If you’ve ever looked up human embryonic stem cells (hESCs) in technical journals or textbooks, you have probably seen them defined as pluripotent cells derived from the inner cell mass of a 5 – 8 day old preimplantation blastocyst. In plain english, this means that human embryonic stem cells are immensely powerful and versatile cells that are carefully isolated from the interior of a fertilized egg, 5 to 8 days after fertilization and before said fertilized egg has had a chance to attach itself to the thickened walls of the uterus. The last part of the statement above is a bit misleading because it’s not like scientists are on constant standby ready to accost people and take their fertilized eggs from them after sexual intercourse. Rather, most human embryonic stem cells are derived from eggs that were fertilized using IVF (in vitro fertilization) techniques. First off, you are probably wondering what the heck “in vitro” means. Well “in vitro” is latin for “in glass” and back in the day, laboratory utensils and equipment were made of glass so in vitro fertilization of a human egg simply means the human egg was fertilized in a laboratory dish rather than in the fallopian tubes of a woman. And yes, you read that correctly… modern science has endowed us with the power to fertilize a human egg right in a laboratory dish provided that the right temperature and chemical conditions are present. These IVF derived embryos are then grown in a laboratory as they go through the multiple cellular divisions that would usually result in the formation of a full human being if it occurred in the womb. After 5 – 8 days of development, the fertilized egg takes the form depicted in the figure below due to multiple cell divisions and physical cell movements. At this stage, the fertilized egg or embryo is called a blastocyst and the tiny clump of cells within its fluid filled cavity is called the ICM or inner cell mass. This tiny clump of cells that we call the inner cell mass will eventually give rise to a full blown human being if normal development is allowed to occur in the womb. The inner cell mass is the source of the super versatile and powerful embryonic stem cells that you have probably heard about in popular scientific culture.
The reason for the hype and buzz around human embryonic stem cells is due to their pluripotency. The word “pluripotent” literally translates into “many powerful” or “many capable”. We describe human embryonic stem cells as pluripotent because of two main reasons.
- They are “immortal” cells which means they can continually undergo cellular division for much longer periods than other bodily cells without dying or senescing
- They have the potential to transform themselves into any of the cell types in the body
When I first learned of the above qualities of human embryonic stem cells, I was gobsmacked. “What do you mean they don’t die?” and “how can a single cell have the ability to become any one of the ~200 odd different cell types in the human body?” were the questions that came tumbling out of my mouth while staring at a scientific review journal in the super quiet section of one of the libraries at Stanford many years ago. As incredulous as it sounds, these qualities of stem cells check out in reality because they have been repeatedly confirmed in many different laboratories around the world.
The immortality of human embryonic stem cells
Every time a cell divides, a bit of the genetic material at the end of each chromosome (which is an intricate combination of protein and DNA that holds all of our genetic information) is lost. Nature in its infinite wisdom compensated for this phenomenon by making sure that the ends of each chromosome don’t actually code for essential proteins. These non coding ends of human chromosomes are called telomeres. You can think of telomeres as loosely being analogous to the plastic tips at the ends of shoelaces that keep shoelaces from fraying too soon after you just started breaking in your nice new pair of shoes. The presence of telomeres facilitates the ability of many of the cells in the human body to keep dividing for long periods of time without missing a beat in terms of functionality. However, father time and his undefeated “bad” self usually wins in the end because repeated cellular divisions will eventually eat far enough into the telomeres to start affecting the actual coding regions of the chromosome. When this happens, cells start to age rapidly and stop functioning properly because the genetic information that tells them what to do is compromised. This is why telomere length is often noted as being inversely related to a cell’s age.
As with most things in nature, there are a few exceptions to the telomere story that we just went through together in the preceding paragraph. The most notable exceptions to the shortening telomere phenomenon are cancer cells and stem cells. One of the reasons why cancer cells and stem cells are basically “immortal” relative to other cell types is because they express an enzyme ( a type of protein which facilitates and speeds up biological reactions) called “telomerase”. Telomerase acts to extend the ends of chromosomes after each cellular division basically negating the natural aging process that occurs in less potent cells due to telomere shortening. This is one of the reasons why cancer is such a stubborn disease… cancer cells are ultra aggressive and can last forever if a suitable host or environment is provided for them. As a measure of perspective, cancer cells that were collected from a cancer patient – Henrietta Lacks (1920 – 1951) – are still in use in laboratories all around the world till this very day. Telomerase is also present in human embryonic stem cells and is one of the major reasons why the initial human embryonic stem cells derived from embryos in the late 1990s are still in use in various labs in the world today. The cells just keep dividing and growing provided they are placed in suitable conditions.
