Embryonic Stem Cell Research | Voices in Bioethics

Introduction

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

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

Personhood and the Scientific Questionability of Embryonic Stem Cell Research

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

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

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

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

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

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

Principle of Beneficence in Embryonic Stem Cell Research

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

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

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

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

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

Conclusion

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

References

Shamblott, M. J., J. Axelman, S. Wang, E. M. Bugg, J. W. Littlefield, P. J. Donovan, P. D. Blumenthal, G. R. Huggins, and J. D. Gearhart. Derivation of Pluripotent Stem Cells from Cultured Human Primordial Germ Cells. Proceedings of the National Academy of Sciences 95, no. 23 (November 10, 1998): 1372631. doi:10.1073/pnas.95.23.13726.

National Institutes of Health, U.S. Department of Health and Human Services. Stem Cell Basics I. Stem Cell Information, 2016. https://stemcells.nih.gov/info/basics/1.htm.

Kitwood, Thomas Marris., Clive Baldwin, and Andrea Capstick. Tom Kitwood on Dementia: A Reader and Critical Commentary. Maidenhead, Berkshire: McGraw-Hill/Open University Press, 2007.

University of Michigan. Stem Cell Research: Frequently Asked Questions, 2013. http://www.stemcellresearch.umich.edu/overview/faq.html#section2.

EuroStemCell. Origins, Ethics and Embryos: The Sources of Human Embryonic Stem Cells, 2016. https://www.eurostemcell.org/origins-ethics-and-embryos-sources-human-embryonic-stem-cells.

Perry, David L. Some Issues in Contemporary Neurological Science and Technology, 2011. https://www.scu.edu/ethics/focus-areas/bioethics/resources/ethics-and-personhood/.

Swirsky, E. Week Fourteen Unit: Minute Paper 5 [Blackboard Assignment], 2018.

OMathna, DP. Personhood in Bioethics and Biomedical Research. Research Practitioner 7 (2006): 16774.

Grobstein, C. External Human Fertilization. Scientific American 240, no. 6 (June 1979): 5767.

Mastin, L. Deontology, 2009. https://www.philosophybasics.com/branch_deontology.html.

Spitzer, Robert. Introduction and Principles of Ethics. In Ten Universal Principles: A Brief Philosophy of the Life Issues, xixii, 1-3, 20-29. San Fransisco, CA: Ignatius Press, 2011. https://www.catholiceducation.org/en/religion-and-philosophy/philosophy/introduction-amp-principles-of-ethics.html.

Eckman, Jim. Human Embryonic Stem Cell Research. Issues In Perspective, 2011. https://graceuniversity.edu/iip/2011/05/14-2/.; Eckman, Jim. The Devaluing of Life in America. Issues In Perspective, 2015. https://graceuniversity.edu/iip/2015/09/the-devaluing-of-life-in-america/.

Outka, Gene (2009) "The Ethics of Embryonic Stem Cell Research and the Principle of "Nothing is Lost","Yale Journal of Health Policy, Law, and Ethics: Vol. 9 : Iss. 3 , Article 7.

Curzer, Howard. The Ethics Of Embryonic Stem Cell Research. The Journal of Medicine and Philosophy 29, no. 5 (October 1, 2004): 53362. doi:10.1080/03605310490514225.

Lo, Bernard, and Lindsay Parham. Ethical Issues in Stem Cell Research. Endocrine Reviews 30, no. 3 (May 2009): 20413. doi:10.1210/er.2008-0031.

Hubbard, James. Embryonic Stem-Cell Research: Experts Debate Pros and Cons. The Survival Doctor, 2013. http://thesurvivaldoctor.com/2013/02/14/doctors-debate-embryonic-stem-cell-research-pros-and-cons/.

Koch, Valerie Gutmann, Beth E. Roxland, Barbara Pohl, and Sarah K. Keech. Contemporary Ethical Issues in Stem Cell Research. In Stem Cells Handbook, 2937. New York, NY: Springer New York, 2013. doi:10.1007/978-1-4614-7696-2_2.

Cahill, Lisa Sowle. "Holland, Suzanne, Karen Lebacqz, and Laurie Zoloth, Eds. The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy." The National Catholic Bioethics Quarterly 2, no. 3 (2002): 559-62. doi:10.5840/ncbq20022344.

Devolder, Katrien. The Ethics of Embryonic Stem Cell Research. Oxford University Press, 2015. doi:10.1093/acprof:oso/9780199547999.001.0001.

