The Alchemist’s Legacy in Modern Medicine
Tracing the Secret Elixir of Life in Regenerative Therapy
In the heart of 14th-century Paris, there was a bookseller named Nicolas Flamel. While many knew him for his shop filled with ancient texts, those close to him were aware of a deeper pursuit. Beyond the desire of many alchemists to turn base metals into gold, Flamel harbored a greater ambition:
He was on a quest for an elixir, a potion that he believed could unlock the mysteries of life and perhaps even grant immortality.
Every morning, before the city streets buzzed with activity and the marketplaces came alive, Flamel was already immersed in his studies. Surrounded by old scrolls, vials of herbs, and arcane symbols, he diligently worked on his concoctions, hoping to discover the secret that would defy the ravages of time.
Little did he realize that, centuries later, scientists would embark on a similar journey. Not with mystical symbols and alchemical brews, but with the very fabric of life itself: our genes and cells.
The Cellular Blueprint: Beyond the Surface
We were all once a single cell.
From that one cell, we grew into complex beings. This cell divided BILLIONS of times to create our entire body. During each cell division, it faithfully copy-pasted the same information: our DNA. Every single cell in your body has the same user’s manual. We have over 200 types of cells in our bodies. It’s epigenetics that guides each cell, turning on and off the necessary parts of our DNA, ensuring that every cell knows its role.
(If you’re wondering how exactly they ensure this or are looking for a more technical dive, I invite you to check out my previous article.)
And then, Shinya Yamanaka, a Japanese researcher, had a thought.
What if we could erase this information? Could we return to that very first cell, the one filled with endless possibilities?
This revolutionary thought earned him a Nobel Prize. In 2012, he was awarded the Nobel Physiology Prize for his discovery of the “4 Yamanaka factors”.
To Be Continued…
Don’t worry, just kidding. BUT —
Before I continue, there are some things that we need to discuss. No need to be scared, just a quick base before I get to the exciting part.
Let’s dig in!!!
First thing to know: Cells that have established their identities, whose epigenomes have already assigned them as one of the hundreds of types of cells in our bodies, are termed “somatic” cells.
We mentioned that our very first cell had the potential to become one of over 200 types of cells. These cells are called “stem cells”. They have the potential to perform different jobs, and haven’t yet taken on their specific roles or — differentiated. However, the only stem cells in our bodies aren’t solely our embryonic cells. Even after our bodies have formed and our cells have differentiated to create our tissues, organs, and systems, we still retain stem cells, standing by just in case.
We can categorize them based on tissue origin into:
- Embryonic stem cells: These are the ones that are formed three to five days after an egg cell is fertilized by a sperm, having all of the potential.
- (Adult) Tissue-specific stem cells: These are the ones that accompany us throughout our lives as backups. They’re usually more specialized than embryonic stem cells, meaning that they don’t have the potential to become any of the +200 cell types. Their name gives a hint: they stand by in specific tissues or organs, ready to replace injured cells as needed. They can play in different positions, but they can only replace the players of the game that they are waiting in the player booth. Unlike embryonic stem cells that are able to play any game in any position.
For example, blood-forming stem cells in the bone marrow can generate red blood cells, white blood cells, and platelets. However, blood-forming stem cells can’t become skin, liver, or brain cells, and stem cells in other tissues and organs can’t generate red or white blood cells or platelets.
For stem cells, we have a classifier: “potency”. They can be a more qualified player according to the amount of the cells that they can replace:
They can be: unipotent, multipotent, pluripotent or totipotent.
Totipotent stem cells (Toti — whole)
These are the aces. The most qualified ones, they can play any game, at any position: they can give rise to any cell types found in the embryo as well as extra-embryonic cells like those in the placenta.
Pluripotent stem cells (Pluri — several)
They are also quite adept. They can also play in different games, in any position, with one exception: roles exclusive to totipotents. (They can give rise to all cell types of the body except extra-embryonic cells.) Even though we mainly find them during our early developmental stages, a few remain with us in specific tissues.
