essay on embryonic stem cells

• Open access
• Published: 26 February 2019

Stem cells: past, present, and future

• Wojciech Zakrzewski 1 ,
• Maciej Dobrzyński 2 ,
• Maria Szymonowicz 1 &
• Zbigniew Rybak 1  

Stem Cell Research & Therapy volume  10 , Article number:  68 ( 2019 ) Cite this article

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In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Stem cell classification

Stem cells are unspecialized cells of the human body. They are able to differentiate into any cell of an organism and have the ability of self-renewal. Stem cells exist both in embryos and adult cells. There are several steps of specialization. Developmental potency is reduced with each step, which means that a unipotent stem cell is not able to differentiate into as many types of cells as a pluripotent one. This chapter will focus on stem cell classification to make it easier for the reader to comprehend the following chapters.

Totipotent stem cells are able to divide and differentiate into cells of the whole organism. Totipotency has the highest differentiation potential and allows cells to form both embryo and extra-embryonic structures. One example of a totipotent cell is a zygote, which is formed after a sperm fertilizes an egg. These cells can later develop either into any of the three germ layers or form a placenta. After approximately 4 days, the blastocyst’s inner cell mass becomes pluripotent. This structure is the source of pluripotent cells.

Pluripotent stem cells (PSCs) form cells of all germ layers but not extraembryonic structures, such as the placenta. Embryonic stem cells (ESCs) are an example. ESCs are derived from the inner cell mass of preimplantation embryos. Another example is induced pluripotent stem cells (iPSCs) derived from the epiblast layer of implanted embryos. Their pluripotency is a continuum, starting from completely pluripotent cells such as ESCs and iPSCs and ending on representatives with less potency—multi-, oligo- or unipotent cells. One of the methods to assess their activity and spectrum is the teratoma formation assay. iPSCs are artificially generated from somatic cells, and they function similarly to PSCs. Their culturing and utilization are very promising for present and future regenerative medicine.

Multipotent stem cells have a narrower spectrum of differentiation than PSCs, but they can specialize in discrete cells of specific cell lineages. One example is a haematopoietic stem cell, which can develop into several types of blood cells. After differentiation, a haematopoietic stem cell becomes an oligopotent cell. Its differentiation abilities are then restricted to cells of its lineage. However, some multipotent cells are capable of conversion into unrelated cell types, which suggests naming them pluripotent cells.

Oligopotent stem cells can differentiate into several cell types. A myeloid stem cell is an example that can divide into white blood cells but not red blood cells.

Unipotent stem cells are characterized by the narrowest differentiation capabilities and a special property of dividing repeatedly. Their latter feature makes them a promising candidate for therapeutic use in regenerative medicine. These cells are only able to form one cell type, e.g. dermatocytes.

Stem cell biology

A blastocyst is formed after the fusion of sperm and ovum fertilization. Its inner wall is lined with short-lived stem cells, namely, embryonic stem cells. Blastocysts are composed of two distinct cell types: the inner cell mass (ICM), which develops into epiblasts and induces the development of a foetus, and the trophectoderm (TE). Blastocysts are responsible for the regulation of the ICM microenvironment. The TE continues to develop and forms the extraembryonic support structures needed for the successful origin of the embryo, such as the placenta. As the TE begins to form a specialized support structure, the ICM cells remain undifferentiated, fully pluripotent and proliferative [ 1 ]. The pluripotency of stem cells allows them to form any cell of the organism. Human embryonic stem cells (hESCs) are derived from the ICM. During the process of embryogenesis, cells form aggregations called germ layers: endoderm, mesoderm and ectoderm (Fig.  1 ), each eventually giving rise to differentiated cells and tissues of the foetus and, later on, the adult organism [ 2 ]. After hESCs differentiate into one of the germ layers, they become multipotent stem cells, whose potency is limited to only the cells of the germ layer. This process is short in human development. After that, pluripotent stem cells occur all over the organism as undifferentiated cells, and their key abilities are proliferation by the formation of the next generation of stem cells and differentiation into specialized cells under certain physiological conditions.

Oocyte development and formation of stem cells: the blastocoel, which is formed from oocytes, consists of embryonic stem cells that later differentiate into mesodermal, ectodermal, or endodermal cells. Blastocoel develops into the gastrula

Signals that influence the stem cell specialization process can be divided into external, such as physical contact between cells or chemical secretion by surrounding tissue, and internal, which are signals controlled by genes in DNA.

Stem cells also act as internal repair systems of the body. The replenishment and formation of new cells are unlimited as long as an organism is alive. Stem cell activity depends on the organ in which they are in; for example, in bone marrow, their division is constant, although in organs such as the pancreas, division only occurs under special physiological conditions.

Stem cell functional division

Whole-body development.

During division, the presence of different stem cells depends on organism development. Somatic stem cell ESCs can be distinguished. Although the derivation of ESCs without separation from the TE is possible, such a combination has growth limits. Because proliferating actions are limited, co-culture of these is usually avoided.

ESCs are derived from the inner cell mass of the blastocyst, which is a stage of pre-implantation embryo ca. 4 days after fertilization. After that, these cells are placed in a culture dish filled with culture medium. Passage is an inefficient but popular process of sub-culturing cells to other dishes. These cells can be described as pluripotent because they are able to eventually differentiate into every cell type in the organism. Since the beginning of their studies, there have been ethical restrictions connected to the medical use of ESCs in therapies. Most embryonic stem cells are developed from eggs that have been fertilized in an in vitro clinic, not from eggs fertilized in vivo.

Somatic or adult stem cells are undifferentiated and found among differentiated cells in the whole body after development. The function of these cells is to enable the healing, growth, and replacement of cells that are lost each day. These cells have a restricted range of differentiation options. Among many types, there are the following:

Mesenchymal stem cells are present in many tissues. In bone marrow, these cells differentiate mainly into the bone, cartilage, and fat cells. As stem cells, they are an exception because they act pluripotently and can specialize in the cells of any germ layer.

Neural cells give rise to nerve cells and their supporting cells—oligodendrocytes and astrocytes.

Haematopoietic stem cells form all kinds of blood cells: red, white, and platelets.

Skin stem cells form, for example, keratinocytes, which form a protective layer of skin.

The proliferation time of somatic stem cells is longer than that of ESCs. It is possible to reprogram adult stem cells back to their pluripotent state. This can be performed by transferring the adult nucleus into the cytoplasm of an oocyte or by fusion with the pluripotent cell. The same technique was used during cloning of the famous Dolly sheep.

hESCs are involved in whole-body development. They can differentiate into pluripotent, totipotent, multipotent, and unipotent cells (Fig.  2 ) [ 2 ].

Changes in the potency of stem cells in human body development. Potency ranges from pluripotent cells of the blastocyst to unipotent cells of a specific tissue in a human body such as the skin, CNS, or bone marrow. Reversed pluripotency can be achieved by the formation of induced pluripotent stem cells using either octamer-binding transcription factor (Oct4), sex-determining region Y (Sox2), Kruppel-like factor 4 (Klf4), or the Myc gene

Pluripotent cells can be named totipotent if they can additionally form extraembryonic tissues of the embryo. Multipotent cells are restricted in differentiating to each cell type of given tissue. When tissue contains only one lineage of cells, stem cells that form them are called either called oligo- or unipotent.

iPSC quality control and recognition by morphological differences

The comparability of stem cell lines from different individuals is needed for iPSC lines to be used in therapeutics [ 3 ]. Among critical quality procedures, the following can be distinguished:

Short tandem repeat analysis—This is the comparison of specific loci on the DNA of the samples. It is used in measuring an exact number of repeating units. One unit consists of 2 to 13 nucleotides repeating many times on the DNA strand. A polymerase chain reaction is used to check the lengths of short tandem repeats. The genotyping procedure of source tissue, cells, and iPSC seed and master cell banks is recommended.

Identity analysis—The unintentional switching of lines, resulting in other stem cell line contamination, requires rigorous assay for cell line identification.

Residual vector testing—An appearance of reprogramming vectors integrated into the host genome is hazardous, and testing their presence is a mandatory procedure. It is a commonly used procedure for generating high-quality iPSC lines. An acceptable threshold in high-quality research-grade iPSC line collections is ≤ 1 plasmid copies per 100 cells. During the procedure, 2 different regions, common to all plasmids, should be used as specific targets, such as EBNA and CAG sequences [ 3 ]. To accurately represent the test reactions, a standard curve needs to be prepared in a carrier of gDNA from a well-characterized hPSC line. For calculations of plasmid copies per cell, it is crucial to incorporate internal reference gDNA sequences to allow the quantification of, for example, ribonuclease P (RNaseP) or human telomerase reverse transcriptase (hTERT).

Karyotype—A long-term culture of hESCs can accumulate culture-driven mutations [ 4 ]. Because of that, it is crucial to pay additional attention to genomic integrity. Karyotype tests can be performed by resuscitating representative aliquots and culturing them for 48–72 h before harvesting cells for karyotypic analysis. If abnormalities are found within the first 20 karyotypes, the analysis must be repeated on a fresh sample. When this situation is repeated, the line is evaluated as abnormal. Repeated abnormalities must be recorded. Although karyology is a crucial procedure in stem cell quality control, the single nucleotide polymorphism (SNP) array, discussed later, has approximately 50 times higher resolution.

Viral testing—When assessing the quality of stem cells, all tests for harmful human adventitious agents must be performed (e.g. hepatitis C or human immunodeficiency virus). This procedure must be performed in the case of non-xeno-free culture agents.

Bacteriology—Bacterial or fungal sterility tests can be divided into culture- or broth-based tests. All the procedures must be recommended by pharmacopoeia for the jurisdiction in which the work is performed.

Single nucleotide polymorphism arrays—This procedure is a type of DNA microarray that detects population polymorphisms by enabling the detection of subchromosomal changes and the copy-neutral loss of heterozygosity, as well as an indication of cellular transformation. The SNP assay consists of three components. The first is labelling fragmented nucleic acid sequences with fluorescent dyes. The second is an array that contains immobilized allele-specific oligonucleotide (ASO) probes. The last component detects, records, and eventually interprets the signal.

Flow cytometry—This is a technique that utilizes light to count and profile cells in a heterogeneous fluid mixture. It allows researchers to accurately and rapidly collect data from heterogeneous fluid mixtures with live cells. Cells are passed through a narrow channel one by one. During light illumination, sensors detect light emitted or refracted from the cells. The last step is data analysis, compilation and integration into a comprehensive picture of the sample.

Phenotypic pluripotency assays—Recognizing undifferentiated cells is crucial in successful stem cell therapy. Among other characteristics, stem cells appear to have a distinct morphology with a high nucleus to cytoplasm ratio and a prominent nucleolus. Cells appear to be flat with defined borders, in contrast to differentiating colonies, which appear as loosely located cells with rough borders [ 5 ]. It is important that images of ideal and poor quality colonies for each cell line are kept in laboratories, so whenever there is doubt about the quality of culture, it can always be checked according to the representative image. Embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers must be performed. It is important to note that colonies cultured under different conditions may have different morphologies [ 6 ].

Histone modification and DNA methylation—Quality control can be achieved by using epigenetic analysis tools such as histone modification or DNA methylation. When stem cells differentiate, the methylation process silences pluripotency genes, which reduces differentiation potential, although other genes may undergo demethylation to become expressed [ 7 ]. It is important to emphasize that stem cell identity, together with its morphological characteristics, is also related to its epigenetic profile [ 8 , 9 ]. According to Brindley [ 10 ], there is a relationship between epigenetic changes, pluripotency, and cell expansion conditions, which emphasizes that unmethylated regions appear to be serum-dependent.

hESC derivation and media

hESCs can be derived using a variety of methods, from classic culturing to laser-assisted methodologies or microsurgery [ 11 ]. hESC differentiation must be specified to avoid teratoma formation (see Fig.  3 ).

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There is a different result, however, when commitment signals (in forms of soluble factors and culture conditions) are applied and enable the selection of progenitor cells

hESCs spontaneously differentiate into embryonic bodies (EBs) [ 12 ]. EBs can be studied instead of embryos or animals to predict their effects on early human development. There are many different methods for acquiring EBs, such as bioreactor culture [ 13 ], hanging drop culture [ 12 ], or microwell technology [ 14 , 15 ]. These methods allow specific precursors to form in vitro [ 16 ].

The essential part of these culturing procedures is a separation of inner cell mass to culture future hESCs (Fig.  4 ) [ 17 ]. Rosowski et al. [ 18 ] emphasizes that particular attention must be taken in controlling spontaneous differentiation. When the colony reaches the appropriate size, cells must be separated. The occurrence of pluripotent cells lasts for 1–2 days. Because the classical utilization of hESCs caused ethical concerns about gastrulas used during procedures, Chung et al. [ 19 ] found out that it is also possible to obtain hESCs from four cell embryos, leaving a higher probability of embryo survival. Additionally, Zhang et al. [ 20 ] used only in vitro fertilization growth-arrested cells.

Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells are formed. Blastocysts with ICM are formed on the sixth day after fertilization. Pluripotent stem cells from ICM can then be successfully transmitted on a dish

Cell passaging is used to form smaller clusters of cells on a new culture surface [ 21 ]. There are four important passaging procedures.

Enzymatic dissociation is a cutting action of enzymes on proteins and adhesion domains that bind the colony. It is a gentler method than the manual passage. It is crucial to not leave hESCs alone after passaging. Solitary cells are more sensitive and can easily undergo cell death; collagenase type IV is an example [ 22 , 23 ].

Manual passage , on the other hand, focuses on using cell scratchers. The selection of certain cells is not necessary. This should be done in the early stages of cell line derivation [ 24 ].

Trypsin utilization allows a healthy, automated hESC passage. Good Manufacturing Practice (GMP)-grade recombinant trypsin is widely available in this procedure [ 24 ]. However, there is a risk of decreasing the pluripotency and viability of stem cells [ 25 ]. Trypsin utilization can be halted with an inhibitor of the protein rho-associated protein kinase (ROCK) [ 26 ].

Ethylenediaminetetraacetic acid ( EDTA ) indirectly suppresses cell-to-cell connections by chelating divalent cations. Their suppression promotes cell dissociation [ 27 ].

Stem cells require a mixture of growth factors and nutrients to differentiate and develop. The medium should be changed each day.

Traditional culture methods used for hESCs are mouse embryonic fibroblasts (MEFs) as a feeder layer and bovine serum [ 28 ] as a medium. Martin et al. [ 29 ] demonstrated that hESCs cultured in the presence of animal products express the non-human sialic acid, N -glycolylneuraminic acid (NeuGc). Feeder layers prevent uncontrolled proliferation with factors such as leukaemia inhibitory factor (LIF) [ 30 ].

First feeder layer-free culture can be supplemented with serum replacement, combined with laminin [ 31 ]. This causes stable karyotypes of stem cells and pluripotency lasting for over a year.

Initial culturing media can be serum (e.g. foetal calf serum FCS), artificial replacement such as synthetic serum substitute (SSS), knockout serum replacement (KOSR), or StemPro [ 32 ]. The simplest culture medium contains only eight essential elements: DMEM/F12 medium, selenium, NaHCO 3, l -ascorbic acid, transferrin, insulin, TGFβ1, and FGF2 [ 33 ]. It is not yet fully known whether culture systems developed for hESCs can be allowed without adaptation in iPSC cultures.

Turning point in stem cell therapy

The turning point in stem cell therapy appeared in 2006, when scientists Shinya Yamanaka, together with Kazutoshi Takahashi, discovered that it is possible to reprogram multipotent adult stem cells to the pluripotent state. This process avoided endangering the foetus’ life in the process. Retrovirus-mediated transduction of mouse fibroblasts with four transcription factors (Oct-3/4, Sox2, KLF4, and c-Myc) [ 34 ] that are mainly expressed in embryonic stem cells could induce the fibroblasts to become pluripotent (Fig.  5 ) [ 35 ]. This new form of stem cells was named iPSCs. One year later, the experiment also succeeded with human cells [ 36 ]. After this success, the method opened a new field in stem cell research with a generation of iPSC lines that can be customized and biocompatible with the patient. Recently, studies have focused on reducing carcinogenesis and improving the conduction system.

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their role as somatic cells and, once again, become pluripotent and can differentiate into any cell type of human body

The turning point was influenced by former discoveries that happened in 1962 and 1987.

The former discovery was about scientist John Gurdon successfully cloning frogs by transferring a nucleus from a frog’s somatic cells into an oocyte. This caused a complete reversion of somatic cell development [ 37 ]. The results of his experiment became an immense discovery since it was previously believed that cell differentiation is a one-way street only, but his experiment suggested the opposite and demonstrated that it is even possible for a somatic cell to again acquire pluripotency [ 38 ].

The latter was a discovery made by Davis R.L. that focused on fibroblast DNA subtraction. Three genes were found that originally appeared in myoblasts. The enforced expression of only one of the genes, named myogenic differentiation 1 (Myod1), caused the conversion of fibroblasts into myoblasts, showing that reprogramming cells is possible, and it can even be used to transform cells from one lineage to another [ 39 ].

Although pluripotency can occur naturally only in embryonic stem cells, it is possible to induce terminally differentiated cells to become pluripotent again. The process of direct reprogramming converts differentiated somatic cells into iPSC lines that can form all cell types of an organism. Reprogramming focuses on the expression of oncogenes such as Myc and Klf4 (Kruppel-like factor 4). This process is enhanced by a downregulation of genes promoting genome stability, such as p53. Additionally, cell reprogramming involves histone alteration. All these processes can cause potential mutagenic risk and later lead to an increased number of mutations. Quinlan et al. [ 40 ] checked fully pluripotent mouse iPSCs using whole genome DNA sequencing and structural variation (SV) detection algorithms. Based on those studies, it was confirmed that although there were single mutations in the non-genetic region, there were non-retrotransposon insertions. This led to the conclusion that current reprogramming methods can produce fully pluripotent iPSCs without severe genomic alterations.

During the course of development from pluripotent hESCs to differentiated somatic cells, crucial changes appear in the epigenetic structure of these cells. There is a restriction or permission of the transcription of genes relevant to each cell type. When somatic cells are being reprogrammed using transcription factors, all the epigenetic architecture has to be reconditioned to achieve iPSCs with pluripotency [ 41 ]. However, cells of each tissue undergo specific somatic genomic methylation. This influences transcription, which can further cause alterations in induced pluripotency [ 42 ].

Source of iPSCs

Because pluripotent cells can propagate indefinitely and differentiate into any kind of cell, they can be an unlimited source, either for replacing lost or diseased tissues. iPSCs bypass the need for embryos in stem cell therapy. Because they are made from the patient’s own cells, they are autologous and no longer generate any risk of immune rejection.

At first, fibroblasts were used as a source of iPSCs. Because a biopsy was needed to achieve these types of cells, the technique underwent further research. Researchers investigated whether more accessible cells could be used in the method. Further, other cells were used in the process: peripheral blood cells, keratinocytes, and renal epithelial cells found in urine. An alternative strategy to stem cell transplantation can be stimulating a patient’s endogenous stem cells to divide or differentiate, occurring naturally when skin wounds are healing. In 2008, pancreatic exocrine cells were shown to be reprogrammed to functional, insulin-producing beta cells [ 43 ].

The best stem cell source appears to be the fibroblasts, which is more tempting in the case of logistics since its stimulation can be fast and better controlled [ 44 ].

