Connect with us

Spatial Biology Reorients Biopharma Development

Molecular profiles that “zoom in” (to reveal the contents of single cells) and “zoom out” (to reveal cell-cell relationships in tissue samples)…

Published

on

The Human Genome Project, which was declared complete in 2003, stimulated the expectation that great medical benefits were imminent. But years passed, and the benefits seemed to recede into the future. What went wrong? Well, nothing—except that the value of knowing the genome’s contents had been overstated, however inadvertently. The word “genome” includes the suffix “ome,” which betokens completeness. That is, it suggests that all that needs to be known is known, at least in one field of endeavor. But even the genome needs context.

Recently, the genome and other “omes”—including the epigenome, the transcriptome, and the metabolome—started to be contextualized in various ways. For example, instead of compiling bulk omics information, many researchers began to collect single-cell omics information. These researchers showed that one needn’t be satisfied with broad averages. Instead, one could explore cellular heterogeneity.

Essentially, researchers demonstrated that they could acquire contextualized views by “zooming in” on single cells. And now researchers are “zooming out,” too. While preserving the granularity of single-cell profiling, researchers are looking at cellular environments. In other words, researchers are putting cellular heterogeneity in spatial contexts.

Although spatial context may be sought at the subcellular level, it is, for now, mostly sought among collections of cells, or in specific tissues. Let’s look at just one example. At the University of Queensland, researchers used a spatial and molecular profiling platform to survey the pulmonary transcriptional landscape of COVID-19, pandemic H1N1 influenza, and uninfected control patients (Kulasinghe et al. Eur. Respir. J. 2021; 2101881). Doing so allowed the researchers to dissect virus-specific host responses and gene signatures.

The researchers described one of their key observations as follows: “SARS-CoV-2 was non-uniformly distributed in lungs (emphasizing the advantages of spatial transcriptomics) with the areas of high viral load associated with an increased type I interferon response.” The researchers concluded that “spatial transcriptomics is a powerful tool to identify novel gene signatures within tissues, offering new insights into the pathogenesis of SARS-CoV-2 to aid in patient triage and treatment.”

Work of this sort—that is, work that puts single-cell omics in spatial contexts—is becoming more common. It is starting to characterize disease states in unprecedented detail. It is also expanding the scope of research into disease mechanisms. Such research is bound to inform drug development. Most important, it promises to realize many of the hopes originally inspired by the Human Genome Project.

Molecular biology gets a slider bar

One of the University of Queensland researchers involved in the study cited earlier is Arutha Kulasinghe, PhD. He leads the “Clinical-O-Mx” group at the University of Queensland’s Diamantina Institute.

Arutha Kulasinghe, PhD
Diamantina Institute, University of Queensland

“Spatial biology is the next generation of tissue imaging combined with genomic readout,” he says. “It enables researchers to profile proteins and genes from tissue samples down to single cell and subcellular resolution.

“It’s the ‘Google maps’ approach, where you can profile diseased tissue at the city level (a tissue region), the street level (a few cells), or the house level (a single cell). This is enabled through advances in molecular barcoding technologies and enables scientists and clinicians to profile tissue samples from patient biopsies with a greater level of understanding of the underlying tissue biology.”

Visualizing genomic organization

“Studies of spatial biology of organs and tissues have emerged because it has been possible to sequence the output from genes (the mRNAs) in single cells,” says Niels Tommerup, MD, DMSc, a professor of medical genetics at the University of Copenhagen. “This has allowed researchers to classify specific RNA profiles for each cell type, and hence to both identify new cell types and to potentially identify which specific cell type that are affected in a given disease.”

The key benefit, Tommerup emphasizes, is the way spatial analysis links interactions at the molecular level to tissue biology. Spatial biology, he suggests, is a concept that can be elaborated across several scales—from individual cells to tissues and organs. For example, if one were to use spatial biology to study genomic organization, one could focus on changes within a single cell, assess which conformations are more common in cell populations, or determine how conformations may vary among cells that occupy certain locations.

Spatial biology across scales has improved, Tommerup says, thanks to techniques such as deep sequencing technology and chromosome conformation capture (3C) technology. According to Tommerup, 3C techniques such as HiC and MicroC assays can help researchers map chromatin interactions genome wide.

