StemCell Therapy

For years, researchers have known that defects in an ancient cellular antenna called the primary cilium are linked with obesity and insulin resistance. Now, researchers at the Stanford University School of Medicine have discovered that the strange little cellular appendage is sensing omega-3 fatty acids in the diet, and that this signal is directly affecting how stem cells in fat tissue divide and turn into fat cells.

The finding represents a missing link between two worlds that of dietary science, and that of molecular and cellular biology. Dietary studies have long found that the consumption of omega-3 fatty acids, essential fatty acids common in fish and nuts, is associated with lower risk of heart disease, stroke, arthritis and even depression.

A paper describing the research was published online Nov. 21 in Cell. The senior author is Peter Jackson, PhD, professor of microbiology and immunology and of pathology. The lead author is postdoctoral scholar Keren Hilgendorf, PhD.

Researchers in Jacksons laboratory werent looking for omega-3s when they started their research. They were only looking for the signaling molecule that fat stem cells were sensing. The molecule could have been anything: signaling pathways in cellular biology often involve esoteric molecules few people have heard of. They only knew that in rare diseases involving a defect in the primary cilium, people are always hungry, cannot stop eating and become obese and insulin resistant. So they were surprised when the signal turned out to be omega-3 fatty acids.

When we saw that the cell was responding to omega-3 fatty acids, we realized that this had changed from just a molecular biology story to a story showing the molecular biology of how diet controls stem cells , Jackson said.

The cells sense the presence of omega-3 fatty acids through a tiny, hair-like appendage called the primary cilium, an ancient structure derived from the many flagella that algae cells first used almost 1 billion years ago to move through the oceans and sense their surroundings. Over time, as single-celled organisms evolved into multicellular creatures that first swam the oceans and then crawled onto land, cells ditched most of their flagella. But most cells kept a single flagellum, the primary cilium, to use as a highly sensitive antenna; it can pick up extremely subtle signals about the world outside the cell, helping to regulate the cells function and fate.

Jackson and his colleagues found that when omega-3 fatty acids bind to a receptor called FFAR4 on the cilia of fat stem cells, it prompts the fat stem cells to divide, leading to the creation of more fat cells. This provides the body with more fat cells with which to store energy, something that is healthier than storing too much fat in existing fat cells. What you want is more, small fat cells rather than fewer, large fat cells, Jackson said. A large fat cell is not a healthy fat cell. The center is farther away from an oxygen supply, it sends out bad signals and it can burst and release toxic contents. Large fat cells are associated with insulin resistance, diabetes and inflammation, he added.

Furthermore, the researchers found that the presence of saturated fats or the blockage of ciliary signaling of the FFAR4 receptor does not lead to an increase in the creation of new fat cells from stem cells, but rather the addition of fat to existing cells. Rather than looking how diet correlates with health, we have gone from molecule to receptor to cell to document why healthy fats are beneficial and unhealthy fats contribute to disease, Hilgendorf said. We have provided a mechanism explaining why omega-3 fatty acids are critical for maintaining healthy fat balance and saturated fats should be limited.

The research also may change scientific understanding of how the body manages fat storage in a healthy person. Researchers often talk about the movement of fat in and out of cells, but what we are showing is the importance of stem cell activity in creating new fat cells as being critical for the bodys energy management, said Carl Johnson, a graduate student in the stem cell biology and regenerative medicine program and a co-author of the paper.

Other Stanford co-authors are associate professor of genetics Will Greenleaf, PhD; postdoctoral scholar Anja Mezger, PhD; research engineer Janos Demeter, PhD; and technician Selena Rice.

The research was supported by the National Institutes of Health (grants 5R01GM114276, 5U01CA199216, 5UL1TR00108502, R01 AR054396, DK106404, GM095941. TG2-01159), the Damon Runyon Cancer Research Foundation, the Swedish Research Council, and the Chan-Zuckerberg Biohub.

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Omega-3 fatty acids health benefit linked to stem cell... - ScienceBlog.com

115 more arazi centres to be set up

LAHORE :The Punjab government will set up 115 arazi centres in different districts of the province by the end of the current year to facilitate the general public at their doorstep.

The arazi centres will provide revenue related facilities to the general public in an efficient and transparent manner.

This was stated by Provincial Minister for Revenue Malik Muhammad Anwar while talking to different delegations at his office on Friday.

The minister said that 153 arazi record centres were already providing different facilities to the people in 36 districts of the province.

He said the Board of Revenue was going to procure 20 state-of-the-art mobile vans so that revenue-related facilities could be provided to the people close to their residence.

The BOR has also taken steps to facilitate the rural population and computer technology has been utilised to facilitate the people.

The PTI led government has given special attention to ensuring complete transparency in revenue matters to save public properties from land grabbers, the minister concluded.

Magistrates: A spokesman for the Provincial Industries and Trade Department has the price control magistrates are conducing raids to check the price of essential commodities across the province.

The spokesman stated the price control magistrates conducted raids on 10,350 shops.

As many as 1,952 complaints relating to price-hike were lodged and 189 cases were registered in which 179 persons were arrested and fines amounting to more than Rs3.5 million were also imposed.

PhDs awarded: Punjab University (PU) has awarded PhD degrees to five scholars.

Ambreen Gul, daughter of Mirza Sultan Ahmed, has been awarded PhD in Molecular Biology after approval of her thesis entitled Overexpression of Aspartic Acid in Cotton Against Insects, Ammara Ahad, d/o Abdul Ahad Khan, in Molecular Biology after approval of her thesis entitled Expression of Flavonoid Pigment Related Genes in Cotton (Gossypium hirsutum), Khadija Aaliya, d/o Asif Hussain, Molecular Biology after approval of her thesis entitled Transformation and Expression Studies of Multiple Frost Tolerant Genes in Solanum Tuberosum L, Mehvish Ajaz, d/o Soofi Ajaz Ahmed, in Microbiology and Molecular Genetics after approval of her thesis entitled Azo Dyes Removal by Bacteria Isolated from Industrial Wastewater and Naveed Ahmad Noor, son of Muhammad Nawaz, in the subject of High Energy Physics after approval of his thesis entitled Under Pressure Study of Fundamental Properties of Perovskite Oxides Using Density Functional Theory (DFT).

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115 more arazi centres to be set up - The News International

Fresh insights from a recent study of the genetics and biology of bipolar disorder could improve the diagnosis and treatment of the debilitating condition. A new study shows how specific genetic differences affect neural circuits and raise the risk of bipolar disorder as a result.

So concluded the scientists at the Picower Institute for Learning and Memory at Massachusetts Institute of Technology (MIT) in Cambridge who carried out the novel research.

In previous work, they had already shown that a protein called candidate plasticity gene 2 (CPG2) helps to regulate the strength of synapses in brain circuits. Synapses are the connectors through which nerve cells, or neurons, relay chemical signals to each other.

In the more recent research, the investigators found that the brains of people with contained unusually low levels of CPG2.

They also linked specific variants in the gene for CPG2 to dysfunction in synapses. These same genetic differences happen to occur in people with bipolar disorder.

The team reports the findings in a that now features in the journal Molecular Psychiatry.

Its a rare situation, says senior study author Elly Nedivi, who is a professor in the Biology and Brain and Cognitive Sciences departments at MIT, where people have been able to link mutations genetically associated with increased risk of a disorder to the underlying cellular dysfunction.

For bipolar disorder this might be the one and only, she adds.

She and her colleagues are not suggesting that the gene variants that they uncovered actually cause bipolar disorder.

What they are proposing, however, is that having those particular genetic differences could make people more susceptible to bipolar disorder.

In laboratory models, for instance, they sometimes observed synapse dysfunction with combined rather than single variants.

According to the National Institute of Mental Health, around in the United States will have bipolar disorder at some point in their lives.

People with bipolar disorder experience episodes of mania and that bring on extreme shifts in mood, activity levels, and energy.

The episodes are much more severe than the ups and downs that affect most people. They can make it very difficult to carry out daily tasks, get along with people, study, and pursue a career.

Bipolar disorder is a and high rates of death by suicide. Drugs do not always work and not everyone with bipolar will experience complete recovery between episodes.

Prof. Nedivi and her team have been studying synapses for many years.

They discovered that CPG2 influences synaptic strength by helping to regulate the number of receptors for the chemical signals that pass between neurons.

The gene that holds the instructions for making CPG2 is Spectrin Repeat Containing Nuclear Envelope Protein 1 (SYNE1).

On learning that studies had linked variants in SYNE1 to raised risk of bipolar disorder, the team decided to investigate the underlying biology in the light of their own findings about CPG2.

The researchers began by examining postmortem brain tissue from various brain banks.

The samples came from people who had received a diagnosis of bipolar disorder, or other psychiatric conditions that share some of its symptoms, such as or major depression. They also examined samples from individuals who did not have any of these conditions.

The examinations revealed that only brain tissue from people with bipolar disorder contained significantly less CPG2.

The bipolar samples did not show lower levels of other proteins known to play a role in synaptic functions: only CPG2 was lower.

Our findings, the authors write, show a specific correlation between low CPG2 levels and incidence of [bipolar disorder] that is not shared with schizophrenia or major depression patients.

The researchers then used deep-sequencing tools to search for SYNE1 variants in the bipolar brain tissue samples that had shown reduced levels of CPG2.

They focused their efforts on the regions of the gene that control CPG2 expression and therefore the amount that cells produce.

In a separate exercise, they also searched genomic archives to identify variants in CPG2-encoding regions of SYNE1. Differences in this coding can affect the structure and function of the protein.

In experiments with cultured neurons, the team then examined the cellular effects of both types of variants: those in the CPG2 expression-altering region of SYNE1 and those in the coding region for the protein.

The results showed that some expression-altering gene variants had no effect on CPG2 level, while others altered it significantly.

The team also found two examples of paired variants that reduced CPG2 expression but that had no effect as single variants.

There was also a range of results in the experiments with protein-coding variants. These identified SYNE1 differences that altered the structure or function of CPG2 in specific ways.

For instance, one SYNE1 variant reduced the ability of CPG2 to attach to the spines that contain excitatory synapses, while another impaired the cycling of receptors in the synapses.

The findings reveal how specific SYNE1 differences that occur in people with bipolar disorder can upset the function of a protein that plays a key role in the connections in brain circuits.

Further research is now needed to determine how bipolar disorder might develop from such cellular disruptions.

Prof. Nedivi and her team are planning to examine the effect of some of the variants on behavior in animals. They also want to look more closely at some of the disrupted cell processes and how they might fix them.

Alongside these studies, they will continue to investigate human samples to find out more about the specific gene variants and their links to the risk and development of bipolar disorder.

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Medical News Today: How do genetic differences affect the risk of bipolar disorder? - Stock Daily Dish

DNA is transcribe into messenger RNA, messenger RNA is translated into protein ORF. During translation, the combination of three nucleotide codons are required for protein synthesis. The nucleotide that starts translation and stops translation is known as ORF. Every DNA has six open reading frame and it is important to determine the correct open reading frame so that the protein is expressed properly. An Open Reading Frame starts with ATG (Met), which is known as start codon and ends with DNA sequence such as TAA, TAG, TGA known as stop codon. ORF clones are eliminates the wearisomesteps of RNA isolation, DNA synthesis, PCR amplification and other tedious sequencing and validation procedures.

To Remain Ahead Of Your Competitors, Request for a Sample Here @https://www.persistencemarketresearch.com/samples/19597

The ORF expression clones are plasmid that contains protein coding DNA, the DNA contains the coding sequence without 5 and 3 end untranslated regions. The ORF expression clones helps to save as it moves directly protein expression and protein analysis. The ORF clones aids to get protein expression and analysis faster. The ORF allows to get gene of interest and expressed protein quickly, and help researchers to conduct clinical and medical applications. Clinical laboratory are highly equipped with assay and instrument systems used for the detection and classification of various disease type such as cancer and risk of cancer progressions, cardiovascular diseases, and others. The advancement in the molecular genetics, bioinformatics, proteomics, increasing number of infection rate is prompting manufacturers to seek newer methods of research, has led to the revenue growth over the forecast period.

Increased demand for research and development for early detection and diagnosis of disease, increased expenditure on healthcare sector, growing number of hospitals and diagnostic laboratories, increased demand for personalized medicines requires the study of individual cell structure and function, rise in prevalence of cell based diseases such as cancer and autoimmune diseases requires the detection and diagnosis of specific cell and tissue, rise in number of biopsy procedures. Technological advancement in the diagnostic and treatment process of infectious diseases, advancement in molecular techniques are the factors fueling the demand of ORF expression clone market in the near future.

