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CCMB team identifies variants of genes that metabolise drugs – BusinessLine

Posted on February 1, 2021 by Danzig

As India emerges a destination of global choice for clinical trials of various drugs, a study on variants of the gene important for drug metabolism seeks to explore how drugs function across diverse populations.

Dr K Thangaraj and his team from CSIR-Centre for Cellular and Molecular Biology (CCMB), Hyderabad, recently published their study of diversity of cytochrome-P450-2C9 (CYP2C9) gene in Pharmacogenomics and Personalized Medicine.

Healthcare is now moving towards personalised medicine. Our studies on the genetic diversity of India will play an important role in this transition, says Dr Rakesh Mishra, Director, CCMB.

The study is important as it seeks to analyse doctor-prescribed dose of drugs based on the gender, age and body mass index (BMI) of patients. However, there are hypersensitive response like rashes, vomiting and nausea.

Individuals in a population have variations in their genes needed for metabolism of a wide range of drugs. Any changes in the sequence of gene may affect the production of protein in human liver. This can cause slower metabolism of a drug and slower or reduced rate of excretion. Many of these drugs have a narrow therapeutic index they are tolerated by human bodies in very specific amounts, according to scientists.

When these drugs are retained in the body for longer, that can lead to toxicity. So, it is important to decide the right dosage for each individual depending on the sequence of their CYP2C9 gene.

Dr Thangarajs team studied the diversity of this gene among 1,488 Indians across 36 population groups, representing different linguistic groups, castes and tribes, among other parameters. They also looked into genes of 1,087 individuals from other countries of South Asia. We found eight new variants of the CYP2C9 gene, making a total of 11 known variants of the gene in South Asia, says Dr Nizamuddin, who is the first author in the study.

They find no correlation between any of these variants with the linguistic and geographical population groups. However, a few Indian populations have more than 20 per cent people with a deleterious variant of the gene. Those with this variant are at a disadvantage in their ability to metabolise drugs. The eight new variants found in this study are also predicted to have similar effect on drug metabolism.

It is important to know the variations in the CYP2C9 gene to help medical practitioners decide the right dosage of medicine for each patient. The knowledge of this variation will also be important for conducting more meaningful clinical trials. This study also suggests that it might not be the best thing to conduct a common clinical trial for the entire world. We need population-specific trials, says Dr Thangaraj, the corresponding author of this paper and presently Director of the Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad.

CCMB team identifies variants of genes that metabolise drugs - BusinessLine

Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program – BioSpace

Posted on February 1, 2021 by Danzig

Jan. 29, 2021 12:00 UTC

Program to screen for congenital, monogenic hearing loss in children diagnosed with auditory neuropathy

BOSTON--(BUSINESS WIRE)-- Decibel Therapeutics, a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, today announced a partnership with Invitae, a leading medical genetics company, to launch AmplifyTM, a no-charge genetic testing program to screen for the genetic cause of congenital hearing loss in children diagnosed with auditory neuropathy.

We are pleased to collaborate with Invitae to introduce AmplifyTM, which is designed to bring patients one step closer to molecular diagnosis and clinical management of auditory neuropathy, a disorder that affects approximately 10 percent of children who are born with hearing loss, said Jonathon Whitton, Au.D., Ph.D., Vice President of Clinical Research at Decibel. This program seeks to provide much-needed answers to patients and families of patients who experience congenital, monogenic hearing loss. We hope that AmplifyTM will provide those patients with a better understanding of their diagnosis and their treatment options.

Auditory neuropathy is a hearing disorder in which the cochlea, the hearing organ located in the inner ear, receives sound normally, yet the transmission of sound to the brain is interrupted. The most common genetic cause of auditory neuropathy is insufficient production of a protein called otoferlin, which facilitates communication between the inner ear sensory cells and the auditory nerve. When this protein is lacking, the ear cannot communicate with the auditory nerve and the brain, resulting in profound hearing loss. Decibels lead investigational gene therapy program, DB-OTO, is designed to treat congenital, monogenic hearing loss caused by a deficiency in the otoferlin gene.

Amplify Program Eligibility

AmplifyTM is available to individuals who meet the following criteria:

AmplifyTM is a no-charge program that offers genetic testing for those who qualify. Although genetic testing can confirm a potential diagnosis, the absence of a genetic alteration does not preclude a diagnosis of genetic hearing loss. For more information about the program, please visit the Amplify program page.

