The search for the fountain of youth has been ongoing ever since man decided that dying wasn’t all that appealing. And now, it appears that this elusive holy grail has been found, albeit by a species that is not ours! So who is the lucky winner of the everlasting life sweepstakes? None other than the humble and dime-sized jellyfish known as Turritopsis nutricula. This creature has accomplished what no other biological being on our planet has ever been known to do: reverse it’s aging to become young again after reaching full maturity! As early as 1992, scientists had observed this phenomenon in Turritopsis and research into its secrets was ongoing. However, a recent spike in the numbers and geographic distribution of this species has once again brought it to the attention of the greater scientific community because of the many important breakthroughs we have witnessed in stem cell research in the past decade. As regenerative medicine continues to grow into the future of medicine, it’s clear that this tiny jellyfish may hold the answers to not only addressing the many aging-related ailments we face, but also our own mortality!

In the picture below, you can see the typical lifecycle of a jellyfish. It starts out as a larva that eventually sinks to the bottom of the ocean and attaches to a sturdy substrate and continues development into a polyp that resembles a sea plant. The polyp then matures to become a free-floating medusa, what we commonly recognize as jellyfish resembling an upside down saucer with tentacles. Not much excitement so far, but Turritopsis has put an interesting twist to this process. It undergoes development much like what I’ve described above and what many of its relatives go through. However, during times of stress like a shortage of food, Turritopsis responds by beginning to reverse the process before eventually becoming a polyp again. From this point then, it can again develop into a sexually mature medusa when conditions become more favorable. Theoretically, it can repeat this process indefinitely as its cells undergo a process called transdifferentiation, a rare biological process whereby any non-stem cell can become a different cell entirely. It is still unclear whether only specific cells can only become other specific cells or if any cell in Turritopsis has the potential to become any other cell.

Ok, what Turritopsis does is admittedly cool, but why would we care? As you know, here at the Hub, one of our favorite topics are stem cells and all the promise they hold for regenerating tissue and treating a vast array of ailments. And while stem cells are one avenue to reach the goal of regenerating damaged or diseased tissues, transdifferentiation is another option that can get us to that goal.

Allow me to digress here and clarify the difference between these two systems (also see the below figure). Stem cells are cells that can differentiate into any type of cell. They can be isolated from a natural state i.e. embryonic stem cells (ESCs), or created by taking already differentiated cells and coaxing them to undifferentiate into stem cells, becoming induced pluripotent stem cells (iPSCs). These stem cells can then differentiate into another type of cell. On the other hand, transdifferentiation doesn’t require the middle step of becoming a stem cell. Any differentiated cell can become any other differentiated cell, given of course that it receives the correct signals.

Much of the advances in stem cell technology have come from having an understanding of how stem cells naturally develop into different cell types. Thus, nature’s methods are teaching us how to manipulate stem cells and turn them into the desired cell type. And when it comes to transdifferentiation, the hope is that we will eventually be able to learn how creatures like Turritopsis skip the stem cell step and go directly from one cell type to another. As such, a recent breakthrough in using transdifferentiation for therapeutic purposes was reached in the laboratory of Dr. Deepak Srivastava of the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco. In a recent article in the journal Cell, Dr. Srivastava’s group describes their success in getting architectural cells in the heart called fibroblasts to differentiate into cardiomyocyte-like cells. In case you’re rusty on your cardiac anatomy, cardiomyocytes are the cells in the heart that contract and result in it’s rhythmic beating. And as Dr. Srivastava explains in the video below, it is the loss of these cells and the development of scar tissue that is debilitating to those fortunate enough to survive a heart attack. So by just switching on three genes in the fibroblasts, the researchers were able to coax them to transdifferentiate into cardiomyocyte-like cells that looked and behaved like cardiomyocytes. Taking it one step further, they implanted these cells into the hearts of mice and found that they behaved just as one would expect them to. In a previous post, we had described similar results, but in that work, the researchers had to first produce stem cells from skin cells before producing the cardiomyocytes. Clearly, Dr. Srivastava’s group has taken this to another level.



So while we still have some hurdles to overcome before this type of treatment is available for use in humans, it is indeed on its way. The amazing work being done in laboratories such as Dr. Srivastava’s are inching us closer to the day when perhaps we’ll be able to not only treat various ailments, but also to turn back the hands of time and reverse our aging like Turritopsis has been able to do. A recent press release by Advanced Cell Technology (ACT) hints at some potentially new technologies they are developing to take advantage of transdifferentiation. While most of their work thus far has focused on stem cell-based treatments, it’s encouraging to see companies like ACT put time and money into exploring transdifferentiation-based treatments as well. Sure everyone is working to get to the same goal, but there may be more than one way to get there!