‘A new instruction manual for life’: Single-cell sequencing is opening up new avenues for potential treatments

first_img STAT+: [email protected] Privacy Policy In the Lab‘A new instruction manual for life’: Single-cell sequencing is opening up new avenues for potential treatments Single-cell sequencing is the center point of his research. The advantage, he said, is that it allows you to measure 5,000 to 10,000 genes in each cell, and do it across many thousands of cells. The work’s been fruitful: This summer, for instance, Lein’s team announced that it used RNA sequencing on a single-cell scale to discover a new breed of neuron, dubbed the “rose hip cell” — so named because the axons, or nerve fibers, resemble a rose without its petals. The cells, which seem to exist only in humans, are thought to control how information flows from one part of the brain to others. The study analyzed just a handful of human brains, obtained postmortem, but included the analysis of thousands of cells in minute detail.“The field has changed so dramatically, and quickly,” Lein said. “Just a few years ago, studying a couple dozen transcriptomes would be a totally reasonable study. Now, we’re getting into the realm of millions of cells for a study.”The technique has also produced some fascinating insights in disease pathology. Take asthma, for instance: Nathan Jackson, a researcher at the Center for Genes, Environment, and Health at National Jewish Health in Denver, discovered the precise cells that misbehave during severe asthma attacks.He assayed the cells involved in type 2-high asthma, which affects about half of the people with the disease. It’s caused by elevated levels of signaling proteins, called type 2 cytokines, which prompt the cells lining the surface of the lungs to excrete a thick mucus. This ends up triggering some of the breathing difficulties associated with asthma.By analyzing the RNA with single-cell sequencing, Jackson and his colleagues found out the specific genes and proteins that prompt mucus production. Furthermore, they found 11 different states of these epithelial lung cells, as they changed in response to triggers in the environment,  morphing from innocuous into irritated cells that caused disease. “Imagine you were a biologist and didn’t have a microscope — and then I handed you one for the first time,” said Dr. Sam Behjati, a pediatric oncologist and single-cell researcher at the Wellcome Sanger Institute in Britain. “That’s how profound single-cell sequencing is. It lets us see what we haven’t seen before; it gives us a new instruction manual for life.” By Meghana Keshavan Nov. 21, 2018 Reprints Single-cell sequencing has tantalized scientists for several years. It was first described in 2009, and by 2013 earned the distinction of “Method of the Year” from Nature. Cost and technology hurdles initially kept its use at bay — but the field has begun to blossom as sequencing becomes more economical, and bioinformatic analysis becomes more reliable. advertisement Every plant, animal, and fungus is made up of an intricate amalgam of cells. Each cell type has its own unique function, life cycle, and reaction to its environment. These factors, in aggregate, inform how living things live, the way disease manifests, and why we die.Much of this synchronous web of biology is still a mystery: There’s so much we don’t understand about how individual cells work in tandem to keep a brain firing or a cancer metastasizing. But scientists, using a powerful technology called single-cell sequencing, have begun to peel apart the precise mechanisms of how individual cells operate. By quickly analyzing thousands — even millions — of cells in a single experiment, it’s now possible to visualize the specific cellular culprits for any given disease, how they might interact with their microscopic peers, and what molecules are involved in the process.advertisement Even if the price isn’t negligible, it’s well within reach for both research labs and larger pharmaceutical companies that are interested in this technology.“We want these instruments in all labs across the world, because we think this is how analysis should be done,” Hindson said.The Human Cell Atlas project — an international effort to create a detailed taxonomy of every cell type in the human body — has helped raise the profile of single-cell sequencing. The project is funded in part by the Chan Zuckerberg Initiative, the effort launched by Facebook CEO Mark Zuckerberg and his wife, Dr. Priscilla Chan, aimed at curing, preventing, or managing all disease “in our children’s lifetime.” Though the initiative is still in its nascency, scientists are already unveiling intriguing new insights into basic human biology thanks to the collaborations spawned by the Human Cell Atlas.Ed Lein, a researcher at the Allen Institute for Brain Science, is working on unraveling the cellular makeup of the human brain. The idea is to reverse-engineer the brain’s cortex, he said, to try and understand all of the types of cells within it — and then build up an understanding of how they’re all wired together.   Leave this field empty if you’re human: Single-cell sequencing, by contrast, can indicate which family has six children, and which has just one, and a dog, he said. It’s orders of magnitude more granular. “The value of single-cell sequencing, in this case, is the ability to look at how mutations work together to drive disease,” Silver said.Here’s how single-cell sequencing works: A cancer biopsy is teased apart, and each of the thousands of cells is locked into its own tiny test tube on a microfluidic chip, and then treated with a series of enzymes and chemicals to coax the necessary genetic material out.From there, the cells are tagged with their own “barcode” — a unique DNA- or RNA-based identifier that’s inserted into its genetic code. The cells are then probed for a predetermined set of variables: Scientists can check whether they carry a certain set of genes, or express specific molecules involved in disease pathogenesis. The data are aggregated, and through the magic of machine learning scientists can use that data to sort cells by their function and characteristics. Instead of averaging the genetic profile of the tissue sample, this analysis quantifies the prevalence of each different cell type — and can isolate the outliers. “If our customers analyze 10,000 cells from a sample, very often they’ll find a handful of these residual cells after a patient’s been