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Embryonic Stem Cell Research | Voices in Bioethics

Researchers Share Insights about Mechanisms of Human Embryo and Create Method to Develop Transcriptionally Similar Cells in Tissue Culture – Newswise

UNDER EMBARGO UNTIL APRIL 28, 2022 at 11:00 AM E

Paper Title: Identification of a retinoic acid-dependent hemogenic endothelial progenitor from human pluripotent stem cells

Journal: Nature Cell Biology

Authors:Christopher Sturgeon, PhD, Associate Professor of Cell, Developmental & Regenerative Biology and Medicine, Hematology & Medical Oncology in the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai, and other coauthors.

Bottom Line:Blood-forming stem cells found in bone marrow are the life-saving component used in bone marrow transplants. However, suitable donors often cannot be found in many cases. This study reveals how the human embryo develops the precursor to blood-forming stem cells, which researchers say can be used in the novel method they developed to generate blood-forming stem cells from cells in tissue culture.

The studyled by researchers from Mount Sinai and the San Raffaele Telethon Institute for Gene Therapy in Milan Italyconfirms many aspects of cell development, including origins and regulation, which are known to occur within both the mouse and human embryo. In the mammalian embryo, blood-forming stem cells emerge from a specialized cell type called hemogenic endothelium. These cells develop in response to a critical signal pathway known as retinoic acid, which is essential for growth. Their analysis found that stem cell populations derived from human pluripotent stem cells were transcriptionally similar to cells in the early human embryo.

Results: For years, researchers in the field of regenerative medicine have been able to obtain hemogenic endothelium from embryonic stem cells, but these cells do not produce blood-forming stem cells. In the embryo, blood-forming stem cell development requires signaling by retinoic acid. But, current state-of-the-art methods for deriving blood progenitors from human pluripotent stem cells do so in the absence of retinoic acid. In this latest study, researchers examined the dependence on retinoic acid in early cell types derived from human pluripotent stem cells. They performed single cell RNA sequencing of stem cells in vitro to better understand patterns of mesodermal cell types during early development. The research team identified a new strategy to obtain cells that are transcriptionally similar to those hemogenic endothelial cells found in the human embryo by stimulating a very discrete original population with retinoic acid.

Why the Research Is Interesting:This new method brings researchers and scientists closer to developing blood-forming stem cells in tissue culture, but also provides a pathway to establishing specialized blood cell types for transfusions and other treatments for cancer since the new method makings it possible to obtain the same original cells in adult blood that are found in a developing embryo.

Said Mount Sinai's Dr. Christopher Sturgeon of the research: We have made a major breakthrough in our ability to direct the development of stem cells in a tissue culture dish into cells that have the same gene expression signature as the immediate progenitor of a blood-forming stem cell found in the developing embryo. With this, now we can focus our efforts at understanding how to capture embryonic blood-forming stem cells, with the goal of using them as a substitute for bone marrow.

Researchers from the Washington University School of Medicine in St. Louis, MO contributed to this study.

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Researchers Share Insights about Mechanisms of Human Embryo and Create Method to Develop Transcriptionally Similar Cells in Tissue Culture - Newswise

Development and regulation of stem cellbased therapies in China – Newswise

Background

Clinical researches of stem cell-based therapies are highly active in China, while it was arduous to determine the most effective way of clinical translation of those advanced therapies.

This article briefly introduced the regulatory framework development, the progress in stem cell clinical researches and clinical trials of commercially developed stem cell-based products, as well as the clinical review concerns of stem cell-based products in China.

The current regulatory framework of stem cell clinical researches in China was launched in 2015, when regulatory authorities issued Administrative Measures on Stem Cell Clinical Research (AMSCCR) detailing the rules of stem cell clinical research. Thereafter, the rapidly growing stem cell clinical researches were rigorously managed and clinical use of stem cell therapy was halted. Meanwhile, commercially developed stem cell-based products are supervised by Drug Administration Law (DAL).

The regulatory framework of stem cell-based therapy in China has progressed in the last few decades, which is currently regulated according to AMSCCR and DAL. Well-designed and patient-focused clinical trial is required for commercially developed stem cell-based products, and definite clinical benefit evidence is crucial to obtain marketing authorization.