“Following fixation, fragmentation, and re-ligation, DNA regions that are physically closer to each other can be co-sequenced, and this has revealed that the genome is organized into structural domains and chromatin loops, bringing specific genes physically together with their potential myriad of regulatory elements that may be situated far from the gene.”

An environmental perspective

At Cold Spring Harbor Laboratory, researchers led by Assistant Professor Je Hyuk Lee, MD, PhD, study how cells interact with their microenvironment to regulate gene expression during development. His online profile states that “single-cell heterogeneity in gene expression can result from spatial differences in cell-cell and cell-extracellular matrix interactions.”

Lee declares that spatial biology and spatial genomics is about “visualizing biological information.” These technologies, he continues, allow formerly dimensionless information to be put in a three-dimensional context and given functional meaning. Such meaning, he insists, is “central to linking genetic information to form and function.”

Lee’s group focuses on the role of noncoding RNA in chromatin remodeling and tumor progression using mouse and organoid models of human cancer. The group’s long-term goal is to improve our understanding of the tumor microenvironment, and to use understanding to support the development of tumor classification tools and anticancer therapeutics.

Enabling diverse applications

As the University of Queensland study cited earlier indicates, spatial techniques are already being used to improve our understanding of infectious diseases. Spatial techniques are also being applied to generate insights into cancer and neurodegenerative diseases. According to Kulasinghe, spatial techniques are broadly applicable because they enable researchers to map cell types to the genes and proteins that are being expressed.

dentate gyrus (DG) region
Image of dentate gyrus (DG) region of the mouse brain with a 40-gene mouse neuro-panel. Spatial genomics and biology is helping researchers to identify disease mechanisms and how they link to expression patterns in more detail than ever before according to Simon Gregory at Duke.

“In cancer, one of the current unmet clinical needs is the need for predictive biomarkers of response for immunotherapies such as immune checkpoint blockade,” he elaborates. “Spatial biology approaches have led to a greater understanding of the tumor and tumor microenvironment.

Besides showing where certain immune cell types are located within the tumor microenvironment, spatial biology can also give clues about the degree of immune activation in a tumor. This kind of information, Kulasinghe notes, can help predict how patients respond to immunotherapies.

Simon Gregory
Simon Gregory, PhD
Duke University School of Medicine

Another researcher using spatial techniques in cancer research is Simon Gregory, PhD, Professor and Vice Chair of Research, Department of Neurology, Duke University School of Medicine. He is also applying the techniques to improve our understanding of neurological diseases.

For example, in multiple sclerosis, Gregory is applying spatial biology to study the impacts of lesions in the central nervous system. “We’re hoping to characterize lesions in different parts of the central nervous system,” he says. Doing so could help Gregory and his colleagues elucidate the role of immune cell function in lesion development. It could also help them distinguish between benign and progressive lesions.

“In Alzheimer’s, we’re characterizing not only what happens within amyloid-β plaques and neurofibrillary tangles, but also what is happening in the peri-plaque region,” he adds. “And in brain tumors, we’re trying to characterize the heterogeneous landscape of the tumor.” This landscape isn’t limited to the cellular and transcriptomic topology of the tumor itself. It extends to the surrounding stroma that is invaded by the tumor.

Clarifying disease mechanisms

“Spatial genomics is still in its infancy, but it has huge potential,” says Tommerup. He is particularly optimistic about using spatial genomics to expand the number of genetic factors that are known to determine common and complex diseases. Many such factors, probably the majority of such factors, have yet to be identified. But Tommerup thinks he knows where more might be hiding: “Conceivably, the missing inheritance factors are of regulatory nature, and hence determined by the 3D genomic organization.”

“Spatial biology of organs and tissues will undoubtedly have the power to refine biological studies,” Tommerup declares. This view is shared by Gregory, who says that in future, spatial methods will offer researchers the ability to fully understand diseases and therapeutic response from the molecular to the whole organism level.

“I see spatial approaches as occupying the intersection of genomics and pathology,” Gregory elaborates. “For more than 100 years, pathology has allowed us to define cellular phenotyping/morphology as it relates to a disease state, but we haven’t been able to understand the underlying biological mechanisms.”

“Using spatial or in situ transcriptomic approaches, we’re not only about to characterize the aberrant transcriptomic profiles of these disease-related cells, but we’re also going to be able to describe the transcriptomic changes that preempt disease-related cellular changes.”

