Connect with us

Government

Synthetic Biology Brings Programmability to Drug Programs

In emulation of computer science, synthetic biology is using “integrated circuits” and “logic boards” to speed the development of powerful therapeutic applications.
The post Synthetic Biology Brings Programmability to Drug Programs appeared first…

Published

on

The term “integrated circuit” is no longer limited to computer chips, and the term “logic board” is no longer limited to computer chassis. These terms are being applied to biological systems by synthetic biologists. What’s more, the synthetic biologists aren’t being metaphorical. They are being literal. They are starting to assemble biological systems from plug-and-play components. And these systems, like computer systems, are meant to be programmable.

Currently, most synthetic biology components are molecular pathways—switches, oscillators, gated pathways, and so on—that are being used to reengineer, and thus repurpose, living cells. Some repurposed cells are enabling exciting applications in drug discovery and development. Sometimes the cells serve as especially flexible and powerful biopharmaceutical production platforms. Sometimes the cells themselves are the drugs. That is, the cells are “living drugs.”

These possibilities will be discussed at an upcoming conference, the Synthetic Biology–Based Therapeutics Summit. The conference, which will be held virtually December 7–9, has scheduled many impressive speakers, several of whom have contributed their insights to this article.

Most of the insights in this article pertain to tools and platforms that are already being used to develop therapies. However, these therapies are, in a sense, mere preliminaries. The real takeaway is that the new tools and platforms reflect synthetic biology’s commitment to programmability. Accordingly, they may be seen as steps to a new frontier—a place where the bold and ambitious needn’t feel obliged to consider only the easiest, most obvious target that a disease might present. For example, if a disease should present multiple targets, the sensible course might be to hit them all at once, via delivery vehicles that provide exquisite spatiotemporal control over therapeutic administration.

A larger set of CRISPR tools

Mammoth Biosciences searches for novel CRISPR systems by sifting through metagenomics data. According to Lucas Harrington, PhD, Mammoth’s co-founder and CSO, the company has genomics data about microbes from a vast number of sites (including volcanoes, hot springs, and Antarctic ice); from varied specimen types (including animal stools); and from living organisms (including humans). “Mining this massive amount of data,” he says, “feeds new applications.”

At Mammoth Biosciences, metagenomics data fuels the search for new Cas enzymes with function-alities specifically suited to different applications. The biggest focus is on CRISPR proteins that have less bulk and machinery than Cas9, and that can be coupled with advanced CRISPR techniques, such as base editing, to facilitate advanced and expanded delivery for in vivo genome editing.

Mammoth takes both a top-down and bottom-up approach to find the best tools for each application to leverage the full CRISPR toolbox. The company’s “discovery first” approach addresses how the enzymes work, and the bottom-up perspective defines the specifications of enzymes that address unmet needs, including those in the healthcare space.

For example, Mammoth used a discovery-to-application process to develop the DETECTR system. Mammoth’s scientists discovered that after a certain Cas enzyme complexed with a guide RNA and found a DNA target, it became a nonspecific cutter that could also cleave a reporter molecule. Because reporter molecules can be added to serve as a fluorescent, colorimetric, or electrical signal, a cutting event may provide a real-time result that a target sequence has been found.

Mammoth recently indicated that it was preparing an Emergency Use Authorization (EUA) application for a high-throughput, CRISPR-based COVID-19 test called DETECTR BOOST. The company has other respiratory viral targets in the pipeline. The pandemic illustrated the need to differentiate infectious agents, such as influenza, respiratory syncytial virus, and SARS-CoV-2.

“The power of the CRISPR assay is its flexibility,” stresses Janice Chen, PhD, Mammoth’s co-founder and CTO. “You can program the guide RNA to go after different targets, allowing multiplexing to simultaneously detect different target sequences and get a differential diagnosis from a single sample.”

On the therapeutics side, one of the most intense areas of inquiry is the search for compact CRISPR proteins. Legacy CRISPR proteins are very large, and delivery to desired tissues can be difficult.

“Although the systems we are developing have less bulk and machinery than Cas9, we have been able to get higher accuracy due to hundreds of millions of years of natural selection,” Harrington asserts. “We can couple our compact proteins with advanced CRISPR-based techniques, such as base editing, and take advantage of the precision of the edits and the delivery advantages of a smaller protein like Cas14. It is exciting to think about all the different things you can do.”