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Development and regulation of stem cellbased therapies in China - Newswise

Cellectis Receives $20 Million Convertible Note Under Collaboration Agreement with its Partner … – The Bakersfield Californian

Cellectis is developing custom TALEN for Cytovia to develop gene-edited iPSC-derived Natural Killer cellsCytovia and Isleworth Healthcare Acquisition Corp. announce business combination agreementand combined company is expected to be listed on NASDAQ under the ticker symbol INKC$20 million noterepresents upfrontcollaboration consideration and would convert into common stock upon completion of the business combination

NEW YORK, April 27, 2022 (GLOBE NEWSWIRE) -- Cellectis (the Company) (Euronext Growth: ALCLS - NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, announces today that its partner Cytovia Therapeutics, LLC (Cytovia), a biopharmaceutical company empowering natural killer (NK) cells to fight cancer through stem cell engineering and multispecific antibodies, entered into a definitive business combination agreement with Isleworth Healthcare Acquisition Corp. (NASDAQ: ISLE) (Isleworth), a Special Purpose Acquisition Company (SPAC).

Concurrent with the business combination agreement, Cellectis received a $20 million convertible note in payment of the upfront collaboration consideration provided for pursuant to the research collaboration and non-exclusive license agreement entered between Cellectis and Cytovia in February 2021. The terms of the note provide for conversion into common stock of the combined company upon completion of the business combination, which is subject to the satisfaction or waiver of customary closing conditions. In connection with this convertible note, Cellectis received a warrant to purchase additional shares of the combined company representing up to 35% of the shares issued upon conversion of the note at a predetermined exercise price, with the number of shares issuable upon exercise and the exercise subject to certain adjustments.

We are impressed by the progress Cytovia has accomplished in the past months. Cytovia shares Cellectis mission to provide life-saving off-the-shelf allogeneic cell therapies to patients, and we are excited to be providing them with best-in-class TALEN gene editing for cell therapy applications. Congratulations to the Cytovia team for this transaction, which is an important milestone as they continue their journey to progress gene-edited NK therapeutics towards a cure for cancer! said Andr Choulika, CEO of Cellectis.

Cellectis and Cytovias research and development collaboration:

In February 2021, Cellectis and Cytovia entered into a strategic research and development collaboration to develop TALEN gene-edited iPSC NK and CAR-NK cells. In November 2021, Cellectis and Cytovia extended their collaboration to include new CAR target and development in China by Cytovias strategic partner, CytoLynx Therapeutics.

Financial terms of the collaboration include the $20 million convertible note as well as up to $805 million of development, regulatory, and sales milestones and single-digit royalty payments on the net sales of all partnered products commercialized by Cytovia.

Cellectis is developing custom TALEN, which Cytovia uses to edit iPSCs. Cytovia is responsible for the differentiation and expansion of the gene-edited iPSC master cell bank into NK cells and is conducting the pre-clinical evaluation, clinical development, and commercialization of the mutually-agreed-upon selected therapeutic candidates. Cellectis has granted Cytovia a worldwide license under the patent rights over which Cellectis has control in this field, including in China, in order for Cytovia to modify NK cells to address multiple gene-targets for therapeutic use in several cancer indications.

About Cellectis

Cellectis is a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies. Cellectis utilizes an allogeneic approach for CAR-T immunotherapies in oncology, pioneering the concept of off-the-shelf and ready-to-use gene-edited CAR T-cells to treat cancer patients, and a platform to make therapeutic gene editing in hemopoietic stem cells for various diseases. As a clinical-stage biopharmaceutical company with over 22 years of expertise in gene editing, Cellectis is developing life-changing product candidates utilizing TALEN, its gene editing technology, and PulseAgile, its pioneering electroporation system to harness the power of the immune system in order to treat diseases with unmet medical needs. Cellectis headquarters are in Paris, France, with locations in New York, New York and Raleigh, North Carolina. Cellectis is listed on the Nasdaq Global Market (ticker: CLLS) and on Euronext Growth (ticker: ALCLS).

For more information, visit http://www.cellectis.com. Follow Cellectis on social media: @cellectis, LinkedIn and YouTube.

