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Where Does Alkermes Plc (ALKS) Stock Fall in the Biotechnology Field After It Is Higher By 0.58% This Week? – InvestorsObserver

Posted: May 25, 2021 at 1:54 am

Alkermes Plc (ALKS) is around the middle of the Biotechnology industry according to InvestorsObserver. ALKS received an overall rating of 40, which means that it scores higher than 40 percent of all stocks. Alkermes Plc also achieved a score of 63 in the Biotechnology industry, putting it above 63 percent of Biotechnology stocks. Biotechnology is ranked 113 out of the 148 industries.

Searching for the best stocks to invest in can be difficult. There are thousands of options and it can be confusing on what actually constitutes a great value. Investors Observer allows you to choose from eight unique metrics to view the top industries and the best performing stocks in that industry. A score of 40 would rank higher than 40 percent of all stocks.

These rankings allows you to easily compare stocks and view what the strengths and weaknesses are of a given company. This lets you find the stocks with the best short and long term growth prospects in a matter of seconds. The combined score incorporates technical and fundamental analysis in order to give a comprehensive overview of a stocks performance. Investors who then want to focus on analysts rankings or valuations are able to see the separate scores for each section.

Alkermes Plc (ALKS) stock is higher by 2.12% while the S&P 500 has fallen -0.05% as of 1:17 PM on Friday, May 21. ALKS is higher by $0.47 from the previous closing price of $21.92 on volume of 5,608,985 shares. Over the past year the S&P 500 is higher by 40.98% while ALKS is higher by 35.04%. ALKS lost -$0.59 per share the over the last 12 months.

Click Here to get the full Stock Score Report on Alkermes Plc (ALKS) Stock.

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Where Does Alkermes Plc (ALKS) Stock Fall in the Biotechnology Field After It Is Higher By 0.58% This Week? - InvestorsObserver

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Is Onconova Therapeutics Inc (ONTX) a Bad Choice in Biotechnology Thursday? – InvestorsObserver

Posted: May 25, 2021 at 1:54 am

Onconova Therapeutics Inc (ONTX) is near the top in its industry group according to InvestorsObserver. ONTX gets an overall rating of 73. That means it scores higher than 73 percent of stocks. Onconova Therapeutics Inc gets a 98 rank in the Biotechnology industry. Biotechnology is number 110 out of 148 industries.

Analyzing stocks can be hard. There are tons of numbers and ratios, and it can be hard to remember what they all mean and what counts as good for a given value. InvestorsObserver ranks stocks on eight different metrics. We percentile rank most of our scores to make it easy for investors to understand. A score of 73 means the stock is more attractive than 73 percent of stocks.

These scores are not only easy to understand, but it is easy to compare stocks to each other. You can find the best stock in an industry, or look for the sector that has the highest average score. The overall score is a combination of technical and fundamental factors that serves as a good starting point when analyzing a stock. Traders and investors with different goals may have different goals and will want to consider other factors than just the headline number before making any investment decisions.

Onconova Therapeutics Inc (ONTX) stock has fallen -11.01% while the S&P 500 has gained 1.05% as of 1:08 PM on Thursday, May 20. ONTX has fallen -$0.10 from the previous closing price of $0.93 on volume of 59,500,813 shares. Over the past year the S&P 500 has gained 39.95% while ONTX has gained 115.79%. ONTX lost -$0.14 per share the over the last 12 months.

Click Here to get the full Stock Score Report on Onconova Therapeutics Inc (ONTX) Stock.

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Should Biotechnology Stock Intra-Cellular Therapies Inc (ITCI) Be in Your Portfolio Thursday? – InvestorsObserver

Posted: May 25, 2021 at 1:54 am

A rating of 87 puts Intra-Cellular Therapies Inc (ITCI) near the top of the Biotechnology industry according to InvestorsObserver. Intra-Cellular Therapies Inc's score of 87 means it scores higher than 87% of stocks in the industry. Intra-Cellular Therapies Inc also received an overall rating of 52, putting it above 52% of all stocks. Biotechnology is ranked 110 out of the 148 industries.

Finding the best stocks can be tricky. It isnt easy to compare companies across industries. Even companies that have relatively similar businesses can be tricky to compare sometimes. InvestorsObservers tools allow a top-down approach that lets you pick a metric, find the top sector and industry and then find the top stocks in that sector.

