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Could the Immune System Hold the Key To Alzheimer’s Disease? – The Wire Science

Photo: Matt Artz.

For nearly 30 years, the hunt for a cure for Alzheimers disease has focused on a protein called beta-amyloid. Amyloid, the hypothesis goes, builds up inside the brain to bring about this memory-robbing disorder, which afflicts some 47 million people worldwide.

Billions of dollars have poured into developing therapies aimed at reducing amyloid thus far, to no avail. Trials of anti-amyloid treatments have repeatedly failed to help patients, sparking a reckoning among the fields leaders.

All along, some researchers have toiled in the relative shadows, developing potential strategies that target other aspects of cells that go awry in Alzheimers: molecular pathways that regulate energy production, or clean up cellular debris, or regulate the flow of calcium, an ion critical to nerve cell function. And increasingly, some of these scientists have focused on what they suspect may be another, more central factor in Alzheimers and other dementias: dysfunction of the immune system.

With the fields thinking narrowed around the amyloid hypothesis, immunological ideas have struggled to win favour and funding. There was no traction, says Mal Tansey, a University of Florida neuroscientist whose work focuses on immunology of the brain. The committees that review grant applications didnt want to hear about immunological studies, she says.

But over the past decade, the immune system connection to Alzheimers has become clearer. In several massive studies that analysed the genomes of tens of thousands of people, many DNA variants that were linked to heightened Alzheimers risk turned out to be in genes involved in immunity specifically, a branch of the bodys defences known as the innate immune system. This branch attacks viruses, bacteria and other invaders quickly and indiscriminately. It works, in part, by triggering inflammation.

A further connection between inflammation and Alzheimers turned up in March 2020, in an analysis of electronic health records from 56 million patients, including about 1.6 million with rheumatoid arthritis, psoriasis and other inflammatory diseases. When researchers searched those records for Alzheimers diagnoses, they found that patients taking drugs that block a key molecular trigger of inflammation, called tumour necrosis factor (TNF), have about 50 to 70% lower odds of having an Alzheimers diagnosis than patients who were prescribed those drugs but did not take them.

This newer wave of studies opened peoples eyes to the idea that the immune system might be a major driver of Alzheimers pathology, says Sharon Cohen, a behavioural neurologist who serves as medical director at the Toronto Memory Program in Canada. Over time, Cohen says, researchers began thinking that maybe inflammation is not just an aftereffect, but actually a pivotal, early effect.

Tansey is trying to harness this growing realisation to develop new therapies. A drug she helped to develop nearly 20 years ago relieved Alzheimers-like features in mice and recently showed encouraging results in a small study of people with the disease. I think we were onto something way back when, she says.

Early hunch

Tansey got interested in neurodegenerative disease in the late 1990s, while working as a postdoctoral fellow at Washington University in St. Louis. Her research focused on molecules that promote the survival of certain neurons that degenerate in Parkinsons disease in lab dish experiments, anyway. But after six years on a meagre postdoc salary, and with her husband about to start neurology training at UCLA, she took a job at a biotech company in the Los Angeles area, called Xencor. She tackled a project that the company had on the back burner: designing new drugs to inhibit that inflammatory molecule TNF.

At the time, doctors already used two such drugs to treat autoimmune disorders such as psoriasis and rheumatoid arthritis. But these drugs have harmful side effects, largely owing to TNFs complicated biology. TNF comes in two forms: one thats anchored to the membranes of cells, and a soluble form that floats around in the spaces in between. The soluble TNF causes inflammation and can kill cells infected with viruses or bacteria its a necessary job but, in excess, destroys healthy tissues. The membrane-bound form of TNF, on the other hand, confers protection against infection to begin with. The drugs in use at the time inhibited both forms of TNF, leaving people at risk for infections by viruses, bacteria and fungi that typically only cause problems for people with weakened immune systems.

Using genetic engineering, Tansey and her Xencor colleagues designed a drug that prevents this potentially dangerous side effect by targeting only the harmful, soluble form of TNF. It gloms onto the harmful TNF and takes it out of circulation. In tests, injections of the drug reduced joint swelling in rats with a condition akin to arthritis.

By the time the work was published in Science in 2003, Tansey had returned to academia, starting up her own lab at the University of Texas Southwestern Medical Centre in Dallas. And as she scoured the scientific literature on TNF, she began to think again about those experiments shed done as a postdoc, on neurons destroyed during Parkinsons disease. She read studies showing that the brains of Parkinsons patients have high levels of TNF and she wondered if TNF could be killing the neurons. There was a clear way to find out: Put the TNF-blocking drug shed helped to develop at Xencor into the brains of rats that were manipulated to develop Parkinsons-like symptoms and watch to see what happened.

Her hunch proved correct the drug slowed the loss of neurons in Parkinsons rats. And that led Tansey to wonder: Could TNF also be involved in the loss of neurons in other forms of neurodegeneration, including Alzheimers disease? Mulling over the nuanced roles of innate immune cells, which seem to help or hurt depending on the context, she started rethinking the prevailing amyloid hypothesis. Perhaps, she thought, amyloid ends up clumping in the Alzheimers brain because immune cells that would normally gobble it up get sluggish as people age: In other words, the amyloid accumulated as a consequence of the disease, not a cause.

