Coming from the embryo at a very early stage of its development, embryonic stem cells are endowed with two important capacities: that of multiplying ad infinitum, by simple division (self-renewal), and that of giving birth to all types cells in the body (pluripotency).
These properties open up many perspectives, not only for regenerative medicine, but also for the study of genetic diseases and the development of treatments.
Understanding stem cells and their value
Human embryonic stem cells are of interest to researchers in more ways than one. They make it possible to acquire new knowledge on:
- normal and pathological human development. From cells from healthy or diseased embryos, researchers can study the different stages of development as well as the fate of the different cells that make up the organism.
- rare genetic diseases, using cells carrying a genetic alteration associated with such a disease. These cells serve as a cellular model of the disease and in particular allow the testing of drugs.
- the functioning of cells of different organs and associated diseases. For this, it is necessary to induce the differentiation of embryonic stem cells into specialized cells to be studied (neurons, heart cells, hepatocytes, pancreas cells, muscle cells …). This approach is particularly useful when it comes to working on cells that renew themselves little (or not) in the body and that are difficult to access, like neurons.
In addition, human embryonic stem cells can be used in cell therapy to regenerate an organ or produce substances necessary to restore biological function. They constitute an inexhaustible reservoir of cells that can be differentiated into cells of therapeutic interest to be delivered to a patient.
Where do the cells used by the researchers come from?
Embryonic stem cells are taken from embryos between the 5th and 7th day following in vitro fertilization (blastocyst stage of embryonic development). The embryo then appears as a balloon containing another small balloon attached to its internal wall: the internal cell mass.
It is in this mass that the thirty or so pluripotent cells are located which will give all the cells of the organism. These cells are removed and placed in culture. Under appropriate conditions, they then multiply spontaneously while retaining their undifferentiated state. But by modifying the culture conditions (use of specific culture media), it is possible to induce and orient their differentiation towards such or such type of specialized cells (neurons, cardiac, muscular, etc.).
In practice, embryonic stem cells are taken from supernumerary embryos obtained by in vitro fertilization and which have been frozen in anticipation of a parental project that has finally been abandoned. Scientists most often work from lines owned and marketed by laboratories, thus avoiding unnecessary sacrifice of embryos. The fact that pluripotent cells multiply endlessly offers an inexhaustible reservoir of cells.
However, it is sometimes necessary to create a new line to study a pathology. In this case, the stem cells come from an embryo carrying the disease in question, identified within the framework of a pre-implantation diagnosis (PGD) carried out following in vitro fertilization. PGD is a highly supervised practice, reserved for couples who are at risk of transmitting a particularly serious and incurable genetic disease to the child. In all cases, the biological parents must sign a consent to transfer the research embryo free of charge
Research, the embryo and ethics
The use of embryonic stem cells poses ethical problems: their removal requires the destruction of an embryo, and therefore of potential human life. Religions and cultures oppose the “value” of the embryo at the stage at which it is destroyed. Thus, Jews are generally not opposed to this research because, according to their beliefs, the embryo comes to life later during development.
The Catholic Church does not have the same position, considering that life begins at the stage of the fertilized ovum. Other beliefs approach the issue differently: for example, Buddhists believe that the benefit that may result from this research in terms of human health justifies this sacrifice. However, all cultures agree that the embryo cannot be instrumentalized for research purposes and therefore cannot be conceived for this sole purpose: an embryo must necessarily be conceived within the framework of a parental project.
In France, since the revision of the bioethics law of 2013, research on embryonic stem cells is authorized, but supervised. The Biomedicine Agency provides this supervision. Authorized projects must meet several criteria relating to their relevance, to ethics, to the objective of bringing major medical progress, to the fact that they cannot be carried out using another type of cell …
In practice, researchers submit their project to the Agency before starting their work. Authorized projects are generally authorized for a period of 4 to 5 years. At the end of this period, the teams must renew their request by justifying the continuation of their work.
The law provides that authorized research may be carried out using supernumerary embryos conceived within the framework of medically assisted procreation no longer the subject of a parental plan, after the written consent and information of the couple concerned. This consent must be confirmed after a three-month cooling-off period and may be revoked without reason by the two members of the couple or the surviving member as long as the research has not started.