A discovery engine for programmable cell therapies

“Our technology for integrated circuit–modified T cells allows the installation of more synthetic therapeutic function into T-cell therapies to treat cancers,” says Aaron Cooper, PhD, senior director of synthetic biology at ArsenalBio. “We consider multiple functions that address multiple problems to create a multidimensional cell therapeutic.”

ArsenalBio generates integrated circuit–modified T cells by making use of its PrimeR logic gates, its CARchitecture derived gene expression controls, and its CellFoundry-mediated nonviral manufacturing platform. The integrated circuit, which incorporates multifunctional DNA, can be used to program a T cell to recognize two antigens and to kill tumor cells only when both antigens are present. This approach can overcome targeting difficulties in solid tumors and reduce off-target effects. The integrated circuit can also tune aspects of T-cell biology to increase cellular proliferation and potency, as well as increase resistance to the suppressive tumor microenvironment.

A key challenge is delivering the DNA for the integrated circuit into cells. The integrated circuit is too large for viral delivery. “We have to use a CRISPR-based delivery approach,” Cooper explains. “It can accommodate more DNA and is faster to implement. We can compress iterations and quickly test, learn, and build.”

Another challenge is safety. To address this challenge, ArsenalBio ensures that the DNA is inserted into the genome at a site far from any genes. “Being able to choose a site means we are able to predict the activity of the inserted program more than we could with random integration with a virus or transposon,” Cooper explains. “We can test hypotheses across many T-cell samples and get a high degree of confidence of what we will see in vivo.”

AresenalBio has been using integrated circuits that contain about 8.3 kb of DNA. The large amount of real estate creates a vast design palette to explore.

“The evolution will be in identifying additional mechanisms to go after in a tumor,” Cooper declares. “A lot of ideas exist, and we need to start executing on more than one at a time for a single therapy. Genetic logic boards can allow you to go after multiple facets all at once so that you can tackle antigen recognition, extend the longevity of therapies, and engineer therapies to be more resistant to suppressors that are in the tumor microenvironment.”

A pair of next-generation drug discovery platforms

SyntheX has two drug discovery platforms: ToRPPIDO and ToRNeDO. They rely on functional intracellular drug selection as opposed to in vitro screening. ToRPPIDO allows discovery of compounds that can disrupt specific protein-protein interactions (PPIs) within cells, whereas ToRNeDO achieves the inverse. It discovers compounds that bring together two proteins, an E3 ubiquitin ligase of choice and a neosubstrate of interest, to achieve targeted protein degradation.

SyntheX platforms
SyntheX platforms use genetically engineered circuits to discover compounds that have novel modes of action and that can modulate protein interactions orthosterically or allosterically. ToRPPIDO can discover disruptors of protein-protein interactions, and ToRNeDO can discover molecular glue–based functional protein degraders using a prespecified E3 ligase and a neosubstrate of interest.

Both technologies rely on the concept of strong and robust negative selection. “In that sense, negative selection is analogous to how a NOR logic gate works,” says Maria Soloveychik, PhD, SyntheX’s co-founder and CEO. “Neither counter-selection nor double-negative reporter circuits can produce a level of negative selection stringency that is robust enough to screen billions of permutations with a very low false-discovery rate. We screen for potent compounds from high-diversity libraries (>1010) with very few off-target hits.

“In addition to the built-in selection circuits, we wanted to expand the chemical space we could sample to achieve the desired functions. For PPI disruption, it is unlikely to find a high-affinity disruptor from a canonical small-molecule library. Therefore, we added a second engineering layer. The same cells that are parsing the selection readouts are also generating highly diversified libraries of genetically encoded molecules (~10 billion) to select from.”

Since PPI interfaces tend to be large, flat surfaces, libraries are focused on peptides and mini-protein scaffolds with diversified variable regions to find hits that can orthosterically block the interaction or to discover new surfaces or pockets that can allosterically interfere with the PPI. This approach lets evolutionary selection reveal the best compounds for producing the desired functional readout in the presence of the engineered selection circuits.

The cellular selection platforms bypass many in vitro bottlenecks. Structural information about the targets of interest is not required, and there is no need to limit constructs to those that can be produced recombinantly and purified in high concentrations. SyntheX identifies molecules that target the proteins of interest while they are expressed in an intracellular milieu and under physiological conditions.

This is particularly useful for ToRNeDO, where the combination of engineered and encoded systems enables the use of a multitude of the more than 600 E3 ligases predicted to be present in the human genome. By screening small-molecule libraries, ToRNeDO can identify functional molecular glues for degraders of a neosubstrate of interest with a desired E3 ligase.

