Stem Cells: Future of Therapeutics
A brief on the future of regenerative medicine
Imagine a world where families are untouched by harmful diseases, imagine a world where billions of dollars that aren’t invested in cures will shift towards education or poverty. Well, how do we get there? The answer lies in stem cells, the key to degenerative diseases. Stem cells are on the rise of being the face of all medical treatments and therapies that are used to combat debilitating diseases, let’s break down why.
“Stem cells are nature’s vital gift towards multicellular beings, including humans”
A few weeks prior to writing this article, I attended a conference about type 1 diabetes (JDRF 2019 Annual Conference) and there were a few speakers from start-ups, research institutes, and universities that talked about how they were looking into technologies that can help cure this degenerative disease. What some of the speakers had to say truly inspired me, I was intrigued enough to research and reach out to experts in the field. To be completely honest, that’s been taking up the most of my time for the past few weeks and I don’t think I’ve ever killed time in such a nerdy way.
But wait, Valmik, we know why you should care about stem cells but why should we?
Well, when I saw what the potential that stem cells had when it could be applied to healthcare, I was shocked. I have a countless number of friends and family that suffers from one type of degenerative disease or another and what these talks told me was that there was hope. Hope, that I could one day see a world without anybody suffering from Cancer or Alzheimer’s, anybody struggling between life and death, anybody passing the pain to their children and loved ones. If those few sappy sentences didn’t bring a tear to your eye, then I don’t know what will.
The discovery of stem cells, way long ago, opened the gateway to a lot of medical applications for degenerative diseases that debilitate mankind to this day. Cancer, Parkinson’s, Alzheimer’s and much more now have the possibility of being cured to a point where the patients can live their lives with happiness and opportunities they never had before. But we can’t just jump to its medical applications right away, first, we have to understand what a stem cell actually is.
Learning about stem cells is very broad and a lot of terms go undefined, a keyword that you might want to remember for the remainder of this article would be the word “iPS cells” or “Induced Pluripotent Stem Cells”. Usually, when I refer to this term, people gasp and say “alright we get it, you’re smart”, there’s no need to fret this is just a term to describe how the stem cell was created and one of its most important traits, potency. In essence, this is a type of stem cell that shows increased abilities in how it can affect its surroundings.
There are three main inquiries that outline the basis of stem cells that I’ll talk about next:
What Is a Stem Cell?
Where Do Stem Cells Come From?
How are Stem Cells Identified?
What Is a Stem Cell?
Originally, stem cells are defined as cells that can self-renew and have the ability to generate differentiated cells. Basically, stem cells can generate daughter cells identical to their mother, as well as produce offspring with more restricted potential. There are two properties recognized: the ability to self renew (daughter cells), and the ability to produce differentiated cells (progeny with more restricted potential). But something else that makes a stem cell what it is would be potency: Does the stem cell produce an unrestricted variation of differentiated cell types (multipotent), or is it limited to one type of differentiated cell type (unipotent)? Therefore, when formulating a description of a stem cell, you must consider its replication capacity, clonality, and potency.
At first, stem cells are defined as cells that can generate daughter cells identical to the parent cell, as well as produce offspring with more restricted potential (e.x. Neural cells, heart cells, skin cells). These “super cells” have three main characteristics that separate them from other cells found in the body:
- Self Renewal
- Clonality
- Potency
Previously we’ve talked about the first two traits, but potency is perhaps one of the most important traits that stem cells could have. Does the stem cell produce an unrestricted variation of adult cell types (multipotent), or is it limited to one type of differentiated cell type(unipotent)?
Nonetheless, all three of these traits should be considered when thinking about what stem cells are.
Self-Renewal
Terminology in stem cell literature is filled with terms such as “immortal”, “unlimited”, and “capable of extensive proliferation”, which are commonly used to describe the self-renewal property that stem cells. The terms that are used don’t fully express the trait, in experiments designed to test the “immortality” would outlast the lives of the audience and conductors alike.
It was noted in an experiment, most somatic cells cultured in vitro display a finite number of population doublings (less than 80) prior to replicative arrest by the formation of tumors. It is reasonable to say that if any cell can undergo more than 320 population doublings without oncogenic/tumor transformation can be termed “capable of extensive proliferation”(self renewable).
There are specific methods to determine the capacity for self-renewal of stem cells, the most effective being single-cell or serial transfer into acceptable hosts, and observing how they perform. Adult stem cells are probably still best defined in vivo, where they must demonstrate enough population doublings in order to last the lifetime of the host. But from why this so important for therapeutics and stem cell therapies?
Self-renewal is basically making a complete copy of the parent cell through mitosis (cell division) or making a daughter cell through mitosis that retains the same quality of differentiation and self-renewal. There are two ways cell division could go in a stem cell:
a) Symmetric
b) Asymmetric
Looking at the name of the process, where the cell divides into two identical daughter cells that either retain traits or two identical cells that have equal limited ability. On the other hand, looking at asymmetric cell division we see one daughter cell retaining all the characteristics of the parent cell, while the other daughter cell has restrictions in terms of ability to differentiate and self-renew. Imagine a couple giving birth to identical twins as symmetric division, while asymmetric would be most cases where both children carry different traits. This specific property of stem cells is often confused with its clonal ability, they may not be the same but are very similar.