Transforming medicine

Spatial techniques in combination with other cutting-edge analytical methods can help scientists understand disease mechanisms and develop novel interventions. In biopharma, spatial techniques could identify and localize diseased cells that currently lack biomarkers (for example, disseminated tumor cells). Spatial techniques could also reveal how immune cells react around diseased cells.

According to Lee, being able to use spatial techniques to characterize the response to “different types of cell or immunotherapies in a robust, scalable, and high-throughput manner would be a game changer, especially in combination with detailed tumor pathology and artificial intelligence–based data processing.”

Lee states that there are also potential applications in tissue engineering. He predicts that spatial techniques will be embraced by cell therapy developers and the wider regenerative medicine sector. “Currently, genetic and phenotypic analyses of engineered cells are done in vitro in a Petri dish,” he relates. “Spatial genomics technologies could potentially upend this. For tissue biology and pathology, the impact may be lower.

“I am not sure that looking at gene expression signatures alone will lead to dramatic advances in our understanding of complex tissue biology or cell-cell interactions. At the end of the day, I believe that spatial biology will have to provide information on genetic mechanisms, molecular functions, and cell engineering solutions to truly transform translational research, biopharma development, and medicine.”

The post Spatial Biology Reorients Biopharma Development appeared first on GEN - Genetic Engineering and Biotechnology News.

Read More

Continue Reading

Uncategorized

Homes listed for sale in early June sell for $7,700 more

New Zillow research suggests the spring home shopping season may see a second wave this summer if mortgage rates fall
The post Homes listed for sale in…

Published

on

  • A Zillow analysis of 2023 home sales finds homes listed in the first two weeks of June sold for 2.3% more. 
  • The best time to list a home for sale is a month later than it was in 2019, likely driven by mortgage rates.
  • The best time to list can be as early as the second half of February in San Francisco, and as late as the first half of July in New York and Philadelphia. 

Spring home sellers looking to maximize their sale price may want to wait it out and list their home for sale in the first half of June. A new Zillow® analysis of 2023 sales found that homes listed in the first two weeks of June sold for 2.3% more, a $7,700 boost on a typical U.S. home.  

The best time to list consistently had been early May in the years leading up to the pandemic. The shift to June suggests mortgage rates are strongly influencing demand on top of the usual seasonality that brings buyers to the market in the spring. This home-shopping season is poised to follow a similar pattern as that in 2023, with the potential for a second wave if the Federal Reserve lowers interest rates midyear or later. 

The 2.3% sale price premium registered last June followed the first spring in more than 15 years with mortgage rates over 6% on a 30-year fixed-rate loan. The high rates put home buyers on the back foot, and as rates continued upward through May, they were still reassessing and less likely to bid boldly. In June, however, rates pulled back a little from 6.79% to 6.67%, which likely presented an opportunity for determined buyers heading into summer. More buyers understood their market position and could afford to transact, boosting competition and sale prices.

The old logic was that sellers could earn a premium by listing in late spring, when search activity hit its peak. Now, with persistently low inventory, mortgage rate fluctuations make their own seasonality. First-time home buyers who are on the edge of qualifying for a home loan may dip in and out of the market, depending on what’s happening with rates. It is almost certain the Federal Reserve will push back any interest-rate cuts to mid-2024 at the earliest. If mortgage rates follow, that could bring another surge of buyers later this year.

Mortgage rates have been impacting affordability and sale prices since they began rising rapidly two years ago. In 2022, sellers nationwide saw the highest sale premium when they listed their home in late March, right before rates barreled past 5% and continued climbing. 

Zillow’s research finds the best time to list can vary widely by metropolitan area. In 2023, it was as early as the second half of February in San Francisco, and as late as the first half of July in New York. Thirty of the top 35 largest metro areas saw for-sale listings command the highest sale prices between May and early July last year. 

Zillow also found a wide range in the sale price premiums associated with homes listed during those peak periods. At the hottest time of the year in San Jose, homes sold for 5.5% more, a $88,000 boost on a typical home. Meanwhile, homes in San Antonio sold for 1.9% more during that same time period.  

