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OPEN ACCESS ARTICLE
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EMBRYONIC STEM CELLS |
aCentre for Bioethics at Karolinska Institutet and Uppsala University, Department of Public Health and Caring Sciences, Uppsala Science Park, Uppsala, Sweden;
bDepartment of Law, Uppsala University, Uppsala, Sweden;
cWhitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Key Words. Stem cells • Patent • Ethics
Correspondence: Mats G. Hansson, Th.D., B.A., Centre for Bioethics at Karolinska Institutet and Uppsala University, Department of Public Health and Caring Sciences, Uppsala Science Park, SE-751 85 Uppsala, Sweden. Telephone: +46186113576 Fax: +4618506404; e-mail: Mats.Hansson{at}bioethics.uu.se
Received November 1, 2006;
accepted for publication February 18, 2007.
First published online in STEM CELLS EXPRESS March 8, 2007.
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ABSTRACT |
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Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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Biological facts are rarely transferable to moral arguments. However, ethical opinions and policy-making in relevant areas should be consistent with such facts. According to paragraph 7 of Directive 98/44/EC on the legal protection of biotechnical inventions, the European Group on Ethics in Science and New Technologies to the European Commission (EGE) evaluates ethical aspects of biotechnology. The EGE has evaluated the ethical aspects of patenting inventions involving human stem cells [3]. They argue that isolated stem cells, which have not been modified, do not, as products, fulfill the legal requirements to be seen as patentable. In its second report to the Council and European Parliament, the European Commission concludes that it would be premature to come to a definitive conclusion with regard to patentability of inventions relating to stem cells [4]. This article argues that, since isolation of stem cells implies modification, product patents may in some cases be a viable option for patent authorities. Furthermore, the modification in question should be taken into consideration in the assessment of applications to patent a particular method or use involving stem cells or stem cell technology.
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THE EPIGENETIC STATE OF THE GENOME AND ADAPTATION TO GROWTH IN TISSUE CULTURE |
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However, the only "unmodified" human stem cells are those still present in the human body or embryo. Embryonic stem (ES) cells are isolated from in vitro fertilized (IVF) embryos that have been cultured in vitro up to the blastocyst stage. If used for infertility treatment, such embryos are transplanted into the uterus of a woman. If used for the derivation of an ES cell line, the blastocysts are explanted into a special culture medium and cultured in vitro for an extended period of time, generating a novel cell type that is not part of the blastocyst. Already, the act of placing a cell into a culture medium implies modification, hence even a "freshly derived" stem cell has been subjected to modification. The main reason is that isolation of ES cells selects for in vitro survival and proliferation of cells under adverse culture conditions [5]. Thus, the isolation process does not select for pluripotency, just for survival, with pluripotency being a useful side product of the procedure. The result of adaptation to tissue culture is the outgrowth of cells that have no equivalent to cells in the embryo. One consequence of this isolation procedure is that chromatin configurations are different, as are methylation of genes and other epigenetic characteristics [6]. For example, the chromosomes inherited from the mother are epigenetically different from the chromosomes inherited from the father. These differences are established during gametogenesis and are crucial for the correct expression of genes such as imprinted genes. Disturbance of methylation differences between the two alleles of imprinted genes results in loss of imprinting and abnormal development [7]. In normal embryogenesis, the epigenetic differences of the two parental genomes persist, but when placed into a different environment, as in isolation of ES cells, or when the parental genomes of the somatic cells are exposed to the egg cytoplasm, as in somatic cell nuclear transfer, the "epigenetic memory" of the genomes will be erased [5]. The process of ES cell derivation inevitably leads to epigenetic instability [6] and tends to equalize the methylation differences between the parental genomes. This can be manifested in the loss of imprinting (LOI) for genes such as Igf2 that occurs readily in mouse [6] but less frequently in human ES cells [8]. Thus, an ES cell basically represents a cultural artifact that has no equivalent to cells of the embryo. It is worth emphasizing that epigenetic changes are, in principle, reversible in contrast to genetic alterations. However, it would not appear possible to reverse the multiple stochastic epigenetic abnormalities created by in vitro culture of cells to the "normal" epigenetic state that is the consequence of gametogenesis and in vivo development. Similarly, the isolation of adult stem cells requires a stringent selection for proliferation and adaptation to growth in tissue culture and, thus, produces cells that have no counterpart in the normal animal [9, 10].