This ranking system incorporates numerous factors used by analysts to compare stocks in greater detail. This allows you to find the best stocks available in any industry with relative ease. These percentile-ranked scores using both fundamental and technical analysis give investors an easy way to view the attractiveness of specific stocks. Stocks with the highest scores have the best evaluations by analysts working on Wall Street.

Intra-Cellular Therapies Inc (ITCI) stock is trading at $39.13 as of 2:16 PM on Thursday, May 20, an increase of $1.05, or 2.76% from the previous closing price of $38.08. The stock has traded between $37.89 and $39.50 so far today. Volume today is less active than usual. So far 352,890 shares have traded compared to average volume of 507,343 shares.

Click Here to get the full Stock Score Report on Intra-Cellular Therapies Inc (ITCI) Stock.

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International Biotechnology Trust : Innovation is the key not the culprit IP waiving is counterproductive – Marketscreener.com

Posted: May 25, 2021 at 1:54 am

You may have heard of the Biden Administration's recent proposal to waive the patents for Covid-19 vaccines in order to speed up production and global distribution. In this blog we wanted to discuss why we think this is a mistake and why patent protection is fundamental to the solution and to innovation.

Covid-19 should probably be seen as an extraordinary event and therefore making decisions based purely on the circumstances of COVID-19 that could have ramifications for the whole pharmaceutical and biotechnology sector going forward can have potential adverse consequences.

Viruses do not respect borders, or wealth, and it is tragic that less developed nations sadly do not get access to the best medical advances in the way the more developed world does. One approach to even out this imbalance is to sell a drug or vaccine on a 'not for profit' basis. This is where the pharmaceutical company manufactures the product and charges less wealthy nations only for the cost of production. This is not a new phenomenon; we have seen this happen previously with HIV and Hepatitis C (HCV) drugs. This not only allows global access to vital medicines but also maintains the motivation at a company level to keep innovating, as profits can still be made in countries which can afford to pay the normal price for their products. We should also remind investors of the honourable decision that AstraZeneca took to sell its Covid-19 vaccine on a 'not for profit' basis even to wealthy countries, which is a decision that should be commended for a company whose goal is to generate profits for shareholders. Sadly, the negative press that AstraZeneca has endured since then may have reduced its appetite (and that of its competitors) for this kind of arrangement in the future.

The need for patent protection

Effective and sustained patent protection is an essential element of the pharmaceutical industry's ability to recoup development and production costs from the revenues generated from marketed products. The cost of successfully bringing a new drug to market has steadily increased and protecting the drug's exclusivity, via patents and other methods, generates revenues in the absence of competition for a fixed period of time. After a fixed period, the drug is then generically available at a fraction of the price to society in perpetuity. These companies also invest a significant portion of those profits back into R&D as they are motivated to find a new innovative product to offset the loss of the old now genericised drug. This model is tried and tested globally and underpins the whole sector. It is particularly important as without it, why would companies spend time and money looking for cures to meet unmet medical need, especially for conditions where patient numbers are relatively few?

Patent basics

Patents have a long history, with the English Crown granting patents in the mid-15th century. A patent in the biotech sector is the granting of exclusive rights, a monopoly, by the state for a fixed period of time in exchange for the public disclosure of certain details of an invention at the end of the patent life. The invention may be a device, method of development or production, process or composition of matter, which is new, inventive and useful or industrially applicable. The term of a therapeutic patent is usually 20 years from the filing date, with a potential extension in specific circumstances of 5 years, and this is the case in Europe, the US and Japan. Bearing in mind that it can be 10 to 15 years from filing to the date it is approved for sale, the period during which the company can recoup the developmental costs is limited and, often less than 10 years.

For a patent to be granted, it must demonstrate novelty, utility, and be non-obvious to a skilled person in the trade. For patents relating to therapeutics, the utility is quite easy to demonstrate, while novelty and non-obviousness may be less clear. Any disclosure of the invention prior to filing a patent application may have detrimental future value as the novelty claim is then compromised. This is not uncommon when scientists, eager to publish novel findings, undermine the value of their own inventions.

What does pharma and biotech patent

When dealing with therapeutics, we tend to have major classes of patentable inventions that

relate to pharmaceuticals, although many patents encompass claims that cover most or

all of these to varying degree.