The global ORF expression clones market is segmented on basis of expression system,application, end user and geography

Segment by Expression System

Segment by Application

Segment by End User

Global ORF expression clones is segmented by expression system, application and end user. On the basis of expression system the, ORF expression clones market is segmented as mammalian expression system, lentiviral expression system, bacterial expression system, yeast expression system, insect, wheat germ cell and others. Based on the application type, global ORF expression clones market is segmented as recombinant protein expression, functional assays, protein characterization, In vitro transcription and other application for research and study purpose. On the basis of end user, the global ORF expression clones market is segmented into biotechnological companies, pharmaceutical companies, contract research organizations, academic/ research institutes. Increasing outsourcing by pharmaceutical and biotechnological companies, declining R&D productivity and patent cliff sales drop leading to increasing research intensity in the pharmaceuticals sector, rapid process/product development due to fewer steps, increased awareness about new product launch and others are some of the factors drive the global ORF expression clones market during the forecast period. Whereas high cost and short reaction scale, low protein expression, inadequate access to health care, lack of standardized tools for research and development are some of the factors that may hamper the growth of global ORF expression clones market.

By Geography, the global ORF Expression Clones market is segmented into five broad regions viz. North America, Latin America, Europe, Asia-Pacific, and the Middle East & Africa. North America is estimated to lead the global ORF expression clones market due to increasing focus on protein expression and production, growing demand for simple and efficient protein production methods, government funding for research and development in developed countries and others. Europe market is also projected to experience high growth due to emphasis on up-scaling and industrial application in the near future. Asia Pacific market is anticipated to grow at the fastest growth rate during the forecast period, owing to factors such as focusing on healthcare expenditures, rise in research and development facilities and others.

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Some of the major players in global ORF expression clones market are Thermo Fisher Scientific, GeneCopoeia, Inc. Dharmacon, Inc., BioCat GmbH, Source BioScience, Kabushiki Kaisha DNAFOR, GenScript, OriGene Technologies, Inc. Sino Biological Inc. Promega Corporation and Others.

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Orf Expression Clones Market Healthy Pace Throughout The Forecast Throughout 2017-2025 - Zebvo

Scientists have discovered an unknown genetic mechanism of cell metabolism that becomes increasingly dysfunctional with aging. Is it possible to combat aging?

Researchers at the cole Polytechnique Fdrale de Lausanne (EPFL) in Switzerland suggest that their findings could lead to new targets for treatments to combat aging and age-related conditions.

Their discovery concerns a protein that alters the function of mitochondria, which are the tiny power units inside cells that give them their energy.

The EPFL team found that brain and muscle tissue from aged animals had high levels of the protein, which is called pumilio RNA binding family member 2 (PUM2).

A in the journal Molecular Cell describes how aging induces higher levels of PUM2, which, in turn, reduce levels of another protein called mitochondrial fission factor (MFF).

MFF helps cells break large mitochondria into smaller units and clear them away. The tissue samples from the aged animals also had lower levels of MFF.

The researchers suggest that as animals age, the PUM2/MFF pathway becomes more and more dysregulated.

As PUM2 levels rise, they bring down levels of MFF. The result is that cells become increasingly unable to break up and clear away smaller mitochondria. As time goes by, cells and tissues accumulate more and more large, unhealthy mitochondria.

PUM2 is an RNA-binding protein. These molecules alter gene expression by binding to the messenger RNA (mRNA) molecules that carry DNA code for cells to process.

In the recent study, the team discovered that when PUM2 binds to mRNA molecules that carry the DNA code for MFF, it blocks cells ability to make MFF protein from those mRNA molecules.

Most research on the molecules that influence aging in cells and tissues tends to focus on gene transcription into mRNA. However, this is just the first step in the complex process of transferring information held in genes into the workings of cells.

The EPFL researchers discovered the PUM2/MFF pathway when they decided to investigate the step that occurs after gene transcription.

When they screened animal cells to identify RNA-binding proteins that changed with age, they found that PUM2 was particularly elevated in older animals.

PUM2 binds only to mRNA molecules that have sites that it recognizes. When it attaches to the mRNA, it stops the translation of the code into the corresponding protein.

By employing a systems genetics approach, the team discovered a previously unknown mRNA that PUM2 binds to. This was the mRNA that carries the code for cells to make MFF.

In another part of the study, the researchers demonstrated how it might be possible to reverse the age-related effect of PUM2 on cells and tissues.

Using CRISPR-Cas9 gene-editing technology, they reduced PUM2 in the muscles of old mice by silencing its corresponding encoding gene.

This led to higher levels of MFF protein, which through increased breakup and waste-clearing improved mitochondrial function in the aged mice.

The team also investigated a similar mechanism in the roundworm Caenorhabditis elegans, which is a model that scientists often use to study molecular pathways.

In the roundworm, aging induces higher levels of the RNA-binding protein PUF-8. The researchers found that silencing the corresponding gene for PUF-8 in older worms improved the functioning of their mitochondria and extended their lifespan.

Other studies have linked RNA-binding proteins to neuromuscular degenerative diseases. They have also demonstrated that they often collect into clumps called pathological granules.

The EPFL researchers found that PUM2 has a similar tendency, with aging, to clump into particles that bind and capture MFF mRNA.

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Medical News Today: Targeting this protein could help combat aging - Stock Daily Dish

Feliciano Lpez got married to Sandra Gago earlier this year. Asked if they planned to have children, the Spanish player replied: "There are guys who take care of every detail and follow their routines while others travel with their family in tournaments.

I may become a father in a too far away future and I would like my child to come to see me play." On his longevity, Lopez added: "I did not expect to compete at the level I am. Turning 30, many of my friends were getting injured, dropping on the rankings and this age seemed difficult to overcome to me.

I was lucky to have a very good body and genetics to play tennis. It made me suffer a few injuries, so I changed the training regime and I started taking care of my eating regime. For a sportsman, dropping two or three kilos is major and so you start playing better.

Winning the Queen's title at 34 years of age and another time at 37 was very satisfying. I started thinking that it could not happen to me. Feeling competitive physically at this age made me stronger mentally because despite I travel with a physiotherapist that has been taking care of my body for years, I do not recover in the same way after matches.

"You have to handle the kind of sponsor because as a famous person you have a social responsibility. Brands like alcohols or betting companies, you have to be very careful."

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Feliciano Lopez planning to have children with wife in the future - Tennis World USA

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With a multi-disciplinary approach, Fact.MR elaborates an extensive analysis of the historical, current and future outlook of the global rheumatoid arthritis stem cell therapy market as well as the factors responsible for such a growth. Our highly dedicated professionals have inputted critical and accurate insights associated with every industry, and region by doing thorough primary and secondary research.

We leverage space-age industrial and digitalization tools to provide avant-garde actionable insights to our clients regarding the rheumatoid arthritis stem cell therapy market. For enhancing readers experience, the report starts with a basic overview about the rheumatoid arthritis stem cell therapy market and its classification. Further, we have considered 2028 as the estimated year, 2018 2028 as the stipulated timeframe.

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Important regions covered in the rheumatoid arthritis stem cell therapy market report include:

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Questionnaire answered in the rheumatoid arthritis stem cell therapy market report include:

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A Comprehensive Analysis of the Rheumatoid Arthritis Stem Cell Therapy Market Available in the Latest Report - Tech Admirers

At the start of this decade, the federal government called out consumer DNA testing as a burgeoning scam industry. Little did we know how it would explode in popularity.

In 2010, the U.S. Government Accountability Office (GAO) published an investigative report that bashed consumer DNA test companies for misleading the public. It accused them of deceptively claiming their products could predict the odds of developing more than a dozen medical conditions; some even went as far to offer equally dubious dietary supplements. The report had followed a similar lambasting of the industry by the GAO in 2006.

Also in 2010, the FDA publicly warned 23andMe and other companies that genetic health tests were considered medical devices and needed to be cleared by the FDA before they could be sold to the public. Three years later, following a lack of response from 23andMe, the agency took the harsh step of temporarily banning 23andMe from selling its health-related tests at all.

Despite these hurdles, the DNA testing industry has nonetheless exploded. According to a report by MIT Technology Review this February, more than 26 million people have had their DNA tested by the biggest names in the industry, with AncestryDNA, 23andMe, and MyHeritage being the top three.

Consumer DNA testing is undoubtedly now mainstreambut its not much less scammy than it was when the decade started.

The industry has existed since the late 1990s. But in 2007, the new kid on the block, 23andMe, became the first company to offer a particular kind of at-home DNA test that was cheap, easy to use, and promised to track back your origins further back than ever before.

23andMes testsand eventually those of its competitorssearch for and analyze the most common genetic variations, called single nucleotide polymorphisms (SNPs), in our autosomal DNA, the 22 of 23 pairs of chromosomes not used to determine sex. For as little as $99 and a spit sample, these SNP-based tests are advertised to determine a persons ancestry or genetic health risks. But much of this realm of consumer DNA testing, as the GAO report showed, can uncharitably be described as complete bullshit.

The crux of the problem is that our genetics are only a piece of the puzzle that influences our health. Sure, you can sometimes point to a specific gene mutation that always makes someone sick in a specific way if they carry it. But much more often, its a complex, barely understood mix of gene variants that predispose us to develop cancer or heart diseaseand that risk can be amplified or muted by our environment (including the crucial months we spend in the womb).

In the earliest days, companies didnt much care for this complexity, using weak evidence to make sweeping health claims about which genes ought to make you more of a fish eater or develop diabetes.

Following the FDAs ban in 2013, 23andMe spent the next two years devising genetic health tests that wouldnt overpromise. In 2015, it was allowed to sell tests that told people if they carried a recessive mutation for genetic conditions like Bloom syndrome and sickle-cell disease. A positive test meant their children would have a 25 percent chance of having the condition if both parents were carriers. Two years later, it became the first company with FDA-approved tests that were allowed to tell people about their risk of developing one of 10 diseases or conditions, such as late-onset Alzheimers or celiac disease.

23andMes return to the health side of things wasnt the only fuse that lit a fire under the consumer DNA industrythe tens of millions in annual advertising now being spent by companies like MyAncestry certainly helped, too. But regardless, the FDAs approval of these tests signaled a new opening in the industry. And unsurprisingly, the industry as a whole has ballooned, as has the glut of scammy services on offer.

Many of these companies now steer clear of making blanket health claims, but it doesnt make them any less laughable. Your DNA results can apparently tell you whether youve found your romantic match, how to be good at soccer, and, like a decade ago, how to find the perfect diet and avoid bloating. Just dont pay attention to the studies showing that theres no consistent link between genes seemingly tied to our nutrition and any actual diet-related conditions.

Its not only the tests vaguely connected to our health that are the problem. As Gizmodo once illustrated, even relying on these DNA tests to figure out your ancestry is a dicey proposition. At best, youre roughly estimating where your recent ancestors lived, but that estimate can vary widely depending on which company does the testing, thanks to the different algorithms they use. And the farther away your lineage is from Europe, the less accurate these tests will be for you, thanks to the fact that the algorithmsas well as the research linking genes to our healthare largely based on the DNA of white Americans and Europeans.

Health and ancestry aside, sharing your DNA with the outside world can have unintended consequences. Law enforcement agencies are now using genealogy databases to solve criminal cases, by connecting anonymous crime scene DNA to DNA submitted to these family tree companies, working backward through distant relatives to identify their suspect. And while some people may be fine with this genetic sleuthing, there are no clear rules on how this data can be used by law enforcementtheres merely the promise by private companies that they will share responsibly. This November, police in Florida obtained a warrant to search through a third-party genealogy database, months after the service had enforced a new opt-in policy meant to let users decide if they wanted their data to be searchable by police in these cases.

At a certain point, it wont even matter whether youve decided to share your DNA. A study last October estimated that once enough peoples DNA is in a databasea scant 2 to 3 percent of any given populationanyone could conceivably track the identity of every person in that population using the same techniques genetic detectives are using now. And researchers have already demonstrated how less scrupulous forces, including hackers, could actively manipulate these databases.

None of this is meant to diminish the real potential of genetics as a field of research and medicine, nor the progress that has been made over the past decade.

Companies like 23andMe rely on detecting thousands of genetic markers still only a tiny slice of our DNA. But the technology that allows a persons entire genome to be sequenced has vastly improved, scaling down its costs and upkeep over the past decade. These techniques can scan a persons whole genome as well as the smaller part of the genome that codes for the proteins our bodys cells make, called the exome.