The double-edged nature of immune activity also meant that our immune systems might, if unchecked, exacerbate problems. In that case, blocking aspects of immune function specifically, inflammation might prove helpful.

The idea that blocking inflammation could preserve cognition and other aspects of brain function has now found support in dozens of studies, including several by Tanseys lab. Using an approach that induced Alzheimers-like neurological symptoms in mice, neuroscientist Michael Heneka, a researcher at Germanys University of Bonn, and his colleagues found that mice engineered to lack a key molecule of the innate immune system didnt form the hallmark amyloid clumps found in Alzheimers.

Tansey and colleagues, for their part, showed that relieving inflammation with the drug Tansey helped develop at Xencor, called XPro1595, could reduce amyloid buildup and strengthen nerve cell connections in mice with Alzheimers-like memory problems and pathology. Her team has also found that mice on a high-fat, high-sugar diet which causes insulin resistance and drives up Alzheimers risk have reduced inflammation and improved behavior on tests of sociability and anxiety when treated with XPro1595.

All told, hints from human genetic and epidemiologic data, combined with growing evidence from mouse models, was shifting or pointing toward the role of the immune system, says Heneka, who coauthored a 2018 article in the Annual Review of Medicine about innate immunity and neurodegeneration. And the evidence is growing: In 2019, a study of more than 12,000 older adults found that people with chronic inflammation suffered greater mental losses over a period of 20 years a clue, again, that inflammation could be an early driver of cognitive decline.

The accumulating data convinced Tansey that it was time to test this idea in people that instead of targeting amyloid, we need to start targeting the immune system, she says. And it needs to be early. Once too much damage is done, it may be impossible to reverse.

Targeting innate immunity

Immune-based strategies against Alzheimers are already being pursued, but most are quite different than what Tansey was proposing. Companies mostly work with the adaptive immune system, which attacks pathogens or molecules very specifically, recognising them and marking them for destruction. Experimental therapies include antibodies that recognise amyloid and target it for removal.

INmune Bio, in La Jolla, California, is one of several biotech companies taking a different approach: trying to fight degenerative brain disease by targeting the less specific innate immune system. The immune system is a 50-50 partnership, says RJ Tesi, the CEO. If youre about to have a prize fight, youre not going to jump in with one hand tied behind your back. Likewise, with Alzheimers or cancer, you dont want to go into the ring with half the immune system being ignored. To pursue this strategy, INmune Bio bought commercial rights to XPro1595. (Tansey is a paid consultant for INmune Bio but is not involved in any of the companys trials.)

INmune Bio initially focused on cancer, so when it designed its Alzheimers trial, it used a strategy commonly used in cancer drug trials. In Tesis view, a key reason that experimental cancer drugs succeed far more often than experimental neurology drugs is the use of molecular disease indicators called biomarkers. These are measures such as genetic variants or blood proteins that help to distinguish patients who, from the outside, may all seem to have the exact same disease, but may actually differ from one another.

By using biomarkers to select participants, cancer researchers can enrol the patients most likely to respond to a given drug but many neurology trials enrol patients based solely on their diagnosis. And thats problematic, says Tesi, because scientists are coming to realise that a diagnosis of Alzheimers, for instance, might actually encompass various subtypes of disease each with its own underlying biology and each, perhaps, requiring a different treatment.

In an ongoing trial of XPro1595, INmune Bio aims to enrol 18 people with mild to moderate Alzheimers disease, all of whom have elevated levels of biomarkers for excessive inflammation, including one called C-reactive protein. In July, the company reported early data from six participants who were treated with the TNF inhibitor once a week for 12 weeks and assessed for brain inflammation using a specialised magnetic resonance imaging (MRI) technique.

Over the 12-week period, brain inflammation fell 2.3 percent in three participants who received the high-dose TNF inhibitor compared with a 5.1 percent increase in 25 Alzheimers patients whose data were collected previously as part of a major long-term study of Alzheimers disease. Three participants who got a low dose of XPro1595 had a smaller 1.7% increase in brain inflammation. In this small trial, the researchers did not track changes in cognition. But their MRI analysis showed that inflammation was reduced by about 40 percent in a particular bundle of nerve fibres called the arcuate fasciculus that is important for language processing and short-term memory.

Its early days, Cohen says interim results in just six people. However, in a small sample size like that, you might not expect to see anything. Past studies of anti-inflammatory drugs did not show a benefit in Alzheimers patients, but scientists are now reexamining these trial failures, Cohen says. Maybe the idea of the immune system is important, but our therapies were too blunt, she says.

Its not just INmune Bio that has researchers excited about the prospect of tinkering with innate immunity to tackle brain disease. Alector, a South San Francisco biotech company, is developing potential therapeutics to activate the innate immune system to fight Alzheimers. Some of their experimental drugs are intended to boost the activity of innate immune cells in the brain called microglia. Tiaki Therapeutics in Cambridge, Massachusetts, meanwhile, is using computational methods to identify potential treatments for people with neuroinflammatory diseases who have specific gene signatures. And another company, Shanghai-based Green Valley, is investigating a drug that includes a mix of seaweed sugars that, the company claims, alters gut bacteria to tamp down brain inflammation.