A bacterial platform for vaccine and drug delivery

“Our engineered Clostridium Assisted Drug Development (CADD) platform provides versatility and broad clinical applicability ranging from vaccines to immunotherapies,” says Edward Green, PhD, founder and CEO, CHAIN Biotechnology.

Clostridium difficile bacteria, anaerobes that live in many people’s intestines, form spores that are well suited for oral delivery in a pill or capsule. The spores survive the highly acidic and proteolytic conditions found in the stomach and upper gastrointestinal tract, and when the spores reach the lower gastrointestinal tract, they germinate to produce viable cells.

Oral Drug Delivery
At CHAIN Biotechnology, the precisely engineered Clostridium Assisted Drug Development (CADD) platform provides versatility and broad clinical applicability.
1. Acid-resistant spores are formulated into tablets or capsules for oral dosing.
2. Rapid germination and cell growth commences in the colon.
3. Cell products impact the host (gut mucosa, immune system) and gut microbiota.

CHAIN Biotech produces spores from C. difficile that have been engineered to release vaccines and drugs. So, when these spores reach the lower gastrointestinal tract, they germinate to prophylactic or therapeutic effect. For example, drugs may be released that impact the gut microbiome and mucosa and activate the immune system.

The C. difficile strain engineered by CHAIN Biotech has a long history of being used safely. The strain naturally produces butyrate in the colon, a beneficial short-chain fatty acid supporting growth of a healthy gut microbiome.

The bacterial cells do not permanently colonize. After spore ingestion stops, the bacteria and secreted therapeutics wash out of the colon. Managing the amount and frequency of spore ingestion is primarily used to control dosage. The spore-based biotherapeutics are easy to manufacture and highly stable, and they do not require cold chain logistics for global distribution.

In most cases, precise engineering relates to a single gene and a gene product providing a describable mechanism of action. “For vaccine applications,” Green details, “we design specific antigenic peptides targeting immune cells in the gut mucosa with the potential to stimulate both mucosal and systemic immunity, which most vaccines delivered by injection do not induce.”

CHAIN Biotech has been focusing on oral vaccines to treat or immunize against infectious disease. The company has preclinical projects on human papilloma virus (HPV), human rotavirus (HRV), and SARS-CoV-2.

The HPV vaccine is designed to work therapeutically by clearing chronic HPV infection and preventing cervical cancer. In vivo proof-of-principle data for this vaccine have been generated in collaboration with the University of Oxford. The HRV prophylactic vaccine mainly targets malnourished children in low- and middle-income countries to prevent and treat childhood diarrheal disease. The oral SARS-CoV-2 candidate is designed to offer a long-term, global, and sustainable vaccine solution, especially for emerging variants.

CHAIN Biotech has also developed a therapeutic candidate for treating ulcerative colitis based on secretion of an anti-inflammatory metabolite called β-hydroxybutyrate. “We have proof-of-concept efficacy data in a disease model,” Green points out. “We will partner to clinically advance this candidate.”

A novel RNA reporter system

Circularis Biotechnology has developed a system to discover, enhance, and validate promoters. At the core of the system are highly structured and self-circularizing RNA reporters. The system does not require cellular cofactors to function, and it can work in any cell type.

Next-generation sequencing is used to follow the expression of barcoded RNA circles in massively parallel report assays to examine hundreds to millions of promoters or promoter variants simultaneously. To take advantage of a wide range of genomic sequences, a combination of human, nonhuman primate, and mouse sequences are used to identify promoters.

“We populate the pool of promoters for testing bioinformatically using a combination of databases such as GENCODE to determine the sequences around the transcription start site,” says Paul Feldstein, PhD, founder and CSO, Circularis Biotechnology. “And we use GTEx to find genes that show tissue- or cell-type-specific expression.”

To identify enhancer regions, a library is built that contains genomic DNA fragments that have been cloned upstream of a core promoter of interest with the barcoded reporter downstream. This library is run through cells, the RNA barcodes are read out, and the genomic fragment are associated to increase library members with cell-type specific expression.

“Assay development is challenging because of the dependence on model organisms, such as mice and rats,” Feldstein notes. “These promoter sequences do not necessarily show the same tissue and cell type specificity when put into human or nonhuman primate cells.”

