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The female reproductive lifespan is regulated by the menstrual cycle. Defined as the interval between the menarche and menopause, it is approximately 35 years in length on average. Based on current average human life expectancy figures, and excluding fertility issues, this means that the female body can bear children for almost half of its lifetime. Thus, within this time span many individuals may consider contraception at some point in their reproductive life. A wide variety of contraceptive methods are now available, which are broadly classified into hormonal and non-hormonal approaches. A normal menstrual cycle is controlled by a delicate interplay of hormones, including estrogen, progesterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), among others. These molecules are produced by the various glands in the body that make up the endocrine system.
Hormonal contraceptives – including the contraceptive pill, some intrauterine devices (IUDs) and hormonal implants – utilize exogenous (or synthetic) hormones to block or suppress ovulation, the phase of the menstrual cycle where an egg is released into the uterus. Beyond their use as methods to prevent pregnancy, hormonal contraceptives are also being increasingly used to suppress ovulation as a method for treating premenstrual syndromes. Hormonal contraceptives composed of exogenous estrogen and/or progesterone are commonly administered artificial means of birth control. Despite many benefits, adverse side effects associated with high doses such as thrombosis and myocardial infarction, cause hesitation to usage.
Scientists at the University of the Philippines and Roskilde University are exploring methods to optimize the dosage of exogenous hormones in such contraceptives. Their overall aim is the creation of patient-specific minimizing dosing schemes, to prevent adverse side effects that can be associated with hormonal contraceptive use and empower individuals in their contraceptive journey. Their research data showed evidence that the doses of exogenous hormones in certain contraceptive methods could be reduced, while still ensuring ovulation is suppressed. Reducing the total exogenous hormone dose by 92% in estrogen-only contraceptives, or the total dose by 43% in progesterone-only contraceptives, prevented ovulation according to the model. In contraceptives combining estrogen and progesterone, the doses could be reduced further.
Mimicking vaginal cells and microbiome interactions on chip microfluidic culture
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Scientists at Harvard University’s Wyss Institute for Biologically Inspired Engineering have developed the world’s first “vagina-on-a-chip,” which uses living cells and bacteria to mimic the microbial environment of the human vagina. It could help to test drugs against bacterial vaginosis, a common microbial imbalance that makes millions of people more susceptible to sexually transmitted diseases and puts them at risk of preterm delivery when pregnant. Vaginal health is difficult to study in a laboratory setting partly because laboratory animals have “totally different microbiomes” than humans. To address this, scientists have created an unique chip, which is an inch-long, rectangular polymer case containing live human vaginal tissue from a donor and a flow of estrogen-carrying material to simulate vaginal mucus.
The organs-on-a-chip mimic real bodily function, making it easier to study diseases and test drugs. Previous examples include models of the lungs and the intestines. In this case, the tissue acts like that of a real vagina in some important ways. It even responds to changes in estrogen by adjusting the expression of certain genes. And it can grow a humanlike microbiome dominated by “good” or “bad” bacteria. The researchers have demonstrated that Lactobacilli growing on the chip’s tissue help to maintain a low pH by producing lactic acid. Conversely, if the researchers introduce Gardnerella, the chip develops a higher pH, cell damage and increased inflammation: classic bacterial vaginosis signs. So, the chip can demonstrate how a healthy / unhealthy microbiome affects the vagina.
The next step is personalization or subject specific culture from individuals. The chip is a real leap forward, it has the prospect of testing how typical antibiotic treatments against bacterial vaginosis affect the different bacterial strains. Critics of organ-on-a-chip technology often raise the point that it models organs in isolation from the rest of the body. There are limitations such as many researchers are interested in vaginal microbiome changes that occur during pregnancy because of the link between bacterial vaginosis and labor complications. Although the chip’s tissue responds to estrogen, but it does not fully mimic pregnancy without feedback loops from other organs. The researchers are already working on connecting the vagina chip to a cervix chip, which could better represent the larger reproductive system.