Its encouraging to see so many different approaches to harnessing the innate immune system to fight Alzheimers, Heneka says. He predicts, however, that a variety of treatments will be needed to tackle such a multifaceted, complicated disease.

But Tansey suspects that chronic inflammation is a crucial factor that takes a toll on the brain over the course of many years. Although lowering inflammation will not solve everything, she says, I think it will buy you a lot. Because its the dark passenger of the journey.

This article originally appeared in Knowable Magazine, an independent journalistic endeavour from Annual Reviews.

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Could the Immune System Hold the Key To Alzheimer's Disease? - The Wire Science

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Global CRISPR Gene Editing Market: Focus on Products, Applications, End Users, Country Data (16 Countries), and Competitive Landscape – Analysis and…

New York, Feb. 01, 2021 (GLOBE NEWSWIRE) -- announces the release of the report "Global CRISPR Gene Editing Market: Focus on Products, Applications, End Users, Country Data (16 Countries), and Competitive Landscape - Analysis and Forecast, 2020-2030" - Application Agricultural, Biomedical (Gene Therapy, Drug Discovery, And Diagnostics), Industrial, and Other Applications [Genetically Modified Foods (GM Foods), Biofuel, And Animal (Livestock) Breeding] End-User - Academic Institutes and Research Centers, Biotechnology Companies, Contract Research Organizations (CROs), and Pharmaceutical and Biopharmaceutical Companies

Regional Segmentation

North America U.S., Canada Europe Germany, France, Italy, U.K., Spain, Switzerland, and Rest-of-Europe Asia-Pacific China, Japan, India, South Korea, Singapore, Australia, and Rest-of-Asia-Pacific (RoAPAC) Latin America Brazil, Mexico, and Rest-of-the-Latin America Rest-of-the-World

Growth Drivers

Prevalence of Genetic Disorders and Use of Genome Editing Government and Private Funding Technology Advancement in CRISPR Gene Editing

Market Restraints

CRISPR Gene Editing: Off Target Effects and Delivery Ethical Concerns and Implications with Respect to Human Genome Editing

Market Opportunities

Expanding Gene and Cell Therapy Area CRISPR Gene Editing Scope in Agriculture

Key Companies ProfiledAbcam, Inc., Applied StemCell, Inc., Agilent Technologies, Inc., Cellecta, Inc., CRISPR Therapeutics AG, Thermo Fisher Scientific, Inc., GeneCopoeia, Inc., GeneScript Biotech Corporation, Horizon Discovery Group PLC, Integrated DNA Technologies, Inc., Merck KGaA, New England Biolabs, Inc., Origene Technologies, Inc., Rockland Immunochemicals, Inc., Synthego Corporation, System Biosciences LLC, ToolGen, Inc., Takara Bio

Key Questions Answered in this Report: What is CRISPR gene editing? What is the timeline for the development of CRISPR technology? How did the CRISPR gene editing market evolve, and what is its scope in the future? What are the major market drivers, restraints, and opportunities in the global CRISPR gene editing market? What are the key developmental strategies that are being implemented by the key players to sustain this market? What is the patent landscape of this market? What will be the impact of patent expiry on this market? What is the impact of COVID-19 on this market? What are the guidelines implemented by different government bodies to regulate the approval of CRISPR products/therapies? How is CRISPR gene editing being utilized for the development of therapeutics? How will the investments by public and private companies and government organizations affect the global CRISPR gene editing market? What was the market size of the leading segments and sub-segments of the global CRISPR gene editing market in 2019? How will the industry evolve during the forecast period 2020-2030? What will be the growth rate of the CRISPR gene editing market during the forecast period? How will each of the segments of the global CRISPR gene editing market grow during the forecast period, and what will be the revenue generated by each of the segments by the end of 2030? Which product segment and application segment are expected to register the highest CAGR for the global CRISPR gene editing market? What are the major benefits of the implementation of CRISPR gene editing in different field of applications including biomedical research, agricultural research, industrial research, gene therapy, drug discovery, and diagnostics? What is the market size of the CRISPR gene editing market in different countries of the world? Which geographical region is expected to contribute to the highest sales of CRISPR gene editing market? What are the reimbursement scenario and regulatory structure for the CRISPR gene editing market in different regions? What are the key strategies incorporated by the players of global CRISPR gene editing market to sustain the competition and retain their supremacy?

Market OverviewThe development of genome engineering with potential applications proved to reflect a remarkable impact on the future of the healthcare and life science industry.The high efficiency of the CRISPR-Cas9 system has been demonstrated in various studies for genome editing, which resulted in significant investments within the field of genome engineering.

However, there are several limitations, which need consideration before clinical applications.Further, many researchers are working on the limitations of CRISPR gene editing technology for better results.

