Heritable human genome editing: Research progress, ethical considerations, and hurdles to clinical practice.

Our genome at conception determines much of our health as an adult. Most human diseases have a heritable component and thus may be preventable through heritable genome editing. Preventing disease from the beginning of life before irreversible damage has occurred is an admirable goal, but the path to fruition remains unclear. Here, we review the significant scientific contributions to the field of human heritable genome editing, the unique ethical challenges that cannot be overlooked, and the hurdles that must be overcome prior to translating these technologies into clinical practice.

Going Germline: Mitochondrial Replacement as a Guide to Genome Editing.

Mitochondrial replacement (MR) serves as a crucial test case and learning guide for the scientific, ethical, and regulatory challenges of future reproductive breakthroughs. The lessons learned from the regulatory review process of MR over the last decade promise to enrich the emerging dialog over genome editing.

Uterus Transplantation: The Translational Evolution of a Clinical Breakthrough.

Women suffering from absolute uterine factor infertility (AUFI), due to either lack of a uterus or one unable to sustain neonatal viability, presented as one of the last frontiers in conquering infertility. Following systematic animal research for over a decade, uterus transplantation was tested as a treatment for AUFI in 2012, which culminated in the first human live birth in 2014. The development of uterus transplantation from mouse to human has followed both the Moore Criteria for introduction of a surgical innovation and the IDEAL concept for evaluation of a novel major surgical procedure. In this article we review the important pre-clinical animal and human studies that paved the way for the successful introduction of human uterus transplantation a decade ago. We discuss this in the context of the Moore Criteria and describe the different procedures of preparation, surgeries, post-operative monitoring, and use of assisted reproduction in human uterus transplantation. We review the world-wide activities and associated results in the context of the IDEAL concept for evaluation of surgical innovation and appraise the ethical considerations relevant to uterus transplantation. We conclude that rigorous application of the Moore Criteria and strict alignment with the IDEAL concept has resulted in the establishment of uterus transplantation as a novel, safe and effective infertility therapy that is now being used worldwide for the treatment of women suffering from AUFI.

Diversity of the National Medical Student Body - Four Decades of Inequities.

A racially and ethnically diverse health care workforce remains a distant goal, the attainment of which is contingent on the inclusivity of the national medical student body. We examined the diversity of medical school applicants and enrollees over the past four decades with an eye toward assessing the progress made. Data on the gender and race or ethnic group of enrollees in all medical doctorate degree-granting U.S. medical schools from 1978 through 2019 were examined. The percentage of female enrollees doubled during this period, and women now constitute more than half the national medical student body. This upturn has been attributed largely to an increase by a factor of 12 in the enrollment of Asian women. The corresponding decrease in the percentage of male enrollees, most notably White men, was offset by an increase by a factor of approximately 5 in the enrollment of Asian men. The percentages of enrollees from Black, Hispanic, and other racial and ethnic groups that are underrepresented in medicine remain well below the percentages of these groups in the national Census.

Medicare Advantage Under Fire: Public Criticism and Implications.

Congressional hearings and public reports have drawn attention to problems afflicting Medicare Advantage (MA), the privatized version of Medicare. Private plans became a staple of Medicare through the passage of the Tax Equity and Fiscal Responsibility Act of 1982 (TEFRA). Congress passed this law during a furor of privatization, when think tanks and powerful financial interests emphasized the power of corporations' profit incentive to improve the efficiency and quality of social enterprise. Yet the surging criticism of MA suggests a misalignment between the financial interest of some MA plans and the well-being of their patient populations. The criticisms range from deceptive marketing, ghost networks, and patient cherry-picking to unethical prior authorization denials and defrauding the government. In total, MA plans cost the federal government 22% more per patient than if these patients in question were enrolled in traditional Medicare. Moreover, it is not clear that this additional funding is producing proportional benefits. These developments raise questions about the presence of a profit incentive in Medicare, and perhaps health care more broadly.

ABCC4 is a PGE2 efflux transporter in the ovarian follicle: A mediator of ovulation and a potential non-hormonal contraceptive target.

