Genetics of Spina Bifida

 

This review is about spina bifida (SB) as a complex congenital disorder of the central nervous system, emphasizing its significant genetic component alongside environmental factors. The authors detail that while the complete cause is not fully understood, research has identified over 250 associated genes in mouse models, pointing to disrupted pathways like the planar cell polarity (PCP) pathway, signaling, and folate metabolism. In humans, SB is considered an omnigenic trait, involving a combination of variants in genes such as VANGL1, VANGL2, CELSR1, and TBXT, as well as genes involved in folate processing like MTHFR. The review also covers the critical role of maternal factors (diabetes, folate deficiency) and the well-established preventive effect of folic acid supplementation. Beyond genetics, the article discusses the pathophysiology of the "two-hit" injury model and the evolution of treatment from postnatal surgical closure to groundbreaking fetal surgery, culminating in the introduction of the first FDA-approved clinical trial using placenta-derived mesenchymal stem cells (PMSCs) to augment in utero repair.

In my opinion, this research paper powerfully illustrates the convergence of genetic discovery and clinical innovation in tackling a devastating birth defect. The genetic narrative is particularly compelling; it moves SB from a condition historically attributed to simple folate deficiency or birth injury to a complex neurogenetic disorder with an "omnigenic" architecture. Understanding that hundreds of genes can disrupt fundamental embryological processes like neural tube closure reframes our approach, shifting focus from a singular cause to a web of vulnerabilities. This genetic complexity explains why folic acid, while hugely preventive, is not a universal cure. The most exciting implication lies in the therapeutic frontier: this genetic understanding lays the groundwork for the pioneering stem cell trial discussed. By identifying the specific cellular and signaling pathways that fail, researchers can now rationally design regenerative strategies, like using PMSCs, to protect or repair the developing spinal cord. This marks a paradigm shift from merely closing a physical defect to attempting a biologically-informed restoration of function, offering real hope for improving outcomes beyond the current limits of fetal surgery alone.

References: 

1. Hassan, A.-E. S., Du, Y. L., Lee, S. Y., Wang, A., & Farmer, D. L. (2022). Spina Bifida: A Review of the Genetics, Pathophysiology and Emerging Cellular Therapies. Journal of Developmental Biology, 10(2), 22. https://doi.org/10.3390/jdb10020022 

2. Spina bifida: MedlinePlus Genetics. (n.d.). Medlineplus.gov. https://medlineplus.gov/genetics/condition/spina-bifida/ 

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Gene Therapy Used to Help Mice Recover From Severed Spinal Cord

A recent study has found that by applying gene therapy they could restore mobility in mice with completely severed spinal cords. It was previously shown that nerve fibers could be regenerated across anatomically complete spinal cord injuries, but this did not restore motor function, as the new fibers failed to connect to the right places on the other side of the lesion. Analyses of mice with severed spines revealed that specific axons (thin fibers that connect neurons) needed to regenerate and reconnect to their natural positions to restore motor function. The team of researchers activated growth in these axons and regenerated nerve fibers, even through scar tissue, by promoting specific supporting proteins. With the help of guidance molecules, the regenerated nerve fibers are able to be directed in a way that restores the spine to a state similar to before the injury. The repairing process did not show full recovery after complete spinal severance, but the mice were as mobile as those with more minimal spinal injuries. This means with more medical developments full mobility restoration is not completely out of the question. In fact, it is hypothesized that multipronged gene therapy could restore spinal injuries more fully. However, one must keep in mind that research in animals does not always pan out in humans. Senior researcher, and co-head of NeuroRestore, Grégoire Courtine had this to say about the research: “We expect that our gene therapy will act synergistically with our other procedures involving electrical stimulation of the spinal cord. We believe a complete solution for treating spinal cord injury will require both approaches — gene therapy to regrow relevant nerve fibers, and spinal stimulation to maximize the ability of both these fibers and the spinal cord below the injury to produce movement." 

I find this research to be very promising for serious spinal injuries and partial spinal injuries alike. While having the ability to walk is an advantage to that of being wheelchair-bound, I also believe that if minor spinal injury recovery can be improved, researchers may be able to develop a therapy that would restore complete bodily autonomy. I also wonder what gene therapies may be capable of being developed to improve brain function for patients with neurons damaged in their heads. It seems the possibilities may be endless as long as funding for similar research continues, who knows how many lives could be saved with this research as a launch pad.

https://www.usnews.com/news/health-news/articles/2023-09-27/in-mice-gene-therapy-helps-restore-movement-after-spinal-cord-injury

https://www.science.org/doi/10.1126/science.adi6412

Bunnies Do Handstands Instead of Hops: Genetic Defects

 

In this article, Erin Garcia de Jesus discusses how a genetic defect may cause bunnies to do handstands instead of hopping as a way to move fast. A rabbit called sauteur d’Alfort sends its back legs sky high and walks on its front paws. That strange form may be the result of a gene tied to limb movement, researchers report March 25 in PLOS Genetics. Mice have also shown this similar trait and walked on their front limbs to run. 

Understanding this genetic defect and how they move, can help improve our knowledge on the spinal cord. A mutation in the RORB gene is a likely candidate for the rabbits’ handstands. That mutation causes faulty versions of the genetic instructions that cells use to make proteins, which means there is less of the RORB protein in specialized nerve cells in rabbits that have the mutation compared with rabbits that don’t. Without the RORB protein in spinal cord nerve cells (interneurons) , the rabbits may lack the ability to coordinate what their hind limbs are doing, which affects their ability to hop regularly. Understanding this, and how one possible mutation affects how animals move, and ultimately help develop ways to repair the body when defects in RORB cause diseases/immobility. 