Composition of matter: Product patents form the mainstay of protection for pharmaceutical companies since they claim a novel chemical entity (NCE) or novel biological entity (NBE) and are considered to hold the best protection as they protect the 'core' invention. Patents for a novel chemical/biological entity are generally filed early in the R&D process so usually also have the shortest patent time and expire before other patents in the family of patents that are developed around a significant product.

Formulation: Formulation patents tend to be filed later in the development cycle, or even when the

drug is marketed and provide coverage of innovative delivery forms for purposes of targeted delivery, extended release and other features that improves the characteristics of the original product. At the same time these patents prohibit any generic company from using the same technology making outright generic substitution more difficult. Even if other patents eg composition of matter, have already expired

Process: these patents describe novel methods of producing therapeutic substances and/or formulations. Previously this category was considered of lower value and relatively easy to circumvent. With the recent development of cell therapies that deal with complexities and heterogenicity when growing, modifying and expanding human cells, process patents have become essential.

Use: these protect the use of a drug for treating a given condition or conditions. They may relate to either the original and established use of a drug or to novel (and unanticipated) uses. In many cases 'old' compounds are no longer under patent because of the time lapsed or due to a successful novelty claim deeming the compounds unpatentable. However, if one finds an unanticipated use for the product, a use patent can be granted and may be as solid as a composition of matter in their specific therapeutic use.

Regulatory protection

In some instances when patents are impossible to enforce or relate to a compound that is very old or widely known, the regulatory agencies have introduced incentives for pharmaceutical developers not to discard promising and potential future drugs, just because patents no longer are applicable.

In US, there is a general five year automatic data protection for any drug approved that applies without any patents whatsoever. Once that is lifted, potential generics may start to copy, a process that tends to take 1-3 years, which in reality provides the originator a seven year market protection. Europe has an even better regulatory protection, offering an eight year data protection, an additional two years market entry hiatus which could be extended by another year (8+2+1) if the product expands its use in additional diseases.

Orphan protection

For rare/orphan diseases, the regulatory agencies have added additional incentives for companies to be able to recoup costs incurred when developing drugs for these conditions, as they recognise that the lower number of patients may otherwise deter companies from investing in innovation in these areas. Below is a description of the terms applied:

Table 1: Legislation in major markets offering commercial incentives for orphan drug development

United States

Europe

Japan

Legislation date

1983

2000

1993

Maximum prevalence criteria

7.5/10,000 people

5/10,000 people

4/10,000 people

Market exclusivity

7 years

10 years

10 years

Fee waiver

Yes

At least partial

No

Source: Frost & Sullivan

We at IBT are always scrutinizing a potential investment prospects IP protection as the basis of our investment decision. Lack of effective IP protection may render a company uninvestable, in our view, and this is core to our thesis. We are seeing new variants of Covid-19 appearing which is a worrying yet predictable result of a pandemic. Removing patent protection may deter the vaccine companies from continuing their work in finding future new vaccines to fight the moving target that is Covid-19. Angela Merkel's comments following the Biden announcement said that such a move would have 'severe complications' for the sector. Although IBT does not currently invest in vaccine companies, we also view this proposal as a deeply concerning for the remainder of the biotech sector.

Disclaimer

International Biotechnology Trust plc published this content on 21 May 2021 and is solely responsible for the information contained therein. Distributed by Public, unedited and unaltered, on 21 May 2021 06:16:02 UTC.

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2-Chlorocinnamic Acid Market to Witness Robust Expansion by 2027 | EMMX Biotechnology LLC, Matrix Scientific, Alfa Aesar Brockville Observer -…

Posted: May 25, 2021 at 1:54 am

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2-Chlorocinnamic Acid Market is growing at a High CAGR during the forecast period 2021-2027. The increasing interest of the individuals in this industry is that the major reason for the expansion of this market.

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Global 2-Chlorocinnamic Acid Market Research Report 2021

Chapter 1 2-Chlorocinnamic Acid Market Overview

Chapter 2 Global Economic Impact on Industry

Chapter 3 Global Market Competition by Manufacturers

Chapter 4 Global Production, Revenue (Value) by Region

Chapter 5 Global Supply (Production), Consumption, Export, Import by Regions

Chapter 6 Global Production, Revenue (Value), Price Trend by Type

Chapter 7 Global Market Analysis by Application

Chapter 8 Manufacturing Cost Analysis

Chapter 9 Industrial Chain, Sourcing Strategy and Downstream Buyers

Chapter 10 Marketing Strategy Analysis, Distributors/Traders

Chapter 11 Market Effect Factors Analysis

Chapter 12 Global 2-Chlorocinnamic Acid Market Forecast

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Biotechnology Based Chemical Market Advancements, Rising Trends and Growth Forecast 2020 to 2025 The Courier – The Courier

Posted: May 25, 2021 at 1:54 am

Biotechnology Based Chemical Market report is a sorted analysis of the local and global market that wills details information and data about the market in its current context. This report has been put together by The Research Insights to enable businesses optimize on their ROI (Return on investment).