In therapies, where a culture of stem cells will be inserted in the host it is very important that the stem cells can sustain themselves long enough to make a positive impact where regeneration is needed. Self-renewal is a property that shows the culture of these cells will remain alive in the host long enough to repair any damage.
Clonality
Stem cells have the ability to produce other cells but what makes clonality a distinct trait of a stem cell is its ability to transfer characteristics to offspring in such a manner it is considered a clone.
There are several methods for tracing the lineage of stem cells, but first what must be understood is what constitutes a cell line?
The minimum would be any population of cells that can be grown in culture, frozen, thawed and consistently used in vitro. While the gold standard would be an almost identical or homogenous population of stem cells in a culture, it must be indicated that the cellular preparations do not derive from a single cell but a mixed population of stem cells and a separate population of supportive cells that are required for these purported stem cells. Therefore, any reference to a stem cell line should indicate it’s derivation to reduce misconception.
There are often misunderstandings between clonality and self-renewal, they’re very similar but do have their differences. When a cell undergoes division, it splits itself into two identical daughter cells and this remains the same with stem cells but what’s fascinating is that only stem cells have two types of division, and this is the difference between clonality and self-renewal. There are two ways stem cells can divide, the symmetric division would refer to how any cell would produce two identical daughter cells that are either both committed to a cell line (neural cells, heart cells, skin cells), or two new and identical cells. Symmetric division is also the method by which stem cells clone themselves or other types of cells, on the other hand, we have an asymmetric division where two cells are produced but each has their own abilities instead of being identified and this would be self-renewal.
Let’s look at an example of how this would work in therapy or treatment.
Let’s presume the patient is facing major degeneration in the heart, where a (most commonly secondary) cancer is killing cells that are causing major debilitation in the host. Cardiac cells are precious as they cannot proliferate, therefore once we lose a significant amount of them there is currently no way to restore function even after curing cancer. If we were to incorporate a culture of stem cells in the heart of the host, in order to combat the degeneration, two things will happen:
1) Stem cells will generate enough cells to “fix” the damage (cloning)
2) Stem cells will also survive in the host for a prolonged amount of time (self-renewal)
Condition #1:
There will be a part of the stem cell population that would constantly be cloning in order to provide the fastest healing process, in this case, that would be by cloning either to create two identical stem cells or two identical committed cells. This would be dependant on the objective of cloning, if it’s for treatment then the culture would produce two committed cells, while on the other hand if it were for producing a population of new stem cells then it would be two identical stem cells.
Condition #2:
This is where the stem cell produces two daughter cells, one being another stem cell and the other being a cell that’s committed to a cell line. In this case, the stem cells, in order to sustain itself within the organ to maximize treatment, will produce one daughter cell that retains all qualities and traits of the parent cell and produces another daughter cell that helps combat the degeneration which would be a heart cell. The stem cells undergo this specific division in order to create a balance between stem cells and committed cells, because if we lose this balance then the whole treatment would fail. Without these stem cells, there would be no ongoing treatment and the degeneration would outlast the regeneration while if we add more stem cells than actually committed cells then there would be no treatment at all.
Potency
The issue of potency may be the most contentious part of the widely accepted definition for stem cells. There is a hierarchy for the type of stem cells, where it goes from cells that have restricted potential (differentiated cells) to multipotent stem cells that have the ability to generate multiple types of adult cells. I’m not going to ask the same question I did for each of the other traits, “why it matters” doesn’t show the full importance of this trait. Potency separates stem cells from any other somatic cell and other stem cells, it really is a game changer. Every other cell in the body has a certain extent of clonality and self-renewal, but every other cell doesn’t have the ability to mature into another type of cell.
But the first question I asked was: what separates pluripotent stem cells and unipotent stem cells?
This question really bugged me out for a while. Why does it matter if a cell can produce different types of adult cells when we can just create cells dedicated to one lineage at a time?
A common misconception is how there is only one type of cell within an organ, even though they constitute a human body they are still very complex with a lot of different types of cells within them.
Take all the different types of brain cells as an example of the complexity of a human organ. But what if there was a way to combat a degenerative disease that affected the whole organ? Which is where we would use pluripotent stem cells.
Pluripotent stem cells can be implemented on a larger scale (inside the body) because they can differentiate into several types of cells and this is very helpful when looking at diseases that cause degeneration within the entire organ (several cell types are affected). We see how these three main traits help stem cells shine from all the other cells when looking at medical applications, but this is all assuming we have already obtained the stem cell. Stem cell research can’t only be theoretical, we must observe how stem cells perform in vivo and in vitro in order to gain the best knowledge. In order to experiment with stem cells, we must look at how we obtain them, naturally or artificially.
Where Do Stem Cells Come From?
So far, I’ve left the impression of there being different types of stem cells, which is exactly what I wanted to do. There are three main types of stem cells, embryonic stem cells and induced pluripotent stem cells (I’ll get to the differences later), and only two and generated naturally.