Multipotent stem cells (Multi — more than one; many)
They might have a narrower scope, but they’re lifelong companions. They can still play in different positions, but they are waiting in the player booth of one single game, and can only replace that game's players. The most of the adult stem cells are pluripotent.
Unipotent Stem Cells (Uni — one; single)
The specialists. Players trained for a singular position. They stand ready to fill in when the situation demands. We find these specialists throughout our lives.
Aaaand that’s it! It wasn’t that complicated was it? Thank you for bearing, and we are now in the part where you have been waiting for.
UNLOCKING THE YAMANAKA FACTORS
Can a differentiated, mature cell forget its specialized function and revert to an embryonic state?
To figure out what gave embryonic stem cells their pluripotency, Yamanaka’s team started by comparing the gene expression profiles of embryonic stem cells with differentiated adult cells. They were searching for genes that were active in the pluripotent state but not in the differentiated state. This way, they could identify genes that, when turned on, could make differentiated cells pluripotent again. These cells are now called Induced Pluripotent Stem Cells (IPCs)
I heard you saying:
You mentioned that epigenetics determine differentiation and give cells their identities, so shouldn’t embryonic stem cells (ESCs) have no epigenetic marks?
Yes, epigenetics do determine cellular differentiation. But this doesn’t mean ESCs have no epigenetic information. In fact, ESCs have a particular epigenetic landscape that maintains their pluripotency and ensures they stay undifferentiated. This balance involves turning on specific genes (those that support pluripotency) and turning off others (those that cause differentiation).
That’s why Dr. Yamanaka’s team started by comparing ESCs with somatic cells. They wanted to find this specific landscape. Starting with 24 candidate genes known to be active in embryonic stem cells, they tested different combinations of these genes to see which were needed to make adult cells pluripotent again.
But how did they test which ones —
Aha! I was just getting there.
To test the function of the genes they identified, Yamanaka’s team used viral vectors. These are essentially viruses that have been engineered to lose their disease-causing ability but still retain the capacity to enter human cells. (And nope! They won’t make you sick — at least, not in the typical sense). By inserting the genes of interest into these vectors, scientists can introduce any gene into human cells.
How the Viral Method Works:
- Scientists take the DNA sequences that represent the genes and insert them into a virus.
- The viral vector, which carries the genes for the desired genes, enters the cells we want to reprogram.
- After entering a cell, the viral vector releases its genetic material. This is a natural process for many viruses; they insert their genetic material into host genomes to ensure their replication.
Even though we have changed the viral vector’s ability to make us sick, it still retains the abilities of viruses. This means that just like viruses, they have the natural ability to integrate their genetic material into the cell’s DNA. Think of it as adding an extra page to a book rather than replacing an existing page. This addition expands the cell’s genome to include the new genes without removing any of the original sequences.
So, by testing 24 candidate genes known to be active in embryonic stem cells using viral vectors, they narrowed it down to key four: Oct4, Sox2, Klf4, and c-Myc.
These genes are already present in our DNA, they were expressed during embryonic development, and are still there. However, by time, when our cells start to differentiate, they just start to get turned off or expressed at very low levels, leading to a loss of pluripotency.
The brilliance of Shinya Yamanaka’s discovery lies in the realization that reintroducing and reactivating these genes in differentiated cells can reverse them to a pluripotent state. It’s important to clarify, though, that the Yamanaka Factors — Oct4, Sox2, Klf4, and c-Myc — are not the genes themselves but the proteins they encode. These proteins are responsible for regulating the expression of specific genes. They know which genes to turn on and off precisely.
What we truly needed was the ability to produce these proteins. With the genes that instruct the production of these proteins present in our DNA (our user manual), we can manufacture these proteins accordingly. This gives us the actual Yamanaka Factors.
In summary, having these genes doesn’t guarantee pluripotency. These genes have always been a part of our DNA. However, as our bodies develop, our cells suppress the expression of these genes to acquire their specific identities and functions. What we do is reintroduce these genes into our DNA to ensure their expression and accessibility, allowing us to produce the associated proteins. Our cells had been silencing this information, preventing these genes from producing the proteins. By reintroducing them, we make this information accessible, enabling us to produce these four proteins according to their instructions or “recipe.”