Embryonic stem cells or IPS, complementary tools
Embryonic stem cells are not the only pluripotent cells: since 2006, we have also known how to produce induced pluripotent stem cells (IPS). IPS cells are obtained from differentiated adult cells into which four pluripotency genes are introduced. This manipulation – we speak of “reprogramming” – gives them the ability to differentiate into any type of cell and to multiply indefinitely.
IPS cells make it possible to overcome the ethical problem posed by the use and sacrifice of embryos. They also make it possible to obtain cellular models of rare diseases unavailable from an embryo (diseases that we do not know / cannot detect during PGD). But embryonic stem cells and IPS cells are not the same:
The DNA of IPS cells is not “native” like that of an embryonic stem cell. It keeps track of epigenetic changes that occurred during the life of the cell before reprogramming, not to mention any mutations that may have changed its sequence.
The genetic modifications necessary for the reprogramming of adult cells into IPS cells are also to be taken into account, without it being known today to what extent they are problematic (in particular in the context of the therapeutic use of IPS cells).
Another major difference, this time in favor of IPS cells, researchers have access to the state of health and the clinical picture of the person from whom these cells come. This can provide valuable information when studying a disease. In the case of embryonic stem cells, researchers do not have this clinical data.
The ES and IPS cells are therefore currently complementary research tools. Researchers are testing these two types of cells for different indications and to study different mechanisms. For example, at the Stem Cell Institute for the Treatment and Study of Monogenic Diseases (I-STEM), a team worked with embryonic stem cells on dystrophic myotonia type 1 and validated their data with IPS cells. In parallel, since this team does not have an embryonic cell model of spinal muscular atrophy, it turned directly to IPS cells to study this disease.
Human embryonic stem cells and therapies
The use of embryonic stem cells in cell therapy has already given rise to several clinical trials. This approach involves obtaining healthy, functional specialized cells from embryonic stem cells, then injecting them into a patient to regenerate an organ or restore its function. The cells used in these tests must meet strict quality standards required for therapeutic use and be approved by the health authorities. These cells are called “clinical grade”.
For example, an American biotechnology company (Ocata Therapeutics) uses human embryonic stem cells differentiated into retina cells to fight against AMD and differentiated into retinal pigment epithelial cells to fight against Stargardt macular dystrophy. In both cases, phase I and II trials are underway to assess the safety of this approach and to assess the therapeutic effect. Another trial is being prepared in AMD, piloted by The London Project to Cure Blindness in partnership with a pharmaceutical laboratory (Pfizer). The idea is the same: to develop retinal cells from embryonic stem cells to inject them into patients over 50 suffering from this visual impairment.
On the Evry Genopole campus, researchers from the I-Stem laboratory (Inserm unit 861) work in close collaboration with the Vision Institute (Inserm unit 968) and AFM-Telethon on other therapy applications based on the use of human embryonic stem cells. This laboratory is developing in particular the use of human embryonic stem cells differentiated into keratinocytes in the treatment of skin ulcers associated with a genetic disease, sickle cell anemia.
In the field of cardiology, a team from the European Georges Pompidou hospital (Inserm unit 970) performed a heart cell transplant in October 2014 derived from human embryonic stem cells, according to a process developed by researchers at the Saint -Louis (Inserm 1160 unit). Ten weeks later, the patient, a 68-year-old woman with severe heart failure, had improved significantly, with no apparent complications.
Another disease targeted by this type of approach is type 1 diabetes. Another American biotechnology company (ViaCyte) is preparing a clinical trial based on the use of insulin-producing pancreatic cells obtained from embryonic stem cells . The cells to be transplanted are encapsulated in a sophisticated disc: this device allows insulin and glucose to diffuse, but protects the graft from an immune reaction from the host. The preclinical results are encouraging. The goal is to restore long-term insulin production in patients.
Is cell therapy treatment used routinely?
In Mexico, Panama and India, companies are offering cell therapies to treat neurodegenerative diseases, leukemias and osteoarthritis, raising hope for patients. Warning ! Although clinical trials of cell therapy are increasing and have proven themselves in certain indications, these therapeutic approaches have not yet been validated and do not offer the guarantees of efficacy and safety recommended for any health product by the health authorities.
Interventions offered abroad have a very significant cost, which can reach several tens of thousands of euros. Despite the dissemination of enthusiastic patient testimonials on the websites of these companies, the greatest caution is recommended.