerative medicine – to facilitate the body’s innate ability to self-repair.  

Researchers, Kevin Strange, Viravuth Yin and Michael Zasloff began examining the regenerative effect of various aminosterols, a class of small molecules, in zebrafish. First, the scientists began by amputating the tails of the fish. When the small molecules were injected in tailless fish, they found that fish receiving a drug called MSI-1436 or trodusquemine experienced exacerbated tail regrowth. Their fins regenerated within four days compared to the ten to fourteen days it would take for the fin to grow back naturally. As the scientists were eencouraged by the results, they began experimenting on the regenerative effects of MSI-1436 on other organs. For example, the researchers tested the impact of trodusquemine on heart regeneration in zebrafish. They removed part of the heart and as before, injected the fish with MSI-1436. Again, the fish demonstrated accelerated regeneration. This result was particularly exciting for its potential applicability in treating human hearts which have little regenerative ability.

Some human tissues and organs such as the skin and liver have a limited natural ability to regenerate by replacing dead or damaged cells with new growth. However, other organs like the heart cannot be restored in this way. When an individual has a heart attack, as the heart heals, the dead muscle scars instead of repairing into fully functional heart muscle. Paradoxically, the body inhibits healing. When proteins called RTKs signal cell regrowth after a heart attack, enzymes cleave their phosphate groups. This inhibits the RTK protein signals, preventing heart muscle regrowth. How does trodusquemine affect this constrained healing process?  

Strange, Yin, and Zasloff claim that trodusquemine inhibits the enzymes that remove the phosphate groups from RTK proteins, thus enabling cell growth signals. Of course, the scientists could not just begin testing MSI-1436 in humans. Therefore, they decided to use mice as a model organism. Like humans, adult mice lack the ability to regenerate heart muscle. After the investigators induced ischemic heart damage by ligating (blocking off) a branch of the left coronary artery in the mice, the experimental rodents were given MSI-1436 every three days. Overall, mice receiving MSI-1436 had a 70 to 80 percent increased survival rate compared to control mice who were not given the MSI-1436 treatment. In looking at the physical differences between the treated and control mice, the researchers found that the mice receiving trodusquemine demonstrated less heart impairment and new muscle formation.

Two years later, MSI-1436 is being researched in pigs, an animal with a heart similar in size and structure to human hearts. Although the results of these experiments have not yet been published, preliminary results are promising. In the future, trodusquemine may be used in clinical trials for individuals who experience a heart attack! Just as encouraging is the fact that trodusquemine is thought to have the ability to facilitate regrowth in other human organs. The National Institute of Diabetes and Digestive and Kidney Diseases recently funded a grant to begin research on the effect of trodusquemine in the kidneys, an organ which experiences damage from chronic conditions like diabetes.

Although the hopes of utilizing trodusquemine as a form of regenerative medicine are high, there are still serious concerns that must be addressed. First, as the drug’s ability to repair the heart has only been tested in fish and animal models, scientists cannot be sure if it will have the same effect in a diverse group of humans. However, researchers are hopeful that some of the same cellular pathways used in their model organisms are also present in humans. Thus, trodusquemine would have a similar effect on human subjects as in animals. Finally, the primary cause of apprehension in using a drug which stimulates cell generation is that growth could become uncontrollable, leading to cancer. However, thus far, research on MSI-1436 suggests that the drug has the ability to specifically target damaged cells without facilitating cell proliferation in undamaged, healthy tissues and organs. Nevertheless, investigators will continue to monitor animals and future subjects for tumor growth and the long-term effect of trodusquemine.

The potential use of trodusquemine as a treatment for organ and tissue impairment in humans could have an astronomical effect on patient outcomes and the health care system. Although organ transplantation is a critical facet of regenerative medicine, the unfortunate fact is there will never be enough donated organs for those that need them. Additionally, there are thousands of people who suffer from congenital disabilities, and many that experience degeneration and complications from aging. Not only must patients endure the physical symptoms of these health conditions, but patients and the health care system are financially burdened for what may be decades of necessary medical care and treatment. Regenerative medicine and the development of drugs like trodusquemine could offer a more cost-effective, permanent, and long-term solution to many debilitating conditions with limited treatment options.