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Can Graphite Bio Realize the Promise of CRISPR Gene Editing to Develop One-time Cures?

Graphite Bio is pioneering a precision gene editing approach that has the potential to transform health by achieving one of medicine’s most elusive goals:…



Josh Lehrer, MD, MPhil, FACC, is
CEO at Graphite Bio.

One dose, one cure. Countless researchers with this dream have worked for decades toward developing life-saving medicines for genetic diseases. That’s gene therapy’s goal: to fix DNA errors and see a pathological condition halted or reversed with just a single shot.

Graphite Bio is pioneering a precision gene editing approach that has the potential to transform health by achieving one of medicine’s most elusive goals: to precisely “find & replace” any gene in the genome. Graphite Bio’s UltraHDR gene editing platform takes CRISPR beyond cutting and harnesses the power of high-efficiency precision DNA repair.

Using an adeno-associated virus called AAV6 as a delivery vehicle, Graphite Bio uses a DNA template to correct genetic mutations, replacing entire defective genes with functional genes or inserting new genes into predetermined, safe locations in stem cells. The company was co-founded by academic pioneers in gene editing and gene therapy, including Maria Grazia Roncarolo, MD, and Matthew Porteus, MD, PhD.

Graphite Bio’s platform is being used to develop genetic medicines targeting several blood diseases. Nula-cel, formerly GPH101, is Graphite Bio’s lead investigational therapy that will be evaluated as a potential cure for sickle cell disease (SCD) patients. Nula-cel uses the UltraHDR platform to directly correct the point mutation in the beta-globin gene that causes SCD, changing sickle hemoglobin (HbS) to normal adult hemoglobin (HbA).

Graphite Bio claims to be one of the first companies advancing a genetic therapy with the potential to change a disease-causing gene back to normal for any indication. The multi-center, open-label clinical study called CEDAR is designed to evaluate the safety, preliminary efficacy, and pharmacodynamics of GPH101 in adult and adolescent patients with severe SCD. In August 2022, Graphite Bio dosed the first patient in the CEDAR trial, with initial proof-of-concept data from the Phase I/II CEDAR trial anticipated in mid-2023.

Graphite also has a research program for treating beta-thalassemia, one of the most common autosomal recessive disorders. This genetic blood disorder is characterized by reduced production of beta-globin, a protein that forms oxygen-carrying hemoglobin with alpha-globin. Graphite seeks to replace the mutated beta-globin gene with a functional gene and restore adult hemoglobin (HbA) expression. In addition, Graphite has an early-stage research program for treating alpha-1 antitrypsin (AAT) deficiency, a severe inherited genetic disorder that can cause progressive lung and liver disease. The program leverages the company’s targeted gene insertion approach to increase AAT protein production permanently.

GEN Edge talked through Graphite Bio’s underlying strategy to develop several genetic cures with CEO Josh Lehrer, MD, MPhil, FACC.

GEN Edge: Josh, how did you end up joining Graphite Bio?

Lehrer: Before joining Graphite Bio, I was the chief medical officer at Global Blood Therapeutics (GBT) and worked for many years on developing Oxbryta, the first approved mechanism-based therapy for sickle cell disease (SCD). We had our co-founder, Matthew Porteus, come to give a seminar at GBT to talk about his groundbreaking work. When I heard what he was doing, I was floored. He had figured out how to make a decades-long dream in the field of genome engineering a reality. He showed us edited cells from a patient with SCD that had been corrected, indistinguishable from the cells of a patient’s unaffected siblings or parents. This was simply incredible. I saw an amazing opportunity to take what I had learned and join with Matt to both build a company around this platform and also rapidly move into the clinic to hopefully transform the lives of people living with SCD.

We started the company at the beginning of the COVID-19 pandemic, in April 2020, and have grown to over 100 employees. We became a public company just over a year ago and are fortunate to have the resources we need to advance our sickle-cell program and, in parallel, several other genetic therapies.

We’ve also thought about not just the technology, the platform, and the cell engineering, but how we can get these genetic therapies to be more than a headline, more than an exciting publication, more than a handful of patients treated to really impact large numbers of people in need. We realized that the conditioning treatment—how a patient’s bone marrow is treated to make room for the gene-edited stem cell therapies—is as critical as the editing technology. We have used our experience in stem cell biology and immunology to begin research on a new approach to conditioning. We are now developing what we hope will become a best-in-class, non-toxic antibody targeting approach, ultimately enabling a one-time cure that wouldn’t require a hospital stay or have chemotherapeutic conditioning risk—a very different paradigm than what we can currently offer patients.