Forward-looking Statements

This press release contains forward-looking statements within the meaning of applicable securities laws, including the Private Securities Litigation Reform Act of 1995. Forward-looking statements may be identified by words such as anticipate, believe, intend, expect, plan, scheduled, could and will, or the negative of these and similar expressions. These forward-looking statements, which are based on our managements current expectations and assumptions and on information currently available to management. Forward-looking statements include statements about the business combination of Cytovia and Isleworth, the conversion of the convertible note, the progress and advancement of the research collaboration with Cytovia, and the receipt by Cellectis of development, regulatory, and sales milestones and royalty payments from Cytovia. These forward-looking statements are made in light of information currently available to us and are subject to numerous risks and uncertainties, including with respect to the numerous risks associated with biopharmaceutical product candidate development, market conditions, and the ability of Cytovia and Isleworth to satisfy the conditions of the business combination agreement. Furthermore, many other important factors, including those described in our Annual Report on Form 20-F and the financial report (including the management report) for the year ended December 31, 2021 and subsequent filings Cellectis makes with the Securities and Exchange Commission from time to time, as well as other known and unknown risks and uncertainties may adversely affect such forward-looking statements and cause our actual results, performance or achievements to be materially different from those expressed or implied by the forward-looking statements. Except as required by law, we assume no obligation to update these forward-looking statements publicly, or to update the reasons why actual results could differ materially from those anticipated in the forward-looking statements, even if new information becomes available in the future.

About Cytovia

Cytovia aims to accelerate patient access to transformational cell therapies and immunotherapies, addressing several of the most challenging unmet medical needs in cancer. Cytovia focuses on harnessing the innate immune system by developing complementary and disruptive NK-cell and NK-engager antibody platforms. Cytovia is developing three types of iPSC-derived (or iNK) cells: unedited iNK cells, TALEN gene-edited iNK cells with improved function and persistence, and TALEN gene-edited iNK cells with chimeric antigen receptors (CAR-iNKs) to improve tumor-specific targeting. The second complementary cornerstone technology is a quadrivalent multifunctional antibody platform designed to engage natural killer cells by targeting NKp46 using Cytovias proprietary Flex-NK technology.

These two technology platforms are being used to develop treatment of patients with solid tumors such as HCC and Glioblastoma as well as hematological malignancies such as Refractory Multiple Myeloma.

Headquartered in Aventura, FL, Cytovia has research and development laboratories in Natick, MA, and a GMP cell manufacturing facility in Puerto Rico. The companys own R&D work is augmented through scientific partnerships with Cellectis, CytoImmune, the Hebrew University of Jerusalem, INSERM, the New York Stem Cell Foundation and the University of California San Francisco (UCSF).

Cytovia has a strategic partnership with CytoLynx Therapeutics, which is focused on research and development, manufacturing, and commercialization activities in Greater China and beyond.

For further information on Cellectis, please contact:

Media contacts: Pascalyne Wilson,Director,Communications,+33 (0)7 76 99 14 33, media@cellectis.com Margaret Gandolfo, Senior Manager, Communications, +1 (646) 628 0300

Investor Relation contact: Arthur Stril, Chief Business Officer, +1 (347) 809 5980, investors@cellectis.com Ashley R. Robinson, LifeSci Advisors, +1 617430 7577

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Cellectis Receives $20 Million Convertible Note Under Collaboration Agreement with its Partner ... - The Bakersfield Californian

Highland Therapeutics Announces Appointment of Stephanie C. Read as President/CEO, Changes to Board of Directors – BioSpace

TORONTO--(BUSINESS WIRE)-- Highland Therapeutics Inc., a privately held pharmaceutical company that through its wholly owned subsidiary, Ironshore Pharmaceuticals Inc., is focused on the commercialization of JORNAY PM (methylphenidate HCl) extended-release capsules (CII) for patients with ADHD, today announced the appointment of Stephanie C. Read as President/Chief Executive Officer, the appointment of Scott Myers as Chair of the Board and the additions of Kevin Bain and Ildiko Mehes as independent members of the Board of Directors. Stefan Antonsson, who has been serving as interim CEO will return to his role as an independent director.

It is my pleasure to congratulate Ms. Read in her transition from the Board of Directors to President/CEO, said Scott Myers, recently appointed Chair of the Board. Ms. Reads leadership in product development, corporate strategy, business development and specialty care commercialization will be key to driving sustainable growth with JORNAY PM, while enabling diversification into new therapeutic areas. I look forward to working closely with her to create value for patients, our employees and stakeholders."

The Board is grateful to interim CEO Stefan Antonsson for providing strategic direction and leadership continuity as we completed the financial restructuring of the company. After a brief transition, Stefan will return to his role as an independent member of the Board of Directors.