Links:

https://www.sciencenews.org/article/rabbit-handstand-front-paws-gene-defect-video

https://www.nature.com/articles/d41586-021-00775-9#:~:text=An%20unusual%20rabbit%20that%20walks,hind%20legs%20in%20the%20air.

Stem cell responsible for spinal regeneration located

Seeing a Gecko slowly regrow its tail may not seem that important to some people until it is pointed out what is inside the gecko's tail.  The article, "Cells driving gecko's ability to regrow its tail identified,"  goes into detail about the study done to examine the gecko's cell functions after the tail has been removed.  Inside the geckos tail, unlike in mammals, is a portion of the spinal cord so when the tail is removed the gecko is able to not only regrow the tail but the spinal cord as well.  The type of cell responsible is called "radial glia," which is a type of stem cell that is usually dormant.  However, once the injury is sustained the cells change function and begin to regenerate tissue rather than create scar tissue.  Discovering the cells responsible for this could mean the knowledge could be applied to human injuries by coaxing those cells to regenerate tissue rather than apply scar tissue.  As humans DNA code for the same type of stem cell as the geckos, for some reason it is not active in the regeneration process.  Putting scar tissue over the wound rather than regenerating tissue is a quick fix but is bad for the long run.  With this knowledge I think a better understanding of how the injuries can be solved preventing the lose of activity in some limbs due to the spinal injury, which would mean saving a lot of people the pain of having surgeries that may or may not work to regain control of their limbs.

New Implantable Device Stops Pain at its Source

Imagine a flexible, implant in the body that stops pain at its source so that it can never be perceived by the brain. And it doesn't require batteries. Researchers from Washington University of Medicine in St. Louis, MO, and the University of Illinois have recently developed a prototype, undergoing trials in lab mice, of the implant.
The research team is utilizing the newly developing field of optogenetics, "a biological technique which involves the use of light to control cells in living tissues, typically neurons". The genetically engineered lab mice being used have nerve cells with light-sensitive proteins on their surfaces. These new devices can be held in place with sutures, and the research team hopes that eventually the technology can be used to "treat pain in very specific locations by providing a kind of 'switch' to turn off the pain signals long before they reach the brain". In their study, the research teams used the device to activate small doses of pain in lab mice to demonstrate the ability of light to induce or block pain in different methods. They believe that their studies demonstrate that optogenetics has future potential in areas of the body other than the brain, such as the bladder, stomach, and joints.
I personally believe that advancing branches of medical fields such as optogenetics will lead to improved healthcare in the future. Technology is rapidly advancing, and implanting a "pain-stopping" device is both exciting and expected sometime in the near future. Beginning research now on these new, prototypical fields will be beneficial in the future.

Aliens of the Sea

     The comb jellyfish, such an interesting sea creature, that gets a little more interesting when one finds out the capabilities this little guy holds. When one of these jellies is cut up, they begin go regrow at amazing speed and some even develop rudimentary brains. An article on natureworldnews.com goes onto explain how researchers are attempting to use these sea creatures to further our knowledge in the regeneration of the spinal cord. Comb jellies are only about the size of a golf ball and actually get their name from the tiny comb-like hairs they use to swim. Researchers are attempting to find out how what gene these creatures turn off and on while they are performing these regenerative mechanisms. These jellyfish can even regenerate their elementary brain in about three to five days if need be which makes them even more interesting. Using a genomic sequencing machine these researchers are trying to understand these sea creatures so that we can one day be able to regenerate our brains and spinal cords. If this were possible, then it would completely change our medical world and open up doors never thought possible. These ideas seem far-fetched but this is one in many studies that is attempting to understand regenerative mechanisms, so a breakthrough could be right around the corner.

Spinal Cord Injury and Stem Cell Therapy

After a spinal cord injury, many of the nerve fibers at the injury site lose their insulating layer of myelin. With this result, the fibers are not able to properly transmit signals between the brain and the spinal cord contributing to paralysis. Unfortunately, the spinal cord lacks the ability to restore these lost myelin-forming cells after trauma. Tissue engineering in the spinal cord involves the implantation of scaffold material to guide cell placement and foster cell development. These scaffolds can also be used to deliver stem cells at the site of injury and maximize their regenerative potential. When the spinal cord is damaged—either accidentally (car accidents, falls) or as the result of a disease (multiple sclerosis, infections, tumors, severe forms of spinal bifida, etc.) it can result in the loss of sensation and mobility and even in

complete paralysis. Using Stem cells as a therapy, they replace the injured neurons. Using embryonic stem cells for transplantation is controversial because it is necessary to first create human embryos to produce the stem cells and then kill the embryos in the process of “harvesting” the stem cells. Apart from the controversy about creating and killing human embryos, stem cell researchers are faced with another challenge which is partly practical and partly ethical. The body’s immune system recognizes what is part of the body and what is not. Every cell in the body has protein molecules on the surface of the cell wall that identify the cell as being part of the body. There is a chance that the cells could be rejected and the immune system would attack them. The use of stem cells can be used for a lot of other great causes, when stem cells can be extracted in a more humane way, they could change the future of health care.