This report Biotechnology Based Chemical Market has look into critical parameters that drives a business like the market in totality, the economy related factors like policies, revenue generation scope for a market segment, resourcing costs and many more.

the globalbio-based chemicals market was valued at $xx billion in 2020. Moreover, it is expected to reach $32.04 billion by 2025, growing with a CAGR of 15.01% during the forecast period.

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The report presents the market competitive landscape and corresponding detailed analysis of the major vendor/key players in the market.

Top Companies:- in the Global Biotechnology Based Chemical Market: Queensland?s world-class agriculture industry, Sarnia-Lambton Research, UK and Norway business funding agencies, Technology Strategy Board (TSB), Innovation Norway, other.

Global Biotechnology Based Chemical Market Split by Product Type and Applications

This report segments the Biotechnology Based Chemical Market on the basis of Types are:-

by Types

Bio-pharma

Agri-biotech

Bio-informatics and

Bio-services

Others

On the basis of Application, the Biotechnology Based Chemical Market segmented into:-

Food and beverages

Agriculture

Fuel

Energy

Animal feed

Pharmaceuticals and nutrition

Paper and pulp

Cosmetics and toiletries

Plastics and fibres

Others

Regional outlook: The regions covered in the reports of the Biotechnology Based Chemical Market are

North America (U.S., Canada, Mexico)

Europe (Germany, U.K., France, Italy, Russia, Spain etc.)

Asia-Pacific (China, India, Japan, Southeast Asia etc.)

South America (Brazil, Argentina etc.)

Middle East & Africa (Saudi Arabia, South Africa etc.)

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Biotechnology Based Chemical Market is a data intensive report that includes analysis by experts to help in drawing conclusions. It will also be an aid in formulating strategies for an existing or a new business. One of the most read topics that will interest the readers is the information and the analysis of the competitive market.

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Biotechnology Based Chemical Market Advancements, Rising Trends and Growth Forecast 2020 to 2025 The Courier - The Courier

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Is Akero Therapeutics Inc (AKRO) a Smart Choice in Biotechnology Friday? – InvestorsObserver

Posted: May 25, 2021 at 1:54 am

Akero Therapeutics Inc (AKRO) is near the top in its industry group according to InvestorsObserver. AKRO gets an overall rating of 48. That means it scores higher than 48 percent of stocks. Akero Therapeutics Inc gets a 81 rank in the Biotechnology industry. Biotechnology is number 113 out of 148 industries.

Analyzing stocks can be hard. There are tons of numbers and ratios, and it can be hard to remember what they all mean and what counts as good for a given value. InvestorsObserver ranks stocks on eight different metrics. We percentile rank most of our scores to make it easy for investors to understand. A score of 48 means the stock is more attractive than 48 percent of stocks.

These scores are not only easy to understand, but it is easy to compare stocks to each other. You can find the best stock in an industry, or look for the sector that has the highest average score. The overall score is a combination of technical and fundamental factors that serves as a good starting point when analyzing a stock. Traders and investors with different goals may have different goals and will want to consider other factors than just the headline number before making any investment decisions.

Akero Therapeutics Inc (AKRO) stock is lower by -4.29% while the S&P 500 has gained 0.34% as of 10:43 AM on Friday, May 21. AKRO has fallen -$1.21 from the previous closing price of $28.23 on volume of 48,271 shares. Over the past year the S&P 500 is higher by 41.53% while AKRO has gained 15.32%. AKRO lost -$2.49 per share the over the last 12 months.

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The biorevolution is kicking off. Here’s how to harness its opportunities early on – World Economic Forum

Posted: May 25, 2021 at 1:53 am

Seven of the last ten Nobel Prizes in Chemistry have been awarded to advances in biochemistry: the study of chemical processes within and relating to living organisms.

Our understanding of genomics, molecular motors and the editing of genes, together with advances in nanotechnology and AI are at an all-time high. Add to this the rapidly falling costs of the same technology and you have a potent combination.