This necessitates using human cell lines as often as possible and cell lines representing a broad range of tissue types to identify promoters with the greatest specificity. Induced pluripotent stem cells or organoid models are valuable alternatives. In an optimal situation, a parallel development track uses a mouse promoter for ease of development and a human or nonhuman primate promoter for clinical trials.

RNA sequencing and quantitative PCR are used to determine if a promoter construct is having off-target effects. If appropriate for the model organism, GFP can better examine a greater range of tissue types.

“We continue to look for improved terminators to better isolate gene expression within the insert from that outside in the genome,” Feldstein says. The Circularis technology can be applied to a variety of gene expression components including the effects on expression of UTRs, terminators, microRNA, and inducible systems.

A microfluidics-based protein engineering platform

A hybrid protein engineering strategy that combines rational design with evolution-based methods can be dramatically enhanced by applying the right technology. “We leverage Rosetta [a flexible computational protein design software] and tools from Bio-Prodict to identify beneficial mutations that enrich our variant libraries,” says Grant Murphy, PhD, director of protein engineering, Merck & Co.

Because Murphy’s group has a range of expression systems—such as Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, CHO, and cell-free expression systems—it can engineer proteins that have different levels of complexity and post-translational modifications. Cell-free expression systems are highly scalable (µL to L) and can produce complex proteins for reasonable cost.

The high-throughput systems that build and express variant libraries are highly automated and key to sampling a large sequence space for challenging hosts such as CHO. Almost every variant produced with a high-throughput system is sequenced.

For protein function, a high-throughput, data-rich approach probes protein function in multiple dimensions, such as stability, solubility, and activity. “We leverage a wide variety of instruments to provide a holistic picture of the protein and how engineering is improving the protein along several dimensions,” Murphy notes.

Droplet-based microfluidics has been applied in protein engineering using cell-based or cell-free systems; however, sorting droplets has required the use of fluorescent surrogate substrates. “Using mass-activated droplet sorting (MADS) technology, we have developed an ultra-high-throughput, microfluidics-based platform for protein engineering that directly measures a desired function instead of having to use fluorescent surrogate substrates,” Murphy asserts. “This platform greatly expands the range of engineering projects that we can tackle.”

In addition to enhanced design, expression, and screening capabilities, new machine learning methods leverage the large internal datasets generated with high-throughput technology.

Advances in protein engineering and design have allowed us to make tremendous progress in optimizing protein structures. We can design specifically for stability and solubility, and we can replace immunogenic hot spots. However, our understanding of how structure and dynamics impact function (catalysis and binding) is still very limited.

If good structural information is available, we can use computational design to improve binding. In the absence of good structures, evolution-based methods are relied on with both positive and negative screens.

“The recent progress of protein design, structure prediction, and structural biology methods for correlated protein motions should enable us to better understand the subtle roles of structure and dynamics on function,” Murphy concludes.

The post Synthetic Biology Brings Programmability to Drug Programs appeared first on GEN - Genetic Engineering and Biotechnology News.

Read More

Continue Reading

Government

Four Years Ago This Week, Freedom Was Torched

Four Years Ago This Week, Freedom Was Torched

Authored by Jeffrey Tucker via The Brownstone Institute,

"Beware the Ides of March,” Shakespeare…

Published

on

Four Years Ago This Week, Freedom Was Torched

Authored by Jeffrey Tucker via The Brownstone Institute,

"Beware the Ides of March,” Shakespeare quotes the soothsayer’s warning Julius Caesar about what turned out to be an impending assassination on March 15. The death of American liberty happened around the same time four years ago, when the orders went out from all levels of government to close all indoor and outdoor venues where people gather. 

It was not quite a law and it was never voted on by anyone. Seemingly out of nowhere, people who the public had largely ignored, the public health bureaucrats, all united to tell the executives in charge – mayors, governors, and the president – that the only way to deal with a respiratory virus was to scrap freedom and the Bill of Rights. 

And they did, not only in the US but all over the world. 

The forced closures in the US began on March 6 when the mayor of Austin, Texas, announced the shutdown of the technology and arts festival South by Southwest. Hundreds of thousands of contracts, of attendees and vendors, were instantly scrapped. The mayor said he was acting on the advice of his health experts and they in turn pointed to the CDC, which in turn pointed to the World Health Organization, which in turn pointed to member states and so on. 

There was no record of Covid in Austin, Texas, that day but they were sure they were doing their part to stop the spread. It was the first deployment of the “Zero Covid” strategy that became, for a time, official US policy, just as in China. 

It was never clear precisely who to blame or who would take responsibility, legal or otherwise. 

