StemCell Therapy

Abstract

Stem cell research offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinsons disease, and myocardial infarction. However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes about the onset of human personhood. The reprogramming of somatic cells to produce induced pluripotent stem cells avoids the ethical problems specific to embryonic stem cell research. In any hSC research, however, difficult dilemmas arise regarding sensitive downstream research, consent to donate materials for hSC research, early clinical trials of hSC therapies, and oversight of hSC research. These ethical and policy issues need to be discussed along with scientific challenges to ensure that stem cell research is carried out in an ethically appropriate manner. This article provides a critical analysis of these issues and how they are addressed in current policies.

I.

Introduction

II.

Multipotent Stem Cells

A.

Cord blood stem cells

B.

Adult blood stem cells

III.

Embryonic Stem Cell Research

A.

Existing embryonic stem cell lines

B.

New embryonic stem cell lines from frozen embryos

C.

Ethical concerns about oocyte donation for research

IV.

Somatic Cell Nuclear Transfer (SCNT)

V.

Fetal Stem Cells

VI.

Induced Pluripotent Stem Cells (iPS Cells)

VII.

Stem Cell Clinical Trials

VIII.

Institutional Oversight of Stem Cell Research

STEM CELL RESEARCH offers great promise for understanding basic mechanisms of human development and differentiation, as well as the hope for new treatments for diseases such as diabetes, spinal cord injury, Parkinsons disease, and myocardial infarction (1). Pluripotent stem cells perpetuate themselves in culture and can differentiate into all types of specialized cells. Scientists plan to differentiate pluripotent cells into specialized cells that could be used for transplantation.

However, human stem cell (hSC) research also raises sharp ethical and political controversies. The derivation of pluripotent stem cell lines from oocytes and embryos is fraught with disputes regarding the onset of human personhood and human reproduction. Several other methods of deriving stem cells raise fewer ethical concerns. The reprogramming of somatic cells to produce induced pluripotent stem cells (iPS cells) avoids the ethical problems specific to embryonic stem cells. With any hSC research, however, there are difficult dilemmas, including consent to donate materials for hSC research, early clinical trials of hSC therapies, and oversight of hSC research (2). Table 1 summarizes the ethical issues that arise at different phases of stem cell research.

TABLE 1

Ethical issues at different phases of stem cell research

TABLE 1

Ethical issues at different phases of stem cell research

Adult stem cells and cord blood stem cells do not raise special ethical concerns and are widely used in research and clinical care. However, these cells cannot be expanded in vitro and have not been definitively shown to be pluripotent.

Hematopoietic stem cells from cord blood can be banked and are widely used for allogenic and autologous stem cell transplantation in pediatric hematological diseases as an alternative to bone marrow transplantation.

Adult stem cells occur in many tissues and can differentiate into specialized cells in their tissue of origin and also transdifferentiate into specialized cells characteristic of other tissues. For example, hematopoietic stem cells can differentiate into all three blood cell types as well as into neural stem cells, cardiomyocytes, and liver cells.

Adult stem cells can be isolated through plasmapheresis. They are already used to treat hematological malignancies and to modify the side effects of cancer chemotherapy. Furthermore, autologous stem cells are being used in clinical trials in patients who have suffered myocardial infarction. Their use in several other conditions has not been validated or is experimental, despite some claims to the contrary (3).

Pluripotent stem cell lines can be derived from the inner cell mass of the 5- to 7-d-old blastocyst. However, human embryonic stem cell (hESC) research is ethically and politically controversial because it involves the destruction of human embryos. In the United States, the question of when human life begins has been highly controversial and closely linked to debates over abortion. It is not disputed that embryos have the potential to become human beings; if implanted into a womans uterus at the appropriate hormonal phase, an embryo could implant, develop into a fetus, and become a live-born child.

Some people, however, believe that an embryo is a person with the same moral status as an adult or a live-born child. As a matter of religious faith and moral conviction, they believe that human life begins at conception and that an embryo is therefore a person. According to this view, an embryo has interests and rights that must be respected. From this perspective, taking a blastocyst and removing the inner cell mass to derive an embryonic stem cell line is tantamount to murder (4).

Many other people have a different view of the moral status of the embryo, for example that the embryo becomes a person in a moral sense at a later stage of development than fertilization. Few people, however, believe that the embryo or blastocyst is just a clump of cells that can be used for research without restriction. Many hold a middle ground that the early embryo deserves special respect as a potential human being but that it is acceptable to use it for certain types of research provided there is good scientific justification, careful oversight, and informed consent from the woman or couple for donating the embryo for research (5).

Opposition to hESC research is often associated with opposition to abortion and with the pro-life movement. However, such opposition to stem cell research is not monolithic. A number of pro-life leaders support stem cell research using frozen embryos that remain after a woman or couple has completed infertility treatment and that they have decided not to give to another couple. This view is held, for example, by former First Lady Nancy Reagan and by U.S. Senator Orrin Hatch.

On his Senate website, Sen. Hatch states: The support of embryonic stem cell research is consistent with pro-life, pro-family values.

I believe that human life begins in the womb, not a Petri dish or refrigerator . To me, the morality of the situation dictates that these embryos, which are routinely discarded, be used to improve and save lives. The tragedy would be in not using these embryos to save lives when the alternative is that they would be discarded (6).

In 2001, President Bush, who holds strong pro-life views, allowed federal National Institutes of Health (NIH) funding for stem cell research using embryonic stem cell lines already in existence at the time, while prohibiting NIH funding for the derivation or use of additional embryonic stem cell lines. This policy was a response to a growing sense that hESC research held great promise for understanding and treating degenerative diseases, while still opposing further destruction of human embryos. NIH funding was viewed by many researchers as essential for attracting scientists to make a long-term commitment to study the basic biology of stem cells; without a strong basic science platform, therapeutic breakthroughs would be less likely.

President Bushs rationale for this policy was that the embryos from which these lines were produced had already been destroyed. Allowing research to be carried out on the stem cell lines might allow some good to come out of their destruction. However, using only existing embryonic stem cell lines is scientifically problematic. Originally, the NIH announced that over 60 hESC lines would be acceptable for NIH funding. However, the majority of these lines were not suitable for research; for example, they were not truly pluripotent, had become contaminated, or were not available for shipping. As of January 2009, 22 hESC lines are eligible for NIH funding. However, these lines may not be safe for transplantation into humans, and long-standing lines have been shown to accumulate mutations, including several known to predispose to cancer. In addition, concerns have been raised about the consent process for the derivation of some of these NIH-approved lines (7). The vast majority of scientific experts, including the Director of the NIH under President Bush, believe that a lack of access to new embryonic stem cell lines hinders progress toward stem cell-based transplantation (8). For example, lines from a wider range of donors would allow more patients to receive human leukocyte agent matched stem cell transplants (9).

Currently, federal funds may not be used to derive new embryonic stem cell lines or to work with hESC lines not on the approved NIH list. NIH-funded equipment and laboratory space may not be used for research on nonapproved hESC lines. Both the derivation of new hESC lines and research with hESC lines not approved by NIH may be carried out under nonfederal funding. Because of these restrictions on NIH funding, a number of states have established programs to fund stem cell research, including the derivation of new embryonic stem cell lines. California, for example, has allocated $3 billion over 10 yr to stem cell research.

Under President Obama, it is expected that federal funding will be made available to carry out research with hESC lines not on the NIH list and to derive new hESC lines from frozen embryos donated for research after a woman or couple using in vitro fertilization (IVF) has determined they are no longer needed for reproductive purposes. However, federal funding may not be permitted for creation of embryos expressly for research or for derivation of stem cell lines using somatic cell nuclear transfer (SCNT) (10, 11).

Women and couples who undergo infertility treatment often have frozen embryos remaining after they complete their infertility treatment. The disposition of these frozen embryos is often a difficult decision for them to make (12). Some choose to donate these remaining embryos to research rather than giving them to another couple for reproductive purposes or destroying them. Several ethical concerns come into play when a frozen embryo is donated, including informed consent from the woman or couple donating the embryo, consent from gamete donors involved in the creation of the embryo, and the confidentiality of donor information.

Since the Nuremburg Code, informed consent has been regarded as a basic requirement for research with human subjects. Consent is particularly important in research with human embryos (13). Members of the public and potential donors of embryos for research hold strong and diverse opinions on the matter. Some consider all embryo research to be unacceptable; others only support some forms of research. For instance, a person might consider infertility research acceptable but object to research to derive stem cell lines or research that might lead to patents or commercial products (14). Obtaining informed consent for potential future uses of the donated embryo respects this diversity of views. Additionally, people commonly place special emotional and moral significance on their reproductive materials, compared with other tissues (15).

In the United States, federal regulations on research permit a waiver of informed consent for the research use of deidentified biological materials that cannot be linked to donors (16). Thus, logistically it would be possible to carry out embryo and stem cell research on deidentified materials without consent. For example, during IVF procedures, oocytes that fail to fertilize or embryos that fail to develop sufficiently to be implanted are ordinarily discarded. These materials could be deidentified and then used by researchers. Furthermore, if infertility patients have frozen embryos remaining after they complete treatment, they are routinely contacted by the IVF program to decide whether they want to continue to store the embryos (and to pay freezer storage fees), to donate them to another infertile woman or couple, or to discard them. If a patient chooses to discard the embryos, it would be possible to instead remove identifiers and use them for research. Still another possibility involves frozen embryos from patients who do not respond to requests to make a decision regarding the disposition of frozen embryos. Some IVF practices have a policy to discard such embryos and inform patients of this policy when they give consent for the IVF procedures. Again, rather than discard such frozen embryos, it is logistically feasible to deidentify them and give them to researchers.

However, the ethical justifications for allowing deidentified biological materials to be used for research without consent do not always hold for embryo research (13). For example, one rationale for allowing the use of deidentified materials is that the ethical risks are very low; there can be no breach of confidentiality, which is the main concern in this type of research. A second rationale is that people would not object to having their materials used in such a manner if they were asked. However, this assumption does not necessarily hold in the context of embryo research. A 2007 study found that 49% of women with frozen embryos would be willing to donate them for research (12). Such donors might be offended or feel wronged if their frozen embryos were used for research that they did not consent to. Deidentifying the materials would not address their concerns.

Frozen embryos may be created with sperm or oocytes from donors who do not participate any further in assisted reproduction or childrearing. Some people argue that consent from gamete donors is not required for embryo research because they have ceded their right to direct further usage of their gametes to the artificial reproductive technology (ART) patients. However, gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. In one study, 25% of women who donated oocytes for infertility treatment did not want the embryos created to be used for research (17). This percentage is not unexpected because reproductive materials have special significance, and many people in the United States oppose embryo research. Little is known about the wishes of sperm donors concerning research.

There are substantial practical differences between obtaining consent for embryo research from oocyte donors and from sperm donors. ART clinics can readily discuss donation for research with oocyte donors during visits for oocyte stimulation and retrieval. However, most ART clinics obtain donor sperm from sperm banks and generally have no direct contact with the donors. Furthermore, sperm is often donated anonymously to sperm banks, with strict confidentiality provisions.

As a matter of respect for gamete donors, their wishes regarding stem cell derivation should be determined and respected (13). Gamete donors who are willing to help women and couples bear children may object to the use of their genetic materials for research. Specific consent for stem cell research from both embryo and gamete donors was recommended by the National Academy of Sciences 2005 Guidelines for Human Embryonic Stem Cell Research and has been adopted by the California Institute for Regenerative Medicine (CIRM), the state agency funding stem cell research (18, 19). This consent requirement need not imply that embryos are people or that gametes or embryos are research subjects.

Confidentiality must be carefully protected in embryo and hESC research because breaches of confidentiality might subject donors to unwanted publicity or even harassment by opponents of hESC research (20). Although identifying information about donors must be retained in case of audits by the Food and Drug Administration as part of the approval process for new therapies, concerns about confidentiality may deter some donors from agreeing to be recontacted.

Recently, confidentiality of personal health care information has been violated through deliberate breaches by staff, through break-ins by computer hackers, and through loss or theft of laptop computers. Files containing the identities of persons whose gametes or embryos were used to derive hESC lines should be protected through heightened security measures (20). Any computer storing such files should be locked in a secure room and password-protected, with access limited to a minimum number of individuals on a strict need-to-know basis. Entry to the computer storage room should also be restricted by means of a card-key, or equivalent system, that records each entry. Audit trails of access to the information should be routinely monitored for inappropriate access. The files with identifiers should be copy-protected and double encrypted, with one of the keys held by a high-ranking institutional official who is not involved in stem cell research. The computer storing these data should not be connected to the Internet. To protect information from subpoena, investigators should obtain a federal Certificate of Confidentiality. Human factors in breaches of confidentiality should also be considered. Personnel who have access to these identifiers might receive additional background checks, interviews, and training. The personnel responsible for maintaining this confidential database and contacting any donor should not be part of any research team.

hESC research using fresh oocytes donated for research raises several additional ethical concerns as well, as we next discuss (21).

Concerns about oocyte donation specifically for research are particularly serious in the wake of the Hwang scandal in South Korea, in which widely hailed claims of deriving human SCNT lines were fabricated. In addition to scientific fraud, the scandal involved inappropriate payments to oocyte donors, serious deficiencies in the informed consent process, undue influence on staff and junior scientists to serve as donors, and an unacceptably high incidence of medical complications from oocyte donation (2224). In California, some legislators and members of the public have charged that infertility clinics downplay the risks of oocyte donation (19). CIRM has put in place several protections for women donating oocytes in state-funded stem cell research.

The medical risks of oocyte retrieval include ovarian hyperstimulation syndrome, bleeding, infection, and complications of anesthesia (25). These risks may be minimized by the exclusion of donors at high-risk for these complications, careful monitoring of the number of developing follicles, and adjusting the dose of human chorionic gonadotropin administered to induce ovulation or canceling the cycle (25).

Because severe hyperovulation syndrome may require hospitalization or surgery, women donating oocytes for research should be protected against the costs of complications of hormonal stimulation and oocyte retrieval (19). The United States does not have universal health insurance. As a matter of fairness, women who undergo an invasive procedure for the benefit of science and who are not receiving payment beyond expenses should not bear any costs for the treatment of complications. Even if a woman has health insurance, copayments and deductibles might be substantial, and if she later applied for individual-rated health insurance, her premiums might be prohibitive. Compensation for research injuries has been recommended by several U.S. panels (26) but has not been adopted because of difficulties calculating long-term actuarial risk and assessing intervening factors that could contribute to or cause adverse events.

Requiring free care for short-term complications of oocyte donation is feasible. In California, research institutions must ensure free treatment to oocyte donors for direct and proximate medical complications of oocyte retrieval in state-funded research. The term direct and proximate is a legal concept to determine how closely an injury needs to be connected to an event or condition to assign responsibility for the injury to the person who carried out the event or created the condition. Commercial insurance policies are available to cover short-term complications of oocyte retrieval. CIRM allows state stem cell grants to cover the cost of such insurance. The rationale for making research institutions responsible for treatment is that they are in a better position than individual researchers to identify insurance policies and would have an incentive to consider extending such coverage to other research injuries.

If women in infertility treatment share oocytes with researcherseither their own oocytes or those from an oocyte donortheir prospect of reproductive success may be compromised because fewer oocytes are available for reproductive purposes (21). In this situation, the physician carrying out oocyte retrieval and infertility care should give priority to the reproductive needs of the patient in IVF. The highest quality oocytes should be used for reproductive purposes (21).

As discussed in Section B. 2, in IVF programs some oocytes fail to fertilize, and some embryos fail to develop sufficiently to be implanted. Such materials may be donated to researchers. To protect the reproductive interests of donors, several safeguards should be in place (20). For the donation of fresh embryos for research, the determination by the embryologist that an embryo is not suitable for implantation and therefore should be discarded is a matter of judgment. Similarly, the determination that an oocyte has failed to fertilize and thus cannot be used for reproduction is a judgment call. To avoid any conflict of interest, the embryologist should not know whether a woman has agreed to research donation and also should receive no funding from grants associated with the research. Furthermore, the treating infertility physicians should not know whether or not their patients agree to donate materials for research.

Many jurisdictions have conflicting policies about payment to oocyte donors. Reimbursement to oocyte donors for out-of-pocket expenses presents no ethical problems because donors gain no financial advantage from participating in research. However, payment to oocyte donors in excess of reasonable out-of-pocket expenses is controversial, and jurisdictions have conflicting policies that may also be internally inconsistent (27, 28).

Good arguments can be made both for and against paying donors of research oocytes more than their expenses (29). On the one hand, some object that such payments induce women to undertake excessive risks, particularly poorly educated women who have limited options for employment, as occurred in the Hwang scandal. Such concerns about undue influence, however, may be addressed without banning payment. For example, participants could be asked questions to ensure that they understood key features of the study and that they felt they had a choice regarding participation (19). Also, careful monitoring and adjustment of hormone doses can minimize the risks associated with oocyte donation (25). A further objection is that paying women who provide research oocytes undermines human dignity because human biological materials and intimate relationships are devalued if these materials are bought and sold like commodities (14, 30).

On the other hand, some contend that it is unfair to ban payments to donors of research oocytes, while allowing women to receive thousands of U.S. dollars to undergo the same procedures to provide oocytes for infertility treatment (29). Moreover, healthy volunteers, both men and women, are paid to undergo other invasive research procedures, such as liver biopsy, for research purposes. Furthermore, bans on payment for oocyte donation for research have been criticized as paternalistic, denying women the authority to make decisions for themselves (31). On a pragmatic level, without such payment, it is very difficult to recruit oocyte donors for research.

In California, CIRM has instituted heightened requirements for informed consent for oocyte donation for research (19). The CIRM regulations go beyond requirements for disclosure of information to oocyte donors (19). The major ethical issue is whether donors appreciate key information about oocyte donation, not simply whether the information has been disclosed to them or not. As discussed previously, in other research settings, research participants often fail to understand the information in detailed consent forms (32). CIRM thus reasons that disclosure, while necessary, is not sufficient to guarantee informed consent. In CIRM-funded research, oocyte donors must be asked questions to ensure that they comprehend the key features of the research (19). Evaluating comprehension is feasible because it has been carried out in other research contexts, such as in HIV prevention trials in the developing world (33). According to testimony presented to CIRM, evaluation of comprehension has also been carried out with respect to oocyte donation for clinical infertility services.

Pluripotent stem cell lines whose nuclear DNA matches a specific person have several scientific advantages. Stem cell lines matched to persons with specific diseases can serve as in vitro models of diseases, elucidate the pathophysiology of diseases, and screen potential new therapies. Lines matched to specific individuals also offer the promise of personalized autologous stem cell transplantation.

One approach to creating such lines is through SCNT, the technique that produced Dolly the sheep. In SCNT, reprogramming is achieved after transferring nuclear DNA from a donor cell into an oocyte from which the nucleus has been removed. However, creating human SCNT stem cell lines has not only been scientifically impossible to date but is also ethically controversial (34, 35).

Some people who object to SCNT believe that creating embryos with the intention of using them for research and destroying them in that process violates respect for nascent human life. Even those who support deriving stem cell lines from frozen embryos that would otherwise be discarded sometimes reject the intentional creation of embryos for research. In rebuttal, however, some argue that pluripotent entities created through SCNT are biologically and ethically distinct from embryos (36).