 

Metropolitan Area Best Time to List Price Premium Dollar Boost
United States First half of June 2.3% $7,700
New York, NY First half of July 2.4% $15,500
Los Angeles, CA First half of May 4.1% $39,300
Chicago, IL First half of June 2.8% $8,800
Dallas, TX First half of June 2.5% $9,200
Houston, TX Second half of April 2.0% $6,200
Washington, DC Second half of June 2.2% $12,700
Philadelphia, PA First half of July 2.4% $8,200
Miami, FL First half of June 2.3% $12,900
Atlanta, GA Second half of June 2.3% $8,700
Boston, MA Second half of May 3.5% $23,600
Phoenix, AZ First half of June 3.2% $14,700
San Francisco, CA Second half of February 4.2% $50,300
Riverside, CA First half of May 2.7% $15,600
Detroit, MI First half of July 3.3% $7,900
Seattle, WA First half of June 4.3% $31,500
Minneapolis, MN Second half of May 3.7% $13,400
San Diego, CA Second half of April 3.1% $29,600
Tampa, FL Second half of June 2.1% $8,000
Denver, CO Second half of May 2.9% $16,900
Baltimore, MD First half of July 2.2% $8,200
St. Louis, MO First half of June 2.9% $7,000
Orlando, FL First half of June 2.2% $8,700
Charlotte, NC Second half of May 3.0% $11,000
San Antonio, TX First half of June 1.9% $5,400
Portland, OR Second half of April 2.6% $14,300
Sacramento, CA First half of June 3.2% $17,900
Pittsburgh, PA Second half of June 2.3% $4,700
Cincinnati, OH Second half of April 2.7% $7,500
Austin, TX Second half of May 2.8% $12,600
Las Vegas, NV First half of June 3.4% $14,600
Kansas City, MO Second half of May 2.5% $7,300
Columbus, OH Second half of June 3.3% $10,400
Indianapolis, IN First half of July 3.0% $8,100
Cleveland, OH First half of July  3.4% $7,400
San Jose, CA First half of June 5.5% $88,400

 

The post Homes listed for sale in early June sell for $7,700 more appeared first on Zillow Research.

Read More

Continue Reading

Government

Survey Shows Declining Concerns Among Americans About COVID-19

Survey Shows Declining Concerns Among Americans About COVID-19

A new survey reveals that only 20% of Americans view covid-19 as "a major threat"…

Published

on

Survey Shows Declining Concerns Among Americans About COVID-19

A new survey reveals that only 20% of Americans view covid-19 as "a major threat" to the health of the US population - a sharp decline from a high of 67% in July 2020.

(SARMDY/Shutterstock)

What's more, the Pew Research Center survey conducted from Feb. 7 to Feb. 11 showed that just 10% of Americans are concerned that they will  catch the disease and require hospitalization.

"This data represents a low ebb of public concern about the virus that reached its height in the summer and fall of 2020, when as many as two-thirds of Americans viewed COVID-19 as a major threat to public health," reads the report, which was published March 7.

According to the survey, half of the participants understand the significance of researchers and healthcare providers in understanding and treating long COVID - however 27% of participants consider this issue less important, while 22% of Americans are unaware of long COVID.

What's more, while Democrats were far more worried than Republicans in the past, that gap has narrowed significantly.

"In the pandemic’s first year, Democrats were routinely about 40 points more likely than Republicans to view the coronavirus as a major threat to the health of the U.S. population. This gap has waned as overall levels of concern have fallen," reads the report.

More via the Epoch Times;

The survey found that three in ten Democrats under 50 have received an updated COVID-19 vaccine, compared with 66 percent of Democrats ages 65 and older.

Moreover, 66 percent of Democrats ages 65 and older have received the updated COVID-19 vaccine, while only 24 percent of Republicans ages 65 and older have done so.

“This 42-point partisan gap is much wider now than at other points since the start of the outbreak. For instance, in August 2021, 93 percent of older Democrats and 78 percent of older Republicans said they had received all the shots needed to be fully vaccinated (a 15-point gap),” it noted.

COVID-19 No Longer an Emergency

The U.S. Centers for Disease Control and Prevention (CDC) recently issued its updated recommendations for the virus, which no longer require people to stay home for five days after testing positive for COVID-19.

The updated guidance recommends that people who contracted a respiratory virus stay home, and they can resume normal activities when their symptoms improve overall and their fever subsides for 24 hours without medication.

“We still must use the commonsense solutions we know work to protect ourselves and others from serious illness from respiratory viruses, this includes vaccination, treatment, and staying home when we get sick,” CDC director Dr. Mandy Cohen said in a statement.