This Friday evening press conference in Austin was just the beginning. By the next Thursday evening, the lockdown mania reached a full crescendo. Donald Trump went on nationwide television to announce that everything was under control but that he was stopping all travel in and out of US borders, from Europe, the UK, Australia, and New Zealand. American citizens would need to return by Monday or be stuck. 

Americans abroad panicked while spending on tickets home and crowded into international airports with waits up to 8 hours standing shoulder to shoulder. It was the first clear sign: there would be no consistency in the deployment of these edicts. 

There is no historical record of any American president ever issuing global travel restrictions like this without a declaration of war. Until then, and since the age of travel began, every American had taken it for granted that he could buy a ticket and board a plane. That was no longer possible. Very quickly it became even difficult to travel state to state, as most states eventually implemented a two-week quarantine rule. 

The next day, Friday March 13, Broadway closed and New York City began to empty out as any residents who could went to summer homes or out of state. 

On that day, the Trump administration declared the national emergency by invoking the Stafford Act which triggers new powers and resources to the Federal Emergency Management Administration. 

In addition, the Department of Health and Human Services issued a classified document, only to be released to the public months later. The document initiated the lockdowns. It still does not exist on any government website.

The White House Coronavirus Response Task Force, led by the Vice President, will coordinate a whole-of-government approach, including governors, state and local officials, and members of Congress, to develop the best options for the safety, well-being, and health of the American people. HHS is the LFA [Lead Federal Agency] for coordinating the federal response to COVID-19.

Closures were guaranteed:

Recommend significantly limiting public gatherings and cancellation of almost all sporting events, performances, and public and private meetings that cannot be convened by phone. Consider school closures. Issue widespread ‘stay at home’ directives for public and private organizations, with nearly 100% telework for some, although critical public services and infrastructure may need to retain skeleton crews. Law enforcement could shift to focus more on crime prevention, as routine monitoring of storefronts could be important.

In this vision of turnkey totalitarian control of society, the vaccine was pre-approved: “Partner with pharmaceutical industry to produce anti-virals and vaccine.”

The National Security Council was put in charge of policy making. The CDC was just the marketing operation. That’s why it felt like martial law. Without using those words, that’s what was being declared. It even urged information management, with censorship strongly implied.

The timing here is fascinating. This document came out on a Friday. But according to every autobiographical account – from Mike Pence and Scott Gottlieb to Deborah Birx and Jared Kushner – the gathered team did not meet with Trump himself until the weekend of the 14th and 15th, Saturday and Sunday. 

According to their account, this was his first real encounter with the urge that he lock down the whole country. He reluctantly agreed to 15 days to flatten the curve. He announced this on Monday the 16th with the famous line: “All public and private venues where people gather should be closed.”

This makes no sense. The decision had already been made and all enabling documents were already in circulation. 

There are only two possibilities. 

One: the Department of Homeland Security issued this March 13 HHS document without Trump’s knowledge or authority. That seems unlikely. 

Two: Kushner, Birx, Pence, and Gottlieb are lying. They decided on a story and they are sticking to it. 

Trump himself has never explained the timeline or precisely when he decided to greenlight the lockdowns. To this day, he avoids the issue beyond his constant claim that he doesn’t get enough credit for his handling of the pandemic.

With Nixon, the famous question was always what did he know and when did he know it? When it comes to Trump and insofar as concerns Covid lockdowns – unlike the fake allegations of collusion with Russia – we have no investigations. To this day, no one in the corporate media seems even slightly interested in why, how, or when human rights got abolished by bureaucratic edict. 

As part of the lockdowns, the Cybersecurity and Infrastructure Security Agency, which was and is part of the Department of Homeland Security, as set up in 2018, broke the entire American labor force into essential and nonessential.

They also set up and enforced censorship protocols, which is why it seemed like so few objected. In addition, CISA was tasked with overseeing mail-in ballots. 

Only 8 days into the 15, Trump announced that he wanted to open the country by Easter, which was on April 12. His announcement on March 24 was treated as outrageous and irresponsible by the national press but keep in mind: Easter would already take us beyond the initial two-week lockdown. What seemed to be an opening was an extension of closing. 

This announcement by Trump encouraged Birx and Fauci to ask for an additional 30 days of lockdown, which Trump granted. Even on April 23, Trump told Georgia and Florida, which had made noises about reopening, that “It’s too soon.” He publicly fought with the governor of Georgia, who was first to open his state. 