In 2010, for instance, the company Illumina initially offered its whole genome sequencing at $50,000 a person; this year, Veritas dropped the price of its service to only $600 and says it may soon charge as little as $100.

These innovations have led to large-scale research projects that collect genetic data from hundreds of thousands of people at once. Scientists can scour through these large datasets to find new links between our genes, traits, and medical conditions. This research has helped us better understand longstanding questions about our biology and health. Someday soon, genetic sequencing may also help us optimize the existing medical treatments people get, particularly for conditions like cancer.

Right now, though, its still up in the air how useful this info dump really is to the average person looking to stay healthy.

In March, 23andMe debuted (or more accurately, reintroduced) a service that tells people about their genetic risk of type 2 diabetes. Unlike the tests approved by the FDA, it relies on whats known as a polygenic risk score. This adds up the very small contribution of many genetic markers to a particular condition, which combined might be enough to nudge your overall risk upwards.

The trouble is that these markers have little to do with why you get type 2 diabetesyour age or weight play a much bigger role. And even if the test does consider you genetically unlucky (an average risk difference of 5 percent from a typical person), the advice youll get is the same that anyone hoping for a long, healthy life would get: eat more vegetables and exercise more. This test, as well as many of those offered by the hundreds of big and small DNA testing companies on the market, illustrates the uncertainty of personalized consumer genetics.

The bet that companies like 23andMe are making is that they can untangle this mess and translate their results back to people in a way that wont cross the line into deceptive marketing while still convincing their customers they truly matter. Other companies have teamed up with outside labs and doctors to look over customers genes and have hired genetic counselors to go over their results, which might place them on safer legal and medical ground. But it still raises the question of whether people will benefit from the information they get. And because our knowledge of the relationship between genes and health is constantly changing, its very much possible the DNA test you take in 2020 will tell you a totally different story by 2030.

Given how popular at-home DNA testing has become, theres really no sealing the genie back in the bottle. So if you want to get your genetic horoscope read this holiday, dont let me stop you. But its a big decision you should sleep on. After all, once your DNA is out there, theres no going back.

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Consumer DNA Testing May Be the Biggest Health Scam of the Decade - Gizmodo

In the 90s, Alzheimers researchers were full of optimism. New genetic studies all pointed to one culprithard clumps of protein, called amyloid, that litter the brains of people with the disease.

With the emergence of the first tangible target, pharmaceutical companies jumped in to develop drugs to clear amyloid from the brain. In animals, the drugs appeared to improve memory. But the results of human clinical trials that followed were disheartening: One after one, these drugsall designed to target amyloidhave failed to slow the disease.

The onslaught of news about these failures has left the public wondering whether amyloid has anything to do with Alzheimersand whether a new approach is needed.

The field has already begun to redirect its focus, says Scott Small, MD, director of Columbias Alzheimers Disease Research Center and theBoris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons.

Theres now reason to be cautiously optimismistic, he says, because we have uncovered new pathways that lead to the disease, and we know that they truly make a difference.

The CUIMC Newsroom spoke with Small about the current state of research into Alzheimers treatments and prevention.

In retrospect, the idea that reducing amyloid in the brainwhich all the failed drugs dois based on an incomplete picture of the disease.

To treat a disease, we need to treat whats broken. But its very difficult to find whats broken in these slowly progressive brain disorders.

One way to find whats broken is through genetics, but the first wave of genetic studies in the 80s and 90s only had the technical capabilities to investigate Alzheimers cases that run in families, those caused by a single gene.

The results of these studies all seemed to converge on one biological process: amyloid.

But these single-gene forms of Alzheimers are rareand account for maybe 2% to 3% of cases. Most cases of Alzheimers are caused by a complex interplay of many genes and the environment.

The field made the assumption that amyloid is the primary culprit in all forms of Alzheimers. It made perfect sense, because we see amyloid in all patients with Alzheimers, whether their disease is caused by a single gene or not.The amyloid finding was extremely exciting, and there was a sense that we were on the cusp of curing this devastating, horrible disease.

The amyloid hypothesis is that amyloid is the trigger of everything in Alzheimers. That seems now to be wrong.

New studies from the past decade tell us that amyloid is part of the story of Alzheimers disease, but its the smoke, not the fire. Weve learned that the single-gene and more common, complex forms of Alzheimers are not identical, though they do overlap.

Theres been a lot of backlash against the amyloid hypothesis lately, but in the 90s, it was the right idea. The pharmaceutical industry was right to jump on the amyloid bandwagon. And theyre now right to give it up, I think.

Back in the 80s and 90s, genetic tools weren't quite developed enough to address the real question we had: What genes are involved in most cases of Alzheimers disease?

Techniques have advanced and we can now answer this question. New studiesmany led by Richard Mayeux, MD[chair of neurology at Columbia]have been pointing to other processes in the brain. We also have better biological tools that can reveal the basic problem inside neurons.

Based on this research, the new consensus in the field is that there are two other pathways that cause the disease.

One involves protein trafficking, which is how proteins are shipped to different sites within a single cell. The health of neurons, more so than other cells, depends on protein trafficking in and out of one particular site: the endosome.

In Alzheimers, the flow of proteins out of the endosome is blocked, and we think that causes the other problems we see in the disease: the amyloid, the tau tangles also common in the Alzheimers brain, and the neurodegeneration. Essentially it's a plumbing problem.

Our research here at Columbia provided some early evidence for an endosomal trafficking problem in Alzheimers. And genetic studiesincluding those led by Dr.Mayeuxhave now found that some endosomal genes are linked to Alzheimers, which provides more support.

The second pathway involves microglia, which are cells in the brain that help maintain the health of neurons and help keep the spaces between neurons clear of pathogens, protein aggregates, and other cellular debris.

Recently discovered genesby Phil De Jager, MD, PhD, in our center and otherspoint us to these cells. But what exactly is wrong with the microglia is still hotly debated. We dont know if theyre working too well or not well enough, but we do know theyre not working properly.

We now, I believe, have evidence to help us understand why the first hypothesis was wrong. Scientifically, we have very good justification to argue why our new hypotheses are correct.

Were now seeing that companies are getting back into drug development because these new pathways are so compelling.

In the coming years, our biggest focus at the Alzheimers Disease Research Center at Columbia will be accelerating drug discovery. One of the most important goals is to develop new biomarkersfor the new Alzheimers pathways. These biomarkers are crucial for developing the new generation of theraputic agents.These biomarkers will be useful for enrolling patients into new anticipated clinical trials, following the logic of precision medicine.Also, just as biomarkers of amyloid were important for testing assumptions about the primacyof amyloid in the disease, these biomarkers are important for testingor potentially refutingthe new pathways.

Were also testing gene therapies and other ways to restore endosomal traffickingto see if that prevents neurodegeneration in animal models.

Frank Provenzano and Adam Brickman are developing new techniques, with imaging and cognitive testing, to detect patients with endosomal defects as early as possible. We think the sooner we can treat people, the better. Sabrina Simoes, one of our newest members, is developing new ways to use spinal fluid and blood to remotely monitor endosomal trafficking. Thats a critical step in measuring a drugs effectiveness when the drug moves to clinical testing.

In science, though, you never can be sure.The only way well know were right is by developing drugs and testing the hypothesis in clinical trials in patients, like we did with the amyloid hypothesis.

In my practice, I encounter many people who have family members with Alzheimer's and theyre worried about that their genes. But in most cases, just because your mother has it, doesnt mean youre going to get it.

In a complex disease, each gene and each environmental factor is like putting a pebble on a scale. None of them by themselves can prevent or cause Alzheimers.So if your parent has Alzheimers, that puts one pebble on the scale. But if you went to college, if you exercise, those are pebbles on the other side of the scale.

Many of the things that we thought historically cause Alzheimer's have been debunkedfor example, the idea that itwas caused by various heavy metals. But we do know that maintaining cardiac health is good: Exercise is good; smoking is bad; developing diabetes or obesity increases the risk.These recommendations, as most people know, are true for any disease.

People often ask me this question, hoping I know something that no one else does. I dont have any other answers at the moment, but everyone in the field is doing their best to find new ways to forestall this disease.

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Will a Treatment for Alzheimer's Ever Be Found? - Columbia University Irving Medical Center

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Personality genes strongly linked to learning, memory

Researchers at Washington University School of Medicine in St. Louis and the University of Granada, Spain, used artificial intelligence techniques to identify gene networks that appear to play a major role in the development of and variation in personality.

Using artificial intelligence techniques, researchers studying the role of genes and the environment in shaping our personalities have identified gene networks largely responsible for the development of and variation in personality.

Those networks include 972 individual genes linked to aspects of personality, such as self-awareness, intentionality which has to do with a person being deliberate or purposeful and creative thinking relating to the purpose and meaning a person hopes to achieve. The findings also suggest that, regardless of genes and environmental factors, individuals still possess the capacity to make choices that also can influence personality and that those choices can result in personality changes over time.

The new research, led by a group at Washington University School of Medicine in St. Louis and the University of Granada, Spain, is published Nov. 21 in the journal Molecular Psychiatry.

Personality is an individuals unique pattern of behaviors, feelings and thoughts, and those factors are strong predictors of physical, mental and social health, said the studys senior investigator, C. Robert Cloninger, MD, a professor emeritus in psychiatry at Washington University. A better understanding of how those factors work together could contribute to improvements in psychiatric and general health for people around the world.

Cloninger

Using computer algorithms, they identified three distinct gene networks connected to personality. The networks are related to learning and memory, but the computer algorithms also found that most of the genes in the three personality networks are not only associated with brain activity but also function in many other organs. As a result, development of a healthy, well-integrated personality may influence a persons physical health as well as his or her mental and social health and well-being, Cloninger said.

In addition to genes, a persons environment which might include home life, family income level, education, exposure to violence or poverty, rural or urban life, and other factors also influences personality, he said. Our personalities develop from the actions of both genetic and environmental factors, as well as interactions between genes, and between genes and environment. Although there are many combinations of genetic and environmental influences, as human beings we still have the capacity to freely choose some aspects of how our personalities develop.

The researchers studied gene-environment relationships in more than 2,100 healthy people in Finland who were part of whats called the Young Finns Study. The scientists then replicated those findings in people from other cultures and backgrounds, studying similar genetic data from more than 900 healthy adults in Germany and more than 1,000 adults in South Korea.

We were able to replicate associations between genetic markers and personality traits in all three groups, said co-investigator Igor Zwir, PhD, an assistant professor in psychiatry and an associate professor in computer science and artificial intelligence at the University of Granada, Spain. In all three populations, we found the same associations between personality traits and genetic markers. However, in people within each country, the same gene networks didnt always lead to the same personality traits.

Zwir

Even with the influence of genes and environmental factors, Cloninger noted that an individuals free will also is involved in how his or her personality develops, as well as how it might change over time.

For a long time, mental health professionals felt that personality traits were fixed early in life and that a persons personality didnt really change much, but weve found that personality can and does change and evolve, he said. Some gene networks influence habit learning, which is the gradual acquisition of associations between stimuli and responses that help us learn to make one choice rather than another. Others influence our capacity to set goals and accomplish them intentionally. But when we change our goals and intentions, or the things we value, we actually also modify the ways that these genes work to influence personality. In other words, our character allows us to regulate the way some of these genes function.

The researchers divided personality into two parts: temperament, representing habits and automatic emotional reactions; and character, representing qualities such as cooperativeness, self-directedness and self-transcendence. The way a person develops his or her character shapes the ability to regulate desires and to satisfy goals and values.

Computer algorithms allowed the researchers to identify clusters of genes related to character that regulate temperament through pathways that involve learning. But in addition to their effects on the brain, those genes also may influence overall health and vulnerability to illness. It turned out the healthiest people were able to create healthy ways of living, using their self-awareness and insight.

The researchers also found that some of both temperament and character were passed on from ones parents. About 50% of a persons temperament and character were heritable. In addition, they found that what was inherited involved three distinct ways of learning that are crucial to being healthy and feeling satisfied with life.

Nature and nurture cannot be separated, Cloninger said. We inherit how we learn, and that means we are then able to deliberately and creatively shape how we adapt to lifes challenges and opportunities.

Added Zwir: Although we inherit some of our personality, that still leaves a great deal of room for change. We are uncovering a dynamic system of relationships between gene networks and environmental factors. If you measure personality with our tools and then come back and do it again six months or a year later, you might see changes because personality seems to develop and evolve. Very little of this is fixed. It can be changed in both positive and negative ways.