The potential of CRISPR gene editing to alter the human genome and modify the disease conditions is incredible but exists with ethical and social concerns. The global CRISPR gene editing market was valued at $846.2 million in 2019 and is expected to reach $10,825.1 million by 2030, registering a CAGR of 26.86% during the forecast.

The growth is attributed to the increasing demand in the food industry for better products with improved quality and nutrient enrichment and the pharmaceutical industry for targeted treatment for various diseases. Further, the continued significant investments by healthcare companies to meet the industry demand and growing prominence for the gene therapy procedures with less turnaround time are the prominent factors propelling the growth of the global CRISPR gene editing market.

Research organizations, pharmaceutical and biotechnology industries, and institutes are looking for more efficient genome editing technologies to increase the specificity and cost-effectiveness, also to reduce turnaround time and human errors.Further, the evolution of genome editing technologies has enabled wide range of applications in various fields, such as industrial biotech and agricultural research.

These advanced methods are simple, super-efficient, cost-effective, provide multiplexing, and high throughput capabilities. The increase in the geriatric population and increasing number of cancer cases, and genetic disorders across the globe are expected to translate into significantly higher demand for CRISPR gene editing market.

Furthermore, the companies are investing huge amounts in the research and development of CRISPR gene editing products, and gene therapies. The clinical trial landscape of various genetic and chronic diseases has been on the rise in recent years, and this will fuel the CRISPR gene editing market in the future.

Within the research report, the market is segmented based on product type, application, end-user, and region. Each of these segments covers the snapshot of the market over the projected years, the inclination of the market revenue, underlying patterns, and trends by using analytics on the primary and secondary data obtained.

Competitive LandscapeThe exponential rise in the application of precision medicine on a global level has created a buzz among companies to invest in the development of novel CRISPR gene editing. Due to the diverse product portfolio and intense market penetration, Merck KGaA, and Thermo Fisher Scientific Inc. have been the pioneers in this field and have been the major competitors in this market. The other major contributors of the market include companies such as Integrated DNA Technologies (IDT), Genscript Biotech Corporation, Takara Bio Inc, Agilent Technologies, Inc., and New England Biolabs, Inc.

Based on region, North America holds the largest share of CRISPR gene editing market due to substantial investments made by biotechnology and pharmaceutical companies, improved healthcare infrastructure, rise in per capita income, early availability of approved therapies, and availability of state-of-the-art research laboratories and institutions in the region. Apart from this, Asia-Pacific region is anticipated to grow at the fastest CAGR during the forecast period.

Countries Covered North America U.S. Canada Europe Germany Italy France Spain U.K. Switzerland Rest-of-Europe Asia-Pacific China India Australia South Korea Singapore Japan Rest-of-Asia-Pacific Latin America Brazil Mexico Rest-of-Latin America Rest-of-the-WordRead the full report:

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Global CRISPR Gene Editing Market: Focus on Products, Applications, End Users, Country Data (16 Countries), and Competitive Landscape - Analysis and...

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Synthetic Biology Used To Develop a New Type of Genetic Design – Technology Networks

Richard Feynman, one of the most respected physicists of the twentieth century, said "What I cannot create, I do not understand". Not surprisingly, many physicists and mathematicians have observed fundamental biological processes with the aim of precisely identifying the minimum ingredients that could generate them. One such example are the patterns of nature observed by Alan Turing. The brilliant English mathematician demonstrated in 1952 that it was possible to explain how a completely homogeneous tissue could be used to create a complex embryo, and he did so using one of the simplest, most elegant mathematical models ever written. One of the results of such models is that the symmetry shown by a cell or a tissue can "break" under a set of conditions. However, Turing was not able to test his ideas, and it took over 70 years before a breakthrough in biology technique was able to evaluate them decisively. Can Turing's dream be made a reality through Feynman's proposal? Genetic engineering has proved it can.

Now, a research team from the Institute of Evolutionary Biology (IBE), a joint centre of UPF and the Spanish National Research Council (CSIC), has developed a new type of model and its implementation using synthetic biology can reproduce the symmetry breakage observed in embryos with the minimum amount of ingredients possible.

The research team has managed to implement via synthetic biology (by introducing parts of genes of other species into the E. coli bacteria) a mechanism to generate spatial patterns observed in more complex animals, such as Drosophila melanogaster (fruit fly) or humans. In the study, the team observed that the strains of modified E. coli, which normally grow in (symmetrical) circular patterns, do as in the shape of a flower with petals at regular intervals, just as Turing had predicted.

"We wanted to build symmetry breaking that is never seen in colonies of E. coli, but is seen in patterns of animals, and then to discover which are the essential ingredients needed to generate these patterns", says Salva Duran-Nebreda, who conducted this research for his doctorate in the Complex Systems laboratory and is currently a postdoctoral researcher at the IBE Evolution of Technology laboratory.

Bacteria E. coli forming patterns induced by the new synthetic system. Credit: Jordi Pla /ACS.

Using the new synthetic platform, the research team was able to identify the parameters that modulate the emergence of spatial patterns in E. coli . "We have seen that by modulating three ingredients we can induce symmetry breaking. In essence, we have altered cell division, adhesion between cells and long-distance communication capacity (quorum sensing), that is to say, perceive when there is a collective decision", Duran-Nebreda comments.