The brief in vitro culture of explanted mouse embryos has been shown to lead to LOI of sensitive genes such as Igf2 in the blastocyst [11] and to gene expression abnormalities after in utero implantation of the cultured embryos [12]. Although LOI has not been investigated in cultured human embryos, the significantly higher incidence of Beckwith-Wiedemann syndrome in IVF babies [13, 14], an imprinting disorder caused by LOI of Igf2 and other imprinted genes, raises the prospect that the brief in vitro culture of human embryos as part of the infertility treatment may cause epigenetic abnormalities [15]. Does this imply that the act of explanting and culturing an IVF embryo creates a "patentable artifact" as defined above? We believe not and give the following reason. Although the in vitro culture of a human embryo can cause some stochastic epigenetic alterations in the embryo's genome, the cells in the embryo remain competent to generate a baby, although with an increased risk of imprinting disorder. In contrast, the process of ES cell derivation creates a novel cell type that is not present and is not part of the normal blastocyst and that has vastly different molecular and biological characteristics from the cells in the embryo. For example, the global DNA methylation level in the blastocyst is highly reduced as compared with somatic cells [16], whereas that of ES cells is as high as in somatic cells [17]. Although ES cells can contribute to normal development when introduced into a host embryo, they do not have the potential to generate an organism in contrast to the blastocyst from which they were derived. Thus, the derivation of ES cells is a process that leads to a novel cell type with novel characteristics that neither exist in the embryo nor in the fetus.
An isolated stem cell should then be distinguished as something other than the stem cell still existing as part of a human body. This opens a possibility for legal consideration of patenting the method for manipulating the growth conditions but also for patenting an isolated stem cell as a unique result of modifying the cell by placing it in an appropriate medium.
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IN LINE WITH EUROPEAN UNION DIRECTIVE 98/44 |
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COMPATIBLE WITH STRONG VIEWS ON POTENTIALITY |
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The legal argumentation for different national patent policies is complex. However, there seems to be one moral consideration that is common to the policies excluding patentability of hESC. Patentability implies, according to this view, research on embryos or variants thereof that carry the potential of developing into a mature human being, and is therefore wrong. An associated argument is that the research involves destruction of embryos carrying such a potentiality, but we will not go into this aspect here, acknowledging for the sake of the argument that there are embryos that really are "spare" in the sense that they are extra numerous embryos created through IVF and would be destroyed anyway [28].
The potentiality of an entity and its moral implications has been an issue regarding the ethics of embryo research for some time [29]. According to a weak view of potentiality, possibility and probability are seen as necessary conditions for potentiality. The embryo must, according to this view, have a real physical possibility of developing into a mature human being (e.g., through implantation and favorable development conditions), and this development must be probable. If these necessary conditions are not fulfilled, the embryo does not carry more potentiality and, therefore, not more moral weight than a sperm and an egg taken together but kept apart in two different Petri dishes. The underlying moral considerations of the referred patent policies seem, however, to be based on another view, where the potentiality of an entity refers to its intrinsic qualities. We call this the strong view of potentiality. The potentiality of the embryo denotes, according to this view, the inherent capacity or potency to develop into a mature human being. As such, it is worthy of moral consideration or protection, even if external conditions are lacking in order to make this development probable or even possible.
As argued above, the derivation of ES cells is a process that leads to a novel cell type with novel intrinsic qualities that do not exist in the embryo. The derivation process is, furthermore, not reversible. The ES cells do not carry any potentiality, not even in the strong sense, and should therefore be, in principle, patentable. Based on the weak view on potentiality, patentability of hESC should not be controversial. Taking the diversity of moral cultures into consideration, it may be seen as an advantage of our proposal that ES cells may be patentable and policy makers can still honor strong views on the potentiality of a human embryo.