Given our knowledge of the immortality of human embryonic stem cells and the fact that they are the source from which all of us humans develop, a very important pair of questions comes to mind. If the cells that give rise to each of us are immortal for all practical purposes, why then do we grow old and die? Why aren’t we are as immortal as the stem cells that we are effectively products of? Well, the answer lies in a process called differentiation which we will discuss next.
The immense potential of human embryonic stem cells
As discussed earlier, human embryonic stem cells have the unique ability to become any type of cell in the human body. In colloquial terms, you can think of human embryonic stem cells as the “renaissance men or women” of the cellular kingdom. The “weirdos” in the pack that can do pretty much anything that they set their intentions to. Although human embryonic stem cells have the potential to become anything they please, each one of the human embryonic stem cells that come from the inner cell mass of the 5 – 8 day old blastocyst must make decisions on which fate they will assume in order to allow for full development of a human being. The reason for this is simple… we need different cell types to function fully as humans. The neurons in your brain, the cardiomyocytes in your heart, and the red blood cells in your blood are all vital for your survival. Nature knows this and therefore forces these pluripotent human embryonic stem cells to get more specialized based on where they are physically located in the fetus as it develops. A good analogy for the differentiation of human embryonic stem cells is to think about our society as a whole. We are all born as babies with mostly empty conscious and subconscious minds… we are pretty much all blank slates at birth with no marketable skills. As we grow up, we each gradually fill our minds with the languages we learn to speak, the musical instruments we learn to play, and the technical skills that we develop through education and training. As adults, we specialize or “differentiate” into lawyers, accountants, professional athletes, artists, scientists, musicians, and so on. This differentiation or specialization process is important because we need people to fill different roles in our society in order for all of us to thrive. In an analogous way, the body needs different cell types such as the cardiomyocytes of the heart to help pump blood throughout the body or the neurons of the brain which facilitate the physical senses and motor functions that help keep each of us alive. The tradeoff in the differentiation process is that once the pluripotent cells pick a fate, they lose a measure of their power just like we humans often do as we get older and more specialized. The above explanation is in line with a general pattern that is often seen in nature where studying the smallest unit of something (a cell in this case) tells us something essential about the whole (man and his kind).
Having extensively studied the differentiation/specialization of different cell types “in vivo” (in vivo is latin for “in a living thing”), the scientific community has made great strides with mimicking those same conditions “in vitro” or in a laboratory dish. That is to say that using the knowledge gained from studying many animal models over many decades, we can now create precise physical and chemical environments which will force human embryonic stem cells to make fate decisions that culminate in their transformation to a more specialized cell type such as a cardiomyocyte (heart cell) for example. The technical phrase ascribed to the ability to differentiate human embryonic stem cells in a laboratory is “in vitro differentiation of human embryonic stem cells”. As we will now see, in vitro differentiation of human embryonic stem cells has huge implications in the field of medicine and the ongoing fight against many life threatening conditions.
Stem cells as a potential cure for medical conditions
Many of the most debilitating conditions of disease that we face today are due to an irreversible loss of a particular important group of cells for a myriad of reasons. In some cases, the important cells die because they are starved of essential nutrients (congestive heart failure setting in as a result of a heart attack or myocardial infarction). In some other cases, we lose important cells because of an unfortunate accident (spinal cord injury in a car accident). In still others, important cells are lost because our own immune systems erroneously identify some cells in our bodies as foreign invaders and destroy them (Type I diabetes). The most practical solution in all of these severe cases mentioned above is to find and fix the root cause of the problem, and then replace the damaged or lost cells. While this proposed fix makes a lot of practical sense, it had proved almost impossible to implement prior to the advent of human embryonic stem cells because we didn’t know how to get the required amount and type of specialized cells required to remedy the malady. With the development of in vitro differentiation techniques for hESCs however, there is a glimmer of hope that we can one day replace diseased heart cells or damaged nerve cells with the appropriate analogs derived from hESCs. This potential method of treatment in which diseased or dead cells are replaced by analogs derived from human embryonic stem cells is called “cell replacement therapy” in scientific circles.
Although cell replacement therapy sounds very promising on the surface, there are a significant number of hurdles to overcome before it becomes a legitimate treatment option in clinics and hospitals all around the world. Let’s take a bit of time to discuss some of these technical and logistical hurdles.