GEN Edge: What is Graphite’s strategy to move these therapies quickly through approval?

Lehrer: Since our founding, our focus has been on advancing our programs with a sense of urgency, and ultimately getting our potentially curative therapies to as many patients as possible.

We are planning to move quickly through our clinical trials, leveraging the experience of other clinical trials in SCD. But we are also thinking about this end-to-end. We’re trying to think of what success means with a long-term view—not just how we get this technology to the initial clinical data readout, but how we generate data to demonstrate the unique advantages of a definitive gene correction approach. This means designing our clinical trials with new endpoints that can measure the benefit of a complete cure versus an indirect approach, and these endpoints could ultimately translate into an approval for a greater number of patients with sickle cell disease.

We are also thinking holistically, beyond our clinical trials for Nula-cel, about the barriers we need to overcome to impact more patients. If the science tells us we should be developing a new antibody to improve conditioning and remove a barrier to access, then it makes sense to do that, even if that wasn’t part of our initial focus or strategy. This also means investing early in advancing how we manufacture our therapies, making the process more scalable and reducing costs. We should invest in these strategic priorities to ensure that our programs have the most extensive potential patient benefit. They may be much more important than adding a third or fourth program to our pipeline.

GEN Edge: Does Graphite Bio consider partnerships to expand the platform’s reach?

Lehrer: We think about partnerships if others can bring unique expertise or resources that help us leverage our gene editing platform in additional directions. We are starting to turn to those conversations a little more, where we think we have the best tools for efficiently integrating DNA in virtually any cell type ex vivo. And that is applicable outside of hematopoietic stem cells—to engineering T cells, NK cells, iPS cells, or other types of cells that could be therapies in other areas. For example, we’re probably not going to identify new cancer targets ourselves. These would be perfect opportunities to collaborate with other companies, where we can do the editing more efficiently and other companies can provide biological or developmental expertise in different therapeutic areas.

GEN Edge: What drove the decision for Graphite Bio to become a public company?

Lehrer: We wanted to leverage a platform broadly and have the opportunity to broadly consider what’s required to cure SCD patients, beyond just one clinical trial and one data readout. If we were focused on creating value as a private company, we’d stay private a company, get the first few patients of data in our SCD program, increase value, and then figure out what’s next. We would be moving forward in serial.

But we needed more resources and a bigger team because we have bigger ambitions. For example, in SCD or any cell therapy, you must think about the commercial manufacturing process from the beginning. If not, you end up with what we’ve seen happen with other companies—making many changes along the way and getting delayed for years. That requires a significant upfront investment, a big team, and a public company’s resources. We were fortunate that the market was very receptive when we decided to go public.

GEN Edge: What milestones has Graphite Bio set for the next five years?

Lehrer: If we’re having this conversation in five years, bringing this technology to people living with SCD and realizing its full potential is a big part of what’s driving us. We are moving that forward, validating the platform, showing that clinically we are different, and then translating that into endpoints demonstrating that we can impact all aspects of the disease and treat all severely affected patients who need a cure. We want to go beyond what others have shown, which is a reduction in pain, to show that our approach can be a definitive cure by producing normal red blood cells, preventing strokes in kids, preventing organ damage, and essentially phenocopying what is the gold standard for cure inSCD: allogeneic transplants.

In five years, if we have a best-in-class antibody conditioning therapy that can be administered in the outpatient setting to create room in the bone marrow niche for engraftment of our stem cell-based cure, then we can bring this therapy to kids with SCD who aren’t yet experiencing complications and stop the disease before the damage begins. That would transform how we think about SCD—every child born with the disease could have a chance to live a completely normal life. And we’re thinking about manufacturing cell therapies as an engineering problem to where we can get costs down from where they are now to make this accessible broadly and see a significant impact from a public health standpoint.

We’d hope to take the same approach to other severe genetic diseases. We have a program in beta-thalassemia that would synergize with our approach in SCD. It was even more technically challenging because we need to use our gene editing technology to replace an entire gene.