Zwir I, et al. Three genetic-environmental networks for human personality. Molecular Psychiatry, published online Nov. 21, 2019. https://doi.org/10.1038/s41380-019-0579-x

Also see Cloninger CR, et al. The complex genetics and biology of human temperament: A review of traditional concepts in relation to new molecular findings. Translational Psychiatry, published online Nov. 11, 2019. https://doi.org/10.1038/s41398-019-0621-4

The Young Finns Study was financially supported by the Academy of Finland; the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Kuopio, Tampere and Turku University Hospitals, the Juho Vainio Foundation; the Paavo Nurmi Foundation, the Finnish Foundation for Cardiovascular Research; the Finnish Cultural Foundation; the Tampere Tuberculosis Foundation; the Emil Aaltonen Foundation; the Yrjo Jahnsson Foundation; the Signe and Ane Gyllenberg Foundation; the Diabetes Research Foundation of the Finnish Diabetes Association; an EU Horizon 2020 grant; and the Tampere University Hospital Supporting Foundation. The American Foundation for Suicide Prevention supported the study of healthy Germans. The national Healthy Twin Family Register of Korea supported the study of healthy Koreans. In addition, the Anthropedia Foundation and the Spanish Ministry of Science and Technology supported the collaboration.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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AI helps identify gene, environment networks that shape personality - Washington University School of Medicine in St. Louis

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School of Medicine leading multicenter study aimed at understanding brain development in babies with the condition

Kelly N. Botteron, MD, a professor of psychiatry and of radiology at Washington University School of Medicine in St. Louis, is leading a multicenter brain-imaging study focused on infants with Down syndrome. The five-year, $11.5 million grant from the National Institutes of Health (NIH) will focus on brain development in babies with the genetic syndrome.

Researchers at Washington University School of Medicine in St. Louis have received a five-year, $11.5 million grant to lead a multicenter effort to understand how brain development in babies with Down syndrome differs from that in other babies. The effort, which involves scanning the babies brains using MRI, will provide a foundation that may lead to therapies to counter developmental delays in children with the condition.

The grant, from the National Institutes of Health (NIH), is part of a $77 million initiative that began in 2018 to bolster basic and clinical research focused on infants and children with Down syndrome. Most people with the genetic condition have mild to severe developmental delays, learning disabilities, and distinct facial and physical features. Some also experience heart and gastrointestinal disorders.

Each year, about 6,000 babies in the U.S. are born with the condition.

It is astounding how sparse the research is involving neuroimaging characterization of neurodevelopment in Down syndrome, especially given that the condition is rather common, said the studys lead investigator, Kelly N. Botteron, MD, a Washington University professor of psychiatry and of radiology. Brain-imaging studies in children with Down syndrome are almost nonexistent. Before we can develop and assess therapies to improve cognitive outcomes, we need to understand more about the alterations in early brain development in these children.

Researchers will conduct behavioral and developmental testing, as well as MRI brain imaging, to examine the brain structure and cognitive function of 140 infants with Down syndrome and 70 babies without the condition. The children will be studied when they are 6 months old and, again, when they are 1 year old and then 2 years old.

The researchers also will compare the brain scans of the two groups of children with scans of autistic infants and toddlers. Such scans in autistic children have been part of a separate multicenter study co-led by Washington University.

This will give us a large set of data to detect differences in neurodevelopmental patterns, Botteron said. It will be eye-opening because there are some developmental characteristics that are unique to children with Down syndrome. They tend to have more motor and coordination delays, in addition to language delays. This information is critical to developing potential innovative treatment trials including additional physical therapy, applied behavior analyses, novel drugs and potential genetic editing techniques to improve both the quality of life and overall health of people with Down syndrome.

The infants will undergo MRI scans, generally in the evening after they fall asleep naturally, nixing the need for anesthesia. The researchers have developed strategies for scanning the brains of babies, based on MRI, without disturbing infants sleep.

Over the past 10 to 15 years, weve learned a lot about conducting brain imaging on infants and children with autism and healthy comparison controls, Botteron said.

One tactic is to introduce the babies beforehand to noise they can expect to hear from the MRI machine. Its important to prepare the babies and toddlers, she said. This means making them comfortable and scanning them at night while theyre naturally sleeping.

The studys other participants include researchers from the University of Washington in Seattle; Childrens Hospital of Philadelphia; University of North Carolina; University of Minnesota; New York University; and the Montreal Neurological Institute in Canada.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Matthew Breen, a professor of genomics at NCState, says his 25-year career has roots in childhood heartbreak.

When I was young, my family had two dogs die from cancer and there was very little we could do to help them, says Breen. There were great strides being made with human cancer research, so why were we unable to help our animal companions more?

We are committed to making that change happen at NCState, he adds.

Today, the internationally recognized researcher specializes in molecular cytogenetics: the study of the structure and function of cells and chromosomes. His work in the College of Veterinary Medicine is helping our pets live longer, healthier lives and unlocking new insights about human cancers along the way.

Since joining NCStates faculty in 2002, Breen has focused on exploring the genetics and genomics of animal diseases, including how they initiate and respond to treatment.

He was a member of the team that sequenced the canine genome 14 years ago. The project sparked a new area of focus in his field: comparing the canine and human genomes to accelerate discoveries for both.

Humans and their furry friends actually share a very similar genetic makeup. And they share certain types of cancers, too. Many cancers diagnosed in humans and dogs have a similar pathology and clinical presentation, says Breen.

But when it comes to canines, its often easier to pinpoint the genetic abnormalities that lead to those cancers. This is especially the case for purebreds. Dogs of the same breed have less genetic variation among them than humans or mixed-breed dogs, making them an ideal genetic model.

Now, Breens lab works extensively in the area and hes become a pioneer in comparative oncology.

By working with human and animal cancers side by side, we are able to find shared features that may help identify the drivers of these cancers and provide opportunities to highlight targets for new therapies, says Breen.

Take, for example, Breens work with the BRAF gene.

Six years ago, his team discovered that a single mutation in the gene was found in 85% of dogs with transitional cell carcinoma (TCC) also called urothelial carcinoma (UC) which is the most common form of bladder cancer in canines. More than 80,000 dogs in the United States will be affected this year alone.

This particular BRAF mutation was already known to exist in some human cancers, but Breens discovery helped unlock its significance for both species. It also revealed an opportunity to create a much-needed tool to aid diagnosis.

By working with human and animal cancers side by side, we are able to find shared features.

In most cases, canine bladder cancer isnt diagnosed until it has reached an advanced stage. Thats because the cancer shares many clinical signs with other, more common urinary tract conditions.

Treatments for the common alternatives may alleviate symptoms temporarily, but they mask the larger problem and buy the cancer more time to progress. In fact, upon diagnosis, more than half of canine bladder cancer cases have already spread.

Identifying the BRAF mutation as a genetic signature of canine bladder cancer was a powerful insight. From there, Breens team began developing a molecular diagnostics test that could identify the mutation and detect the cancer earlier than ever.

That molecular test called CADET BRAF was developed in Breens research laboratory in 2014. Using a urine sample, the system detects cells that possess the BRAF mutation and can monitor changes in the number of mutated cells being shed during treatment of canine TCC and UC.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine, says Breen.

It offers several improvements over current alternatives. Requiring only a simple free-catch urine sample, CADET BRAF is the only non-invasive approach. Other methods often involve costly procedures, such as sedation or anesthesia, that carry additional risks.

The test can also detect bladder cancer in the early stages of the disease, potentially leading to improved outcomes.

CADET BRAF represents the worlds first liquid biopsy for the detection of cancer in veterinary medicine.

We can detect the cancer in dogs that have already presented with clinical signs and avoid repeated attempts to treat solely the signs, says Breen. That allows more time for the veterinarian and owner to develop a plan to treat the root cause. In addition, we have been able to detect the presence of very early disease, several months before the dog has any clinical signs.

Now we have to determine how to manage these preclinical patients, and that is part of ongoing work by our team at NCStates College of Veterinary Medicine, he adds.

The test is also dependable. After rigorous validation of thousands of dogs, Breen says hes found that the presence of the BRAF mutation in canine urine is a highly reliable indicator of the presence of TCC/UC. Weve shown the BRAF mutation isnt found in the urine of healthy dogs or dogs that have other common conditions such as bladder polyps, inflammation or chronic cystitis, he says.

In the two years following the development of CADET BRAF, Breen focused on developing a strong proof of concept. Teaming up with the American Kennel Club, he recruited urine samples from hundreds of dogs to show that the approach could work with real patients.

His next step was commercialization. Breens startup, Sentinel Biomedical, was formed in 2015. Located right on NCStates campus, the company works to develop and scale diagnostic tests for the health care industry.

Since its formation, theyve developed another product called CADET BRAF-PLUS. The test is designed for dogs who dont have the BRAF mutation but do show clinical signs of TCC/UC. It can detect over two-thirds of bladder cancer cases not identified by CADET BRAF, increasing the overall detection sensitivity of the tests to over 95%.

Headquartered right on NCStates campus, Sentinel Biomedical seeks to improve diagnosis and treatment for dogs and their owners.

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Whats next for Sentinel Biomedical? It recently announced a joint venture with Antech Diagnostics, part of MARS. Together theyve formed Antech Molecular Innovations, also based on NCStates Centennial Campus, and work to broaden access to CADET BRAF and CADET BRAF-PLUS.

With the distribution channels of one of the worlds largest animal health providers, we are providing veterinarians with easy access to the tests we develop and enhancing our ability to become a global leader in innovation for veterinary molecular diagnostics, says Breen. And because our work is translational, we also have greater potential to translate our findings to humans.

This will bring the innovations developed at NCState to a whole new level.

Today, the National Cancer Institute spends $6 billion on cancer research annually, and its estimated that less than 0.5% is directed toward veterinary oncology. But Breen sees his innovations and those of his colleagues across the nation as promising steps in the right direction.

Currently, hes involved in a clinical study in the College of Veterinary Medicine that will evaluate the timeline between when a BRAF mutation is detected in a dogs urine and when that dog begins to show clinical signs of TCC/UC. Breen hopes this knowledge will lead to earlier intervention, improved quality of life and increased survival rates.

This will bring the innovations developed at NCState to a whole new level.

Recent collaborations with colleagues at Duke Cancer Institute are also exploring the genetic and environmental factors shared between canine and human bladder cancers. A study proposed by this multidisciplinary team was awarded funding from the V Foundation for Cancer Research in 2019. Such comparative oncology studies, Breen says, have the potential to realize the true value that dogs can bring to our fight against cancer.

Through Antech Molecular Innovations, Sentinel Biomedical has begun pursuing more projects to provide rapid, accessible molecular diagnostics for a variety of cancers that impact our pets and ourselves.

For now, Breen is excited to see his work take on a wider reach. These cancer detection tests will help a new generation of canine companions and their human friends (maybe even kids who are experiencing what Breen did as a child). Whats more, the increased volumes of data theyll collect may unlock insights that lead to the development of new treatment opportunities for cancers in both species.

Although we may not be able to help all dogs with cancer today, we are driven to learn from their cancers to help the dogs of tomorrow, and the families who care for them, says Breen.

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Sniffing Out Cancer in Canines And Humans, Too - NC State News

Delirium is the most common post-surgical complication in older adults. Marked by acute temporary confusion, disorientation and/or agitation, it strikes as many as half of adults over 65 who undergo high-risk procedures such as cardiac surgery and hip replacements.

Postoperative delirium is also tightly linked to Alzheimers disease. Although each can occur independently, Alzheimers is a leading risk factor for delirium, and an episode of delirium puts patients at increased risk for cognitive decline and Alzheimers.

However, the physiological mechanisms that link delirium and Alzheimers disease remain largely unknown.

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Now, in a paper published Nov. 22 in Alzheimers & Dementia: The Journal of the Alzheimers Association, researchers at Harvard Medical School and Beth Israel Deaconess Medical Center shed light on a genetic risk factor for Alzheimers disease that may indirectly influence patients risk of postoperative delirium.

In a study of older adults without dementia undergoing major noncardiac surgery, researchers observed that patients carrying a specific variant of a gene appeared to be much more vulnerable to delirium under certain conditions than people without the variant.

The teams findings could open the door to future interventions to prevent or mitigate postoperative delirium in at-risk patients.