• Teratoma formation assay

The self-renewal and differentiation capabilities of iPSCs have gained significant interest and attention in regenerative medicine sciences. To study their abilities, a quality-control assay is needed, of which one of the most important is the teratoma formation assay. Teratomas are benign tumours. Teratomas are capable of rapid growth in vivo and are characteristic because of their ability to develop into tissues of all three germ layers simultaneously. Because of the high pluripotency of teratomas, this formation assay is considered an assessment of iPSC’s abilities [ 45 ].

Teratoma formation rate, for instance, was observed to be elevated in human iPSCs compared to that in hESCs [ 46 ]. This difference may be connected to different differentiation methods and cell origins. Most commonly, the teratoma assay involves an injection of examined iPSCs subcutaneously or under the testis or kidney capsule in mice, which are immune-deficient [ 47 ]. After injection, an immature but recognizable tissue can be observed, such as the kidney tubules, bone, cartilage, or neuroepithelium [ 30 ]. The injection site may have an impact on the efficiency of teratoma formation [ 48 ].

There are three groups of markers used in this assay to differentiate the cells of germ layers. For endodermal tissue, there is insulin/C-peptide and alpha-1 antitrypsin [ 49 ]. For the mesoderm, derivatives can be used, e.g. cartilage matrix protein for the bone and alcian blue for the cartilage. As ectodermal markers, class III B botulin or keratin can be used for keratinocytes.

Teratoma formation assays are considered the gold standard for demonstrating the pluripotency of human iPSCs, demonstrating their possibilities under physiological conditions. Due to their actual tissue formation, they could be used for the characterization of many cell lineages [ 50 ].

Directed differentiation

To be useful in therapy, stem cells must be converted into desired cell types as necessary or else the whole regenerative medicine process will be pointless. Differentiation of ESCs is crucial because undifferentiated ESCs can cause teratoma formation in vivo. Understanding and using signalling pathways for differentiation is an important method in successful regenerative medicine. In directed differentiation, it is likely to mimic signals that are received by cells when they undergo successive stages of development [ 51 ]. The extracellular microenvironment plays a significant role in controlling cell behaviour. By manipulating the culture conditions, it is possible to restrict specific differentiation pathways and generate cultures that are enriched in certain precursors in vitro. However, achieving a similar effect in vivo is challenging. It is crucial to develop culture conditions that will allow the promotion of homogenous and enhanced differentiation of ESCs into functional and desired tissues.

Regarding the self-renewal of embryonic stem cells, Hwang et al. [ 52 ] noted that the ideal culture method for hESC-based cell and tissue therapy would be a defined culture free of either the feeder layer or animal components. This is because cell and tissue therapy requires the maintenance of large quantities of undifferentiated hESCs, which does not make feeder cells suitable for such tasks.

Most directed differentiation protocols are formed to mimic the development of an inner cell mass during gastrulation. During this process, pluripotent stem cells differentiate into ectodermal, mesodermal, or endodermal progenitors. Mall molecules or growth factors induce the conversion of stem cells into appropriate progenitor cells, which will later give rise to the desired cell type. There is a variety of signal intensities and molecular families that may affect the establishment of germ layers in vivo, such as fibroblast growth factors (FGFs) [ 53 ]; the Wnt family [ 54 ] or superfamily of transforming growth factors—β(TGFβ); and bone morphogenic proteins (BMP) [ 55 ]. Each candidate factor must be tested on various concentrations and additionally applied to various durations because the precise concentrations and times during which developing cells in embryos are influenced during differentiation are unknown. For instance, molecular antagonists of endogenous BMP and Wnt signalling can be used for ESC formation of ectoderm [ 56 ]. However, transient Wnt and lower concentrations of the TGFβ family trigger mesodermal differentiation [ 57 ]. Regarding endoderm formation, a higher activin A concentration may be required [ 58 , 59 ].

There are numerous protocols about the methods of forming progenitors of cells of each of germ layers, such as cardiomyocytes [ 60 ], hepatocytes [ 61 ], renal cells [ 62 ], lung cells [ 63 , 64 ], motor neurons [ 65 ], intestinal cells [ 66 ], or chondrocytes [ 67 ].

Directed differentiation of either iPSCs or ESCs into, e.g. hepatocytes, could influence and develop the study of the molecular mechanisms in human liver development. In addition, it could also provide the possibility to form exogenous hepatocytes for drug toxicity testing [ 68 ].

Levels of concentration and duration of action with a specific signalling molecule can cause a variety of factors. Unfortunately, for now, a high cost of recombinant factors is likely to limit their use on a larger scale in medicine. The more promising technique focuses on the use of small molecules. These can be used for either activating or deactivating specific signalling pathways. They enhance reprogramming efficiency by creating cells that are compatible with the desired type of tissue. It is a cheaper and non-immunogenic method.

One of the successful examples of small-molecule cell therapies is antagonists and agonists of the Hedgehog pathway. They show to be very useful in motor neuron regeneration [ 69 ]. Endogenous small molecules with their function in embryonic development can also be used in in vitro methods to induce the differentiation of cells; for example, retinoic acid, which is responsible for patterning the nervous system in vivo [ 70 ], surprisingly induced retinal cell formation when the laboratory procedure involved hESCs [ 71 ].

The efficacy of differentiation factors depends on functional maturity, efficiency, and, finally, introducing produced cells to their in vivo equivalent. Topography, shear stress, and substrate rigidity are factors influencing the phenotype of future cells [ 72 ].

The control of biophysical and biochemical signals, the biophysical environment, and a proper guide of hESC differentiation are important factors in appropriately cultured stem cells.

Stem cell utilization and their manufacturing standards and culture systems

The European Medicines Agency and the Food and Drug Administration have set Good Manufacturing Practice (GMP) guidelines for safe and appropriate stem cell transplantation. In the past, protocols used for stem cell transplantation required animal-derived products [ 73 ].

The risk of introducing animal antigens or pathogens caused a restriction in their use. Due to such limitations, the technique required an obvious update [ 74 ]. Now, it is essential to use xeno-free equivalents when establishing cell lines that are derived from fresh embryos and cultured from human feeder cell lines [ 75 ]. In this method, it is crucial to replace any non-human materials with xeno-free equivalents [ 76 ].

NutriStem with LN-511, TeSR2 with human recombinant laminin (LN-511), and RegES with human foreskin fibroblasts (HFFs) are commonly used xeno-free culture systems [ 33 ]. There are many organizations and international initiatives, such as the National Stem Cell Bank, that provide stem cell lines for treatment or medical research [ 77 ].

Stem cell use in medicine

Stem cells have great potential to become one of the most important aspects of medicine. In addition to the fact that they play a large role in developing restorative medicine, their study reveals much information about the complex events that happen during human development.

The difference between a stem cell and a differentiated cell is reflected in the cells’ DNA. In the former cell, DNA is arranged loosely with working genes. When signals enter the cell and the differentiation process begins, genes that are no longer needed are shut down, but genes required for the specialized function will remain active. This process can be reversed, and it is known that such pluripotency can be achieved by interaction in gene sequences. Takahashi and Yamanaka [ 78 ] and Loh et al. [ 79 ] discovered that octamer-binding transcription factor 3 and 4 (Oct3/4), sex determining region Y (SRY)-box 2 and Nanog genes function as core transcription factors in maintaining pluripotency. Among them, Oct3/4 and Sox2 are essential for the generation of iPSCs.

Many serious medical conditions, such as birth defects or cancer, are caused by improper differentiation or cell division. Currently, several stem cell therapies are possible, among which are treatments for spinal cord injury, heart failure [ 80 ], retinal and macular degeneration [ 81 ], tendon ruptures, and diabetes type 1 [ 82 ]. Stem cell research can further help in better understanding stem cell physiology. This may result in finding new ways of treating currently incurable diseases.

Haematopoietic stem cell transplantation

Haematopoietic stem cells are important because they are by far the most thoroughly characterized tissue-specific stem cell; after all, they have been experimentally studied for more than 50 years. These stem cells appear to provide an accurate paradigm model system to study tissue-specific stem cells, and they have potential in regenerative medicine.

Multipotent haematopoietic stem cell (HSC) transplantation is currently the most popular stem cell therapy. Target cells are usually derived from the bone marrow, peripheral blood, or umbilical cord blood [ 83 ]. The procedure can be autologous (when the patient’s own cells are used), allogenic (when the stem cell comes from a donor), or syngeneic (from an identical twin). HSCs are responsible for the generation of all functional haematopoietic lineages in blood, including erythrocytes, leukocytes, and platelets. HSC transplantation solves problems that are caused by inappropriate functioning of the haematopoietic system, which includes diseases such as leukaemia and anaemia. However, when conventional sources of HSC are taken into consideration, there are some important limitations. First, there is a limited number of transplantable cells, and an efficient way of gathering them has not yet been found. There is also a problem with finding a fitting antigen-matched donor for transplantation, and viral contamination or any immunoreactions also cause a reduction in efficiency in conventional HSC transplantations. Haematopoietic transplantation should be reserved for patients with life-threatening diseases because it has a multifactorial character and can be a dangerous procedure. iPSC use is crucial in this procedure. The use of a patient’s own unspecialized somatic cells as stem cells provides the greatest immunological compatibility and significantly increases the success of the procedure.

Stem cells as a target for pharmacological testing

Stem cells can be used in new drug tests. Each experiment on living tissue can be performed safely on specific differentiated cells from pluripotent cells. If any undesirable effect appears, drug formulas can be changed until they reach a sufficient level of effectiveness. The drug can enter the pharmacological market without harming any live testers. However, to test the drugs properly, the conditions must be equal when comparing the effects of two drugs. To achieve this goal, researchers need to gain full control of the differentiation process to generate pure populations of differentiated cells.

Stem cells as an alternative for arthroplasty

One of the biggest fears of professional sportsmen is getting an injury, which most often signifies the end of their professional career. This applies especially to tendon injuries, which, due to current treatment options focusing either on conservative or surgical treatment, often do not provide acceptable outcomes. Problems with the tendons start with their regeneration capabilities. Instead of functionally regenerating after an injury, tendons merely heal by forming scar tissues that lack the functionality of healthy tissues. Factors that may cause this failed healing response include hypervascularization, deposition of calcific materials, pain, or swelling [ 84 ].

Additionally, in addition to problems with tendons, there is a high probability of acquiring a pathological condition of joints called osteoarthritis (OA) [ 85 ]. OA is common due to the avascular nature of articular cartilage and its low regenerative capabilities [ 86 ]. Although arthroplasty is currently a common procedure in treating OA, it is not ideal for younger patients because they can outlive the implant and will require several surgical procedures in the future. These are situations where stem cell therapy can help by stopping the onset of OA [ 87 ]. However, these procedures are not well developed, and the long-term maintenance of hyaline cartilage requires further research.

Osteonecrosis of the femoral hip (ONFH) is a refractory disease associated with the collapse of the femoral head and risk of hip arthroplasty in younger populations [ 88 ]. Although total hip arthroplasty (THA) is clinically successful, it is not ideal for young patients, mostly due to the limited lifetime of the prosthesis. An increasing number of clinical studies have evaluated the therapeutic effect of stem cells on ONFH. Most of the authors demonstrated positive outcomes, with reduced pain, improved function, or avoidance of THA [ 89 , 90 , 91 ].

Rejuvenation by cell programming

Ageing is a reversible epigenetic process. The first cell rejuvenation study was published in 2011 [ 92 ]. Cells from aged individuals have different transcriptional signatures, high levels of oxidative stress, dysfunctional mitochondria, and shorter telomeres than in young cells [ 93 ]. There is a hypothesis that when human or mouse adult somatic cells are reprogrammed to iPSCs, their epigenetic age is virtually reset to zero [ 94 ]. This was based on an epigenetic model, which explains that at the time of fertilization, all marks of parenteral ageing are erased from the zygote’s genome and its ageing clock is reset to zero [ 95 ].

In their study, Ocampo et al. [ 96 ] used Oct4, Sox2, Klf4, and C-myc genes (OSKM genes) and affected pancreas and skeletal muscle cells, which have poor regenerative capacity. Their procedure revealed that these genes can also be used for effective regenerative treatment [ 97 ]. The main challenge of their method was the need to employ an approach that does not use transgenic animals and does not require an indefinitely long application. The first clinical approach would be preventive, focused on stopping or slowing the ageing rate. Later, progressive rejuvenation of old individuals can be attempted. In the future, this method may raise some ethical issues, such as overpopulation, leading to lower availability of food and energy.

For now, it is important to learn how to implement cell reprogramming technology in non-transgenic elder animals and humans to erase marks of ageing without removing the epigenetic marks of cell identity.

Cell-based therapies

Stem cells can be induced to become a specific cell type that is required to repair damaged or destroyed tissues (Fig.  6 ). Currently, when the need for transplantable tissues and organs outweighs the possible supply, stem cells appear to be a perfect solution for the problem. The most common conditions that benefit from such therapy are macular degenerations [ 98 ], strokes [ 99 ], osteoarthritis [ 89 , 90 ], neurodegenerative diseases, and diabetes [ 100 ]. Due to this technique, it can become possible to generate healthy heart muscle cells and later transplant them to patients with heart disease.

Stem cell experiments on animals. These experiments are one of the many procedures that proved stem cells to be a crucial factor in future regenerative medicine

In the case of type 1 diabetes, insulin-producing cells in the pancreas are destroyed due to an autoimmunological reaction. As an alternative to transplantation therapy, it can be possible to induce stem cells to differentiate into insulin-producing cells [ 101 ].

Stem cells and tissue banks

iPS cells with their theoretically unlimited propagation and differentiation abilities are attractive for the present and future sciences. They can be stored in a tissue bank to be an essential source of human tissue used for medical examination. The problem with conventional differentiated tissue cells held in the laboratory is that their propagation features diminish after time. This does not occur in iPSCs.

The umbilical cord is known to be rich in mesenchymal stem cells. Due to its cryopreservation immediately after birth, its stem cells can be successfully stored and used in therapies to prevent the future life-threatening diseases of a given patient.

Stem cells of human exfoliated deciduous teeth (SHED) found in exfoliated deciduous teeth has the ability to develop into more types of body tissues than other stem cells [ 102 ] (Table  1 ). Techniques of their collection, isolation, and storage are simple and non-invasive. Among the advantages of banking, SHED cells are:

Guaranteed donor-match autologous transplant that causes no immune reaction and rejection of cells [ 103 ]

Simple and painless for both child and parent

Less than one third of the cost of cord blood storage

Not subject to the same ethical concerns as embryonic stem cells [ 104 ]

In contrast to cord blood stem cells, SHED cells are able to regenerate into solid tissues such as connective, neural, dental, or bone tissue [ 105 , 106 ]

SHED can be useful for close relatives of the donor

Fertility diseases

In 2011, two researchers, Katsuhiko Hayashi et al. [ 107 ], showed in an experiment on mice that it is possible to form sperm from iPSCs. They succeeded in delivering healthy and fertile pups in infertile mice. The experiment was also successful for female mice, where iPSCs formed fully functional eggs .

Young adults at risk of losing their spermatogonial stem cells (SSC), mostly cancer patients, are the main target group that can benefit from testicular tissue cryopreservation and autotransplantation. Effective freezing methods for adult and pre-pubertal testicular tissue are available [ 108 ].

Qiuwan et al. [ 109 ] provided important evidence that human amniotic epithelial cell (hAEC) transplantation could effectively improve ovarian function by inhibiting cell apoptosis and reducing inflammation in injured ovarian tissue of mice, and it could be a promising strategy for the management of premature ovarian failure or insufficiency in female cancer survivors.

For now, reaching successful infertility treatments in humans appears to be only a matter of time, but there are several challenges to overcome. First, the process needs to have high efficiency; second, the chances of forming tumours instead of eggs or sperm must be maximally reduced. The last barrier is how to mature human sperm and eggs in the lab without transplanting them to in vivo conditions, which could cause either a tumour risk or an invasive procedure.

Therapy for incurable neurodegenerative diseases

Thanks to stem cell therapy, it is possible not only to delay the progression of incurable neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease (AD), and Huntington disease, but also, most importantly, to remove the source of the problem. In neuroscience, the discovery of neural stem cells (NSCs) has nullified the previous idea that adult CNS were not capable of neurogenesis [ 110 , 111 ]. Neural stem cells are capable of improving cognitive function in preclinical rodent models of AD [ 112 , 113 , 114 ]. Awe et al. [ 115 ] clinically derived relevant human iPSCs from skin punch biopsies to develop a neural stem cell-based approach for treating AD. Neuronal degeneration in Parkinson’s disease (PD) is focal, and dopaminergic neurons can be efficiently generated from hESCs. PD is an ideal disease for iPSC-based cell therapy [ 116 ]. However, this therapy is still in an experimental phase ( https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4539501 /). Brain tissue from aborted foetuses was used on patients with Parkinson’s disease [ 117 ]. Although the results were not uniform, they showed that therapies with pure stem cells are an important and achievable therapy.

Stem cell use in dentistry

Teeth represent a very challenging material for regenerative medicine. They are difficult to recreate because of their function in aspects such as articulation, mastication, or aesthetics due to their complicated structure. Currently, there is a chance for stem cells to become more widely used than synthetic materials. Teeth have a large advantage of being the most natural and non-invasive source of stem cells.

For now, without the use of stem cells, the most common periodontological treatments are either growth factors, grafts, or surgery. For example, there are stem cells in periodontal ligament [ 118 , 119 ], which are capable of differentiating into osteoblasts or cementoblasts, and their functions were also assessed in neural cells [ 120 ]. Tissue engineering is a successful method for treating periodontal diseases. Stem cells of the root apical areas are able to recreate periodontal ligament. One of the possible methods of tissue engineering in periodontology is gene therapy performed using adenoviruses-containing growth factors [ 121 ].

As a result of animal studies, dentin regeneration is an effective process that results in the formation of dentin bridges [ 122 ].

Enamel is more difficult to regenerate than dentin. After the differentiation of ameloblastoma cells into the enamel, the former is destroyed, and reparation is impossible. Medical studies have succeeded in differentiating bone marrow stem cells into ameloblastoma [ 123 ].

Healthy dental tissue has a high amount of regular stem cells, although this number is reduced when tissue is either traumatized or inflamed [ 124 ]. There are several dental stem cell groups that can be isolated (Fig.  7 ).

Localization of stem cells in dental tissues. Dental pulp stem cells (DPSCs) and human deciduous teeth stem cells (SHED) are located in the dental pulp. Periodontal ligaments stem cells are located in the periodontal ligament. Apical papilla consists of stem cells from the apical papilla (SCAP)

Dental pulp stem cell (DPSC)

These were the first dental stem cells isolated from the human dental pulp, which were [ 125 ] located inside dental pulp (Table  2 ). They have osteogenic and chondrogenic potential. Mesenchymal stem cells (MSCs) of the dental pulp, when isolated, appear highly clonogenic; they can be isolated from adult tissue (e.g. bone marrow, adipose tissue) and foetal (e.g. umbilical cord) [ 126 ] tissue, and they are able to differentiate densely [ 127 ]. MSCs differentiate into odontoblast-like cells and osteoblasts to form dentin and bone. Their best source locations are the third molars [ 125 ]. DPSCs are the most useful dental source of tissue engineering due to their easy surgical accessibility, cryopreservation possibility, increased production of dentin tissues compared to non-dental stem cells, and their anti-inflammatory abilities. These cells have the potential to be a source for maxillofacial and orthopaedic reconstructions or reconstructions even beyond the oral cavity. DPSCs are able to generate all structures of the developed tooth [ 128 ]. In particular, beneficial results in the use of DPSCs may be achieved when combined with other new therapies, such as periodontal tissue photobiomodulation (laser stimulation), which is an efficient technique in the stimulation of proliferation and differentiation into distinct cell types [ 129 ]. DPSCs can be induced to form neural cells to help treat neurological deficits.

