Medical Bulletin 28/ February / 2024

A team of engineers and biologists at the University of Michigan, the Weizmann Institute of Science, and the University of Pennsylvania have pioneered the first stem cell culture method capable of producing a full model of the early stages of the human central nervous system.

The findings published in the journal Nature showed a 3D human organoid, demonstrating stem cell cultures that mimic essential structural and functional features of human organ systems, albeit as incomplete or imperfect replicas.

"Models like this will open doors for fundamental research to understand early development of the human central nervous system and how it could go wrong in different disorders," said Jianping Fu, U-M professor of mechanical engineering and corresponding author of the study.

"We try to understand not only the basic biology of human brain development, but also diseases—why we have brain-related diseases, their pathology, and how we can come up with effective strategies to treat them," said Guo-Li Ming and Hongjun Song, Perelman Professors of Neuroscience at UPenn and co-authors of the study. They developed protocols for growing and guiding the cells and characterized the structural and cellular characteristics of the model.

Organoids developed using patient-derived stem cells may be used for identifying which drugs offer the most successful treatment. Human brain and spinal cord organoids are being used to study neurological and neuropsychiatric diseases, but they often mimic one part of the central nervous system and are disorganized. The new model, in contrast, recapitulates the development of all three sections of embryonic brain and spinal cord simultaneously.

The model began with stem cells resembling the neural tube of a 4-week-old embryo, adhered to a chip with channels for growth guidance. Adding a gel enabled three-dimensional growth, while chemical signals directed cells to become neural precursors, forming a tubular structure. Further signals prompted cell specialization, mimicking forebrain, midbrain, hindbrain, and spinal cord development over 40 days, akin to 11 weeks post-fertilization. This allowed the team to study gene roles in spinal cord development and cell differentiation in the early human nervous system.

"The system itself is really groundbreaking," said Orly Reiner, the Berstein-Mason Professorial Chair of Neurochemistry at Weizmann and co-author of the study who developed cellular tools to identify neural cell types in the model. "A model that mimics this structure and organization has not been done before, and it offers numerous possibilities for studying human brain development and especially developmental brain diseases."

Reference: A patterned human neural tube model using microfluidic gradients (DOI: 10.1038/s41586-024-07204-7)

New research sheds light on the relationship between parental age and congenital disorders.

A new paper published in Genome Biology and Evolution, under Oxford University Press, revealed the association between paternal age and rare congenital disorders is more intricate than previously thought.

While it's been known that advanced paternal age increases the likelihood of offspring with conditions like bone and heart malformations (e.g., Achondroplasia, Apert, or Noonan syndrome) as well as neurodevelopmental disorders such as schizophrenia and autism, recent research suggests that while certain pathogenic mutations correlate with paternal age, others do not. Moreover, some mutations may arise in the father's testis before sexual maturity.

Delayed fatherhood heightens the risk of new mutations causing congenital disorders in children. Fibroblast growth factor receptor 3 (FGFR3) is a human protein found in tissues like cartilage, the brain, intestines, and kidneys. Driver mutations, more prevalent in older men's sperm, significantly elevate the risk of congenital disorders.

For the study, researchers collected sperm samples from anonymous donors, aged 23 to 59, and examined the variant frequency for genetic mutations in ten different FGFR3 variants.

They discovered that the FGFR3 variant linked to Achondroplasia, the most prevalent form of short-limbed dwarfism, increases with paternal age. Similarly, another variant associated with Thanatophoric dysplasia, a severe skeletal disorder in children, also showed an increase with advancing paternal age.

However, many other FGFR3 variants were found to have no correlation with paternal age.

“Young dads also face a higher risk of having kids with pathogenic mutations, said the paper’s lead author, Irene Tiemann-Boege.

Reference: Genome Biology and Evolution; DOI: 10.1093/gbe/evae015

Research reveals health risks from endocrine-disrupting chemicals in plastics, pesticides and other sources

A recent report from the Endocrine Society raised concerns about the significant threats to human health posed by ubiquitous endocrine-disrupting chemicals (EDCs) in our environment and daily activities. The report included detailed analyses on exposure to EDCs from four sources: plastics, pesticides, consumer products (including children’s products), and per-and poly-fluoroalkyl substances (PFAS), a class of thousands of chemicals known or suspected to be EDCs.

“A well-established body of scientific research indicates that endocrine-disrupting chemicals that are part of our daily lives are making us more susceptible to reproductive disorders, cancer, diabetes, obesity, heart disease, and other serious health conditions,” said the report’s lead author, Andrea C. Gore, PhD, of the University of Texas at Austin. “These chemicals pose particularly serious risks to pregnant women and children.”

Hormones play a vital role in normal bodily functions and health. However, exposure to endocrine-disrupting chemicals (EDCs) can interfere with hormone actions, leading to various health issues. Evidence links environmental EDC exposure to serious conditions including diabetes, neurological and reproductive disorders, inflammation, and compromised immune function.

The report highlighted two analyses focusing on endocrine-disrupting chemicals (EDCs) in plastics and pesticides. Despite increasing global production, scientists warn of the rising crisis of chemical and plastic pollution. Glyphosate, the most widely used herbicide, exhibits eight out of ten key characteristics of an EDC, with studies linking it to adverse reproductive health outcomes. Plastics contain thousands of toxic substances, including known or suspected EDCs like bisphenols and phthalates.

Lead exposure can lead to endocrine-related issues like delayed puberty and early menopause. Arsenic, a common metal associated with cancer and other health problems, has been found to disrupt multiple endocrine systems. PFAS, found in various products like clothing and food packaging, have been shown in recent studies to disrupt hormones such as estrogen and testosterone, as well as impair thyroid hormone functions.

“EDCs are different than other toxic chemicals, but most regulations fail to address these differences,” said Science Advisor Sara Brosché, Ph.D. “For example, we know that even very low doses of endocrine-disrupting chemicals can cause health problems and there may be no safe dose for exposure to EDCs. However, regulations typically do not protect against low-dose effects. We need a global approach to controlling EDCs based on the latest science with a goal of protecting the human right to a healthy environment.”

Reference: “Latest science shows endocrine disrupting chemicals in plastics, pesticides, and other sources pose health threats globally”- THE ENDOCRINE SOCIETY