All these information indicate that the human vagina chip offers a new model to study host-vaginal microbiome interactions in both optimal and non-optimal states, as well as providing a human relevant preclinical model for development and testing of reproductive therapeutics, including live bio-therapeutics products for bacterial vaginosis. This microfluidic human vagina chip that enables flow through an open epithelial lumen also offers a unique advantage for studies on the effect of cervicovaginal mucus on vaginal health as clinical mucus samples or commercially available mucins can be flowed through this channel. The role of resident and circulating immune cells in host-microbiome interactions also can be explored by incorporating these cells into the vagina chip in the future, as this has been successfully done in various other organ chip models.
Sperm damage and fertility problem due to COVID-19
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Many couples initially deferred attempts at pregnancy or delayed fertility care due to concerns about coronavirus disease 2019 (COVID-19). One significant fear during the COVID-19 pandemic was the possibility of sexual transmission. Many couples have since resumed fertility care while accepting the various uncertainties associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2), including the evolving knowledge related to male reproductive health. Significant research has been conducted exploring viral shedding, tropism, sexual transmission, the impact of male reproductive hormones, and possible implications to semen quality. However, to date, limited definitive evidence exists regarding many of these aspects, creating a challenging landscape for both patients and physicians to obtain and provide the best clinical care.
According to a new study, which looked at sperm quality in patients who suffered symptomatic coronavirus (COVID-19) infections, showed that it could impact fertility for weeks after recovery from the virus. The data showed 60% COVID-19 infected men had reduction in sperm motility and 37% had drop in sperm count, but, 2 months after recovery from COVID-19 the value came down to 28% and 6% respectively. The researchers also of the view that COVID-19 could not be sexually transmitted through semen after a person had recovered from illness. Patients with mild and severe cases of COVID-19 showed similar rate of drop in sperm quality. But further work is required to establish whether or not COVID-19 could have a longer-term impact on fertility. The estimated recovery time is three months, but further follow-up studies are still required to confirm this and to determine if permanent damage occurred in a minority of men.
Some viruses like influenza are already known to damage sperm mainly by increasing body temperature. But in the case of COVID-19, the researchers found no link between the presence or severity of fever and sperm quality. Tests showed that higher concentrations of specific COVID-19 antibodies in patients’ blood serum were strongly correlated with reduced sperm function. So, it was believed the sperm quality reduction cause could be linked to the body’s immune response to the virus. While the study showed that there was no COVID-19 RNA present in the semen of patients who had got over the virus, the fact that antibodies were attacking sperm suggests the virus may cross the blood-testis barrier during the peak of an infection.
It was found in a previous report that SARS-CoV-2 can be present in the semen of patients with COVID-19, and SARS-CoV-2 may still be detected in the semen of recovering patients. Due to imperfect blood-testes/deferens/epididymis barriers, SARS-CoV-2 might be seeded to the male reproductive tract, especially in the presence of systemic local inflammation. Even if the virus cannot replicate in the male reproductive system, it may persist, possibly resulting from the privileged immunity of testes.
If it could be proved that SARS-CoV-2 can be transmitted sexually in future studies, sexual transmission might be a critical part of the prevention of transmission, especially considering the fact that SARS-CoV-2 was detected in the semen of recovering patients. Abstinence or condom use might be considered as preventive means for these patients. In addition, it is worth noting that there is a need for studies monitoring fetal development. Therefore, to avoid contact with the patient’s saliva and blood may not be enough, since the survival of SARS-CoV-2 in a recovering patient’s semen maintains the likelihood to infect others. But further studies are required with respect to the detailed information about virus shedding, survival time, and concentration in semen.
Infertility is a major reproductive health issue that affects about 12% of women of reproductive age in the United States. Aneuploidy in eggs accounts for a significant proportion of early miscarriage and in vitro fertilization failure. Recent studies have shown that genetic variants in several genes affect chromosome segregation fidelity and predispose women to a higher incidence of egg aneuploidy. However, the exact genetic causes of aneuploid egg production remain unclear, making it difficult to diagnose infertility based on individual genetic variants in mother’s genome. Although, age is a predictive factor for aneuploidy, it is not a highly accurate gauge because aneuploidy rates within individuals of the same age can vary dramatically.