There are several compelling objections to using SCNT for human reproduction. First, because of errors during reprogramming of genetic material, cloned animal embryos fail to activate key embryonic genes, and newborn clones misexpress hundreds of genes (37, 38). The risk of severe congenital defects would be prohibitively high in humans. Second, even if SCNT could be carried out safely in humans, some object that it violates human dignity and undermines traditional, fundamental moral, religious, and cultural values (34). A cloned child would have only one genetic parent and would be the genetic twin of that parent. In this view, cloning would lead children to be regarded more as products of a designed manufacturing process than gifts whom their parents are prepared to accept as they are. Furthermore, cloning would violate the natural boundaries between generations (34). For these reasons, cloning for reproductive purposes is widely considered morally wrong and is illegal in a number of states. Moreover, some people argue that because the technique of SCNT can be used for reproduction, its development and use for basic research should be banned.

Because of the shortage of human oocytes for SCNT research, some scientists wish to use nonhuman oocytes to derive lines using human nuclear DNA. These so-called cytoplasmic hybrid embryos raise a number of ethical concerns. Some opponents fear the creation of chimerasmythical beasts that appear part human and part animal and have characteristics of both humans and animals (39). Opponents may feel deep moral unease or repugnance, without articulating their concerns in more specific terms. Some people view such hybrid embryos as contrary to a moral order embodied in the natural world and in natural law. In this view, each species has a particular moral purpose or goal, which mankind should not try to change. Others view such research as an inappropriate crossing of species barriers, which should be an immutable part of natural design. Finally, some are concerned that there may be attempts to implant these embryos for reproductive purposes.

In rebuttal, supporters of such research point out that the biological definitions of species are not natural and immutable but empirical and pragmatic (4042). Animal-animal hybrids of various sorts, such as the mule, exist and are not considered morally objectionable. Moreover, in medical research, human cells are commonly injected into nonhuman animals and incorporated into their functioning tissue. Indeed, this is widely done in research with all types of stem cells to demonstrate that cells are pluripotent or have differentiated into the desired type of cell. In addition, some concerns can be addressed through strict oversight (40), for example prohibiting reproductive uses of these embryos and limiting in vitro development to 14 d or the development of the primitive streak, limits that are widely accepted for other hESC research. Finally, some people regard repugnance per se an unconvincing guide to ethical judgments. People disagree over what is repugnant, and their views might change over time. Blood transfusion and cadaveric organ transplantation were originally viewed as repugnant but are now widely accepted practices. Furthermore, after public discussion and education, many people overcome their initial concerns.

Pluripotent stem cells can be derived from fetal tissue after abortion. However, use of fetal tissue is ethically controversial because it is associated with abortion, which many people object to. Under federal regulations, research with fetal tissue is permitted provided that the donation of tissue for research is considered only after the decision to terminate pregnancy has been made. This requirement minimizes the possibility that a womans decision to terminate pregnancy might be influenced by the prospect of contributing tissue to research. Currently there is a phase 1 clinical trial in Battens disease, a lethal degenerative disease affecting children, using neural stem cells derived from fetal tissue (43, 44).

Somatic cells can be reprogrammed to form pluripotent stem cells (45, 46), called induced pluripotential stem cells (iPS cells). These iPS cell lines will have DNA matching that of the somatic cell donors and will be useful as disease models and potentially for allogenic transplantation.

Early iPS cell lines were derived by inserting genes encoding for transcription factors, using retroviral vectors. Researchers have been trying to eliminate safety concerns about inserting oncogenes and insertional mutagenesis. Reprogramming has been successfully accomplished without known oncogenes and using adenovirus vectors rather than retrovirus vectors. A further step was the recent demonstration that human embryonic fibroblasts can be reprogrammed to a pluripotent state using a plasmid with a peptide-linked reprogramming cassette (47, 48). Not only was reprogramming accomplished without using a virus, but the transgene can be removed after reprogramming is accomplished. The ultimate goal is to induce pluripotentiality without genetic manipulation. Because of unresolved problems with iPS cells, which currently preclude their use for cell-based therapies, most scientists urge continued research with hESC (49).

iPS cells avoid the heated debates over the ethics of embryonic stem cell research because embryos or oocytes are not used. Furthermore, because a skin biopsy to obtain somatic cells is relatively noninvasive, there are fewer concerns about risks to donors compared with oocyte donation. The Presidents Council on Bioethics called iPS cells ethically unproblematic and acceptable for use in humans (39). Neither the donation of materials to derive iPS cells nor their derivation raises special ethical issues.

Some potential downstream uses of iPS cell derivatives may be so sensitive as to call into question whether the original somatic cell donors would have agreed to such uses (50). iPS cells will be shared widely among researchers who will carry out a variety of studies with iPS cells and derivatives, using common and well-accepted scientific practices, such as:

Genetic modifications of cells

Injection of derived cells into nonhuman animals to demonstrate their function, including the injection into the brains of nonhuman animals.

Large-scale genome sequencing

Sharing cell lines with other researchers, with appropriate confidentiality protections, and

Patenting scientific discoveries and developing commercial tests and therapies, with no sharing of royalties with donors (51).

These standard research techniques are widely used in other types of basic research, including research with stem cells from other sources. Generally, donors of biological materials are not explicitly informed of these research procedures, although such disclosure is now proposed for whole genome sequencing (52, 53).

Such studies are of fundamental importance in stem cell biology, for example to characterize the lines and to demonstrate that they are pluripotent. Large-scale genome sequencing will yield insights about the pathogenesis of disease and identify new targets for therapy. Injection of human stem cells into the brains of nonhuman animals will be required for preclinical testing of cell-based therapies for many conditions, such as Parkinsons disease, Alzheimers disease, and stroke.

However, some downstream research could also raise ethical concerns. For example, large-scale genome sequencing may evoke concerns about privacy and confidentiality. Donors might consider it a violation of privacy if scientists know their future susceptibility to many genetic diseases. Furthermore, it may be possible to reidentify the donor of a deidentified large-scale genome sequence using information in forensic DNA databases or at an Internet company offering personal genomic testing (54, 55). Other donors may object to their cells being injected into animals. For example, they may oppose all animal research, or they may have religious objections to the mixing of human and animal species. The injection of human neural progenitor cells into nonhuman animals has raised ethical concerns about animals developing characteristics considered uniquely human (56, 57). Still other donors may not want cell lines derived from their biological materials to be patented as a step toward developing new tests and therapies. People are unlikely to drop such objections even if the cell lines were deidentified or even if many years had passed since the original donation. Thus there may be a tension between respecting the autonomy of donors and obtaining scientific benefit from research, which can be resolved during the process of obtaining consent for the original donation of materials.

It would be unfortunate if iPS cell lines that turned out to be extremely useful scientifically (for example because of robust growth in tissue culture) could not be used in additional research because the somatic cell donor objected. One approach to avoid this is to preferentially use somatic cells from donors who are willing to allow all such basic stem cell research and to be contacted for future sensitive research that cannot be anticipated at the time of consent (50). Donors could also be offered the option of consenting to additional specific types of sensitive but not fundamental downstream research, such as allogenic transplantation into other humans and reproductive research involving the creation of totipotent entities.

Because these concerns about consent for sensitive downstream research also apply to other types of stem cells, it would be prudent to put in place similar standards for consent to donate materials for derivation of other types of stem cells. However, these concerns are particularly salient for iPS cells because of the widespread perception that these cells raise no serious ethical problems and because they are likely to play an increasing role in stem cell research.

Transplantation of cells derived from pluripotent stem cells offers the promise of effective new treatments. However, such transplantation also involves great uncertainty and the possibility of serious risks. Some stem cell therapies have been shown to be effective and safe, for example hematopoietic stem cell transplants for leukemia and epithelial stem cell-based treatments for burns and corneal disorders (58). However, there are some clinics around the world already exploiting patients hopes by purporting to offer effective stem cell therapies for seriously ill patients, typically for large sums of money, but without credible scientific rationale, transparency, oversight, or patient protections (58). Although supporting medical innovation under very limited circumstances, the International Society for Stem Cell Research has decried such use of unproven hSC transplantation.

These clinical trials should follow ethical principles that guide all clinical research, including appropriate balance of risks and benefits and informed, voluntary consent. Additional ethical requirements are also warranted to strengthen trial design, coordinate scientific and ethics review, verify that participants understand key features of the trial, and ensure publication of negative findings (59). These measures are appropriate because of the highly innovative nature of the intervention, limited experience in humans, and the high hopes of patients who have no effective treatments.

The risks of innovative stem cell-based interventions include tumor formation, immunological reactions, unexpected behavior of the cells, and unknown long-term health effects (58). Evidence of safety and proof of principle should be established through appropriate preclinical studies in relevant animal models or through human studies of similar cell-based interventions. Requirements for proof of principle and safety should be higher if cells have been manipulated extensively in vitro or have been derived from pluripotent stem cells (58).

Even with these safeguards, however, because of the highly innovative nature of the intervention and limited experience in humans, unanticipated serious adverse events may occur. In older clinical trials of transplantation of fetal dopaminergic neurons into persons with Parkinsons disease, transplanted cells failed to improve clinical outcomes (60, 61). Indeed, about 15% of subjects receiving transplantation late developed disabling dyskinesias, with some needing ablative surgery to relieve these adverse events (60, 61). Although the transplanted cells localized to the target areas of the brain, engrafted, and functioned to produce the intended neurotransmitters, appropriately regulated physiological function was not achieved. Participants in phase I trials may not thoroughly understand the possibility that hESC transplantation might make their condition worse.

Problems with informed consent are well documented in phase I clinical trials. Participants in cancer clinical trials commonly expect that they will benefit personally from the trial, although the primary purpose of phase I trials is to test safety rather than efficacy (62). This tendency to view clinical research as providing personal benefit has been termed the therapeutic misconception (32, 63). Analyses of cancer clinical trials reveal that the information in consent forms generally is adequate. However, in early phase I gene transfer clinical trials, researchers descriptions of the direct benefit to participants commonly were vague, ambiguous, and indeterminate (64).

Participants in phase I stem cell-based clinical trials might overestimate their benefits and underestimate the risks. The scientific rationale for hSC transplantation and preclinical results may seem compelling. In addition, highly optimistic press coverage might reinforce unrealistic hopes.

Several measures may enhance informed consent in early stem cell-based clinical trials (59). First, researchers should describe the risks and prospective benefits in a realistic manner. Researchers need to communicate the distinction between the long-term hope for effective treatments and the uncertainty inherent in any phase I trial. Participants in phase I studies need to understand that the intervention has never been tried before in humans for the specific condition, that researchers do not know whether it will work as hoped, and that the great majority of participants in phase I studies do not receive a direct benefit.

Second, investigators in hESC clinical trials should discuss a broader range of information with potential participants than in other clinical trials. The doctrine of informed consent requires researchers to discuss with potential participants information that is pertinent to their decision to volunteer for the clinical trial (65). Generally, the relevant information concerns the nature of the intervention being studied and the risks and prospective benefits. However, in hESC transplantation, nonmedical issues may be prominent or even decisive for some participants. Individuals who regard the embryo as having the moral status of a person would likely have strong objections to receiving hESC transplants. Although this intervention might benefit them medically, such individuals might regard it as complicit with an immoral action. Thus researchers in clinical trials of hESC transplantation should inform eligible participants that transplanted materials originated from human embryos.

Third, and most important, researchers should verify that participants have a realistic understanding of the clinical trial (59). The crucial ethical issue about informed consent is not what researchers disclose in consent forms or discussions, but rather what the participants in clinical trials understand. In other contexts, some researchers have ensured that participants understand the key features of the trial by assessing their comprehension. In HIV clinical trials in developing countries, where it has been alleged that participants did not understand the trial, many researchers are now testing each participant to be sure he or she understands the essential features of the research (33). Such direct assessment of participants understanding of the study has been recommended more broadly in contexts in which misunderstandings are likely (26). We urge that such tests of comprehension be carried out in phase I trials of hSC transplantation (58, 59).

Careful attention to consent in highly innovative clinical trials might prevent controversies later. In early clinical trials of organ transplantation, the implantable totally artificial heart, and gene transfer, the occurrence of serious adverse events led to allegations that study participants had not truly understood the nature of the research (6668). The resulting ethical controversies brought about negative publicity and delays in subsequent clinical trials.

Human stem cell research raises some ethical issues that are beyond the mission of institutional review boards (IRBs) to protect human subjects, as well as the expertise of IRB members. There should be a sound scientific justification for using human oocytes and embryos to derive new human stem cell lines. However, IRBs usually do not carry out in-depth scientific review. Some ethical issues in hESC research do not involve human subjects protection, for example the concern that transplanting human stem cells into nonhuman animals might result in characteristics that are regarded as uniquely human.

See more here:
Ethical Issues in Stem Cell Research | Endocrine Reviews ...

An embryo is an early stage of development of a multicellular diploid eukaryotic organism. In general, in organisms that reproduce sexually, an embryo develops from a zygote, the single cell resulting from the fertilization of the female egg cell by the male sperm cell. The zygote possesses half the DNA from each of its two parents. In plants, animals, and some protists, the zygote will begin to divide by mitosis to produce a multicellular organism. The result of this process is an embryo.

In human pregnancy, a developing fetus is considered as an embryo until the ninth week, fertilization age, or eleventh-week gestational age. After this time the embryo is referred to as a fetus.[1]

First attested in English in the mid-14c., the word embryon derives from Medieval Latin embryo, itself from Greek (embruon), lit. "young one",[2] which is the neuter of (embruos), lit. "growing in",[3] from (en), "in"[4] and (bru), "swell, be full";[5] the proper Latinized form of the Greek term would be embryum.

In animals, the development of the zygote into an embryo proceeds through specific recognizable stages of blastula, gastrula, and organogenesis. The blastula stage typically features a fluid-filled cavity, the blastocoel, surrounded by a sphere or sheet of cells, also called blastomeres. In a placental mammal, an ovum is fertilized in a fallopian tube through which it travels into the uterus. An embryo is called a fetus at a more advanced stage of development and up until birth or hatching. In humans, this is from the eleventh week of gestation. However, animals which develop in eggs outside the mother's body, are usually referred to as embryos throughout development; e.g. one would refer to a chick embryo, not a "chick fetus", even at later stages.

During gastrulation the cells of the blastula undergo coordinated processes of cell division, invasion, and/or migration to form two (diploblastic) or three (triploblastic) tissue layers. In triploblastic organisms, the three germ layers are called endoderm, ectoderm, and mesoderm. The position and arrangement of the germ layers are highly species-specific, however, depending on the type of embryo produced. In vertebrates, a special population of embryonic cells called the neural crest has been proposed as a "fourth germ layer", and is thought to have been an important novelty in the evolution of head structures.

During organogenesis, molecular and cellular interactions between germ layers, combined with the cells' developmental potential, or competence to respond, prompt the further differentiation of organ-specific cell types.[citation needed] For example, in neurogenesis, a subpopulation of ectoderm cells is set aside to become the brain, spinal cord, and peripheral nerves. Modern developmental biology is extensively probing the molecular basis for every type of organogenesis, including angiogenesis (formation of new blood vessels from pre-existing ones), chondrogenesis (cartilage), myogenesis (muscle), osteogenesis (bone), and many others.

In botany, a seed plant embryo is part of a seed, consisting of precursor tissues for the leaves, stem (see hypocotyl), and root (see radicle), as well as one or more cotyledons. Once the embryo begins to germinategrow out from the seedit is called a seedling (plantlet).

Bryophytes and ferns also produce an embryo, but do not produce seeds. In these plants, the embryo begins its existence attached to the inside of the archegonium on a parental gametophyte from which the egg cell was generated. The inner wall of the archegonium lies in close contact with the "foot" of the developing embryo; this "foot" consists of a bulbous mass of cells at the base of the embryo which may receive nutrition from its parent gametophyte. The structure and development of the rest of the embryo varies by group of plants. As the embryo has expanded beyond the enclosing archegonium, it is no longer termed an embryo.

Embryos are used in various fields of research and in techniques of assisted reproductive technology. An egg may be fertilized in vitro and the resulting embryo may be frozen for later use.The potential of embryonic stem cell research, reproductive cloning, and germline engineering are currently being explored. Prenatal diagnosis or preimplantation diagnosis enables testing embryos for diseases or conditions.

Cryoconservation of animal genetic resources is a practice in which animal germplasms, such as embryos are collected and stored at low temperatures with the intent of conserving the genetic material.

The embryos of Arabidopsis thaliana have been used as a model to understand gene activation, patterning, and organogenesis of seed plants.[6]

In regards to research using human embryos, the ethics and legalities of this application continue to be debated.[7][8][9]

Researchers from MERLN Institute and the Hubrecht Institute in the Netherlands managed to grow samples of synthetic rodent embryoids, combining certain types of stem cells. This method may assist scientists to understand the very first moments of the process of the birth of a new life, which, in turn, can lead to the emergence of new effective methods to combat infertility and other genetic diseases.[10]

Fossilized animal embryos are known from the Precambrian, and are found in great numbers during the Cambrian period. Even fossilized dinosaur embryos have been discovered.[11]

Some embryos do not survive to the next stage of development. When this happens naturally, it is called spontaneous abortion or miscarriage.[12] There are many reasons why this may occur. The most common natural cause of miscarriage is chromosomal abnormality in animals[13] or genetic load in plants.[14]

In species which produce multiple embryos at the same time, miscarriage or abortion of some embryos can provide the remaining embryos with a greater share of maternal resources. This can also disturb the pregnancy, causing harm to the second embryo. Genetic strains which miscarry their embryos are the source of commercial seedless fruits.

Abortion is the process of artificially (non-naturally) removing the embryo through deliberate pharmaceutical or surgical methods.

Read more:
Embryo - Wikipedia

Jul 30, 2019|Fred Greguras

My wife has had osteoarthritis, sometimes called wear-and-tear arthritis, in both of her knees since 2011. She first saw an advertisement for stem cell treatment in 2012 and continued to do research on the treatment. Late in 2018, after ultrasounds on her knees and consultation with several doctors and clinics in California and Colorado, she decided to have stem cell therapy that could regenerate the meniscus cartilage of her knees. Such therapy is a minimally invasive procedure that has the potential to slow the progress of the arthritic damage, repair joint cartilage and avoid or delay invasive knee replacement surgery.Such therapy can help the body repair itself naturally.

We thought it was best to act now before her knees worsened since the earlier the stem cell treatment began, the greater the chances for a successful outcome there would be. The present lack of health insurance coverage was considered, but the treatment cost was reasonable given the potential to avoid more invasive surgery and the timing of treatment. Most insurance plans, including Medicare, define the procedure as experimental and investigational and do not cover the therapy.

Based on her research, my wife selected Dr. Jason Glowney of Boulder Biologics to perform the treatment. Her treatment took place in the second week of January, 2019, as an outpatient at a hospital in Boulder, Colorado. The procedure was completed in under four hours. She was injected with her own stem cells (called an autologous donation), reducing the risk of immune rejection and other complications.

The medical team used ultrasound to identify the best sites for injection into the damaged tissue of her knees. The same needle remained in each knee site during the treatment, but the injections in each step described below were all done with separate syringes in sequence. There was no mixture of any of the multiple components in a single syringe.

The doctor gave her light oral sedationto help her relax for the procedure and used local anesthetic at the points of cell harvest and injection. No general anesthetic was administered. The procedure began with a harvest of platelet-rich plasma (PRP) from her blood. Her blood was quickly processed through a centrifuge to separate the blood and concentrate the platelets in the plasma, which was then injected to fertilize the knee sites to enhance cell growth. The concentrated platelets contain growth factors along with bioactive proteins that help initiate and stimulate tissue repair and regeneration. (In late May, 2019, she had another PRP injection to stimulate and enhance the growth of the stem cells.)

