Written by C. Christian Monson
As a human being it’s probably a rare occurrence that you feel jealous of salamanders, but when it comes to limb generation, they definitely seem to have an unfair advantage. If you’ve ever wondered why so many other animals seem to be able to regrow body parts while yours are all one and done, the answer is simple: it’s stem cells.
For example, when an axolotl loses a leg, a blastema of stem cells migrates to the wound. These stem cells are undifferentiated, meaning they have the potential to turn into whatever type of tissue the axolotl’s body needs. After receiving necessary information, these stem cells differentiate and reform the axolotl’s leg.
In the human body, however, the use of stem cells is limited. There are adult stem cells called somatic stem cells, but they cannot differentiate into every type of tissue like the embryonic stem cells that result from the fertilization of a human egg. Nevertheless, the discovery of both adult and embryonic stem cells has led to considerable enthusiasm within the scientific and lay community. Could the regeneration of body parts be a future medical reality?
OF MICE AND MEN
Although stem cells were already known to biologists in the late 19th Century, their function and properties weren’t fully understood until the work of Ernest McCulloch and James Till at the University of Ontario in the early 1960s. By injecting stem cells from bone marrow into mice that had been exposed to lethal levels of radiation, they were able to discover how the stem cells were able to replicate into large colonies of specialized blood cells.
The importance of McCulloch and Till’s discovery was not fully recognized for some time, but it did open the door for more research into stem cells and how their properties could benefit humans. Perhaps the biggest milestone in this research came in 1981 when Martin Evans and Matt Kauffman isolated embryonic stem cells, again from mice, and were able to culture them in a lab.
Evans would go on to win the Nobel Prize in Medicine in 2007 for further work he did with Mario Capecchi and Oliver Smithies creating “knockout mice,” which isn’t as cruel as it sounds. Basically, they took stem cells from a mouse embryo, changed their genetic code, and then put them back. Then the embryo grew into a fully formed mouse with the desired change. For example, they were able to create fat mice, bald mice, even mice with cured genetic diseases.
While it seems like this would be easy enough to apply to humans, it’s not so simple, primarily due to ethical issues. Changing a human’s genetic code and cloning human cells are all controversial issues, not to mention the stem cell research or therapies that would require destroying a human embryo.
However, this problem was given a solution in 2006 when Shinya Yamanaka and his team developed “induced pluripotent stem cells,” also known as iPS cells. First using—you guessed it—mice, they took fibroblasts, a type of cell important for wound healing found in connective tissue, and, by altering just four genes, were able to convert them back into stem cells that could differentiate into any type of cell.
Yamanaka’s work ushered in the modern age of stem cell research and its many promising applications. As a result, in 2012, he won the Nobel Prize in Medicine for the discovery of iPS cells.
BAD TO THE BONE
Currently, despite wide interest in stem cells going back several decades, there’s only one established and medically accepted therapy that uses them: hematopoietic stem cell transplantation, commonly known as bone marrow transplantation. This is primarily used to treat people with cancers like leukemia and lymphoma that affect the blood.
Doctors generally treat these cancers with chemotherapy, but those chemicals also kill the patients’ hematopoietic stem cells, those located within the bone marrow that differentiate into the various types of blood cells. These then have to be replaced with a bone marrow transplant. These transplants are usually performed using adult stem cells extracted from a donor, but the FDA has also approved five different stem-cell products derived from umbilical cord blood.
Bone marrow transplants have been performed since the mid-20th Century, even before scientists fully understood the function of stem cells. While they’re dangerous procedures that have the potential for many complications, their increased safety in recent years has led doctors to use the therapy for conditions beyond cancer. For example, it’s now used as a treatment for sickle cell anemia and multiple sclerosis.
In fact, bone marrow stem cell transplantation appears to be a possible cure for HIV. In 2007, Gero Hütter and his team in Berlin, Germany, gave Timothy Ray Brown a bone marrow transplant from a donor with a mutation for a specific cell surface receptor. A rare gene found in only one of every 1,000 people of European ancestry, it provides resistance to HIV, so by implanting stem cells with this gene into Brown, the scientists effectively cleared him of the virus. In 2019, this treatment was successfully repeated in London.
No stem cell therapy is as widespread as bone marrow transplantation, but a few others have gained scientific recognition. For example, in 2015, the European Commission approved the stem cell product Holoclar for the treatment of limbal stem cell deficiency. Limbal stem cells are responsible for replacing eye cells in the cornea, but they can be destroyed due to chemical burns, radiation or infection. Holocar therapy involves extracting a few of the patients’ remaining limbal stem cells, replicating them in the lab then implanting them back into the eye.