treated that are still indicative of disease,” Silver said. “That’s the population that ends up relapsing and progressing.”Mission Bio is working with top institutions around the country — including MD Anderson, Mount Sinai, the National Cancer Institute, and the Stanford Cancer Center — to pore through patient tissue samples in search of residual cancer.Single-cell sequencing might ultimately help clinicians know whether a therapy is tailored to target the specific cell types that have gone rogue. The tool has particular implications for combination therapies, and could prove useful in clinical trial design, Silver said. Single-cell sequencing still isn’t cheap.10X Genomics, a biotech specializing in single-cell analysis, offers the microfluidics instruments necessary for this technology for about $75,000. It’ll cost about $1,280 — plus sequencing costs, which vary based on what’s being studied — for the necessary materials to study about 10,000 cells, said Ben Hindson, chief scientific officer of the company. Though the epithelial cells were obviously studied in a lab setting, they were cross-examined with the RNA expression from the nasal swabs of 698 children with type 2-high asthma — and the findings held up.Understanding the precise cellular processes that go awry in asthma could potentially lead to a new wave of asthma therapeutics, Jackson said. And it’s not just asthma: Identifying the pathways that lead to dysfunction in a specific cell type, such as the epithelial cells he analyzed, could allow scientists to develop drugs targeted exclusively to that particular population. “Once this technology became available, we realized there was so much low-hanging fruit,” Jackson said. “There are so many obvious questions we can answer with single-cell sequencing.” Celsius Therapeutics is using single-cell sequencing to drive its entire drug discovery process. Freshly launched this year with a $65 million series A round, the company is zeroing in on cancer and autoimmune disease.“We think these are two areas where whole genome sequencing has little impact,” said CEO Langaeur. Instead, his company is analyzing the RNA from the single cells involved in cancers and conditions like inflammatory bowel disease to find drug targets. The company’s agnostic on therapeutic modality — it’s open to both biologics and small molecule drugs — but thinks the single-cell approach will be very revealing.Indeed, single-cell sequencing could open the door for entirely different ways of approaching drug development. Newsletters Sign up for Daily Recap A roundup of STAT’s top stories of the day. About the Author Reprints Academics and drug makers alike are increasingly looking for ways to exploit this powerful new technology. Interrogating individual cells on their identity and purpose is turning up stunning new insights on basic biology — and providing rich fodder for drug discovery. Try to picture a mass of cancer cells. Tumors are bedeviling in their complexity: They can comprise both of mutant and healthy cell types, and operate in their own ever-expanding microenvironment.Although it’s possible to identify tissue as cancerous by examining it under a microscope, or even by sequencing a biopsy, it’s difficult to isolate which specific cells are benign — and which might evade therapy, mutate, and lead to further metastasis. “It’s Darwinian evolution, literally,” said Charlie Silver, CEO of Mission Bio, a biotech spinout of the University of California, San Francisco, that provides single-cell sequencing services to cancer hospitals, researchers, and pharmaceutical companies. “Cancer is not one mutation — it’s many mutations on different cells that work together to drive disease.”Most clinical sequencing efforts work by the law of averages: Genetic analysis is conducted on entire populations of cells, so subtle differences between them aren’t clear, making it hard to to isolate the most malignant. And those subtle differences are what drive each individual cancer’s pathology.Standard genetic analysis techniques give us some insights, but they can be murky — not unlike population surveys, as Christoph Lengauer, CEO of Celsius Therapeutics, a Cambridge, Mass., biotech, points out.“Population surveys tell us the average American family has 1.2 children. That’s useless. That’s not helpful. Not a single family has 1.2 children,” said Lengauer, whose company is using single-cell sequencing to find new drug targets. Exclusive analysis of biopharma, health policy, and the life sciences. Human cell showing the nucleus in red and the tubulin component of the cytoskeleton in green. The blue staining is a single cytoplasmic protein. Matthew Daniels/Wellcomecenter_img Offering free DNA sequencing, Nebula Genomics opens for business. But there’s an itsy-bitsy catch NewslettersSign up for The Readout Your daily guide to what’s happening in biotech. Trending Now: Comparing the Covid-19 vaccines developed by Pfizer, Moderna, and Johnson & Johnson Leave this field empty if you’re human: Behjati of Wellcome Sanger made a startling observation in his own cancer research. After sequencing reams of kidney cancer cells, he has — as expected— found a litany of unique mutations. But he noticed that while the kidney cancer cells may be genetically disparate from one another, they generally behaved and looked alike. The cancer cells’ instruction manuals may have been worded differently, but the end result was more or less the same, he said. “On the DNA level, kidney cancers are very heterogeneous — but if you looked at the cancer on a cellular level, all the cancer cells are the same,” he said. “I think we’re getting distracted by the heterogeneity.”So Behjati has a slightly unorthodox viewpoint on the future of drug development — using insight gleaned from his work with single-cell sequencing.His hypothesis, when it comes to drug development, would be to focus more on the cell type and less on the intricacies of DNA and RNA that drive the mutations. “Let’s look for drugs that change the cell type, and disrupt the cancer that way,” he said. “At the end of the day, what kills you is not the mutation, but the cancer cell.” Related: Please enter a valid email address. Cartoons offer a peek into cancer immunotherapy — and scientists’ minds Privacy Policy Please enter a valid email address. @megkesh Related: Biotech Correspondent Meghana covers biotech and contributes to The Readout newsletter. Meghana Keshavan Tags geneticsresearchlast_img read more