Researchers described a technique combining genomic sequencing with machine-learning methods to predict the possibility a woman will undergo a miscarriage because of egg aneuploidy—a term describing a human egg with an abnormal number of chromosomes. The scientists were able to examine genetic samples of patients using a technique called “whole exome sequencing,” which allowed researchers to home in on the protein coding sections of the vast human genome. Then they created software using machine learning, an aspect of artificial intelligence in which programs can learn and make predictions without following specific instructions. To do so, the researchers developed algorithms and statistical models that analyzed and drew inferences from patterns in the genetic data.
As a result, the scientists were able to create a specific risk score based on a woman’s genome. The scientists also identified three genes—MCM5, FGGY and DDX60L—that when mutated and are highly associated with a risk of producing eggs with aneuploidy. So, the report demonstrated that sequencing data can be mined to predict patients’ aneuploidy risk thus improving clinical diagnosis. The candidate genes and pathways that were identified in the present study are promising targets for future aneuploidy studies. Identifying genetic variations with more predictive power will serve women and their treating clinicians with better information.
Infertility has been primarily treated as a female predicament but around one-half of infertility cases can be tracked to male factors. Clinically, male infertility is typically determined using measures of semen quality recommended by World Health Organization (WHO). A major limitation, however, is that standard semen analyses are relatively poor predictors of reproductive capacity and success. Despite major advances in understanding the molecular and cellular functions in sperm over the last several decades, semen analyses remain the primary method to assess male fecundity and fertility.
Chronological age is a significant determinant of human fecundity and fertility. The disease burden of infertility is likely to continue to rise as parental age at the time of conception has been steadily increasing. While the emphasis has been on the effects of advanced maternal age on adverse reproductive and offspring health, new evidence suggests that, irrespective of maternal age, higher male age contributes to longer time-to-conception, poor pregnancy outcomes and adverse health of the offspring in later life. The effect of chronological age on the genomic landscape of DNA methylation is profound and likely occurs through the accumulation of maintenance errors of DNA methylation over the lifespan, which have been originally described as epigenetic drift.
In recent years, the strong relation between age and DNA methylation profiles has enabled the development of statistical models to estimate biological age in most somatic tissue via different epigenetic ‘clock’ metrics, such as DNA methylation age and epigenetic age acceleration, which describe the degree to which predicted biological age deviates from chronological age. In turn, these epigenetic clock metrics have emerged as novel biomarkers of a host of phenotypes such as allergy and asthma in children, early menopause, increased incidence of cancer types and cardiovascular-related diseases, frailty and cognitive decline in adults. They also display good predictive ability for cancer, cardiovascular and all-cause mortality.
Epigenetic clock metrics are powerful tools to better understand the aging process in somatic tissue as well as their associations with adverse disease outcomes and mortality. Only a few studies have constructed epigenetic clocks specific to male germ cells and only one study reported that smokers trended toward an increased epigenetic age compared to non-smokers. These results indicate that sperm epigenetic clocks hold promise as a novel biomarker for reproductive health and/or environmental exposures. However, the relation between sperm epigenetic clocks and reproductive outcomes has not been examined.
There is a critical need for new measures of male fecundity for assessing overall reproductive success among couples in the general population. Data shows that sperm epigenetic clocks may fulfill this need as a novel biomarker that predicts pregnancy success among couples not seeking fertility treatment. Such a summary measure of sperm biological age is of clinical importance as it allows couples in the general population to realize their probability of achieving pregnancy during natural intercourse, thereby informing and expediting potential infertility treatment decisions. With the ability to customize high throughput DNA methylation arrays and capture sequencing approaches, the integration of the epigenetic clocks as part of standard clinical care can enhance our understanding of idiopathic infertility and the paternal contribution to reproductive success and offspring health.