Our findings confirmed our hypothesis that patients risk of postoperative delirium differs by genetic predisposition, said Sarinnapha Vasunilashorn, assistant professor of medicine at HMS and Beth Israel Deaconess and first author of the study. We observed a strong and significant association between high postoperative inflammation and delirium incidence, duration and severity among patients carrying a variant of the gene considered to be risky, while the association was weaker and nonsignificant among noncarriers.

Vasunilashorn and colleagues focused on a gene called APOE, short for apolipoprotein E. The risky version of the gene, notated as APOE 4, is the strongest known genetic risk factor for late-onset Alzheimers disease and a widely studied genetic risk marker for delirium.

While recent studies have shown no direct relationship between APOE 4 and delirium, Vasunilashorns team hypothesized that the gene variant might indirectly influence risk of delirium by modifying the bodys response to inflammationpart of the immune systems natural defense systemindicated by the presence of an inflammatory marker in the blood called C-reactive protein, or CRP.

Using data from the Successful Aging after Elective Surgery (SAGES) study, an ongoing prospective cohort study investigating risk factors and long-term outcomes of delirium, the scientists looked at the incidence, severity and duration of delirium in 560 patients who were at least 70 years old and who underwent major noncardiac surgeries under general or spinal anesthesia. Patients were monitored for delirium, assessed by daily cognitive assessments of attention, memory and orientation throughout their hospital stay.

Analyzing data from patients blood drawn before surgery, immediately after surgery, two days after and one month after revealed that, among carriers of the APOE 4 gene variant, patients with high levels of inflammation had an increased risk of postoperative delirium. However, among noncarriers of the APOE 4 gene variant, the scientists found no such association.

Our findings suggest that APOE 4 may be an indicator of brain vulnerability, said Vasunilashorn. This work may inform the targeting of future interventions, such as anti-inflammatory treatments, for prevention of postoperative delirium and its associated adverse long-term cognitive outcomes in patients with this genetic susceptibility.

Edward Marcantonio, professor of medicine at HMS and Beth Israel Deaconess, is senior author of the study.

This work was supported by the National Institute of Aging of the National Institutes of Health (grants K01AG057836, R03AG061582, P01AG031720, R24AG054259, K07AG041835, R21AG057955, R01AG041274, R21AG048600, R01AG051658 and K24AG035075); the Charles A. King Trust Postdoctoral Research Fellowship Program; Bank of America, N.A., Co-Trustee, and the Alzheimers Association (AARF-18-560786).

Adapted from a Beth Israel Deaconess news release.

Image: kemalbas/Getty Images

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Gene linked to Alzheimers disease plays indirect role in risk for... - ScienceBlog.com

Dr Sadaf Farooqi

BRIGHTON, UK The obesity epidemic is not simply the result of changes in the lived environment but a complex interplay between genes and surroundings that has driven people who would have been genetically susceptible but remained thin in previous eras to become obese, says one expert.

This was the argument put forward as part of a debate on whether an individual's body weight is determined by "nature or nurture" at the recent Society for Endocrinology BES Conference 2019 in Brighton, UK.

Before the debate began, Rob Semple, MD, University of Edinburgh, UK, introduced the speakers and polled the audience on their "baseline" views onthe statement: "This house believes that nature not nurture determines our body weight."

The response was 36% "for" the statement (ie, nature) and 64% "against,"which Semple noted suggested that the first speaker, Sadaf Farooqi, MBChB, PhD, "will have her work cut out" to convince the audience that nature is the main driver of obesity.

Farooqui is professor of metabolism and medicine at the University of Cambridge, UK, and was the winner of the 2019 American Diabetes Association Outstanding Scientific Achievement Award.

Farooqi's adversary in the debate was John Wilding, DM, of the University of Liverpool, UK, who Semple described as "similarly formidable."

Farooqi began by saying that the question before the audience is "fundamentally important," and noted that there is plenty of evidence to suggest there is a biological system for regulating body weight.

Experiments have shown that animals and humans maintain a set point for weight that they return to after periods of limited food intake, regardless of how much weight they lose.

Initially, the hypothalamus was found to play a key role in weight regulation, but it was the discovery of leptin that allowed the whole system, with its links to adipose tissue, the pancreas, and the intestines, to be elucidated, she explained.

Work with children then revealed the influence of genetic factors on the body weight "set point."

Identical twins reared apart were found to have a very similar body weight, and adoptive children were shown to have a similar weight to their biologic, rather than adoptive, parents.

Tying these observations to individual or small numbers of genetic variants has, however, proven difficult, beyond the known variants associated with thinness and the rare variants in 15 genes linked to severe obesity.

That is, Farooqi said, until the publication of US research earlier this year testing a polygenic risk predictor involving 2.1 million common variants in more than 300,000 individuals.

The research showed that, across polygenic score deciles, there was a 13-kg gradient in weight and a 25-fold gradient in the risk of severe obesity.

Moreover, another 2019 study, this time by Farooqi's team, revealed some loss of function variants in the melanocortin 4 receptor gene are linked to an increased risk of obesity, type 2 diabetes, and coronary artery disease, and some gain in function variants are linked to a lower risk of obesity and cardiometabolic disorders.

Farooqi believes the reason there is an obesity epidemic is that the physiological system for regulating weight "evolved to stop us starving" but is now faced with "an abundance of food."

The impact of this is all the greater because we live in a "complex food environment," with high sugar and high fat foods that are seen as "very rewarding," as demonstrated on brain scans of people shown pictures of such foods.

Individuals also engage in stress-related eating, which is played out via neural circuits linking the hypothalamus to the limbic system.

She characterized such eating as a "biologically appropriate thing to do because it gives you a rewarding, pleasurable feeling."

She said that, together, this underlines that the "biology of appetite" is a mixture of both innate and learned behaviors.

Farooqi concluded: "I hope I've made the case for you that there is clear, strong, compelling evidence" that weight is regulated by a homeostatic system centered on the hypothalamus, and genetic disorders, tumors, surgery, radiotherapy, and medications can all "perturb" weight regulation.

"In some people, that promotes obesity, in some people it protects them against obesity," she said.

Dr John Wilding

Taking to the podium, Wilding proceeded to present the case for the notion that body weight is determined "by nurture."

He pointed to data from the World Obesity Federation on adult obesity showing that, between the 1960s and 1990s, the prevalence of obesity topped more than 15% in only a few developed countries and no developing nations.

But from 2000 onwards, the situation has completely reversed. At least 15% of the population is obese in most developed countries, rising to over 25% in the United States, Canada, Australia, and the UK, among others. The prevalence of obesity is also rising rapidly in many middle-income countries.

Yet, Wilding pointed out, humanity cannot have evolved genetically to a sufficient extent over that period to account for the change.

He turned to the UK Government's obesity system map, which is a visual representation of the different factors that influence obesity levels.

Although it places physiological energy balance at the heart of the map, and a large part of that is devoted to biologic processes, Wilding highlighted that the visual also places a great degree of emphasis on food production and consumption, societal influences, individual psychology and movement, and the "activity environment."

He also showed data suggesting it is not so much energy and fat intake that is associated with obesity trends as the increase in the number of cars per household and hours spent watching television.

For example, it is estimated that, compared with the 1950s, the average adult now walks, on average, a marathon (approximately 26 miles) less per week, he said.

The Cuban economic crisis of the 1990s also provides an illuminating example, Wilding added.

The sudden end of Soviet subsidies to Cuba led to food shortages, the loss of public and private transport, and the importof 1.5 million bicycles from China.

The subsequent drop in the prevalence of obesity was associated with a reduction in the incidence of diabetes and diabetes-related mortality, with all three increasing substantially once food and transport levels were restored.

Taking a more recent example, Wilding showed longitudinal findings from the HUNT study, which involved almost 119,000 individuals with repeated body mass index (BMI) measurements from 1963, and over 67,000 who were tested for 96 known obesity genes.

The HUNT authors concluded that, although "genetically predisposed people are at greater risk for higher BMI and that genetic predisposition interacts with the obesogenic environment resulting in higher BMI...BMI has increased for both genetically predisposed and nonpredisposed people, implying that the environment remains the main contributor."

Wilding said that, taken together, obesity is "common and increasing almost everywhere," and that the epidemic "is driven by societal change," despite the underlying biology determining an individual's susceptibility.

He ended his pitch to much laughter with a quote by Farooqi from a 2014 review that supports his argument: "Evidence clearly shows that both increases in energy intake and reductions in energy expenditure during physical activity have driven increases in the mean BMI seen in many countries over the past 30years."

Both speakers were then invited back to the podium, allowing Farooqi to respond that, although she did indeed pen that statement in a 2014 review, if one were to look "carefully," the article discussed the last 30 years, and indeed, "our genes haven't changed in that time, but the environment has."

"We agree on that point, and hence my quote," she said, "but what our environment has done is it has unmasked the genetic susceptibility of some individuals, so what we see when we look at the pattern of BMI in the population is that the mean BMI has increased...but also the proportion of people with severe obesity has increased."

She clarified that what this suggests is that, within any population, there are some people who are genetically more susceptible to obesity, so some of those who may not have been obese 30 years ago now are because of the environment.

"It is the environment acting on genetic susceptibility that is contributing to the distribution of BMI," she emphasized.

Wilding again pointed to the HUNT study, which showed that, even in individuals with "thin genes," there has been a rise in mean BMI.

Farooqi said this, in fact, underlines a limitation of that study, which is they only used 96 well-known genetic variants associated with obesity, but the polygenic risk study she highlighted earlier used 2.1 million genetic variants.

Consequently, data from the HUNT study "captures some of the variation but not all," she stressed.

The debate continued, with questions from the floor covering many aspects of obesity.

The final question was directed at Farooqi: "What proportion of somebody's weight is considered to be genetic...as opposed to the nurtured weight?"

She replied this is a "hugely important" question, because "if we don't recognize that theres a biological role for the regulation of weight, how on earth can politicians, with their somewhat different capacity for taking on new information, do that?"

The "evidence suggests around 40% of a person's weight is influenced by genetic factors," she said.

"In some people it's higher, where there are penetrant genes having an effect, in other people it's about 40% with a combination of genes which, added together, influence their risk of either gaining weight or staying thin."

In response, Wilding was keen to stress: "No matter which side of the argument you're on, the point is that this is not the individual's fault."

"It's either a response to their environment...or it's something that they've inherited and don't have individual control over," he noted.

"Sadaf [Farooqi] said it herself, 40% of our body weight is genetic, that means that 60% is environmental, and I rest my case," Wilding said.

However, that did not hold sway with the audience, who, when they voted again at the end of the debate, indicated they had changed their minds: 53% agreed with the statement that nature, not nurture, determines body weight, and 47% disagreed.

A win for the lady, it would seem.

Society for Endocrinology BES 2019. Presented November 11, 2019.

For more diabetes and endocrinology news, follow us on Twitter and Facebook.

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Nature vs Nurture: What's Fueling the Obesity Epidemic? - Medscape

Posted By: Staff WriterNovember 18, 2019

With artificial intelligence and genetic engineeringcontinuing to shape the future of scientific innovation and discovery,questions about the ethical implications only seem to get more complicated.

Additionally, CRISPR a tool for DNA sequencing and geneediting is bringing new technological changes and advancements in a rapidlyshifting landscape.

A panel discussion at Stanford University later thisweek, moderated by Russ Altman a professor of Bioengineering, Genetics,Medicine, Biomedical Data Science and Computer Science at the university, seeksto discuss how AI and CRISPR are influencing these ethical quandaries and howthey might influence the evolutionary process.

The two panelists for the free, sold-out event areleaders in the field. Jennifer Doudna, a professor of chemistry and molecularand cell biology at UC Berkeley, helped discover CRISPR-Cas9. Fei-Fei Li is acomputer science professor at Stanford in the universitys Institute forHuman-Centered Artificial Intelligence. She previously worked at the schoolsAI Lab and at Google.

The Institute for Human-Centered Artificial Intelligenceis hosting for forum at Stanfords CEMEX Auditorium, 655 Knight Way. It is setfor Tuesday, November 19, from 7 to 8:30 p.m.

While the event has sold out of pre-registration tickets,limited general admission will be available at the site. It will also belivestreamed.

To see more details, click here.

To watch the livestream, click here.

Originally posted here:
Examining the ethics of scientific discovery - Cupertino Today

Mila Makovec has high pigtails in her dark hair and a cloth doll tucked under her arm as she wakes up in a hospital bed, where shes just been injected with a one-of-a-kind drug intended to save her life.

The drug works for only one person in the world this 9-year-old girl from Boulder.