Champions for Charity next step in golf’s return

first_imgThe PGA Tour may still be three weeks away from resuming tournament play, but the sport will take another star-studded step toward returning to competition this weekend. Last week’s TaylorMade Driving Relief match featuring Rory McIlroy, Dustin Johnson, Rickie Fowler and Matthew Wolff marked the first live televised golf since the Tour entered a competitive hiatus in March in the wake of the COVID-19 pandemic. This weekend it’ll be another four-man outing with the Champions for Charity match, albeit with only two Tour members. Tiger Woods and Phil Mickelson will go head to head at Medalist Golf Club in Florida, 18 months after their initial duel in Las Vegas. But this time they’ll be joined by a pair of NFL quarterbacks past and present, with Peyton Manning joining Woods and Tom Brady pairing with Mickelson. Like last week’s match at Seminole Golf Club, charity will be a key component to Sunday’s competition. More than $10 million is expected to be donated to coronavirus relief. And just as golf fans saw when McIlroy and Johnson teamed to defeat Fowler and Wolff in a skins match that extended to a 19th hole, a unique format will once again be on display. The match at Medalist will be split into two nines, with the front featuring best-ball competition and the back nine utilizing modified-alternate-shot format. Manning and Brady may be elite on the football field, but they’ll need some help to keep pace with Woods and Mickelson in a best-ball format. As a result, both quarterbacks will be given shots on three front-nine holes: one par-3, one par-4 and one par-5. But the modified alternate shot over the final nine holes won’t provide any such cushion for Manning, who plays to a 6.4 handicap index, or Brady with an 8.1 index. All four players will tee off on each hole, with Manning and Brady playing from a forward tee, and teammates will alternate after choosing the better drive. Manning on ‘Tiger,’ ‘Phil’ code names for offense While the quarterbacks will look to provide a few highlights with their clubs instead of their arms, much of the interest will focus on their two decorated partners. Most Tour players have been out of action for nearly three months, but Woods’ hiatus extends a month longer. The reigning Masters champ hasn’t played since finishing last among those who made the cut at the Genesis Invitational on Feb. 16, clearly plagued by injury issues that led him to skip three subsequent events, including The Players.  As a Medalist member, Woods will have home-course advantage and revenge on his mind after Mickelson edged him in their 2018 match in Vegas. But there are still questions to be answered by his southpaw counterpart, as Mickelson is now less than a month away from turning 50. Mickelson was hit or miss during 2020 before coronavirus halted play, mixing missed cuts with a pair of T-3 finishes. But he’s been staying busy recently in California, playing regular practice rounds with area pros like Xander Schauffele and Charley Hoffman. As for the team arrangements, the dividing lines were rather apparent. Woods and Manning have played together often over the years, teaming in five pro-ams including each of the last two years at the Memorial. Manning once shared that when he was leading the Indianapolis Colts, the team’s no-huddle offense included a snap-count call where “Tiger” meant hiking the ball on 1 and “Phil” meant hiking the ball on 2. “We’d say it a lot. ‘Tiger, Tiger,’ ‘Phil, Phil,’” Manning said. “Tiger was on 1, and Phil was on 2. Tiger always liked that. He could hear it. I think he liked the fact that Phil was on 2 a lot as well.” Their partnership means Mickelson will be joined by Brady, who recently moved to Florida after signing with the Tampa Bay Buccaneers. It’s a duo that continues to successfully battle Father Time, with Brady about to enter his 21st NFL season and Mickelson still hitting bombs past players half his age. As with last week’s televised showcase, there’s sure to be some rust on display as players look to return to competitive form – and it likely won’t be limited to the play of the quarterbacks. But another chance to promote the game with a significant charitable aspect will be embraced by fans across the country, and it signals another important element of progress as the Tour inches closer toward a return to full-fledged competition after an unexpected hiatus.last_img read more