The recent publication in Nature Medicine on genetic risk prediction in pre-implementation embryos(1) has already engendered heated discussion.(2,3) Kumar et al.(1) advocate the integration of polygenic risk scores (PRS) derived from pre-implantation genetic testing (PGT) with standard monogenic prediction. The paper focuses primarily on BRCA1 (and breast cancer) and APC (and colon cancer). Genetic tests for inherited disorders such as Tay-Sachs disease and breast cancers caused by BRCA1 and BRCA2 have been approved, but these are potentially devastating conditions with relatively simple inheritance; in most counseling situations the risks are straightforward to calculate.
The limitation on the amount and quality of DNA available from early embryo biopsies has made it difficult to produce genomic profiles of embryos in the IVF situation. Kumar et al. genotyped more than one-hundred embryos at hundreds of thousands of nucleotide sites and combined these genotype data with whole genome sequences of the prospective parents to produce reconstructed embryo genomes. These genomes were compared with those of ten born siblings and polygenic risk scores (PRS) were calculated for twelve conditions related to diseases. The PRS were claimed to be 97–99 percent accurate.
The primary market for this procedure would be couples seeking IVF, and Kumar and his colleagues, most of whom are employees of biotech companies, show that it is feasible to calculate a PRS for an embryo. The authors do present several caveats for the use of their procedure for PGT. For example, if a couple has a family history of a disease, they “may unintentionally prioritize” a mutant embryo for PGT-based only on PRS. They also acknowledge that results from research cohorts may not generalize to sibling embryos in IVF, which could limit the clinical utility of their approach. Kumar et al. also acknowledge the “portability” problem, namely PRSs have limited predictive accuracy in people with non-European ancestry(2,3) or of different ages or socioeconomic status.(4,5) They also mention the issue of unequal access to IVF technology in general.(2)
It is also important, However, to stress the limited predictive utility of PRS for common traits, not only diseases. There is increasing use of PRS among social scientists for characteristics such as years of education, which have heritabilities in the 10–15 percent range. Such studies, and potentially this one by Kumar et al., can lead to reduced emphasis on environmental and social associations with diseases or other traits. For omnigenic traits, such as height or body mass index (BMI), that have hundreds or thousands of associated nucleotide polymorphisms, and high heritability, the public might receive the mistaken impression that PGT or other genomic interventions can allow parents to choose their offspring’s phenotype.
For example, a recent study(6) of BMI in 881 subjects from Quebec found that PRS could explain only between 1.2 percent and 7.5 percent of the variance in BMI of these participants. Even when PRSs are statistically significant, their predictive value is too weak to be applied. The use of polygenic risk scores to select embryos, abbreviated ESPS for embryo selection based on polygenic scores, has been criticized before.(7) One of the important points raised by Turley et al.(7) concerns the environmental context of the children of IVG customers, which may be quite different from that of the sample of people from which the PRS was calculated. Because of gene-environment interactions, the predictive power of PRS for any complex trait is limited. As pointed out by Turley et al. (p. 79), “the predictive power of a polygenic score is maximized when the person is from the same environment as the research participants from whom the polygenic scores were derived. But this will never be the case in ESPS.”
PGT and ESPS raise ethical issues beyond IVG that more generally concern designer babies.(7,8) PRSs have been calculated for non-disease related traits such as educational attainment, income, or IQ, and it is conceivable that some prospective parents might regard these as important enough for intervention. There are also traits related to social constructs of race including skin pigmentation or facial features, and parental choice based on these phenotypes could enhance racial prejudices.
References
Kumar, A., K. Im, M. Banjevic, P.C. Ng, T. Tunstall, G. Garcia, L. Galhardo, J. Sun,O.N. Schaedel, B. Levy, D. Hongo, D. Kijacic, M. Kiehl, N.D. Tran, P.C. Klatsky, and M. Rabinowitz. 2022. Whole-genome risk prediction of common diseases in human preimplantation embryos. Nature Medicine28: 514–516. doi: 10.1038/s41591-022-01735-0.