The next step in the procedure was to harvest her bone marrow, centrifuge it into an injectable volume of aspirate concentrate and then inject the concentrate in both knees. The bone marrow aspirate contains stem cells that can help regenerate bone and cartilage.

The adipose (fat-derived) stem cells used in the next step compliment the bone marrow stem cells. The adipose cells were harvested by a minimally invasive liposuction procedure, centrifuged to isolate the cells and then injected in both knees. The fat on our bodies can be a rich source of stem cells.

Hundreds of thousands of cells were harvested and injected in each step in order to have an adequate number of stem cells for the treatment. The stem cells decide whether to differentiate into bone, meniscus or other cartilage or to simply renew.

My wife was given antibiotic (doxycycline) tablets to take at the end of the procedure and, for a period thereafter, to assist the differentiation process and to help decrease cartilage degradation.

As discussed in more detail below, the doctors procedure was designed to involve only simple human cellular and tissue products from the same patient and not to be a new biological product or drug which requires FDA approval. The procedure would be a new biological product or drug requiring FDA approval if there had been more than minimal manipulation of each component part. Even a mixture of a patients own stem cells and an antibiotic administered from the same syringe would be deemed a new biological product or drug by the FDA.

The doctor gave my wife guidelines for physical activity and medications during the post-injection period. The guidelines were designed to promote the growth of the stem cells to regenerate tissue. The cells are fragile, and she had to be careful not to cause too much stress or shearing on them which could impede growth. Her pain was intense during the first 24 hours, and she stayed in bed much of the time. She used a walker for about the first week. She started physical therapy about six days after the injections with the doctors approval. The doctor recommended that she not take any anti-inflammatory medications (like ibuprofen or motrin), for six weeks since they could impede the differentiation of the stem cells. The doctor advised her that most patients dont feel any knee improvement for at leastthree weeksand possibly for up to six to eight weeks. If there is no improvement by the six-month point after the injections, then the therapy has not worked.

A self-reporting instrument is used for assessing a patients knee status. The 33 items measured are intended to represent all major indicators of knee status. My wifes measures are all very positive at this six-month point after the procedure. The measurement factors include: (1) knee symptoms such as knee swelling, stiffness and frequency of pain; (2) amount of pain in activities such as walking, standing and going up and down stairs; and (3) degree of difficulty in activities such as walking, bending down and going up and down stairs. Each item is rated on a five-point scale relating to the extent of its occurrence or severity during the past week.

Stem cells are different from other cell types in our bodies because they are capable of renewing (copying) themselves through cell division, sometimes after long periods of inactivity. Stem cells also have the potential to differentiate into other cell types in our body. When a stem cell divides, each new cell has the potential either to remain a stem cell or to differentiate into more specialized cells that form the bodys tissues and organs. In some organs, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, stem cells only divide under special conditions.

There are several types of stem cells that are formed at different times in our lives orcome from different places in our body. Embryonic stem cells(ESCs) exist in the embryo only at the earliest stages of human development. ESCs are pluripotent, meaning they have the potential to differentiate into almost all cell types in the body. There are social and ethical issues relating to the use of ESCs, since harvesting the cells causes the destruction of an embryo. Many countries, including the U.S., have government-imposed restrictions on either ESC research or the production of new ESC lines.

Somatic or adult non-embryonic tissue-specific stem cells (ASCs) exist in specific tissues throughout the body after early human development. The stem cells injected into my wifes knees were ASCs. ASCs are multipotent, meaning they can differentiate into more than one type of specialized cell of the body, but not all types. ASCs are generally limited to differentiating into cell types of their tissue of origin, which can help with the replacement of cells from damaged tissue. ASCs can be an autologous stem cell donation, which is less likely to be rejected.

Amniotic stem cells (AMSCs) exist in the amniotic sac, which surrounds a baby in the uterus and remains until the babys birth. AMSCs are harvested right after the mother gives birth, without harming the baby. Some clinics make exaggerated claims about the therapeutic potential of ASMCs. AMSCs, however, are also multipotent, and the tissues they can differentiate into are substantially the same as stem cells from adipose (fat) and bone marrow. AMSCs exist only for a limited time, but adipose and bone marrow ASCs continue to be produced throughout our lives and can be harvested from the patient seeking therapy.

Some tissues and organs contain small amounts of ASCs whose function is to replace cells from that same tissue that deteriorate over time or are damaged by injury. For example, blood-forming stem cells in bone marrow can differentiate into red blood cells, white blood cells and platelets. However, blood-forming stem cells dont generate liver or lung or brain cells, and stem cells in other tissues and organs dont generate red or white blood cells or platelets.

Pluripotent stem cells have great therapeutic potential but still have major technical issues. Scientists cant control their differentiation into the many types of cells in the body which can result in unwanted tissue such as tumors. Since such stem cells are not from the recipient, they may also lack the compatibility needed to prevent rejection by the immune system.

Over 10 years ago, researchers identified conditions that enabled some specialized ASCs to be reprogrammed genetically back to an ESC-like state. The reprogrammed cells function similarly to ESCs and are called induced pluripotent stem cells (iPSCs). The iPSCs function similarly to ESCs, with the ability to differentiate into almost any cell of the body and to create an unlimited source of cells. iPSCs may ultimately help address the ethical concerns of ESCs and provide new potential for therapy, but there are still technical issues including whether they are actually equivalent to ESCs and the capability to control the differentiation process.

While the U.S. Food and Drug Administration (FDA) moves agonizingly slowly, its priority is human safety which is not the case in many other countries. Some other countries are the Wild West of stem cell therapy and have become medical tourism destinations for high-risk stem cell treatment. The FDA recommends that stem cell therapy is either FDA-approved or is done pursuant to an Investigational New Drug Application (IND), a clinical investigation plan submitted to and permitted to proceed by the FDA.There are many active clinical trials investigating the potential of ASCs listed on the U.S. National Institutes of Healths website.[1] Stem cell products approved by the FDA are listed on its web site.[2] There is no FDA-approved therapy involving the transplantation of ESCs. ESCs must be not be added to an injection, such as PRP, before it goes into a human.

The FDA regulates human tissues intended for transplant under 21 C.F.R. Part 1271: Human Cells, Tissues and Cellular and Tissue-Based Products (HCT/Ps). Cellular and tissue-based therapies are regulated by the Office of Cellular, Tissue and Gene Therapies within the FDA Center for Biologics Evaluation. There are two primary regulatory pathways for these products. Cellular therapy products that meet all the criteria in 21 CFR 1271.10(a) are regulated solely as HCT/Ps and are not required to be licensed, approved or cleared by the FDA. These products are often referred to as 361 products because they are regulated solely under Section 361 of the Public Health Service Act (PHSA).[3]The regulatory purpose for such products is to prevent the introduction, transmission and spread of communicable diseases.

If a cellular therapy product does not meet all the criteria in 21 CFR 1271.10(a), it is regulated as a drug, device and/or biological product under the Federal Food, Drug and Cosmetic Act (FDCA)[4] and Section 351 of the PHSA (a 351 product). The FDA requires premarket approval for such a product. The criteria that determine whether a product is a Section 361 HCT/P or a Section 351 biological product include, primarily, whether a product has been minimally manipulated and is intended for homologous use. Stem cell therapies generally do not satisfy these criteria and therefore are usually regulated as Section 351 products.

In the 2014 decision, United States of America v. Regenerative Sciences, LLC,[5] the court held that a mixture of autologous ASCs and other components was a 351 product and subject to FDA approval. Regenerative Sciences, LLC argued that its process did not create a mixture but only expanded the patients own cells and, therefore, was a simple 361 product which does not require FDA approval. The FDAs position is that any process involving human cellular and tissue products that includes culturing, expansion and added growth components or antibiotics requires FDA approval as a biological product or new drug because the process constitutes significant manipulation.

The FDA alleged that the product was a 351 product for failure to comply with its minimal manipulation provisions and because the resulting stem cells were not intended for homologous use. Homologous use means that a human cellular or tissue product is used clinically in a manner that is essentially the same as the natural function. The homologous use definition is strictly interpreted by the FDA, so that most innovative ways to use stem cells to potentially treat patients would be through non-homologous usage. The FDA will generally define even modestly different uses as non-homologous.

There are many clinics offering stem cell therapy in the U.S., some which carefully follow the law and others which do not. The FDA has only has brought a small number of enforcement actions because of resource limitations and proof concerns. Enforcement usually occurs in high-profile situations where a patient has died or is severely harmed.

The two important types of intellectual property protection relating to stem cell therapy are trade secret and patent protection. For example, the cell harvesting techniques and settings for the centrifuge processing in each step in my wifes treatment can be protected as trade secret know-how. The culturing and cocktails of growth factors and/or other components in the Regenerative Sciences, LLC case are another example.

There are many patents registered with the USPTO that contain the term stem cell, but recently, many human stem-based inventions have been rejected for not being eligible patentable subject matter. Patent-eligible subject matter is defined in 35 U.S.C. Section 101 as: Whoever invents or discovers any new and useful process, machine, manufacture or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. There are three exceptions to subject matter eligibility: laws of nature, physical phenomena and abstract ideas.[6] The laws of nature exception has been the basis for rejection of patent eligibility for certain stem cell-related inventions.

There were two important court decisions in 1977 and 1980 relating to patent protection eligibility for the biotechnology industry.[7] The USPTO issued many stem cell patents following these decisions.

Several Supreme Court decisions in the past 10 years, however, have narrowed the scope of patent-eligible subject matter under Section 101.[8] In the Mayo decision, the Court held the invention was not patentable, stating that it effectively claimed the underlying laws of nature. The Court held that a claim that encompasses the use of a natural law must also include additional elements, sometimes referred to as an inventive concept, sufficient to ensure that the patent amounts to significantly morethan a patent upon the natural law itself.

The scope of patent-eligible subject matter was further narrowed in the Myriaddecision, which held that a naturally occurring DNA segment is a product of nature and not eligible for patent protection merely because it had been isolated. The Court looked for markedly different characteristics from any found in nature of the isolated gene to determine patent eligibility. The changes resulting from isolation of a gene sequence were considered incidental and not enough to make the isolated gene markedly different.

Three recent decisions in the Federal Circuit indicate that method-of-treatment claims that may involve a law of nature are patent-eligible.[9] Each of the patents required an affirmative treatment step. The decisions seem to hold that a patent directed to detecting a condition in a patient is not Section 101-eligible under Mayo, while a patent directed to using that detection to change some aspect of the patient is eligible. The patent may have been based upon the inventors discovery of a law of nature but the patent did not simply claim that law of nature. Rather, it was directed to a specific method of treatment.

The United States Patent and Trademark Office (USPTO) has published guidelines for patent examiners on how to analyze a claim which includes a nature-based product for patent eligibility.[10] Claims are to be examined for an inventiveness that has markedly different characteristics from naturally occurring products. Patent eligibility for a natural product is to be determined primarily by whether the claimed product possesses any structural, functional and/or other properties that represent markedly different characteristics from the natural counterpart. If the claim includes a nature-based product that has markedly different characteristics, then the claim is not within the product of nature exception. On the other hand, if the claim includes a nature-based product that does not have markedly different characteristics from its naturally occurring counterpart in its natural state, then the claim is within the product of nature exception and is not eligible for patent protection.[11]

The first step in the analysis is to select the counterpart(s) to compare to the nature-based product. The second step is to identify characteristics to compare, since the analysis is based on comparing the characteristics of the claimed nature-based product and its counterpart. Characteristics can be expressed as the nature-based products structure, function and/or other properties, and are evaluated on a case-by-case basis. The final step is to compare the characteristics of the claimed nature-based product to the characteristics of its naturally occurring counterpart in its natural state to determine if the characteristics of the claimed product are markedly different. If there is a change in at least one characteristic resulting from, or produced by, the patent applicants efforts or influences, then the change will generally be found to be a markedly different characteristic.

My wife was provided with disclosures from the doctors office and requested to sign a number of consents and waivers as a condition of receiving therapy. One of the waivers was a no assurance of successful treatment agreement.

State laws protecting consumers against deceptive advertising are applicable to representations about the effectiveness of stem cell treatment. Several state legislatures have debated additional protections for consumers relating to such treatment. California enacted a consumer protection law in late 2017 that requires clinics offering stem cell treatments to disclose if the treatment is not approved by the FDA.

The Federal Trade Commission (FTC) and FDA are pursuing enforcement actions in selected cases that may cause stem cell clinics to be more careful about their representations and activity. In late 2018, the FTC settled charges with a California-based physician and his businesses of deceptively advertising that amniotic stem cell therapy can treat serious diseases.[12] The settlement prohibits the defendants from making any health claims in the future unless the claims are true and supported by competent and reliable scientific evidence. This was the first enforcement action brought by the FTC against a stem cell clinic.

In early June, 2019, a federal judge granted the FDA an injunction to prevent the U.S. Stem Cell Clinic (based in Florida) from offering treatments using adipose stem cells injected into the spinal cords of patients to treat Parkinsons disease, chronic obstructive pulmonary disease and other serious conditions.[13] The court held that the defendants misbranded the possible therapeutic effects. The court also determined the clinic failed to prevent microbiological contamination of products which put patients at risk for infections.

As indicated, the status measures for my wifes knees are all very positive six months after the procedure. She is glad she tried it. I would try the therapy if I have problems with my knees.

The FDA will continue to move slowly to approve stem cell therapies since its priority is human safety. Some other countries have become medical tourism destinations for high-risk stem cell treatment. Many of the claims of such foreign clinics and of some clinics in the U.S. are medically unproven. The FDA and other regulators will continue to bring enforcement actions based on the severity of patient risk and available resources. Obtaining patent protection for stem cell-related inventions is challenging because of the subject matter eligibility issue under Section 101. The recent method-of-treatment decisions in the Federal Circuit may provide a helpful eligibility precedent for some inventions.

[1] See the NIHs website.

[2] See the Approved Cellular and Gene Therapy Products page on the FDAs website.

[3]42 U.S.C.(The Public Health and Welfare), Chapter 6A (Public Health Service).

[4] 21 U.S.C.

[5] 741 F.3d 1314 (D.C. Cir. 2014)

[6] Diamond v. Diehr, 450 U.S. 175 (1981).

[7] Diamond v. Chakrabarty, 447 U.S. 303 (1980); In re Bergy, 563 F.2d 1031 (1977)

[8] Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012); Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S.576 (2013).

[9] SeeVanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals International Ltd.,887 F.3d 1117 (Fed. Cir. 2018) andNatural Alternatives International v. Creative Compounds, LLC, 2019 WL 1216226 (Fed. Cir. Mar. 15, 2019);Endo Pharmaceuticals Inc. v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2019)

[10] See the 2106 Patent Subject Matter Eligibility [R-08.2017] page on the USPTOs website. The USPTOs Revised Patent Subject Matter Eligibility Guidance published in January, 2019, does not appear to add any guidance on claims including a natural product.

[11] A process claim is generally not subject to the markedly different analysis for nature-based products used in the process. The analysis of a process claim is supposed to focus on the active steps of the process rather than the products used in those steps.

[12] See the Federal Trade Commissions press release FTC Stops Deceptive Health Claims by a Stem Cell Therapy Clinic.

[13] See the U.S. Department of Justices news release Florida Company Barred from Using Experimental Stem Cell Drugs on Patients.

Go here to see the original:
Legal Issues in Stem Cell Therapy in the U.S. - Royse Law Firm

Code of Medical Ethics Opinion 7.3.8

Human stem cells are widely seen as offering a source of potential treatment for a range of diseases and are thus the subject of much research. Clinical studies have validated the use of adult stem cells in a limited number of therapies, but have yet to confirm the utility of embryonic stem cells.

Physicians who conduct research using stem cells obtained from any source (established tissue, umbilical cord blood, or embryos) must, at a minimum:

(a) Adhere to institutional review board (IRB) requirements.

(b) Ensure that the research is carried out with appropriate oversight and monitoring.

(c) Ensure that the research is carried out with appropriate informed consent. In addition to disclosure of research risks and potential benefits, at minimum, the consent disclosure should address:

a. The process by which stem cells will be obtained

b. What specifically will be done with the stem cells

c. Whether an immortal cell line will result

d. The primary and anticipated secondary uses of donated embryos and/or derived stem cells, including potential commercial uses

2. For a recipient of stem cells in clinical research

a. The types of tissue from which the stem cells derive (e.g., established tissue, umbilical cord blood, or embryos)

b. Unique risks posed by investigational stem cell products (when applicable), such as tumorigenesis, immunological reactions, unpredictable behavior of cells, and unknown long-term health effects

The professional community as well as the public remains divided about the use of embryonic stem cells for either research or therapeutic purposes. The conflict regarding research with embryonic stem cells centers on the moral status of embryos, a question that divides ethical opinion and that cannot be resolved by medical science. Regardless whether they are obtained from embryos donated by individuals or couples undergoing in vitro fertilization, or from cloned embryos created by somatic cell nuclear transfer (SCNT), use of embryonic stem cells currently requires the destruction of the human embryo from which the stem cells derive.

The pluralism of moral visions that underlies this debate must be respected. Participation in research involving embryonic stem cells requires respect for embryos, research participants, donors, and recipients. Embryonic stem cell research does not violate the ethical standards of the profession. Every physician remains free to decide whether to participate in stem cell research or to use its products. Physicians should continue to be guided by their commitment to the welfare of patients and the advancement of medical science.

Physicians who conduct research using embryonic stem cells should be able to justify greater risks for subjects, and the greater respect due embryos than stem cells from other sources, based on expectations that the research offers substantial promise of contributing significantly to scientific or therapeutic knowledge.

Code of Medical Ethics: Special issues in research

Visit theEthics main pageto access additional Opinions, the Principles of Medical Ethics and more information about the Code of Medical Ethics.

More here:
Research With Stem Cells | American Medical Association

While some researchers still claim that embryonic stem cells (ESCs) offer the best hope for treating many debilitating diseases, there is now a great deal of evidence contrary to that theory. Use of stem cells obtained by destroying human embryos is not only unethical but presents many practical obstacles as well.

"Major roadblocks remain before human embryonic stem cells could be transplanted into humans to cure diseases or replace injured body parts, a research pioneer said Thursday night. University of Wisconsin scientist James Thomson said obstacles include learning how to grow the cells into all types of organs and tissue and then making sure cancer and other defects are not introduced during the transplantation. 'I don't want to sound too pessimistic because this is all doable, but it's going to be very hard,' Thomson told the Wisconsin Newspaper Association's annual convention at the Kalahari Resort in this Wisconsin Dells town. 'Ultimately, those transplation therapies should work but it's likely to take a long time.'....Thomson cautioned such breakthroughs are likely decades away."

-Associated Press reporter Ryan J. Foley "Stem cell pioneer warns of roadblocks before cures," San Jose Mercury News Online, posted on Feb. 8, 2007, http://www.mercurynews.com/mld/mercurynews/16656570.htm

***

"Although embryonic stem cells have the broadest differentiation potential, their use for cellular therapeutics is excluded for several reasons: the uncontrollable development of teratomas in a syngeneic transplantation model, imprinting-related developmental abnormalities, and ethical issues."

-Gesine Kgler et al., "A New Human Somatic Stem Cell from Placental Cord Blood with Intrinsic Pluripotent Differentiation Potential," Journal of Experimental Medicine, Vol. 200, No. 2 (July 19, 2004), p. 123.