Stem cells of human exfoliated deciduous teeth (SHED) have a faster rate of proliferation than DPSCs and differentiate into an even greater number of cells, e.g. other mesenchymal and non-mesenchymal stem cell derivatives, such as neural cells [ 130 ]. These cells possess one major disadvantage: they form a non-complete dentin/pulp-like complex in vivo. SHED do not undergo the same ethical concerns as embryonic stem cells. Both DPSCs and SHED are able to form bone-like tissues in vivo [ 131 ] and can be used for periodontal, dentin, or pulp regeneration. DPSCs and SHED can be used in treating, for example, neural deficits [ 132 ]. DPSCs alone were tested and successfully applied for alveolar bone and mandible reconstruction [ 133 ].

Periodontal ligament stem cells (PDLSCs)

These cells are used in periodontal ligament or cementum tissue regeneration. They can differentiate into mesenchymal cell lineages to produce collagen-forming cells, adipocytes, cementum tissue, Sharpey’s fibres, and osteoblast-like cells in vitro. PDLSCs exist both on the root and alveolar bone surfaces; however, on the latter, these cells have better differentiation abilities than on the former [ 134 ]. PDLSCs have become the first treatment for periodontal regeneration therapy because of their safety and efficiency [ 135 , 136 ].

Stem cells from apical papilla (SCAP)

These cells are mesenchymal structures located within immature roots. They are isolated from human immature permanent apical papilla. SCAP are the source of odontoblasts and cause apexogenesis. These stem cells can be induced in vitro to form odontoblast-like cells, neuron-like cells, or adipocytes. SCAP have a higher capacity of proliferation than DPSCs, which makes them a better choice for tissue regeneration [ 137 , 138 ].

Dental follicle stem cells (DFCs)

These cells are loose connective tissues surrounding the developing tooth germ. DFCs contain cells that can differentiate into cementoblasts, osteoblasts, and periodontal ligament cells [ 139 , 140 ]. Additionally, these cells proliferate after even more than 30 passages [ 141 ]. DFCs are most commonly extracted from the sac of a third molar. When DFCs are combined with a treated dentin matrix, they can form a root-like tissue with a pulp-dentin complex and eventually form tooth roots [ 141 ]. When DFC sheets are induced by Hertwig’s epithelial root sheath cells, they can produce periodontal tissue; thus, DFCs represent a very promising material for tooth regeneration [ 142 ].

Pulp regeneration in endodontics

Dental pulp stem cells can differentiate into odontoblasts. There are few methods that enable the regeneration of the pulp.

The first is an ex vivo method. Proper stem cells are grown on a scaffold before they are implanted into the root channel [ 143 ].

The second is an in vivo method. This method focuses on injecting stem cells into disinfected root channels after the opening of the in vivo apex. Additionally, the use of a scaffold is necessary to prevent the movement of cells towards other tissues. For now, only pulp-like structures have been created successfully.

Methods of placing stem cells into the root channel constitute are either soft scaffolding [ 144 ] or the application of stem cells in apexogenesis or apexification. Immature teeth are the best source [ 145 ]. Nerve and blood vessel network regeneration are extremely vital to keep pulp tissue healthy.

The potential of dental stem cells is mainly regarding the regeneration of damaged dentin and pulp or the repair of any perforations; in the future, it appears to be even possible to generate the whole tooth. Such an immense success would lead to the gradual replacement of implant treatments. Mandibulary and maxillary defects can be one of the most complicated dental problems for stem cells to address.

Acquiring non-dental tissue cells by dental stem cell differentiation

In 2013, it was reported that it is possible to grow teeth from stem cells obtained extra-orally, e.g. from urine [ 146 ]. Pluripotent stem cells derived from human urine were induced and generated tooth-like structures. The physical properties of the structures were similar to natural ones except for hardness [ 127 ]. Nonetheless, it appears to be a very promising technique because it is non-invasive and relatively low-cost, and somatic cells can be used instead of embryonic cells. More importantly, stem cells derived from urine did not form any tumours, and the use of autologous cells reduces the chances of rejection [ 147 ].

Use of graphene in stem cell therapy

Over recent years, graphene and its derivatives have been increasingly used as scaffold materials to mediate stem cell growth and differentiation [ 148 ]. Both graphene and graphene oxide (GO) represent high in-plane stiffness [ 149 ]. Because graphene has carbon and aromatic network, it works either covalently or non-covalently with biomolecules; in addition to its superior mechanical properties, graphene offers versatile chemistry. Graphene exhibits biocompatibility with cells and their proper adhesion. It also tested positively for enhancing the proliferation or differentiation of stem cells [ 148 ]. After positive experiments, graphene revealed great potential as a scaffold and guide for specific lineages of stem cell differentiation [ 150 ]. Graphene has been successfully used in the transplantation of hMSCs and their guided differentiation to specific cells. The acceleration skills of graphene differentiation and division were also investigated. It was discovered that graphene can serve as a platform with increased adhesion for both growth factors and differentiation chemicals. It was also discovered that π-π binding was responsible for increased adhesion and played a crucial role in inducing hMSC differentiation [ 150 ].

Therapeutic potential of extracellular vesicle-based therapies

Extracellular vesicles (EVs) can be released by virtually every cell of an organism, including stem cells [ 151 ], and are involved in intercellular communication through the delivery of their mRNAs, lipids, and proteins. As Oh et al. [ 152 ] prove, stem cells, together with their paracrine factors—exosomes—can become potential therapeutics in the treatment of, e.g. skin ageing. Exosomes are small membrane vesicles secreted by most cells (30–120 nm in diameter) [ 153 ]. When endosomes fuse with the plasma membrane, they become exosomes that have messenger RNAs (mRNAs) and microRNAs (miRNAs), some classes of non-coding RNAs (IncRNAs) and several proteins that originate from the host cell [ 154 ]. IncRNAs can bind to specific loci and create epigenetic regulators, which leads to the formation of epigenetic modifications in recipient cells. Because of this feature, exosomes are believed to be implicated in cell-to-cell communication and the progression of diseases such as cancer [ 155 ]. Recently, many studies have also shown the therapeutic use of exosomes derived from stem cells, e.g. skin damage and renal or lung injuries [ 156 ].

In skin ageing, the most important factor is exposure to UV light, called “photoageing” [ 157 ], which causes extrinsic skin damage, characterized by dryness, roughness, irregular pigmentation, lesions, and skin cancers. In intrinsic skin ageing, on the other hand, the loss of elasticity is a characteristic feature. The skin dermis consists of fibroblasts, which are responsible for the synthesis of crucial skin elements, such as procollagen or elastic fibres. These elements form either basic framework extracellular matrix constituents of the skin dermis or play a major role in tissue elasticity. Fibroblast efficiency and abundance decrease with ageing [ 158 ]. Stem cells can promote the proliferation of dermal fibroblasts by secreting cytokines such as platelet-derived growth factor (PDGF), transforming growth factor β (TGF-β), and basic fibroblast growth factor. Huh et al. [ 159 ] mentioned that a medium of human amniotic fluid-derived stem cells (hAFSC) positively affected skin regeneration after longwave UV-induced (UVA, 315–400 nm) photoageing by increasing the proliferation and migration of dermal fibroblasts. It was discovered that, in addition to the induction of fibroblast physiology, hAFSC transplantation also improved diseases in cases of renal pathology, various cancers, or stroke [ 160 , 161 ].

Oh [ 162 ] also presented another option for the treatment of skin wounds, either caused by physical damage or due to diabetic ulcers. Induced pluripotent stem cell-conditioned medium (iPSC-CM) without any animal-derived components induced dermal fibroblast proliferation and migration.

Natural cutaneous wound healing is divided into three steps: haemostasis/inflammation, proliferation, and remodelling. During the crucial step of proliferation, fibroblasts migrate and increase in number, indicating that it is a critical step in skin repair, and factors such as iPSC-CM that impact it can improve the whole cutaneous wound healing process. Paracrine actions performed by iPSCs are also important for this therapeutic effect [ 163 ]. These actions result in the secretion of cytokines such as TGF-β, interleukin (IL)-6, IL-8, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), platelet-derived growth factor-AA (PDGF-AA), and basic fibroblast growth factor (bFGF). Bae et al. [ 164 ] mentioned that TGF-β induced the migration of keratinocytes. It was also demonstrated that iPSC factors can enhance skin wound healing in vivo and in vitro when Zhou et al. [ 165 ] enhanced wound healing, even after carbon dioxide laser resurfacing in an in vivo study.

Peng et al. [ 166 ] investigated the effects of EVs derived from hESCs on in vitro cultured retinal glial, progenitor Müller cells, which are known to differentiate into retinal neurons. EVs appear heterogeneous in size and can be internalized by cultured Müller cells, and their proteins are involved in the induction and maintenance of stem cell pluripotency. These stem cell-derived vesicles were responsible for the neuronal trans-differentiation of cultured Müller cells exposed to them. However, the research article points out that the procedure was accomplished only on in vitro acquired retina.

Challenges concerning stem cell therapy

Although stem cells appear to be an ideal solution for medicine, there are still many obstacles that need to be overcome in the future. One of the first problems is ethical concern.

The most common pluripotent stem cells are ESCs. Therapies concerning their use at the beginning were, and still are, the source of ethical conflicts. The reason behind it started when, in 1998, scientists discovered the possibility of removing ESCs from human embryos. Stem cell therapy appeared to be very effective in treating many, even previously incurable, diseases. The problem was that when scientists isolated ESCs in the lab, the embryo, which had potential for becoming a human, was destroyed (Fig.  8 ). Because of this, scientists, seeing a large potential in this treatment method, focused their efforts on making it possible to isolate stem cells without endangering their source—the embryo.

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate into desired cell types

For now, while hESCs still remain an ethically debatable source of cells, they are potentially powerful tools to be used for therapeutic applications of tissue regeneration. Because of the complexity of stem cell control systems, there is still much to be learned through observations in vitro. For stem cells to become a popular and widely accessible procedure, tumour risk must be assessed. The second problem is to achieve successful immunological tolerance between stem cells and the patient’s body. For now, one of the best ideas is to use the patient’s own cells and devolve them into their pluripotent stage of development.

New cells need to have the ability to fully replace lost or malfunctioning natural cells. Additionally, there is a concern about the possibility of obtaining stem cells without the risk of morbidity or pain for either the patient or the donor. Uncontrolled proliferation and differentiation of cells after implementation must also be assessed before its use in a wide variety of regenerative procedures on living patients [ 167 ].

One of the arguments that limit the use of iPSCs is their infamous role in tumourigenicity. There is a risk that the expression of oncogenes may increase when cells are being reprogrammed. In 2008, a technique was discovered that allowed scientists to remove oncogenes after a cell achieved pluripotency, although it is not efficient yet and takes a longer amount of time. The process of reprogramming may be enhanced by deletion of the tumour suppressor gene p53, but this gene also acts as a key regulator of cancer, which makes it impossible to remove in order to avoid more mutations in the reprogrammed cell. The low efficiency of the process is another problem, which is progressively becoming reduced with each year. At first, the rate of somatic cell reprogramming in Yamanaka’s study was up to 0.1%. The use of transcription factors creates a risk of genomic insertion and further mutation of the target cell genome. For now, the only ethically acceptable operation is an injection of hESCs into mouse embryos in the case of pluripotency evaluation [ 168 ].

Stem cell obstacles in the future

Pioneering scientific and medical advances always have to be carefully policed in order to make sure they are both ethical and safe. Because stem cell therapy already has a large impact on many aspects of life, it should not be treated differently.

Currently, there are several challenges concerning stem cells. First, the most important one is about fully understanding the mechanism by which stem cells function first in animal models. This step cannot be avoided. For the widespread, global acceptance of the procedure, fear of the unknown is the greatest challenge to overcome.

The efficiency of stem cell-directed differentiation must be improved to make stem cells more reliable and trustworthy for a regular patient. The scale of the procedure is another challenge. Future stem cell therapies may be a significant obstacle. Transplanting new, fully functional organs made by stem cell therapy would require the creation of millions of working and biologically accurate cooperating cells. Bringing such complicated procedures into general, widespread regenerative medicine will require interdisciplinary and international collaboration.

The identification and proper isolation of stem cells from a patient’s tissues is another challenge. Immunological rejection is a major barrier to successful stem cell transplantation. With certain types of stem cells and procedures, the immune system may recognize transplanted cells as foreign bodies, triggering an immune reaction resulting in transplant or cell rejection.

One of the ideas that can make stem cells a “failsafe” is about implementing a self-destruct option if they become dangerous. Further development and versatility of stem cells may cause reduction of treatment costs for people suffering from currently incurable diseases. When facing certain organ failure, instead of undergoing extraordinarily expensive drug treatment, the patient would be able to utilize stem cell therapy. The effect of a successful operation would be immediate, and the patient would avoid chronic pharmacological treatment and its inevitable side effects.

Although these challenges facing stem cell science can be overwhelming, the field is making great advances each day. Stem cell therapy is already available for treating several diseases and conditions. Their impact on future medicine appears to be significant.

After several decades of experiments, stem cell therapy is becoming a magnificent game changer for medicine. With each experiment, the capabilities of stem cells are growing, although there are still many obstacles to overcome. Regardless, the influence of stem cells in regenerative medicine and transplantology is immense. Currently, untreatable neurodegenerative diseases have the possibility of becoming treatable with stem cell therapy. Induced pluripotency enables the use of a patient’s own cells. Tissue banks are becoming increasingly popular, as they gather cells that are the source of regenerative medicine in a struggle against present and future diseases. With stem cell therapy and all its regenerative benefits, we are better able to prolong human life than at any time in history.

Abbreviations

Basic fibroblast growth factor

Bone morphogenic proteins

Dental follicle stem cells

Dental pulp stem cells

Embryonic bodies

Embryonic stem cells

Fibroblast growth factors

Good Manufacturing Practice

Graphene oxide

Human amniotic fluid-derived stem cells

Human embryonic stem cells

Human foreskin fibroblasts

Inner cell mass

Non-coding RNA

Induced pluripotent stem cells

In vitro fertilization

Knockout serum replacement

Leukaemia inhibitory factor

Monocyte chemotactic protein-1

Fibroblasts

Messenger RNA

Mesenchymal stem cells of dental pulp

Myogenic differentiation

Osteoarthritis

Octamer-binding transcription factor 3 and 4

Platelet-derived growth factor

Platelet-derived growth factor-AA

Periodontal ligament stem cells

Rho-associated protein kinase

Stem cells from apical papilla

Stem cells of human exfoliated deciduous teeth

Synthetic Serum Substitute

Trophectoderm

Vascular endothelial growth factor

Transforming growth factors

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Embryonic Cells in Stem Cell Research Essay

Introduction, works cited.

Stem cell research (SCR) has been the subject of many controversies over the past few decades. Studies have shown that the exploration of the options that SCR provides may lead to the creation of the cure for diseases such as cardiovascular (CVD) health issues, Parkinson’s disease, Alzheimer’s disease, and diabetes, to name just a few (Zhang et al. 85). Therefore, despite possible ethical concerns associated with the implications of SCR on human nature, I believe that the use of embryonic cells as one of the key aspects of CSR should be promoted as a possible source for solutions for numerous diseases and disorders.

The use of embryo cells in SCR opens various possibilities for addressing some of the most complex health issues, which means that the research has to be supported. SCR, in general, and the use of embryonic cells, in particular, are likely to have huge positive implications for healthcare and the management of diseases such as CVD, Parkinson’s, and Alzheimer’s (“Chapter 9 – Cell Communication”). Although the opponents of SCR may claim that it implies playing God and tampering with human nature, the positive outcomes that SCR may have should be explored and used to their full potential.

Due to the potential in managing the diseases and disorders that are presently deemed as incurable, I am certain that CSR should be continued despite the ethical concerns that it raises. Since the possible positive outcomes outweigh the ostensible negative implications, the research should continue, with a greater focus on the treatment opportunities that the utilization of embryonic cells provides. Despite the fact that the use of the specified material may be seen as challenging to the concept of morality and the current social norms, the treatment opportunities that it potentially has been tremendous. Thus, the opportunity described above should not be missed.

“Chapter 9 – Cell Communication.” Georgia Highlands College , n.d. Web.

Zhang, Qingxi, et al. “Stem Cells for Modeling and Therapy of Parkinson’s Disease.” Human Gene Therapy , vol. 28, no. 1, 2017, pp. 85-98.

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On March 9, 2009, President Barack Obama lifted, by Executive Order , the Bush administration's eight-year ban on federal funding of embryonic stem cell research .

Remarked the President, "Today... we will bring the change that so many scientists and researchers, doctors and innovators, patients and loved ones have hoped for, and fought for, these past eight years."

In Obama's Remarks on Lifting the Embryonic Stem Cell Research Ban, he also signed a Presidential Memorandum directing the development of a strategy for restoring scientific integrity to government decision-making.

Bush Vetoes

In 2005, H.R. 810, the Stem Cell Research Enhancement Act of 2005, was passed by the Republican-led House in May 2005 by a vote of 238 to 194. The Senate passed the bill in July 2006 by a bipartisan vote of 63 to 37.

President Bush opposed embryonic stem cell research on ideological grounds. He exercised his first presidential veto on July 19, 2006, when he refused to allow H.R. 810 to become law. Congress was unable to muster enough votes to override the veto.

In April 2007, the Democratic-led Senate passed the Stem Cell Research Enhancement Act of 2007 by a vote of 63 to 34. In June 2007, the House passed the legislation by a vote of 247 to 176.

President Bush vetoed the bill on June 20, 2007.

Public Support for Embryonic Stem Cell Research

For years, all polls report that the American public STRONGLY supports federal funding of embryonic stem cell research.

Reported the Washington Post in March 2009 : "In a January Washington Post-ABC News poll, 59 percent of Americans said they supported loosening the current restrictions, with support topping 60 percent among both Democrats and independents. Most Republicans, however, stood in opposition (55 percent opposed; 40 percent in support)."

Despite public perceptions, embryonic stem cell research was legal in the U.S. during the Bush administration: the President had banned the use of federal funds for research. He did not ban private and state research funding, much of which was being conducted by pharmaceutical mega-corporations.

In Fall 2004, California voters approved a $3 billion bond to fund embryonic stem cell research. In contrast, embryonic stem cell research is prohibited in Arkansas, Iowa, North and South Dakota and Michigan.

Developments in Stem Cell Research

In August 2005, Harvard University scientists announced a breakthrough discovery that fuses "blank" embryonic stem cells with adult skin cells, rather than with fertilized embryos, to create all-purpose stem cells viable to treat diseases and disabilities.

This discovery doesn't result in the death of fertilized human embryos and thus would effectively respond to pro-life objections to embryonic stem cell research and therapy.

Harvard researchers warned that it could take up to ten years to perfect this highly promising process.

As South Korea, Great Britain, Japan, Germany, India and other countries rapidly pioneer this new technological frontier, the US is being left farther and farther behind in medical technology. The US is also losing out on billions in new economic opportunities at a time when the country sorely needs new sources of revenues.

Therapeutic cloning is a method to produce stem cell lines that were genetic matches for adults and children.