Nature editorial. 2022. The alarming rise of complex genetic testing in human embryo testing. Nature603: 549–550. doi: 10.1038/d41586-022-00787-z.
Rosenberg, N., M. Edge, J. Pritchard, and M. Feldman. 2019. Interpreting polygenic scores, polygenic adaptation, and human phenotypic differences. Evol. Med. Public Health 2019: 26–34. doi: 10.1093/emph/eoy036.
Duncan, L.E., H. Shen, B. Gelaye, J. Meijsen, K.J. Ressler, M.W. Feldman, R.E. Peterson, and B.W. Domingue. 2019. Analysis of polygenic score usage and performance in diverse human populations. Nat. Comm. 10: 3328. doi: 10.1038/s41467-019-11112-0.
De Toro-Martin, J.E., F. Guenard, C. Bouchard, A. Tremblay, L. Perusse, and M.-C. Vohl. 2019. The challenge of stratifying obesity: attempts in the Quebec family study. Front. Genet. 10:994. doi: 10.3389/fgene.2019.00994.
Turley, P., M.N. Meyer, N. Wang, D. Cesarini, E. Hammonds, A.R. Martin, B.M. Neale, H.L. Rehm, L. Wilkins-Haug, D.J. Benjamin, S. Hyman, D. Laibson, and P.M. Visscher. 2021. Problems with using polygenic scores to select embryos. N. Engl. J. Med385(1): 78–86.
Forzano, F., O. Antonova, A. Clarke, G. de Wert, S. Hentze, Y. Jamshidi, Y. Moreau, M. Perola, I. Prokopenko, A. Read, A. Reymond, V. Stefansdottir, C. van El, and M. Genuardi. 2021. The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice. European Journal of Human Genetics. doi: 10.1038/s41431-021-01000-x.
There has been much opinion, either as commentary in literature, meeting proceedings, or communiques from professional societies warning that this type of “high-impact” genetic information should not be given directly to the consumer as consumers will not fully understand the information presented to them, be unable to make proper risk-based decisions, results could cause panic and inappropriate action such as prophylactic oophorectomy or unwarranted risk-reduction mastectomy, or false reassurance in case of negative result and reduced future cancer screening measures taken by the consumer. However, there have been few studies to investigate these concerns.
The article by Kumar The alarming rise of complex genetic testing in human embryo selection
discusses the common trend of DTC (direct to consumer) and other genetic consutancy groups to offer disease risk assesment based on genetic predispostion genetic information in preimplantation embryos upon in vitro fertilization. Although this editorial discusses some caveats and potential ethical issues the opinion of this reviewer feels a certain number of key issues points have not been addressed (which will be discussed below) including:
the underlying risk of disclosure of all parties involved in decision making based on genetic testing including other family members
complicating ethical issues not addressed through proper guideline establishment and regulation as seen in countries that allow such advances to go without proper review board
a lack of discussion of the health disparities which may result of this type of genetic information or “selection” where groups of people would be shut out of such services due to socioeconomic status
Although the editorial highlights the issue that most genome wide association studies, on which most of the genetic counseling is based upon is from cohorts of European descent (and misses a large cohort which is Asian or African descent), there is little attention given to the issue that most panels of these agreed upon risk associated variants have not been validated in larger GWAS studies or that these panels only focus on the most common variants. An example of this would be BRCA1/2 and assumed future breast cancer risk.
PGS and PGT-A diagnoses have been built on biologically incorrect assumptions and on unvalidated guidelines dating back to 2016. These guidelines, which remain influential to this day, were published without a description of methods, without peer review, with no author identification, and without any references1 . The guidelines changed the binary diagnosis of euploid and aneuploid to normal, mosaic and aneuploid.
In fact most family risk assesment programs are more effective upon counseling of young women, not at the embryonic stage where genetic risk factors may not be evident or resulting from epigenetic changes or accumulated somatic mutation.