***

From a major foundation promoting research in pancreatic islet cells and other avenues for curing juvenile diabetes:

"Is the use of embryonic stem cells close to being used to provide a supply of islet cells for transplantation into humans?

"No. The field of embryonic stem cells faces enormous hurtles to overcome before these cells can be used in humans. The two key challenges to overcome are making the stem cells differentiate into specific viable cells consistently, and controlling against unchecked cell division once transplanted. Solid data of stable, functioning islet cells from embryonic stems cells in animals has not been seen."

-"Q & A," Autoimmune Disease Research Foundation, http://www.cureautoimmunity.org/Q%20&%20A.htm, accessed July 2004.

***

"'I think the chance of doing repairs to Alzheimer's brains by putting in stem cells is small,' said stem cell researcher Michael Shelanski, co-director of the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at the Columbia University Medical Center in New York, echoing many other experts. 'I personally think we're going to get other therapies for Alzheimer's a lot sooner.'...

"[G]iven the lack of any serious suggestion that stem cells themselves have practical potential to treat Alzheimer's, the Reagan-inspired tidal wave of enthusiasm stands as an example of how easily a modest line of scientific inquiry can grow in the public mind to mythological proportions.

"It is a distortion that some admit is not being aggressively corrected by scientists.

"'To start with, people need a fairy tale,' said Ronald D.G. McKay, a stem cell researcher at the National Institute of Neurological Disorders and Stroke. 'Maybe that's unfair, but they need a story line that's relatively simple to understand.'"

-Rick Weiss, "Stem Cells an Unlikely Therapy for Alzheimer's," Washington Post, June 10, 2004, p. A3.

***

"ES [embryonic stem] cells and their derivatives carry the same likelihood of immune rejection as a transplanted organ because, like all cells, they carry the surface proteins, or antigens, by which the immune system recognizes invaders. Hundreds of combinations of different types of antigens are possible, meaning that hundreds of thousands of ES cell lines might be needed to establish a bank of cells with immune matches for most potential patients. Creating that many lines could require millions of discarded embryos from IVF clinics."

-R. Lanza and N. Rosenthal, "The Stem Cell Challenge," Scientific American, June 2004, pp. 92-99 at p. 94. [Editor's note: A recent study found that only 11,000 frozen embryos are available for research use from all the fertility clinics in the U.S., and that destroying all these embryos for their stem cells might produce a total of 275 cell lines. See Fertility and Sterility, May 2003, pp. 1063-9 at p. 1068.]

***

"Embryonic stem cells have too many limitations, including immune rejection and the potential to form tumors, to ever achieve acceptance in our lifetime. By that time, umbilical cord blood stem cells will have been shown to be a true 'gift from the gods.'"

-Dr. Roger Markwald, Professor and Chair of Cell Biology and Anatomy at the Medical University of South Carolina, quoted in "CureSource Issues Statement on Umbilical Cord Blood Stem Cells vs. Embryonic Stem Cells," BusinessWire, May 12, 2004, also at http://curesource.net/why.html.

***

"'We're not against stem-cell research of any kind,' said [Tulane University research professor Brian] Butcher. 'But we think there are advantages to using adult stem cells. For example, with embryonic stem cells, a significant number become cancer cells, so the cure could be worse than the disease. And they can be very difficult to grow, while adult stem cells are easy to grow.'"

-Heather Heilman, "Great Transformations," The Tulanian (Spring 2004 issue), at http://www2.tulane.edu/article_news_details.cfm?ArticleID=5155.

***

"There are still many hurdles to clear before embryonic stem cells can be used therapeutically. For example, because undifferentiated embryonic stem cells can form tumors after transplantation in histocompatible animals, it is important to determine an appropriate state of differentiation before transplantation. Differentiation protocols for many cell types have yet to be established. Targeting the differentiated cells to the appropriate organ and the appropriate part of the organ is also a challenge."

-E. Phimister and J. Drazen, "Two Fillips for Human Embryonic Stem Cells," New England Journal of Medicine, Vol. 350 (March 25, 2004), pp. 1351-2 at 1351.

***

Harvard researchers, trying to create human embryonic stem cell lines that are more clinically useful than those now available, find that their new cell lines are already genetically abnormal:

"After prolonged culture, we observed karyotypic changes involving trisomy of chromosome 12..., as well as other changes... These karyotypic abnormalities are accompanied by a proliferative advantage and a noticeable shortening in the population doubling time. Chromosomal abnormalities are commonplace in human embryonal carcinoma cell lines and in mouse embryonic stem-cell lines and have recently been reported in human embryonic stem-cell lines."

-C. Cowan et al., "Derivation of Embryonic Stem-Cell Lines from Human Blastocysts," New England Journal of Medicine, Vol. 350 (March 25, 2004), pp. 1353-6 at 1355.

***

"[Johns Hopkins University] biologist Michael Shamblott said...major scientific hurdles await anybody wishing to offer a treatment, let alone a cure, based on cells culled from embryos.

"Among the major obstacles is the difficulty of getting embryonic stem cells master cells that generate every tissue in the human body to become exactly the type of cell one wants... Scientists...haven't been able to guarantee purity cells, for instance, that are destined to become muscle cells and nothing else...

"Transplanting a mixed population of cells could cause the growth of unwanted tissues. The worst case could see stem cells morphing into teratomas, particularly gruesome tumors that can contain hair, teeth and other body parts.

"Another issue is timing... Stem cells pass through many intermediate stages before they become intermediate cells such as motor neurons or pancreatic or heart cells. Deciding when to transplant remains an open question, and the answer might differ from disease to disease.

"...In tackling Lou Gehrig's disease, [Johns Hopkins neurologist Dr. Jeffrey] Rothstein figured that cells that haven't committed themselves to becoming motor neurons would stand the best chance, once implanted, of reaching out and connecting with the cells that surround them. What he found, however, is that these immature cells didn't develop much once transplanted into lab animals."

-Jonathan Bor, "Stem Cells: A long road ahead," Baltimore Sun, March 8, 2004, p. 12A.

***

"Tony Blau, a stem-cell researcher at the University of Washington, said it is 'extremely laborious' to keep embryonic cells growing, well-nourished and stable in the lab so they don't die or turn into a cell type with less potential. Researchers need to know how to channel the stem cells to create a specific kind of cell, how to test whether they're pure, and how to develop drugs that could serve as a sort of antidote in case infused stem cells started creating something dangerous, such as cancer.

"Big companies, Blau said, want to know that their drugs will be almost completely stable, standard, pure and consistent, because they can behave differently if they aren't. Stem cells never will achieve that kind of standardization, Blau said, because living cells are more complex than chemically synthesized drugs."

-Luke Timmerman, "Stem-cell research still an embryonic business," Seattle Times, Business & Technology section, February 22, 2004, at http://seattletimes.nwsource.com/html/businesstechnology/2001862747_stemcells22.html.

***

"[W]ithin the ESC research community, realism has overtaken early euphoria as scientists realize the difficulty of harnessing ESCs safely and effectively for clinical applications. After earlier papers in 2000 and 2001 identified some possibilities, research continued to highlight the tasks that lie ahead in steering cell differentiation and avoiding side effects, such as immune rejection and tumorigenesis."

-Philip Hunter, "Differentiating Hope from Embryonic Stem Cells," The Scientist, Vol. 17, Issue 34 (December 15, 2003), at http://www.the-scientist.com/yr2003/dec/hot_031215.html.

***

"Long-term culture of mouse ES [embryonic stem] cells can lead to a decrease in pluripotency and the gain of distinct chromosomal abnormalities. Here we show that similar chromosomal changes, which resemble those observed in hEC [human embryonal carcinoma] cells from testicular cancer, can occur in hES [human embryonic stem] cells.... The occurrence and potential detrimental effects of such karyotopic changes will need to be considered in the development of hES cell-based transplantation therapies."

-J. Draper et al., "Recurrent gain of chromosomes 17q and 12 in cultured human embryonic stem cells," Nature Biotechnology, Vol. 22 (2003), pp. 53-4.

***

"James A. Thompson of the University of Wisconsin, Madison, and his colleagues managed to isolate and culture the first human embryonic stem cells in 1997. Five years later, big scientific questions remain. [Harvard embryonic stem cell researcher Doug] Melton and his colleagues, for instance, don't yet know how to instruct the totipotent stem cells to become the specific cells missing in a diabetic person, the pancreatic beta cell.

"'Normally, if you take an embryonic stem cell, it will make all kinds of things, sort of willy-nilly,' says Melton."

-J. Mitchell, "Stem Cells 101," PBS Scientific American Frontiers, May 28, 2002, http://www.pbs.org/saf/1209/features/stemcell.htm.

***

"Unlike stem cells isolated from the embryo, [adult stem cells] do not carry the same risks of cancer or uncontrollable growth after transplant, and they can be isolated from patients requiring treatment, thus avoiding all problems of immune rejection and the need for immune suppressive drugs that carry their own risks.

"...Embryonic stem cells are promoted on grounds that they are developmentally more flexible than adult stem cells. But too much flexibility may not be desirable. Transplant of embryonic cells into the brains of Parkinson's patients turned into an irredeemable nightmare because the cells grew uncontrollably. Embryonic stem cells also show genetic instability and carry considerable risks of cancer... When injected under the skin of certain mice, they grow into teratomas, tumors consisting of a jumble of tissue types, from gut to skin to teeth, and the same happens when injected into the brain."

-Dr. Mae-Wan Ho and Prof. Joe Cummins on behalf of the Institute of Science in Society (ISIS), "Hushing Up Adult Stem Cells," ISIS report, February 11, 2002, at http://www.i-sis.org.uk/HUASC.php.

***

"'I even hear from patients whose fathers have lung cancer,' said Dr. Hogan, a professor at Vanderbilt School of Medicine. 'They have a whole slew of problems they think can be treated. They think stem cells are going to cure their loved ones of everything.'

"If it ever happens, it will not happen soon, scientists say. In fact, although they worked with mouse embryonic stem cells for 20 years and made some progress, researchers have not used these cells to cure a single mouse of a disease...

"Scientists say the theory behind stem cells is correct: the cells, in principle, can become any specialized cell of the body. But between theory and therapy lie a host of research obstacles...the obstacles are so serious that scientists say they foresee years, if not decades, of concerted work on basic science before they can even think of trying to treat a patient."

-Gina Kolata, "A Thick Line Between Theory and Therapy, as Shown with Mice," New York Times, December 18, 2001, p. F3.

***

"Mice cloned from embryonic stem cells may look identical, but many of them actually differ from one another by harboring unique genetic abnormalities, scientists have learned...

"The work also shows for the first time that embryonic stem cells...are surprisingly genetically unstable, at least in mice. If the same is true for human embryonic stem cells, researchers said, then scientists may face unexpected challenges as they try to turn the controversial cells into treatments for various degenerative conditions."

-Rick Weiss, "Clone Study Casts Doubt on Stem Cells," Washington Post, July 6, 2001, p. A1.

***

"ES cells have plenty of limitations... For one, murine ES cells have a disturbing ability to form tumors, and researchers aren't yet sure how to counteract that. And so far reports of pure cell populations derived from either human or mouse ES cells are few and far between fewer than those from adult stem cells."

-Gretchen Vogel, "Can Adult Stem Cells Suffice?", Science, Vol. 292 (June 8, 2001), pp. 1820-1822 at 1822.

***

"Rarely have specific growth factors or culture conditions led to establishment of cultures containing a single cell type.... [T]he possibility arises that transplantation of differentiated human ES cell derivatives into human recipients may result in the formation of ES cell-derived tumors... Irrespective of the persistence of stem cells, the possibility for malignant transformation of the derivatives will also need to be addressed."

-J. S. Odorico et al, "Multilineage differentiation from human embryonic stem cell lines," Stem Cells Vol. 19 (2001), pp. 193-204 at 198 and 200, at http://stemcells.alphamedpress.org/cgi/reprint/19/3/193.pdf.

Originally posted here:
Practical Problems with Embryonic Stem Cells - usccb.org

Ok, I admit it. I am a Dummie! Especially when it comes to Science! I do hold a Bachelor of Arts in Political Science from Berkeley but its not exactly the type of Science degree you need when your children are dying from a rare cholesterol disease that causes dementia.

All of a sudden topics like gene therapy and stem cells are very important topics in our household as research into these areas could lead to life-saving treatments for our twins. But learning complex scientific topics like stem cells can be intimidating to many people.

Dr. Larry Goldstein, professor of cellular and molecular medicine and director of University of California San Diegos stem cell program, has written a book in plain English on stem cells called Stem Cells for Dummies. The book is intended for anyone who wishes to learn more about stem cells, where they come from and the potential use of stem cells in medical research and in treating disease.

What is the difference between Embryonic stem cells (ESCs), Adult stem cells (ASCs) or iPS cells (Induced Pluripotent Stem Cells)? What are the many objections to stems cell use in research and why is it such a highly controversial topic? The book is written for the layperson, doctors or even someone in the medical research field who is not familiar with stem cells.

Stem cell derived neurons will someday allow scientists like Dr. Goldstein determine whether breakdowns in the transport of proteins and lipids within cells trigger the neuronal death and neurodegeneration that is a hallmark in Alzheimers and Niemann-Pick Type C disease.

Stem Cells for Dummies is a fantastic book that allows anyone to brush up on basic biology and learn about critical stem cell research at the same time. You can read the index of topics here. Learning about stem cells today could be life-saving for you or someone you love in the future as the world moves closer to regenerative medicine.

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Stem Cells For Dummies: The Controvery, Pros and Cons ...

Human cloning is the creation of a genetically identical copy (or clone) of a human. The term is generally used to refer to artificial human cloning, which is the reproduction of human cells and tissue. It does not refer to the natural conception and delivery of identical twins. The possibility of human cloning has raised controversies. These ethical concerns have prompted several nations to pass laws regarding human cloning and its legality.

Two commonly discussed types of theoretical human cloning are: therapeutic cloning and reproductive cloning. Therapeutic cloning would involve cloning cells from a human for use in medicine and transplants, and is an active area of research, but is not in medical practice anywhere in the world, as of April2017[update]. Two common methods of therapeutic cloning that are being researched are somatic-cell nuclear transfer and, more recently, pluripotent stem cell induction. Reproductive cloning would involve making an entire cloned human, instead of just specific cells or tissues.

Although the possibility of cloning humans had been the subject of speculation for much of the 20th century, scientists and policy makers began to take the prospect seriously in the mid-1960s.

Nobel Prize-winning geneticist Joshua Lederberg advocated cloning and genetic engineering in an article in The American Naturalist in 1966 and again, the following year, in The Washington Post.[1] He sparked a debate with conservative bioethicist Leon Kass, who wrote at the time that "the programmed reproduction of man will, in fact, dehumanize him." Another Nobel Laureate, James D. Watson, publicized the potential and the perils of cloning in his Atlantic Monthly essay, "Moving Toward the Clonal Man", in 1971.[2]

With the cloning of a sheep known as Dolly in 1996 by somatic cell nuclear transfer (SCNT), the idea of human cloning became a hot debate topic.[3] Many nations outlawed it, while a few scientists promised to make a clone within the next few years. The first hybrid human clone was created in November 1998, by Advanced Cell Technology. It was created using SCNT - a nucleus was taken from a man's leg cell and inserted into a cow's egg from which the nucleus had been removed, and the hybrid cell was cultured, and developed into an embryo. The embryo was destroyed after 12 days.[4]

In 2004 and 2005, Hwang Woo-suk, a professor at Seoul National University, published two separate articles in the journal Science claiming to have successfully harvested pluripotent, embryonic stem cells from a cloned human blastocyst using somatic-cell nuclear transfer techniques. Hwang claimed to have created eleven different patent-specific stem cell lines. This would have been the first major breakthrough in human cloning.[5] However, in 2006 Science retracted both of his articles on clear evidence that much of his data from the experiments was fabricated.[6]

In January 2008, Dr. Andrew French and Samuel Wood of the biotechnology company Stemagen announced that they successfully created the first five mature human embryos using SCNT. In this case, each embryo was created by taking a nucleus from a skin cell (donated by Wood and a colleague) and inserting it into a human egg from which the nucleus had been removed. The embryos were developed only to the blastocyst stage, at which point they were studied in processes that destroyed them. Members of the lab said that their next set of experiments would aim to generate embryonic stem cell lines; these are the "holy grail" that would be useful for therapeutic or reproductive cloning.[7][8]

In 2011, scientists at the New York Stem Cell Foundation announced that they had succeeded in generating embryonic stem cell lines, but their process involved leaving the oocyte's nucleus in place, resulting in triploid cells, which would not be useful for cloning.[10][11]

In 2013, a group of scientists led by Shoukhrat Mitalipov published the first report of embryonic stem cells created using SCNT. In this experiment, the researchers developed a protocol for using SCNT in human cells, which differs slightly from the one used in other organisms. Four embryonic stem cell lines from human fetal somatic cells were derived from those blastocysts. All four lines were derived using oocytes from the same donor, ensuring that all mitochondrial DNA inherited was identical. A year later, a team led by Robert Lanza at Advanced Cell Technology reported that they had replicated Mitalipov's results and further demonstrated the effectiveness by cloning adult cells using SCNT.[3][12]

In 2018, the first successful cloning of primates using somatic cell nuclear transfer, the same method as Dolly the sheep, with the birth of two live female clones (crab-eating macaques named Zhong Zhong and Hua Hua) was reported.[13][14][15][16][17].

In somatic cell nuclear transfer ("SCNT"), the nucleus of a somatic cell is taken from a donor and transplanted into a host egg cell, which had its own genetic material removed previously, making it an enucleated egg. After the donor somatic cell genetic material is transferred into the host oocyte with a micropipette, the somatic cell genetic material is fused with the egg using an electric current. Once the two cells have fused, the new cell can be permitted to grow in a surrogate or artificially.[18] This is the process that was used to successfully clone Dolly the sheep (see section on History in this article).[3]

Creating induced pluripotent stem cells ("iPSCs") is a long and inefficient process. Pluripotency refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous tissue).[19] A specific set of genes, often called "reprogramming factors", are introduced into a specific adult cell type. These factors send signals in the mature cell that cause the cell to become a pluripotent stem cell. This process is highly studied and new techniques are being discovered frequently on how to better this induction process.