The observations made in the E. coli model could be applied to more complex animal models or to insect colony design principles. "In the same way that organoids or miniature organs can help us develop therapies without having to resort to animal models, this synthetic system paves the way to understanding as universal a phenomenon as embryonic development in a far simpler in vitro system", says Ricard Sol, ICREA researcher with the Complex Systems group at the IBE, and head of the research.

The model developed in this study, the first of its kind, could be key to understanding some embryonic development events. "We must think of this synthetic system as a platform for learning to design different fundamental biological mechanisms that generate structures, such as the step from a zygote to the formation of a complete organism. Moreover, such knowledge on the frontier between mechanical and biological processes, could be very useful for understanding developmental disorders", Duran-Nebreda concludes.

Reference: Duran-Nebreda S, Pla J, Vidiella B, Piero J, Conde-Pueyo N, Sol R. Synthetic Lateral Inhibition in Periodic Pattern Forming Microbial Colonies. ACS Synth Biol. 2021. doi:10.1021/acssynbio.0c00318.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Synthetic Biology Used To Develop a New Type of Genetic Design - Technology Networks

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Experts Predict the Hottest Life Science Tech in 2021 and Beyond – The Scientist

Through the social and economic disruption that COVID-19 caused in 2020, the biomedical research community rose to the challenge and accomplished unprecedented feats of scientific acumen. With a new year ahead of us, even as the pandemic grinds on, we at The Scientist thought it was an opportune time to ask what might be on the life science innovation radar for 2021 and beyond. We tapped three members of the independent judging panel that helped name our Top 10 Innovations of 2020 to share their thoughts (via email) on the year ahead.

Paul Blainey: Value is shifting from the impact of individual technologies (mass spectrometry, cloning, sequencing, PCR, induced pluripotent stem cells, next generation sequencing, genome editing, etc.) to impact across technologies. In 2021, I think researchers will increasingly leverage multiple technologies together in order to generate new insights, as well as become more technology-agnostic as multiple technologies present plausible paths toward research goals.

Kim Kamdar: Partially in reaction to the COVID-19 pandemic, one 2021 headline will be the continued innovation focused on consumerization of healthcare, which is redefining how consumers engage with providers across each stage of care. Consumers are even selective about their healthcare choices now, and the retail powerhouses like CVS and Walmart have and will continue to develop solutions to meet the needs of their customers. While this was already underway prior to the pandemic, the crisis has spurred on this activity with the goal of making healthcare more accessible and affordable and ultimately delivering on better health outcomes for all Americans.

Robert Meagher: I think this is easymRNA delivery. This is something that has been in development for years for numerous applications, but the successful development and FDA emergency use authorization of two COVID-19 vaccines based on this technology shines a very bright spotlight on this technology. The vaccine trials and now widespread use of the vaccines will give developers a lot of data about the technology, and sets a baseline for understanding safety and side effects when considering future therapeutic applications outside of infectious disease.

PB:Single-cell technology is here to stay, although its use will continue to change. One analogy to be drawn is the shift we saw from the popularity ofde novo genome sequencing (during the human genome project and the early part of the NGS [next-generation sequencing] era to the rich array of re-sequencing applications practiced today. I expect new ways to use single-cell technology will continue to be discovered for some time to come.

KK: Innovation in single-cell technology has the potential to transform biological research driving to a level of resolution that provides a more nuanced picture of complex biology. Cost has been a key barrier for broader adoption of single-cell analysis. As better technology is developed, cost will be reduced and there will be an explosion in single-cell research. This dynamic will also allow for broader adoption of single-cell technology from translational research to clinical applications particularly in oncology and immunology.

RM: Yesthere is continuing innovation in this space, and room for continued innovation. One area that we have seen development recently, and I see it continuing, is to study single cells not just in isolation, but coupled with spatial information: understanding single cells and their interactions with their neighbors. I also wonder if the COVID-19 pandemic will spur increased interest in applying single-cell techniques to problems in infectious disease, immunology, and microbiology. A lot of the existing methods for single-cell RNA analysis (for example) work well for human or mammalian cells, but dont work for bacteria or viruses.

PB: The promises of CRISPR and gene editing are extraordinary. I cant wait to see how that field continues to develop.

KK: Much of the CRISPR technology focus since it was unveiled in 2012 has been on its utility to modify genes in human cells with the goal of treating genetic disease. More recently, scientists have shown the potential of using the CRISPR gene-editing technology for treatment of viral disease (essentially a programmable anti-viral that could be used to treat diseases like HIV, HBV, SARS, etc. . . .). These findings, published in Nature Communications, showed that CRISPR can be used to eliminate simian immunodeficiency virus (SIV) in rhesus macaque monkeys. If replicated in humans, in studies that will be initiated this year, CRISPR could be utilized to address HIV/AIDS and potentially make a major impact by moving a chronic disease to one with a functional cure.

PB: New therapeutic modalities that expand the addressable set of diseases are particularly exciting. Cell-based therapies offer versatile platforms for biological engineering that leverage the power of human biology. It is also encouraging to see somatic cell genome editing technology advance toward the clinic for the treatment of serious diseases.