Steps in therapeutic cloning are:

• An egg is obtained from a human donor.
• The nucleus (DNA) is removed from the egg.
• Skin cells are taken from the patient.
• The nucleus (DNA) is removed from a skin cell.
• A skin cell nucleus is implanted in the egg.
• The reconstructed egg, called a blastocyst, is stimulated with chemicals or electric current.
• In 3 to 5 days, the embryonic stem cells are removed.
• The blastocyst is destroyed.
• Stem cells can be used to generate an organ or tissue that is a genetic match to the skin cell donor.

The first 6 steps are same for reproductive cloning . However, instead of removing stem cells, the blastocyst is implanted in a woman and allowed to gestate to birth. Reproductive cloning is outlawed in most countries.

Before Bush stopped federal research in 2001, a minor amount of embryonic stem cell research was performed by US scientists using embryos created at fertility clinics and donated by couples who no longer needed them. The pending bipartisan Congressional bills all propose using excess fertility clinic embryos.

Stem cells are found in limited quantities in every human body and can be extracted from adult tissue with great effort but without harm. The consensus among researchers has been that adult stem cells are limited in usefulness because they can be used to produce only a few of the 220 types of cells found in the human body. However, evidence has recently emerged that adult cells may be more flexible than previously believed.

Embryonic stem cells are blank cells that have not yet been categorized or programmed by the body and can be prompted to generate any of the 220 human cell types. Embryonic stem cells are extremely flexible.

Embryonic stem cells are thought by most scientists and researchers to hold potential cures for spinal cord injuries, multiple sclerosis, diabetes, Parkinson's disease, cancer, Alzheimer's disease, heart disease, hundreds of rare immune system and genetic disorders and much more.

Scientists see almost infinite value in the use of embryonic stem cell research to understand human development and the growth and treatment of diseases.

Actual cures are many years away, though, since research has not progressed to the point where even one cure has yet been generated by embryonic stem cell research.

Over 100 million Americans suffer from diseases that eventually may be treated more effectively or even cured with embryonic stem cell therapy. Some researchers regard this as the greatest potential for the alleviation of human suffering since the advent of antibiotics.

Many pro-lifers believe that the proper moral and religious course of action is to save existing life through embryonic stem cell therapy.

Some staunch pro-lifers and most pro-life organizations regard the destruction of the blastocyst, which is a laboratory-fertilized human egg, to be the murder of human life. They believe that life begins at conception, and that destruction of this pre-born life is morally unacceptable.

They believe that it is immoral to destroy a few-days-old human embryo, even to save or reduce suffering in existing human life.

Many also believe that insufficient attention been given to explore the potential of adult stem cells, which have already been used to successfully cure many diseases. They also argue that too little attention has been paid to the potential of umbilical cord blood for stem cell research. They also point out that no cures have yet been produced by embryonic stem cell therapy.

At every step of the embryonic stem cell therapy process, decisions are made by scientists, researchers, medical professionals and women who donate eggs...decisions that are fraught with serious ethical and moral implications. Those against embryonic stem cell research argue that funding should be used to greatly expand adult stem research, to circumvent the many moral issues involving the use of human embryos.

Lifting the Ban

Now that President Obama has lifted the federal funding ban for embryonic stem cell research, financial support will soon flow to federal and state agencies to commence the necessary scientific research. The timeline for therapeutic solutions available to all Americans could be years away.

President Obama observed on March 9, 2009, when he lifted the ban:

"Medical miracles do not happen simply by accident. They result from painstaking and costly research, from years of lonely trial and error, much of which never bears fruit, and from a government willing to support that work...

"Ultimately, I cannot guarantee that we will find the treatments and cures we seek. No President can promise that.

"But I can promise that we will seek them -- actively, responsibly, and with the urgency required to make up for lost ground."

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Embryonic Stem Cell Research An Ethical Dilemma

Article sidebar.

Main Article Content

Introduction

In November 1998, two teams of U.S. scientists confirmed successful isolation and growth of stems cells obtained from human fetuses and embryos. Since then, research that utilizes human embryonic cells has been a widely debated, controversial ethical issue. Human embryonic cells possess the ability to become stem cells, which are used in medical research due to two significant features. First, they are unspecialized cells, meaning they can undergo cell division and renew themselves even with long periods of inactivity. Secondly, stem cells are pluripotent, with the propensity to be induced to become specified tissue or any “organ-specific cells with special functions” depending on exposure to experimental or physiologic conditions, as well as undergo cell division and become cell tissue for different organs.

The origin of stem cells themselves encapsulates the controversy: embryonic stem cells, originate from the inner cell mass of a blastocyst, a 5-day pre-implantation embryo. The principal argument for embryonic stem cell research is the potential benefit of using human embryonic cells to examine or treat diseases as opposed to somatic (adult) stem cells. Thus, advocates believe embryonic stem cell research may aid in developing new, more efficient treatments for severe diseases and ease the pain and suffering of numerous people. However, those that are against embryonic stem cell research believe that the possibility of scientific benefits of research do not outweigh the immoral action of tampering with the natural progression of a fetal development and interfering with the human embryo’s right to live. In light of these two opposing views, should embryonic stem cells be used in research? It is not ethically permissible to destroy human embryonic life for medical progress.

Personhood and the Scientific Questionability of Embryonic Stem Cell Research

The ethics behind embryonic stem cell research are controversial because the criteria of ‘personhood’ is “notoriously unclear.” Personhood is defined as the status of being a person, entitled to “moral rights and legal protections” that are higher than living things that are not classified as persons. Thus, this issue touches on existential questions such as: When does life begin? and What is the moral status that an embryo possesses? There is a debate on when exactly life begins in embryonic development and when the individual receives moral status. For example, some may ascribe life starting from the moment of fertilization, others may do so after implantation or the beginning of organ function. However, since the “zygote is genetically identical to the embryo,” which is also genetically identical to the fetus, and, by extension, identical to the baby, inquiring the beginning of personhood can lead to an occurrence of the Sorites paradox, also acknowledged as “the paradox of the heap.”

The paradox of the heap arises from vague predicates in philosophy. If there is a heap of sand and a grain is taken away from that heap one by one, at what point will it no longer be considered a heap – what classifies it as a heap? The definition of life is similarly arbitrary. When, in the development of a human being, is an embryo considered a person with moral standing? The complexity of the ethics of embryonic stem cell research, like the Sorites paradox, demonstrates there is no single, correct way to approach a problem; thus, there may be multiple different solutions that are acceptable. Whereas the definition of personhood cannot be completely resolved on a scientific basis, it serves a central role in the religious, political, and ethical differences within the field of embryonic stem cell research. Some ethicists attempt to determine what or who is a person by “setting boundaries” (Baldwin & Capstick, 2007).

Utilizing a functionalist approach, supporters of embryonic stem cell research argue that to qualify as a person, the individual must possess several indicators of personhood, including capacity, self-awareness, a sense of time, curiosity, and neo-cortical function. Proponents argue that a human embryo lacks these criteria, thereby is not considered a person and thus, does not have life and cannot have a moral status. Supporters of stem cell research believe a fertilized egg is just a part of another person’s body until the cell mass can survive on its own as a viable human. They further support their argument by noting that stem cell research uses embryonic tissue before its implantation into the uterine wall. Researchers invent the term “pre-embryo” to distinguish a pre-implantation state in which the developing cell mass does not have the full respects of an embryo in later stages of embryogenesis to further support embryonic stem cell research. Based on this reductionist view of life and personhood, utilitarian advocates argue that the result of the destruction of human embryos to harvest stem cells does not extinguish a life. Further, scientists state that any harm done is outweighed by the potential alleviation of the suffering enduring by tremendous numbers of people with varying diseases. This type of reasoning, known as Bentham’s Hedonic (moral) calculus, suggests that the potential good of treating or researching new cures for ailments such as Alzheimer’s disease, Parkinson’s disease, certain cancers, etc. outweighs any costs and alleviate the suffering of persons with those aliments. Thus, the end goal of stem cell use justifies sacrificing human embryos to produce stem cells, even though expending life is tantamount to murder. Opponents of embryonic stem cell research would equate the actions done to destroy the embryos as killing. Killing, defined as depriving their victims of life, will therefore reduce their victims to mere means to their own ends. Therefore, this argument touches on the question: if through the actions of embryotic stem cell research is “morally indistinguishable from murder?” (Outka, 2013). The prohibition of murder extends to human fetuses and embryos considering they are potential human beings. And, because both are innocent, a fetus being aborted and an embryo being disaggregated are direct actions with the intention of killing. Violating the prohibition of murder is considered an intolerable end. We should not justify this evil even if it achieves good. Under the deontological approach, “whether a situation is good or bad depends on whether the action that brought it about was right or wrong,” hence the ends do not justify the means. Therefore, under this feeble utilitarian approach, stem cell research proceeds at the expense of human life than at the expense of personhood.

One can reject the asserted utilitarian approach to stem cell research as a reductionist view of life because the argument fails to raise ethical concerns regarding the destruction embryonic life for the possibility of developing treatments to end certain diseases. The utilitarian approach chooses potential benefits of stem cell research over the physical lives of embryos without regard to the rights an embryo possesses. Advocates of embryonic stem cell research claim this will cure diseases but there is a gap in literature that confirms how many diseases these cells can actually cure or treat, what diseases, and how many people will actually benefit. Thus, killing human embryos for the potentiality of benefiting sick people is not ethically not ethically permissible.

Where the argument of personhood is concerned, the development from a fertilized egg (embryo) to a baby is a continuous process. Any effort to determine when personhood begins is arbitrary. If a newborn baby is a human, then surely a fetus just before birth is a human; and, if we extend a few moments before that point, we would still have a human, and so on all the way back to the embryo and finally to the zygote. Although an embryo does not possess the physiognomies of a person, it will nonetheless become a person and must be granted the respect and dignity of a person. Thus, embryotic stem cell research violates the Principle of “Full Human Potential,” which states: “Every human being […] deserves to be valued according to the full level of human development, not according to the level of development currently achieved.” As technology advances, viability outside the womb inches ever closer to the point of inception, making the efforts to identify where life begins after fertilization ineffectual. To complicate matters, as each technological innovation arrives, stem-cell scientists will have to re-define the start of life as many times as there are new technological developments, an exhausting and never-ending process that would ultimately lead us back to moment of fertilization. Because an embryo possesses all the necessary genetic information to develop into a human being, we must categorically state that life begins at the moment of conception. There is a gap in literature that deters the formation of a clear, non-arbitrary indication of personhood between conception and adulthood. Considering the lack of a general consensus of when personhood begins, an embryo should be referred to as a person and as morally equivalent to a fully developed human being.

Having concluded that a human embryo has the moral equivalent of a fully-fledged human being, this field of research clearly violates the amiable rights of personhood, and in doing so discriminates against pre-born persons. Dr. Eckman asserts that “every human being has a right to be protected from discrimination.” Thus, every human, and by extension every embryo, has the right to life and should not be discriminated against their for “developmental immaturity.” Therefore, the field of embryonic stem cell research infringes upon the rights and moral status of human embryos.

Principle of Beneficence in Embryonic Stem Cell Research

The destruction of human embryos for research is not ethically permissible because the practice violates the principle of beneficence depicted in the Belmont Report, which outlines the basic ethical principles and guidelines owed to human subjects involved in research. Stem cell researchers demonstrate a lack of respect for the autonomy and welfare of the human embryos sacrificed in stem cell research.

While supporters of embryonic stem cell research under the utilitarian approach argue the potential benefits of the research, the utilitarian argument however violates the autonomy of the embryo and its human rights, as well as the autonomy of the embryo donors and those that are Pro-Life. Though utilitarian supporters argue on the basis of rights, they exclusively refer to the rights of sick individuals. However, they categorically ignore the rights of embryos that they destroy to obtain potential disease curing stem cells. Since an embryo is regarded as a human being with morally obligated rights, the Principle of Beneficence is violated, and the autonomy and welfare of the embryo is not respected due to the destruction of an embryo in stem cell research. Killing embryos to obtain stem cells for research fails to treat embryos as ends in an of themselves. Yet, every human ought to be regarded as autonomous with rights that are equal to every other human being. Thus, the welfare of the embryo is sacrificed due to lack of consent from the subject.

The Principle of Beneficence is violated when protecting the reproductive interests of women in infertility treatment, who are dependent on the donations of embryos to end their infertility. Due to embryonic stem cell research, these patients’ “prospects of reproductive success may be compromised” because there are fewer embryos accessible for reproductive purposes. The number of embryos necessary to become fully developed and undergo embryonic stem cell research will immensely surpass the number of available frozen embryos in fertility clinic, which also contributes to the lack of embryos available for women struggling with infertility. Therefore, the basis of this research violates women’s reproductive autonomy, thus violating the Principle of Beneficence.

It is also significant to consider the autonomy and welfare of the persons involved. The autonomous choice to donate embryos to research necessitates a fully informed, voluntary sanction of the patient(s), which poses difficulty due to the complexity of the human embryonic stem cell research. To use embryos in research, there must be a consensus of agreement from the mother and father whose egg and sperm produced the embryo. Thus, there has to be a clear indication between the partners who has the authority or custody of the embryos, as well as any “third party donors” of gametes that could have been used to produce the embryo because these parties’ intentions for those gametes may solely have been for reproductive measures only. Because the researchers holding “dispositional authority” over the embryos may exchange cell lines and its derivatives (i.e., genetic material and information) with other researchers, they may misalign interests with the persons whose gametes are encompassed within the embryo. This mismatch of intent raises complications in confidentiality and autonomy.

Lastly, more ethical complications arise in the research of embryonic stem cells because of the existence viable alternatives that to not destroy human embryos. Embryonic stem cells themselves pose as a higher health risk than adult stem cells. Embryonic stem cells have a higher risk of causing tumor development in the patient’s body once the cells are implanted due to their abilities to proliferate and differentiate. Embryonic stem cells also have a high risk of immunorejection, where a patient’s immune system rejects the stem cells. Since the embryonic stem cells are derived from embryos that underwent in vitro fertilization, when implanted in the body, the stem cell’s marker molecules will not be recognized by the patient’s body, resulting in the destruction of the stem cells as a defensive response to protect the body (Cahill, 2002). With knowledge of embryonic stem cells having higher complications than the viable adult stem cells continued use of embryonic stem cells violates the Principle of Beneficence not only for the embryos but for the health and safety of the patients treated with stem cells. Several adult stem cell lines (“undifferentiated cells found throughout the body”) exist and are widely used cell research. The use of adult stem cells represents research that does not treat human beings as means to themselves, thus, complying with the Principle of Beneficence. This preferable alternative considers the moral obligation to discover treatments, and cures for life threating diseases while avoiding embryo destruction.

It is not ethically permissible to destroy human embryonic life for medical progress due to the violations of personhood and human research tenets outlined in the Belmont Report. It is significant to understand the ethical implications of this research in order to respect the autonomy, welfare, beneficence, and basic humanity afforded to all parties involved. Although embryonic stem cell research can potentially provide new medical advancements to those in need, the harms outweigh the potential, yet ill-defined benefits. There are adult stem cell alternatives with equivalent viability that avoid sacrificing embryos. As society further progresses, humans must be cautious of compromising moral principles that human beings are naturally entitled to for scientific advancements. There are ethical boundaries that are crossed when natural processes of life are altered or manipulated. Though there are potential benefits to stem cell research, these actions are morally and ethically questionable. Thus, it is significant to uphold ethical standards when practicing research to protect the value of human life.

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The Ethics of Embryonic Stem Cell Research

By Belin Mirabile

Published: July 31, 2016

What if I told you that researchers could cure diseases such as Parkinson's disease and multiple sclerosis? Odds are, you would be in favor of ending the suffering of the thousands of people who currently battle such diseases. These cures and many more are the potential results of embryonic stem cell research. Embryonic stem cells are stem cells isolated from embryos during a specific stage of development known as the blastocyst stage. These stem cells can renew themselves and reproduce to form all cell types of the body. Research utilizing these stem cells requires the destruction of an embryo, making the practice a point of moral, scientific, religious, and political controversy. Many argue that the destruction of embryos for research purposes is unethical based on the belief that embryos qualify as forms of life that deserve respect. Those in favor of embryonic stem cell research deem such a loss acceptable for the future benefits that this research could have on thousands of lives. While various arguments surround this debate, the main point of controversy is the source of stem cells used and the method with which they are obtained. In this paper, I will establish what stem cells are and the difference between embryonic and adult stem cells; then I will evaluate the two main arguments in the embryonic stem cell research debate; and finally, I will analyze the ethics of these arguments to come to the conclusion that embryonic stem cell research is ethical under certain circumstances.

Overview of Stem Cell Research

As defined by "The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy," human embryonic stem cells are "a self-renewing cell line that gives rise to all cells and tissues of the body" (Holland 3). Most stem cells are only able to differentiate into a single form of offspring cells, otherwise known as progeny cells. For example, hematopoietic stem cells are a type of stem cells that can only form blood cells and skin stem cells can similarly only produce skin cells. These types of stem cells are referred to as adult stem cells or somatic stem cells because they are gathered from patients after birth (Devolder 5). Meanwhile, embryonic stem cells are pluripotent, meaning they have the capacity to produce all cells and tissues of the body (Holland 5). Embryonic stem cells, however, only have this pluripotent potential for the particular five-to-seven-day stage of embryonic development known as the blastocyst stage, after which they can only reproduce a single cell type ("The Ethics of Embryonic Stem Cell Research" 123).

Stem cells, in general, hold great promise for the future of medicine. Thus far, stem cell-based therapies have been developed to treat illnesses that previously had no cure. One example is bone marrow transplantation to treat leukemia and other blood disorders. The hematopoietic stem cells in bone marrow are injected into a patient who has severely reduced blood cell levels and these stem cells generate new blood cells, restoring the patient's immune system (Devolder 5). Therapies such as this will continue to be discovered with the support of stem cell research.

In addition to the development of revolutionary therapies, stem cell research also provides valuable information about mechanisms regulating cell growth, migration, and differentiation. Scientists can learn about these processes by studying stem cells that have been stimulated to differentiate into different types of body cells. The discovery of new information about these concepts will allow scientists to better understand early human development and how tissues are maintained throughout life (8).

Embryonic stem cells are particularly valuable not only because of their pluripotent qualities, but also because of their ability to renew themselves. This is done by "divid[ing] asynchronously – at different times – into one differentiated daughter cell 1 and one stem cell-like daughter cell." This unique self-renewing quality of embryonic stem cells allows them to continuously grow even in laboratory conditions. Other types of stem cells eventually lose the ability to divide, making them less valuable for research purposes. Embryonic stem cells' ability to be produced in large quantities allows researchers to make progress in regenerative medicine, using these cells to develop new functional cells, tissues, and organs. The healthy cells are implanted into the patient, serving as treatment to permanently repair failing organs (Holland 5). The otherwise lack of treatment for loss of organ function displays the valuable potential of embryonic stem cells.

The sources of embryonic stem cells are a main point of controversy in the debate regarding embryonic stem cell research. Some possible sources for these stem cells include embryos created via in vitro fertilization (for either research or reproduction); five-to-nine-week old embryos or fetuses obtained through elective abortion; and embryos created through cloning or what is known as somatic cell nuclear transfer (Liu 1). Somatic cell nuclear transfer is the laboratory creation of a viable embryo by implanting a donor nucleus from a body cell into an egg cell. The ethics of obtaining embryonic stem cells via these sources can be questionable and have led to disputes that I will later address.