Depending on the method used, reprogramming of adult cells into iPSCs for implantation could have severe limitations in humans. If a virus is used as a reprogramming factor for the cell, cancer-causing genes called oncogenes may be activated. These cells would appear as rapidly dividing cancer cells that do not respond to the body's natural cell signaling process. However, in 2008 scientists discovered a technique that could remove the presence of these oncogenes after pluripotency induction, thereby increasing the potential use of iPSC in humans.[20]

Both the processes of SCNT and iPSCs have benefits and deficiencies. Historically, reprogramming methods were better studied than SCNT derived embryonic stem cells (ESCs). However, more recent studies have put more emphasis on developing new procedures for SCNT-ESCs. The major advantage of SCNT over iPSCs at this time is the speed with which cells can be produced. iPSCs derivation takes several months while SCNT would take a much shorter time, which could be important for medical applications. New studies are working to improve the process of iPSC in terms of both speed and efficiency with the discovery of new reprogramming factors in oocytes.[citation needed] Another advantage SCNT could have over iPSCs is its potential to treat mitochondrial disease, as it utilizes a donor oocyte. No other advantages are known at this time in using stem cells derived from one method over stem cells derived from the other.[21]

Work on cloning techniques has advanced our basic understanding of developmental biology in humans. Observing human pluripotent stem cells grown in culture provides great insight into human embryo development, which otherwise cannot be seen. Scientists are now able to better define steps of early human development. Studying signal transduction along with genetic manipulation within the early human embryo has the potential to provide answers to many developmental diseases and defects. Many human-specific signaling pathways have been discovered by studying human embryonic stem cells. Studying developmental pathways in humans has given developmental biologists more evidence toward the hypothesis that developmental pathways are conserved throughout species.[22]

iPSCs and cells created by SCNT are useful for research into the causes of disease, and as model systems used in drug discovery.[23][24]

Cells produced with SCNT, or iPSCs could eventually be used in stem cell therapy,[25] or to create organs to be used in transplantation, known as regenerative medicine. Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplantation is a widely used form of stem cell therapy.[26] No other forms of stem cell therapy are in clinical use at this time. Research is underway to potentially use stem cell therapy to treat heart disease, diabetes, and spinal cord injuries.[27][28] Regenerative medicine is not in clinical practice, but is heavily researched for its potential uses. This type of medicine would allow for autologous transplantation, thus removing the risk of organ transplant rejection by the recipient.[29] For instance, a person with liver disease could potentially have a new liver grown using their same genetic material and transplanted to remove the damaged liver.[30] In current research, human pluripotent stem cells have been promised as a reliable source for generating human neurons, showing the potential for regenerative medicine in brain and neural injuries.[31]

In bioethics, the ethics of cloning refers to a variety of ethical positions regarding the practice and possibilities of cloning, especially human cloning. While many of these views are religious in origin, the questions raised by cloning are faced by secular perspectives as well. Human therapeutic and reproductive cloning are not commercially used; animals are currently cloned in laboratories and in livestock production.

Advocates support development of therapeutic cloning in order to generate tissues and whole organs to treat patients who otherwise cannot obtain transplants,[32] to avoid the need for immunosuppressive drugs,[33] and to stave off the effects of aging.[34] Advocates for reproductive cloning believe that parents who cannot otherwise procreate should have access to the technology.[35]

Opposition to therapeutic cloning mainly centers around the status of embryonic stem cells, which has connections with the abortion debate.[36]

Some opponents of reproductive cloning have concerns that technology is not yet developed enough to be safe - for example, the position of the American Association for the Advancement of Science as of 2014[update],[37] while others emphasize that reproductive cloning could be prone to abuse (leading to the generation of humans whose organs and tissues would be harvested),[38][39] and have concerns about how cloned individuals could integrate with families and with society at large.[40][41]

Religious groups are divided, with some[which?] opposing the technology as usurping God's role in creation and, to the extent embryos are used, destroying a human life; others support therapeutic cloning's potential life-saving benefits.[42][43]

In 2015 it was reported that about 70 countries had banned human cloning.[44]

Human cloning is banned by the Presidential Decree 200/97 of 7 March 1997.[45]

Australia has prohibited human cloning,[46] though as of December2006[update], a bill legalizing therapeutic cloning and the creation of human embryos for stem cell research passed the House of Representatives. Within certain regulatory limits, and subject to the effect of state legislation, therapeutic cloning is now legal in some parts of Australia.[47]

Canadian law prohibits the following: cloning humans, cloning stem cells, growing human embryos for research purposes, and buying or selling of embryos, sperm, eggs or other human reproductive material.[48] It also bans making changes to human DNA that would pass from one generation to the next, including use of animal DNA in humans. Surrogate mothers are legally allowed, as is donation of sperm or eggs for reproductive purposes. Human embryos and stem cells are also permitted to be donated for research.[citation needed]

There have been consistent calls in Canada to ban human reproductive cloning since the 1993 Report of the Royal Commission on New Reproductive Technologies. Polls have indicated that an overwhelming majority of Canadians oppose human reproductive cloning, though the regulation of human cloning continues to be a significant national and international policy issue. The notion of "human dignity" is commonly used to justify cloning laws. The basis for this justification is that reproductive human cloning necessarily infringes notions of human dignity.[49][50][51][52]

Human cloning is prohibited in Article 133 of the Colombian Penal Code.[53]

The European Convention on Human Rights and Biomedicine prohibits human cloning in one of its additional protocols, but this protocol has been ratified only by Greece, Spain and Portugal. The Charter of Fundamental Rights of the European Union explicitly prohibits reproductive human cloning. The charter is legally binding for the institutions of the European Union under the Treaty of Lisbon and for member states of the Union implementing EU law.[54][55]

India does not have specific law regarding cloning but has guidelines prohibiting whole human cloning or reproductive cloning. India allows therapeutic cloning and the use of embryonic stem cells for research proposes.[56][57]

The Federal Assembly of Russia introduced the Federal Law N 54-FZ "On the temporary ban on human cloning" in April 19, 2002. On May 20, 2002 President Vladimir Putin signed this moratorium on the implementation of human cloning. On March 29, 2010 The Federal Assembly introduced second revision of this law without time limit.[58]

Human cloning is explicitly prohibited in Article 24, "Right to Life" of the 2006 Constitution of Serbia.[59]

In terms of section 39A of the Human Tissue Act 65 of 1983,[60] genetic manipulation of gametes or zygotes outside the human body is absolutely prohibited. A zygote is the cell resulting from the fusion of two gametes; thus the fertilised ovum. Section 39A thus prohibits human cloning.[citation needed]

On January 14, 2001 the British government passed The Human Fertilisation and Embryology (Research Purposes) Regulations 2001[61] to amend the Human Fertilisation and Embryology Act 1990 by extending allowable reasons for embryo research to permit research around stem cells and cell nuclear replacement, thus allowing therapeutic cloning. However, on November 15, 2001, a pro-life group won a High Court legal challenge, which struck down the regulation and effectively left all forms of cloning unregulated in the UK. Their hope was that Parliament would fill this gap by passing prohibitive legislation.[62][63] Parliament was quick to pass the Human Reproductive Cloning Act 2001 which explicitly prohibited reproductive cloning. The remaining gap with regard to therapeutic cloning was closed when the appeals courts reversed the previous decision of the High Court.[64]

The first license was granted on August 11, 2004 to researchers at the University of Newcastle to allow them to investigate treatments for diabetes, Parkinson's disease and Alzheimer's disease.[65] The Human Fertilisation and Embryology Act 2008, a major review of fertility legislation, repealed the 2001 Cloning Act by making amendments of similar effect to the 1990 Act. The 2008 Act also allows experiments on hybrid human-animal embryos.[66]

On December 13, 2001, the United Nations General Assembly began elaborating an international convention against the reproductive cloning of humans. A broad coalition of states, including Spain, Italy, the Philippines, the United States, Costa Rica, and the Holy See sought to extend the debate to ban all forms of human cloning, noting that, in their view, therapeutic human cloning violates human dignity. Costa Rica proposed the adoption of an international convention to ban all forms of human cloning. Unable to reach a consensus on a binding convention, in March 2005 a non-binding United Nations Declaration on Human Cloning, calling for the ban of all forms of human cloning contrary to human dignity, was adopted.[67][68]

The Patients First Act of 2017 (HR 2918, 115th Congress) aims to promote stem cell research, using cells that are ethically obtained, that could contribute to a better understanding of diseases and therapies, and promote the derivation of pluripotent stem cell lines without the creation of human embryos.[69]

In 1998, 2001, 2004, 2005, 2007 and 2009, the US Congress voted whether to ban all human cloning, both reproductive and therapeutic (see Stem Cell Research Enhancement Act). Each time, divisions in the Senate, or an eventual veto from the sitting President (President George W. Bush in 2005 and 2007), over therapeutic cloning prevented either competing proposal (a ban on both forms or on reproductive cloning only) from being passed into law. On March 10, 2010 a bill (HR 4808) was introduced with a section banning federal funding for human cloning.[70] Such a law, if passed, would not have prevented research from occurring in private institutions (such as universities) that have both private and federal funding. However, the 2010 law was not passed.

There are currently no federal laws in the United States which ban cloning completely. Fifteen American states (Arkansas, California, Connecticut, Iowa, Indiana, Massachusetts, Maryland, Michigan, North Dakota, New Jersey, Rhode Island, South Dakota, Florida, Georgia, and Virginia) ban reproductive cloning and three states (Arizona, Maryland, and Missouri) prohibit use of public funds for such activities.[71]

Science fiction has used cloning, most commonly and specifically human cloning, due to the fact that it brings up controversial questions of identity.[72][73] Humorous fiction, such as Multiplicity (1996)[74] and the Maxwell Smart feature The Nude Bomb (1980), have featured human cloning.[75] A recurring sub-theme of cloning fiction is the use of clones as a supply of organs for transplantation. Robin Cook's 1997 novel Chromosome 6 and Michael Bay's The Island are examples of this; Chromosome 6 also features genetic manipulation and xenotransplantation.[76] There is also a series named Orphan Black which follows human clones' stories and experiences as they deal with issues and react to being the property of a chain of scientific institutions.

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Human cloning - Wikipedia

Stem cell, an undifferentiated cell that can divide to produce some offspring cells that continue as stem cells and some cells that are destined to differentiate (become specialized). Stem cells are an ongoing source of the differentiated cells that make up the tissues and organs of animals and plants. There is great interest in stem cells because they have potential in the development of therapies for replacing defective or damaged cells resulting from a variety of disorders and injuries, such as Parkinson disease, heart disease, and diabetes. There are two major types of stem cells: embryonic stem cells and adult stem cells, which are also called tissue stem cells.

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cardiovascular disease: Cardiac stem cells

Cardiac stem cells, which have the ability to differentiate (specialize) into mature heart cells and therefore could be used to repair damaged or diseased heart tissue, have garnered significant interest in the development of treatments for heart disease and cardiac defects. Cardiac stem

Embryonic stem cells (often referred to as ES cells) are stem cells that are derived from the inner cell mass of a mammalian embryo at a very early stage of development, when it is composed of a hollow sphere of dividing cells (a blastocyst). Embryonic stem cells from human embryos and from embryos of certain other mammalian species can be grown in tissue culture.

The most-studied embryonic stem cells are mouse embryonic stem cells, which were first reported in 1981. This type of stem cell can be cultured indefinitely in the presence of leukemia inhibitory factor (LIF), a glycoprotein cytokine. If cultured mouse embryonic stem cells are injected into an early mouse embryo at the blastocyst stage, they will become integrated into the embryo and produce cells that differentiate into most or all of the tissue types that subsequently develop. This ability to repopulate mouse embryos is the key defining feature of embryonic stem cells, and because of it they are considered to be pluripotentthat is, able to give rise to any cell type of the adult organism. If the embryonic stem cells are kept in culture in the absence of LIF, they will differentiate into embryoid bodies, which somewhat resemble early mouse embryos at the egg-cylinder stage, with embryonic stem cells inside an outer layer of endoderm. If embryonic stem cells are grafted into an adult mouse, they will develop into a type of tumour called a teratoma, which contains a variety of differentiated tissue types.

Mouse embryonic stem cells are widely used to create genetically modified mice. This is done by introducing new genes into embryonic stem cells in tissue culture, selecting the particular genetic variant that is desired, and then inserting the genetically modified cells into mouse embryos. The resulting chimeric mice are composed partly of host cells and partly of the donor embryonic stem cells. As long as some of the chimeric mice have germ cells (sperm or eggs) that have been derived from the embryonic stem cells, it is possible to breed a line of mice that have the same genetic constitution as the embryonic stem cells and therefore incorporate the genetic modification that was made in vitro. This method has been used to produce thousands of new genetic lines of mice. In many such genetic lines, individual genes have been ablated in order to study their biological function; in others, genes have been introduced that have the same mutations that are found in various human genetic diseases. These mouse models for human disease are used in research to investigate both the pathology of the disease and new methods for therapy.

Extensive experience with mouse embryonic stem cells made it possible for scientists to grow human embryonic stem cells from early human embryos, and the first human stem cell line was created in 1998. Human embryonic stem cells are in many respects similar to mouse embryonic stem cells, but they do not require LIF for their maintenance. The human embryonic stem cells form a wide variety of differentiated tissues in vitro, and they form teratomas when grafted into immunosuppressed mice. It is not known whether the cells can colonize all the tissues of a human embryo, but it is presumed from their other properties that they are indeed pluripotent cells, and they therefore are regarded as a possible source of differentiated cells for cell therapythe replacement of a patients defective cell type with healthy cells. Large quantities of cells, such as dopamine-secreting neurons for the treatment of Parkinson disease and insulin-secreting pancreatic beta cells for the treatment of diabetes, could be produced from embryonic stem cells for cell transplantation. Cells for this purpose have previously been obtainable only from sources in very limited supply, such as the pancreatic beta cells obtained from the cadavers of human organ donors.

The use of human embryonic stem cells evokes ethical concerns, because the blastocyst-stage embryos are destroyed in the process of obtaining the stem cells. The embryos from which stem cells have been obtained are produced through in vitro fertilization, and people who consider preimplantation human embryos to be human beings generally believe that such work is morally wrong. Others accept it because they regard the blastocysts to be simply balls of cells, and human cells used in laboratories have not previously been accorded any special moral or legal status. Moreover, it is known that none of the cells of the inner cell mass are exclusively destined to become part of the embryo itselfall of the cells contribute some or all of their cell offspring to the placenta, which also has not been accorded any special legal status. The divergence of views on this issue is illustrated by the fact that the use of human embryonic stem cells is allowed in some countries and prohibited in others.

In 2009 the U.S. Food and Drug Administration approved the first clinical trial designed to test a human embryonic stem cell-based therapy, but the trial was halted in late 2011 because of a lack of funding and a change in lead American biotech company Gerons business directives. The therapy to be tested was known as GRNOPC1, which consisted of progenitor cells (partially differentiated cells) that, once inside the body, matured into neural cells known as oligodendrocytes. The oligodendrocyte progenitors of GRNOPC1 were derived from human embryonic stem cells. The therapy was designed for the restoration of nerve function in persons suffering from acute spinal cord injury.

Embryonic germ (EG) cells, derived from primordial germ cells found in the gonadal ridge of a late embryo, have many of the properties of embryonic stem cells. The primordial germ cells in an embryo develop into stem cells that in an adult generate the reproductive gametes (sperm or eggs). In mice and humans it is possible to grow embryonic germ cells in tissue culture with the appropriate growth factorsnamely, LIF and another cytokine called fibroblast growth factor.

Some tissues in the adult body, such as the epidermis of the skin, the lining of the small intestine, and bone marrow, undergo continuous cellular turnover. They contain stem cells, which persist indefinitely, and a much larger number of transit amplifying cells, which arise from the stem cells and divide a finite number of times until they become differentiated. The stem cells exist in niches formed by other cells, which secrete substances that keep the stem cells alive and active. Some types of tissue, such as liver tissue, show minimal cell division or undergo cell division only when injured. In such tissues there is probably no special stem-cell population, and any cell can participate in tissue regeneration when required.

The epidermis of the skin contains layers of cells called keratinocytes. Only the basal layer, next to the dermis, contains cells that divide. A number of these cells are stem cells, but the majority are transit amplifying cells. The keratinocytes slowly move outward through the epidermis as they mature, and they eventually die and are sloughed off at the surface of the skin. The epithelium of the small intestine forms projections called villi, which are interspersed with small pits called crypts. The dividing cells are located in the crypts, with the stem cells lying near the base of each crypt. Cells are continuously produced in the crypts, migrate onto the villi, and are eventually shed into the lumen of the intestine. As they migrate, they differentiate into the cell types characteristic of the intestinal epithelium.

Bone marrow contains cells called hematopoietic stem cells, which generate all the cell types of the blood and the immune system. Hematopoietic stem cells are also found in small numbers in peripheral blood and in larger numbers in umbilical cord blood. In bone marrow, hematopoietic stem cells are anchored to osteoblasts of the trabecular bone and to blood vessels. They generate progeny that can become lymphocytes, granulocytes, red blood cells, and certain other cell types, depending on the balance of growth factors in their immediate environment.

Work with experimental animals has shown that transplants of hematopoietic stem cells can occasionally colonize other tissues, with the transplanted cells becoming neurons, muscle cells, or epithelia. The degree to which transplanted hematopoietic stem cells are able to colonize other tissues is exceedingly small. Despite this, the use of hematopoietic stem cell transplants is being explored for conditions such as heart disease or autoimmune disorders. It is an especially attractive option for those opposed to the use of embryonic stem cells.

Bone marrow transplants (also known as bone marrow grafts) represent a type of stem cell therapy that is in common use. They are used to allow cancer patients to survive otherwise lethal doses of radiation therapy or chemotherapy that destroy the stem cells in bone marrow. For this procedure, the patients own marrow is harvested before the cancer treatment and is then reinfused into the body after treatment. The hematopoietic stem cells of the transplant colonize the damaged marrow and eventually repopulate the blood and the immune system with functional cells. Bone marrow transplants are also often carried out between individuals (allograft). In this case the grafted marrow has some beneficial antitumour effect. Risks associated with bone marrow allografts include rejection of the graft by the patients immune system and reaction of immune cells of the graft against the patients tissues (graft-versus-host disease).

Bone marrow is a source for mesenchymal stem cells (sometimes called marrow stromal cells, or MSCs), which are precursors to non-hematopoietic stem cells that have the potential to differentiate into several different types of cells, including cells that form bone, muscle, and connective tissue. In cell cultures, bone-marrow-derived mesenchymal stem cells demonstrate pluripotency when exposed to substances that influence cell differentiation. Harnessing these pluripotent properties has become highly valuable in the generation of transplantable tissues and organs. In 2008 scientists used mesenchymal stem cells to bioengineer a section of trachea that was transplanted into a woman whose upper airway had been severely damaged by tuberculosis. The stem cells were derived from the womans bone marrow, cultured in a laboratory, and used for tissue engineering. In the engineering process, a donor trachea was stripped of its interior and exterior cell linings, leaving behind a trachea scaffold of connective tissue. The stem cells derived from the recipient were then used to recolonize the interior of the scaffold, and normal epithelial cells, also isolated from the recipient, were used to recolonize the exterior of the trachea. The use of the recipients own cells to populate the trachea scaffold prevented immune rejection and eliminated the need for immunosuppression therapy. The transplant, which was successful, was the first of its kind.

Research has shown that there are also stem cells in the brain. In mammals very few new neurons are formed after birth, but some neurons in the olfactory bulbs and in the hippocampus are continually being formed. These neurons arise from neural stem cells, which can be cultured in vitro in the form of neurospheressmall cell clusters that contain stem cells and some of their progeny. This type of stem cell is being studied for use in cell therapy to treat Parkinson disease and other forms of neurodegeneration or traumatic damage to the central nervous system.

Following experiments in animals, including those used to create Dolly the sheep, there has been much discussion about the use of somatic cell nuclear transfer (SCNT) to create pluripotent human cells. In SCNT the nucleus of a somatic cell (a fully differentiated cell, excluding germ cells), which contains the majority of the cells DNA (deoxyribonucleic acid), is removed and transferred into an unfertilized egg cell that has had its own nuclear DNA removed. The egg cell is grown in culture until it reaches the blastocyst stage. The inner cell mass is then removed from the egg, and the cells are grown in culture to form an embryonic stem cell line (generations of cells originating from the same group of parent cells). These cells can then be stimulated to differentiate into various types of cells needed for transplantation. Since these cells would be genetically identical to the original donor, they could be used to treat the donor with no problems of immune rejection. Scientists generated human embryonic stem cells successfully from SCNT human embryos for the first time in 2013.

