Making babies from skin cells: the future fertility treatment of IVG will open Pandora’s Box for better or worse!

Researchers have successfully demonstrated a new advancement in Reproductive Technology called In vitro gametogenesis (IVG), in which they could make gametes, produce an off spring from pluripotent stem cells derived from parent’s skin cells in mice.

Field of Reproductive medicine has come a long way since the discovery of IVF and birth of Louise Brown in 1978, and applying this technique in humans may be possible in near future.

The paper by Japanese scientist was published in the SCIENCE TRANSLATIONAL MEDICINE[1]

The techniques allows for creation of eggs and sperms from induced pluripotent stem cells (iPSCs) derived from adult body tissue such as skin in culture dish.  Though currently successful in mice, this opens doors to immense possibilities in reproductive and regenerative medicines.

Dr. Joyce Harper, professor of human genetic and embryology and Deputy Chair on the board of  the British Fertility Society said "It is hard to predict when innovative fertility technologies will be ready for use in humans. Ten years ago, we didn't think that egg freezing would arrive so quickly but it did. We just don't know when in-vitro gametogenesis will be used in humans, but the fact that it has been done successfully in mice makes is very interesting - if fertility treatments work in mice they usually end up working in humans at a later stage.

Three experts Dr I. Glenn Cohen^,, George Q. Daley^, and Eli Y. Adashi wrote  a  perspective essay ‘Disruptive reproductive technologies’ in Science Translational Medicine   discussing  the helpful aspects and the ethical, societal and  policy dilemmas if IVG is applied to humans.

It could be of great benefit in cancer survivors who have undergone chemotherapy and have lost reproductive function as a result.

It could help egg donors who have lost the capacity to produce eggs, especially elderly women who decide to start families in their 40s and 50. This would pave the way for same-sex couples to have babies of their own using both parents' genetic material. It could refine the current IVF procedure and save women from undergoing ovarian stimulation.

It could lead us to better understanding of embryonic development. Three parent baby is the recent example of it, thereby eliminating mitochondrial diseases.

Dr Cohen  further added “Combined with rapidly advancing gene-editing techniques like CRISPR, in vitro gametogenesis could also conceivably allow scientists to edit out some inherited diseases or install new traits. These technologies could allow you to get “closer to your vision of perfection” in children.”

Dr Sonia M. Suter, professor of law at George Washington University, calls this procedure ‘Solo IVG’ since theoretically eggs and sperms can be derived from the same women, she can conceive ‘on her own’. But, this will increase the risk of many genetic diseases

Her paper published in journal of law and bioscience could be accessed here. In the paper, she raises questions about ‘designer babies’, question of lineage of the offspring, legal aspects of IVG and the ‘unnaturalness’ of the whole procedure.

The ability to create embryos on large scale will open the doors for ‘embryo farming’ and devaluing human life.

Whatever the future of IVG might be it is going to be debated hotly in the world of science and translational medicine because of many ethical implications of the procedure.

In the future, our grandchildren could be coming from unexpected places, as the two cells that started us all might be coming from culture dish ,instead of being gonadal in origin. 


Could we make babies from skin cells?

CNN's Kristi Lu Stout spoke with George Daley, Dean of Harvard Medical School, about a new advancement in reproductive technology called IVG. 

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[1] http://science.sciencemag.org/content/338/6109/971.full





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First in vitro culture of Human embryos through implantation stage (13 days).

Developmental biologist could grow the human embryos in the lab up to 9 days till now, but according to a recent paper published in Nature and Nature cell biology they have grown human embryos in the lab up to 13 days’ post fertilization. 

The technique has already made it possible for the scientist to visualize features never seen before in human embryos or to know the reasons behind early pregnancy loss.

The authors reported that it was fascinating to watch as the human embryos derived from IVF self-organized themselves in the absence of maternal tissue in a petri dish eventually differentiating into founding cell lineage of the fetus and its supporting tissue.  

This is the first glimpse of beginning of human life at a time when it usually implants itself into the endometrium making it impossible to visualize.

An improved culture medium of gel matrix with higher level of oxygen seems to be the key towards this advancement.