This combination is about to be both transformative and highly disruptive across many parts of our lives. Just like the ascent of organic chemistry at the turn of the 19th century, our increased focused on proteins is now creating the biorevolution.

We felt just how much the biorevolution has advanced during the pandemic; first, through the speed with which we understood how the virus was disrupting our societies, and then through witnessing vaccine development at unprecedented degrees of speed and efficacy.

Our hope of defeating COVID-19 would have been drastically reduced without the existence of major advances in biological sciences.

Across the globe, millions of people have now benefited from research and vaccination campaigns, allowing us to make important steps in overcoming this terrible pandemic. Undoubtedly, we owe this to scientists to a substantial degree. They have used mRNA vaccines also called gene vaccines to help cells form a spike protein similar to the one that exists on the surface of COVID-19 pathogens.

The technology available has led scientists to be able to create safe and effective vaccines that will eventually allow us to resume our normal lives or at least some new rendition of it.

Bluntly put, our hope of defeating COVID-19 would have been drastically reduced without the existence of these advances in biological sciences. The development of COVID-19 vaccines is an example of biological transformation that has greatly impacted the world and our lives, but mRNA vaccines and gene sequencing are only the tip of the iceberg for the biorevolution.

Beyond being COVID-19's rescue parachute

The biorevolution has the potential to help address some of the most urgent global challenges, from climate change to pandemics, chronic diseases and food security for our growing world population.

Biology, life sciences and digitisation are moving ever closer together, enabling new inventions that significantly impact our daily lives. The list goes on as rapid increases in computing power and the emergence of new capabilities in AI, automation and data analytics are further accelerating the pace of innovation and the promise of higher R&D productivity in the life sciences.

Using the biorevolution to build a better world

I do not think it is an overstatement to sat that, with the right intentions and significant levels of investment, the biorevolution could be this generations vehicle towards a better world.

The biorevolution could address around 45% of global diseases using science and technology that already exists.

Biological scientists have been driving revolutionary scientific breakthroughs and advancements for years. McKinsey Global Institute (MGI) estimates that 60% of physical inputs, including food, energy and even the materials for clothes, could be produced through biotechnology. Its estimates also show that biology-based innovations will generate $4 trillion in economic impact over the next few decades.

This is not a concept for some far-away future; similar to the mRNA technology that helped identify and sequence COVID-19, the biorevolution could address around 45% of global diseases using science and technology that already exists. At the convergence of science and technology, advances in biotechnology are already bringing about progress in clinical trials of vaccines, inspiring a search for gene and microbiome therapies and giving scientists invaluable insights into how viruses work.

Bayer aims to play a central role in the biorevolution by harnessing the power of these innovations.

Our investment arm, Leaps by Bayer, collaborates with and invests in companies pioneering gene editing and advancing therapies to cure cancer and genetic diseases. Recently, we announced promising initial results achieved by BlueRock Therapeutics, a Bayer subsidiary that began clinical trials with a new therapeutic approach for Parkinsons disease. The trials will hopefully pave the way for major advances in the battle against this debilitating illness.

Disease treatment and prevention are not only important for human life, but for plant life as well.

In agriculture, biological tools and gene-editing technologies stemming from CRISPR ("clustered regularly interspaced short palindromic repeats" a family of DNA sequences) can make crops more weather- or disease-resistant. This helps farmers to grow more food and to persevere through harsh or changing conditions.

Moreover, biotechnology can help farmers produce a more sustainable food supply and significantly reduce agricultures global environmental footprint. At Bayer, our investments in biotechnology for its application in the agricultural sector are broad and driven by our firm belief in its potential.

They include the use of gene technology to contribute to increased yields and the reduction of the amount of land needed for agriculture thanks to developments in seeds.

Through Leaps, we are working with other companies like Joyn Bio that are using agricultural biotechnology to reduce the environmental impact of synthetic nitrogen. This could be big: ammonium-based fertilisers today are not only the highest input cost for farmers but also a significant contributor to greenhouse gas emissions.

A successful biorevolution requires collaboration

We are convinced that the biorevolution has the potential to advance industries, disrupt supply chains as we know them, and create opportunities for business and innovation. But like with many innovations that hold great potential, challenges do exist.

These challenges are further complicated by the fact that the biorevolution is starting to gain momentum in times in which the world is diverging. Global partnerships in addressing the pressing ethical and regulatory challenges will be key to unleashing the potential of an age focussed not on bytes but on proteins.