The level of innovation that occurred in 2020 to combat COVID-19 will provide a more rapid, focused, and actionable reaction to future pandemics.

Kim Kamdar, Domain Associates

RM: Besides the great success with mRNA-based vaccines that sets the stage for other clinical technologies based on mRNA delivery, the other area that is really in the spotlight this year is diagnostics. There are a lot of labs and companies, both small and large, that have some really innovative products and ideas for portable and point-of-care diagnostics. For a long time, this was often thought of in terms of a problem for the developing world, or resource-limited locations: think, for example, of diagnostics for neglected tropical diseases. But the COVID-19 pandemic and the associated need for diagnostic testing on a massive scale has caused us to rethink what resource-limited means, and to understand the challenge posed by bottlenecks in supply chains, skilled personnel, and high-complexity laboratory facility. There has been a lot of foundational research over the past couple of decades in rapid, portable, easy-to-use diagnostics, but translating these to clinically useful products often seemed to stall, I suspect for lack of a lucrative market for such tests. But we are now starting to see FDA [emergency use authorization for] home-based tests and other novel diagnostic technologies to address needs with the COVID-19 pandemic, and I suspect that this paves the way for these technologies to start being applied to other diagnostic testing needs.

PB: Seeing the suffering and destruction wrought by COVID-19, it is obvious that we need to be prepared with more extensive, equitable, and better-coordinated response plans going forward. While rapid vaccine development and testing were two bright spots last year, there are so many important areas that demand progress. As we learn about how important details become in a crisisno matter how small or mundanediagnostic technologies and the calibration of public health measures are two areas that merit major focus.

KK: The life science community response to the COVID-19 pandemic has already proven to be light-years ahead of previous responses particularly in areas such as vaccine development and diagnostics. It took more than a year to sequence the genome of the SARS virus in 2002. The COVID-19 genome was sequenced in under a month from the first case being identified. Scientists and clinicians were able to turn that initial information to multiple approved vaccines at a blazing speed. Utilizing messenger RNA (mRNA) as a new therapeutic modality for vaccine development has now been validated. Vaccine science has been forever changed. The pandemic has also focused a much-needed level of attention to diagnostics, forcing a rethink of how to increase access, affordability, and actionability of diagnostic testing. The level of innovation that occurred in 2020 to combat COVID-19 will provide a more rapid, focused, and actionable reaction to future pandemics. In addition, the elevation of a science advisor (Dr. Eric Lander) to a cabinet level position in the Biden administration bodes well for our future ability to ground in data and as President Biden himself framed, refresh and reinvigorate our national science and technology strategy to set us on a strong course for the next 75 years, so that our children and grandchildren may inhabit a healthier, safer, more just, peaceful, and prosperous world.

RM: One thing that really kick-started research to address COVID-19 was the early availability of the complete genome sequence of the SARS-CoV-2 virus, and the ongoing timely deposition of new sequences in nearreal-time as isolates were sequenced. This is in contrast to cases where deposition of large number of sequences may lag an outbreak by months or even years. I foresee the nearreal-time sharing of sequence information to become the new standard. Making the virus itself widely and inexpensively available, in inactivated form, as well as well-characterized synthetic viral RNA standards and proteins also helped spur research.

A trend Im less fond of is the rapid publication of nonpeer reviewed results as preprints online. Theres a great benefit to getting new information out to the community ASAP, but unfortunately I think the rush to get preprints up in some cases results in spreading misleading information. This problem is compounded with uncritical, breathless press releases accompanying the posting of preprints, as opposed to waiting for peer-review acceptance of a manuscript to issue a press release. I think the solution may lie in journals considering innovative approaches to speeding up peer review, or a way to at least perform a basic check for rigor prior to posting a preliminary version of the manuscript. Right now the extremes are: post an unreviewed preprint, or wait months or even years with multiple rounds of peer review including extensive additional experiments to satisfy the curiosity of multiple reviewers for high impact publications. Is there a way to prevent manuscripts from being published as preprints with obvious methodological errors or errors in statistical analysis, while also enabling interesting, well-done yet not fully polished manuscripts to be available to the community?

Paul Blaineyis an associate professor of biological engineering at MIT and a core member of the Broad Institute of MIT and Harvard University. The Blainey lab integrates new microfluidic, optical, molecular, and computational tools for application in biology and medicine. The group emphasizes quantitative single-cell and single-molecule approaches, aiming to enable studies that generate data with the power to reveal the workings of natural and engineered biological systems across a range of scales. Blainey has a financial interest in several companies that develop and/or apply life science technologies: 10X Genomics, GALT, Celsius Therapeutics, Next Generation Diagnostics, Cache DNA, and Concerto Biosciences.

Kim Kamdaris managing partner at Domain Associates, a healthcare-focused venture fund creating and investing in biopharma, device, and diagnostic companies. She began her career as a scientist and pursued drug-discovery research at Novartis/Syngenta for nine years.

