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A Great Deal of Work Lies Ahead in the Development of In Vivo Reprogramming as a Therapy

The latest from Calico. A bit technical.


Reprogramming of ordinary somatic cells into induced pluripotent stem cells (iPSCs) was initially thought to be a way to obtain all of the patient matched cells needed for tissue engineering or cell therapies. A great deal of work has gone towards realizing that goal over the past fifteen years or so; the research community isn’t there yet, but meaningful progress has taken place. Of late, another line of work has emerged, in that it might be possible to use partial reprogramming as a basis for therapy, delivering reprogramming factors into animals and humans in order to improve tissue function, without turning large numbers of somatic cells into iPSCs and thus risking cancer or loss of tissue structure and function.

Reprogramming triggers some of the same mechanisms of rejuvenation that operate in the developing embryo, removing epigenetic marks characteristic of aged tissues, and restoring youthful mitochondrial function. It cannot do much for forms of damage such as mutations to nuclear DNA or buildup of resilient metabolic waste, but the present feeling is there is nonetheless enough of a potential benefit to make it worth developing this approach to treatments for aging. Some groups have shown that partial reprogramming — via transient expression of reprogramming factors — can reverse functional losses in cells from aged tissues without making those cells lose their differentiated type. But this is a complicated business. Tissues are made up of many cell types, all of which can need subtly different approaches to safe reprogramming.

Today’s open access preprint is illustrative of the amount of work that lies ahead when it comes to the exploration of in vivo reprogramming. Different cell types behave quite differently, will require different recipes and approaches to reprogramming, different times of exposure, and so forth. It makes it very hard to envisage a near term therapy that operates much like present day gene therapies, meaning one vector and one cargo, as most tissues are comprised of many different cell types all mixed in together. On the other hand, the evidence to date, including that in the paper here, suggests that there are ways to create the desired rejuvenation of epigenetic patterns and mitochondrial function without the risk of somatic cells dedifferentiating into stem cells.

The FDA Has Approved An Obesity Drug That Helped Some People Drop Weight

Regulators on Friday said a new version of a popular diabetes medicine could be sold as a weight-loss drug in the U.S.

The Food and Drug Administration approved Wegovy, a higher-dose version of Novo Nordisk’s diabetes drug semaglutide, for long-term weight management.

In company-funded studies, participants taking Wegovy had average weight loss of 15%, about 34 pounds (15.3 kilograms). Participants lost weight steadily for 16 months before plateauing. In a comparison group getting dummy shots, the average weight loss was about 2.5%, or just under 6 pounds.

‘Amazing Natural Experiment’: In This Amazonian Tribe, Brains Don’t Age Like Ours

The Tsimane, an indigenous people who live in the Bolivian peripheries of the Amazon rainforest, lead lives that are very different to ours. They seem to be much healthier for it.

This tribal and largely isolated population of forager-horticulturalists still lives today by traditional ways of farming, hunting, gathering, and fishing – continuing the practices of their ancestors, established in a time long before industrialization and urbanization transformed most of the world.

For the Tsimane, the advantages are considerable. A study published in 2017 found that they effectively have the healthiest hearts in the world, with the lowest reported levels of coronary artery disease of any population ever recorded.

Biden’s Proposed New Health Agency Would Emphasize Innovation. Here’s How It Might Work

The White House recently announced its vision for an Advanced Research Projects Agency for Health, or ARPA-H. RAND researchers explain what it might take to ens… See More.


DARPA also maintains an extremely high tolerance for failure. The modest budgets of the NIH, combined with an enormous pool of applicants, force these institutions to bet on low-risk research that guarantees incremental progress. ARPA-H could take a different approach than NIH by accepting a much higher tolerance for failure, so that researchers are not discouraged from dreaming big.

The scientific methods behind the products of ARPA-H might gain public trust if the agency made a point of being transparent and accessible. Consider how the rapid development of the COVID-19 vaccine was met with incredulity and suspicion, slowing progress toward herd immunity. An investment in ARPA-H could accelerate the time it takes to get innovative ideas from “bench to bedside,” but it could benefit from informing the public about incremental advancements in a way that is easy to understand.

The president’s vision for ARPA-H could help get more medical treatments to market sooner. Building on lessons from DARPA and NIH, the proposed health agency has the potential to pursue the kind of high-risk research that can lead to high-reward results.

Quantum holds the key to secure conference calls

The world is one step closer to ultimately secure conference calls, thanks to a collaboration between Quantum Communications Hub researchers and their German colleagues, enabling a quantum-secure conversation to take place between four parties simultaneously.

The demonstration, led by Hub researchers based at Heriot-Watt University and published in Science Advances, is a timely advance, given the global reliance on remote collaborative working, including calls, since the start of the C19 pandemic.

There have been reports of significant escalation of cyber-attacks on popular teleconferencing platforms in the last year. This advance in quantum secured communications could lead to conference calls with inherent unhackable security measures, underpinned by the principles of quantum physics.