Before the 15 days was over, Congress passed and the president signed the 880-page CARES Act, which authorized the distribution of $2 trillion to states, businesses, and individuals, thus guaranteeing that lockdowns would continue for the duration. 

There was never a stated exit plan beyond Birx’s public statements that she wanted zero cases of Covid in the country. That was never going to happen. It is very likely that the virus had already been circulating in the US and Canada from October 2019. A famous seroprevalence study by Jay Bhattacharya came out in May 2020 discerning that infections and immunity were already widespread in the California county they examined. 

What that implied was two crucial points: there was zero hope for the Zero Covid mission and this pandemic would end as they all did, through endemicity via exposure, not from a vaccine as such. That was certainly not the message that was being broadcast from Washington. The growing sense at the time was that we all had to sit tight and just wait for the inoculation on which pharmaceutical companies were working. 

By summer 2020, you recall what happened. A restless generation of kids fed up with this stay-at-home nonsense seized on the opportunity to protest racial injustice in the killing of George Floyd. Public health officials approved of these gatherings – unlike protests against lockdowns – on grounds that racism was a virus even more serious than Covid. Some of these protests got out of hand and became violent and destructive. 

Meanwhile, substance abuse rage – the liquor and weed stores never closed – and immune systems were being degraded by lack of normal exposure, exactly as the Bakersfield doctors had predicted. Millions of small businesses had closed. The learning losses from school closures were mounting, as it turned out that Zoom school was near worthless. 

It was about this time that Trump seemed to figure out – thanks to the wise council of Dr. Scott Atlas – that he had been played and started urging states to reopen. But it was strange: he seemed to be less in the position of being a president in charge and more of a public pundit, Tweeting out his wishes until his account was banned. He was unable to put the worms back in the can that he had approved opening. 

By that time, and by all accounts, Trump was convinced that the whole effort was a mistake, that he had been trolled into wrecking the country he promised to make great. It was too late. Mail-in ballots had been widely approved, the country was in shambles, the media and public health bureaucrats were ruling the airwaves, and his final months of the campaign failed even to come to grips with the reality on the ground. 

At the time, many people had predicted that once Biden took office and the vaccine was released, Covid would be declared to have been beaten. But that didn’t happen and mainly for one reason: resistance to the vaccine was more intense than anyone had predicted. The Biden administration attempted to impose mandates on the entire US workforce. Thanks to a Supreme Court ruling, that effort was thwarted but not before HR departments around the country had already implemented them. 

As the months rolled on – and four major cities closed all public accommodations to the unvaccinated, who were being demonized for prolonging the pandemic – it became clear that the vaccine could not and would not stop infection or transmission, which means that this shot could not be classified as a public health benefit. Even as a private benefit, the evidence was mixed. Any protection it provided was short-lived and reports of vaccine injury began to mount. Even now, we cannot gain full clarity on the scale of the problem because essential data and documentation remains classified. 

After four years, we find ourselves in a strange position. We still do not know precisely what unfolded in mid-March 2020: who made what decisions, when, and why. There has been no serious attempt at any high level to provide a clear accounting much less assign blame. 

Not even Tucker Carlson, who reportedly played a crucial role in getting Trump to panic over the virus, will tell us the source of his own information or what his source told him. There have been a series of valuable hearings in the House and Senate but they have received little to no press attention, and none have focus on the lockdown orders themselves. 

The prevailing attitude in public life is just to forget the whole thing. And yet we live now in a country very different from the one we inhabited five years ago. Our media is captured. Social media is widely censored in violation of the First Amendment, a problem being taken up by the Supreme Court this month with no certainty of the outcome. The administrative state that seized control has not given up power. Crime has been normalized. Art and music institutions are on the rocks. Public trust in all official institutions is at rock bottom. We don’t even know if we can trust the elections anymore. 

In the early days of lockdown, Henry Kissinger warned that if the mitigation plan does not go well, the world will find itself set “on fire.” He died in 2023. Meanwhile, the world is indeed on fire. The essential struggle in every country on earth today concerns the battle between the authority and power of permanent administration apparatus of the state – the very one that took total control in lockdowns – and the enlightenment ideal of a government that is responsible to the will of the people and the moral demand for freedom and rights. 

How this struggle turns out is the essential story of our times. 

CODA: I’m embedding a copy of PanCAP Adapted, as annotated by Debbie Lerman. You might need to download the whole thing to see the annotations. If you can help with research, please do.