Our gene editing technology can also precisely insert genes into stem cells to give them new functions, potentially bringing one-time cures to many other types of genetic diseases using our platform. These cells can repopulate brain microglia within the central nervous system (CNS) and permanently deliver proteins across the blood-brain barrier to fight neurodegenerative diseases, for example. We could also engineer stem cells to produce red cell precursors as protein factories to make enzymes and proteins to treat diseases like alpha 1 anti-trypsin deficiency or to produce clotting factors for hemophilia. Having some of these programs in the clinic to show the broader potential of our platform is something else we’d like to see in a five-year timeframe.

Beyond that, we’re starting discussions about how to leverage our platform outside of hematopoietic stem cells. We want to pursue new programs where we think we can solve a different need or have a differentiated therapy. An example would be if there’s a strong hypothesis around a better CAR T that requires multiplex editing, or insertion of several different transgenes. We have a highly efficient way of doing this, and this could be a productive collaboration with a company that brings cancer biology expertise.

GEN Edge: What are the rate-limiting factors to getting Graphite Bio to these milestones?

Lehrer: The rate-limiting factor in demonstrating clinical data and clinical translation with these therapies is manufacturing—the CMC (chemistry, manufacturing, and controls). I’ve previously worked in small molecules and biologics; the difference here with gene editing is that there’s no target risk. If you can do what you’re trying to do, you can cure a patient because you’re changing a dysfunctional gene back to a functional one. You can also get to proof of concept in the lab or even animal models. A postdoc project can lead to a development candidate. So, that part is fast, and that’s exciting.

But where things can be slower, because the steps are not as efficient and the standards are still evolving, is going from that to the clinical material and then commercial supply. This requires strict controls and analytics. And this is a new field, so to some extent, the testing required by the FDA is a moving target. Regarding manufacturing, there’s a lot of experimentation, continued investigation, and learning that has to happen in tandem with your clinical experience. That isn’t true if you make an antibody or a small molecule.

Initially, we’re using a GMP facility built at Stanford, where we did our initial work to support our IND. But we also are prepared to move beyond the academic facility to one that can scale with us. One of the ways to prevent these bottlenecks is to move as early as possible to a manufacturing facility that can also supply us and scale all the way to a commercial product. We’ve decided that we aren’t going to build a $200-million plant for commercial supply ourselves. We have great partners that can start working with us now and then scale with us over time.

GEN Edge: Where does the company name originate?

Lehrer: It has a lot of meaning for us internally. One connection people make, which was part of the reason for the name, is that of a graphite pencil rewriting genes. There’s also the idea of graphite being made from carbon—the element of life.

But the company name comes from Rosalind Franklin’s story. Rosalind Franklin took the famous X-ray fraction photograph that Watson and Crick used to solve the structure of DNA. She didn’t get much credit and was largely written out of the history of this discovery. Rosalind Franklin was a woman in science who didn’t get her fair shake. The crystal structure she solved before working on DNA was the atomic structure of graphite. So, it’s a connection to the origin story of DNA and a reference to Rosalind Franklin’s contributions, which have historically been neglected—much like SCD and many of the patient communities that we serve.

The post Can Graphite Bio Realize the Promise of CRISPR Gene Editing to Develop One-time Cures? appeared first on GEN - Genetic Engineering and Biotechnology News.

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Climate-Change Lockdowns? Yup, They Are Actually Going There…

Climate-Change Lockdowns? Yup, They Are Actually Going There…

Authored by Michael Snyder via The End of The American Dream blog,

I suppose…



Climate-Change Lockdowns? Yup, They Are Actually Going There...

Authored by Michael Snyder via The End of The American Dream blog,

I suppose that we should have known that this was inevitable.  After establishing a precedent during the pandemic, now the elite apparently intend to impose lockdowns for other reasons as well.  What I have detailed in this article is extremely alarming, and I hope that you will share it with everyone that you can.  Climate change lockdowns are here, and if people don’t respond very strongly to this it is likely that we will soon see similar measures implemented all over the western world.  The elite have always promised to do “whatever it takes” to fight climate change, and now we are finding out that they weren’t kidding.