Commenting on her appointment, Ms. Read said, Highland and its subsidiaries are a rare instance of a privately held company with an exciting commercial product and experiencing rapid growth. I am pleased to join this seasoned executive team who have been successful in developing and launching JORNAY PM. With new capital from our shareholders and fresh perspectives from the new Board, we have the opportunity to continue to develop our products, people, processes and culture as we explore additional populations who may benefit from JORNAY PM."

Board of Directors:

Scott Myers, Chair of Board

Mr. Myers is a proven executive who brings nearly three decades of global pharmaceutical and medical technology most recently as CEO of AMAG, sold to Covis Pharmaceuticals, SA in November of 2020. Mr. Myers is a serial CEO, serving as Chairman and Chief Executive Officer of Rainier Therapeutics, a clinical-stage biotechnology company focused on metastatic bladder cancer that was purchased by Fusion Pharmaceuticals in March of 2020. Prior to joining Rainier, Mr. Myers served as Chief Executive Officer, President and as a director of Cascadian Therapeutics Inc. prior to its acquisition by SeaGen in March of 2018. Mr. Myers also served as Chief Executive Officer of Aerocrine AB, a medical device company from 2011 to 2015 prior to its acquisition by Circassia. Mr. Myers is currently an independent director of Selecta Biosciences where he serves as the Chair of the Compensation and Benefits Committee, as well as a member of the Nominating and Governance Committee. Mr. Myers also serves as the Chairman of the Board and Chairman of the Nomination and Governance committees and is a member of the Audit Committee for Harpoon Therapeutics, a clinical stage oncology company. Mr. Myers is also Chairman of the Board for Sensorion, SA, a gene therapy company focused on inner ear diseases. Mr. Myers is also Chairman of the Board of Dynavax Technologies, a Hepatitis B vaccine and COVID Adjuvant commercial stage company.

Stefan Antonsson, Independent Director

Mr. Antonsson has over 30 years of commercial experience in the pharmaceutical industry, primarily as a senior marketing executive, and he has established a proven track record of contributing to the success of rapidly growing pharmaceutical companies. Stefan was a key member of the Richwood/Shire senior management team and played a leadership role in launching Adderall and developing Adderall XR, acquiring and launching Carbatrol, and initiating the development of Intuniv. Stefan has also held senior marketing positions with Pharmacia and Forest Laboratories and executive positions with Vela Pharmaceuticals and Xanodyne Pharmaceuticals. Stefan has also been involved in several entrepreneurial ventures which successfully developed, licensed, and commercialized CNS products. Stefan also completed a long-term consulting assignment as Senior Vice-President of Marketing for Supernus Pharmaceuticals where he was part of the senior management team that established the commercial function for the company and successfully launched two anti-epilepsy drugs. Stefan earned his BA from Columbia College and MBA from The Stern School of Business, NYU.

Kevin Bain, Independent Director and Chair of Audit Committee

Mr. Bain is currently Chief Corporate Development Officer of Cell Research Corporation, a Singapore-based biologics company. This is a clinical-stage company developing a platform of products using stem cells from the umbilical cord lining membrane. From early 2006 through mid-2020, Kevin worked in the generic pharmaceutical and biosimilar business in companies founded and led by Robert Wessman. Kevin joined Alvogen in August 2009 as Chief Financial Officer, with responsibility for all Finance and Information Technology functions for the global Alvogen business. In November 2015, Kevin moved to a sister company named Alvotech as Chief Financial Officer. He has led several financing rounds, raising more than $1.5 billion in total value. Prior to joining Alvogen and Alvotech he spent almost four years with Actavis as Vice President of Finance for the US business of Actavis. From mid-2001 to early 2006, Mr. Bain was VP of Finance with a division of Danaher Corporation. From 1979 to 2001, Mr. Bain held positions of increasing responsibility within the finance organization of the Johnson & Johnson Family of Companies in both Canada and the US, including Vice President of Finance for J&J Medical Products. Mr. Bain graduated from the Accounting program at Fanshawe College in London, Ontario, Canada, and later earned his Certified Management Accountant (CMA) designation. Kevin is currently a Board member and Chair of the Audit Committee of Akorn Pharmaceuticals, a leading US-based specialty pharmaceuticals company.