*  *  *

Jeffrey Tucker is the author of the excellent new book 'Life After Lock-Down'

Tyler Durden Mon, 03/11/2024 - 23:40

Read More

Continue Reading

Government

CDC Warns Thousands Of Children Sent To ER After Taking Common Sleep Aid

CDC Warns Thousands Of Children Sent To ER After Taking Common Sleep Aid

Authored by Jack Phillips via The Epoch Times (emphasis ours),

A…

Published

on

CDC Warns Thousands Of Children Sent To ER After Taking Common Sleep Aid

Authored by Jack Phillips via The Epoch Times (emphasis ours),

A U.S. Centers for Disease Control (CDC) paper released Thursday found that thousands of young children have been taken to the emergency room over the past several years after taking the very common sleep-aid supplement melatonin.

The Centers for Disease Control and Prevention (CDC) headquarters in Atlanta, Georgia, on April 23, 2020. (Tami Chappell/AFP via Getty Images)

The agency said that melatonin, which can come in gummies that are meant for adults, was implicated in about 7 percent of all emergency room visits for young children and infants “for unsupervised medication ingestions,” adding that many incidents were linked to the ingestion of gummy formulations that were flavored. Those incidents occurred between the years 2019 and 2022.

Melatonin is a hormone produced by the human body to regulate its sleep cycle. Supplements, which are sold in a number of different formulas, are generally taken before falling asleep and are popular among people suffering from insomnia, jet lag, chronic pain, or other problems.

The supplement isn’t regulated by the U.S. Food and Drug Administration and does not require child-resistant packaging. However, a number of supplement companies include caps or lids that are difficult for children to open.

The CDC report said that a significant number of melatonin-ingestion cases among young children were due to the children opening bottles that had not been properly closed or were within their reach. Thursday’s report, the agency said, “highlights the importance of educating parents and other caregivers about keeping all medications and supplements (including gummies) out of children’s reach and sight,” including melatonin.

The approximately 11,000 emergency department visits for unsupervised melatonin ingestions by infants and young children during 2019–2022 highlight the importance of educating parents and other caregivers about keeping all medications and supplements (including gummies) out of children’s reach and sight.

The CDC notes that melatonin use among Americans has increased five-fold over the past 25 years or so. That has coincided with a 530 percent increase in poison center calls for melatonin exposures to children between 2012 and 2021, it said, as well as a 420 percent increase in emergency visits for unsupervised melatonin ingestion by young children or infants between 2009 and 2020.

Some health officials advise that children under the age of 3 should avoid taking melatonin unless a doctor says otherwise. Side effects include drowsiness, headaches, agitation, dizziness, and bed wetting.

Other symptoms of too much melatonin include nausea, diarrhea, joint pain, anxiety, and irritability. The supplement can also impact blood pressure.

However, there is no established threshold for a melatonin overdose, officials have said. Most adult melatonin supplements contain a maximum of 10 milligrams of melatonin per serving, and some contain less.

Many people can tolerate even relatively large doses of melatonin without significant harm, officials say. But there is no antidote for an overdose. In cases of a child accidentally ingesting melatonin, doctors often ask a reliable adult to monitor them at home.

Dr. Cora Collette Breuner, with the Seattle Children’s Hospital at the University of Washington, told CNN that parents should speak with a doctor before giving their children the supplement.

“I also tell families, this is not something your child should take forever. Nobody knows what the long-term effects of taking this is on your child’s growth and development,” she told the outlet. “Taking away blue-light-emitting smartphones, tablets, laptops, and television at least two hours before bed will keep melatonin production humming along, as will reading or listening to bedtime stories in a softly lit room, taking a warm bath, or doing light stretches.”

In 2022, researchers found that in 2021, U.S. poison control centers received more than 52,000 calls about children consuming worrisome amounts of the dietary supplement. That’s a six-fold increase from about a decade earlier. Most such calls are about young children who accidentally got into bottles of melatonin, some of which come in the form of gummies for kids, the report said.

Dr. Karima Lelak, an emergency physician at Children’s Hospital of Michigan and the lead author of the study published in 2022 by the CDC, found that in about 83 percent of those calls, the children did not show any symptoms.

However, other children had vomiting, altered breathing, or other symptoms. Over the 10 years studied, more than 4,000 children were hospitalized, five were put on machines to help them breathe, and two children under the age of two died. Most of the hospitalized children were teenagers, and many of those ingestions were thought to be suicide attempts.