Over in the UK, residents of Oxfordshire will now need a special permit to go from one “zone” of the city to another.  But even if you have the permit, you will still only be allowed to go from one zone to another “a maximum of 100 days per year”

Oxfordshire County Council yesterday approved plans to lock residents into one of six zones to ‘save the planet’ from global warming. The latest stage in the ’15 minute city’ agenda is to place electronic gates on key roads in and out of the city, confining residents to their own neighbourhoods.

Under the new scheme if residents want to leave their zone they will need permission from the Council who gets to decide who is worthy of freedom and who isn’t. Under the new scheme residents will be allowed to leave their zone a maximum of 100 days per year, but in order to even gain this every resident will have to register their car details with the council who will then track their movements via smart cameras round the city.

Are residents of Oxfordshire actually going to put up with this?

[ZH: Paul Joseph Watson notes that the local authorities in Oxford tried to ‘fact check’ the article claiming they’re imposing de facto ‘climate lockdowns’, but ended basically admitting that’s exactly what they’re doing...]

I never thought that we would actually see this sort of a thing get implemented in the western world, but here we are.

Of course there are a few people that are loudly objecting to this new plan, but one Oxfordshire official is pledging that “the controversial plan would go ahead whether people liked it or not”.


Meanwhile, France has decided to completely ban certain short-haul flights in an attempt to reduce carbon emissions…

France can now make you train rather than plane.

The European Commission (EC) has given French officials the green light to ban select domestic flights if the route in question can be completed via train in under two and a half hours.

The plan was first proposed in 2021 as a means to reduce carbon emissions. It originally called for a ban on eight short-haul flights, but the EC has only agreed to nix three that have quick, easy rail alternatives with several direct connections each way every day.

This is nuts.

But if the French public accepts these new restrictions, similar bans will inevitably be coming to other EU nations.

In the Netherlands, the government is actually going to be buying and shutting down approximately 3,000 farms in order to “reduce its nitrogen pollution”

The Dutch government is planning to purchase and then close down up to 3,000 farms in an effort to comply with a European Union environmental mandate to slash emissions, according to reports.

Farmers in the Netherlands will be offered “well over” the worth of their farm in an effort to take up the offer voluntarily, The Telegraph reported. The country is attempting to reduce its nitrogen pollution and will make the purchases if not enough farmers accept buyouts.

“There is no better offer coming,” Christianne van der Wal, nitrogen minister, told the Dutch parliament on Friday.

This is literally suicidal.

We are in the beginning stages of an unprecedented global food crisis, and the Dutch government has decided that now is the time to shut down thousands of farms?

I don’t even have the words to describe how foolish this is.

Speaking of suicide, Canada has found a way to get people to stop emitting any carbon at all once their usefulness is over.  Assisted suicide has become quite popular among the Canadians, and the number of people choosing that option keeps setting new records year after year

Last year, more than 10,000 people in Canada – astonishingly that’s over three percent of all deaths there – ended their lives via euthanasia, an increase of a third on the previous year. And it’s likely to keep rising: next year, Canada is set to allow people to die exclusively for mental health reasons.

If you are feeling depressed, Canada has a solution for that.

And if you are physically disabled, Canada has a solution for that too

Only last week, a jaw-dropping story emerged of how, five years into an infuriating battle to obtain a stairlift for her home, Canadian army veteran and Paralympian Christine Gauthier was offered an extraordinary alternative.

A Canadian official told her in 2019 that if her life was so difficult and she so ‘desperate’, the government would help her to kill herself. ‘I have a letter saying that if you’re so desperate, madam, we can offer you MAiD, medical assistance in dying,’ the paraplegic ex-army corporal testified to Canadian MPs.

“Medical assistance in dying” sounds so clinical.

But ultimately it is the greatest lockdown of all.

Because once you stop breathing, you won’t be able to commit any more “climate sins”.

All over the western world, authoritarianism is growing at a pace that is absolutely breathtaking.

If they can severely restrict travel and shut down farms today, what sort of tyranny will we see in the future?

Sadly, most people in the general population still do not understand what is happening.

Hopefully they will wake up before it is too late.

*  *  *

It is finally here! Michael’s new book entitled “End Times” is now available in paperback and for the Kindle on Amazon.