In a spectacular example of what the future might hold for precision medicine, the drug was made only for her in a quest to save Mila from a neurological disease that is destroying her brain. Her DNA is in the formula. The 22-letter genome sequence in the drugs recipe matches the one in Milas cells that is broken.

It is the first time the FDA has approved a drug for a single person.

The drug appropriately called milasen might not have come soon enough to save Mila, as it can only slow the process of degeneration, not replace the brain cells that have already died.

But this story is no longer just about Mila; it never actually was.

This is not just for my daughter anymore, said Julia Vitarello, who took to social media to fundraise and find a researcher and drug manufacturer who would help her. This is for something much bigger.

Milas case catapulted specialized drug development at least a decade into the future, her doctors say, opening a new path for other children with rare genetic diseases that have no cure.

Childrens Hospital Colorado, where Mila was diagnosed three years ago and now receives her treatment, and Boston Childrens, where her drug was designed, are leading the way in creating a model in which academic researchers could help perhaps a handful of children each year by crafting one-of-a-kind medicines. Next year, Childrens Colorado will begin whole-genome sequencing with a new machine called a Novaseq, a major step in the process of finding mutations in DNA.

The whole concept raises ethical questions for sure: How safe is it to initiate a clinical trial for a single child? Who makes sure the children who could benefit most not just those whose families have money or the ability to raise money get the specialized treatment?

Vitarello, who created Milas Miracle Foundation and raised $3 million while trying to save her daughter, wants to establish funding for children who need drugs tailored to their own cellular biology. She suggests an admissions process where the researchers deciding whether to help a child do not know that childs name, face or ability to pay.

There are going to be parents who are going to do anything for their kid, Vitarello said. They are going to come with money. Thats totally fine, no judgment. I would do the same thing. But in an ideal world, there would be patients coming through a funnel with no names or faces or money attached. Whoever is at the table makes the best decision.

The path forward is likely in the academic, nonprofit space, Vitraello said. She is initiating talks with the National Institutes of Health, the largest public funder of biomedical research, as well as research institutions, the FDA and the pharmaceutical industry. An estimated 1.3 million people with rare genetic diseases could potentially benefit from a treatment like Milas, she said.

There are 1.3 million kids that are dying that have no other treatment, no pharma company is going to help them, there is nothing that we can do, and now suddenly, weve opened up a pathway for that, she said Tuesday at the hospital in Aurora, as Mila rested following her injection. The only way to get it is to have more academic institutions treat more kids one, two, five, 10. Open it up.

The goal is that kids with flaws in their DNA could receive precision medicine sooner, halting neurological diseases before they steal the ability to walk, talk, eat or see.

Mila was a perfectly healthy child the first three years of her life. She was learning to ski, went hiking with her parents and had a vocabulary advanced beyond her years.

Her mom noticed the subtle changes before anyone the way she pulled books close to her face because she couldnt see, how her feet turned inward, that she began bumping into things and fell for no reason, how she stuttered sometimes but it wasnt like typical stuttering.

Vitarello brought her to 100 doctors and therapists from the East Coast to the West and in Canada, many of whom told her to calm down and that her daughter seemed fine. I had doctors tell me I was pretty much crazy. Very top level doctors told me to chill out, she said. Well, I wasnt going to chill out. I just kept going.

By age 7, Mila was having trouble walking and eating and was going blind. Her body was wracked with multiple seizures each day.

I spent three years trying to figure out what was wrong with her, Vitarello said. I basically gave up and brought her to the ER at Childrens Colorado.

Mila was admitted and her case assigned to Dr. Austin Larson, a geneticist whose main job at the hospital is to figure out whats wrong with patients who have an undiagnosed disease. An MRI found that the part of Milas brain that is responsible for balance, the cerebellum, was smaller than expected. But it was a genetic test that for the first time gave Vitarello a name for Milas illness: Batten disease, and a specific type of Batten that is so rare, just 25 people in the world are known to have it.

The disease occurs when both of a childs two CNL7 genes are mutated one mutation from each parent.

Larson was able to identify the defective gene from Milas father, but could not find one from her mother. At the time, Childrens Colorado along with most places didnt have the technology to search that deeply into Milas DNA through whole-genome sequencing, and Larson warned Milas family that it was likely impossible to find a clinical lab that could. She would need a researcher.

Vitarello turned to Facebook, begging for help for Mila but also so she could find out if her son, who was 2 at the time and completely healthy, had the same devastating disease that was taking away her daughter.

I was going to get nowhere with Mila unless I just opened up my story fully, to everyone, her mom said.

Dr. Larson had given her enough information and the right words to make a plea. A Boston physician saw her message and connected her with Dr. Timothy Yu, a neurogeneticist at Boston Childrens.

At the same time, the FDA had just approved a new drug called Spinraza, the first drug to treat a separate genetic condition called spinal muscular atrophy. The drug, injected into the fluid around the spinal cord, helped babies in clinical trials improve head control, sitting and standing.

The way Spinraza was designed was a game-changer for medicine and key in helping Mila. Yu and his team in Boston wondered if they could make a similar drug for the Colorado girl.

The Boston team spent days staring at screens of Milas DNA sequences until they discovered the other piece of the genetic puzzle in addition to the gene mutation from her father, Mila had inherited extra genetic material from her mother. The combination meant that, in the most basic terms, Mila had a sequence of broken DNA in her cells.

The drug created only for Mila contains little pieces of synthetic genetic material that search for a specific 22-letter sequence and cover it up so that her cells cannot read it. We are taking a Band-Aid and sticking it onto that part, said Dr. Scott Demarest, a pediatric neurologist at Childrens Colorado and a specialist in rare genetic epilepsies. That is literally what is happening. It is sticking to that spot so that the cell skips over that and goes to the next part that is correct.

The only difference between Spinraza and milasen is the genetic sequence inside the drugs send Band-Aids to different addresses.

After discovering the genetic flaw, Yu in Boston and Larson in Colorado called Milas mom together to give her the news. Her son did not have either of the recessive genes, and her daughter had both.

It was a huge mix of extreme happiness and, within the same second, just extreme falling-to-the-floor sadness for Mila, Vitarello recalled. My daughter had gotten both of the bad mutations and my son had gotten both of the good ones.

Next, Vitarello had to persuade a drugmaker to make a drug for one, and the FDA to allow doctors to inject it in her daughters spinal fluid.

The stars aligned, she says, still in disbelief.

Milas team made it happen by emphasizing that although this drug had the potential to work only on one person, the process could become a blueprint for other patients. Only the DNA sequence in the medicine would change.

They persuaded a drug manufacturer in California, TriLink Biotechnologies, to make Milas drug. And the FDA agreed to speed up the clinical trial process by allowing Yu to test the drug on rats at the same time Mila was receiving her first dose. The doctor had first tested it on Milas skin cells.

Milasen is technically now in clinical trial a trial of one patient involving two childrens hospitals.

The night before Milas first injection in January 2018, as Vitarello went for a run in subzero Boston, she told herself she was OK with whatever happened. Mila was out of time. Vitarello had seen the descriptions online and knew where Mila was headed.

My daughters trajectory of not treating her was so black and white, Vitarello said. Everyone always wonders what is going to happen to your life. When you have a rare disease, you can see exactly what is going to happen to your child ahead of time and its not a good thing.

I figured the worst-case scenario was not her dying, it was her being in pain, Vitarello said, recalling that she asked Yu to tell the FDA that she thought the drugs potential benefits outweighed the risk. I said, If my daughter dies on the spot, Im OK with that.

Instead, the injections that first year seemed to stop the diseases progression. Mila quit eating through a g-tube and started eating her moms pureed food again. She could hold up her head and her upper body, and her walking improved. Her seizures decreased from 30 a day to two or three.

Quality of life, those are huge, Vitarello said.

Now in the second year of treatment, some of Milas symptoms have declined, but not as steeply as other children with her disease. Milas team has upped her doses and started injecting them every two months instead of every three, but they have no precedent to follow.

They could find out years from now that they were giving Mila 1,000 times too little, her mother said.

I honestly dont know if it was in time for Mila, Vitarello said. She was really progressed when she received her treatment. There is still hope.

The key to saving more children from rare genetic diseases is diagnosing them earlier ideally at birth.

What if we found this three years sooner? Larson asked. I think about that a lot. What would it have taken to have found this the first time that (Vitarello) took Mila to a physician and said, I am concerned about the subtle difference in the way she walks?

The answer is it takes having a very broad test and being very good at interpreting that very broad swath of information.

Science is a ways off from being able to detect diseases as rare as Milas in newborns. But breakthroughs are coming for other genetic diseases.

Starting in January, spinal muscular atrophy will become one of 38 genetic diseases newborn babies are screened for via blood tests, said Raphe Schwartz, chief strategy officer for Childrens.

Childrens intends to take what it has learned through Milas case, partner with other institutions and use it to help more children, Schwartz said. What we learn reveals the roadmap for the future, he said. The future ones we do are more effective and less expensive over time.

There is a sense of urgency, but also caution.

We want to make sure we are doing it right, we are doing it safely, we are doing it for kids who are going to benefit the most, Demarest said. There are ethical challenges around it. We need to be very thoughtful and careful that we are doing this the right way, but were also doing it in a way that allows this to be a reality for kids as soon as possible and for as many as possible.

For now, Vitarello is grateful that Mila can receive her treatments in Colorado. Until September, they were traveling to Boston every other month for 10 days, but now they can leave home after breakfast on treatment days and return by dinner.

On Tuesday, Vitarello recited Goldilocks and the Three Bears and sang camp songs while Mila, bundled in blankets, received the 10-minute injection in her lower back, which Vitarello said doesnt seem to hurt Mila. They celebrated Milas 9th birthday last week, and her little brother, now 5, picked out a squishy toy and a sequined mermaid for her birthday presents.

Im faced with a huge amount of sadness around this, but at the same time, its making such a huge difference that it gives a lot of purpose to her life and it gives a lot of purpose to my life, Vitarello said. We are still fighting hard for Mila. But I can see this making a much bigger impact.

This reporting is made possible by our members. You can directly support independent watchdog journalism in Colorado for as little as $5 a month. Start here: coloradosun.com/join

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This miracle drug was designed and manufactured for just one person a 9-year-old Boulder girl - The Colorado Sun

News Release

Wednesday, November 20, 2019

Studies in cell and animal models reveal insights into cancer cells vulnerability that could lead to new strategies against brain cancers.

Researchers have devised a new plan of attack against a group of deadly childhood brain cancers collectively called diffuse midline gliomas (DMG), including diffuse intrinsic pontine glioma (DIPG), thalamic glioma and spinal cord glioma. Scientists at the National Institutes of Health, Stanford University, California, and Dana-Farber Cancer Institute, Boston, identified a drug pair that worked together to both kill cancer cells and counter the effects of a genetic mutation that causes the diseases.

The researchers showed that combining the two drugs panobinostat and marizomib was more effective than either drug by itself in killing DMG patient cells grown in the laboratory and in animal models. Their studies also uncovered a previously unrecognized vulnerability in the cancer cells that scientists may be able to exploit to develop new strategies against the cancer and related diseases. The results were published Nov. 20 in Science Translational Medicine.

DMGs are aggressive, hard-to-treat tumors that represent the leading cause of brain cancer-related death among U.S. children. DMGs typically affect a few hundred children a year between ages 4 to 12; most children die within a year of diagnosis. Most cases of DMG are caused by a specific mutation in histone genes. Histones are protein complexes in the cell nucleus. DNA wraps around histones to form chromatin, which packages DNA in the nucleus. How DNA winds and unwinds around histones is influenced by enzymes, including histone deacetylases. These enzymes add or remove chemical tags, which indirectly controls if genes are turned on or off.

In an earlier study, Stanford neuro-oncologist Michelle Monje. M.D., Ph.D., and her colleagues showed that panobinostat, which blocks key histone deacetylase enzymes, could restore the DIPG histone function to a more normal state. While panobinostat is already in early clinical testing in DIPG patients, its usefulness may be limited because cancer cells can learn to evade its effects. So Monjes team wanted to identify other possible drugs and combinations of them that could affect the cancer.

Very few cancers can be treated by a single drug, said Monje, a senior author of the study who treats children with DIPG and other diffuse midline gliomas. Weve known for a long time that we would need more than one treatment option for DIPG. The challenge is prioritizing the right ones when there are thousands of potential options. Were hopeful that this combination will help these children.