Lack of communication to all related and involved parties
Many times it is women, who having undergone these testings, have problems in communicating these risk findings to their children and family members, resulting in familial strains.
For instance, some women who discover they have the BRCA gene mutation, which puts them at higher risk for breast cancer, choose to tell their children about it before the children are old enough to understand the significance or deal with it, a new study found.
“Parents with the BRCA mutation are discussing their genetic test results with their offspring often many years before the offspring would need to do anything,” said study author Dr. Angela Bradbury, director of the Fox Chase Cancer Center’s Family Risk Assessment Program, in Philadelphia.
According to Bradbury, more than half of parents she surveyed told their children about genetic test results. Some parents reported that their children didn’t seem to understand the significance of the information, and some had initial negative reactions to the news.
“A lot of genetic information is being shared within families and there hasn’t been a lot of guidance from health-care professionals,” Bradbury said. “While this genetic risk may be shared accurately, there is risk of inaccurate sharing.”
In the study, Bradbury’s team interviewed 42 women who had the BRCA mutation. The researchers found that 55 percent of parents discussed the finding and the risk of breast cancer with at least one of their children who was under 25.
Also, most of the women didn’t avail themselves of the services of a doctor or genetic counselor in helping to tell their children, Bradbury’s group found.
The identification of familial risk factors can have very stressful impacts on the affected and their family however an IVF selection might even augment that familial stress. More research is needed on the psychological impact of such testing and a patient’s choice.
2. Lack of health disparity considerations in IVF selection research or guidelines
Another major concern, which has been highlighted in multiple articles on this site, is the growing health disparities between those who can obtain access to quality health care and those who are left out in the void of the medical system, either for economic or sociological reasons. This has been very apparent in the cancer treatment and personalized medicine world (for example the disparities of health care access for cancer treatment in the southern poorer rural parts of the US versus metropolitan areas and the gaping disparities seen between rich and poor countries in Africa). These health disparities have been also apparant in the genetic testing market, and although the DTC market meant to make genetic testing more affordable, interestingly these disparities still exist in this niche market.
3. Lack of proper establishment of Institutional Review Board oversight in countries allowing this technique have been problematic with regard to addressing bioethical concerns
The third concern is, of course, a bioethical concern on the use of advanced genetic technologies in the human and clinical setting. It has come to many people’s attention at the speed at which countries that do not seem to have strong bioethical review boards readily allow this type of research to be carried out without regulatory oversight or consequence. A prime example of this included the shunned Chinese research carried out to produce cloned humans, which was rapidly condemmed in the biomedical world however this research was conducted nonetheless. This lack of attention is addressed in Kumar’s article yet little guidance is given as to best practices to establish review boards overseeing such work and or research.
Reporter and Curator: Mr. Srinjoy Chakraborty (Junior Research Felllow) and Dr. Sudipta Saha, Ph.D.
Coronavirus disease 2019 (COVID-19), which is caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emerged as a serious global health issue with high transmission rates affecting millions of people worldwide. The SARS-CoV-2 is known to damage cells in the respiratory system, thus causing viral pneumonia. The novel SARS-CoV-2 is a close relative to the previously identified severe acute respiratory syndrome-coronavirus (SARS-CoV) and Middle East respiratory syndrome-coronavirus (MERS-CoV) which affected several people in 2002 and 2012, respectively. Ever since the outbreak of covid-19, several reports have poured in about the impact of Covid-19 on pregnancy. A few studies have highlighted the impact of the viral infection in pregnant women and how they are more susceptible to the infection because of the various physiological changes of the cardiopulmonary and immune systems during pregnancy. It is known that SARS-CoV and MERS-CoV diseases have influenced the fatality rate among pregnant women. However, there are limited studies on the impact of the novel corona virus on the course and outcome of pregnancy.
Figure: commonly observed clinical symptoms of COVID-19 in the general population: Fever and cough, along with dyspnoea, diarrhoea, and malaise are the most commonly observed symptoms in pregnant women, which is similar to that observed in the normal population.