Computer simulations of the brain can predict language recovery in stroke survivors

At Boston University, a team of researchers is working to better understand how language and speech is processed in the brain, and how to best rehabilitate people who have lost their ability to communicate due to brain damage caused by a stroke, trauma, or another type of brain injury. This type of language loss is called aphasia, a long-term neurological disorder caused by damage to the part of the brain responsible for language production and processing that impacts over a million people in the US.

“It’s a huge problem,” says Swathi Kiran, director of BU’s Aphasia Research Lab, and College of Health & Rehabilitation Sciences: Sargent College associate dean for research and James and Cecilia Tse Ying Professor in Neurorehabilitation. “It’s something our lab is working to tackle at multiple levels.”

For the last decade, Kiran and her team have studied the brain to see how it changes as people’s improve with speech . More recently, they’ve developed new methods to predict a person’s ability to improve even before they start therapy. In a new paper published in Scientific Reports, Kiran and collaborators at BU and the University of Texas at Austin report they can predict recovery in Hispanic patients who speak both English and Spanish fluently—a group of aphasia patients particularly at risk of long-term language loss—using sophisticated computer models of the brain. They say the breakthrough could be a game changer for the field of speech therapy and for stroke survivors impacted by aphasia.

Expression of human‐specific ARHGAP11B in mice leads to neocortex expansion and increased memory flexibility

Generation of an ARHGAP11B-transgenic mouse line.

To generate a stable transgenic mouse line that expresses an ARHGAP11B protein, we first determined the temporal and spatial expression patterns of human ARHGAP11A and human ARHGAP11B mRNAs by qPCR of foetal human neocortical tissue at various developmental stages (gestational weeks 12–21; Fig EV1A and B) and by analysing previously published RNA-seq data sets of defined isolated NPC and neuron populations (Florio et al, 2015) (Fig EV1C and D), respectively. As the expression patterns of ARHGAP11A and ARHGAP11B mRNAs were found to be similar, we decided to generate the transgenic mouse line by converting one allele of the mouse Arhgap11a gene into a mutant mouse ARHGAP11B gene (mARHGAP11B), using the CRISPR/Cas9 genome editing technology (for details, see Materials and Methods). In m ARHGAP11B, the 55 nucleotides of Arhgap11a that in humans would be deleted from the ARHGAP11B mRNA by splicing using the new splice-donor site are replaced by the 141 nucleotides encoding the human-specific 47-amino acid sequence plus three nucleotides to generate a translational stop codon (Fig EV1E). Unless indicated otherwise, the ARHGAP11B-transgenic mice obtained (referred to as 11B mice hereafter) were used as heterozygous animals, that is, with one mouse Arhgap11a allele being replaced by m ARHGAP11B. The resulting ARHGAP11B protein will be expressed in developing mouse neocortex under the control of the native mouse Arhgap11a promotor.

Sonothermogenetics for noninvasive and cell-type specific deep brain neuromodulation

Critical advances in the investigation of brain functions and treatment of brain disorders are hindered by our inability to selectively target neurons in a noninvasive manner in the deep brain.

This study aimed to develop sonothermogenetics for noninvasive, deep-penetrating, and cell-type-specific neuromodulation by combining a thermosensitive ion channel TRPV1 with focused ultrasound (FUS)-induced brief, non-noxious thermal effect.

The sensitivity of TRPV1 to FUS sonication was evaluated in vitro. It was followed by in vivo assessment of sonothermogenetics in the activation of genetically defined neurons in the mouse brain by two-photon calcium imaging. Behavioral response evoked by sonothermogenetic stimulation at a deep brain target was recorded in freely moving mice. Immunohistochemistry staining of ex vivo brain slices was performed to evaluate the safety of FUS sonication.

A Massive New Gene Editing Project Is Out to Crush Alzheimer’s

The idea is simple: decades of research have found certain genes that seem to increase the chance of Alzheimer’s and other dementias. The numbers range over hundreds. Figuring out how each connects or influences another—if at all—takes years of research in individual labs. What if scientists unite, tap into a shared resource, and collectively solve the case of why Alzheimer’s occurs in the first place?

The initiative’s secret weapon is induced pluripotent stem cells, or iPSCs. Similar to most stem cells, they have the ability to transform into anything—a cellular genie, if you will. iPSCs are reborn from regular adult cells, such as skin cells. When transformed into a brain cell, however, they carry the original genes of their donor, meaning that they harbor the original person’s genetic legacy—for example, his or her chance of developing Alzheimer’s in the first place. What if we introduce Alzheimer’s-related genes into these reborn stem cells, and watch how they behave?

By studying these iPSCs, we might be able to follow clues that lead to the genetic causes of Alzheimer’s and other dementias—paving the road for gene therapies to nip them in the bud.