The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in cultured human GCs is mediated by ABCC4 thus regulating its extracellular concentration. The ABCC4 inhibitor probenecid demonstrated effective blocking of ovulation and affects key ovulatory genes in female mice in vivo. We postulate that the reduction in PGE2 efflux caused by the inhibition of ABCC4 activity in GCs decreases the extracellular concentration of PGE2 and its ovulatory effect. Treatment of female mice with low dose of probenecid as well as with the PTGS inhibitor indomethacin or Meloxicam synergistically blocks ovulation. These results support the hypothesis that ABCC4 has an important role in ovulation and might be a potential target for non-hormonal contraception, especially in combination with PGE2 synthesis inhibitors. These findings may fill the gap in understanding the role of ABCC4 in PGE2 signaling, enhance the understanding of ovulatory disorders, and facilitate the treatment and control of fertility.

The unbearable ignorance of the composition of IVF culture media.

Culture media play an essential role in the success of IVF. Their composition has undergone major modifications over the 45 years since the birth of Louise Brown. Most IVF programmes now rely on commercially produced media, which they buy in small vials, guaranteed to be sterile and non-embryotoxic. Unfortunately, information about the components of the culture media and their concentrations is no longer available. Arguing that culture media recipes are proprietary, relevant commercial interests have stopped labelling their products with this vital information. Given the critical role that is played by culture media in the success of IVF, as well as the subsequent health of the children who are born after IVF, this information should not remain a 'company secret'. Clinicians and scientists working in IVF must insist that the labelling of culture media includes all of the constituents and their concentrations. Only in this way can we monitor the influence of culture media on IVF outcomes, innovate and continue to advance the field of IVF.

The Mifepristone Litigation: Untangling the Implications of the Fifth Circuit's Decision for Abortion Access and the U.S. Food and Drug Administration.

In August 2023, a federal appeals court issued an opinion in Alliance for Hippocratic Medicine v FDA, a case wherein a group of antiabortion medical organizations and physicians have challenged U.S. Food and Drug Administration (FDA) approval and regulation of mifepristone. This opinion contained some good news for the FDA, drug makers, and patients: the appeals court declined to halt the marketing of mifepristone altogether (as the trial court judge would have). But the court also decided that the FDA's 2016 and 2021 actions expanding the indication for mifepristone, lowering the drug's dose, and loosening restrictions on its distribution and use were likely unlawful, and it thus affirmed the trial court's order staying these actions. In this article, we explain key aspects of the opinion to health care professionals and consider the ways in which the appeals court's reasoning and conclusions, if followed by the Supreme Court, could undermine abortion access and public health going forward.

Unraveling Light-Activated Insulin Action in Regulating Blood Glucose: New Photoactivatable Insight as a Novel Modality in Diabetes Management.

Diabetes, particularly type 2 diabetes (T2D), is the main component of metabolic syndrome. It is highly prevalent and has drastically increased with sedentary lifestyles, notably behaviors linked to ease of access and minimal physical activity. Central to this condition is insulin, which plays a pivotal role in regulating glucose levels in the body by aiding glucose uptake and storage in cells, and what happens to diabetes? In diabetes, there is a disruption and malfunction in insulin regulation. Despite numerous efforts, effectively addressing diabetes remains a challenge. This article explores the potential of photoactivatable drugs in diabetes treatment, with a focus on light-activated insulin. We discuss its advantages and significant implications. This article is expected to enrich the existing literature substantially, offering a comprehensive analysis of potential strategies for improving diabetes management. With its minimal physical intrusion, light-activated insulin promises to improve patient comfort and treatment adherence. It offers precise regulation and localized impact, potentially mitigating the risks associated with conventional diabetes treatments. Additionally, light-activated insulin is capable of explicitly targeting RNA and epigenetic factors. This innovative approach may pave the way for more personalized and effective diabetes treatments, addressing not only the symptoms but also the underlying biological causes of the disease. The advancement of light-activated insulin could revolutionize diabetes management. This study represents a pioneering introduction to this novel modality for diabetes management.

Therapeutic Germline Editing: Sense and Sensibility.