The CDC said that while the virus remains a threat, it is now less likely to cause severe illness because of widespread immunity and improved tools to prevent and treat the disease.

Importantly, states and countries that have already adjusted recommended isolation times have not seen increased hospitalizations or deaths related to COVID-19,” it stated.

The federal government suspended its free at-home COVID-19 test program on March 8, according to a website set up by the government, following a decrease in COVID-19-related hospitalizations.

According to the CDC, hospitalization rates for COVID-19 and influenza diseases remain “elevated” but are decreasing in some parts of the United States.

Tyler Durden Sun, 03/10/2024 - 22:45

Read More

Continue Reading

Government

Rand Paul Teases Senate GOP Leader Run – Musk Says “I Would Support”

Rand Paul Teases Senate GOP Leader Run – Musk Says "I Would Support"

Republican Kentucky Senator Rand Paul on Friday hinted that he may jump…

Published

on

Rand Paul Teases Senate GOP Leader Run - Musk Says "I Would Support"

Republican Kentucky Senator Rand Paul on Friday hinted that he may jump into the race to become the next Senate GOP leader, and Elon Musk was quick to support the idea. Republicans must find a successor for periodically malfunctioning Mitch McConnell, who recently announced he'll step down in November, though intending to keep his Senate seat until his term ends in January 2027, when he'd be within weeks of turning 86. 

So far, the announced field consists of two quintessential establishment types: John Cornyn of Texas and John Thune of South Dakota. While John Barrasso's name had been thrown around as one of "The Three Johns" considered top contenders, the Wyoming senator on Tuesday said he'll instead seek the number two slot as party whip. 

Paul used X to tease his potential bid for the position which -- if the GOP takes back the upper chamber in November -- could graduate from Minority Leader to Majority Leader. He started by telling his 5.1 million followers he'd had lots of people asking him about his interest in running...

...then followed up with a poll in which he predictably annihilated Cornyn and Thune, taking a 96% share as of Friday night, with the other two below 2% each. 

Elon Musk was quick to back the idea of Paul as GOP leader, while daring Cornyn and Thune to follow Paul's lead by throwing their names out for consideration by the Twitter-verse X-verse. 

Paul has been a stalwart opponent of security-state mass surveillance, foreign interventionism -- to include shoveling billions of dollars into the proxy war in Ukraine -- and out-of-control spending in general. He demonstrated the latter passion on the Senate floor this week as he ridiculed the latest kick-the-can spending package:   

In February, Paul used Senate rules to force his colleagues into a grueling Super Bowl weekend of votes, as he worked to derail a $95 billion foreign aid bill. "I think we should stay here as long as it takes,” said Paul. “If it takes a week or a month, I’ll force them to stay here to discuss why they think the border of Ukraine is more important than the US border.”

Don't expect a Majority Leader Paul to ditch the filibuster -- he's been a hardy user of the legislative delay tactic. In 2013, he spoke for 13 hours to fight the nomination of John Brennan as CIA director. In 2015, he orated for 10-and-a-half-hours to oppose extension of the Patriot Act

Rand Paul amid his 10 1/2 hour filibuster in 2015

Among the general public, Paul is probably best known as Capitol Hill's chief tormentor of Dr. Anthony Fauci, who was director of the National Institute of Allergy and Infectious Disease during the Covid-19 pandemic. Paul says the evidence indicates the virus emerged from China's Wuhan Institute of Virology. He's accused Fauci and other members of the US government public health apparatus of evading questions about their funding of the Chinese lab's "gain of function" research, which takes natural viruses and morphs them into something more dangerous. Paul has pointedly said that Fauci committed perjury in congressional hearings and that he belongs in jail "without question."   

Musk is neither the only nor the first noteworthy figure to back Paul for party leader. Just hours after McConnell announced his upcoming step-down from leadership, independent 2024 presidential candidate Robert F. Kennedy, Jr voiced his support: 

In a testament to the extent to which the establishment recoils at the libertarian-minded Paul, mainstream media outlets -- which have been quick to report on other developments in the majority leader race -- pretended not to notice that Paul had signaled his interest in the job. More than 24 hours after Paul's test-the-waters tweet-fest began, not a single major outlet had brought it to the attention of their audience. 

That may be his strongest endorsement yet. 

Tyler Durden Sun, 03/10/2024 - 20:25

Read More

Continue Reading

Trending