This week’s question comes from Will all the way in Australia, who asks “I heard recently about how they cloned a human embryo for the first time to make stem cells. Can you explain how this works and what the potential implications are?”
Well Will, this is indeed a very exciting discovery and I am very glad you asked this question so soon after the announcement. For those of you who are not aware of this, a group of stem cell biologists led by Shoukhrat Mitalipov at the Oregon Health and Science University were able to recently clone a human embryo and make it divide. This had never been done previously and has been a long standing hurdle in the stem cell world. Previously, stem cells were had to either be harvested from fertilized embryos, growing fetuses, or somehow created or harvested from the blood or other organs. By having a cloned embryo grow normally, a near endless supply of genetically identical stem cells can be created from it. This would allow for custom stem cell sources that are completely compatible with an individual’s own cells, with potential to create new tissues and organs without the fear of rejection.
Now that we have the run down without much explanation, let’s dig into a few of the details.
First, let’s define what a stem cell actually is. Many of us are familiar with the term “stem cell” but are lost on their source, function, and overall role in the big picture. A stem cell is, at its core, a cell that creates other cells. When the human egg is first fertilized, it is a single cell and must divide many, many times to create the miniature human that emerges on the other end roughly 40 weeks later. All of these early cells are stem cells, which divide constantly, eventually taking shape as the many different tissues and organs we see as the end product. Once we are born, we still have many stem cells within our bodies. These cells are responsible for replacing tissues that are constantly lost or turned over. Bone marrow, for example, is filled with stem cells responsible for the many different types of blood cells. In the absence of stem cells to replace them, somatic (normal body cells) have varying rates of replication, with most only rarely, if ever, doing so.
However, not all stem cells are created equally. There are five major categories of stem cells: totipotent, pluripotent, multipotent, oligopotent, and unipotent. Totipotent stem cells are able to transform into any type of cell at any stage of development and are reflective of the cells present in our earliest developmental stages. Pluripotent stem cells all of the cell types present in the three germ layers, but cannot form the trophoblast. This means that the cell can produce any organ or tissue in the body (all organs and tissues come from one of the three germ layers), but can’t produce the cell layer necessary for implantation. Aside from trophoblast formation, totipotent and pluripotent cells have the same cell forming capacity. Multipotent stem cells are more restricted than pluripotent ones. They can transform into a variety of cell types but they are all normally related (ie. multiple different types of blood cells). Multipotent cells cannot transform into other types of tissues, but instead have a span of diversity across a given type. Following this line of reasoning, oligopotent stem cells are able to create an even more narrow set of cells, but can still create multiple different types. Like multipotent, oligopotent cells are restricted to related cells, but now the relation must now be much closer; for example, a given oligopotent stem cell could only create certain types of bone cells but not all of the cells responsible for a complete bone. Finally, unipotent cells only create one type of cell directly.
It is at this point then that we must make a change in our nomenclature to reflect the differences. While “stem cell” is used informally to refer to all types, each type has a particular name. Totipotent and pluripotent stem cells are the true stem cells and from now on will be the only cells referred to as such. Multipotent and oligopotent cells are known as progenitor cells and unipotent cells are known as precursor cells. While progenitor and precursor cells are extremely important to body function and absolutely have therapeutic value in their own right, this discussion focuses directly on stem cells so we will have to cast those aside for the time being.
So, returning back to the discovery, the method used was relatively simple (though obviously in real life it was incredibly complicated and took many years). This method, called somatic cell nuclear transfer (SCNT), involves removing a human egg cell’s nucleus and replacing it with that of a somatic cell. Given that an egg cell is normally unfertilized, it only comes with half the required genetic material. However, the other mechanisms involved in division and production of new cells are still active. By replacing the original nucleus with the somatic nucleus, which has the correct amount of genetic material, these mechanisms can be utilized without having to actually fertilize an egg. Prior to this study, most cells created this way could not get very far past the 8 cell stage for unknown reasons. Thus, the successful production of embryonic pluripotent stem cells by SCNT required an alteration of the given protocol. Interestingly enough, the addition of caffeine to the existing protocol (the exact details of which are not important) proved to be the major break through. Repeated experiments presented in the paper demonstrate that the protocol is reproducible using at least a small number of different cell types and with different egg donors, which is an important element for determining its applicability.
Clearly, this discovery could pave the way for the possibility of tremendous advances in regenerative medicine; the near-endless cultivation of pluripotent embryonic stem cells without actually having to create an embryo by the traditional method alleviates a tremendous amount of the ethical burden. Importantly, the lack of a trophoblast makes it physiologically impossible for the embryo to implant and grow in the womb; thus, it has not life potential. It is also important to note that by this method the pluripotent cells created are simply harvested as they grow, leaving the overall embryo structure intact. This creates what is known as a “cell line,” where stem cells can be produced by and harvested from the same set of embryonic cells in perpetuity.
However, there are some issues with this method that will prevent its wide applicability for at least the foreseeable future. Primarily, it is an incredibly labor intensive process to both transfer the nucleus and cultivate the cells, making any clinical application extremely expensive. Second, the system relies on donor eggs, which can range tremendously in quality. Thus the process would have to be repeated many times to ensure at least one creates viable cells. Finally, the discovery only demonstrates that the cells can be made. It does not make any comment on the effectiveness of the produced cells to form coherent, functional tissues or organs ready for transplant. In fact, we know little about this research beyond simply that it was successful in producing the intended cells; even that seems to be in doubt at the moment pending successful independent reproduction. It is safe to say that it will be a fair amount of time till these make it to the clinical arsenal, if ever since there are certainly other more readily available sources of the desired cells (albiet with much greater amounts of ethical and religious baggage). In short, it is definitely a positive step that overcomes a major hurdle in stem cell research, but still in the very early research stages. Only time will tell if it will truly live up to the tremendously lofty expectations.
Thanks for the question, Will! As always, if you want to submit a question feel free to do so at the top of the page.
Until next time, may the force be with you.
Original research paper:
Tachibana et al. “Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer.” Cell, 2013 Jun; 153: 1-11