Marta Shahbazi, a researcher at Britain's University of Cambridge who was part of the research teams quoted "Embryo development is an extremely complex process and while our system may not be able to fully reproduce every aspect of this process, it has allowed us to reveal a remarkable self-organizing capacity ... that was previously unknown."

The recent achievement has wider implications for scientists and fertility industry around the world. Martin Pera, a stem-cell researcher at the University of Melbourne in Australia said “Studying embryos in vitro could help researchers who are trying to grow stem cells into embryo-like structures to judge the accuracy of their work.”

About 50% of embryos that are implanted in the mother’s womb do not go far in pregnancy and studies of embryos in vitro could give a new insight into the process.

 Norbert Gleicher, head of the Center for Human Reproduction, an IVF clinic in New York City said “The implantation process is a big black box for us clinicians.”

This work could also help the scientists and researchers to understand the role of signaling molecules from extraembryonic tissues for the developing embryo. This in turn could lead to a better understanding of how to induce a human stem cell to grow into cell lines that have therapeutic potential.

The researchers terminated the experiment at 13 days because raising embryos past 14 days or primitive streak formation raises many ethical and policy issues.  At least 12 countries including U.K. prohibit the scientists to work past the 14 days’ limit.  This is also the latest time when an embryo can split into monozygotic twins, and it is also the beginning of an individual existence.

George Daley, a stem-cell researcher at Children’s Hospital Boston in Massachusetts said “Their achievements in the lab may be grounds for re-examining the limit.” Other researchers also agreed that this work raises questions around the 14 days’ limit because if scientist succeed in growing stem cells into embryo-like structures, then will the 14 days’ limit also apply to them?

At the same time longer and improved culture does provide important information about human biology, and improves success rates in ARTs. But, it does raise the question that when it comes to human embryos, where should we put the limit. 

http://www.nature.com/news/human-embryos-grown-in-lab-for-longer-than-ever-before-1.19847

http://www.nature.com/articles/nature17894.epdf?referrer_access_token=vubLDzCfD5TDQyqH6QzUO9RgN0jAjWel9jnR3ZoTv0MAKMqR86sjveS-ESetrmIKqQaq3DATJvUDgDzNgE6sDfLJOtZ1bXbi1b4AnEr1jpcvgIMGql_i9013Z240k-uuD7VB6IhLhfPxexI2hdGGpFidX0_ZW_9lsvBfAopIvlH1EBB21P-dTFrrZ9pZHXBLJqznVlYQVN2k2-MCXs7wNZwTl4XWhg5yI-uetIYAUlo%3D&tracking_referrer=www.nature.com

 http://www.nature.com/ncb/journal/vaop/ncurrent/full/ncb3347.html#tables

Uterine stem cells deficiency linked to Recurrent Pregnancy Loss (RPL).

Stem cells have the potential to treat a myriad of diseases and have acted as a powerful tool to treat many life threatening diseases. Researchers have opened up a new avenue in stem cell therapy by tying stem cell deficiency in endometrium to recurrent pregnancy loss.

According to a recent paper published in February issue of Stem cells by Lucas E S et al researchers postulated that stem cell deficiency in the endometrial tissue and accelerated stromal aging is responsible for RPL by limiting the endometrial capacity to decidualize. Most miscarriages are sporadic and are due to chromosomal aberration in the conceptus, but RPL is a distinct entity.  In about 50% of RPL, the etiology is not defined. It is estimated that roughly 5% of women suffer from 2 clinical miscarriage and 1% ending up with 3 or more losses. While many factors seems to play role in RPL, the underlying endometrial pathology is not yet explored.

It is indicated that RPL is associated with impaired differentiation of endometrial stromal cells (HESCs) into specialized decidual cells. The differentiation termed as decidualization, predicts the end of implantation window and confers endometrium the ability to recognize, respond to and eliminate implanting compromised embryos, theory of natural selection. The theory suggests that it is the response of the decidualized endometrium to embryonic signals, which decides the future implantation and development of the  embryo or its rapid demise through menstruation-like shedding. Current evidence suggests that it is the abnormal decidualization which causes the loss of selectivity leading to implantation without further progress leading to pregnancy loss. So, the endometrium acts as a ‘biosensor’ detecting the embryo derived signal and deciding the fate of the embryo.

