The True Origin of Human Embryonic Stem Cells

The use of stem cells in research has been a topic of intense ethical debate for years, with many questions and misconceptions about the origin and use of these remarkable cells. This article delves into the original 1998 paper that describes the first isolation of human embryonic stem cells.

To fully grasp the origin of stem cells, we need to dive into the beginnings of human life…

We all start out as a single fertilized cell called an egg. In this stage, called the cleavage stage, the egg cell starts dividing to form a ball of many smaller cells called the blastula. The blastula cells then begin differentiating, or turning into the different types of cells in your body, to form the next developmental stage called a blastocyst. The cells inside the blastocyst continue to differentiate and form three main types of cells called “germ layers,” labeled endoderm, mesoderm, and ectoderm. After this stage, more dramatic differentiation and structural changes happen, ending with a fully formed human baby. 

Human embryonic stem cells or “hESCs” come from a portion of the cells within the blastocyst that can turn into nearly any type of cell in the human body: a state called “pluripotent.” Alone, hESCs cannot form a full organism. However, these human stem cells have the potential to turn into any of the three germ layers: endoderm: from which cells of the gut are derived, mesoderm, from which cartilage, bone, and muscle cells are derived, and ectoderm, from which brain and skin cells are derived. For this reason, stem cells are valued in research for their clinical potential to replace damaged cells in organs like the heart or brain. However, the fact that these cells ultimately come from human embryos ignited controversy surrounding the ethics of their use in research.

Additional types of stem cells have since been discovered: induced pluripotent stem cells or iPSCs. These non-embryonic stem cells come from a biopsy of adult cells which are then genetically reprogrammed to behave more like pluripotent stem cells. However, embryonic stem cells still have considerable value in research and medicine, because they do not contain the artificial genetic manipulation required for iPSCs. Current research using human embryonic stem cells often involves “cell lines”. Cell lines are stocks of an original group of cells that grows on its own and thus can be maintained indefinitely, so no new embryos are destroyed in the process. Some such hESC lines were ultimately derived from very early stage embryos over 25 years ago. 

Let’s take a look at the original paper published in 1998 that generated several of the human embryonic stem cell lines that are still used in research today. 

Thomson, James A., et al. "Embryonic stem cell lines derived from human blastocysts." Science. 282.5391 (1998): 1145-1147.

Human embryos in the cleavage stage that had been produced through in vitro fertilization (IVF) were donated by individuals at their informed consent. The embryos were grown in the lab to the stage of blastocysts, and the inner cell masses (the part of the blastocyst that will ultimately go on to form the fetus) of 14 of these embryos were isolated. The authors found that five of these would grow on their own in a petri dish, and could be successfully cultured and maintained in the lab. Three of these cell lines (labeled H1, H13, and H14) had an XY or male genetic composition. The other two (H7 and H9) possessed an XX, or female, genetic makeup. 

The finding that these five lines could be grown in the lab  was a valuable discovery because cells don’t always just grow and divide indefinitely. The life-span of cellular colonies is determined in large part by the length of telomeres, which are structures at the end of chromosomes protecting them from degradation. The authors observed that these stem cell lines possessed high levels of telomerase activity. Telomerase is a molecule that adds DNA segments to the telomere length, maintaining it. This is likely why the cell lines were able to grow indefinitely on the plastic dishes, a state called “immortalized”. The authors confirmed that the cell lines consistently showed characteristics of human embryonic stem cells at the molecular level. For example, they observed the presence of stage-specific embryonic antigen (SSEA)-4, a protein seen on the surface of stem cells.

The researchers wanted to make sure that their stem cell lines possessed all of the incredible qualities of pluripotency. So, they took things to the next level by injecting the cells into mice. The mice developed teratomas - fascinating tumors that contain a mix of different cell types including gut, bone, cartilage, skin, and muscle cells all in one place. This would seem to suggest that the injected cells indeed had the ability to turn into many different types of cells found in the body. However, if the purpose of stem cell research is to repair and renew parts of the body, why would injecting stem cells cause cancer? 

Exact timing and many chemical and physical cues influence what kinds of cells stem cells will differentiate into and how they will grow. For example, the researchers observed that when the stem cells became overgrown on the petri dish and piled up, they spontaneously differentiated into masses of different cell types. Understanding the mechanisms controlling what types of cells pluripotent cells will ultimately turn into is a key area of research. For example, diseases like Parkinson’s and Type I Diabetes result from loss of cell function in just a few types of cells. The ability to precisely guide cells to become a desired type of cell could open up valuable avenues for clinical therapies. 

Much of the stem cell research today uses these human embryonic stem cell lines that are already in existence, or induced pluripotent stem cells which don’t involve embryos. Other avenues of research though indeed conduct experiments with donated early-stage embryos leftover from IVF. Human embryonic stem cell research could of course yield valuable discoveries in technology and medicine but we must always remain ethically vigilant as we do not yet accurately understand all of the complex mechanisms that control cellular life, death, and human development.