Lifeboat Foundation

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

CRISPR corrects genetic defect so cells can normalize blood sugar.

More than 20 years ago, the human genome was first sequenced. While the first version was full of “holes” representing missing DNA sequences, the genome has been gradually improved in successive rounds. Each has increased the quality of the genome and, in so doing, resolved most of the blank spaces that prevented us from having a complete reading of our genetic material.

The fundamental difficulty researchers faced in reading the genome from end to end is the enormous number of repeated sequences that populate it. The 20,000 or so genes we humans have occupy barely 2% of the entire genome. The remaining 98% is essentially made up of these families of repeated sequences, mobile elements known as transposons and retrotransposons, and—to a lesser but functionally important extent— gene expression regulatory sequences. These function as switches that determine when and where genes are turned on and off.

In March 2022, a major revision of the genome was published in the journal Science. An international consortium of researchers known as “T2T” (telomere to telomere, which are the ends of chromosomes) used a novel strategy based a type of cell (CHM13) that retains only one copy of each chromosome.

Scientists already have their ways of coaxing human cells into new forms, using a special concoction of chemicals to nudge humble skin cells into malleable tissues known as induced pluripotent stem cells.

In spite of this new lease on life, these particular cells still retain a few genetic reminders of their time as a fully developed tissue, affecting their use as a blank slate.

Now an international team of researchers has gone one better: finding a new way of wiping a cell’s memory clean so it can be better reprogrammed as a stem cell.

Stem cells in organoids self-organize into tissue patterns with unknown mechanisms. Here, we use skin organoids to analyze this process. Cell behavior videos show that the morphological transformation from multiple spheroidal units with morphogenesis competence (CMU) to planar skin is characterized by two abrupt cell motility–increasing events before calming down. The self-organizing processes are controlled by a morphogenetic module composed of molecular sensors, modulators, and executers. Increasing dermal stiffness provides the initial driving force (driver) which activates Yap1 (sensor) in epidermal cysts. Notch signaling (modulator 1) in epidermal cyst tunes the threshold of Yap1 activation. Activated Yap1 induces Wnts and MMPs (epidermal executers) in basal cells to facilitate cellular flows, allowing epidermal cells to protrude out from the CMU. Dermal cell–expressed Rock (dermal executer) generates a stiff force bridge between two CMU and accelerates tissue mixing via activating Laminin and β1-integrin. Thus, this self-organizing coalescence process is controlled by a mechano-chemical circuit. Beyond skin, self-organization in organoids may use similar mechano-chemical circuit structures.

Life runs on ribosomes. Every cell across the globe requires ribosomes to convert genetic data into the vital proteins required for the organism’s operation, and, subsequently, for the production of more ribosomes. However, scientists still lack a clear understanding of how these essential nanomachines are assembled.

Now, new high-resolution images of the large ribosomal subunit are shedding light on how arguably nature’s most fundamental molecule coalesces in human cells. The findings, published in Science, bring us one step closer to a complete picture of ribosome assembly.

“We now have a pretty good idea of how the large ribosomal subunit is assembled in humans,” says Rockefeller’s Sebastian Klinge. “We still have quite a few gaps in our understanding, but we certainly now have a much better idea than we had before.”

Scientists have recently reviewed the available literature to examine the critical roles played by mitochondria in maintaining homeostasis. The review summarized the involvement of mitochondria in age-related disease progression and highlighted its potential as a therapeutic target of these diseases. This review has been published in Experimental & Molecular Medicine.

Mitochondria is a cytoplasmic organelle in most eukaryotic cells and is enclosed by two phospholipid membranes: the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM). These membranes separate functionally compartmentalized structures, i.e., matrix and intermembrane space. Mitochondria contain a unique genetic code, mitochondrial DNA (mtDNA).

During evolution, most mitochondrial genes were lost or translocated to nuclei. However, genes that remained in mtDNA encode for essential translational apparatus, i.e., ribosomal RNAs and transfer RNAs. In addition, these genes also encode proteins that are key components of oxidative phosphorylation system (OXPHOS) complexes embedded in the IMM.

The findings suggest that adenosine base editing raised the expression of fetal hemoglobin to higher, more stable, and more uniform levels than other genome editing technologies that use CRISPR/Cas9 nuclease in human hematopoietic stem cells.

“Ultimately, we showed that not all genetic approaches are equal,” said Jonathan Yen, PhD, genome engineering group director at St. Jude Children’s Research Hospital. “Base editors may be able to create more potent and precise edits than other technologies. But we must do more safety testing and optimization.”

SCD and beta-thalassemia are blood disorders caused by mutations in the gene encoding hemoglobin affecting millions of people. Restoring gene expression of an alternative hemoglobin subunit active in a developing fetus has previously shown therapeutic benefit in SCD and beta-thalassemia patients. The researchers wanted to find and optimize genomic technology to edit the fetal hemoglobin gene.

Continue reading “Base Editing Beats Other Genome Editing Strategies for Treating Sickle Cell Disease” »

Scientists from the University of Rochester have had the naked mole-rat (Heterocephalus glaber) in their crosshairs for some time, previously identifying how their unique cellular aging mechanisms lay the foundation for their long lifespans – up to 41 years, during which the females also remain fertile – and resistance to age-related diseases.

The modification directly led to the improved overall health of the aging mice and an approximate 4.4% increase in median lifespan.

They weigh about an ounce, spend their lives underground in sub-Saharan Africa and are unlikely to be making the shortlist for any cute animal calendars, but the naked mole-rat continues to show scientists it has incredible age-resistant biology beneath its pale, wrinkly skin.

Continue reading “Naked mole-rat’s ‘longevity’ gene extends lifespan and health of mice” »

Scientists have found a way to reprogram human cells so that they mimic the highly plastic embryonic stem cells that have so much promise for use in regenerative medicine. By essentially wiping the cell’s “memory”, the team have created so-called induced pluripotent stem (iPS) cells, which could be used to regenerate or repair diseased tissue and organs.

IPS cells are a type of pluripotent cell that can be obtained by reprogramming mature human adult cells (“somatic” cells) into an embryonic stem cell-like state. This means that they have the capacity to differentiate into any cell of the body. They were first demonstrated in 2006, and have myriad potential biomedical and therapeutic uses, including disease modeling, drug screening, and cell-based therapies.

Despite this promise, researchers have continually hit a stumbling block that has prevented iPS cells from realizing their potential. “A persistent problem with the conventional reprograming process is that iPS cells can retain an epigenetic memory of their original somatic state, as well as other epigenetic abnormalities,” Professor Ryan Lister, lead author of a paper presenting the latest breakthrough, said in a statement.