Paralympic Deepa Malik appeals to Jats to protest peacefully

first_imgChandigarh, Feb 19 (PTI) With Haryana on the edge due to Jat agitation, Rio paralympic medallist Deepa Malik today appealed to the Jat community to put forth their demands in a peaceful manner so as not to sully their image.Recalling the unfortunate incidents which occurred last year as violence broke out during the Jat stir claiming 30 lives, Malik, a Jat herself said, “The thing you are fighting for, if it brings bad name to its very identity, then such a movement goes in a negative way.””I feel in a democratic country everyone has the right to put forward their views. My only appeal to everybody in this movement is that look at our sportspersons and take things in a sportsmans spirit.”We also fight for whatever we want in the play field, but with a feeling of brotherhood and with a feeling of sportsman spirit. Whatever you have to say, please adopt peaceful kind of way to do it,” Malik, who hails from Haryana, said here.Malik had won a silver medal in the womens shot put event at the Paralympics and was felicitated by Prime Minister Narendra Modi at a function held at Gurugram in November last year with a cash award of Rs 4 crore.Malik, who made the entire country proud with her rare feat, said, “when one talks of things in a peaceful and and non-violent manner, when one keeps point of view in a peaceful manner, it holds more weight.””Being a Jat myself, its an appeal lets put forward everything in a peaceful manner so that we do not destroy the very significance and image we are standing for,” Malik told PTI here on the sidelines of a function.advertisementShe said the positive side was that the stir this year so far has remained peaceful.She also said that nobody wants a repeat of the incidents of violence as witnessed during last years stir.During the height of the Jat agitation last year, many sports personalities had appealed to the community to adopt peaceful ways of protest.Cricketer Virendra Sehwag, former national chess champion Anuradha Beniwal, boxers Vijender Singh and Manoj Kumar, had made an appeal to the Jat protesters to end the stir.Notably, as the protesting Jats are observing “Balidan Divas” (day of sacrifice) today, Haryana is on high alert with maximum deployment of forces to prevent any untoward incident.The agitation seeking reservation in education and government jobs for the Jat community among other demands entered its 22nd day today.The All-India Jat Aarakshan Sangarsh Samiti (AIJASS), the body spearheading the fresh stir, had announced that they would decide the future course of action today.PTI SUN DVlast_img read more