While promising, the generation and use of SCNT-derived embryonic stem cells is controversial for several reasons. One is that SCNT can require more than a dozen eggs before one egg successfully produces embryonic stem cells. Human eggs are in short supply, and there are many legal and ethical problems associated with egg donation. There are also unknown risks involved with transplanting SCNT-derived stem cells into humans, because the mechanism by which the unfertilized egg is able to reprogram the nuclear DNA of a differentiated cell is not entirely understood. In addition, SCNT is commonly used to produce clones of animals (such as Dolly). Although the cloning of humans is currently illegal throughout the world, the egg cell that contains nuclear DNA from an adult cell could in theory be implanted into a womans uterus and come to term as an actual cloned human. Thus, there exists strong opposition among some groups to the use of SCNT to generate human embryonic stem cells.

Due to the ethical and moral issues surrounding the use of embryonic stem cells, scientists have searched for ways to reprogram adult somatic cells. Studies of cell fusion, in which differentiated adult somatic cells grown in culture with embryonic stem cells fuse with the stem cells and acquire embryonic stem-cell-like properties, led to the idea that specific genes could reprogram differentiated adult cells. An advantage of cell fusion is that it relies on existing embryonic stem cells instead of eggs. However, fused cells stimulate an immune response when transplanted into humans, which leads to transplant rejection. As a result, research has become increasingly focused on the genes and proteins capable of reprogramming adult cells to a pluripotent state. In order to make adult cells pluripotent without fusing them to embryonic stem cells, regulatory genes that induce pluripotency must be introduced into the nuclei of adult cells. To do this, adult cells are grown in cell culture, and specific combinations of regulatory genes are inserted into retroviruses (viruses that convert RNA [ribonucleic acid] into DNA), which are then introduced to the culture medium. The retroviruses transport the RNA of the regulatory genes into the nuclei of the adult cells, where the genes are then incorporated into the DNA of the cells. About 1 out of every 10,000 cells acquires embryonic stem cell properties. Although the mechanism is still uncertain, it is clear that some of the genes confer embryonic stem cell properties by means of the regulation of numerous other genes. Adult cells that become reprogrammed in this way are known as induced pluripotent stem cells (iPS).

Similar to embryonic stem cells, induced pluripotent stem cells can be stimulated to differentiate into select types of cells that could in principle be used for disease-specific treatments. In addition, the generation of induced pluripotent stem cells from the adult cells of patients affected by genetic diseases can be used to model the diseases in the laboratory. For example, in 2008 researchers isolated skin cells from a child with an inherited neurological disease called spinal muscular atrophy and then reprogrammed these cells into induced pluripotent stem cells. The reprogrammed cells retained the disease genotype of the adult cells and were stimulated to differentiate into motor neurons that displayed functional insufficiencies associated with spinal muscular atrophy. By recapitulating the disease in the laboratory, scientists were able to study closely the cellular changes that occurred as the disease progressed. Such models promise not only to improve scientists understanding of genetic diseases but also to facilitate the development of new therapeutic strategies tailored to each type of genetic disease.

In 2009 scientists successfully generated retinal cells of the human eye by reprogramming adult skin cells. This advance enabled detailed investigation of the embryonic development of retinal cells and opened avenues for the generation of novel therapies for eye diseases. The production of retinal cells from reprogrammed skin cells may be particularly useful in the treatment of retinitis pigmentosa, which is characterized by the progressive degeneration of the retina, eventually leading to night blindness and other complications of vision. Although retinal cells also have been produced from human embryonic stem cells, induced pluripotency represents a less controversial approach. Scientists have also explored the possibility of combining induced pluripotent stem cell technology with gene therapy, which would be of value particularly for patients with genetic disease who would benefit from autologous transplantation.

Researchers have also been able to generate cardiac stem cells for the treatment of certain forms of heart disease through the process of dedifferentiation, in which mature heart cells are stimulated to revert to stem cells. The first attempt at the transplantation of autologous cardiac stem cells was performed in 2009, when doctors isolated heart tissue from a patient, cultured the tissue in a laboratory, stimulated cell dedifferentiation, and then reinfused the cardiac stem cells directly into the patients heart. A similar study involving 14 patients who underwent cardiac bypass surgery followed by cardiac stem cell transplantation was reported in 2011. More than three months after stem cell transplantation, the patients experienced a slight but detectable improvement in heart function.

Patient-specific induced pluripotent stem cells and dedifferentiated cells are highly valuable in terms of their therapeutic applications because they are unlikely to be rejected by the immune system. However, before induced pluripotent stem cells can be used to treat human diseases, researchers must find a way to introduce the active reprogramming genes without using retroviruses, which can cause diseases such as leukemia in humans. A possible alternative to the use of retroviruses to transport regulatory genes into the nuclei of adult cells is the use of plasmids, which are less tumourigenic than viruses.

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stem cell | Definition, Types, Uses, Research, & Facts ...

Stem cells have been used in medicine since the 1950s when bone marrow transplants were first used to treat leukemia. Congressional involvement in stem cell policy started as early as 1974.The first major amendment related to the use of federal funds for research involving embryonic stem (ES) cells occurred in 1996.From this point onward, this timeline provides policy landmarks affecting the course of stem cell research in the U.S.For information prior to 1996,click here (link is external).

Congress bans federal funding for research on embryos through the Dickey-Wicker Amendment, named after Reps. Jay Dickey (R-AR) and Roger Wicker (R-MS). The amendment prohibits the use of federal funds for the creation of a human embryo or embryos for research purposes, or research in which a human embryo or embryos are destroyed, discarded or knowingly subjected to risk of injury or death greater than that allowed for research on fetuses in utero.

The National Institutes of Health (NIH), interpreting the Dickey-Wicker Amendment, releases guidelines for research on ES cells.

The guidelines stipulate that:

President George W. Bush prohibits the federal funding of any research using ES cell lines derived after August 9, 2001, but his policy does not affect research in the private sector or research conducted with state funding. The President claims that more than 60 stem cell lines are still available for funding. Research on adult stem cells is not affected by this executive order.

H.R. 810, which would have expanded federal funding for stem cell research to include stem cells derived from embryos created for, but subsequently not used in, the in vitro fertilization process, passes both the House and the Senate in the 109th Congress, attracting bipartisan support. However, the bill is quickly vetoed by President Bush. The House votes 235-193 in favor of the bill, but the two-thirds majority needed to override the veto is not reached.

In the 110th Congress, the Senate passes their version of The Stem Cell Research Enhancement Act (S. 5) with strong bipartisan support, 63-34. The House also passes the Senate's version of the bill 247-176. Again, the bill is vetoed by President Bush, and again Congress cannot override the veto.

President Barack Obama issues an executive order,titled "Removing Barriers to Responsible Scientific Research Involving Human Stem Cells."See the full text here (link is external).

A group of plaintiffs led by adult stem cell scientists James Sherley, M.D., Ph.D., and Theresa Deisher, Ph.D., file a lawsuit against the National Institutes of Health (NIH) and the Department of Health and Human Services, arguing that federal funding of ES cell research is in violation of the Dickey-Wicker amendment. The case was brought up against Kathleen Sebelius, the U.S. Secretary of Health and Human Services at that time.

"Therefore this Court, following the [U.S. Court of Appeals for the D.C. Circuit] reasoning and conclusions, must find that defendants reasonably interpreted the Dickey-Wicker Amendment to permit funding for human embryonic stem cell research because such research is not 'research in which a human embryo or embryos are destroyed' ...The NIH reasonably concluded, as expressed in the notice of proposed rulemaking, that the fundamental policy question of whether to provide federal funds for embryonic stem cell research wasnt a question for it to decide. That policy question is not answered by any congressional law, and it has fallen on three presidential administrations to provide an answer. For all three such administrations, Democratic and Republican, the answer has been to permit federal funding. They have differed only as to the path forward." Royce C. Lamberth, Chief Judge. See the full text of the ruling here.

Researchers at Cedars-Sinai Medical Center and Johns Hopkins University publish results from a clinical trial in which adult stem cells were extracted from patients following a heart attack. The stem cells were grown in a petri dish and were then returned to the patients heart. In the first demonstrated case of therapeutic regeneration, the treatment decreases scarring and leads to regrowth of heart tissue.

In a decision favorable to proponents of ES cell research, the U.S. Court of Appeals for the D.C. Circuit upholds a lower court ruling that dismisses a lawsuit challenging the Obama administrations expansion of federal funding for stem cell research.

The Supreme Court announces that it will not hearSherley v. Sebelius, thereby upholding the previous ruling of the D.C. Circuit Court's ruling. This is a major victory for scientifically and ethically responsible innovative research, Bernard Siegel, spokesperson for the Stem Cell Action Coalition and executive director of the Genetics Policy Institute, says in a statement.

Researchers at the Oregon Health and Science University successfully reprogram human skin cells into ES cells, using a technique called somatic cell nuclear transfer (SCNT). By removing the DNA from an egg cell and replacing it with genetic material from a skin cell, scientists create stem cells that can be programmed into becoming many different cell types, including the contracting cardiomyocytes that make up our heart muscle. Nuclear transfer (NT)-ES cells hold great promise for regenerative medicine because the resulting stem cells are a genetic match to the skin cell donor.

An FDA-approved clinical trial finds that treatment with ES cells improves sight in over half of 18 patients suffering from macular degeneration. The study, published in The Lancet, shows that transplantation of ES cells is safe in the long-term.

The 21stCentury Cures Act includes provisions intended to assure timely regulatory review of regenerative therapies, including cell therapies enabled by stem cell therapy research.

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Timeline of major events in stem cell research policy ...

Signed by President Bill Clinton in 1996, Congress passed the Dickey-Wicker Amendment, in which Jay Dickey and Roger Wicker argued against funding research in which human embryos were created and then destroyed for the purpose of stem cells.

In 2001 President George Bush passed an executive order further limiting research on stem cells by preventing the creation of additional embryonic stem cell lines to add to the 22 in existence at the time. Federal funds were confined for use only in stem cell lines already in existence. In 2009 our current President, Barack Obama had authorized a new executive order highlighting three conditions to be fulfilled for federal funding of embryonic stem cell research.According to How Stem Cells Work, by Stephanie Watson and Craig Freudenrich, these three conditions were:1) The cell line was one of the 22 in existence during the Bush administration or was created from embryos that had been discarded after in vitro fertilization procedures.2) The donors of the embryos were not paid in any way.3) The donors clearly knew that the embryos would be used for research purposes prior to giving consent.

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stem-cells | ETHICAL, LEGAL, AND SOCIAL ISSUES

Many people are also concerned that clones would be produced with a specific need and purpose in mind and such cloned individuals would be traded or sold, amounting to human trafficking which is illegal.

At the other end of spectrum are some experts who are of the opinion that the embryo does not require any particular moral consideration. They say that, at the stage when an embryo is cloned, it is just a bunch of cells that contain DNA, which are not very different from the millions of skin cells that we shed everyday. The embryonic cells at that stage cannot be considered equivalent to a human being because it does not have thoughts, self-awareness, memory, awareness of its environment, sensory organs, internal organs, legs, arms, and so on. They think that the embryo attains human identity or individuality much later during gestation, perhaps at the point when the brain develops so that it becomes aware of itself.

In view of the highly debatable aspects about cloning and weighing in on the pros and cons of this process, UNESCO passed a non-binding "United Nations Declaration on Human Cloning", in March 2005, which states: "Practices which are contrary to human dignity, such as reproductive cloning of human beings, shall not be permitted." In the United States there are no federal laws that ban cloning completely, yet 13 states have banned reproductive cloning. Although many countries have banned cloning, many countries allow therapeutic cloning, a system in which the stem cells are extracted from the pre-embryo, with the intention of generating a whole organ or tissue, so that it can be transplanted back into the person who gave the DNA.

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The Legal and Ethical Issues of Cloning That Make it ...

such de-identified material to be exempted from its coverage (Clayton et al., 1995; Clayton, 1995; Bradburn, 2001; OHRP, 2004; Clayton, 2004).

While the de-identification may clear the institution of any obligations under HIPAA or the need for an IRB-approved informed consent procedure, Clayton (2004) explains that public opinion is different, and that most patients still believe they should be informed of all potential research uses of their biological materials and retain some autonomy over their use. Thus, she concludes that research institutions would be best served by working with patients collectively and individually to ensure appropriate oversight.

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Bradburn NM. 2001. Medical privacy and research. Journal of Legal Studies 30(2):687701.

Burgess MM, Laberge CM, Knoppers BM. 1998. Bioethics for clinicians. 14. Ethics and genetics in medicine. Canadian Medical Association Journal 158(10):13091313.

Clayton EW. 1995. Why the use of anonymous samples for research matters. Journal of Law, Medicine and Ethics 23(4):375377.

Clayton EW. 2004. So what are we going to do about research using clinical information and samples? IRB 26(6):1415.

Clayton EW, Steinberg KK, Khoury MJ, Thomson E, Andrews L, Kahn MJ, Kopelman LM, Weiss JO. 1995. Informed consent for genetic research on stored tissue samples. Journal of the American Medical Association 274(22):17861792.

FDA (Food and Drug Administration). 2004. Eligibility determination for donors of human cells, tissues, and cellular and tissue-based products. Final rule. Federal Register 69(101): 2978529834.

Fernandez CV, Gordon K, Van den Hof M, Taweel S, Baylis F. 2003. Knowledge and attitudes of pregnant women with regard to collection, testing and banking of cord blood stem cells. Canadian Medical Association Journal 168(6):695698.

Fernandez MN. 1998. Eurocord position on ethical and legal issues involved in cord blood transplantation. Bone Marrow Transplantation 22(Suppl. 1):S84S85.

Gluckman E. 2000. Ethical and legal aspects of placental/cord blood banking and transplant. Hematology Journal 1(1):6769.

Haley NR. 1999. Linking donors to stored cord blood units: Duties to donors and recipients. Cancer Research Therapy and Control 8(4):345346.

HHS (U.S. Department of Health and Human Services Office for Civil Rights). December 3, 2002, revised April 3, 2003. General Overview of Standards for Privacy of Individually Identifiable Health Information. [Online] Available: http://www.hipaadvisory.com/regs/finalprivacymod/goverview.htm [accessed March 2005].

HHS. 2003. Privacy and Your Health Information. [Online] Available: http://www.hhs.gov/ocr/hipaa/consumer_summary.pdf [accessed March 2005].

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5 Ethical and Legal Issues | Cord Blood: Establishing a ...

GvHD is a transplant associated disease representing an outcome of two immune systems crashing into each other. In many transplantations from donors, and especially in Bone Marrow Transplantations (BMT), the transplanted immune mature cells (as opposed to stem cells) attack the host (patient receiving the transplant) and create severe morbidity and in many cases even death.

This disease happens as a result of current practices being unable to separate the GvHD causing cells from the much needed stem cells.Cellect's ApoGraft was designed to eliminate immune responses in any transplantation of foreign cells and tissues.

Cellect's AppoGraft technology can be utilized already today to help thousands of development and research centers globally engaged in adult stem cells based therapeutics by providing them with a simplified and cost efficient enriched stem cells for use as a raw material for a wide range of stem cells based therapeutics R&D. Before Cellect's ApoGraft, such procedures were extremely complex, inefficient and required substantial resources in both cost, time and infrastructure requirements. ApoGraft can now be used to significantly advance the use of stem cells across multiple therapeutics indications as well as research and biobanking purposes.

The FDA Orphan Drug Act provides incentives for companies to develop products for rare diseases affecting fewer than 200,000 people inthe United States. Incentives may include tax credits related to clinical trial expenses, an exemption from theFDAuser fee, FDAassistance in clinical trial design and potential market exclusivity for seven years following approval.

About Cellect Biotechnology Ltd.

Cellect Biotechnology (NASDAQ: "APOP", "APOPW") has developed a breakthrough technology for the selection of stem cells from any given tissue that aims to improve a variety of stem cell applications.

The Company's technology is expected to provide pharma companies, medical research centers and hospitals with the tools to rapidly isolate stem cells in quantity and quality that will allow stem cell related treatments and procedures. Cellect's technology is applicable to a wide variety of stem cell related treatments in regenerative medicine and that current clinical trials are aimed at the cancer treatment of bone marrow transplantations.

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss the Company's pathway for commercialization of its technology. These forward-looking statements and their implications are based on the current expectations of the management of the Company only, and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; we may encounter delays or obstacles in launching and/or successfully completing our clinical trials; our products may not be approved by regulatory agencies, our technology may not be validated as we progress further and our methods may not be accepted by the scientific community; we may be unable to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties may develop with our process; our products may wind up being more expensive than we anticipate; results in the laboratory may not translate to equally good results in real clinical settings; results of preclinical studies may not correlate with the results of human clinical trials; our patents may not be sufficient; our products may harm recipients; changes in legislation; inability to timely develop and introduce new technologies, products and applications, which could cause the actual results or performance of the Company to differ materially from those contemplated in such forward-looking statements. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2016 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov. and in the Company's period filings with the SEC and the Tel-Aviv Stock Exchange.

ContactCellect Biotechnology Ltd. Eyal Leibovitz, Chief Financial Officerwww.cellect.co +972-9-974-1444

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FDA Grants Orphan Drug Status to Cellect's ApoGraft for Acute GvHD and Chronic GvHD - PR Newswire (press release)

A spate of new laws goes into effect today following the passage of about 1,200 pieces of legislation by the state legislature during its regular session.

Texans as a whole will be able to text less unless they find themselves in a city like Amarillo where the new state law will trump more restrictive city ordinances and force a more relaxed approach.

That guy walking down the street with a sword wont be subject to arrest.

Jails will follow new mental health procedures and indigent citizens will have new pathways for dealing with minor criminal offenses.

Public safety was at the top of legislators minds during the session that ran from mid-January until the end of May and saw more than 10,000 bills filed for consideration.

Here are a few of the most watched bills that become law today and some insight into how they apply to Amarillo.

Texting and driving (HB 62)

The push for a statewide texting and driving ban has been an ongoing battle for nearly a decade, and this year it was approved by both chambers and signed into law by Gov. Greg Abbott.

The bill bans drivers from texting while a vehicle is moving and makes doing so a misdemeanor offense punishable by a fine of up to $99 on the first offense and up to $200 for repeat offenders. The law only addressees reading, writing or sending electronic messages. So theres going to be a learning curve for police, because certain defenses such as using the phone for a map, for music or for anything other than texting could be used.

Amarillo adopted a hands-free ordinance in September 2012 that was enacted on Jan. 3, 2013. Amarillos local ordinance only allowed drivers to send or view text messages while legally parked, not stopped at a red light, and banned all use of mobile or electronic devices while driving unless they are connected to a hands-free device or for certified emergencies.

The texting and driving law will be uniform for the whole state. This way people can travel from town to town and not have to worry about the laws being different, Amarillo Police Department Office Jeb Hilton said of the new law. The major difference in the state law and the previous city ordinance is that you can now text while stopped at a stop sign or stop light. Our officers will continue to do their best to enforce the law.

Hilton said that from January 1 through July 31, APD wrote 619 citations and issued 244 warnings for use of wireless comunication devices.

While APD will enforce the new law, not everyone associated with the city was happy with the development while it was in special session.

Im really proud of the leadership our city showed five years ago when we enacted that law, Amarillo Mayor Ginger Nelson said of the citys ban on texting and driving. Because this is a public safety issue that will actually decrease the level safety, I am concerned about that.