Those researchers also suggested that COVID-19 lockdowns and virtual learning forced more children to be at home all day, meaning there were more opportunities for kids to access melatonin. Also, those restrictions may have caused sleep-disrupting stress and anxiety, leading more families to consider melatonin, they suggested.

The Associated Press contributed to this report.

Tyler Durden Mon, 03/11/2024 - 21:40

Read More

Continue Reading

International

Red Candle In The Wind

Red Candle In The Wind

By Benjamin PIcton of Rabobank

February non-farm payrolls superficially exceeded market expectations on Friday by…

Published

on

Red Candle In The Wind

By Benjamin PIcton of Rabobank

February non-farm payrolls superficially exceeded market expectations on Friday by printing at 275,000 against a consensus call of 200,000. We say superficially, because the downward revisions to prior months totalled 167,000 for December and January, taking the total change in employed persons well below the implied forecast, and helping the unemployment rate to pop two-ticks to 3.9%. The U6 underemployment rate also rose from 7.2% to 7.3%, while average hourly earnings growth fell to 0.2% m-o-m and average weekly hours worked languished at 34.3, equalling pre-pandemic lows.

Undeterred by the devil in the detail, the algos sprang into action once exchanges opened. Market darling NVIDIA hit a new intraday high of $974 before (presumably) the humans took over and sold the stock down more than 10% to close at $875.28. If our suspicions are correct that it was the AIs buying before the humans started selling (no doubt triggering trailing stops on the way down), the irony is not lost on us.

The 1-day chart for NVIDIA now makes for interesting viewing, because the red candle posted on Friday presents quite a strong bearish engulfing signal. Volume traded on the day was almost double the 15-day simple moving average, and similar price action is observable on the 1-day charts for both Intel and AMD. Regular readers will be aware that we have expressed incredulity in the past about the durability the AI thematic melt-up, so it will be interesting to see whether Friday’s sell off is just a profit-taking blip, or a genuine trend reversal.

AI equities aside, this week ought to be important for markets because the BTFP program expires today. That means that the Fed will no longer be loaning cash to the banking system in exchange for collateral pledged at-par. The KBW Regional Banking index has so far taken this in its stride and is trading 30% above the lows established during the mini banking crisis of this time last year, but the Fed’s liquidity facility was effectively an exercise in can-kicking that makes regional banks a sector of the market worth paying attention to in the weeks ahead. Even here in Sydney, regulators are warning of external risks posed to the banking sector from scheduled refinancing of commercial real estate loans following sharp falls in valuations.

Markets are sending signals in other sectors, too. Gold closed at a new record-high of $2178/oz on Friday after trading above $2200/oz briefly. Gold has been going ballistic since the Friday before last, posting gains even on days where 2-year Treasury yields have risen. Gold bugs are buying as real yields fall from the October highs and inflation breakevens creep higher. This is particularly interesting as gold ETFs have been recording net outflows; suggesting that price gains aren’t being driven by a retail pile-in. Are gold buyers now betting on a stagflationary outcome where the Fed cuts without inflation being anchored at the 2% target? The price action around the US CPI release tomorrow ought to be illuminating.

Leaving the day-to-day movements to one side, we are also seeing further signs of structural change at the macro level. The UK budget last week included a provision for the creation of a British ISA. That is, an Individual Savings Account that provides tax breaks to savers who invest their money in the stock of British companies. This follows moves last year to encourage pension funds to head up the risk curve by allocating 5% of their capital to unlisted investments.

As a Hail Mary option for a government cruising toward an electoral drubbing it’s a curious choice, but it’s worth highlighting as cash-strapped governments increasingly see private savings pools as a funding solution for their spending priorities.

Of course, the UK is not alone in making creeping moves towards financial repression. In contrast to announcements today of increased trade liberalisation, Australian Treasurer Jim Chalmers has in the recent past flagged his interest in tapping private pension savings to fund state spending priorities, including defence, public housing and renewable energy projects. Both the UK and Australia appear intent on finding ways to open up the lungs of their economies, but government wants more say in directing private capital flows for state goals.

So, how far is the blurring of the lines between free markets and state planning likely to go? Given the immense and varied budgetary (and security) pressures that governments are facing, could we see a re-up of WWII-era Victory bonds, where private investors are encouraged to do their patriotic duty by directly financing government at negative real rates?

That would really light a fire under the gold market.

Tyler Durden Mon, 03/11/2024 - 19:00

Read More

Continue Reading

Trending