Monje and the National Cancer Institutes Katherine Warren, M.D., now at Dana-Farber Cancer Institute and Boston Childrens Hospital, collaborated with Craig Thomas, Ph.D., and his colleagues at the NIHs National Center for Advancing Translational Sciences (NCATS). Thomas and his team used NCATS drug screening expertise and matrix screening technology to examine drugs and drug combinations to see which ones were toxic to DIPG patient cells.

NCATS robotics-enabled, high-throughput screening technologies enable scientists to rapidly test thousands of different drugs and drug combinations in a variety of ways. Scientists can examine the most promising single drugs and combinations, determine the most effective doses of each drug and learn more about the possible mechanisms by which these drugs act.

The NCATS researchers first studied the effects of single approved drugs and investigative compounds on DIPG cell models grown in the laboratory from patient cells. They focused on agents that could both kill DIPG cells and cross the brains protective blood-brain barrier, a necessity for a drug to be effective against DIPG in patients. The team then tested the most effective single agents in various combinations.

Such large, complex drug screens take a tremendous collaborative effort, said Thomas, also a senior study author. NCATS was designed to bring together biologists, chemists, engineers and data scientists in a way that enables these technically challenging studies.

While there were multiple, promising outcomes from these screens, the team focused on the combination of histone deacetylase inhibitors (like panobinostat) with drugs called proteasome inhibitors (such as marizomib). Proteasome inhibitors block cells normal protein recycling processes. The panobinostat-marizomib combination was highly toxic to DIPG cells in several models, including DIPG tumor cell cultures that represented the main genetic subtypes of the disease and mice with cells transplanted from patient tumors. The combination also reduced tumor size in mice and increased their survival. A similar response was found in spinal cord and thalamic DMG models developed from cells grown in culture from patient cells.

The screening studies also provided important clues to the ways the drugs were working. Building on these data, the collaborative team subsequently conducted a series of experiments that showed the DIPG cells responded to these drugs by turning off a biochemical process in the cells mitochondria that is partly responsible for creating ATP, which provides energy to cells. The drug combination essentially shuts down tumor cell ATP production.

The panobinostat-marizomib drug combination exposed an unknown metabolic vulnerability in DIPG cells, said first author Grant Lin, Ph.D., at Stanford University School of Medicine. We didnt expect to find this, and it represents an exciting new avenue to explore in the development of future treatment strategies for diffuse midline gliomas.

Plans are underway for clinical trials of the drug combination and of marizomib alone.

Many drugs that we test have multiple effects on DIPG cells, said Warren, a senior study author. Panobinostat, for example, inhibits a specific enzyme, but it has other mechanisms working in tumor cells that may contribute to its effectiveness. Were still trying to understand the various Achilles heels in these cancer cells. This work is an important step in translating our preclinical data into patients.

Monje stressed the panobinostat-marizomib combination might be an important component of a multitherapy strategy, including approaches that harness the immune system and those that disrupt factors in the tumor microenvironment that the glioma cells depend on to grow. Like Warren, Monje emphasized the need to better understand how drugs target and impact the DIPG cells vulnerabilities.

Our work with NCATS showed the need to gather more preclinical data in a systematic, high-throughput way to understand and prioritize the strategies and agents to combine, Monje said. Otherwise were testing things one or two drugs at a time and designing clinical trials without preclinical data based on hypothesized mechanisms of action. We want to move past this guesswork and provide preclinical evidence to guide clinical decisions and research directions.

Lin added, The idea is to get as many effective tools as possible to work with that can have an impact on patients.

The research was funded by Alexs Lemonade Stand Foundation, Izzys Infantry Foundation, McKenna Claire Foundation, Unravel Pediatric Cancer, Defeat DIPG Foundation, ChadTough Foundation, N8 Foundation, Kortney Rose Foundation, Cure Starts Now Foundation and the DIPG Collaborative, Sam Jeffers Foundation, Lyla Nsouli Foundation, Abbies Army Foundation, Waxman Family Research Fund, Virginia and D.K. Ludwig Fund for Cancer Research, National Institute for Neurological Disorders and Stroke (R01NS092597) and NIH Directors Common Fund (DP1NS111132), Maternal and Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases, The DIPG All-In Initiative and the NCATS and NCI intramural programs.

Reference:GL Lin et al. Therapeutic Strategies for Diffuse Midline Glioma from High-Throughput Combination Drug Screening. Science Translational Medicine. DOI: 10.1126/scitranslmed.aaw0064

About the National Center for Advancing Translational Sciences (NCATS):NCATS conducts and supports research on the science and operation of translation the process by which interventions to improve health are developed and implemented to allow more treatments to get to more patients more quickly. For more information about how NCATS is improving health through smarter science, visithttps://ncats.nih.gov.

About the National Institutes of Health (NIH):NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NIHTurning Discovery Into Health

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Scientists find promising drug combination against lethal childhood brain cancers - National Institutes of Health

Autoimmune diseases are immune system disorders where the bodys immune system attacks its own tissues. Examples of common autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, type 1 diabetes, multiple sclerosis (MS) and others.

A peculiarity of autoimmune diseases is that they have many genes in common, but they develop differently. For example, why does a patient with an autoimmune disease become a type 1 diabetic rather than have rheumatoid arthritis?

Decio L. Eizirik, a researcher at Universit Libre de Bruxelles Centre for Diabetes Research in Belgium, who is also a senior research fellow at the Indiana Biosciences Research Institute, recently published research in the journal Nature Genetics that found significant insight into this question. Eizirik took time to speak with BioSpace about the research and how a researcher in Belgium came to collaborate with researchers in Indiana, Spain, the UK and the U.S. National Institutes of Health.

Several autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, etc., have as much as 30 to 50% of their candidates genes in common, said Eizirik, raising the question on why in some individuals the immune system attacks, for instance, the insulin-producing beta cells, causing type 1 diabetes, while in others it targets joint tissues, leading to rheumatoid arthritis. Most of the research in the field has focused on the role for these candidate genes on the immune system, but our work indicated that many of these candidates genes affect the function and survival of pancreatic beta cells, leading to a misguided dialogue between them and the immune system that culminates in diabetes.

The early stages of type 1 diabetes, for example, show local autoimmune inflammation and progressive loss of the pancreatic beta cells that produce insulin. How these genetic transcription factors, or cytokines, interact with the beta-cell regulatory environment, and the changes that occur, suggest a key role in how the immune system gets triggered to attack the beta cells.

The research was conducted by Eizirik, Lorenzo Pasquali from the Institucio Catalana de Recerca I Estudis Avancats (ICREA) in Barcelona, Spain, and colleagues from Oxford, UK; Pisa, Italy, and the NIH. For about 20 years, Eizirik has run a diabetes-focused laboratory in Brussels. In August 2019, he launched a new laboratory at the IBRI, where, he said, three top scientists and assistants, Donalyn Scheuner, senior staff scientist at IBRI, Bill Carter, research analyst at IBRI, and Annie Rocio Pineros Alvarez, postdoctoral fellow in medicine at Indiana University, are already working. These two laboratories are working closely togetherfor instance, we have weekly meetings by videoconference, and besides my regular visits to the IBRI, scientists are moving between our European and USA labs on a temporary or permanent basis.

The IBIR was created by the State of Indiana and the states leading life science companies, academic research universities and medical school, as well as philanthropic organizations. The focus is on metabolic disease, including diabetes, cardiovascular disease obesity and poor nutrition. Its laboratories and offices are housed in about 20,000 square feet of space in Indian University School of Medicines Biotechnology Research and Training Center in Indianapolis. It expects to move into a new 68,000-square-feet site in mid-2020.

Eizirik said, The IBRI offers a unique opportunity to translate our basic research findings to the clinic, and we are working closely together with colleagues at Indiana University, particularly Carmella Evans-Molina, director of the Indiana Diabetes Research Center (IDRC) and the IDRC Islet and Physiology Core, to confirm our basic research findings in patients samples, and to eventually bring them to the clinic.

The specific research study looked at the binding of tissue-specific transcription factors. Transcription factors are basically proteins whose job it is to turn genes on or off by binding to DNA. So, for example, there are specific transcription factors whose job it is to regulate insulin production in pancreatic beta cells. In the case of this research, Eizirik and his team studied tissue-specific transcription factors that open the chromatin. Chromatin is a complex of DNA and protein found in the nucleus of the cell. It allows long DNA molecules to be packaged, typically in the form of chromosomes.

For gene transcription to occur, Eizirik said, chromatin must open and provide access to transcription factors. This allows binding of pro-inflammatory transcription factors induced in the beta cells by local inflammation.

For certain people who are genetically predisposed to type 1 diabetes, this leads to the generation of signals by the beta cells, Eizirik said, that contribute to attract and activate immune cells, rendering beta cells a potential target to the immune system.

Eizirik said, These observations have clarified the role for pancreatic beta cells in type 1 diabetes and provided an explanation for the reasons behind the immune system targeting beta cells.

The amplifying loop mechanism observed potentially explains other autoimmune diseases. Eizirik notes, Binding of tissue-specific transcription factors, within an inflammatory context and in genetically predisposed individuals, could generate signals that would attract and activate immune cells against specific target tissues.

Testing the theory in other autoimmune diseases will be required to verify it, but potentially could open up new therapies or preventive treatments for type 1 diabetes and other autoimmune diseases.

Type 1 diabetes has a strong genetic component, Eizirik said. At least 50% of the disease risk is due to genetic causesand understanding the role for candidate genes in the disease may point to novel therapies. For instance, up to now, nearly all therapeutic approaches to prevent type 1 diabetes have targeted the immune system, with little success. Our findings suggest that we must also take steps to directly boost beta cell survival.

He compared targeting the immune system only in type 1 diabetes to trying to fly a plane with only one wing. Our present and previous data suggest that we need two wings: first, to re-educate the immune system to stop its attack on the beta cells, and second, to increase the beta cell resistance to the immune attack, and to find means to restore the lost beta cell mass. Unfortunately, to achieve these goals in both type 1 diabetes and other autoimmune diseases is not easy, and we must redouble our efforts.

The next stages of the research will be to study the function of two novel candidate genes for type 1 diabetes that were discovered in the research. They both act at the beta cell level. He expects to conduct that research with Pasquali. The second stage is to evaluate the impact of other immune mediators that act earlier in the disease course at the beta cell level. And the third stage is to test their hypothesis regarding the role for the target tissue in other autoimmune diseases.

In addition to that ambitious agenda, Eizirik and his group are establishing an Inducible Pluripotential Cell Core at the IBRI.

Eizirik said, This will allow us to de-differentiate, for instance, skin cells from patients into pluripotential cells, and then to differentiate them into pancreatic beta cells. This will allow us to study the impact of the novel candidate genes we are discovering on beta cell function and survival, again in collaboration with Lorenzo Pasquali and Carmella Evans-Molina. This will also provide an excellent model to test new drugs to protect the beta cells in early type 1 diabetes.

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Researchers Working to Understand Why Some Patients with Autoimmune Diseases Develop Diabetes Instead of Arthritis - BioSpace

A serving of Golden Rice contains half the beta-carotene children need daily.

By Erik StokstadNov. 20, 2019 , 3:00 PM

Soon. That has long been scientists' answer when asked about the approval of Golden Rice, a genetically modified (GM) crop that could help prevent childhood blindness and deaths in the developing world. Ever since Golden Rice first made headlines nearly 20 years ago, it has been a flashpoint in debates over GM crops. Advocates touted it as an example of their potential benefit to humanity, while opponents of transgenic crops criticized it as a risky and unnecessary approach to improve health in the developing world.

Now, Bangladesh appears about to become the first country to approve Golden Rice for planting. "It is really important to say we got this over the line," says Johnathan Napier, a plant biotechnologist at Rothamsted Research in Harpenden, U.K., who was not involved in the crop's development. He says approval would show that agricultural biotechnology can be successfully developed by publicly funded research centers for the public good. Still, environmental groups haven't dropped their oppositionand the first harvest isn't expected until at least 2021. And more research will be needed to show the extent of real-world benefits from Golden Rice.

Golden Rice was developed in the late 1990s by German plant scientists Ingo Potrykus and Peter Beyer to combat vitamin A deficiency, the leading cause of childhood blindness. Low levels of vitamin A also contribute to deaths from infectious diseases such as measles. Spinach, sweet potato, and other vegetables supply ample amounts of the vitamin, but in some countries, particularly those where rice is a major part of the diet, vitamin A deficiency is still widespread; in Bangladesh it affects about 21% of children.