Safe and effective heritable editing of the human genome is years away from the clinic because of formidable technical, statutory, regulatory, and societal challenges. In particular, we note the fledgling state of the science, the imperatives of editing efficiency, specificity, and uniformity, and the extant legal roadblock.

The Regulation of Mitochondrial Replacement Techniques Around the World.

Mitochondrial replacement techniques (MRTs, also referred to as mitochondrial replacement therapies) have given hope to many women who wish to have genetically related children but have mitochondrial DNA mutations in their eggs. MRTs have also spurred deep ethical disagreements and led to different regulatory approaches worldwide. In this review, we discuss the current regulation of MRTs across several countries. After discussing the basics of the science, we describe the current law and policy directions in seven countries: the United Kingdom, the United States, Canada, Australia, Germany, Israel, and Singapore. We also discuss the emerging phenomenon of medical tourism (also called medical travel) for MRTs to places like Greece, Spain, Mexico, and Ukraine. We then pull out some key findings regarding similarities and differences in regulatory approaches around the world.

Persistent Inpatient Harm: the Unremitting Challenge of Patient Safety.

The sobering realization that little has changed in the scope of inpatient harm makes it plain that efforts intent on improving patient safety must be redoubled if the status quo is to be reversed. Living up to the recommendations of the iconic Institute of Medicine (IOM) Report (To Err Is Human: Building a Safer Health System) must remain top of mind. Much can and must be done to assure to the degree possible the safety of the inpatient population.

Traveling Across States for Prohibited Treatments: Medical Aid in Dying and Looming Battles Over Abortion.

This JGIM Perspective discusses new and emerging challenges with accessing controversial medical therapies like medical aid in dying and abortion. While some states permit these therapies for only their residents, other states prohibit these therapies for their own residents. We summarize recent developments and growing challenges for clinicians treating "medical tourism" patients from other jurisdictions.

Acceptance of genetic editing and of whole genome sequencing of human embryos by patients with infertility before and after the onset of the COVID-19 pandemic.

RESEARCH QUESTION: Has acceptance of heritable genome editing (HGE) and whole genome sequencing for preimplantation genetic testing (PGT-WGS) of human embryos changed after the onset of COVID-19 among infertility patients? DESIGN: A written survey conducted between April and June 2018 and July and December 2021 among patients at a university-affiliated infertility practice. The questionnaire ascertained the acceptance of HGE for specific therapeutic or genetic 'enhancement' indications and of PGT-WGS to prevent adult disease. RESULTS: In 2021 and 2018, 172 patients and 469 patients (response rates: 90% and 91%, respectively) completed the questionnaire. In 2021, significantly more participants reported a positive attitude towards HGE, for therapeutic and enhancement indications. In 2021 compared with 2018, respondents were more likely to use HGE to have healthy children with their own gametes (85% versus 77%), to reduce disease risk for adult-onset polygenic disorders (78% versus 67%), to increase life expectancy (55% versus 40%), intelligence (34% versus 26%) and creativity (33% versus 24%). Fifteen per cent of the 2021 group reported a more positive attitude towards HGE because of COVID-19 and less than 1% a more negative attitude. In contrast, support for PGT-WGS was similar in 2021 and 2018. CONCLUSIONS: A significantly increased acceptance of HGE was observed, but not of PGT-WGS, after the onset of COVID-19. Although the pandemic may have contributed to this change, the exact reasons remain unknown and warrant further investigation. Whether increased acceptability of HGE may indicate an increase in acceptability of emerging biomedical technologies in general needs further investigation.

REI clinics and fellowship training-a national snapshot to improve access to reproductive care.