Adult stem cells or differentiated cells are mature stem cells that are found within specific organs in the body, their location is also known as a niche. Within their niches, adult stem cells follow only two of the three traits that the other stem cells possess which would be clonality and self-renewal and this is because they remain “dormant” until the organ or niche they serve requires repair from any damage. But why do they only have two of the three traits?
Adult stem cells are already lineage committed because they are originated in an organ, this means they are unipotent or known as progenitors (unipotent cells). They lack potency because they are already situated in the area of repair, for example, a heart stem cell can’t mature into a brain cell because it’s committed to only the different types of cells in the heart.
Induced pluripotent stem cells (iPS cells) are unlike embryonic stem cells and adult stem cells, they were formed from already mature cells found in the body. IPS technology was invented in 2006, this gave hope to cures for a lot of diseases but this technology still hasn’t been developed to a point of regulated therapies.
But wait how do convert normal somatic cells of a patient into induced pluripotent stem cells? There are four main growth genes that “trick” the somatic cell into believing that it can mature it any other type of cell and by artificially providing the four main growth genes (’inducing pluripotency’), researchers can now truly turn any cell into any other type of cell.
Another source of stem cells, Embryonic Stem cells (ES cells), are cells that originate before germ layer commitment, unlike iPS cells that form due to the genetic engineering of any somatic cell after maturing. They are found within the embryos of any host, which means that they are undifferentiated or immature stem cells. What that means is that ES cells show the potency trait that other stem cells do, that means they could have the same medical application that iPS cells do right? Currently, there is a lot of ethical issues that surround the use of embryonic stem cells in medical therapies and treatments, but that’s a talk for another day; let’s focus on what embryonic stem cells are used for today.
Due to all the ethical issues that surround ES cells for treatments and therapies, stem cell researchers use embryonic stem cells for research purposes, to further our current knowledge on pluripotent stem cells. How do researchers obtain these embryos when they are supposed to be a key factor is a childbirth? A common misconception with childbirth is that there is only one embryo produced during fertilization when in reality when the egg is fertilized there are several embryos that are produced. In a process called in vitro fertilization, where the egg and sperm are brought together in a lab dish, throughout this process more than one embryo is produced with the sperm and egg since the couple has no use for the other embryos they often donate them to research institutes for scientific purposes. This is where biologists get these embryos for their research, but never applied in treatments or therapies.
How are Stem Cells Identified?
At this point, we’re all aware of the different types of stem cells but how are they identified other than their properties?
Stem cells are identified by their method of creation.
There are three main types of stem cells, but we could go further to find different types of ES cells, adult stem cells. Within ES cells, we have:
- Embryonic stem cells derived by somatic cell nuclear transfer (SCNT)
- Embryonic stem cells derived by parthenogenesis
Okay first, what in the world is somatic cell nuclear transfer? Somatic cell nuclear transfer is a process where the nucleus of an egg cell is inserted in a somatic cell, the nucleus will reprogram the somatic cell in order to create a pluripotent stem cell. This escapes some of the ethical views that citizens have but doesn’t completely avoid using egg cells in the process which still leaves some concern. This method of deriving embryonic stem cells gives it the name, nuclear transfer embryonic stem cells (ntES cells).
While parthenogenesis is a chemical method of “tricking” the egg into producing embryos without sperm, I don’t want to focus on the specifics on the method but really how does this help further our research in the field?
One big obstacle in conducting thorough research on stem cells is the ethical issues, but what parthenogenesis provides is a solution to obtaining stem cells without any ethical concerns.
There are different types of adult stem cells that are found within the human body, examples being neural cells, heart cells, skin cells. There is really a lot of types that are and aren’t included in the picture above, essentially there is a stem cell for every vital organ. Coming back to the main question, how do we identify them?
Adult stem cells can remain “dormant” years on end, only every helping when the niche has undergone damage and needs cellular repair. This means if we were to look at a patient with an organ-specific disease, and distinguish the cells that show the two traits of adult stem cells: self-renewal and clonality (limited potency is some cases). We can then identify the stem cells within their respective niches.
We hear, very frequently, on the news about hopes for cancer cures or a cure for diabetes but never see actually curing people. In 2019, there are expected 606,880 deaths just from cancer alone in North America, living in a world, where friends and families suffer every single day watching a loved one in pain going through treatment after treatment, therapy after therapy just to find out none of them worked, is nowhere close to a paradise.
Right now, we have researchers, start-ups, and institutes working hard day and night to make stem cells that ideal solution to all our medical problems. Stem cells, the future of therapeutics…
Key Takeaways:
- Stem cells demonstrate amazing cellular healing abilities because of their three unique traits: Self-Renewal, Clonality, Potency
- There are different ways to obtain stem cells, but the method of derivation banned them from being used in clinics. With the development of iPS cells, which are derived from any somatic cell from the host and reprogrammed to mature into any other type of cell, this roadblock is lifted
- Stem cells are currently being experimented in cell therapies to engage and provide cellular repair, but this is just the beginning. Their immense potential must be fully uncovered so they can change the face of regenerative medicine forever!
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