Tyler Durden Fri, 12/09/2022 - 06:30

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How Noggin Boss Became the Next Big Thing in Sports Apparel

The Brian Robinson photo was just the latest moment in company history.
The post How Noggin Boss Became the Next Big Thing in Sports Apparel appeared first…



The story of Noggin Boss really begins three times.

Most recently, it began in late November, when a photo of Washington Commanders RB Brian Robinson wearing a giant hat lit the internet ablaze.

After that, Noggins started popping up everywhere.

Buffalo Bills QB Josh Allen was awarded one from Amazon Prime’s Thursday Night Football crew as the player of the game after Buffalo’s win over New England. Players from the Orlando Magic did a photo shoot wearing the hats. Players from the University of Georgia wore them after winning the SEC Championship.

ESPN’s Scott Van Pelt also notably sported one on SportsCenter, having gotten in on the action long ago when Noggin Boss co-founders Gabe Cooper and Sean Starner were just trying to spread the good word about their product.

“We have planted seeds for years, and we will do whatever it takes to try to find people that we feel would be good promoters of the brand,” Cooper told Front Office Sports. “We literally shipped those years ago to Scott Van Pelt and never heard anything back, but all of a sudden, it resurfaced.”

Those promoters all notably wore Noggins with logos that Noggin Boss is unlicensed to sell — but Cooper says that’s a fortunate piece of serendipity for the company.

Noggin Boss has never sold a hat with an unlicensed logo on it, doing everything “100% above board.”

“Fans will take liberties on their own,” Cooper says. “We are very interested in going down the paths of obtaining the proper [league] licensing ourselves, so we wouldn’t do anything to jeopardize that.”

A Hot Item

Of course, the sudden popularity of the brand means that everyone wants one.

After the Robinson photo, several outlets reported that Noggin Boss saw a 2,000% spike in sales. Cooper says that number was misrepresented — but the company has certainly seen a wild spike in orders, especially at this time of year.

“We’re just thankful for the grace that our fans are extending to us during the holiday season, which is crazy enough,” Cooper says.

Brian Robinson Photo Leads to 2,000% Spike for Big Hat Company

Monday was one of the biggest sales days in Noggin Boss history.
November 30, 2022

Noggin Boss was ready for this moment. That’s because its second pivotal moment happened in the studios of the extremely popular television series “Shark Tank.”

Cooper and Starner appeared on the show earlier this year, very quickly striking a deal with apparel magnate Daymond John.

But that wasn’t all: Dallas Mavericks owner Mark Cuban verbally agreed to sell Mavs Noggin Bosses in the team’s store. Cuban held up his end of the deal — and even delayed the Dallas Stars from selling Noggins because he wanted an exclusive selling period for his Mavericks.

The Noggin Boss founders purposely came into the Tank with a very low company valuation — realizing that what John and Cuban could offer them was much more valuable than money.

“These professionals have more connections than we could possibly ask for,” says Cooper, “so why would we disrespect them with an offer that we wouldn’t even give to a friend if we were trying to invite them into the business?”

Those connections are already paying dividends: Besides the Dallas teams, Noggin Boss has sold hats — through approved buyers — to the Arizona Cardinals, New Jersey Devils, New York Islanders, and San Jose Sharks.

Cooper also says that the company will have a strong presence during college football bowl season — and that it is finalizing licensing for a much more expansive offering.

How It All Started

But for all of its high-profile moments in the last few months, Noggin Boss’ story really began in early 2020 at the notorious Waste Management Phoenix Open. The raucous atmosphere of the golf tournament provided the perfect proving ground for the product.

“[It] was just such a huge hit, and that was the validation of like, ‘Okay, this is the good kickoff that we needed,’” Cooper says.

That success began to roll over into MLB Spring Training in Arizona — but then, of course, the world shut down because of COVID-19.

But that didn’t dampen Cooper or Starner’s spirit in the slightest. The pair knew they had something here — and they believe it could last in the long term.

Outside of the sports world, Noggin Boss has had a strong presence at bachelor and bachelorette parties, college campuses, and charity events — where Cooper says the hats get auctioned off for over $1,000.

He says the product’s universal appeal will keep it relevant for years to come.

“It just brings so much joy to people,” says Cooper. “We call it the Noggin Boss effect: When they wear it, they have so many smiles and so many conversations with complete strangers. It’s better than any medicine out there.”