Research utilizing human embryonic stem cell lines has focused on the potential to generate replacement tissues for malfunctioning cells or organs (Liu 1). A specific technique has been isolated to utilize stem cells in order to repair a damaged tissue or organ:

"If a damaged tissue or organ cannot repair itself, stem cells could be obtained from these different stem cell sources [organs and tissues from individuals after birth; gametes, tissues, and organs from aborted fetuses; inner cell mass of early embryos]. Scientists could then culture these stem cells by creating conditions that enable them to replicate many times in a petri dish without differentiating. Such a population of proliferating stem cells originating from a single parent group of stem cells is a stem cell line. Stem cells from this stem cell line could then be coaxed to differentiate in to the desired cell type, and be transferred into the patient so that they can repair the damaged tissue or organ" (Devolder 6).

Other examples of research efforts include treatment of spinal cord injury, multiple sclerosis, Parkinson's disease, Alzheimer's disease, and diabetes. Researchers also hope to use specialized cells to replace dysfunctional cells in the brain, spinal cord, pancreas, and other organs (2).

Federal funding of embryonic research has been strictly regulated since 1994 when President Clinton declared such research would not be funded by the government. Following this executive order, Congress passed the Dickey Amendment in 1996, prohibiting "federally appropriated funds from being used for either the creation of human embryos for research purposes or for research in which a human embryo or embryos are destroyed, discarded, or knowingly subjected to risk of injury or death" (Liu 2). Embryonic research has continued nonetheless by means of alternative funding. In 2001, President Bush declared that federal funding would be granted to human embryonic research on a restricted basis. However, these funds were only to be awarded for research on already existing stem cell lines. No funding was to be granted for "the use of stem cell lines derived from newly destroyed embryos, the creation of any human embryos for research purposes, or cloning of human embryos for any purposes" (3-4).

The debate over funding for embryonic stem cell research depends heavily on the ethical status of the research. There are two main arguments surrounding the ethics of embryonic stem cell research: the research is ethical because of the unique potential that embryonic stem cells have to cure currently untreatable diseases; and the research is unethical because it requires the destruction of life in the form of an embryo or fetus. Ultimately, the possible benefits and controversial status of life that an embryo embodies qualify embryonic stem cell research as ethical, as long as the stem cells are obtained in an ethical manner.

Arguments for Embryonic Stem Cell Research

In the realm of stem cell research, embryonic and adult stem cells are often compared. The controversial use of embryonic stem cells is supported on the basis of the many advantages that they have over adult stem cells. Embryonic stem cells are easier to obtain; they have a greater cell growth, otherwise known as proliferation, capacity; and they are more versatile. Embryonic stem cells are isolated from embryos in the blastocyst stage and the process damages the structure of the embryo to a point from which the embryo can no longer develop. Because these stem cells are obtained at a point when the inner cell mass is concentrated in the embryo, they are more easily obtained than adult stem cells, which are limited in quantity. Another valuable benefit of embryonic stem cells is their ability to multiply readily and proliferate indefinitely when cultured in the proper conditions (Devolder 9). Lastly, embryonic stem cells' pluripotent quality is the main factor that distinguishes them from adult stem cells (10). The ability to differentiate into any cell type creates greater possibilities for the application of embryonic stem cells.

Supporters of embryonic stem cell research argue that the research is justified, though it requires the destruction of an embryo, because of the potential for developing cures and preventing unavoidable suffering. These backers often disagree with the belief that "a blastocyst – even one that is not implanted in a woman's uterus – has the same ethical status as a further-developed human" (Clemmitt 702). Arthur Caplan, professor of medical ethics at the University of Pennsylvania, asserts that "an embryo in a dish is more like a set of instructions or blueprint for a house. It can't build the house. For the cells to develop into a human being requires an interactive process in the uterus between the embryo and the mother" (Clemmitt 702).

Others in favor of the research, such as Heron, a biotechnology company, claim that "not to develop the technology would do great harm to over 100 million patients in the United States alone who are affected by diseases potentially treatable by the many medical applications of hES [human Embryonic Stem] cells" (Holland 11-12). One example is the previously stated method of using embryonic stem cells to repair damaged tissue or organs. The only way to restore cellular function in an organ is to literally replace the lost cells and embryonic stem cells provide the best option for producing these cells (3).

Embryonic stem cells do also have some disadvantages that should be considered when making the argument for further support of embryonic stem cell research. Unlike adult stem cells, embryonic stem cells have a higher risk of causing tumor formation in the patient's body after the stem cells are implanted. This is due to their higher capacities for proliferation and differentiation (Devolder 11). Embryonic stem cell-based therapies also possess the risk of immunorejection – rejection of the stem cells by the patient's immune system. Because embryonic stem cells are derived from embryos donated for research after in vitro fertilization treatment, the marker molecules on the surfaces of the cells may not be recognized by the patient's body, and therefore may be destroyed as the result of a defense mechanism by the body (Holland 11). This is a problem that will require a solution if embryonic stem cell research is to be the basis for future therapeutic medicine.

Arguments against Embryonic Stem Cell Research

Currently, the isolation of embryonic stem cells requires the destruction of an early embryo. Many people hold the belief that a human embryo has significant moral status, and therefore should not be used merely as a means for research. One position that opponents of embryonic stem cell research assert is what "The Ethics of Embryonic Stem Cell Research" calls the full moral status view (14). This view holds that "the early embryo has the same moral status, that is, the same basic moral rights, claims, or interests as an ordinary adult human being." This moral status is believed to be acquired at the point of fertilization or an equivalent event such as the completion of somatic cell nuclear transfer. Therefore, with full moral status as a human being, an embryo should not be deliberately destroyed for research purposes simply because it is human (Devolder 15). The Roman Catholic Church is a strong supporter of this view, opposing stem cell research on the grounds that it is a form of abortion. Several other groups, including American evangelicals and Orthodox ethicists, consider "blastocysts to have the same status as fully developed human beings" and therefore oppose embryonic stem cell research for this reason. Beliefs regarding the moral status of an embryo are subjective, and also their own controversial issue, which complicates the task of creating a universal law for the use of embryonic stem cells for research.

Others in opposition, such as Kevin T. Fitzgerald, a Jesuit priest who is a bioethicist and professor of oncology at Georgetown University Medical School, do not consider the moral status of an embryo, but rather assert that Embryos should be protected because they are "that which we all once were" (Clemmitt 701). This view is very similar to moral philosopher and professor of philosophy as the University of California at Irvine Philip Nickel's "Loss of Future Life Problem" in regards to embryonic stem cell research. The Loss of Future Life Problem holds that it is unethical to take the lives of future humans by destroying embryos for research (Tobis 64). This stance stresses the potential of those future lives that will never have the chance to reach fulfillment if destroyed for research. In a retroactive sense, this can cause us to question "what if the embryo that developed into Albert Einstein was destroyed for embryonic stem cell research?" It is impossible for one to know the value that is lost in each embryo taken for research purposes, if that embryo is created with the plan of developing into an adult human being.

The response to this problem is that the particular blastocysts that are harvested for embryonic stem cell research are taken from (1) embryos that are frozen during in vitro fertilization procedures and never implanted, (2) donated egg cells, and (3) embryos created specifically for the purpose of generating new stem cell lines. In each of these cases, the embryo at hand does not have a future life in plan and therefore, nothing is lost by using such embryonic stem cells for research. For embryos created via in vitro fertilization, the researchers using the embryos are not making a decision that results in the loss of a future life. The future life of said embryo is lost when the decision is made to not implant it. Therefore, the Loss of Future Life Problem is not a valid objection to research using embryonic stem cells from frozen IVF embryos that are never implanted. Donated egg cells can be fertilized in a lab or through somatic cell nuclear transfer, a process described earlier in this paper. Embryos created specifically for the purpose of contributing to stem cell research have no actual future life to be lost from the moment of conception. In both of these cases, the intent of fertilization is not to create a future adult human being, and so the Loss of Future Life Problem does not apply to these sources of embryonic stem cells.

"In terms of the Loss of Future Life Problem, the key question is again whether the embryo is being deprived of future life, and again the answer depends on whether the embryo is removed from a woman's reproductive system, in which case it is likely that it is being deprived of future life that it would otherwise go on to have. If fertilization takes place outside a woman's body, by contrast, then the embryo is not already on its way toward a future life, so destroying it does not deprive it of that particular future" (Tobis 66-67).

As shown by the various arguments in this essay, the debate over embryonic stem cell research is a multifaceted scientific, moral, ethical, and political issue. Embryonic stem cells, with their pluripotent potential and self-renewing quality, hold great value for scientific researchers in search of cures for untreatable diseases, progress in regenerative medicine, or a better understanding of early human development. However, the ethical question still arises, "do the ends justify the means?"

Varying views regarding the ethical status of an embryo answer this question in different ways, though it is commonly accepted that if the means of obtaining the embryonic stem cells are ethical, then the resulting research of those stem cells is also ethical. For example, if a donated egg is fertilized in a lab with the intention of being used for future research purposes, the resulting research is therefore morally justified.

This is not to be said that the life of an early-stage embryo is to be taken lightly. More so that our moral perception of these embryos is different than that of a later-stage fetus, an infant, or an adult human being. Phillip Nickel asserts this subconscious difference, claiming that,

"while it's well known that many embryos are shed naturally, in very early abortions and miscarriages, no one makes an effort to save or grieve for them, as frequently happens with later-stage fetuses. This shows that people do view embryos as somewhat different from people, even though they may not realize it" (Clemmitt 702).

Thus, the moral distinction between a blastocyst and a developed fetus weakens the moral arguments in opposition to embryonic stem cell research. After all, if this research can reduce suffering for thousands of people, are we not morally obligated to pursue it?

Scientists in support of embryonic stem cell research are currently restricted by the limited amounts of federal funding and embryonic stem cell lines available for research. Many argue that these restrictions are preventing further scientific development and weakening the United States' position as a leading nation in biomedical research. Some scientists worry that if strict regulations of stem cell research continue, private companies may bypass the standards put in place by the National Institute of Health and conduct unregulated research (Clemmitt 700). If the United States wishes to remain a premiere country in biomedical research and maintain order and control of embryonic research being performed, action must be taken to address this issue.

Overall, though the destruction of a life is typically held to be unethical, the moral status of an embryo in the blastocyst stage is unclear and therefore cannot be equated to the moral status of an adult human being. Also, ethical sources of embryonic stem cells exist that do not take the life of future beings (i.e. unwanted frozen embryos produced via in vitro fertilization, donated egg cells fertilized in a laboratory). For these reasons, in combination with the possibility of reducing suffering for future beings, embryonic stem cell research is ethical under certain circumstances. As long as the stem cells are isolated in a manner that does not harm an embryo with the plan of developing into an adult human, the subsequent research is ethically justified. With this in mind, embryonic stem cell research should receive greater government funding so that continued progress can be made.

1 In cell division, a parent cell divides into two or more daughter cells.

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Tobis, Jerome S., Ronald Baker Miller, and Kristen R. Monroe. Fundamentals Of The Stem Cell Debate : The Scientific, Religious, Ethical, And Political Issues . Berkeley: University of California Press, 2008. eBook Collection (EBSCOhost) . Web. 17 Nov. 2015.

Belin Mirabile

Belin Mirabile was born and raised in Phoenixville, Pennsylvania, a suburb of Philadelphia. She is currently majoring in Mechanical Engineering at Notre Dame with a minor in Catholic Social Tradition. When tasked with the assignment of writing a rhetorical essay that evaluates a point of ethical controversy, Belin wanted to choose a topic that relates to her interest in Bioengineering. Embryonic stem cell research stood out as a current issue that would be interesting to evaluate in the form of a researched essay. After her four years at Notre Dame, Belin plans to pursue a career related to Bioengineering that contributes in some fashion to the betterment of human health. Belin would like to thank her Writing and Rhetoric professor, John Duffy, for transforming her opinion of writing and giving her every tool to be a successful writer .

The Ethics of Embryonic Stem Cell Research

Devolder, K., (2015), ' The Ethics of Embryonic Stem Cell Research ', (Oxford: Oxford University Press)

Oxford University Press

Embryonic stem cell research holds unique promise for developing therapies for currently incurable diseases and conditions, and for important biomedical research. However, the process through which embryonic stem cells are obtained involves the destruction of early human embryos. Katrien Devolder focuses on the tension between the popular view that an embryo should never be deliberately harmed or destroyed, and the view that embryonic stem cell research, because of its enormous promise, must go forward. She provides an in-depth ethical analysis of the major philosophical and political attempts to resolve this tension. One such attempt involves the development of a middle ground position, which accepts only types or aspects of embryonic stem cell research deemed compatible with the view that the embryo has a significant moral status. An example is the position that it can be permissible to derive stem cells from embryos left over from in vitro fertilisation but not from embryos created for research. Others have advocated a technical solution. Several techniques have been proposed for deriving embryonic stem cells, or their functional equivalents, without harming embryos. An example is the induced pluripotent stem cell technique. Through highlighting inconsistencies in the arguments for these positions, Devolder argues that the central tension in the embryonic stem cell debate remains unresolved. This conclusion has important implications for the stem cell debate, as well as for policies inspired by this debate.

"As an academic bioethicist with experience in the clinical setting, it is important to me that context and morality are married. Devolder's book accomplishes this task nicely, beginning in the introduction with a consideration of the potential use of embryonic stem cell (if not the embryo as a whole) for the alleviation of pain and disease. She convincingly directs us towards our moral obligation to allieviate suffering, underscoring that embryonic stem cell research is thus a moral enterprise." - Ayesha Ahmad, London School of Economics, Times Higher Education

"In her small but well written and insightful monograph Katrien Devolder is focusing on these "middle-ground positions" together with technical solutions to the dilemma. The author has been working on reproductive ethics in general and on embryo and stem cell research ethics in particular for more than ten years. Her book is based on several previously published articles, but it is far more than a mere collection or a re-use of essays." - Marco Stier, Ethical Theory and Moral Practice

"Devolders study is a tour de force, exhibiting real skill and imagination in the use of analogies to test our moral intuitions... The Ethics of Embryonic Stem Cell Research is a solid contribution to our stem cell debates. Neither partisan nor committed to advocacy for any side, it displays epistemic honesty and exhibits the value of philosophical analysis at its best." - Ronald M. Green, Monash Bioethics Review

2020 Articles

Justification for Stem Cell Research Considering Embryos Have Some Moral Status

Ingram, Elizabeth

Our ethical commitments and moral values are evolving rapidly in response to advancements in technology. Embryonic stem cell research (ESCR) has the potential to create breakthrough treatments for incurable human diseases but only by a process that destroys human embryos. The arguments regarding whether the destruction of embryos in ESCR is justified rely on establishing the moral status of human embryos. Most arguments conclude either that human embryos have moral status equal to that of developed humans and ESCR is morally impermissible, or that human embryos have no moral status even as organisms distinct from humans. Alternatively, Lawrence J. Nelson argues embryos have some moral status that grants them the right to be respected in ESCR and other research during which they might be harmed or destroyed. This essay argues in favor of Nelson's position supporting embryos having a moral status that does not condemn ESCR. I.      Background: Positions of an Embryo's Moral Status             Lawrence J. Nelson argues that human embryos have some moral status and conditionally supports ESCR.[1]  They assert that human embryos have moral status because they are alive, they have a special relationship with the humans that constitute them (donors), and they are valued by sincere moral authorities. They also argue that, like all living things, embryos have some inherent good.[2]  Embryos have distinct characteristics from humans precluding moral status equal to humans. Nelson reasons embryo destruction or harm is permissible only if they are respected as organisms with some moral status and used as needed for substantial reasons, for example, advancing our understanding of, and creating effective treatment for, untreatable diseases to improve human quality of life. II.    Counterarguments a.     Embryos and Humans Have Equal Moral Status precluding ESCR           Positions against ESCR generally argue human embryos have equal moral status to humans which automatically condemns ESCR as a process that violates human rights. According to deontological ethics, granting embryos equal moral status to humans also grants embryos should never be used as a means to some end as they are in ESCR.[3] However, the utilitarian approach argues that while embryos may have moral status equal to humans, the potential good of ESCR outweighs the harm of using and sacrificing those embryos.  This argument benefits from the less identifiable potential of ESCR versus the easily identified harm. Also, some are concerned the use of embryos in ESCR may lead to the devaluing or demoralization of human life. Accepting the utilitarian view leads to the slippery slope argument where justifying harming embryos for research if it has potentially good outcomes could also justify research that harms humans. If the moral status of humans and embryos were equal, ESCR also violates the Kantian imperative to treat humans as ends in themselves rather than using them as a means to an end. Therefore, ESCR is unethical despite the potentially good outcomes. b.     Embryos Have No Moral Status Making ESCR Permissible             Those arguing that embryos have no moral status generally base their arguments on the distinguishing characteristics between developed humans and human embryos. Differences include possession of cortical function and consciousness, having an interest in being protected from harm, and having autonomy.[4] Having personal interests is important because those interests are what is protected when preserving human rights, and rights are derived from moral status.[5] Furthermore, consciousness is necessary for having personal interests to be protected and for beings to perceive physical or emotional harm, and thus be harmed and protected from it.          c.     Distinguishing characteristics do not preclude moral status          Dr. Geoffrey Chu, a proponent of equal moral status, criticizes these distinctions and how they are used to justify ESCR. They identify problems with arguments denying embryos have any moral status but does not sufficiently argue for embryos having equal moral status to humans.[6]  First, Chu criticizes the use of distinguishing characteristics between humans and embryos to determine moral status. Some research facilities find ESCR to be morally permissible for a periodof up to fourteen days, because they determine[7] rights attach after this period, which Chu explains is another unfortunate arbitrary definition of who is human. Chu admits distinctions such as cortical function and self-awareness are useful descriptions but argues they do not explain how human embryos are not persons or otherwise lacking equal moral status to developed humans. For example, cortical function cannot define moral worth because severely intellectually impaired humans lack cortical function, but they are not considered to have less moral worth than humans without impairment. Similarly, comatose patients lack brain function like human embryos, but comatose patients have the same moral status as those who are awake. Chu also notes it is simply inaccurate to equivocate living embryos to dead cadavers. By explaining how some characteristics used to distinguish human embryos to developed humans are arbitrary, Chu concludes these arbitrary characterizations lead to inappropriate judgments about moral status. Second, Chu argues creating and using embryos for ESCR without consent of the embryos is unethical. Some embryos are created for ESCR directly and some are created during in vitro fertilization (IVF) for the purpose of implantation. Creating embryos for IVF is controversial because more embryos are produced than will be implanted, and non-implanted embryos can be donated to ESCR or discarded. If the reason that overproduction of embryos in IVF is unethical is that the excess embryos are wasted, ESCR is a worthy use.[8] Although there are no ethical or legal rights assigned to embryos, many argue embryos deserve rights because they have the potential to develop into humans. III.    Analysis: Supporting Nelson's Contention that Embryos have Some Moral Status a.     Nelson: Embryos Have Some Moral Status          The appropriate uses of a human embryo, according to Nelson, include pursuing research which harms human embryos only when it is intended to improve human life, such as research aimed at understanding and treating diseases. Because their position does not rely on removing all moral status from embryos, it has a sufficient justification for morally permitted ESCR. By acknowledging embryos have some moral status and that humans have a higher status, Nelson recognizes an ethical boundary which permits the use and destruction of embryos for research without supporting the use or destruction of humans for research or other purposes with some potential good. Also, acknowledging embryos have some moral status unequal to humans prevents the use of embryos for research from violating Kant's humanity imperative, as neither humans nor beings with equal moral status to humans are being used as a means to some end. b.     Distinguishing Characteristics are Useful in Determining Moral Status             While distinctions such as brain activity, personhood, or personal interests do not justify an organism’s moral status, they are useful for recognizing an organism’s rights in different circumstances. [9] We usually have the right to be autonomous, but when we lose the capacity to be autonomous, we rely on those assigned to make our decisions without our moral status changing[10]       These distinguishing characteristics are not useful for determining moral status, but Nelson uses morally relevant characteristics which justify why embryos have some moral status. c.     Response to arguments that embryos have potential to become humans           Nelson acknowledges embryos only have the potential to become fully developed humans with equal moral status if they are implanted in a womb where they are intended to develop. Embryos used in ESCR do not have the potential to develop into born persons because they are not to be implanted.[11]  Roy Perrett adds  "The fact that persons have certain rights does not by itself entail that potential persons have those rights too. On the contrary, it is often the case that a potential X does not have the rights of an actual X: Prince Charles is presently a potential king, but this does not now give him the rights of an actual king."[12] Perrett concludes, "there is no reason to suppose it is intrinsically wrong to kill a potential person,"[13] and the argument from potentiality does not justify embryos having equal rights to humans. IV.  Why ESCR Should Be Pursued: ASC and iPSC Are Not Replacements             One suggested alternative to ESCR is using adult stem cells (ASC) which occur naturally in developed humans. While ASC can differentiate as needed, as embryonic stem cells (ESC) do, without the ethical issues of ESC, ASC do not multiply as readily as ESC. Because ASC do not grow easily outside of the body, they have limited therapeutic use and cannot replace ESCR.             The other suggested alternative is induced pluripotent stem cells (iPSC) which are reprogrammed adult cells. To be pluripotent means that cells, like ESC, can be manipulated to multiply into any kind of cell making them very useful for treatment of an array of cellular loss diseases.[14] However, the process for iPSC through nuclear reprogramming is not efficient or effective enough to be a replacement for ESCR. Additionally, ESCR promises breakthroughs in how we understand human biology and diseases which ASC and iPSC cannot offer. V.    ESCR is a valuable tool that respects the partial moral status of embryos             Embryos have some moral status ensuring them the right to be respected as a living organism with morally relevant connections to the humans that constitute them with moral worth recognized by moral authorities.  The partial moral status allows conditional use of embryos for substantial reasons like research.             Using Nelson’s philosophical reasoning acknowledging embryos as organisms distinct from humans and not potential humans, the problems of violating Kant's imperative against using humans as means to an end and the possible slippery slope of permitting destructive research on embryos leading to permitting harmful or destructive research on humans are avoided. Some distinguishing characteristics are morally relevant and help identify embryos as having some moral status and some moral rights, albeit not equal to humans. Although it remains controversial, ESCR should be pursued as long as there is no sufficient alternative that matches the potential for understanding human biology and treating human disease. Photo by Sharon McCutcheon on Unsplash [1] Nelson, Lawrence J. "A Brief Case for the Moral Permissibility of Stem Cell Research." Markkula Center for Applied Ethics (Santa Clara University, 2000). [2] Nelson, "A Brief Case for the Moral Permissibility of Stem Cell Research." [3] Kant, Immanuel, Groundwork of the metaphysic of morals. Translated and analysed by Herbert James Paton (Harper & Row, 1964), 96 - 429. [4] Steinbock, Bonnie. “Chapter 18: Moral Status, Moral Value, and Human Embryos: Implications for Stem Cell Research.” in The Oxford Handbook of Bioethics (Oxford University Press , 2007), 416–40. [5] Steinbock, Bonnie. “Chapter 18: Moral Status, Moral Value, and Human Embryos: Implications for Stem Cell Research.” in The Oxford Handbook of Bioethics (Oxford University Press , 2007), 428. [6] Chu, Geoffrey. "Embryonic stem‐cell research and the moral status of embryos." Internal medicine journal 33, no. 11 (2003): 530-531. [7] Chu, Geoffrey. "Embryonic stem‐cell research and the moral status of embryos." Internal medicine journal 33, no. 11 (2003): 530-531. [8] Steinbock, Bonnie. "What does “respect for embryos” mean in the context of stem cell research?." Women's Health Issues 10, no. 3 (2000): 127-130. [9] Banja, John. "Personhood: Elusive but not illusory." The American Journal of Bioethics 7, no. 1 (2007): 60-62. [10] Varelius, Jukka. "The value of autonomy in medical ethics." Medicine, Health Care and Philosophy 9, no. 3 (2006): 377-388. [11] Nelson, "A Brief Case for the Moral Permissibility of Stem Cell Research." [12] Perrett, Roy W. "Taking life and the argument from potentiality." Midwest Studies in Philosophy 24, no. 1 (2000): 186-197. [13] Perrett, "Taking life and the argument from potentiality." [14] Wilson, Kitchener D., and Joseph C. Wu. "Induced pluripotent stem cells." Jama 313, no. 16 (2015): 1613-1614.