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NOT NECESSARILY LEADING TO BROAD PATENTS |
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The fundamental principle of a patent is to protect reasonable commercial claims and inventive achievements as a means to promote technological development and application of research into different sectors of society. The two WARF patents seem to have violated this principle by granting claims with an unreasonable scope leading to a situation that, in fact, may be detrimental to stem cell research. In analogy to the development in gene patenting, whether the result in terms of an isolated stem cell in a specific culture medium or a propagated stem cell line carries enough novelty, inventive step, and potential for industrial application has to be proven by the researcher. We suggest that the patent authorities may consider them as objects both for product and method patents that fulfill, in principle, the legal requirements for such patents, but that the scope of the patents must be reasonable and well informed by the scientific development and the foreseen effects of a patent on research and other commercial interests. In order not to frustrate research that could advance knowledge regarding the many detailed steps involved, we suggest as a preliminary guideline that patent authorities should take a conservative view regarding the scope of patents with a limitation to the intrinsic qualities of both the patented ES cells and the patented methodologies (i.e., on its potentiality in the strong sense described above).
Product and method patents of ES cells and related technologies may be broadly categorized as related to: (a) isolation of ES cells, (b) derivations of ES cells (through genetic modification or otherwise), (c) methods of culturing ES cells, and (d) methods of using ES cells (differentiation/transplantation). A conservative policy would, for example, imply that claims may be restricted to ES cells deriving from a particular species, and that the scope of potential differentiation should be restricted to derivates of one specified tissue only. The patent should only cover a particular cell line and only specific uses (i.e., differentiation into one specific kind of tissue or a specific kind of transplantation). If the next step in a process (e.g., derivation) is an obvious next step without any need for further invention, this step does not provide the necessary prerequisite for a patent. It should be observed that these are only examples of what a conservative view may imply. It should also be noted that there are two possibilities of limiting patents, on the one hand through restrictions on the area of patentability and on the other through determining the extent of protection for the patent. Due account shall be taken of any element that is equivalent to an element specified in the claims. The closer determination of scope of protection and equivalent elements is, however, a question that must be decided in future infringement trials.
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COMMERCIALIZATION AND CONSENT |
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Secondly, EGE argues in accord with Article 3 of the Charter of Fundamental Rights and with Recital 26 of the 1998 European Union (EU) Patent Directive, which states that "... the person from whose body the material is taken must have had an opportunity of expressing free and informed consent thereto ..." [3]. Such consent based on information about the purpose of research is intrinsic to all regulations of human stem cell research. However, it should be observed that the right to withdraw a previously given consent is limited in relation to stem cell research. The Convention of Biomedicine and Human Rights grants such a right with regard to all kinds of research using human tissue [31]. However, this right does not apply regarding the results of a research study, and since stem cells placed in a culture medium and being viable are results in this sense, the donor has no right to withdraw consent at that point, requiring that the cells should either be destroyed or made unidentifiable.
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CONCLUSION |
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DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST |
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ACKNOWLEDGMENTS |
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REFERENCES |
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This article has been cited by other articles:
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  K. Triller Vrtovec and B. Vrtovec Commentary: Is Totipotency of a Human Cell a Sufficient Reason to Exclude Its Patentability Under the European Law? Stem Cells, December 1, 2007; 25(12): 3026 - 3028. [Abstract] [Full Text] [PDF]
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 A. P. Beltrami, D. Cesselli, N. Bergamin, P. Marcon, S. Rigo, E. Puppato, F. D'Aurizio, R. Verardo, S. Piazza, A. Pignatelli, et al. Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow) Blood, November 1, 2007; 110(9): 3438 - 3446. [Abstract] [Full Text] [PDF]
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Abstract
Introduction