This is true for the relationship between the East and the West but also for the way in which the European Union opens up to leverage the possibilities for health and farms alike.

Increasing understanding of the bioevolution

Companies, innovators and scientists alike must be transparent about both advancements in and uses of biotechnology. What's more, in order to promote innovation and to ensure the safety of biotechnology globally, we urgently need regulation that not only allows for, but facilitates, the fast pace of scientific progress.

We are still a long way away from fully realising the potential of the bioevolution. A major game changer would be global collaboration and coordination between regulators, the private sector, governments, associations and institutions, in order to embrace the benefits, but also manage the risks.

Can you imagine a world without hunger, in which humans could live longer lives with fewer diseases, and farmers could produce more food with fewer resources? We are convinced that the bioevolution holds the promise to get us closer to it.

The views expressed in this article are those of the author alone and not the World Economic Forum.

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Is Vistagen Therapeutics Inc (VTGN) a Winner in the Biotechnology Industry? – InvestorsObserver

Posted: May 25, 2021 at 1:53 am

Vistagen Therapeutics Inc (VTGN) is the highest overall rated company in the Biotechnology industry with an overall score of 91. VTGN is up 448.94% so far this year after the company closed yesterday at $2.58. The overall score measures the company's performance based-off both short and long term indicators and means that VTGN scores better than 91% of the overall market.

Vistagen Therapeutics Inc is a strong performer in the Biotechnology industry, which has an average overall score of 36. This means that, on average, the stocks in this industry score higher than 36% of the stock market.

To see InvestorsObserver's Sentiment Score for Vistagen Therapeutics Inc click here.

VTGN has been trading neutral recently. The stock is trading up 21.13% this week following yesterday's decline. VTGN has an average analyst ranking of Strong Buy with an average price target of $5.5.

Click Here to get the full Stock Score Report on Vistagen Therapeutics Inc (VTGN) Stock.

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Newly Discovered Glycosylated RNA Is All Over Cells: Study – The Scientist

Posted: May 25, 2021 at 1:52 am

The emergence of nucleic acids and that of proteins have sometimes been called the first and second evolution revolutions, as they made life as we know it possible. Some experts argue that glycosylationthe addition of glycans to other biopolymersshould be considered the third, because it allowed cells to build countless molecular forms from the same DNA blueprints. Its long been believed that only proteins and lipids receive these carbohydrate constructs, but a May 17 paper in Cellthat builds upon a 2019 bioRxiv preprint posits that RNAs can be glycosylated, too, and these sugar-coated nucleic acids seem to localize to cell membranes.

Anna-Marie Fairhurst, who studies autoimmunity at the Agency for Science, Technology and Research in Singapore, describes the study as exciting. Obviously, its the first time ever that weve seen this with RNA, she says, adding that the diversity of methods used to demonstrate the presence of glycoRNAs makes the findings especially robust.

What really intrigues her are the parts present in the 2021 Cellpaper that arent in the 2019 preprintin particular, that glycoRNAs appear to predominantly end up on the cells outer membrane. There, they can attach to two kinds of sialic acid-binding immunoglobulin-type lectins (Siglecs)a family of immune receptors implicated in several diseases, including systemic lupus erythematosus (SLE). All of this suggests glycoRNAs may play a role in immune signaling. Its a really exciting era of science, Fairhurst says.

Ryan Flynn, the first author on the new paper and an RNA biologist at Harvard University and Boston Childrens Hospital, says he made the startling discovery of glycoRNAs while working in chemical biologist Carolyn Bertozzis lab at Stanford University. Bertozzi says she was skeptical at first but came around after thinking about how her own assumptions might be shaping her views. We bring to every experiment all this unconscious bias, she explains, and once she re-examined her own, she found no reason to think glycoRNAs shouldnt exist. These are ancient molecules, she says. Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

These are ancient molecules . . . Theres no reason to just presume that they wouldnt have found a way to connect and to create new biology.

Carolyn Bertozzi, Stanford University

As it happens, Flynn did set out to overturn glycosylation dogma when he joined Bertozzis lab as a postdoc in 2017although it didnt happen the way he expected. At first, he explains, he had his eye on a quirky cytosolic protein glycosylation pathway because hed noticed that one of its key enzymes has an RNA-binding domain. If theres a glycosylation enzyme with the potential to bind RNA, and its functioning in the cytosol where RNAs tend to be, he reasoned, it could be sticking sugars to RNAs, too.