It is already known that decidualization of the endometrium in not dependent on embryo. It happens in post ovulatory phase of every cycle due to increase in progesterone levels and cAMP. It is because of cyclic activation of mesenchymal stem cells which differentiate into stromal cells in regenerating endometrium.

The authors hypothesized that defect in cyclic regeneration of endometrium in RPL patients is impacted due to defect in DNA methylation status of human endometrial stromal cells (HESCs).

A total of 183 endometrial biopsies were taken from patients with  normal women and those with RPL, except 8 random samples, all other were timed between 6 and 10 days after the preovulatory luteinizing hormone surge.  HESCs were isolated from the samples and cultured in laboratory. They were further tested for epigenetic markers for recurrent pregnancy loss.

It was seen that endometrial lining in patients with RPL showed loss of plasticity, with included increased senescence, deficiency and limited capacity to differentiate. Epigentic signature was lacking in women who experienced RPL as compared to their normal counterparts.

The endometrium also had decreased number of stem cells that had limited capacity to renew the endometrium, resulting in aging. Aging cells mount an inflammatory response that is enough for implantation but not for development and sustaining the embryo.

In an interview with medscape  Dr. Brosens said “"We also found that the greater the number of miscarriages a woman had experienced...the more depleted the lining was."

"Cultured cells from women who had had three or more consecutive miscarriages showed that aging cells in the lining of the womb don't have the ability to prepare adequately for pregnancy," Dr. Brosens notes.

He futher explained hat medicine usually regards recurrent miscarriage as being associated with an underlying disease, and normal practice is to investigate clotting abnormalities, hormonal imbalances, or immune responses. In the United States, patients are referred to specialist care after two consecutive losses; patients are referred after three losses in the United Kingdom. "It is often stated that a cause for recurrent miscarriage can be found in 50% of patients. However, for every woman with an apparent known 'cause' of miscarriage, there will be 50 to 100 women who have the same disorder but do not experience miscarriage. So current tests completely lack specificity."

With sporadic miscarriages, the majorities are caused by chromosomal abnormalities in the fetus, but with recurrent miscarriages, the majority involves normal fetuses. The more miscarriages a woman has, the greater the likelihood pregnancy loss involves a fetus with normal chromosomes. "Also, as the number of miscarriages increases, there is a higher chance of recurrent miscarriage," Dr. Brosens added.

According to Dr. Brosens, the real challenge lies in translating these findings into something clinically meaningful. He believes that this could further lead to development of some sort of screening tests, eventually ending up with some sort of treatment for women at risk. "The abnormalities we have identified all precede pregnancy, so it is possible to test the uterine lining for these markers and help predict if a patient is at risk of recurrent miscarriages."

He also pointed that stem cells in the uterine lining were highly dynamic and active pool, that are undergoing  cyclic shedding and regeneration, so intermittently the defects in the uterine lining could undergo self-repair, changing from an unsupportive environment to a supportive one. This explains why many women have a successful pregnancy even after recurrent miscarriages.

The authors concluded that “These findings open up new avenues to screen women prior to pregnancy for the risk of miscarriage and point to the potential of cell-based therapies in the prevention of RPL.”

References:

Lucas, E. S., Dyer, N. P., Murakami, K., Hou Lee, Y., Chan, Y.-W., Grimaldi, G., Muter, J., Brighton, P. J., Moore, J. D., Patel, G., Chan, J. K.Y., Takeda, S., Lam, E. W.-F., Quenby, S., Ott, S. and Brosens, J. J. (2016), Loss of Endometrial Plasticity in Recurrent Pregnancy Loss. STEM CELLS, 34: 346–356. doi: 10.1002/stem.2222

http://www.ncbi.nlm.nih.gov/pubmed/22835448

http://www.ncbi.nlm.nih.gov/pubmed/1975862

http://www.ncbi.nlm.nih.gov/pubmed/20847090