The post How Noggin Boss Became the Next Big Thing in Sports Apparel appeared first on Front Office Sports.

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First-ever social responsibility report of Chinese enterprises in Saudi Arabia incorporates BGI Genomics projects

On December 1, 2022, the Social Responsibility Report of Chinese Companies in Saudi Arabia was officially launched, which is the first such report released…



On December 1, 2022, the Social Responsibility Report of Chinese Companies in Saudi Arabia was officially launched, which is the first such report released by the Contact Office of Chinese Companies in Saudi Arabia. BGI Genomics projects in the Kingdom have been incorporated into this report.

Credit: BGI Genomics

On December 1, 2022, the Social Responsibility Report of Chinese Companies in Saudi Arabia was officially launched, which is the first such report released by the Contact Office of Chinese Companies in Saudi Arabia. BGI Genomics projects in the Kingdom have been incorporated into this report.

This event was attended by around 150 representatives of Chinese and Saudi enterprises, Saudi government officials, experts in the field of sustainable development, CCTV, Xinhua News Agency, Saudi Press Agency, Arab News and other media professionals. This Report presents the key projects and best practices of Chinese enterprises to fulfil their social and environmental responsibilities while advancing the Kingdom’s industry development.

Chen Weiqing, the Chinese ambassador to Saudi Arabia, said in his video speech that the Report highlighted Chinese enterprises’ best practices in serving the local community, safe production, green and low-carbon development and promoting local employment. The release of the Report helps Chinese enterprises in the Kingdom to strengthen communication with the local community, laying a stronger foundation for future collaboration.

Epidemic control and accelerating post-COVID 19 recovery

BGI Genomics has been fulfilling its corporate social responsibilities and worked with the Saudi people to fight the COVID-19 epidemic.

In March 2020, Saudi Arabia was hit by the pandemic. The Saudi government decided to adopt BGI Genomics’ Huo-Yan laboratory solution in April 2020. At the forefront of the fight against the epidemic, the company has built six laboratories in Riyadh, Makkah, Madinah, Dammam and Asir within two months, with a total area of nearly 5,000 square meters and a maximum daily testing throughput of 50,000 samples.

By the end of December 2021, BGI Genomics had sent 14 groups of experts, engineers and laboratory technicians to Saudi Arabia, amounting to over 700 people, and tested more than 16 million virus samples, accounting for more than half of the tests conducted during this period. The company has successfully trained over 400 qualified Saudi technicians, and all laboratories have been transferred to local authorities for the operation.

In the post-epidemic era, the Huo-Yan laboratories can continue to make positive contributions to public health, working with local medical institutions and the public health system to make breakthroughs in areas such as reproductive health, tumour prevention and control, and prevention.

Enhancing genomic technology localization and testing capabilities

In July 2022, BGI Almanahil and Tibbiyah Holdings, a wholly owned subsidiary of the Saudi Faisaliah Group, announced a joint venture (JV) to establish an integrated, trans-omics medical testing company specializing in genetic testing.

This JV company will help improve Saudi Arabia’s local clinical and public health testing and manufacturing capabilities, promote the localization of strategic products that have long been imported, contribute to the implementation and realization of the Kingdom’s Vision 2030 roadmap, and significantly enhance local capacity for third-party medical testing services as well as local production of critical medical supplies.

BGI Genomics attaches great importance to fulfilling its corporate social responsibility and has released its social responsibility report for four consecutive years since 2017. Since its establishment, the company has always been guided by the goal of enhancing health outcomes for all, relying on its autonomous multi-omics platform to accelerate technological innovation, promote reproductive health, strengthen tumour prevention and control, and accurately cure infections, and is committed to becoming a global leader in precision medicine and covering the entire public health industry chain.

The company will continue to work together with all stakeholders to contribute to the Kingdom’s Vision 2030 and the Belt and Road Initiative and looks forward to growing with our partners.


About BGI Genomics

BGI Genomics, headquartered in Shenzhen China, is the world’s leading integrated solutions provider of precision medicine. Our services cover over 100 countries and regions, involving more than 2,300 medical institutions. In July 2017, as a subsidiary of BGI Group, BGI Genomics (300676.SZ) was officially listed on the Shenzhen Stock Exchange.


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