The WHO and the Indian Council of Medical Research (ICMR) have proposed detailed guidelines for treating pregnant women; these guidelines must be strictly followed by the pregnant individual and their families. According to the guidelines issued by the ICMR, the risk of pregnant women contracting the virus to that of the general population. However, the immune system and the body’s response to a viral infection is altered during pregnancy. This may result in the manifestation of more severe symptoms. The ICMR guidelines also state that the reported cases of COVID-19 pneumonia in pregnancy are milder and with good recovery. However, by observing the trends of the other coronavirus infection (SARS, MERS), the risks to the mother appear to increase in particular during the last trimester of pregnancy. Cases of preterm birth in women with COVID-19 have been mentioned in a few case report, but it is unclear whether the preterm birth was always iatrogenic, or whether some were spontaneous. Pregnant women with heart disease are at highest risk of acquiring the infection, which is similar to that observed in the normal population. Most importantly, the ICMR guidelines highlights the impact of the coronavirus epidemic on the mental health of pregnant women. It mentions that the since the pandemic has begun, there has been an increase in the risk of perinatal anxiety and depression, as well as domestic violence. It is critically important that support for women and families is strengthened as far as possible; that women are asked about mental health at every contact.
With the available literature available on the impact of SARS and MERS on reproductive outcome, it has been mentioned that SARS infection did increase the risk of miscarriage, preterm birth and, intrauterine foetal growth restriction. However, the same has not been demonstrated in early reports from COVID-19 infection in pregnancy. According to a study that included 8200 participants conducted by the centre for disease control and prevention, pregnant women may be at a higher risk of acquiring severe infection and need for ICU admissions as compared to their non-pregnant counterparts. However, a detailed and thorough study involving a larger proportion of the population is needed today.
A highly effective platforms for the ex utero culture of post-implantation mouse embryos have been developed in the present study by scientists of the Weizmann Institute of Science in Israel. The study was published in the journal Nature. They have grown more than 1,000 embryos in this way. This study enables the appropriate development of embryos from before gastrulation (embryonic day (E) 5.5) until the hindlimb formation stage (E11). Late gastrulating embryos (E7.5) are grown in three-dimensional rotating bottles, whereas extended culture from pre-gastrulation stages (E5.5 or E6.5) requires a combination of static and rotating bottle culture platforms.
At Day 11 of development more than halfway through a mouse pregnancy the researchers compared them to those developing in the uteruses of living mice and were found to be identical. Histological, molecular and single-cell RNA sequencing analyses confirm that the ex utero cultured embryos recapitulate in utero development precisely. The mouse embryos looked perfectly normal. All their organs developed as expected, along with their limbs and circulatory and nervous systems. Their tiny hearts were beating at a normal 170 beats per minute. But, the lab-grown embryos becomes too large to survive without a blood supply. They had a placenta and a yolk sack, but the nutrient solution that fed them through diffusion was no longer sufficient. So, a suitable mechanism for blood supply is required to be developed.
Till date the only way to study the development of tissues and organs is to turn to species like worms, frogs and flies that do not need a uterus, or to remove embryos from the uteruses of experimental animals at varying times, providing glimpses of development more like in snapshots than in live videos. This research will help scientists understand how mammals develop and how gene mutations, nutrients and environmental conditions may affect the fetus. This will allow researchers to mechanistically interrogate post-implantation morphogenesis and artificial embryogenesis in mammals. In the future it may be possible to develop a human embryo from fertilization to birth entirely outside the uterus. But the work may one day raise profound questions about whether other animals, even humans, should or could be cultured outside a living womb.
Important but Unseen Human Embryo Developmental Stages Mimicked in Lab
Reporter and Curator: Dr. Sudipta Saha, Ph.D.
Scientists have created embryo-like structures that mimic a crucial yet not much known stage of human development. The structures, created from stem cells and called gastruloids, are the first to form a 3D assembly that lays out how the body will take shape. The gastruloids developed rudimentary components of a heart and nervous system, but lacked the components to form a brain and other cell types that would make them capable of becoming a viable fetus.