To create Golden Rice, Potrykus and Beyer collaborated with agrochemical giant Syngenta to equip the plant with beta-carotene genes from maize. They donated their transgenic plants to public-sector agricultural institutes, paving the way for other researchers to breed the golden rice genes into varieties that suit local tastes and growing conditions.

Over the past 2 years, regulators in the United States, Canada, New Zealand, and Australia approved Golden Rice for consumption. There are no plans to grow the crop in these countries, but approval will prevent problems if Golden Rice somehow accidentally turns up in food supplies.

The Golden Rice under review in Bangladesh was created at the International Rice Research Institute (IRRI) in Los Baos, Philippines. Researchers bred the beta-carotene genes into a rice variety named dhan 29, which is grown widely during the dry season in Bangladesh and contributes about 14% of the national harvest. In tests of dhan 29 Golden Rice at multiple locations, researchers at the Bangladesh Rice Research Institute (BRRI) in Gazipur found no new farming challenges and no significant differences in qualityexcept for the presence of vitamin A.

BRRI submitted data to the Bangladeshi Ministry of Environment, Forest, and Climate Change in November 2017. The Biosafety Core Committee, a group of eight officials and scientists, has since been reviewing environmental risks, such as the plant's potential to become a weed, as well as food safety. The review is nearing completion; on 28 October, the Dhaka Tribune reported that a decision would be made by 15 November.

That date has come and gone; the holdup appears to be due to the death of a committee member. But a source familiar with the committee's deliberations says some members remain skeptical of Golden Rice, wondering for example why it is needed when people could also eat more vegetables.

Proponents are optimistic, however. The scientific evidence is strong, the committee previously approved another transgenic crop, and Golden Rice enjoys high-level political support in Bangladesh, they say. "We are hopeful that Golden Rice might get the green light soon," says Arif Hossain, director of Farming Future Bangladesh in Dhaka, which is funded by the Bill &Melinda Gates Foundation to inform policymakers and others about biotechnology.

After the environment ministry signs off, Golden Rice must be registered by a seed certification agency within the Ministry of Agriculture, which requires field trials in multiple places to test for seed quality. If all goes smoothly, farmers might have Golden Rice seed to plant by 2021.

How popular it will be is uncertain. Farmers in Bangladesh quickly adopted an eggplant variety engineered to kill certain insect pests after its 2014 introduction, but that crop offered an immediate benefit: Farmers need fewer insecticides. Golden Rice's health benefits will emerge more slowly, says agricultural economist Justus Wesseler of Wageningen University &Research in the Netherlands, so adoption may be slower as well. The government may need to promote Golden Rice and, Hossain says, even subsidize farmers to grow it.

Consumer acceptance may be another challenge, given the golden hue, says Sherry Tanumihardjo, who studies vitamin A and global health at the University of Wisconsin in Madison. "People have a difficult time changing the color of food they eat," and many people in Bangladesh prefer to eat white rice. On the other hand, cooked Golden Rice resembles khichuri, a popular dish of rice and lentils cooked with turmeric, which may increase its appeal. With Gates Foundation support, IRRI and BRRI are developing a strategy for directing farmers' harvest to rural regions and cities with high poverty and malnutrition rates.

Opposition from nongovernmental organizations could still hobble the introduction. Last month, two groups in Bangladeshthe Agricultural Farm Labour Federation and the National Women Farmers &Workers Associationcalled for a ban on both Golden Rice and transgenic eggplant.

If Golden Rice does make inroads in Bangladesh, additional varieties better adapted to other seasons or locations may follow. Bred at BRRI, they are now in greenhouse trials. Like all local versions of Golden Rice, these varieties were created not with genetic engineering, but by traditional backcrossing, so they will likely not need biosafety approval. "There will be no problem for a year-round supply of biofortified rice," says Partha Biswas, a plant breeder at BRRI.

But for now, all eyes are on dhan 29. "It would be great to see it approved," Napier says. "It's been a long time coming."

Read more:
Bangladesh could be the first to cultivate golden rice, genetically altered to fight blindness - Science Magazine

Last month, when Attorney General Bill Barr gave a speech at Notre Dame about religious liberty, I praised him for his take on the importance of religion to our Constitutional order, and for pointing fingers at those carrying out the organized destruction of religions place in the public square. I stand by that praise. But in his column today, taking on that speech, and a more recent one Barr delivered to the Federalist Society, about law and the presidency, Ross Douthat says the Attorney General is guilty of propping up Zombie Reaganism. Douthat writes:

What Barrs speeches presuppose, basically, is What if everything you believed before Trump, you can still believe today?

In the Notre Dame speech, this reassurance manifests itself in a restatement of the assumptions that have guided organized religious conservatism since the 1960s: that the chief threat to religious faith comes from secularizing elites; that the great moral debates of our time pit Christian rigorists on the right against moral relativists on the left; that religious conservatives and limited-government conservatives can be natural allies because the welfare state is an ersatz religious institution that crowds out private charity and churches.

Douthat goes on to say that Barrs diagnosis is correct, but limited in important ways. He goes on:

But theres no attempt in the speech to address the recent trends that complicate religious conservatisms 70s-era vision even though those trends helped make Barrs boss the president of the United States.

For instance, theres no mention of the extent to which conservative lawyers already won a series of battles against the harder sort of secularism even liberal jurisprudence today is less strictly secularist than in the 70s and it didnt matter much to the cultural erosion of their faith.

Theres no mention of how much of that erosion has happened under administrations friendly to conservative Christianity, and therefore probably reflects internal weakness, division and scandal more than pressure from outside. [Emphasis mine RD]

Theres no reckoning with the tension between the G.O.P.s religious and libertarian wings, the clear support of many religious conservatives for the welfare state that official conservatism decries or the extent to which Trump won the Republican nomination by running against the familiar critique of big government that Barr recycles in his speech.

Thats really true, and I wish I had caught that when I first wrote about Barrs speech. After all, I wrote a book based in large part on the fact that the culture has changed so much that its simply not plausible to believe that if only we elect the right politicians, we can re-Christianize the public square. The dog that did not bark was the Christian churches in the fight to preserve traditional marriage. In France secular France! almost a million people turned out in Paris to protest (unsuccessfully) the proposed pro-LGBT changes in the law. In America, nothing. In 1993, hundreds of thousands of gay folks turned out on the Mall in Washington, DC, to demand pro-LGBT laws. I was there covering the story. They cared enough to demonstrate; we conservative Christians did not. We thought having the right opinions, and voting Republican, and donating to conservative Christian PACs, would be enough.

Meanwhile, we lost the culture. Dont get me wrong, AG Barrs diagnosis is correct, as far as it goes. There really are elites doing their best to demonize Christian belief. But if thats the only diagnosis from the Right of our dire condition, it isnt enough. As Douthat points out later in his piece, after he issues a similar, even stronger, critique of Barrs speech on law and the imperial presidency, this rhetoric is the kind of thing that soothes conservative audiences but doesnt actually describe the world into which conservatives find themselves thrown in 2019.

Douthat points to Damon Linkers critique of Barrs Federalist Society speech, which Linker sees as a harbinger of future right-wing authoritarianism. Douthat is not quite buying it:

The other, which Im drawn to bymy own obsession with decadence, would emphasize futility instead. A conservatism that constantly reconverts itself to the worldview of the Reagan era isnt poised to claim sweeping, authoritarian power, in the service of religious revolution or any other cause. Its poised for repetition, gridlock and failure ever-imagining itself seizing the initiative, but really letting itself be carried backward, a boat against the current, into the world of Bill Barrs youth and past.

Douthat is consciously referring to the final line of The Great Gatsby:

Gatsby believed in the green light, the orgastic future that year by year recedes before us. It eluded us then, but thats no mattertomorrow we will run faster, stretch out our arms farther. . . . And one fine morning

So we beat on, boats against the current, borne back ceaselessly into the past.

Douthat is saying that Barrs two speeches are a form of willed optimism, of an old Reaganaut trying to convince himself and his listeners that its still 1980, and the Reagan-era verities still hold. Like Douthat, I am inclined to think of this in terms of decadence decadence not in the vulgar understanding of the term (e.g., licentiousness), but decadence in the sense of having no new ideas, and being compelled therefore to repeat old ones for lack of anything useful to say.Anyway, read the whole thing.

This is a problem on the Right, for sure. I think of the conservative Christians I know who are still captive to a more or less Reaganite view of the world, and who think that sending their kids to a Christian school, and attending a conservative Christian church, is sufficient to hold the line. They really do think that the line between good and evil is drawn between institutions and political parties.

I often return to this 1999 PBS Frontline episode, The Lost Children Of Rockdale County.My wife and I watched it when it was first aired, 20 years ago. Our firstborn child was not even one month old. It shocked us deeply. It made us vow that we would do everything we possibly could not to be parents like the Rockdale County moms and dads in this show. Heres a transcript of the program, and heres a link to a YouTube version.

The show takes an outbreak of syphilis among high schoolers in this upscale, politically conservative Atlanta suburb, and uses it to take a closer look at their lives. What they found, along with state health investigators, was a sexual free-for-all culture, abetted by the unwillingness of parents to pay close attention. From the transcript:

NARRATOR: There were lots of parties back then, anywhere that adults werent around. The kids would meet in empty homes all over Conyers, sometimes even in rented motel rooms. Kevin did not take part in their activities, but he knew about them.

KEVIN: There was a lot of sex going on then. Like, one girl would come in the group and shed be passed around, or one guy would go in the girls group and get passed around.

INTERVIEWER: Passed around?

KEVIN: Yeah, theyd just- one guy would do it with her one night. The next night somebody else has her. The next night somebody else has her.

INTERVIEWER: Was this a game?

KEVIN: Pretty much.

NICOLE: There was a lot of sex then, about 16 years old- a lot of sex. We would fight. There was about four of the guys that drove BMWs and had everything, and those were- all the girls wanted to be with those guys, so we would all fight over them or do whatever. And then youd have sex with them, so youd be, like, Yeah, I had sex with your man last night, da, da, da, do. And thats- I think thats how the syphilis came about. It was everybody just having sex with everybody.

D.J.: Actually, I mean, it was a social thing, but it was more of an underground railroad thing. Everybody was secretively having sex with everybody, and everybody knew it. The teenagers knew it. But the parents never knew.

Prof. CLAIRE STERK: A lot of the adolescents had parents who worked, were at home alone, had parents who put in 40, 60, 80-hour work weeks and were doing that to insure that all the resources that they wanted to give to their children were available.

BETH ROSS, Dir. Counseling, Rockdale County Schools: The activities they were involved in, whether it would be sexual or otherwise, the majority of their behavior was taking place between right after school and right before parents came home from work, like between 3:00 and 7:00, and some of it late at night then, after midnight, after the parents would go to sleep.

NICOLE: Most of my friends parents were not the kind of parents that really cared. They cared what went on, but if it interfered with their lives they didnt really- wouldnt- they didnt want to bother with it.

About halfway through the film, theres a town meeting with the parents to discuss the crisis:

Dr. KATHLEEN TOOMEY: What was so extraordinary to me is these parents started looking for externally who to blame. This has caused this, T.V. has caused that, External groups have caused this. But few of them none of them that I can recall ever looked to themselves. And the minister turned to me and said, They dont see. Its them. Its the parents. They have done this. The kids dont talk to them.

What was extraordinary to me, a year after this outbreak, was here was a community in total denial about what happened.

NARRATOR: In the end, the syphilis outbreak had come and gone, leaving barely a ripple behind. But some believe that the community, by regarding the outbreak as an anomaly, had missed a larger point about all its kids.

CLAIRE STERK: I would say its very sad because there are so many lessons we could have learned from this. And part of me feels that were not picking up on all those lessons and still leave adolescents hanging there, forcing them to take care of themselves when we know that theyre not always able to do that.

WES BONNER, Pastor: Theyre coming from middle class homes, upper middle class homes. They have so many things, you know, every convenience. They all have a cell phone, a pager, you know, anything that they need. But what theyre looking for is, you know, Wheres the road? Wheres the path? I dont see that. You know, everythings so spread out. I dont know, you know, where to go.

The children of Rockdale County are now parents. I wonder how theyre raising their kids? I wonder what narrative they tell themselves about life in America, to allow themselves to sleep at night? I wonder if theyre #MAGA nostalgists, or if theyre Silicon Valley Soixante-Huitards who believe that if we just tear down more barriers, then we will finally reach utopia.

Everybody in America is a nostalgist. Because we are a decadent society.

Go here to read the rest:
Bill Barr's Blindness -- And Our Own - The American Conservative