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This story is part of a series on the current progression in Regenerative Medicine. In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

As part of a trio of stories on advances in stem cell gene therapy, this piece discusses how to alter blood stem cells using mRNA technology. Previous installments describe how the same platform could reinvent how we prepare patients for bone marrow transplants and correct pathogenic DNA.

At present, the only way to cure genetic blood disorders such as sickle cell anemia and thalassemia is to reset the immune system with a stem cell transplantation. Only a fraction of patients elects this procedure, as the process is fraught with significant risks, including toxicity and transplant rejection. A preclinical study published in Science explores a solution that may be less toxic yet equally effective: mRNA technology. The cell culture and mouse model experiments offer a compelling avenue for future research to enhance or replace current stem cell transplantations altogether.

A team of geneticists and systems biologists at Stanford University has associated 169 genes that with the production of melanin in the skin, hair and eyes. In their study, reported in the journal Science, the group conducted a flow cytometry analysis and genome-wide CRISPR screen of cell samples.

Prior research has shown that the production and distribution of melanin in the body is responsible for skin tone, hair color and eye pigmentation. Such characteristics are important for more than appearance’s sake; skin with more melanin, for example, is better able to protect against ultraviolet radiation. In this new effort, the researchers noted that while many of the genes responsible for melanin production have been identified, many more have not.

The researchers began with an effort to differentiate high and low melanin melanocytes—the cells that make melanin. They used the light-reflecting properties of melanin to sort cells in a lab dish by aiming a fluorescent lamp at them. Once they had the cells sorted, they edited them using CRISPR-Cas9. Genes were systematically mutated to switch them off and then tested to see how well the cell continued to produce melanin.

PNP editing is emerging as a versatile and programmable tool for site-specific DNA manipulations. An innovative genome-editing technique could enhance the delivery, specificity and targeting of gene-modifying tools for treatments.

The KAUST-developed method combines two molecular technologies: a synthetic family of DNA-like molecules known as peptide nucleic acids (PNAs), and a class of DNA-cutting enzymes known as prokaryotic Argonautes (pAgos).

The PNAs first unzip and slip inside the DNA helix. The pAgos, guided by short fragments of genetic material, then bind the loosened helix at specific target sequences and nick each opposing strand of DNA.

Summary: Researchers successfully sequenced the entire Y chromosome, previously considered the most elusive part of the human genome.

This feat enhances DNA sequencing accuracy for this chromosome, aiding the identification of genetic disorders. Using state-of-the-art technologies, the team pieced together over 62 million letters of genetic code.

This breakthrough, in tandem with the previous reference genome T2T-CHM13, offers the first complete genome for those with a Y chromosome.

Dr. Joni L. Rutter, Ph.D., (https://ncats.nih.gov/director/bio) is the Director of the National Center for Advancing Translational Sciences (NCATS — https://ncats.nih.gov/) at the U.S. National Institutes of Health (NIH) where she oversees the planning and execution of the Center’s complex, multifaceted programs that aim to overcome scientific and operational barriers impeding the development and delivery of new treatments and other health solutions. Under her direction, NCATS supports innovative tools and strategies to make each step in the translational process more effective and efficient, thus speeding research across a range of diseases, with a particular focus on rare diseases.

By advancing the science of translation, NCATS helps turn promising research discoveries into real-world applications that improve people’s health. The NCATS Strategic Plan can be found at — https://ncats.nih.gov/strategicplan.

Continue reading “Dr. Joni L. Rutter, Ph.D. — Director, National Center for Advancing Translational Sciences — NIH” »

“Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a therapeutic target for central nervous system (CNS) disorders, including those affecting the retina,” wrote the researchers. “Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate the potential of microglial cell replacement as a strategy for retinal diseases, we first employed an efficient protocol to generate a significant quantity of human-induced pluripotent stem cells (hiPSC)-derived microglia.”

“Our understanding of microglia function comes predominantly from rodent studies due to the difficulty of sourcing human tissue and isolating the microglia from these tissues. But there are genetic and functional differences between microglia in mice and humans, so these studies may not accurately represent many human conditions,” explained lead author Wenxin Ma, a PhD, biologist at the Retinal Neurophysiology Section, National Eye Institute, National Institutes of Health.

“To address this concern, researchers have been growing human microglia from human stem cells. We wanted to take this a step further and see if we could transplant human microglia into the mouse retina, to serve as a platform for screening therapeutic drugs as well as explore the potential of microglia transplantation as a therapy itself,” added senior author Wai Wong, vice president of retinal disease, Janssen Research and Development.

The team used acupuncture needles to deliver the trigger for 10 seconds a day, and the blood sugar levels in the mice returned to normal within a month. The rodents even regained the ability to manage blood sugar levels after a large meal without the need for external insulin, a normally difficult feat.

Called “electrogenetics,” these interfaces are still in their infancy. But the team is especially excited for their potential in wearables to directly guide therapeutics for metabolic and potentially other disorders. Because the setup requires very little power, three AA batteries could trigger a daily insulin shot for more than five years, they said.

The study is the latest to connect the body’s analogue controls—gene expression—with digital and programmable software such as smartphone apps. The system is “a leap forward, representing the missing link that will enable wearables to control genes in the not-so-distant future,” said the team.

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Summary: Researchers uncovered how distinct neuron types in the Drosophila fruit fly differentiate their functions despite originating from a similar genetic framework.

In the study, two closely related neuronal subtypes expressed more than 800 different genes (~5% of the fly genome) differently. This gene expression directly influenced the observable distinctions between the neuron types.

The findings help illuminate the brain’s intricate cell development and how disease could affect it.