Ildiko Mehes, Independent Director

Ms. Mehes is an advisor to investment management firms, consulting firms and pharmaceutical companies about a wide range of risks and opportunities in the pharmaceutical industry. She previously spent 12 years at Teva Pharmaceuticals in a variety of business and legal roles including, most recently, Senior Vice President & General Counsel. Her areas of responsibility in the U.S. and Canada spanned New Product & Portfolio, R&D, Regulatory Affairs, and Legal Affairs. She has extensive expertise in intellectual property, including related to ADHD drugs, and also has significant pharmaceutical M&A experience. Prior to Teva, Ildiko was a pharmaceutical patent and commercial litigator. Ildiko is admitted to the Bars of Massachusetts and Ontario, Canada. She is also the recipient of several awards, including the National Post/ ZSA Canadian General Counsel Award for Litigation Management and the Association of Corporate Counsels Global Award for Litigation Management. Ildiko holds a B.A. (Honors) in Economics from Queens University, a J.D. from Osgoode Hall Law School, both in Canada, and completed the Advanced Management Program at the Wharton Business School.

Stephanie C. Read, Chief Executive Officer

In addition to serving as the newly appointed President/CEO, Stephanie will continue to have a seat on the Board of Directors. Ms. Read also serves as a Non-Executive Director on the Board of ALSP Orchid Acquisition Corporation I. Ms. Read's 24-year biopharmaceutical career spans Global Research and Development, Medical Affairs, Alliance Management, Commercial and Business Development and Equity Investing. All leadership roles have included driving transformational change within organizations to accelerate top- and bottom-line growth, and diversification of company portfolios. Ms. Read's therapy area expertise includes Psychiatry (inventorship of MYDAYIS), Gastroenterology, Oncology & Pain, Infectious Disease, Immunology and Rare Diseases. Ms. Read's industry appointments include the last 6.5 years with CSL as global VP, Corporate Strategy and Business Development, 7.5 years with AstraZeneca/MedImmune in a variety of Medical Affairs, Commercial and Business Development roles, and over six years with Shire PLC in R&D and Global Medical Affairs (including inventing, developing and launching new treatments for ADHD). Stephanie holds a M.Sc. in Biotechnology from The Johns Hopkins University and a B.Sc. in Biology from Virginia Tech.

WARNING: ABUSE AND DEPENDENCE

See full prescribing information for complete boxed warning.

See additional important safety information below.

IMPORTANT SAFETY INFORMATION

WARNING: ABUSE AND DEPENDENCE

CNS stimulants, including JORNAY PM, other methylphenidate-containing products, and amphetamines, have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

PREGNANCY AND LACTATION

Please visit http://ironshorepharma.com/labeling.pdf for additional important safety information and the Full Prescribing Information, including Boxed Warning, for JORNAY PM.

About Highland Therapeutics Inc.

Highland Therapeutics Inc. is a pharmaceutical company whose mission is to develop and commercialize innovative, patient-centric treatment options. Based in North Carolina, subsidiary Ironshore Pharmaceuticals Inc. is responsible for the sales, marketing and distribution of pharmaceutical products within the US. Based in Grand Cayman, subsidiary Ironshore Pharmaceuticals & Development, Inc. develops novel therapeutics by leveraging its proprietary drug-delivery technology.

Forward-Looking Statements

This press release contains forward-looking information, which reflects the companys current expectations regarding future events. Forward-looking information is based on a number of assumptions and is subject to a number of risks and uncertainties, many of which are beyond the companys control that could cause actual results and events to differ materially from those that are disclosed in or implied by such forward-looking information. These forward-looking statements are made as of the date of this press release and, except as expressly required by applicable law, the company assumes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220426006027/en/

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Highland Therapeutics Announces Appointment of Stephanie C. Read as President/CEO, Changes to Board of Directors - BioSpace

An international consortium, led by IRB Barcelona and the biotechnology company Merus, reports the discovery of MCLA-158, the first clinical candidate…

image:Schematic depiction of MCLA-158 showing monovalent affinities of the EGFR (Fab232) and LGR5 (Fab072) Fab arms. view more

Credit: IRB Barcelona and Merus N.V.

Barcelona, 25 April 2022- Scientists from an international consortium led by Dr. Eduard Batlle, head of the Colorectal Cancer laboratory at IRB Barcelona, ICREA researcher and group leader of CIBER de Cncer (CIBERONC), together with the Dutch company Merus N.V., reveal the preclinical data that has led to the discovery of MCLA-158 and its mechanism of action on cancer stem cells. Named Petosemtamab, the antibody MCLA-158 prevents the onset of metastasis (that is, the spread of cancer to other vital organs) and slows the growth of primary tumours in experimental models of cancer.