To search for the existence of these structures, it was really important that I had access to things that were not dependent on high temperatures, and not dependent on metals that might otherwise degrade the RNA, he says, and thats exactly what Bertozzis lab had to offer. Shes a pioneer in the field of bioorthogonal chemistry, which aims to develop chemical methods for tracking biomolecules in their native environments. Her lab was brimming with reagents that label specific kinds of glycans without harming other molecules or setting off side-reactions.

Flynn set to work adding these glycan-labeling compounds to HeLa cells and then isolating RNA from them to see if any glycan signal remained after hed removed all proteins and lipids. He says he thought he might see a signal when he labeled the kind of glycans used in that cytosolic glycosylation pathway.

However, months of experiments failed to support that hypothesis.

Instead, something strange kept happening with what was supposed to be a negative control: cells treated with ManNAz, an azide-labeled precursor for sialoglycans, a group of glycans known for their role as modifiers of secretory and cell surface proteins and lipids. Once the cells were given the chance to incorporate ManNAz, they were lysed with TRIzol, which breaks apart cellular components without damaging RNAs, and any surviving proteins were chopped up with proteases. The idea was that thered be no azide signal at the end, as sialoglycans are attached to proteins and lipids in the endoplasmic reticulum and Golgi, where RNAs have no business being. I was like, theres no way that a reagent that labels sialoglycans is going to end up labeling an RNA, even a glycoRNA, Bertozzi says, but those experiments consistently gave Flynn positive signals.

So, the team dug further. Not only did the glycoRNAs the team found contain this specific subgroup of glycans, they appeared to largely consist of YRNAs, a family of small, highly conserved noncoding RNAs whose cellular functions remain unclear, although previous studies have suggested they may play a role in oncogenesis and autoimmunity. The specificity of both the glycans and the type of RNAs involved strongly point to their being attached to one another with an enzyme, says Bertozzi.

Furthermore, once the researchers started looking for them, they found these glycoRNAs in numerous established cell lines, including cancer-derived ones such as HeLa and T-ALL 4118 cells, as well as stem cellderived CHO and H9 cells. They were even able to detect glycoRNAs in liver and spleen cells extracted from live mice that received intraperitoneal injections of ManNAz, suggesting that glycoRNAs are everywhere.

By 2019, the team members felt they had enough supportive data to submit their findings, so they put the preprint version up on bioRxiv. It made a splash in the scientific community, but without peer review, some remained skeptical. Now, after even more experiments and a rigorous review process, the team says its data have become even more compelling.

They clearly have isolated a covalent RNA-glycan conjugate, says Laura Kiessling, a chemical biology researcher who studies carbohydrates at MIT and was not involved in the study. However, big questions remain, including what these glycoRNAs do and how they form. For instance, its unclear exactly how the RNAs and glycans are physically connected to one another, she notes, and without that information, shes not quite convinced that the binding happens enzymatically.

Flynn and Bertozzi suggest that the RNAs are glycosylated much in the same way proteins are, and that it even requires some of the same proteins. As noted in the original preprint, when they inhibited key enzymes involved in glycosylation, glycoRNAs disappeared in a dose-dependent manner. Similarly, cell lines engineered to have errors in protein glycosylation produced very little glycoRNA. But for RNAs to be glycosylated by the same pathway as proteins would be weird, Kiessling says, noting that multiple glycosylation steps only proceed after a check for proper protein folding. Its hard for me to imagine exactly how that would occur with RNA.

The researchers were even able to detect glycoRNAs in liver and spleen cells extracted from live mice, suggesting that glycoRNAs are everywhere.

Fairhurst says she also wants to know more about the synthesis pathway. She has lots of other questions, too, which she says is a good sign. A really good, exciting paper leaves a lot more questions than it does answers, she notes.

While the 2019 preprint raised many of these questions, some are unique to the new data presented in the Cell version. Perhaps the biggest addition to the work was the discovery of where these glycoRNAs spend their timestuck on the outsides of cells, explains Flynn. The team demonstrated this by briefly exposing some ManNAz-labeled HeLa cells toan enzyme that can cleave sialic acid glycans from the cell surface. If the glycoRNAs were on the outside, they would be cut off, and the total amount of glycoRNAs remaining would drop. And thats exactly what they found: the glycoRNA signal started to decrease after as little as 20 minutes of incubation with the sialidase and was reduced by more than 50 percent after an hour, which the team suggests means that more than half of a cells glycoRNAs are stuck on its outer membrane.