Large knives (HB 1935)

Its not getting the same chatter as gun laws, but starting next month citizens can openly carry large knives.

State Rep. John Frullo, R-Lubbock, championed a bill that got passed allowing citizens to openly carry large knives in most areas of the state. The bill allows individuals to now carry knives with blades longer than 5 inches, except in certain areas like schools, hospitals and places of worship.

The new knife laws change the wording form illegal knives to location-restricted knives. What this means is that every knife is now legal to carry whether concealed or in the open, Hilton explained. There will still be places that you cannot carry a knife that has a blade that is over 5 inches in length. These include schools, polling places, secure areas of airports, hospitals, churches and bars.

Swords, machetes, Bowie knives and sabers will now be perfectly fine to tote around.

We might see people carrying swords or machetes when the law first goes into effect, but I think once they realize how inconvenient it is things will change, Hilton added. APD wants to stress that there is no reason to call the police just because someone is carrying a large knife or sword in the open, but if they are carrying or using the weapon in a threatening manner be sure to give us a call.

Misdemeanor fines (HB 351)

State lawmakers passed a law aimed at keeping low-income individuals who commit minor offenses out of jail trying to prevent whats often referred to as debtors prisons.

The new law gives judges more leeway in issuing fines and costs for things such as failing to pay parking or speeding tickets, and even the ability to substitute community service for legal fees.

The law aims to make it easier for low-income and low-level offenders to get out of jail, something that local attorneys and prosecutors support with some reservations.

Randall County Distrct Attorney James Farren said he thinks getting low-level and low-income offenders out of jail quickly could help to ease costs by freeing up jail cells, which are a daily expense for taxpayers when occupied. It would also free up space for those who commit the more serious offenses.

Potter County Attorney Scott Brumley agrees with the bills intent but still has some reservations about what costs the city and county might incur.

As I understand, the major impact would be on misdemeanors and non-violent crimes, Brumley said earlier this year when the bill was passed by the House. My reaction I dont oppose looking at the way we improve criminal cases at the pre-trial stage, our office is aware and in agreement, but at some point the county will need a pre-trial services center.

That pre-trial services center or the lack of one in Potter County is one reason Brumley and Farren remain skeptical. The law does not address assisting counties financially to help make pre-trial arrangements for people who could be released early under the bill.

Sandra Bland Act

Lawmakers approved a bill in response to the death of Sandra Bland, who was found dead in a county jail after being held there following a routine traffic stop.

Lawmakers passed a watered-down version of what was originally discussed. The bill that goes into effect Friday mandates that county jails divert people with mental health and substance abuse issues toward treatment and mandates that independent investigations be had if a person dies in custody. The Sandra Bland Act also makes it easier for defendants to receive a personal bond if they have a mental illness or intellectual disability.

Ten other new Texas laws starting today

(HB 25) Eliminates straight-ticket party voting when casting an election ballot.

(HB 29) Allows state lottery winners who win more than $1 million to remain anonymous and prohibits the release of all personal information to the public.

(HB 1424) Prohibits drones and other small aircraft from flying over correction facilities like jails and prisons, and sports venues such as stadiums or facilities with more than 30,000 seats.

(SB 693) Mandates that a school bus be equipped with a three-point seat belt for every passenger. The bill only applies to buses that are 2018-and-newer models.

(SB 16) Reduces the first-time fee for a license to carry from $140 to $40 and the annual renewal fee from $70 to $40.

(HB 810) Allows patients with a severe chronic disease to use stem cell treatment.

(SB 179) Mandates that schools adopt policies related to cyberbullying and requires that schools report offenses. This law also created a new definition of cyberbullying.

(HB 478) If a person enters into a motor vehicle to remove a vulnerable individual, such as a child, that person is immune from civil liability for damage that may occur from entry.

(HB 214) Requires the Supreme Court of Texas and the Court of Criminal Appeals to have audio and video recordings of oral arguments and public meetings available if funds are made available.

(HB 1099) Says landlords cannot prohibit a tenants right to call police or emergency assistance.

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Of cell phones and swords things Amarilloans should know about new state laws - Amarillo.com

About Cellect Biotechnology Ltd.

Cellect Biotechnology is traded the NASDAQ (NASDAQ: "APOP", "APOPW). The Company has developed a breakthrough technology for the isolation of stem cells from any given tissue that aims to improve a variety of stem cells applications.

The Company's technology is expected to provide pharma companies, medical research centers and hospitals with the tools to rapidly isolate stem cells for in quantity and quality that will allow stems cell related treatments and procedures. Cellect's technology is applicable to a wide variety of stem cells related treatments in regenerative medicine and that current clinical trials are aimed at the cancer treatment of bone marrow transplantations.

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss the anticipated benefits of a sole listing on Nasdaq. These forward-looking statements and their implications are based on the current expectations of the management of the Company only, and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: changes in technology and market requirements; we may encounter delays or obstacles in launching and/or successfully completing our clinical trials; our products may not be approved by regulatory agencies, our technology may not be validated as we progress further and our methods may not be accepted by the scientific community; we may be unable to retain or attract key employees whose knowledge is essential to the development of our products; unforeseen scientific difficulties may develop with our process; our products may wind up being more expensive than we anticipate; results in the laboratory may not translate to equally good results in real clinical settings; results of preclinical studies may not correlate with the results of human clinical trials; our patents may not be sufficient; our products may harm recipients; changes in legislation; inability to timely develop and introduce new technologies, products and applications, which could cause the actual results or performance of the Company to differ materially from those contemplated in such forward-looking statements. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2016 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov. and in the Company's period filings with the SEC and the Tel-Aviv Stock Exchange.

ContactCellect Biotechnology Ltd.Eyal Leibovitz, Chief Financial Officerhttp://www.cellect.co+ 972-9-974-1444

SOURCE Cellect Biotechnology Ltd.

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Cellect Shares Will Be Traded From Next Week Exclusively on NASDAQ - PR Newswire (press release)

The guidelines are expected to have a negative list of around 10 items in which research would be prohibited. Besides, outlining areas in which research is permitted, detailed regulatory and technical guidelines would also be laid out.

Indian Council of Medical Research (ICMR) is set to come out with guidelines for stem cell research in two weeks.

The guidelines are expected to have a negative list of around 10 items in which research would be prohibited. Besides, outlining areas in which research is permitted, detailed regulatory and technical guidelines would also be laid out.

The research wing of ministry of health & family welfare is also going to reduce the time taken for approvals in cord and adult stem cell research.

"These two areas would be decentralized at the institutional level to reduce the bureaucratic hurdles. The ethics committee within each institution can look into it and would be required to report to ICMR," said an ICMR official.

However, for embryonic stem cell research, the National Apex Committee would scan every proposal. "This is so because we want to know how the embryos are procured, what's the procedure etc. This is the area that is most vulnerable to abuse", added the official.

The team of experts are meeting in January-end to finalize the guidelines.

In 2002, draft guidelines were issued that ICMR should be the regulatory authority for biological research and a National Apex Committee for cell-based research & therapy should be set up.

The latter should be vested with powers to examine scientific, technical, ethical, legal and social issues in all the three types of stem cell.

See the article here:
ICMR to release stem cell research guidelines soon - BSI bureau (press release)

Representative imageBy Priyanka V Gupta

New Delhi: Indian Council of Medical Research (ICMR) will soon release the final document on guidelines for stem cell research, the draft of which was available on the ICMR and the DBT (Department of Biotechnology) websites for public reviews till July 31 this year. The guidelines are expected to help in curbing the unethical practices in regenerative medicine. The information was shared by Dr Geeta Jotwani, deputy director general, ICMR, at a recent event where MoU was signed between ABLE (Association of Biotechnology Led Enterprise) and FIRM (Forum for Innovative Regenerative Medicine) for industry research collaborations.

Dr Jotwani said, On the directives of DCGI (Drug Controller General of India), ICMR has been framing the guidelines for stem cell research and therapy since 2001. Unfortunately, there is no therapy available other than bone marrow transplantation, for which also no standard of care has been laid out. In that direction, we have been making periodic efforts by releasing the guideline documents in 2002, 2007, 2013 and now the updated documentation for 2017 is under finalization.

ICMR has been proactively working towards educating the stakeholders about the ethical practices in stem cell research and therapy, for which a special committee, called National Apex Committee for Stem Cell Research and Therapy (NAC-SCRT), has been formed to advise the scientists community. Regenerative medicine is an innovative science. As part of ICMR, more research is involved than getting into conclusion that we are ready for application. We are proactively making efforts to educate, create awareness and give directions to our scientists community and clinicians on how they should go about the research part of stem cell therapy, said Dr Jotwani.

There are many clinicians entering into unethical practices and promising general public about the available care in almost all sorts of incurable conditions, including autism, according to Dr Jotwani.

She said, We are always concerned about what the end users are getting and the promises that are being made to them. Hence, we are proactively being involved in interacting with different government agencies as well as the industry to curb the unethical practices for which we also established NAC-SCRT under the Department of Health Research, Government of India. The committee, which comprises of different government agencies as well as ethics and social groups, legal experts, representatives of drug controllers office and CDSCO (Central Drug Standard Control Organization), deliberates on the issues of upcoming technologies and takes proactive role in the regenerative medicine.

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ICMR's stem cell research guidelines soon to be released - ETHealthworld.com

Almost four and a half years ago, then minister for health Dr James Reilly ordered the Health Service Executive not to destroy more than one million blood samples taken from newborn children in the Republic between 1984 and 2002.

The heel-prick tests, known as Guthrie tests, are carried out on all babies to screen for genetic conditions.

The decision to destroy the cards with the blood samples on them came after it emerged that those taken before July 1st, 2011, were being retained without consent, and therefore in breach of national and EU data protection law.

The Royal College of Physicians at the time said there was an explosion of molecular genetics every day that was being added to and that the museum piece cards could prove to be even more valuable in the future.

The Irish Heart Foundation, which had campaigned to save the cards, said some 1,400 families that had lost a member through sudden adult death syndrome would, as a result, be able to get a genetic diagnosis to see if they were at risk.

The debate over those cards and the legality of retaining them still rumbles on, as do ethical questions about the privacy of highly sensitive medical data obtained for one purpose and whether it should ever be used for another without the consent of the original subject, in the absence of a legal exemption.

Meanwhile, medical and scientific researchers are closely watching the new EU General Data Protection Regulation (GDPR) and what it might mean for them and their work after it takes effect next May.

While the regulation allows certain exemptions for processing special cateogories of data, including genetic and biometric data, the Irish legislation hasnt been written yet and researchers are waiting to see what it will mean for their work.

In some cases, they are worried about what the new law will mean for historic datasets and longitudinal studies and whether they will have to delete them on the grounds that they will not have the appropriate standards of explicit consent post May 2018 to retain them.

Even in just a few years, the medical, legal, ethical and social dilemmas involved in processing health data, including biological samples obtained from patients or research study volunteers have become vastly more complex.

The ethical issues that arise around areas such as stem cell research, embryo research and reproductive cloning, genome sequencing, gene editing and population-scale biobanks are huge.

Opportunities for uncovering the causes of disease, for resolving fertility issues, for fixing genetic conditions, for treating cancers, are within the grasp of scientists and researchers, but there is still no international consensus on many issues.

Concerns are evolving too in light of new models for funding research, such as venture capital-backed projects where highly sensitive data used for research, and effectively a permanent record, may ultimately end up being used by or sold for profit to companies or other third parties anywhere in the world.

Researchers are still uncertain what exactly the GDPR will mean for them in terms of the exemptions from data protection legislation that will apply to so-called special categories of data including genetic and biometric health data used for research.

At a recent event in Dublin, the Irish Platform for Patients Organisations, Science and Industry (IPPOSI) explored the concerns about data protection, consent and the forthcoming regulation.

IPPOSI chief executive Dr Derick Mitchell told the event: Patients are aware that the altruistic benefit of being involved in research far outweighs the risks, but they do expect that they will be consulted on the use of their data.

He said empowerment of the data owner was fundamental to the forthcoming changes in the law, and the event explored a model of so-called dynamic consent to allow people consent to have their data used for research, possibly allowing broad consent at the outset and opt-outs at a later stage where they did not agree to new uses. The legal jury is still out on whether such a model is even possible.

Dr Mitchell said a national response was required to GDPR and not just for health research.

He hoped that guidance on the question of consent for processing of personal data expected later in the year from the independent body representing all of the EUs national data protection authorities would be a step forward.

But I think the real crux is the code of conduct and each institution in effect will have to develop their own code of conduct as to how they approach data protection from the beginning of projects rather than having it as a kind of tick-box exercise at the end of a project, he said.

Dr Mitchell said the explicit consent referred to in the EU regulation, for example, had very real consequences for the continuation of large-scale population biobanks, for example.

There was also an ethical argument going on as to whether a persons consent could be said to be informed if they ultimately did not know what the research project might ultimately examine.

Prof Jane Grimson, a member of the e-health Ireland committee and a former director of Health Information in the Health Information and Quality Authority, said the potential of health data and research had to be balanced with a patients right to privacy.

Ownership of patient records was critical, she said.

I think the way we are moving now is much more towards electronic health records that will be owned and controlled by the individual. Its their information and they should be in control of who has a right to see information and the information (that is used in research).

Ethics research committees were critical and needed to operate to a very high standard to ensure the trust of people, she added.

Its an absolute minefield but I really think that ethics committees are critical.

Prof Orla Sheils, director of the Trinity Translational Medicine Institute and director of medical ethics at the School of Medicine, TCD, said she believed GDPR would have immediate consequences for data already being processed by researchers. It was a very grey area.

The difficulty with that is that if data has been collected over a long period of time that a person may not want to be reminded of the time that they were ill. Thats the balance you are trying to find there. So the way to get around that is to try to give people enough options up front to decide yes, I want to gift my sample and provided the research thats going to be done is ethical and has been approved, thats okay by me.

Prof Sheils, who sits on the St Jamess and Tallaght hospital research ethics committee, said all research involving humans had to be approved by such a committee.

Its never an ethical issue if the answer is easy, she said.

Like everything else in life, its about finding that happy balance that people are comfortable with, she said.

There is never really a right answer when there is an ethical dilemma. What I always say to students is that you are hoping for the least bad option.

Cathal Ryan of the office of the Data Protection Commissioner told the IPPOSI event the new EU regulation would bring harmonisation, transparency and accountability to a very dense and complex area. The regulation was very pragmatic and the code of conduct within it would act as a form of self-regulation, with the additional oversight of an independent monitoring body. But he said adequate transparency on data protection in the sector had been lacking.

If there is an erosion of trust, if the health sector doesnt treat an individuals data in the right way, there will be problems.

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Should your medical data be off the record? - The Irish Times - Irish Times

Vaccines are one of humanitys greatest achievements. Credited with saving millions of lives each year from diseases like smallpox, measles, diphtheria, and polio, one would expect vaccines to be enthusiastically celebrated or, at the very least, widely embraced. Why is it, then, that we are witnessing the widespread proliferation of anti-vaccination sentiment? Why is it that some communities in North America, including, for example, areas of Vancouver, are now turning their backs on vaccines in numbers large enough to threaten herd immunity? Current research has shown that over 25% of Canadian parents are concerned or uncertain about the association between vaccines and autism. A similar percentage of parents worry that vaccines could cause serious harm to their children. What are the social forces contributing to this rise in vaccine hesitancy?

There are multiple interrelated reasons for the existence and spread of both aggressive anti-vaccination and subtle vaccine-hesitant perspectives, but they often stem from issues surrounding trust, personal choice, and fear. Vaccination myths are being circulated in communities and wide social networks, and these myths create scientifically unwarranted concerns about the risks and safety of vaccines. While many parties contribute to the proliferation of these myths, there is little doubt that complimentary and alternative (CAM) practitioners are playing a role.

Numerous studies have demonstrated links between CAM and anti-vaccination attitudes; CAM use is associated with not vaccinating children, and CAM training is associated with anti-vaccination attitudes. In our recent investigation of 330 naturopath websites in the Canadian western provinces of British Columbia and Alberta, we found 53 websites containing vaccine-hesitant discourse. That is to say, these websites explicitly denounced vaccinations, raised issues with the harms and risks of vaccines, and/or offered alternative vaccination services such as homeopathic prophylaxes. This easily accessible discourse can contribute to confirmation bias for those already critical of vaccines, and can also heighten skepticism among those with doubts. With increasing numbers of the population going online for health information, it is reasonable to be concerned that discourse of this kind might plant unwarranted seeds of doubt in the minds of some individuals previously comfortable with vaccines. These messages could also spread: if youve ever seen someone share fake news on Facebook, you know what we are talking about.

Notably, it is incorrect and unfair to arrive at the conclusion that CAM = antivaxx. It is, however, important to recognize the presence of significant anti-vaccination sentiment in these communities. We must begin to think of ways to tackle myths and behaviours that put both individuals and communities in harms way.

The solutions, of course, will vary by jurisdiction. As outlined in our paper, in Canada the Competition Bureau and Health Canada could modify advertising standards to curb treatment and performance claims online, and the latter institution could even act to entirely prevent the sale of demonstrably ineffective natural health products like homeopathic remedies. In addition, the right of CAM practitioners like naturopaths to self-regulate their profession could be reconsidered, as there is little indication that evidence-based standards are enforced. Alternatively, third party oversight could force the adoption of such standards. Lastly, better application and enforcement of existing law could help. As more naturopaths and other CAM practitioners position themselves as primary care providers, they become legally responsible to uphold existing common law standards of informed consent. Failing to disclose the overwhelming scientific evidence supporting vaccines when recommending not to vaccinate or to use an ineffective vaccine alternative likely constitutes negligence.

Vaccines are a matter of life and death. We live in a society privileged to have access to incredible medical developments that empower us to make decisions that improve life for ourselves and others. We owe it to ourselves and others to ensure the science of vaccines is not obscured by those attempting to inject doubt and fear into the conversation.

Featured image credit: Virus by qimono. CC0 public domain via Pixabay.

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Combatting the spread of anti-vaccination sentiment - OUPblog (blog)

Embryonic stem cells (ES cells) are pluripotent stem cells derived from the inner cell mass of a blastocyst, an early-stage preimplantation embryo.[1][2] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. Isolating the embryoblast or inner cell mass (ICM) results in destruction of the blastocyst, which raises ethical issues, including whether or not embryos at the pre-implantation stage should be considered to have the same moral or legal status as embryos in the post-implantation stage of development.[3][4]

Human ES cells measure approximately 14 m while mouse ES cells are closer to 8 m.[5]

Embryonic stem cells, derived from the blastocyst stage early mammalian embryos, are distinguished by their ability to differentiate into any cell type and by their ability to propagate. Embryonic stem cell's properties include having a normal karyotype, maintaining high telomerase activity, and exhibiting remarkable long-term proliferative potential.[6]

Embryonic stem cells of the inner cell mass are pluripotent, that is, they are able to differentiate to generate primitive ectoderm, which ultimately differentiates during gastrulation into all derivatives of the three primary germ layers: ectoderm, endoderm, and mesoderm. These include each of the more than 220 cell types in the adult body. Pluripotency distinguishes embryonic stem cells from adult stem cells found in adults; while embryonic stem cells can generate all cell types in the body, adult stem cells are multipotent and can produce only a limited number of cell types. If the pluripotent differentiation potential of embryonic stem cells could be harnessed in vitro, it might be a means of deriving cell or tissue types virtually to order. This would provide a radical new treatment approach to a wide variety of conditions where age, disease, or trauma has led to tissue damage or dysfunction.