Once a shepherd, Alireza Beiranvand is now Iran’s goalkeeper at the World Cup

first_imgHe has played two matches till now and has let in just one goal and that one goal also sneaked in because of the striker’s pure luck and he still has a chance to guide Iran to the Round of 16 in the 2018 FIFA World Cup.Alireza Beiranvand has been a solid figure for Iran at the back. Along with his hard-working defenders, he cuts a formidable figure under the sticks.On Wednesday, he conceded his first World Cup goal, against the mighty Spain, up against one of the best strikers in the business Diego Costa.2018 FIFA WORLD CUP: FULL COVERAGEHow did that goal happen though? It was a stroke of luck. Beiranvand was deceived because Costa’s strike got deflected, bounced back off the Spaniard and then went into the goal. Alireza Beiranvand kept a clean sheet against Morocco and pulled off some good saves versus Spain (Reuters Photo)Beiranvand’s determination to guard his goal perhaps comes from the staunch personality he has developed through the various struggles he has undergone to reach to the top of his country’s football.FIFA WORLD CUP: FIXTURES | POINTS TABLEHaving been born in a nomadic family and being the eldest son, he was a shepherd back in time. It was in his free time that he used to play football and a local game named Dal Paran, which involved throwing stones to long distances.It was at the age of 12 that his family settled down and he began training at a local club. Though he started as a striker, an injury to the goalkeeper meant he took the place, made a brilliant save and sealed his place.advertisementHowever, it was then that his real troubles began.Iranian women watch football in Tehran stadium for first time since 1979His father disapproved of him taking up football as a professional career, even tore his clothes and gloves. It was then that Beiranvand decided to leave his home.Borrowing money from a relative, he decided to take a bus to Tehran. It was in that bus that he met a football coach, Hossein Feiz, who managed a local team. Feiz told him that he could train at the club in return for some money.In Russia, a plea to support Iranian women to enter stadiumsOf course, Beiranvand had no money, no place to sleep.For days he slept at the roads. One day he decided to sleep outside the club where he trained on trial every day.”I slept by the club’s door and when I got up in the morning I noticed the coins that people had dropped for me,” he told the Guardian. “They had thought I was a beggar! Well, I had a delicious breakfast for the first time in a long while.”Finally Feiz took him in and asked the captain of the club to help him. He slept at the captain’s place for two weeks before starting to work at another colleague’s father’s dressmaking factory so he could sleep there.Iran captain says World Cup not the right place to discuss women issuesDespite coming such a long way, there was far more road to cover.He next used to wash SUVs for money and soon, he met a Naft-e-Tehran coach and moved there. In the beginning, he slept at the club’s prayer room but soon he had to move out.From working at a pizza shop to working as a street cleaner, Beiranvand was soon finding it difficult to stay fit and was soon sacked by Naft for training with another team and getting injured.He then went to another club, Homa, but the manager there was reluctant to take him in.However, it was a few days that luck finally decided to smile at him.The Naft U-23 manager called him asking him to come back if he had not signed elsewhere. He joined back and the rest is history. Alireza Beiranvand is Iran’s first choice goalkeeper in this year’s FIFA World Cup (Reuters Photo)He is now Iran’s first-choice keeper, playing at the biggest stage in world football and holding his ground.On June 25, he will have perhaps one of the toughest job in the world — stopping Cristiano Ronaldo from finding the back of the net — when Iran will take on Portugal in their final group game.Like he has shown in the two matches till now though, he will be up for the challenge.last_img read more

10 months agoAzpilicueta: Pulisic deal a warning to Chelsea players

first_imgAzpilicueta: Pulisic deal a warning to Chelsea playersby Paul Vegas10 months agoSend to a friendShare the loveChelsea defender Cesar Azpilicueta says the deal for Borussia Dortmund winger Christian Pulisic is a warning for the players.Azpilicueta has welcomed the USA international’s move to Stamford Bridge, but feels it also sends a message to the current group.He told the London Evening Standard: “Of course. Chelsea is a top club and the competition is very high.”Every moment we need to get results, we need to perform. That has been the case for a long time at Chelsea and will be the same now.”Obviously I am very happy that Chelsea have signed Pulisic. He is a talented young player and will come in the summer. “For the next six months he will be with Borussia, but I’m happy that we are getting young players. Hopefully he can be very good for us.” TagsTransfersAbout the authorPaul VegasShare the loveHave your saylast_img read more

Video: OU QB Baker Mayfield Snags Ridiculous 1-Handed Catch After Practice

first_imgBaker Mayfield of the Cleveland BrownsOAKLAND, CA – SEPTEMBER 30: Baker Mayfield #6 of the Cleveland Browns tells to the crowd to be quiet after the Browns scored a touchdown against the Oakland Raiders at Oakland-Alameda County Coliseum on September 30, 2018 in Oakland, California. (Photo by Ezra Shaw/Getty Images)There are many who believe that Oklahoma quarterback Baker Mayfield, who transferred in from Texas Tech a year ago, is going to wind up starting over Trevor Knight this fall. Perhaps the Sooners should also be taking a look at what other positions Mayfield can play. Friday afternoon, Mayfield posted a video of himself making a ridiculous turn-around one-handed catch on his high school’s practice field.The pass came from former Lake Travis High School quarterback Dominic DeLira, who is signed with Iowa State ahead of the 2015 campaign.Mayfield could be poised for a big 2015 – maybe Oklahoma should figure out a way to work him into the scheme, regardless of whether he wins the starting job.last_img read more