Human embryos take a momentous leap in their third week, when the largely homogeneous ball of cells starts to differentiate and develop specific characteristics of the body parts they will become, a process known as gastrulation. During this process, the embryo elongates and lays down a body plan with a head and tail, often called the head-to-tail axis. But scientists have never seen this process live in action. That is partly because many countries have regulations that stop embryos from being grown in the laboratory for research beyond 14 days.
Over the past years, several research groups have cultured embryonic stem-cell structures that model when cells start to differentiate. The latest model developed at the University of Cambridge, UK and their collaborators in the Netherlands, Showed for the first time what happens when the blueprint for the body’s development is laid out, around 18–21 days after conception. Genetic analysis showed that the cells formed were those that would eventually go on to form muscles in the trunk, vertebrae, heart and other organs.
If everything is done properly, the cells develop into 3D structures on their own — and then spontaneously mimic the gastrulation process. Although they display certain key features of a 21-day-old embryo, the gastruloids reach that stage after just 72 hours and survive for maximum 4 days before collapsing. Scientists will probably use the model to make structures that are even more realistic representations of early development.
The model could help scientists to understand the role of genetics and environmental factors in different disorders. The artificial structures make it possible to avoid ethical concerns about doing research on human embryos. But as the structures become more advanced and life-like, there may be ethical restrictions.
In-vitro fertilisation (IVF) is now regarded as a huge clinical success which has benefitted an estimated 16 million parents, at the time the development not only sparked moral outrage but led to political and legislative constraints. Patients undergoing IVF may be presented with numerous assisted reproductive treatments purportedly increasing the chances of pregnancy. Such commercialised “IVF add-ons” often come at high costs without clinical evidence of validity. Additionally, long-term studies of children born through IVF have historically been scarce and inconsistent in their data collection. This has meant that potential genetic predispositions, such as increased body fat composition and blood pressure, as well as congenital abnormalities long associated with IVF births, lack proof of causality.
With Preimplantation genetic testing mutated embryos are automatically discarded, whereas CRISPR could correct mutations to increase the number of viable embryos for implantation. Moreover, in instances where all embryos in a given cycle are destined to develop with severe or lethal mutations, CRISPR could bring success for otherwise doomed IVF treatments. Genetic screening programs offered to couples in hot-spot areas of carrier frequency of monogenic disorders have had huge success in alleviating regional disease burdens. Carried out since the 1970s these programs have altered the course of natural evolution, but few would dispute their benefits in preventing heritable disease transmission.
Mutations are as inevitable as death and taxes. Whilst age is considered one of the largest factors in de-novo mutation generation, it appears that these are inherited primarily from the paternal line. Thus, the paternal age of conception predominantly determines the mutation frequency inherited by children. Whereas advanced maternal age is not associated with mutagenic allele frequency but chromosomal abnormalities. The risk of aneuploidy rises steadily in mothers over the age of 26. Although embryos are screened for aneuploidy prior to implantation, with so many other factors simultaneously being screened the probability of having enough embryos remaining to allow for 50% rate of blastocyte development in-vitro are often fairly low.
Despite IVF being used routinely for over 40 years now, it’s not abundantly clear if, or how often, IVF may introduce genomic alternations or off-target affects in embryos. Likewise, scientists and clinicians are often unable to scrutinise changes produced through natural cellular processes including recombination and aging. So, it may be OK to do controlled experiments on using CRISPR to try and prevent multi-generational suffering. But, there has to be a long term investigation on the side effects of germline genome editing. Science has advanced a lot but still there are lot of things that are yet to be described or discovered by science. Trying to reduce human suffering should not give rise to new bigger sufferings and care must be taken not to create a Frankenstein.
2012pharmaceutical
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Alan F. Kaul, PharmD., MS, MBA, FCCP
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David Orchard-Webb, PhD
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