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Varmus H. The Art and Politics of Science. New York: W.W. Norton & Company; 2009.

The Art and Politics of Science.

Chapter 13 embryos, cloning, stem cells, and the promise of reprogramming.

Over the past decade, stem cell research has become the most visible and contentious manifestation of the promise of biological science, akin to the Human Genome Project in the 1990s or recombinant DNA research and biotechnology in the 1970s and 1980s. The term “ stem cells ”—shorthand for the controversial type, human embryonic stem cells—is now widely recognized, and it represents a defining issue for candidates in national and local politics.

To a biologist, “ stem cells ” has a precise meaning, encompassing more than the human embryonic type that attracts political attention. All of the many specialized cells in animals and human beings have developed through an orderly process in which cells divide and differentiate. At the beginnings of these developmental pathways are immature cells with the capacity to produce two types of daughter cells when they divide: one daughter cell is indistinguishable from its parent (and has the same capacities), while the other has taken a step toward specialization. These immature cells, which both renew themselves and produce differentiated offspring, are called stem cells. Many stem cells reside in adult tissue and have restricted abilities to differentiate, becoming cells only in a particular organ, such as the skin, the liver, the brain, or the blood system. But stem cells with much greater potential are abundant much earlier in animal development, in the first stages, the early embryo . These early embryonic stem cells can serve as precursors to all of the cells that form the tissues and organs of a mature animal; because of this “plural” potential, they are called pluripotent.

Embryonic stem cells have achieved prominence in part because of the still unsubstantiated hopes that therapies that use them can ameliorate a variety of human ailments. They have attracted controversy mainly because the cells are obtained from human embryos, linking stem cell research to historical battles over abortion and over the legal and moral status of the human embryo and fetus .

The current debates about stem cells and the policies governing their use were influenced by three pivotal events that occurred during my tenure as director of the NIH in the 1990s: an NIH panel’s prophetic report in 1994 about the prospects for research on the early human embryo ; the birth of the lamb named Dolly, the first animal cloned from an adult cell, in 1997; and the isolation and growth of pluripotent stem cells from very early human embryos in 1998. To understand the nature and history of the debates, it is helpful to consider how these three topics—embryo research, reproductive cloning , and embryonic stem cells—are interwoven, both biologically and politically. It will also be important to describe newer methods, less controversial than those involving the use of embryos, that can also produce pluripotent cells. Together, these developments have changed our concepts of biological systems and driven political discussions of science to new levels of complexity.

Each of the three events in the 1990s had a defining characteristic. The 1994 report on human embryo research, inspired by scientific opportunities arising largely from then recent work with mouse embryos, recommended that many (but not all) of those opportunities be pursued by the NIH with human cells and embryos. The report also anticipated important advances in mammalian biology that might allow embryo-related research to be applied beneficially in clinical settings. Although written in response to a new and potentially permissive political environment, changes in the political climate soon led to prohibitions that continue to limit much of the research recommended in the report. The birth of Dolly in 1997 was a remarkable scientific accomplishment, which fundamentally altered the way that biologists view the control of genetic information in animal cells. It revealed a greater than expected capacity to “reprogram” cells—to reset the genetic program that guides development. But Dolly’s birth also unleashed fears about human reproductive cloning , and these have restricted the pursuit of a promising method for reprogramming cells for therapeutic purposes. Finally, the advent of research on human embryonic stem cells , following the growth of the first lines of such cells in 1998, moved the ethical debates about the use of human embryos from speculation to pragmatic immediacy, with clear implications for the pace at which such research would proceed in this country.

• Thinking about Research with Human Embryos

Any account of recent developments in embryo research, cloning , and stem cells must begin at least a few decades before animal clones and human embryonic stem cells were announced, with brief descriptions of two underlying accomplishments: the successful development in the United Kingdom of in vitro fertilization (IVF) procedures in the late 1970s and the flowering of genetic engineering with experimental mice in the 1980s.

The birth of Louise Brown, the first child conceived by IVF, in England in 1978, fundamentally changed the perspectives of society toward the early stages of human development. 1 The idea of manipulating life, by allowing fertilization of an egg by a sperm cell to occur in a test tube, and then implanting a tiny embryo into a receptive uterus days later, met with expected resistance. But the initial resistance has by now been overwhelmed by the success of IVF procedures to treat reproductive failures, allowing many thousands of infertile couples to enjoy the satisfactions of bearing and raising children.

In the years immediately following the initial successes of IVF, the U.S. government established a requirement that any proposed research on human fertilization, embryos, or the later fetal stage of development must be reviewed by an ethics advisory board before federal funds could be used to support it. From 1980 until 1993, in the administrations of Ronald Reagan and George H. W. Bush, no board was ever assembled and no federal dollars were ever spent on such research. Consequently, IVF work in this country was largely confined to clinical use, often in the private sector; improvements in IVF methods came largely from research done abroad. Furthermore, no federally supported research was performed to explore the use of cells or tissues from aborted fetuses or from unused early embryos to treat human diseases, such as Parkinson’s disease, that were caused by loss of normal cells.

In 1993, Bill Clinton’s arrival in Washington reactivated the possibility of supporting research on the developing forms of human beings—embryos and fetuses. Among the new president’s first actions was to sign a new NIH reauthorization bill that removed prior constraints on the use of federal funds for research with human fetal tissue and embryos. 2 Soon thereafter, NIH began to fund fetal tissue research—for example, clinical trials of fetal brain cell treatments for Parkinson’s disease—under guidelines that already existed for the ethical acquisition and use of fetal tissues. *

But no administration had considered the prospects of research on human materials from a much earlier stage of development, the preimplantation embryo . This stage normally begins with the fertilization of an egg by a single sperm cell, forming a one-cell embryo, also called the zygote , that divides several times during the next ten to fourteen days, after which the embryo normally implants in the wall of the uterus. At that point, the embryo begins to form the three basic tissue layers that are precursors to many types of cells present in mature organs, even though no recognizable nervous system or other organs are yet discernible.

Preimplantation human embryos had been produced commonly for many years by IVF, the union of a donated egg and sperm in a test tube, with the intention of producing offspring for otherwise infertile couples. A few days after IVF, embryos that appear viable are placed in a woman’s birth canal in hopes that one or more will implant in the uterine wall and develop into a normal baby. However, not all embryos produced by in vitro fertilization are actually used in efforts to produce new offspring, either because the embryos do not appear normal or, more commonly, because the IVF clinic has generated more embryos than were needed to achieve a couple’s reproductive goals.

Because research on the IVF process or the resulting early embryos had never been conducted with federal funds in the United States, either before or after the birth of Louise Brown, there were no guidelines or regulations for such studies. This meant that the federal funding of human embryo research in any of its aspects—in vitro fertilization, formation of the zygote (the fertilized egg), the early cell divisions, and first steps in differentiation of these tiny clumps of human cells—would have to be deferred until the various types of embryo research could be more carefully evaluated and guidelines proposed.

There were good reasons to examine the prospects. During the preceding two or three decades, biologists had made enormous progress by studying the early development of embryos of mice, the most widely studied mammal. It is relatively easy to obtain fertilized eggs from laboratory mice and then observe the subsequent cell divisions until the embryos comprise fifty to one hundred cells or more and are ready for implantation into the female reproductive tract. At this stage, disaggregated cells from the mouse embryos can grow and divide indefinitely in petri dishes when fed appropriately. These cells are also able to develop into all kinds of organs or tissues. For instance, if they are injected into an intact embryo , which is then allowed to mature into a newborn mouse, descendants of the stem cells can contribute to any part of the mature animal. Thus they meet the definition of a pluripotent stem cell: they divide to yield daughter cells that are indistinguishable from the starting cells (“self-renewal”), and they differentiate into a wide variety of types (“pluripotency”).

Over the past couple of decades, work with early mouse embryos—and with stem cells derived from them—has been dramatically enhanced by some powerful new methods that allow genetic modification of the mouse germ line and rigorous study of mammalian gene functions. DNA mapping and sequencing—features of the Mouse Genome Project—have defined the genetic composition and organization of mouse chromosomes and identified genes that are involved in the formation and function of specific tissues. Genes that govern normal development and produce disease are now routinely studied in mice by altering the genetic makeup of the early embryo . This can be done in either of two ways. First, genes can be added to the mouse germ line, putting them directly into fertilized eggs, and the genes will then be transmitted to mouse progeny. 3 Before this maneuver, the genes can be mutated to mimic genetic alterations observed in human diseases or engineered to be expressed as an investigator wishes. In the second approach, any gene in a cultured embryonic stem cell can be specifically targeted to make mutations that explore normal functions of the gene or recapitulate mutations found in human diseases. 4 Again, by appropriate manipulations, these mutations can enter the germ line of mature mice. These two methods have been extraordinarily important for studying normal functions and many diseases in a mammalian species, but they are currently, and appropriately, forbidden in human beings. *

By 1993, work with mouse embryos had stimulated many provocative and testable ideas about how early cells differentiate to form mature tissues and about how diseases arise. These ideas are pertinent to analogous human events, in part because of the great similarities observed between mice and human beings when their genomes, biochemical properties, and cell functions are compared. By the early 1990s, it was also widely appreciated that many human embryos were stored in freezers and destined for destruction at IVF clinics in the United States and elsewhere, because they had been kept in a frozen state too long for efficient implantation in a uterus or because the sperm and egg donors had either already achieved parenthood or had abandoned attempts to reproduce for other reasons. Thus, many kinds of work on human embryos would be feasible without creating additional embryos for research purposes.

But what work ought to be pursued? Late in 1993, after legal constraints on federal funding of human embryo and fetal tissue research had been eased, my NIH colleagues and I assembled a group to think about this question. The Human Embryo Research Panel was asked to survey the experimental possibilities in the realm of human embryo research and recommend the ones that deserved to be pursued with federal funds, on the basis of scientific merit, possible medical applications, and ethical implications. **

We were fortunate to attract a wide range of eminent people, from several fields of medical science, jurisprudence, and ethics, to serve on the panel, including, as chair, Dr. Steven Muller, a former president of Johns Hopkins University. The group met repeatedly over the next year, in both open and closed sessions; commissioned reports on several ethical, medical, and scientific aspects of embryo research; and debated each decision with vigor and intelligence. * As requested, the panel offered thoughtful judgments about the kinds of studies that should be supported with federal funds, which should not be supported, and which should be postponed for consideration until more information was available or further discussion had occurred.

Looking back on the panel’s lengthy report today, 5 with our much deeper knowledge about embryos, cloning , and stem cells , I find its prescience truly astonishing. The panel anticipated by a few years several major developments, including the derivation of stem cells from human embryos and the use of cloning methods in embryo research. And it made prophetic observations about how those developments might be used for medical benefit. In particular, the panel foresaw in 1994 the prospect of growing human embryonic cells from early embryos, even though no stem cells from any primate embryo had yet been grown in the laboratory. From earlier work with mice, members of the panel knew that embryonic stem cells were likely to have the potential to develop into many specific tissue types; if so, they could be used to repair damaged tissues or to treat chronic degenerative diseases of the brain or spinal cord, endocrine organs (such as the pancreatic islets), muscles, joints, or other tissues.

But the panel also recognized the biological difficulties such therapies might pose. For example, cells from preexisting embryos would likely be different genetically from the patients who received embryonic stem cell therapies. If so, the immune system of the patient would reject the transplanted cells as foreign. For this reason, the panel argued that it might sometimes be acceptable to create embryos that more adequately represent the full range of human genetic diversity. This would be done using IVF, with sperm and eggs donated by adults from varied ethnic origins. Stem cells derived from these embryos would increase the likelihood of good matches between the cells used in therapy and the recipients (patients). But the generation of immunological diversity in this fashion would also cross an ethical line that a couple of panel members were unwilling to cross: the creation of human embryos for purposes other than reproduction—in this case, medical research and treatment.

In considering other ways to overcome the problem of immune rejection in the imagined use of human stem cells in medicine, the panel also discussed an especially prophetic strategy, one that depended on the possibility of “reprogramming” the genes in mature (adult) cells so that the resulting cells would behave like embryonic stem cells. This strategy was based on the only method then known to “reprogram” cells to an earlier phase of development: somatic cell nuclear transfer. This method, later used in the course of producing Dolly, involves the transfer of a cell nucleus , with the full repertoire of an individual’s DNA , from a somatic cell, such as skin cell from an adult, to an unfertilized egg from which the nucleus had been removed.

Nuclear transfer was not an entirely new idea, even in 1994. More than three decades earlier, British developmental biologists, led by John Gurdon at Oxford University, had electrified the scientific community when they transferred nuclei from mature frog skin cells into a frog egg deprived of its nucleus . 6 The reengineered cells divided repeatedly and ultimately gave rise to tadpoles, implying that the genes in the transferred skin cell nuclei had been “reprogrammed” to direct many steps in the early development of frogs. Each tadpole was a clone , genetically an identical twin, of the frog from which the skin cells were obtained. But mature animals—full-fledged frogs with reproductive capacity—never emerged after the tadpole stage; presumably the reprogramming was incomplete. Analogous experiments with mammals were so uniformly unsuccessful that many biologists had come to think that the kind of reprogramming of genes required for true cloning of animals by nuclear transfer might be impossible.

Still, the panel recognized, a few years before the advent of Dolly, that if nuclear transfer could be made to work in mammals—even just to get development started, not necessarily to produce a mature animal—the impact would be large. For example, if the nucleus of a patient’s cell could be transferred into an egg to generate an early embryo from which therapeutically useful stem cells could be derived, the stem cells would have a genetic makeup identical to that of the person to be treated. Then immune rejection would be unlikely to occur. In the absence of any evidence that reproductive cloning of mammals, yielding full-fledged progeny, was possible, the panel thought about nuclear transfer simply as a means to generate cloned embryos and useful stem cell lines for study and therapy—a strategy now called therapeutic cloning.

The panel astutely noted that nuclear transfer, unlike IVF, is an asexual process, generating embryos (and embryonic stem cells ) genetically indistinguishable from cells in the nuclear donor, the prospective patient—not embryos (and cells) with entirely novel combinations of genes. This was sensibly viewed as more acceptable on ethical grounds than creating new embryos by fertilization. In other words, nuclear transfer would use an already existing combination of genes, the combination present in the donor, to make an early embryo through which pluripotent stem cells would be derived. In contrast, the production of genetically varied embryos and stem cell lines would mix genes from many different pairings of sperm and eggs, yielding embryos with unique combinations of genes—new biological entities that warrant greater ethical concern.