Encountering Challenges
Even though this method was revolutionary. We soon realized that there were limitations to it.
Oncogene Activation: First of all, one of the Yamanaka factors, c-Myc, is known to be an oncogene, which means it has the potential to cause cancer. When cells are reprogrammed using c-Myc, the risk of them becoming tumorigenic, or cancer-forming, increases significantly. This poses a real safety concern for potential therapies derived from cells reprogrammed with these factors.
Identity Crisis: Even when cells are successfully reprogrammed to a pluripotent state, directing them to differentiate into a specific cell type isn’t always straightforward. When pluripotent cells are introduced into the body without a clear identity or function, they might not integrate well with existing tissues, or worse, they could differentiate in unpredictable ways.
Cellular Environment Matters: Stem cells, whether naturally occurring or reprogrammed, rely on signals from their environment to determine how they should behave. If a stem cell doesn’t receive the right signals, or if it’s placed in an environment where the signals are confusing, it may not differentiate correctly or might remain in an undifferentiated state.
An unfortunate example of the risks associated with stem cell therapies can be seen in a case from Florida. Patients seeking treatment for macular degeneration were injected with stem cells derived from their own fat tissue. These cells were not properly characterized or suitable for eye injections. The result? Several of these patients experienced severe vision loss.
The Time-Traveling Cells
Now, let’s skip to the December of 2020. Yuancheng Lu’s, a Harvard Graduate students research was published.
At the heart of the study was an experiment involving the eyes of aged mice. As mammals age, including humans and mice, the nerve cells responsible for vision, known as retinal ganglion cells, suffer from a decline in function. This decline is associated with a loss of youthful epigenetic information, leading to decreased visual acuity.
In their experiment, Lu’s team targeted these retinal ganglion cells. They also used Yamanaka factors with one exception — excluding the problematic c-Myc oncogene.
The study focused on inducing epigenetic changes without entirely erasing cellular identity. They only partially reprogrammed the cells, — didn't reset the cell to point 0 but rather to point 1 — a stage where it is differentiated enough to recognize its identity but still at the very beginning of its life. They maintained their original function and identity, which reduced the risk of them differentiating unpredictably when reintroduced into the body.
Excluding c-Myc oncogene and this partial reprogramming to rejuvenate cells without pushing them all the way back to a stem cell state, also lowered the risk of tumorigenesis.
The results were nothing short of remarkable. By using their partial reprogramming technique, the team was able to reverse age-related vision loss in mice. Not only did this provide a proof-of-concept for the potential of cellular reprogramming in treating age-related conditions, but it also showcased a safer and more controlled method than previous techniques.
Modern Alchemists of Life
Imagine having a clock that you could rewind. Not just once or twice, but many times. Each rewind offers the promise of youth, of a fresh start, a new dawn. With this new research, we might be closer to doing that for our own bodies.
As we stand on the precipice of this groundbreaking discovery, one can’t help but wonder: How many times can we rewind this biological clock? Once? Twice? A hundred times?
We’re stepping into new territory, and there’s so much we still don’t know.
The horizon of possibilities lies down infinitely before us, shining with the promise of longevity, health, and perhaps, a touch of immortality.
And as we chase this dream, our minds drift back to the legends of old, to tales of alchemists and their persistent pursuit of the elixir of life. Flamel, the legendary alchemist rumored to have found the secret of immortality, seems not so distant now. Today, as we stand on the cusp of scientific breakthroughs that promise rejuvenation, we must ask ourselves:
Are we, in our own way, becoming the modern-day Flamels? Have we unlocked the alchemical secrets of life, or are we only at the first chapter of a much longer saga?
Only time, that ever-constant force, will tell.
Sources:
- https://www.nejm.org/doi/full/10.1056/nejmoa1609583
- https://www.closerlookatstemcells.org/types-of-stem-cells/#embryonic
- https://www.technologynetworks.com/cell-science/webinars/ask-me-anything-psychedelics-379816
- https://sinclair.hms.harvard.edu/research
- https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-021-01158-7