Robert Meagheris a principal member of Technical Staff at Sandia National Laboratories. His main research interest is the development of novel techniques and devices for nucleic acid analysis, particularly applied to problems in infectious disease, biodefense, and microbial communities. Most recently this has led to approaches for simplified molecular diagnostics for emerging viral pathogens that are suitable for use at the point of need or in the developing world. Meaghers comments represent his professional opinion but do not necessarily represent the views of the US Department of Energy or the United States government.

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Experts Predict the Hottest Life Science Tech in 2021 and Beyond - The Scientist

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Uncertain future: Will Europe’s Green Deal encourage or cripple crop gene-editing innovation? – Genetic Literacy Project

The EU Green Deal and its Farm-to-Fork and Biodiversity Strategies stipulate ambitious policy objectives that will fundamentally impact agricultural businesses and value chains. Are these objectives realistic? And how do they fit with the EUs policies on food security, the internal market, international trade and multilateral economic agreements? As significant conflicts of goals become apparent, the discussion on expectations, preconditions and consequences is now underway.

The Farm to Fork Strategy concretely foresees a reduction of pesticide and fertilizer use of 50% and 20% by 2030, respectively. In addition, 25% of EUs agricultural land is supposed to be put under organic farming conditions, which generally means a reduction in productivity. Unfortunately, the strategy is less concrete about the important role of innovation in general and plant breeding innovation specifically to compensate for productivity losses and to contribute to a more sustainable agriculture.

On July 25, 2018 the European Court of Justice (ECJ) published its ruling on mutagenesis breeding, including targeted genome editing techniques. This ruling subjected new tools like CRISPR Cas-9 to the EUs strict rules and requirements for GMOs, and with that effectively prohibited European plant breeders and farmers from utilizing these powerful technologies. These regulatory obstacles are not based on evidence showing that genome editing poses a risk to human health or the environment, but rather on political interference in the regulatory approval process. The COVID pandemic made this abundantly clear. In July 2020, for example, the EU suspended some of its excessive genetic engineering rules to facilitate the development of COVID vaccines, and has since celebrated the approval of these important drugs while trying to prevent the use of biotechnology in agriculture.

Since the discovery of the laws of genetics by Gregory Mendel in 1866, plant breeders have continuously integrated the latest plant biology innovations into their toolbox to develop enhanced crops that help farmers sustainably grow the food we all depend on.

Europes seed sector, technology developers and public researchers have always been important actors in this evolving effort and remain global leaders in developing improved plant breeding methods. They work tirelessly to provide farmers with crop varieties that fit the needs of a highly productive and sustainable agriculture system and meet the exacting demands of consumers. It is no secret that these experts understand the value of new breeding techniques (NBTs) like CRISPR and want to employ them.

Contrary to the claim of some environmental groups that genome editing provides new avenues of control through modifying specific plant traits, most notably insect and herbicide resistance, industrial applications of this sort are only one aspect of NBT research, and a minor one at that. Our recent survey of 62 private plant breeding companies, 90% of which are small and medium size firms (SMEs), confirms that EU plant breeders are able and willing to use these technologies to develop a wide range of crop species and traits for farmers. From grape vine to wheat, NBTs can generate innovation to protect Europes traditional crops from pests and diseases and other threats posed by climate change.

Independent of their size, many companies are already using NBTs in their R&D pipelines for technology development, gene discovery and to produce improved plant varieties. These activities cover a wide range of agricultural and horticultural cropsfrom the so-called cash crops like maize and soybean to minor crops like pulses, forage crops and chicoryand span a wide diversity of characteristics, including yield, plant architecture, disease and pest resistance, food-quality traits and abiotic stresses like drought and heat.

Uncertain future: Will Europe's Green Deal encourage or cripple crop gene-editing innovation? - Genetic Literacy Project

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Inherited blindness has a new cure, thanks to CRISPR – Genetic Literacy Project

In recent months, even as our attention has been focused on the coronavirus outbreak, there have been a slew of scientific breakthroughs in treating diseases that cause blindness.

Researchers at U.S.-based Editas Medicine and Ireland-based Allergan have administeredCRISPR for the first time to a person with a genetic disease. This landmark treatment uses the CRISPR approach to a specific mutation in a gene linked to childhood blindness. The mutation affects the functioning of the light-sensing compartment of the eye, called the retina, and leads to loss of the light-sensing cells.

According to the World Health Organization,at least 2.2 billion peoplein the world have some form of visual impairment. In the United States, approximately200,000 people suffer from inherited forms of retinal diseasefor which there is no cure. But things have started to change for good. We can now see light at the end of the tunnel.

I am an ophthalmology and visual sciences researcher, and am particularly interested in these advances becausemy laboratory is focusingon designing new and improved gene therapy approaches to treat inherited forms of blindness.

Gene therapy involves inserting the correct copy of a gene into cells that have a mistake in the genetic sequence of that gene, recovering the normal function of the protein in the cell. The eye is an ideal organ for testing new therapeutic approaches, including CRISPR. That is because the eye is the most exposed part of our brain and thus is easily accessible.