These speculations led to the panel’s most controversial and politically difficult recommendations. Citing the potential clinical benefits, the panel approved (with a couple of dissenters, and only under defined conditions, ethical guidelines, and careful supervision) the use of federal funds in special situations for two controversial methods to generate pluripotent stem cells likely to be useful in therapy: IVF to create genetically diverse embryos from which stem cells could be derived, and reprogramming by somatic cell nuclear transfer to make pluripotent cells immunologically compatible with prospective patients. The panel approved these recommendations even though neither growth of human embryonic stem cells nor nuclear transfer with mammalian cells had yet been accomplished.

• Political Consequences of the Human Embryo Research Panel Report

Although well received by scientists who were watching its work, the panel’s report ignited a storm of government opposition, even within the liberal Clinton administration. I had made several visits to the Old Executive Office Building to brief White House staff well in advance of the planned presentation of the panel’s formal report in early December 1994. At these sessions, I explained the methods and goals of embryo research, showed pictures that displayed the amorphous, undifferentiated character of the tiny early human embryos, and outlined the panel’s forthcoming recommendations, some of which had unexpectedly appeared in the press as early as August.

Despite my efforts, the president’s senior advisers remained uneasy. We had planned to release the report officially following the meeting of my advisory council on December 2, but the White House was in shock from the Democratic Party’s loss of control of both congressional chambers in the midterm elections held a month earlier. Democrats across the nation, especially those at the highest ranks of the Clinton administration, were concerned about a shift in the electorate toward the conservative policies of Newt Gingrich and his Republican revolutionaries, and already anxious about the presidential election of 1996.

I remember getting a call from Leon Panetta, then the White House chief of staff, telling me that I was expected to repudiate some of the panel’s recommendations, in particular any that might permit the use of federal funds to create embryos for research purposes. I refused to reject the recommendations of my panel summarily. I was not fired, as the tone of Panetta’s call had threatened. But on December 2, a few hours after the panel’s report was approved by my advisory council and officially released, the White House issued an executive order, signed by the president, prohibiting the NIH from supporting any studies that entailed the creation of embryos for research. *

Many people thought (and still think) that the executive order was more prohibitive than it was, perhaps because it came so suddenly and from such high authority, and because it was then followed by more severe restrictions imposed by the newly Republican Congress. In fact, the studies that the president ruled ineligible for federal funding made up a very small part of the panel’s recommendations, and the executive order did not oppose the vast majority of the recommendations in support of embryo research. Most obviously, it did not limit the many experiments that would use donated embryos originally created for reproductive purposes but slated for disposal. For instance, it would have been possible to proceed with nearly all of what is now called stem cell research, including the derivation, study, and use of new lines of stem cells from human embryos donated by infertile couples treated at IVF clinics.

Now, nearly fourteen years later, federal funding of research on human embryos remains stalled by a twelve-year-old congressional ban, and President George W. Bush’s six-year-old policy limits funding of human embryonic stem cell research to work on cells derived before August 9, 2001. So viewed from the current perspective, Clinton’s executive order of 1994 seems relatively mild and even permissive. Still, the directive had a strong impact. Our subsequent deliberations at the NIH were tinged with fear that any rapid movement toward funding any of the permitted embryo research would be attacked by the newly powerful Republican right wing and might adversely affect the agency’s budget, which, as always, was the major concern for the NIH and its constituency. The administration was certainly not urging us to initiate embryo research. And those of us in charge of NIH policy were strongly advised by knowledgeable people, both inside and outside government, to move cautiously in this contentious arena. So we were cautious. No guidelines were drawn up, no applications for funds were solicited, and no grants were issued for human embryo research of any kind.

Given this atmosphere, conservative members of Congress who were eager for broader restrictions may have been emboldened by the executive order. Indeed, several months later, early in 1995, during negotiations over the 1996 budget for the NIH, two Republican members of the House Appropriations Subcommittee for HHS, Labor, and Education, Jay Dickey of Arkansas and Roger Wicker of Mississippi, wrote an amendment to that year’s spending bill to prevent any use of funds under the committee’s jurisdiction for experiments that would create, damage, or destroy a human embryo . This prohibition included many types of research acceptable to the Clinton administration, including work with donated embryos, and was written to make the definition of an embryo as broad as possible. The so-called Dickey-Wicker amendment has been attached as a “rider” to every subsequent NIH appropriations bill. It continues to prohibit federal funding for essentially any kind of work with human embryos.

• The Birth of Dolly and the Specter of Human Reproductive Cloning

One weekend in the winter of 1997, as I was preparing for my annual hearings on the NIH budget before the House Appropriations Subcommittee, I was stunned by a story on the front page of the Sunday New York Times by Gina Kolata. Her article described a report, soon to appear in Nature magazine, in which Ian Wilmut and his colleagues at the Roslin Institute in Scotland announced the birth of Dolly, the first well-documented case of an animal (a Finn Dorset lamb) cloned from an adult cell. 8

Even before getting my hands on the actual report in Nature , I could see that this news was explosive. For those familiar with biological research, the feat of making a cloned animal by transferring a nucleus from an adult cell to an egg would reverse a long-held presumption: that it was not possible to “reprogram” a cell so completely. The Human Embryo Research Panel had noted John Gurdon’s partial success in reprogramming nuclei from frog skin cells, and it had recommended using nuclear transfer to make cloned human stem cells . But Wilmut had gone much further than Gurdon. His team had fully reset the program of a single, highly specialized, mature cell—a cell derived from the breast tissue of an adult ewe—so that the nucleus could direct formation of a complete, complex organism with its many varieties of mature cell types. For the general public, however, the birth of Dolly would raise a troubling issue: the prospect of human cloning —the generation of new individuals with genetic constitutions essentially identical to those of the person who had provided cells for the cloning process. This possibility would engender a wide range of questions about the purposes, applications, and ethics of modern biological research.

All of these issues were rapidly and publicly aired in the few weeks following the publication of Wilmut’s paper—in countless news reports, columns, and letters in the press; at the White House, where the president asked his recently formed National Bioethics Advisory Commission (NBAC) to consider the implications of the new experiments; and at congressional hearings, both those I had been preparing for in the course of NIH’s appropriations cycle and others.

We were not very far into the usual to-and-fro regarding the president’s proposal for the NIH’s 1998 budget before John Porter, the chair of the Appropriations Subcommittee, brought up the very recent news from Scotland. Pointing out that the story “shocked many in the scientific community because they said it couldn’t be done,” Porter then asked “whether this is valid science, whether it would lead to cloning of adult human beings, what the implications are, both positive and negative, for science itself, and what are the ethical implications . . . for all of society.” This was a very good summary of what well-informed people were wondering. I asked, “How much time do I have, Mr. Porter?” He said, “As much as you’d like.”

Given this unprecedented liberty, I spoke at unprecedented length, in an answer that took up nearly six pages of the published transcript of the hearing. 9 (After I was done, Porter said, “Dr. Varmus, that’s probably the longest answer ever not interrupted by a member of Congress.”) I told the subcommittee about Gurdon’s classic experiments on nuclear transfer with frog cells; about Wilmut’s earlier work, showing that nuclei from very early lamb embryos (not yet from sheep cells) could be transferred into enucleated sheep eggs, producing embryos that matured into full-fledged lambs when implanted in a uterus; and, finally, about Wilmut’s latest success, doing the same kind of experiment with nuclei from older embryos, from fetuses, and, most dramatically, from adult sheep breast cells growing in tissue culture.

I didn’t stop there. I then talked about the significance of cloning , making new animals with nuclei derived from existing adult animals. While acknowledging the inevitability that public attention would be given first to the “sensational aspects”—the possibility of making clones of mature human beings—I also pointed out the potential benefits in agriculture and in medicine that could result from cloning animals or making cloned human cells. I placed the greatest emphasis on the prospects for “a much deeper understanding” of development, of the process that determines whether a cell behaves like a nerve cell or a liver cell. The birth of Dolly, I said, demonstrated that “a cell derived from an adult mammary gland has been reprogrammed to become . . . fully potent . . . to make every component of a sheep.” Learning the rules of reprogramming, I argued to the subcommittee, could provide unexpected opportunities in medicine—for making skin cells, bone marrow, or neurons from a patient’s normal cells to treat burns, to replace blood cells destroyed by chemotherapy, or to counteract degenerative brain diseases.

In the final part of my answer to Porter’s questions, I summarized the arguments against human reproductive cloning that had been developed by the NIH panel on human embryo research. In addition, I pointed out that congressional restrictions (the Dickey-Wicker amendment) and Clinton’s executive order already prevented the use of federal funds to clone human beings. In response to a follow-up question by Representative Nita Lowey, I said there was reason to be “concerned about the rush to legislation in this arena. We have a new finding. It needs to be absorbed and discussed. . . . (The) National Bioethics Advisory Commission . . . is very well suited . . . to discuss these issues and to make some recommendations.”

Mine may have been a temperate, reasoned statement, but the immediate response to Dolly in Washington, and throughout the country, was a political impulse—to use persuasion, moral authority, and legislation to discourage or prevent the creation of cloned human offspring, even if the possibility of human reproductive cloning was likely to be at least years away. The White House quickly issued an executive order to reduce the likelihood of human cloning by prohibiting federal funding to pay for it and by urging scientists with access to other sources of support to respect a moratorium on cloning.

The president’s announcement to the press of this new executive order was accompanied by a directive to the recently formed NBAC, asking it to recommend how to respond to the new developments in the longer run. The press event was preceded by a short briefing with Harold Shapiro (the chair of NBAC and the president of Princeton University at the time), several presidential advisers, and me. I was seated next to the president and, as the discussion was drawing to a close, began to explain to him why the methods that led to Dolly had potential importance for understanding basic principles of biology and for producing therapeutically useful cells, without ever allowing an early embryo to grow past very early stages in a petri dish. For these reasons, I maintained, any effort to legislate should be treated with caution, lest we cut off worthwhile avenues of investigation.

Overhearing my colloquy with Clinton, perhaps thinking I was trying to undermine the president’s resolve about the executive order, Vice-President Al Gore broke in, saying that he didn’t want to be harsh, but time was short and the cloning matter needed urgent resolution. Then, to my amazement, he said that human cloning was already likely being performed elsewhere and that, when he was in the House of Representatives, one of his committees heard testimony about the successful cloning of human beings in India. It was neither necessary nor prudent to challenge him in front of the others. But as we reassembled for the press briefing in the Oval Office, he came up to me, apologized for his abruptness during the briefing, and, recognizing my skepticism about his claims, said he’d ask his staff to send me the transcripts from the hearing. I wasn’t surprised that they never arrived.

The president’s new executive order and attempts to legislate a ban on the cloning of human beings were more useful as means of public reassurance than as necessary or effective deterrents. We knew at the time that reproductive cloning from adult animal cells was a low probability event—Dolly was the only success out of 277 attempts in the reported experiments with sheep. We know now that the success rate is also low (if sometimes a bit better) in other species and that animals generated by cloning are rarely, if ever, entirely normal: they may age rapidly and die early, and their DNA bears marks of the cloning process. 10 Thus the utility of a legislated ban on the cloning of human beings has remained unclear. Responsible scientists would not undertake human reproductive cloning, because of its safety, ethical concerns, and difficulty. Determined outlaws would simply break the law or go to one of the many places where such laws did not exist. Still, most scientists favor a legislated ban (which still does not exist at the federal level), if only to put the issue to rest and to show support for a reasonable ethical position.

In the immediate aftermath of the Wilmut paper and the executive order, several congressional committees held hearings to show legislative concern, and many ethicists, public figures, and other talking heads filled the airwaves and newspapers with anxiety about cloning human beings. Exactly two weeks after the House appropriations hearings (which had followed by days the announcement of Dolly’s birth), Senator Bill Frist organized a hearing of the Senate Committee on Health and Human Resources to debate the news, discuss possible legislation, and take advantage of Ian Wilmut’s coincidental visit to Washington. 11 I appeared as a witness with Wilmut and delivered another lengthy discourse on the biological meaning of his work. For this occasion, I had had enough time to prepare drawings that illustrated the normal processes of fertilization and early development and to enlarge photographs that showed the delicate process of nuclear transfer and the amorphous appearance of early embryos. Again, I reviewed the potentially beneficial uses of nuclear transfer and reprogramming, described the safeguards already in place against efforts to misuse the new technology, and urged that public discussion precede “efforts to legislate in areas where the issues are complex.”

But my efforts to hold off legislation seemed mild compared with a speech given later in the hearing by Senator Tom Harkin. Although I sometimes sparred with Harkin about the funding and oversight of research on alternative medical practices, he has been a consistent supporter of basic research and the NIH budget. On this occasion, he took his defense of research to an unexpected plane:

I do not think there are any appropriate limits to human knowledge—none whatsoever. . . . Now some would have us believe that Dolly is a “wolf in sheep’s clothing,” but I do not think so. I think there is enormous potential for good in this kind of research. . . . To those like my friend, Senator Bond [who had introduced a highly restrictive bill that would ban all human nuclear transfer], and President Clinton [who had issued the executive order to block federal funding of human reproductive cloning and to request a moratorium in the private sector], who are saying stop, that we cannot play God, well, I say, okay, fine. You can take your side and your ranks alongside Pope Paul V who, in 1616, tried to stop Galileo.

Before concluding his defense of the free play of science, he stepped the argument up another notch:

I will make a statement right here. Cloning will continue. The human mind will continue to inquire into this. Human cloning will take place, and it will take place in my lifetime, and I do not fear it at all. I welcome it. *

Dolly’s Significance: Genetic Reprogramming

Dolly is now the most famous sheep in history, and her birth is viewed as one of the most dramatic moments in the history of science in the twentieth century. The experiment that produced her upset existing dogma, which argued that mature (differentiated) cells in a complex organism could not be “reprogrammed” to behave like a fertilized egg (the zygote ), the primordial embryonic cell that gives rise to a complete organism. The birth of Dolly convinced most scientists that a new organism, genetically identical to a previously existing individual, could be produced by means of the full set of chromosomes derived from a specialized adult cell. In Wilmut’s experiment, the genetic program that directs a cell to behave like a breast epithelial cell was replaced by a genetic program responsive to cues present in the egg’s cytoplasm. In this way, the cell newly formed by nuclear transfer generated daughter cells that ultimately led to the formation of a complete, complex organism.

What does reprogramming mean? In earlier chapters, I introduced the idea that individual cell types make use of only a subset of the genes in the genome to produce RNA and protein ; the pattern of expressed genes is often called the program. During normal differentiation—in development of an embryo or in formation of specialized cells in an animal after birth—successive patterns of gene expression are observed. Generally, the sequence of patterns occurs in only one direction. The possibility of reversion to an earlier stage of development (“de-differentiation” or “reprogramming”) has been a perennial topic of debate. It has long been acknowledged that a dramatic reprogramming must occur without experimental intervention during reproduction, when two specialized cells, a sperm cell and an egg cell, combine to produce the zygote , a single cell from which all subsequent cells in an organism arise. The cloned animal called Dolly showed that such dramatic reprogramming can also occur when the nucleus of a fully differentiated cell is moved into a new environment, the cytoplasm of an egg.

So what are the molecular events that control the genetic program, determining whether a region of DNA , a gene , remains silent or is read out to make RNA and, usually, protein ? And what triggers those events? Although we are far from knowing the answers to these questions in satisfying detail, a few things are evident. For any cell type, there is a characteristic pattern (or program) of gene expression, with some of its roughly twenty-two thousand genes silent, some turned on at low levels, some at higher levels. To change from one cell type to another, the activities of many thousands of genes would have to be altered. How this happens is not fully understood, but part of the answer involves master regulators, proteins affecting the behavior of large numbers of genes, in a kind of hierarchy.

To envision how this happens, imagine the consequences of pushing (“expressing”) some of the keys on a twelve-key piano. One combination produces one harmonic sound; another combination produces a different sound. A change in sounds would require a change in programming, something that would be relatively easy to do with such a simple piano. But if the instrument had a much larger number of keys, perhaps thousands, it would be more efficient to control changes in sound by designing a hierarchy, with some keys as regulators of large sets of other keys. If the regulatory keys governed partly overlapping rather than distinct sets of keys. the situation would be similar to what appears to occur in animal cells.

We now know what some of the regulatory genes are, we know something about what genes they regulate, and we even know a bit about how they are themselves regulated, especially in normal development. Dolly’s birth and other experiments tell us that it is possible to reset the program without resorting to the usual process of fertilization—observations that are fundamentally exciting and rich with possibility. But what components of the egg’s cytoplasm triggered the critical changes in gene expression to convert a breast cell nucleus into the nucleus of a one-cell embryo ? Could the same effect be achieved in an adult cell without laboriously manipulating the cell’s nucleus into a new cell? Or without requiring an egg cell as recipient? Could this be done with chemical triggers (hormones or drugs)? By some kind of physical shock? Or by delivering a few master regulatory genes into the cell?

Dolly’s birth inspired additional efforts—increasingly successful (though still relatively inefficient)—to clone several other kinds of animals (mice, cats, dogs, horses, cows, and even nonhuman primates). The extent to which the cloning of animals has succeeded can be gauged by the current debates over the use of cloned animals for food in Europe and the United States. 12

These successes have encouraged efforts to recapitulate reprogramming by other means. Most dramatically, a small number of labs have used retroviruses carrying regulatory genes to reprogram mature cells, mostly skin cells, from mice and, more recently, human beings. 13 The infected, reprogrammed cells have many features of embryonic stem cells , including the crucial ability to form a variety of differentiated cell types, such as muscle and nerve cells. The “induced pluripotent stem cells” (iPS cells) have opened exciting new prospects for understanding and treating disease, as will be noted near the end of this chapter.

• Avoiding Legislation to Criminalize Nuclear Transfer

In response to the continuing debates about the reproductive cloning of human beings—Is human cloning possible? Is it safe? Could it ever be justified ethically?—most scientists have taken a conservative stance and remained receptive to a legislative ban. This is based in part on evidence that cloned animals are not entirely healthy, in part on the inefficiency and expense of the process, and in part on the complex ethical and political issues raised by reproductive cloning. But the birth of Dolly also raised a question on which most scientists take a position that diverges from public policy in the United States. Should the government support therapeutic cloning, by means of nuclear transfer into an egg to produce embryonic stem cells for treatment of serious medical conditions?

Seen in this context, the announcement of Dolly’s birth had a special poignancy. Dolly’s existence showed that it was possible, after all, as speculated by the Human Embryo Research Panel, to “turn back the biological clock”—to reset the program of the genome of an adult mammalian cell so that it would behave like the genome of a fertilized egg. This new cell could lead to the complete development of a complex organism. But nuclear transfer could also be the first step toward a different, beneficial and much less contentious, outcome: the production of cloned early embryos from which cloned, pluripotent stem cells could be derived. Even in 1994, it was apparent to the embryo research panel that such cells might be among the best prospects for cell-based therapies, as well as important tools for the study of normal and abnormal development, for understanding diseases, and for screening for new drugs to treat disease.

But could the distinction between reproductive and therapeutic intentions be preserved? My colleagues and I hoped that any legislative efforts to prohibit reproductive human cloning , by making it a criminal act, would be flexible enough to allow nuclear transfer for creation of cloned pluripotent cells. Initially, only a few in Congress seemed concerned about preserving the option of reprogramming the human nucleus by nuclear transfer as a method that would promote discoveries and therapies. The embryo research panel’s view—that nuclear transfer to generate embryonic cells from adult nuclei is an asexual, therapeutically beneficial, and ethically more acceptable method than IVF—was generally ignored. A bill introduced in 1997 by Senator Kit Bond of Missouri and endorsed by Senator Frist would have made nuclear transfer illegal, as part of an effort to ban the cloning of human beings. They viewed the method as the first step down the “slippery slope” to reproductive cloning. But with orchestrated lobbying by scientists and help from a bipartisan coalition of legislators—including, prominently, Senators Orrin Hatch, Arlen Specter, and Tom Harkin—the bill was blocked by a modest margin, an effort that demonstrated how scientists could beneficially influence debate on complex issues.