- Appropriate Delivery
- Risk of Immune Rejection
- Regulatory Approval
Even in a world where the perfect method for transforming human embryonic stem cells into heart cells exists, there is still the formidable challenge of delivering these synthetically derived cells to the right place in the heart. Upon initially hearing of this potential problem, one may naively think that the best answer would be to inject the cells right into the specific location in the body that they are needed. Upon deeper reflection however, one can see that it is not enough to simply make sure the cells get introduced to the site in the body at which they are needed, but that in addition, the introduced cells must actually attach to that site, stay there, and perform the function that they are needed for. This is a formidable hurdle that must be resolved before cell replacement therapy can really become a recognized method of treatment for several debilitating conditions.
On a related note to the notion immediately above, there is also the very real quandary of knowing the right stage of cellular development at which it is best to implant in vitro differentiated stem cells into the human body. Is it best to implant these derived cells before they reach full maturity? or is it better to wait until the cells are fully differentiated before implanting them at the anatomical site where they are most needed? There is a non zero threat of inadvertently introducing stem cells that haven’t fully differentiated to the desired specialized cell types into the human body. The danger here is that cells that aren’t fully differentiated into a specialized lineage may retain some power to proliferate aggressively. Thus a case of unwanted and overtly aggressive cellular proliferation could occur, culminating in a tumor growth of some sort. On the other hand, if we implant fully differentiated cells into the human body, we run the risk of the cells being too specialized to be able to adapt to a new foreign environment (the host human body) because they are already so “set in their ways”. A classic case of not being able to “teach an old dog new tricks”.
The glorious human immune system is programmed to react aggressively to any foreign objects or materials that are introduced into the body without its “permission”. This is the major reason why folks who have had a heart transplant (or any other organ transplant for that matter) stay on immunosuppressant drugs for the rest of their natural lives. Our immune systems are designed to recognize cells of self as “friend”, and to recognize the cells of others as “foe”. The ingenious mechanism through which this works is as follows. Cells in your body have proteins called “cell surface markers” that prominently feature on the outer surface of each cell. Your immune system features cells called “natural killer cells” that have the ability to bind to cell surface markers and check to see if the cells encountered are friendly (i.e. your own cells) or “from a foe” (i.e. cells from a donor). If the natural killer cells detect cells that are not of self, they will mount an attack that will ruthlessly destroy the foreign cells in question. Now please let’s not go thinking that natural killer cells are “mean” because they aren’t… they are actually doing their job perfectly in an attempt to protect you. The phenomena of immune rejections throws a wrench in the cell replacement ideology because it is likely that any replacement cells generated in vitro will be from a different embryo than the one that developed in your mother’s womb and eventually gave rise to you. As far as the immune system is concerned, any cell replacement therapy cells are foreign and need to be destroyed unless we are clever enough to find a way to trick the immune system into accepting them as self.
Although the great potential of human embryonic stem cells when it comes to treating some of our most stubborn diseases is very exciting, we have to work collectively to ensure that any technology that spawns from research on them is released to the public in a responsible and safe manner. Thus, our medical governing bodies like the Food and Drug Administration (FDA) in the states and analogous governing bodies around the world have to get involved and impose strict rules and guidelines that govern the release of any stem cell related products and treatments. This will naturally take a fair bit of time and a lot of politicking to get all the stakeholders involved to agree on a unified set of rules and regulations to govern stem cell therapy. Although this isn’t a scientific challenge per se, it is one that cannot be overlooked in the odyssey to viable and safe stem cell therapy for all.
There is a mountain of research currently ongoing in an attempt to solve some of the hurdles to cell replacement therapy that we discussed above. For instance, families are now being advised to save some cord blood at the time of their child’s birth as this blood may contain some stem cells from the child itself. The hope here is that if said child loses an organ for whatever unfortunate reason in the future, technology would have advanced enough by then to allow for a brand new replacement organ to be grown in a laboratory for the child using his or her own stem cells. This would negate the threat of an immune rejection. Still other research groups are examining the process of cellular differentiation and how irreversible it really is. Preliminary work has been showing that it is actually possible to trick fully mature cells into “de-differentiating” into a much more naive and pliable state by artificially introducing specific genes into these cells. These de-differentiated stem like cells are called “induced pluripotent stem cells” and could prove immensely useful in the future because they would negate the threat of immune rejection associated with cell replacement therapy for essentially all of us.
In conclusion, stem cells are powerful and look quite promising as a potential future cure for many debilitating health conditions that we collectively face today. Like anything else with great potential though, stem cells can also be dangerous if used irresponsibly. We as the group of conscious intelligent beings on this planet must be prudent in how we unleash the latent power within these cells to avoid causing more harm than good. Till next time friends, take care of yourselves and each other.
Oyolu B.C. Ph.D.
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