PURPOSE: To analyze the geographic distribution of REI fellowships and clinics across the USA and to strategize ways to improve patient access to care. METHODS: Cross-sectional study using population data obtained from publicly available United States Census Bureau, Society for Assisted Reproductive Technology (SART), and National Resident Matching Program websites. Outcomes include the number of REI clinics, REI fellowship-trained physicians, and REI fellowship programs. RESULTS: In 2020, there were 643 assisted reproductive technology (ART) clinics reporting to SART and 1351 fellowship-trained REI physicians. Most clinics are located in the south (n = 209); however, the northeast has the highest density of REI clinics. Out of 301,316 in vitro fertilization (IVF) cycles in the USA in 2020, northeastern states initiated the most cycles (n = 93,565), and Midwestern states initiated the fewest cycles (n = 50,000). The northeast has the most REI physicians per million women aged 20-44 years (42.4) while the Midwest has the lowest ratio (19.5). There are fewer REI physicians per million women aged 20-44 years in states with a lower proportion of patients with health insurance (r = 0.56, 95% confidence interval ([CI] 0.34-0.73) and in states with a lower average income per resident (r = 0.65, 95% CI 0.46-0.79). Most of the 49 accredited REI fellowship programs in the USA are in the northeast (n = 18), and there are fewest in the south (n = 10) and west (n = 10). CONCLUSION: Access to REI care has large geographic disparities from a clinic, physician, and training program perspective. Creative solutions are needed to remedy this problem.

CRISPR immunity: a case study for justified somatic genetic modification?

The current SARS-CoV-2 pandemic has killed thousands across the world. SARS-CoV-2 is the latest but surely not the last such global pandemic we will face. The biomedical response to such pandemics includes treatment, vaccination, and so on. In this paper, though, we argue that it is time to consider an additional strategy: the somatic (non-heritable) enhancement of human immunity. We argue for this approach and consider bioethics objections we believe can be overcome.

Hyperthecosis: an underestimated nontumorous cause of hyperandrogenism.

Hyperthecosis is defined as the presence of nests of luteinized theca cells in the ovarian stroma. Persistent testosterone released by ovarian theca cells is unmasked postmenopausally through the loss of granulosa cell-mediated aromatization of testosterone to estradiol. Ovarian hyperthecosis (OH) usually presents with symptoms of hyperandrogenism and is often described as a severe or extreme form of Polycystic Ovary Syndrome (PCOS). Serum testosterone levels in excess of 150 ng/dl (>5.2 nmol/l) are seen in affected patients and this threshold is used to confirm a diagnosis. Treatment of hyperthecosis is multi-faceted. It addresses the attendant hyperandrogenism (hirsutism and virilization) as well as metabolic complications such as obesity and insulin resistance. Ultimately, laparoscopic bilateral salpingo-oophorectomy is definitive treatment. This remains the treatment of choice in postmenopausal women whereas treatment using GnRH agonists may be used in women of reproductive age, especially younger women. Nevertheless, if serum testosterone remains elevated despite several months of therapy with a GnRH agonist, surgery is often required for biopsy sample collection and further definitive therapy. In order to mitigate the common clinical manifestations of hyperandrogenism, anti-androgen therapy (either cyproterone acetate or spironolactone) may be used to suppress the actions of testosterone on tissues. In patients with impaired glucose metabolism and insulin resistance, Metformin should also be considered as part of treatment. Combined, such a treatment regimen will often lead to decreased ovarian androgen secretion.

The Genetic Backdrop of Hypogonadotropic Hypogonadism.

The pituitary is an organ of dual provenance: the anterior lobe is epithelial in origin, whereas the posterior lobe derives from the neural ectoderm. The pituitary gland is a pivotal element of the axis regulating reproductive function in mammals. It collects signals from the hypothalamus, and by secreting gonadotropins (FSH and LH) it stimulates the ovary into cyclic activity resulting in a menstrual cycle and in ovulation. Pituitary organogenesis is comprised of three main stages controlled by different signaling molecules: first, the initiation of pituitary organogenesis and subsequent formation of Rathke's pouch; second, the migration of Rathke's pouch cells and their proliferation; and third, lineage determination and cellular differentiation. Any disruption of this sequence, e.g., gene mutation, can lead to numerous developmental disorders. Gene mutations contributing to disordered pituitary development can themselves be classified: mutations affecting transcriptional determinants of pituitary development, mutations related to gonadotropin deficiency, mutations concerning the beta subunit of FSH and LH, and mutations in the DAX-1 gene as a cause of adrenal hypoplasia and disturbed responsiveness of the pituitary to GnRH. All these mutations lead to disruption in the hypothalamic-pituitary-ovarian axis and contribute to the development of primary amenorrhea.