Still, because the public’s introduction to nuclear transfer occurred in the context of Dolly’s birth, the method became inextricably linked to cloning in the most dramatic sense—the making of cloned human beings. Efforts to emphasize that nuclear transfer was just an early step in an elaborate method that could lead to reproductive cloning, but that it was also essential for achieving the more acceptable objective of “therapeutic cloning,” has not fared well. For instance, it is still not possible to use federal funds to support research on nuclear transfer, because the method is considered a means of creating an embryo and thus federal support of it would violate the Dickey-Wicker amendment. *

Not surprisingly, nuclear transfer has been pursued more actively in countries in Asia and Europe, especially the United Kingdom. American scientists have used funds from industry, state initiatives, and private philanthropy to support work on nuclear transfer, but progress has inevitably been slowed by the exclusion of the NIH, our major source of funding for research and training and the predominant influence on research trends in the United States. Still, reproducible success with human nuclear transfer has yet to be achieved in any country. Furthermore, the procurement of human eggs for the procedure remains difficult for ethical and medical reasons. Newer approaches to reprogramming seem likely to overtake nuclear transfer as the preferred method for making cloned pluripotent stem cells .

• Growing Human Embryonic Stem Cells

When Dolly appeared on the scene in 1997, scientists still did not know how to grow embryonic stem cells from early human embryos, despite the repeatedly successful cultivation of mouse embryonic stem cells. So the potential medical utility of nuclear transfer and other kinds of human embryo research remained theoretical in the first year or two after Dolly’s birth.

But debates about cloning and embryo research became much more sharply focused on the prospects for treating human disease late in 1998, when Jamie Thomson, at the University of Wisconsin, reported the prolonged growth in culture dishes of human cells derived from early embryos. 14 For those following Thomson’s work closely, this step might have been anticipated, since a couple of years earlier he had reported a method for growing pluripotent stem cells derived from embryos of non-human primates. 15 But to most of the scientific community and to the public at large, Thomson’s announcement about human embryonic stem cells was stunning.

To make his embryonic stem cell lines, Thomson and his colleagues disassembled early human embryos that were provided by sperm and egg donors at IVF clinics. * Suddenly it was possible to learn the rules of normal human development—the recipes required to turn the early embryo cells, not yet committed to any particular tissue type, into specialized cells of virtually any type—in simple experimental systems. It also meant that medical scientists could focus on making large numbers of differentiated human cells that could be used to repair many kinds of injured or diseased tissues: the deficient pancreas in a diabetic patient, the paucity of dopamine-producing cells in the brains of patients with Parkinson’s disease, the exhausted cardiac muscle cells in patients with congestive heart failure.

Thomson’s success in developing human embryonic stem cell lines, his interest in promoting their widespread use, and the generation of other similar lines elsewhere in the United States and abroad created an important opportunity. Now that such lines had been created without the use of federal funds, there didn’t seem to be any obvious obstacle to the use of federal funds to support studies of the lines themselves. Since no further damage would be done to human embryos by working with the newly produced stem cells , there was no reason to think that federal funding of the research would violate the Dickey-Wicker amendment. Still, there was reason to fear that spending federal money to study cells that had been derived by destroying human embryos would incite a congressional backlash against the NIH.

For this reason, early in 1999 I asked Harriet Rabb, then the general counsel of the Department of HHS (now head of legal affairs at Rockefeller University), for a detailed legal opinion. In a widely known brief, she argued that since stem cells themselves were not embryos, research on them could legitimately be supported with NIH funds. 16 No embryos would be damaged by doing so; the damage had already been done, legally, by use of nonfederal funds. This provided the basis on which to proceed to finance human embryonic stem cell research with NIH dollars. But we needed other kinds of assurances as well. So I recruited a panel, headed by Shirley Tilghman, the molecular biologist and mouse embryologist who is now president of Princeton University, to write guidelines for regulating the ethical use of such cells in NIH-funded research. However, by the time her panel had completed its report, sought and responded to public comments, and posted the rules, the presidential campaigns of 2000 were in full swing, and the political sensitivities to the issue were acute. (I was, by then, gone from the NIH.)

• Stem Cells in the Era of George W. Bush

Whatever the explanations, no NIH money was used to pay for human embryonic stem cell research until President Bush gave his famous speech of August 9, 2001. It is a measure of the importance the stem cell debate had achieved in the political arena that this was the topic of the new president’s first televised address to the nation, nearly eight months after he assumed office. The speech was well written, and its effort to make all sides happy was clever in conception; but its apparent benefits were doomed to be relatively short-lived. * Rather than close the door on any federal funding of stem cell research, as many had predicted, Bush agreed to allow funds to be used to study only those lines that existed before he began speaking at nine that night. This policy allowed him to say to his right-wing supporters that the prospect of federal funding could not be an incentive for deriving additional lines from additional embryos, while also saying to medical scientists that he was allowing federal support of research with existing lines of human embryonic stem cells for the first time.

The Bush policy unarguably permitted the first federal funding of human embryonic stem cell research. Coming from a conservative president, the policy was less prone to attack from the right wing than similar actions from a Democrat; still, many of his supporters voiced disappointment. But, predictably, his compromise quickly passed the limits of usefulness. The number of cell lines eligible for funding was always much smaller than the sixty or more claimed to exist. This was true, in part, because the speech conflated truly established cell lines that exhibited reliable properties with frozen samples of disaggregated embryo cells that had yet to show reproducible growth patterns in culture. In addition, some lines were difficult to obtain because of the licensing requirements of those who had filed for patent protection of their cell lines. Furthermore, none of the existing cell lines was likely to be useful for the ultimate goal of therapy, because they had been initially propagated on “supporting” layers of mouse cells that might produce viruses dangerous to patients. In the meantime, new and better stem cell lines have been generated with funds from nonfederal sources, principally the Howard Hughes Medical Institute, private philanthropies, laboratories abroad, and industry. But these lines cannot be studied with NIH grants unless legislation to broaden the repertoire of eligible cell lines—legislation that has twice been passed by the U.S. Congress and twice vetoed by President Bush—is enacted into law. This seems unlikely to happen until after the election of 2008.

During the years of adjustment to the Bush stem cell policies, the landscape has been altered by the emergence of knowledgeable and committed stem cell advocacy groups, by important discoveries about the behavior of embryonic stem cells , and by new strategies for engaging state governments and philanthropists in the pursuit of stem cell research. As a result, stem cell research has not fallen drastically behind similar efforts in other countries, as some had feared, although progress has surely been compromised by legal and bureaucratic obstacles. In this area of research, a traditional strength of American science policy—a centralized, well-coordinated, and openly competitive process for making grants at the NIH—has been replaced by an uneven patchwork of state-based programs and other, nongovernmental funding opportunities. Some wealthy institutions have been able to pursue human stem cell research through philanthropy, while many others lack access to such resources. Some states have enacted bans on both cloning and the methods used for cloning (e.g., somatic cell nuclear transfer), while others, most famously California, have passed measures to finance many kinds of human stem cell research handsomely.

More Californians supported the state’s bond initiative for stem cell research in 2004 than voted for the Democratic presidential candidate, John Kerry. The bill provides $3 billion in bonds over ten years for stem cell research. Nevertheless, roadblocks thrown up by legislative dissents and legal challenges significantly delayed the spending of taxpayers’ funds. Other states, notably Connecticut, New Jersey, Wisconsin, and Michigan, have passed progressive policies that provide financial support for stem cell research. In 2007, following the election of Eliot Spitzer as governor, my own state, New York, allocated at least $600 million for stem cell and related research over the next decade, without attracting significant attention or objection. * Meanwhile, private monies, such as the $50 million given by the Starr Foundation to support collaborative work on stem cells at MSKCC, Rockefeller University, and Weill Cornell Medical College, are supporting broad programs of stem cell science at many leading U.S. research centers—at least, at those with the good fortune to have wealthy, enlightened donors.

Still, despite the alternative means for funding stem cell research, investigators must consider carefully whether they want to work in such a financially confusing (if scientifically exciting) field and, if so, where they should work. For instance, although few scientists have yet left the United States to pursue stem cell research abroad, other countries offer temptations to our scientists. The United Kingdom asked a parliamentary committee to determine what kind of research ought to be permitted and then issued guidelines that resemble the recommendations of the NIH’s 1994 embryo research panel. Other European and some Asian countries have aggressively promoted stem cell research, sensing not only opportunities for discovery and medical progress but also a chance to move ahead of a confused American enterprise in this arena. This was most obviously the case in South Korea, where a large, well-supported team, headed by Professor Woo-Suk Hwang, reported having taken somatic cell nuclear transfer to the point of making embryonic stem cells with nuclei from patients with injuries and diseases that might be suitable candidates for cell therapies. Regrettably, much of Dr. Hwang’s work is now acknowledged to have been fabricated, an admission that has significantly tarnished the reputation of the entire field. 17

To me and to many of my colleagues, the way in which our government has handled the dramatic developments in research on embryos and stem cells reflects the undue influence of a few religious groups on the conduct of science in a diverse society. The opposition of the Catholic Church and other conservative Christians to this new scientific arena has been unremitting, and reflected in the positions taken by some leading members of the legislative and executive branches, including President Bush, Senator Sam Brownback, and Representative Dave Weldon, all of whom have proposed or endorsed highly restrictive legislation. Few arguments can seem as insulting to medical scientists as the claim that we are ethically irresponsible when we toil to extract stem cells from donated early human embryos, which would otherwise be destroyed, and use them for beneficial, potentially lifesaving purposes.

But there are reasons for optimism, too. The country has taken the debate about stem cells and cloning seriously, and most indicators point to increasing support for liberalization of existing policies. Second, the issues have further stimulated the public’s interest in modern biology and its potential for medical benefit. Third, recent work in Japan and the United States offers grounds for optimism that cells closely resembling embryonic stem cells, iPS cells, can be produced by introducing a “genetic cocktail” into adult cells, thereby reprogramming them. *

If the study of cell reprogramming continues to deliver on its promise, human cells of the sort most desirable for research and treatment may eventually be obtainable without the use of embryos or nuclear transfer at all. This would fulfill a long-held dream of redeploying mature cells to behave like embryonic cells, then using those cells to treat patients from whom the cells were derived. For the foreseeable future, however, early human embryos and cells derived from them will be a staple of research, providing the “gold standards” against which reprogrammed cells must be compared. The absence of absolute prohibitions of embryo and stem cell research has allowed such research to proceed in this country, if not in an optimal fashion, despite restrictions on federal funding. Because of their promise, embryonic stem cells have become a useful political bellwether and have kept the promise of biomedical research at the forefront of public discourse. All in all, not bad outcomes.

Such tissues are usually obtained, with parental consent, after medically supervised abortions, performed about two to four months after conception.

Three scientists who developed the methods for making targeted mutations in mice received the 2007 Nobel Prize in Physiology or Medicine.

It is important to note that the panel was not asked to rule on whether or not certain kinds of experiment should be done at all, as might be the case in the United Kingdom and other European and some Asian nations. In those countries, government policies that guide the conduct of research apply to all work, regardless of the source of funding. In the United States, tradition dictates that scientific work is generally not deemed forbidden or illegal; only rarely has scientific work been outlawed and subjected to civil or criminal prosecution. Instead, certain kinds of controversial work may be deemed ineligible for use of taxpayer’s funds, usually federal. Despite the restrictions on public funding, such work can be pursued with private money or with nonprohibited public funds, as has recently occurred with human embryonic stem cell research.

The panel members—and I—also received literally thousands of nearly identical postcard messages, telling us not to encourage research on early embryos, because they were innocent human beings.

A more detailed account of these dramatic events can be found in Merchants of Immortality by the distinguished science historian Stephen S. Hall. 7

This extraordinary moment was later incorporated into an episode of a popular television series, The X Files . My cameo appearance boosted my standing with friends and relatives under the age of twenty-five.

No penalties are associated with such research conducted in the United States with other sources of funds.

To circumvent the Dickey-Wicker amendment, which prohibited federal funding of research that destroyed human embryos, Thomson’s group used money from two nonfederal sources: the Wisconsin Alumni Research Fund, a state resource fed by philanthropy and by royalties from earlier research at the university, and the Geron Corporation, a privately financed company focused on the disorders of aging. These funding strategies presaged the pattern that now prevails in the face of continued severe restrictions on federal support of research on human embryos and stem cells —funding from philanthropy, commercial investments, private research organizations, and state budgets.

According to an article that appeared in the January 2008 issue of Commentary magazine by Jay Lefkowitz, one of Bush’s policy advisers at the time, the president devoted a large portion of his first months in office to discussions of this issue with many physicians, scientists, ethicists, patient advocates, and others. However, Lefkowitz’s claim that I “sat down” with President Bush at Yale to talk about stem cells is an exaggeration that raises doubt about other claims in the article. In fact, I met the president in a receiving line at the 2001 Yale graduation, where we were both receiving honorary degrees. When I surprised him by saying that I’d like to talk about three things, one of which was stem cells, he looked uneasy and called out to Andrew Card, his chief of staff, “Andy, Andy, come on over here and talk to the doc!” Card and I then chatted briefly about my views. I never sat down with President Bush to discuss stem cells or anything else.

In September 2007, I was appointed as a commissioner on the funding subcommittee of the New York stem cell program.

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• Cite this Page Varmus H. The Art and Politics of Science. New York: W.W. Norton & Company; 2009. Chapter 13, Embryos, Cloning, Stem Cells, and the Promise of Reprogramming.
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Embryonic Stem Cell Research

Science has continuously provided the pathway towards innovative solutions to solve the issues of the 21st century; however, in order to attain such solutions the question of what is morally acceptable or wrong comes into play. Embryonic stem cell research has faced the negative spotlight for many years. The false misconceptions surrounding stem cells is clouded by the idea that they are acquired through intentionally killing a life of a potential human being. These false statements facilitated by anti-abortion organizations has slowed down the progress that could have been achieved through science on a logical and ethnically driven basis.

Embryonic stem cells should be used for medical research because they harness the potential to improve the quality of life and medically treat millions of sick individuals. Consequently, misconceptions are often bred from not fully understanding the issue at hand and in the case of embryonic stem cell research the scientific jargon can further the publics confusion. In simpler terms within the field of stem cell research, the main two cells used for used for medical experiments and treatments are adult stem cells and embryonic stem cells.

The formation of embryonic stem cells is produced during the intricate process of fertilization of a zygote by a sperm. Once reached fertilization results in millions of cells dividing and replicating in order to form a blastocyst. Beau Watts an emergency room physician further explains in his essay “Embryonic Stem Cell Research; A Moral Evil or Obligation? ” that “the blastocyst consists of an outer layer of cells which surround another cluster of cells known as the inner cell mass. It is this inner cell mass that contains stem cells considered to be pluripotent . . .” (459).

To attain the preferred pluripotent cells, which can potentially give rise to different cell types, they need to be extracted from the embryo . The extraction process is often portrayed by anti-abortion groups as intentionally destroying a human life when in reality the embryo does not contain any individual characteristics until it has implanted in a female uterus. Picture a world where dozens of degenerative illnesses and diseases are effectively treated: cancer, type I diabetes, and Parkinson’s disease .

Additionally, not only will the treatments of these diseases save lives but will also improve the quality of life for millions of sick individuals. Such accomplishments can be achieved with embryonic stem cells, unfortunately; the use of these cells has garnered opposition from numerous sides. The opposition for the use of embryonic stem cells in medical research originates from the idea that using embryonic cells is in turn destroying potential life.

J. C. Willke a former obstetrician and now an anti-abortion activists states in the article “I’m Pro-Life and Oppose Embryonic Stem Cell Research” that “. . to terminate [a] life at any stage . . . can be called nothing other than a killing” (464-65). However, at what developmental stage is a fertilized zygote considered a life? Each is entitled to their opinion regarding the conception of life although there is also a point where personal and religious beliefs interfere with reaching a consensus on the issue. In such cases, where the morality of research is put into question the professional conduct of scientific researchers is subjected to a code of ethics.

Misconceptions are often formed when a certain subject is not fully understood especially in the case of how embryonic stem cells are acquired. Embryonic stem cells are not acquired through the intentional killing of a fetus but through legal fertility clinics that have left over embryos soon to be discarded. When a couple or individual undergoes in vitro fertilization, several embryos are created in the lab to increase the chance of the embryo successfully implanting in the womb of the female . There are various scenarios in which several embryos are left over from the process and are either discarded or donated to scientific research .

It seems logical to harness each embryo’s potential contribution to scientific research instead of discarding them in the trash. Regardless of this fact, much of the opposition continues to argue that embryos should be respected as a human life. Beau Watts counters this argument by stating that the embryos used for research do not “. . . contain any individualized components until after implantation into the uterus” (460). Ultimately, an embryo has the potential to become a life but scientifically is not an individual since it cannot grow into a fetus with individual characteristics until it has fully attached to a female uterus.

Additionally, the embryonic stem cells used for research never reach that particular stage of fetal development. Through the process, a human life is not destroyed but instead an embryo is being used to create potentially effective cures and treatments to improve the quality of life for millions of individuals across the world. In reality, any type of medical procedure carries a risk which is why thorough understanding of the field by scientists is required to ensure success. For instance, the use of embryonic stem cells in therapeutic treatments runs the risk of tumor formation and the rejection of the cells after implantation (Mehta 107).

After implantation there is a risk that the cells will not differentiate into the affected cell and cause unregulated cell growth resulting in tumors. Furthermore, in their research of human embryonic stem cell cultivation scientists Nina Desai, Pooja Rambhia, and Arsela Gishto noted that “[t]o reach the full therapeutic potential of [embryonic stem cells], defined and reproducible culture systems must be integrated in order to generate quantities of [embryonic stem cells] . . . that are able to sustain therapeutic applications” (1).

Harnessing the true potential of embryonic stem cells requires numerous samples and thorough understanding by scientists of how to attain such success. Since the therapeutic potential of embryonic stem cells requires extensive research the subject should be further looked into to increase understanding of how the cells can be used to treat illnesses. Embryonic stem cell research should be legal under the circumstances that the individual providing the embryos has issued consent and that the embryos are obtained from donations from fertility clinics.

In this case, the slippery slope of the acquirement of the stem cells is diminished and thoroughly regulated . In the event that, the embryos are acquired through an intentional abortion the morality of the research is put into question and should not be allowed to proceed. Intentionally growing a fetus only to be used for embryonic stem cells is wrong and is why there needs to be strict rules and regulations as to where research facilities will acquire their samples. Reservations regarding stem cells research is primarily based on religious beliefs and the lack of understanding of the matter.

Under certain religious doctrines Among scientific research it is true that adult stem cells have successfully treated certain diseases and illness in clinical trials; nevertheless, scientific innovations in the medical field is crucial to the ever-growing understanding of the human body . Adult stem cells do not pose such a grand ethical dilemma as much as embryonic stem cells do and is part of the reason why researchers choose not to look into the matter any further. The fear of uncertainty has limited the progression of science by the growing debate of what is morally wrong and right.

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