ALL CREATURES GREAT AND SMALL
Because of the inherent controversy involved in much of stem cell research, its applications have advanced more for animals than humans. It’s not just lab mice, though. In fact, veterinary medicine for domestic animals like dogs and horses has begun extensively taking advantage of stem cells.
For example, race horses often suffer injuries to soft tissue made of cartilage like tendons and ligaments. Veterinarians have been able to inject embryonic stem cells into the injured area to repair the damaged tissue. The horses weren’t just able to race again afterwards, but they actually had lower rates of re-injury.
In fact, veterinarians have even been able to treat spinal injuries with stem cell therapy. By implanting stem cells into dogs’ injured spinal cords, researchers at Seoul National University in South Korea counteracted scar formation and promoted the regeneration of nerve tissue. The dogs who received this treatment improved considerably compared to those receiving conventional treatment, and some were even able to support their own weight again, something never seen before using conventional therapies.
Once again, it seems like humans have a reason to be jealous of other animals when it comes to stem cells, but don’t worry. Scientists are taking advantage of these veterinary stem cell therapies to evaluate their potential for use in humans.
Perhaps most impressively, the nTRACK project funded by the European Union is developing a way to use nanoparticles to track stem cells used for muscle regeneration in sheep. The project wants to “label” stem cells with gold nano-particles that can be seen with imaging systems. This will give them information and insights into the migration and distribution patterns of stem cells with the aim of informing future human stem cell therapies.
IRONS IN THE FIRE
While the axolotl-like limb regeneration we see in science-fiction movies might be a bit of an exaggeration, the future of stem cell therapy is definitely promising. Many applications are in clinical trials, and many more are theorized for testing and research.
For example, in 2021, the FDA approved the first clinical trial for stem cell therapy to treat Parkinson’s disease. The team led by stem cell biologist Lorenz Studer at the Memorial Sloan Kettering Cancer Center has developed a treatment that uses stem cells to replace a patient’s neurons that have stopped making dopamine, a neurotransmitter necessary for a number of physical and mental processes.
Despite the associated controversy, there’s been an increase in clinical trials involving embryonic stem cells as well. In 2009, California company Geron Corporation submitted a 28,000-page application for testing GRNOPC1, a product derived from embryonic stem cells aimed at promoting nerve regeneration in people with spinal cord injuries.
The first subject, Timothy J. Atchinson, had suffered a spinal cord injury in a car accident just two weeks before the study. The scientists injected him with a dose of GRNOPC1 containing 2 million cells.
In 2011, it was reported that Atchinson had regained some sensation in his legs. Nevertheless, Geron discontinued the study that year and decided to shift towards cancer research. However, they still monitor the participants in the study.
Diabetes is another disease that scientists believe could be treated with stem cells. In type 1 diabetes, the body’s own immune system attacks and destroys beta cells in the pancreas responsible for producing the insulin needed to use sugar for energy and moderate glucose levels in the bloodstream. A company called ViaCyte has been researching stem cells extensively in an effort to replace these beta cells in affected patients.
Most recently, in February of 2022, they partnered with CRISPR Therapeutics, the company you may recognize as the inventor of the CRISPR gene editing technology. Together, the companies designed VCTX210, a diabetes treatment drug now in Phase 1 clinical trials.
Using CRISPR technology, the scientists edited stem cell DNA so that the cells aren’t recognized and subsequently attacked by the body’s immune system. Theoretically, they should then be able to replace the patient’s pancreatic beta cells and start producing insulin.
If none of that is sci-fi enough for you, there are a few applications being developed that would have a little more pop on screen. For instance, scientists hope to be able to heal wounds more effectively with stem cells. In adults, wounds heal by developing scar tissue, which has a number of disadvantages compared to normal tissue. However, fetuses are able to simply regenerate wounded tissue thanks to stem cells. In the future, scientists hope to be able to implant stem cells into a wound, allowing it to heal without scarring, essentially returning to the state it was before the injury.
Additionally, scientists have even been able to regrow teeth since 2004 when a team at King’s College London did so in, of course, mice. Later, Dr. Duanqing Pei of the Chinese Academy of Sciences discovered a way to use iPSC cells isolated from your urine—you heard me right—to grow tooth buds in the lab. When implanted into mice, these grew into teeth with pulp, dentin and enamel.
So imagine a world where not just mice, but humans too can regrow their teeth whenever they get in a bar fight, forget to floss or eat too many gummy bears. That’s what science suggests may be in our future. More significantly, stem cells may represent a cure or treatment for devastating diseases like diabetes, Parkinson’s, AIDS and cancer as well as severe injury. And maybe, if we’re really lucky, stem cells will see me someday narrating these posts with a new, luscious head of hair.
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