Published today in Nature Cancer, the study also lays the groundwork for the use of organoids in the drug discovery process undertaken by pharmaceutical companies. Organoids are patient-derived samples that can be grown in the laboratory, and they reproduce certain aspects of the tumour compartment. Until now, their usefulness was being explored in personalised cancer medicinemeaning their value in helping physicians make decisions about the best treatment for each patient. However, for the selection of MCLA-158, a biobank of organoids from cancer patients was used for the first time to discriminate which new antibody, among hundreds, was most effective and believed to be most suitable for the majority of patients.

In October 2021, Merus N. V. reported preliminary data corresponding to interim efficacy analysis based on investigator review of its sponsored ongoing phase 1 dose expansion clinical trial investigating the safety, tolerability, and anti-tumour activity of MCLA-158 monotherapy in advanced head and neck squamous cell carcinoma (HNSCC). Three of seven HNSCC patients achieved partial responses, with one achieving complete response after the data cutoff date of August 2021. Tumour reduction was observed in all seven patients.

It is highly satisfying to see that our discoveries are helping patients. We started studying cancer stem cells 15 years ago. The journey to this point has been exciting but also very complex, and it has required a large investment of resources, as well as a great deal of work by many researchers. This study and the collaboration with Merus. N.V. reflects IRB Barcelona's focus: The medicine of the future starts here, says Dr. Batlle.

MCLA-158: a double-action antibody

Antibodies are proteins that are naturally produced by our bodies to recognise infectious agents or altered cells so that these can be removed by the lymphocytes of the immune system (white blood cells). The antibody described in this work, Petosemtamab (Peto, MCLA-158: LGR5 x EGFR Biclonics), is a bi-specific antibody that recognises two proteins, namely EGFR and LGR5, on the surface of cancer stem cells.

EGFR activity promotes uncontrolled cell growth, while LGR5 marks the surface of cancer stem cells, which are responsible for tumour expansion. Dr. Batlle's laboratory is recognised worldwide for its work on the identification and characterisation of colorectal cancer stem cells, and it has led work not only on the development of MCLA-158/ Petosemtamab but also on the characterisation of its mechanism of action.

In short, MCLA-158/ Petosemtamab degrades the EGFR protein in cancer stem cells that have the LGR5 marker, thereby blocking the growth and survival pathways in the cells that initiate and spread cancer. However, this antibody does not interfere with the functioning of healthy stem cells, which are essential for the proper functioning of tissues.

The MCLA-158 antibody is a potent inhibitor of colorectal cancer organoid growth and it blocks the initiation of metastasis, as well as growth in several preclinical models of cancer, including tumours of the head and neck, oesophagus, and stomach.

An organoid biobank for drug discovery

For the development and characterisation of this antibody, researchers from HUB Organoids built a large biobank comprising organoids derived from patients with colon cancer, organoids from colon cancer metastasis to the liver, and organoids from normal non-cancerous tissue. Scientists from OcellO B.V. (Crown Bioscience) performed high content screening with the organoids.

The use of organoids in the early stages of drug developmentin this case, therapeutic antibodiesfacilitates the identification of those that are effective for most patients or even against tumours carrying a specific mutation. Using organoids from healthy tissue, an additional advantage is the possibility to identify unwanted side effects of the drugs on organs. This approach has allowed the researchers to assess the harmful effects of the drug on healthy cells and thus withdraw antibodies with greater toxicity in the earliest stages of the study.

In the coming months, the company Merus N. V. plans to publish new data on the clinical trials underway with Petosemtamab. We are hopeful that the anti-tumour activity reported in the preliminary data will be confirmed, says Dr. Batlle.

This preclinical research published today in Nature Cancer includes work carried out within the framework of the suppresSTEM consortium, funded by the EU and involving collaborative work by various international research institutionsIRB Barcelona, the Hubrecht Institute and the Sanger Instituteand companies, namely Merus N. V. and OcellO B.V./Crown Bioscience. The Vall d'Hebron Institute of Oncology (VHIO), the Catalan Institute of Oncology (acronym ICO in Catalan) and the company Xenopat also collaborated in data for this publication.

Experimental study

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25-Apr-2022

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An international consortium, led by IRB Barcelona and the biotechnology company Merus, reports the discovery of MCLA-158, the first clinical candidate...