Beyond representing the future of medicine, stem cells are a part of our past and present. Every person developed from the embryonic stem cells within a fertilised embryo and our critical organs are maintained on a daily basis by adult stem cells. The future of stem cell biology and their use in treatments and biotechnology (e.g. toxicity testing) lies in our ability to unlock the characteristics that make these cells “tick”.
Key features of stem cells to consider are how do they remain stem cells and how do we change them into other cells, but first we need to ask ourselves: What is a stem cell? Stem cells can be considered “blank slate” cells like brand new dough, until external signals prompt the “blank” cell to form new cells, much like one would mould and shape dough. This is a process known as differentiation. Differentiation is a process initiated by the stem cell that upsets an initial process called self-renewal. Effectively this shifts the cell from a cycle of self-renewal (i.e. remaining as-is) to a state of change. Further to this question we can pose the query: How many types of stem cells are there? This question however leads us into the murky waters that have grown with the stem cell field, the controversial aspect of stem cells.
Types of Stem Cells
Before we can discuss the controversy that weaves its way along with the development of stem cells, we have to discuss the types of stem cells. We will focus on two types: pluripotent and adult stem cells. To understand these cells, we need to introduce the concept of potency (illustrated). Cell potency is best described as a cell’s potential to become different. If we consider development of a human being (or any organism), an entire being forms from a fertilised embryo this is termed totipotency. The cells within the embryo do all the hard work in that they possess the potential to form any cell type of the germ layers, except that they cannot form a whole embryo; therefore embryonic stem cells are pluripotent. As an organism develops, small pockets of stem cells remain in special protected areas called stem cell niches. These cells are the adult stem cells and possess reduced potency, to a degree where they can only form cells within a specific tissue type e.g. haematopoietic stem cells in the bone marrow form cells of the entire blood system.
Controversy and Ethics
The stem cell controversy is linked to both potency and the source of the cells. Embryonic stem cells, as the name suggests, are isolated from fertilised blastocysts (known as the inner cell mass). This naturally raises a religious and ethical debate around the use of these cells. Many people have pointed out that typically the embryos used to source the inner mass cells were created for in vitro fertilization (IVF) purposes and were going to be destroyed if not used in IVF procedures. It should be noted that human embryos would not purposefully be created for embryonic stem cell isolation.
On the other end of the spectrum, many argue that adult stem cells are more ethically viable for cell-based therapy as a strong point is made that no possible embryo needs to be destroyed to harvest these cells. However, the issues of availability and cell potency do come into play. Adult stem cells only make up small percentages of the total number of cells within a specific tissue type and in all known cases can only form cells of that specific tissue type. To illustrate, the most well known, routinely performed transplantation technology that uses stem cells as its core is that of bone marrow transplants. Bone marrow is the site of haematopoiesis (making blood cells) and was later discovered to be the haematopoietic stem cell niche. The haematopoietic stem cells compose a fraction of the total cell population in bone marrow with the average estimate of 1 haematopoietic stem cell to every 10000 differentiated cell.
An added issue is that of compatibility, the human immune system is designed to recognize self from non-self (foreign) cells. Bone marrow donors need to be compatible, often close relatives to avoid rejection. Beyond this example, for stem cells to be considered viable for transplantation in regenerative medicine, the immune compatibility issue needs to be solved. This is where cell reprogramming is viewed as the saviour of stem cells in transplantation.
Induced Pluripotent Stem Cells
The laboratory of Dr Shinya Yamanaka, then at Kyoto University, published a series of research articles in 2006 and 2007 detailing a technique that seemingly changed normal fibroblasts (skin cells) into stem cells. Not just any old stem cell; pluripotent stem cells. Upon introduction of genes encoding proteins normally associated with stem cell activity, Yamanaka and co-workers unlocked a phenotype in the cells that allowed the newly-induced stem cell to gain characteristics of an embryonic stem cell. The new cells could differentiate into all three germ layers and when introduced into a fertilised embryo could contribute to the normal development of a mouse. This technology was then shown to be applicable to human cells. Thus was born the era of the so-called ethical stem cell. We can now create human pluripotent stem cells from skin, lymphocytes, or even kidney cells harvested from urine, all with the capacity to form new cells.
But we are still at a disadvantage: how do we make specific cell types (e.g. heart, liver or nerve) in the laboratory?
Differentiation, Tissue engineering, Drug Discovery and Personalised Medicine
We are discovering ways to manipulate the signals given by the body to differentiate stem cells in vitro, but these signals are often costly in economic and timescale terms. Efforts are underway to reduce these costs and research is ongoing but when asking the question of “Can I use stem cells to grow a new heart?” the short answer is “Yes! ... but”. Tissues create specific environments to maintain and develop the cells within three-dimensional space. To engineer new tissues or organs we need to understand this 3-D scaffold, questions that need to be asked are:
- what makes up the 3-D space between cells?
- how many cell types make up an organ? e.g. the heart contains not just cardiac cells but nerve cells too.
- how will the deeper layers of cells receive nutrients? We also need to consider the blood system that delivers nutrients and removes waste.
The list above oversimplifies the issue but does give one an idea of the complexity of potentially custom designing new organs. This firmly places the use of stem cells for tissue and organ engineering in the near future, but this does not mean that they are not useful currently in biomedical biotechnology. On the contrary, the capacity of stem cells, specifically induced pluripotent stem cells, to act as a source of any cell type that makes up the human body makes them invaluable in drug discovery research. Before, to test whether a new drug only affected the diseased tissue and not the healthy tissue, the sources of normal primary cells were limited and often unavailable. We can now create heart and nerve cells to test new drugs for toxicity and induced pluripotent cell lines from specific disease types have been made allowing for the possibility of making cells with a specific diseases characteristic in culture. An example of this is the creation of induced pluripotent stem cells from Amyotrophic Lateral Sclerosis (ALS) patients.
Nerve tissue can now be made in vitro to
- investigate the factors controlling the disease and
- develop new drugs to treat the disease or investigate why drugs were not effective in reducing specific individuals symptoms.
- In the case described above, cells were made from a living ALS patient. This has been applied to other debilitating diseases like Alzheimer’s and Parkinson’s. Hence, building the future potential of personalised medicine!
While this is going to take some time, we are on the path to these realities.
* Dr Earl Prinsloo lectures Biotechnology at Rhodes University and is with the Biomedical Biotechnology Research Unit
Figure 1: Stem cells, cell potency and differentiation