The researchers further probed the hypothesis of extracellular localization by labeling living cells with an antibody that binds to double-stranded RNA. About one-fifth of a culture of HeLa cells were positive for antibody staining, and the label was sensitive to RNase treatment, further supporting the idea that glycoRNAs are indeed present on the outer cell membrane. That opens up a lot of ideas, and a lot of possibilities, functionally and mechanistically, for what they could be doing, says Flynn.

One of those possibilities is that glycoRNAs are involved in cell-to-cell signaling, especially in an immune context, as thats a known function of membrane glycolipids and glycoproteins. Bertozzi had already been investigating the ligands of Siglecs, a group of sugar-binding receptors that modulate immune reactions, so the team decided to see if any of them bound to glycoRNAs. They first treated HeLa cells with different Siglecs to show that the receptors bound normally, then treated the cells with RNase. Lo and behold, the binding of Siglec-11 and Siglec-14 dropped precipitously, suggesting that their ligands were cleaved from the surface by the RNA-cutting enzyme.

Bertozzi says the experiment indicated glycoRNAs are ligands for Siglec-11 and Siglec-14, and if so, theyd be the first identified for Siglec-11.

As a receptor family, [Siglecs have] kind of been ignored, notes Fairhurst, so the fact that these glycoRNAs can interact with them is very exciting, she says. My immediate desire is to see whether they are associated with diseases, particularly in SLE, she adds.

Lan Lin, an RNA biologist at the University of Pennsylvania and the Childrens Hospital of Philadelphia, says she found the 2019 preprint so interesting that she applied for and received a pilot grant from the Frontiers in Congenital Disorders of Glycosylation (CDG) Consortium to study the roles glycoRNAs may play in CDG, a group of rare congenital conditions arising from mutations in protein glycosylation pathways. Because RNA glycosylation may be related to protein glycosylation, she tells The Scientist, it was only rational or reasonable for [my colleagues and I] to hypothesize that . . . some of these patients might have differences in the glycoRNA in their system, and therefore, CDG conditions could be used to examine the potential functions of glycoRNAs.

So far, she says, her team hasnt detected any consistent differences in glycoRNAs between the cells of healthy controls and CDG patients. She says that may be because differences are more qualitative than quantitative, such as alterations to the sugars themselves or the subset of RNAs that are glycosylated. Alternatively, she notes, the new data in the 2021 Cell paper may provide an explanation: the membrane localization of glycoRNAs wasnt in the preprint, so maybe we are looking in the wrong place, she muses.

Its also possible that new methods are needed to detect glycoRNA differences between cells. She points out that a major limitation of the study is that the ManNAz labeling method cant readily be applied to preserved human tissue samples or blood samples.

Fairhurst says shed like to see more work in primary cell cultures rather than immortalized ones, especially leukocyte subtypes, where one might expect pronounced differences if the RNAs have a role in immunity. For example, she says shed like to see whether, in people with conditions like SLE, different cell types have fewer or more glycoRNAs, though obviously, those experiments are really challenging.

Seeing these big milestones is amazing

Anna-Marie Fairhurst, Agency for Science, Technology and Research in Singapore

Still, she says, seeing these big milestones is amazing.

Kiessling says she thinks glycoRNAs could be really important in the field of glycobiology. Her lab focuses on how carbohydrate-binding proteins can read glycans on the surfaces of cells, she explains, so these glycoRNAs could be a new kind of information to read. Lin points out that the findings are especially impactful for RNA researchers, as they suggest a whole new kind of post-transcriptional modification in need of investigation. Because glycoRNA sits at the intersection of glycobiology, immunology, and RNA biology, says Bertozzi, Ryans discovery has brought together these disparate worlds.

Flynn and Bertozzi say theyre hoping to start answering some of the many questions that remain, including how the glycans attach to RNAs and how and where that happens. The most exciting part, they say, will be the investigations into what glycoRNAs do.

R. Flynn et al., Small RNAs are modified with N-glycans and displayed on the surface of living cells,Cell, doi:10.1016/j.cell.2021.04.023, 2021.

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Newly Discovered Glycosylated RNA Is All Over Cells: Study - The Scientist

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