In 2012, the Nobel Prize for Medicine was attributed conjointed to John B. Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent.[7]

Additionally, under defined conditions, embryonic stem cells are capable of propagating themselves indefinitely in an undifferentiated state and have the capacity when provided with the appropriate signals to differentiate, presumably via the formation of precursor cells, to almost all mature cell phenotypes.[8] This allows embryonic stem cells to be employed as useful tools for both research and regenerative medicine, because they can produce limitless numbers of themselves for continued research or clinical use.

Because of their plasticity and potentially unlimited capacity for self-renewal, embryonic stem cell therapies have been proposed for regenerative medicine and tissue replacement after injury or disease. Diseases that could potentially be treated by pluripotent stem cells include a number of blood and immune-system related genetic diseases, cancers, and disorders; juvenile diabetes; Parkinson's disease; blindness and spinal cord injuries. Besides the ethical concerns of stem cell therapy (see stem cell controversy), there is a technical problem of graft-versus-host disease associated with allogeneic stem cell transplantation. However, these problems associated with histocompatibility may be solved using autologous donor adult stem cells, therapeutic cloning. Stem cell banks or more recently by reprogramming of somatic cells with defined factors (e.g. induced pluripotent stem cells). Embryonic stem cells provide hope that it will be possible to overcome the problems of donor tissue shortage and also, by making the cells immunocompatible with the recipient. Other potential uses of embryonic stem cells include investigation of early human development, study of genetic disease and as in vitro systems for toxicology testing.[6]

According to a 2002 article in PNAS, "Human embryonic stem cells have the potential to differentiate into various cell types, and, thus, may be useful as a source of cells for transplantation or tissue engineering."[9]

Current research focuses on differentiating ES into a variety of cell types for eventual use as cell replacement therapies (CRTs). Some of the cell types that have or are currently being developed include cardiomyocytes (CM), neurons, hepatocytes, bone marrow cells, islet cells and endothelial cells.[10] However, the derivation of such cell types from ESs is not without obstacles and hence current research is focused on overcoming these barriers. For example, studies are underway to differentiate ES in to tissue specific CMs and to eradicate their immature properties that distinguish them from adult CMs.[11]

Besides in the future becoming an important alternative to organ transplants, ES are also being used in field of toxicology and as cellular screens to uncover new chemical entities (NCEs) that can be developed as small molecule drugs. Studies have shown that cardiomyocytes derived from ES are validated in vitro models to test drug responses and predict toxicity profiles.[10] ES derived cardiomyocytes have been shown to respond to pharmacological stimuli and hence can be used to assess cardiotoxicity like Torsades de Pointes.[12]

ES-derived hepatocytes are also useful models that could be used in the preclinical stages of drug discovery. However, the development of hepatocytes from ES has proven to be challenging and this hinders the ability to test drug metabolism. Therefore, current research is focusing on establishing fully functional ES-derived hepatocytes with stable phase I and II enzyme activity.[13]

Researchers have also differentiated ES into dopamine-producing cells with the hope that these neurons could be used in the treatment of Parkinsons disease.[14][15] Recently, the development of ESC after Somatic Cell Nuclear Transfer (SCNT) of Olfactory ensheathing cells (OEC's) to a healthy Oocyte has been recommended for Neuro-degenerative diseases.[16] ESs have also been differentiated to natural killer (NK) cells and bone tissue.[17] Studies involving ES are also underway to provide an alternative treatment for diabetes. For example, DAmour et al. were able to differentiate ES into insulin producing cells[18] and researchers at Harvard University were able to produce large quantities of pancreatic beta cells from ES.[19]

Several new studies have started to address this issue. This has been done either by genetically manipulating the cells, or more recently by deriving diseased cell lines identified by prenatal genetic diagnosis (PGD). This approach may very well prove invaluable at studying disorders such as Fragile-X syndrome, Cystic fibrosis, and other genetic maladies that have no reliable model system.

Yury Verlinsky, a Russian-American medical researcher who specialized in embryo and cellular genetics (genetic cytology), developed prenatal diagnosis testing methods to determine genetic and chromosomal disorders a month and a half earlier than standard amniocentesis. The techniques are now used by many pregnant women and prospective parents, especially those couples with a history of genetic abnormalities or where the woman is over the age of 35, when the risk of genetically related disorders is higher. In addition, by allowing parents to select an embryo without genetic disorders, they have the potential of saving the lives of siblings that already had similar disorders and diseases using cells from the disease free offspring.[20]

Scientists have discovered a new technique for deriving human embryonic stem cell (ESC). Normal ESC lines from different sources of embryonic material including morula and whole blastocysts have been established. These findings allows researchers to construct ESC lines from embryos that acquire different genetic abnormalities; therefore, allowing for recognition of mechanisms in the molecular level that are possibly blocked that could impede the disease progression. The ESC lines originating from embryos with genetic and chromosomal abnormalities provide the data necessary to understand the pathways of genetic defects.[21]

A donor patient acquires one defective gene copy and one normal, and only one of these two copies is used for reproduction. By selecting egg cell derived from embryonic stem cells that have two normal copies, researchers can find variety of treatments for various diseases. To test this theory Dr. McLaughlin and several of his colleagues looked at whether parthenogenetic embryonic stem cells can be used in a mouse model that has thalassemia intermedia. This disease is described as an inherited blood disorder in which there is a lack of hemoglobin leading to anemia. The mouse model used, had one defective gene copy. Embryonic stem cells from an unfertilized egg of the diseased mice were gathered and those stem cells that contained only healthy hemoglobin genes were identified. The healthy embryonic stem cell lines were then converted into cells transplanted into the carrier mice. After five weeks, the test results from the transplant illustrated that these carrier mice now had a normal blood cell count and hemoglobin levels.[22]

Differentiated somatic cells and ES cells use different strategies for dealing with DNA damage. For instance, human foreskin fibroblasts, one type of somatic cell, use non-homologous end joining (NHEJ), an error prone DNA repair process, as the primary pathway for repairing double-strand breaks (DSBs) during all cell cycle stages.[23] Because of its error-prone nature, NHEJ tends to produce mutations in a cells clonal descendants.

ES cells use a different strategy to deal with DSBs.[24] Because ES cells give rise to all of the cell types of an organism including the cells of the germ line, mutations arising in ES cells due to faulty DNA repair are a more serious problem than in differentiated somatic cells. Consequently, robust mechanisms are needed in ES cells to repair DNA damages accurately, and if repair fails, to remove those cells with un-repaired DNA damages. Thus, mouse ES cells predominantly use high fidelity homologous recombinational repair (HRR) to repair DSBs.[24] This type of repair depends on the interaction of the two sister chromosomes formed during S phase and present together during the G2 phase of the cell cycle. HRR can accurately repair DSBs in one sister chromosome by using intact information from the other sister chromosome. Cells in the G1 phase of the cell cycle (i.e. after metaphase/cell division but prior the next round of replication) have only one copy of each chromosome (i.e. sister chromosomes arent present). Mouse ES cells lack a G1 checkpoint and do not undergo cell cycle arrest upon acquiring DNA damage.[25] Rather they undergo programmed cell death (apoptosis) in response to DNA damage.[26] Apoptosis can be used as a fail-safe strategy to remove cells with un-repaired DNA damages in order to avoid mutation and progression to cancer.[27] Consistent with this strategy, mouse ES stem cells have a mutation frequency about 100-fold lower than that of isogenic mouse somatic cells.[28]

The major concern with the possible transplantation of ESC into patients as therapies is their ability to form tumors including teratoma.[29] Safety issues prompted the FDA to place a hold on the first ESC clinical trial (see below), however no tumors were observed.

The main strategy to enhance the safety of ESC for potential clinical use is to differentiate the ESC into specific cell types (e.g. neurons, muscle, liver cells) that have reduced or eliminated ability to cause tumors. Following differentiation, the cells are subjected to sorting by flow cytometry for further purification. ESC are predicted to be inherently safer than IPS cells because they are not genetically modified with genes such as c-Myc that are linked to cancer. Nonetheless, ESC express very high levels of the iPS inducing genes and these genes including Myc are essential for ESC self-renewal and pluripotency,[30] and potential strategies to improve safety by eliminating c-Myc expression are unlikely to preserve the cells' "stemness". However, N-myc and L-myc have been identified to induce iPS cells instead of c-myc with similar efficiency.[31][32]

In 1964, Lewis Kleinsmith and G. Barry Pierce Jr. isolated a single type of cell from a teratocarcinoma, a tumor now known to be derived from a germ cell.[33] These cells isolated from the teratocarcinoma replicated and grew in cell culture as a stem cell and are now known as embryonal carcinoma (EC) cells.[34] Although similarities in morphology and differentiating potential (pluripotency) led to the use of EC cells as the in vitro model for early mouse development,[35] EC cells harbor genetic mutations and often abnormal karyotypes that accumulated during the development of the teratocarcinoma. These genetic aberrations further emphasized the need to be able to culture pluripotent cells directly from the inner cell mass.

In 1981, embryonic stem cells (ES cells) were independently first derived from mouse embryos by two groups. Martin Evans and Matthew Kaufman from the Department of Genetics, University of Cambridge published first in July, revealing a new technique for culturing the mouse embryos in the uterus to allow for an increase in cell number, allowing for the derivation of ES cells from these embryos.[36]Gail R. Martin, from the Department of Anatomy, University of California, San Francisco, published her paper in December and coined the term Embryonic Stem Cell.[37] She showed that embryos could be cultured in vitro and that ES cells could be derived from these embryos. In 1998, a breakthrough occurred when researchers, led by James Thomson at the University of Wisconsin-Madison, first developed a technique to isolate and grow human embryonic stem cells in cell culture.[38]

On January 23, 2009, Phase I clinical trials for transplantation of oligodendrocytes (a cell type of the brain and spinal cord) derived from human ES cells into spinal cord-injured individuals received approval from the U.S. Food and Drug Administration (FDA), marking it the world's first human ES cell human trial.[39] The study leading to this scientific advancement was conducted by Hans Keirstead and colleagues at the University of California, Irvine and supported by Geron Corporation of Menlo Park, CA, founded by Michael D. West, PhD. A previous experiment had shown an improvement in locomotor recovery in spinal cord-injured rats after a 7-day delayed transplantation of human ES cells that had been pushed into an oligodendrocytic lineage.[40] The phase I clinical study was designed to enroll about eight to ten paraplegics who have had their injuries no longer than two weeks before the trial begins, since the cells must be injected before scar tissue is able to form. The researchers emphasized that the injections were not expected to fully cure the patients and restore all mobility. Based on the results of the rodent trials, researchers speculated that restoration of myelin sheathes and an increase in mobility might occur. This first trial was primarily designed to test the safety of these procedures and if everything went well, it was hoped that it would lead to future studies that involve people with more severe disabilities.[41] The trial was put on hold in August 2009 due to FDA concerns regarding a small number of microscopic cysts found in several treated rat models but the hold was lifted on July 30, 2010.[42]

In October 2010 researchers enrolled and administered ESTs to the first patient at Shepherd Center in Atlanta.[43] The makers of the stem cell therapy, Geron Corporation, estimated that it would take several months for the stem cells to replicate and for the GRNOPC1 therapy to be evaluated for success or failure.

In November 2011 Geron announced it was halting the trial and dropping out of stem cell research for financial reasons, but would continue to monitor existing patients, and was attempting to find a partner that could continue their research.[44] In 2013 BioTime (NYSEMKT:BTX), led by CEO Dr. Michael D. West, acquired all of Geron's stem cell assets, with the stated intention of restarting Geron's embryonic stem cell-based clinical trial for spinal cord injury research.[45]

BioTime company Asterias Biotherapeutics (NYSE MKT: AST) was granted a $14.3 million Strategic Partnership Award by the California Institute for Regenerative Medicine (CIRM) to re-initiate the worlds first embryonic stem cell-based human clinical trial, for spinal cord injury. Supported by California public funds, CIRM is the largest funder of stem cell-related research and development in the world.[46]

The award provides funding for Asterias to reinitiate clinical development of AST-OPC1 in subjects with spinal cord injury and to expand clinical testing of escalating doses in the target population intended for future pivotal trials.[47]

AST-OPC1 is a population of cells derived from human embryonic stem cells (hESCs) that contains oligodendrocyte progenitor cells (OPCs). OPCs and their mature derivatives called oligodendrocytes provide critical functional support for nerve cells in the spinal cord and brain. Asterias recently presented the results from phase 1 clinical trial testing of a low dose of AST-OPC1 in patients with neurologically-complete thoracic spinal cord injury. The results showed that AST-OPC1 was successfully delivered to the injured spinal cord site. Patients followed 2-3 years after AST-OPC1 administration showed no evidence of serious adverse events associated with the cells in detailed follow-up assessments including frequent neurological exams and MRIs. Immune monitoring of subjects through one year post-transplantation showed no evidence of antibody-based or cellular immune responses to AST-OPC1. In four of the five subjects, serial MRI scans performed throughout the 2-3 year follow-up period indicate that reduced spinal cord cavitation may have occurred and that AST-OPC1 may have had some positive effects in reducing spinal cord tissue deterioration. There was no unexpected neurological degeneration or improvement in the five subjects in the trial as evaluated by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam.[48]

The Strategic Partnership III grant from CIRM will provide funding to Asterias to support the next clinical trial of AST-OPC1 in subjects with spinal cord injury, and for Asterias product development efforts to refine and scale manufacturing methods to support later-stage trials and eventually commercialization. CIRM funding will be conditional on FDA approval for the trial, completion of a definitive agreement between Asterias and CIRM, and Asterias continued progress toward the achievement of certain pre-defined project milestones.[49]

In vitro fertilization generates multiple embryos. The surplus of embryos is not clinically used or is unsuitable for implantation into the patient, and therefore may be donated by the donor with consent. Human embryonic stem cells can be derived from these donated embryos or additionally they can also be extracted from cloned embryos using a cell from a patient and a donated egg.[50] The inner cell mass (cells of interest), from the blastocyst stage of the embryo, is separated from the trophectoderm, the cells that would differentiate into extra-embryonic tissue. Immunosurgery, the process in which antibodies are bound to the trophectoderm and removed by another solution, and mechanical dissection are performed to achieve separation. The resulting inner cell mass cells are plated onto cells that will supply support. The inner cell mass cells attach and expand further to form a human embryonic cell line, which are undifferentiated. These cells are fed daily and are enzymatically or mechanically separated every four to seven days. For differentiation to occur, the human embryonic stem cell line is removed from the supporting cells to form embryoid bodies, is co-cultured with a serum containing necessary signals, or is grafted in a three-dimensional scaffold to result.[51]

Embryonic stem cells are derived from the inner cell mass of the early embryo, which are harvested from the donor mother animal. Martin Evans and Matthew Kaufman reported a technique that delays embryo implantation, allowing the inner cell mass to increase. This process includes removing the donor mother's ovaries and dosing her with progesterone, changing the hormone environment, which causes the embryos to remain free in the uterus. After 46 days of this intrauterine culture, the embryos are harvested and grown in in vitro culture until the inner cell mass forms egg cylinder-like structures, which are dissociated into single cells, and plated on fibroblasts treated with mitomycin-c (to prevent fibroblast mitosis). Clonal cell lines are created by growing up a single cell. Evans and Kaufman showed that the cells grown out from these cultures could form teratomas and embryoid bodies, and differentiate in vitro, all of which indicating that the cells are pluripotent.[36]

Gail Martin derived and cultured her ES cells differently. She removed the embryos from the donor mother at approximately 76 hours after copulation and cultured them overnight in a medium containing serum. The following day, she removed the inner cell mass from the late blastocyst using microsurgery. The extracted inner cell mass was cultured on fibroblasts treated with mitomycin-c in a medium containing serum and conditioned by ES cells. After approximately one week, colonies of cells grew out. These cells grew in culture and demonstrated pluripotent characteristics, as demonstrated by the ability to form teratomas, differentiate in vitro, and form embryoid bodies. Martin referred to these cells as ES cells.[37]

It is now known that the feeder cells provide leukemia inhibitory factor (LIF) and serum provides bone morphogenetic proteins (BMPs) that are necessary to prevent ES cells from differentiating.[52][53] These factors are extremely important for the efficiency of deriving ES cells. Furthermore, it has been demonstrated that different mouse strains have different efficiencies for isolating ES cells.[54] Current uses for mouse ES cells include the generation of transgenic mice, including knockout mice. For human treatment, there is a need for patient specific pluripotent cells. Generation of human ES cells is more difficult and faces ethical issues. So, in addition to human ES cell research, many groups are focused on the generation of induced pluripotent stem cells (iPS cells).[55]

On August 23, 2006, the online edition of Nature scientific journal published a letter by Dr. Robert Lanza (medical director of Advanced Cell Technology in Worcester, MA) stating that his team had found a way to extract embryonic stem cells without destroying the actual embryo.[56] This technical achievement would potentially enable scientists to work with new lines of embryonic stem cells derived using public funding in the USA, where federal funding was at the time limited to research using embryonic stem cell lines derived prior to August 2001. In March, 2009, the limitation was lifted.[57]

The iPSC technology was pioneered by Shinya Yamanakas lab in Kyoto, Japan, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells.[58] He was awarded the 2012 Nobel Prize along with Sir John Gurdon "for the discovery that mature cells can be reprogrammed to become pluripotent." [59]

In 2007 it was shown that pluripotent stem cells highly similar to embryonic stem cells can be generated by the delivery of three genes (Oct4, Sox2, and Klf4) to differentiated cells.[60] The delivery of these genes "reprograms" differentiated cells into pluripotent stem cells, allowing for the generation of pluripotent stem cells without the embryo. Because ethical concerns regarding embryonic stem cells typically are about their derivation from terminated embryos, it is believed that reprogramming to these "induced pluripotent stem cells" (iPS cells) may be less controversial. Both human and mouse cells can be reprogrammed by this methodology, generating both human pluripotent stem cells and mouse pluripotent stem cells without an embryo.[61]

This may enable the generation of patient specific ES cell lines that could potentially be used for cell replacement therapies. In addition, this will allow the generation of ES cell lines from patients with a variety of genetic diseases and will provide invaluable models to study those diseases.

However, as a first indication that the induced pluripotent stem cell (iPS) cell technology can in rapid succession lead to new cures, it was used by a research team headed by Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, to cure mice of sickle cell anemia, as reported by Science journal's online edition on December 6, 2007.[62][63]

On January 16, 2008, a California-based company, Stemagen, announced that they had created the first mature cloned human embryos from single skin cells taken from adults. These embryos can be harvested for patient matching embryonic stem cells.[64]

The online edition of Nature Medicine published a study on January 24, 2005, which stated that the human embryonic stem cells available for federally funded research are contaminated with non-human molecules from the culture medium used to grow the cells.[65] It is a common technique to use mouse cells and other animal cells to maintain the pluripotency of actively dividing stem cells. The problem was discovered when non-human sialic acid in the growth medium was found to compromise the potential uses of the embryonic stem cells in humans, according to scientists at the University of California, San Diego.[66]

However, a study published in the online edition of Lancet Medical Journal on March 8, 2005 detailed information about a new stem cell line that was derived from human embryos under completely cell- and serum-free conditions. After more than 6 months of undifferentiated proliferation, these cells demonstrated the potential to form derivatives of all three embryonic germ layers both in vitro and in teratomas. These properties were also successfully maintained (for more than 30 passages) with the established stem cell lines.[67]

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