The second reason is that retinal tissue in the eye is shielded from the bodys defense mechanism, which would otherwise consider the injected material used in gene therapy as foreign and mount a defensive attack response. Such a response would destroy the benefits associated with the treatment.

In recent years, breakthrough gene therapy studies paved the way to thefirst ever Food and Drug Administration-approved gene therapy drug, Luxturna TM, for a devastating childhood blindness disease,Leber congenital amaurosisType 2.

This form of Leber congenital amaurosis is caused by mutations in a gene that codes for a protein called RPE65. The protein participates in chemical reactions that are needed to detect light. The mutations lessen or eliminate the function of RPE65, which leads to our inability to detect light blindness.

The treatment method developed simultaneously by groups at University of Pennsylvania and at University College London and Moorefields Eye Hospital involvedinserting a healthy copy of the mutated genedirectly into the space between the retina and the retinal pigmented epithelium, the tissue located behind the retina where the chemical reactions takes place. This gene helped the retinal pigmented epithelium cell produce the missing protein that is dysfunctional in patients.

Although the treated eyes showed vision improvement, as measured by the patients ability to navigate an obstacle course at differing light levels,it is not a permanent fix. This is due to the lack of technologies that can fix the mutated genetic code in the DNA of the cells of the patient.

Lately, scientists have been developing a powerful new tool that is shifting biology and genetic engineering into the next phase. This breakthroughgeneeditingtechnology, which is called CRISPR, enables researchers to directly edit the genetic code of cells in the eye and correct the mutation causing the disease.

Children suffering from the disease Leber congenital amaurosis Type 10 endure progressive vision loss beginning as early as one year old. This specific form of Leber congenital amaurosis is caused by a change to the DNA that affects the ability of the gene called CEP290 to make the complete protein. The loss of the CEP290 protein affects the survival and function of our light-sensing cells, called photoreceptors.

One treatment strategy is to deliver the full form of the CEP290 gene using a virus as the delivery vehicle. But the CEP290 gene is too big to be cargo for viruses. So another approach was needed. One strategy was to fix the mutation by using CRISPR.

The scientists at Editas Medicine first showed safety and proof of the concept of the CRISPR strategy in cells extracted from patient skin biopsy and in nonhuman primate animals.

These studies led to the formulation of thefirst ever in human CRISPR gene therapeutic clinical trial. This Phase 1 and Phase 2 trial will eventually assess the safety and efficacy of the CRISPR therapy in 18 Leber congenital amaurosis Type 10 patients. The patients receive a dose of the therapy while under anesthesia when the retina surgeon uses a scope, needle and syringe to inject the CRISPR enzyme and nucleic acids into the back of the eye near the photoreceptors.

To make sure that the experiment is working and safe for the patients, the clinical trial has recruited people with late-stage disease and no hope of recovering their vision. The doctors are also injecting the CRISPR editing tools into only one eye.

An ongoing project in my laboratory focuses on designing a gene therapy approach for the same gene CEP290. Contrary to the CRISPR approach, which can target only a specific mutation at one time, my team is developing an approach that would work for all CEP290 mutations in Leber congenital amaurosis Type 10.

This approach involves usingshorter yet functional forms of the CEP290 proteinthat can be delivered to the photoreceptors using the viruses approved for clinical use.

Gene therapy that involves CRISPR promises a permanent fix and a significantly reduced recovery period. A downside of the CRISPR approach is the possibility of an off-target effect in which another region of the cells DNA is edited, which could cause undesirable side effects, such as cancer. However, new and improved strategies have made such likelihood very low.

Although the CRISPR study is for a specific mutation in CEP290, I believe the use of CRISPR technology in the body to be exciting and a giant leap. I know this treatment is in an early phase, but it shows clear promise. In my mind, as well as the minds of many other scientists, CRISPR-mediated therapeutic innovation absolutely holds immense promise.

In another study just reported in the journal Science, German and Swiss scientists have developeda revolutionary technology, which enables mice and human retinas to detect infrared radiation. This ability could be useful for patients suffering from loss of photoreceptors and sight.

The researchers demonstrated this approach, inspired by the ability of snakes and bats to see heat, by endowing mice and postmortem human retinas with a protein that becomes active in response to heat. Infrared light is light emitted by warm objects that is beyond the visible spectrum.

The heat warms a specially engineered gold particle that the researchers introduced into the retina. This particle binds to the protein and helps it convert the heat signal into electrical signals that are then sent to the brain.

In the future, more research is needed to tweak the ability of the infrared sensitive proteins to different wave lengths of light that will also enhance the remaining vision.

This approach is still being tested in animals and in retinal tissue in the lab. But all approaches suggest that it might be possible to either restore, enhance or provide patients with forms of vision used by other species.

Hemant Khanna is an Associate Professor of Ophthalmology at the University of Massachusetts Medical School. His lab investigates molecular and cell biological bases of severe photoreceptor degenerative disorders, such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA). Find Hemant on Twitter @khannacilialab

A version of this article was originally published at the Conversation and has been republished here with permission. The Conversation can be found on Twitter @ConversationUS

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Inherited blindness has a new cure, thanks to CRISPR - Genetic Literacy Project

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