About DB-OTO

DB-OTO is Decibels investigational gene therapy to restore hearing in children with congenital hearing loss due to a deficiency in the otoferlin gene. The program, developed in collaboration with Regeneron Pharmaceuticals, uses a proprietary, cell-selective promoter to precisely control gene expression in cochlear hair cells. DB-OTO is in preclinical studies, and Decibel expects to initiate clinical testing in 2022.

About Invitae

Invitae Corporation (NYSE: NVTA) is a leading medical genetics company whose mission is to bring comprehensive genetic information into mainstream medicine to improve healthcare for billions of people. Invitae's goal is to aggregate the world's genetic tests into a single service with higher quality, faster turnaround time, and lower prices. For more information, visit the company's website.

About Decibel Therapeutics

Decibel Therapeutics is a clinical-stage biotechnology company dedicated to discovering and developing transformative treatments to restore and improve hearing and balance, one of the largest areas of unmet need in medicine. Decibel has built a proprietary platform that integrates single-cell genomics and bioinformatic analyses, precision gene therapy technologies and expertise in inner ear biology. Decibel is leveraging its platform to advance gene therapies designed to selectively replace genes for the treatment of congenital, monogenic hearing loss and to regenerate inner ear hair cells for the treatment of acquired hearing and balance disorders. Decibels pipeline, including its lead investigational gene therapy program, DB-OTO, to treat congenital, monogenic hearing loss, is designed to deliver on our vision of a world in which the privileges of hearing and balance are available to all. For more information about Decibel Therapeutics, please visit http://www.decibeltx.com or follow @DecibelTx.

View source version on businesswire.com: https://www.businesswire.com/news/home/20210129005089/en/

Decibel Therapeutics and Invitae Announce Launch of Amplify Genetic Testing Program - BioSpace

Are Gene Therapies the Medicine of the Future? – BioSpace

Posted on February 1, 2021 by Danzig

Over the next 10 years, gene therapies are expected come into their own as a treatment option for a variety of diseases. So far, two such therapies have snagged regulatory approval, Novartis Zolgensma for spinal muscular atrophy, and Sparks Luxturna for a rare form of genetic blindness. More are waiting their turn.

Multiple companies are delving into gene therapy research with hopes of developing a one-time treatment for devastating genetic diseases. Gene therapies offer great reward in the form of treating various devastating diseases, but there are also significant risks. Over the past year, several clinical studies have been halted or scrapped due to safety concerns.

Bay Area-based Audentes Therapeutics had a temporary hold placed on the gene therapy under development for X-linked myotubular myopathy following reports of several patient deaths. That hold has since been lifted by the U.S. Food and Drug Administration. Uniqure also saw a hold placed on its hemophilia B trial after a patient in the study developed liver cancer. The hold was placed weeks after the company announced promising Phase III results at a conference in December.

Despite those risks, hundreds of millions of dollars in research dollars are being invested in gene therapies because of the potential near-curative capabilities the technology could offer. In December, life sciences giant Bayer launched a cell and gene therapy platform within its pharmaceutical division in order to become a leading company within a rapidly emerging and evolving field that offers the potential of life-saving therapies. Eli Lilly also dove into the field in December with the acquisition of Prevail Therapeutics. That deal was expected to extend Eli Lillys research efforts through the creation of a gene therapy program that will be anchored by Prevail's portfolio of clinical-stage and preclinical neuroscience assets.

This week, German scientists reported they were able to use gene therapy to help paralyzed mice run again. The researchers were able to genetically engineer a unique protein dubbed hyper-interleukin-6, which was then able to stimulate the regeneration of nerve cells in the visual system. A few weeks after the treatment, the injured animals were able to walk again.

Scientists in China announced the development of a gene therapy that could potentially reverse the effects of ageing. Initial research was conducted with mice, but if it is proven to be safe, human testing could begin. As Reuters reported, the method involved inactivating a gene called kat7 which the scientists found to be a key contributor to cellular ageing. Researchers used CRISPR/Cas9 to screen thousands of genes for those which were particularly strong drivers of cellular senescence, the term used to describe cellular ageing, Reuters said.

Earlier this month, a public-private partnership in Boston formed to open a new facility to boost advances in cell and gene therapies. This creation of this new facility is being helmed by Harvard University and the Massachusetts Institute of Technology. Those prestigious universities are partnering with industry members such as Fujifilm Diosynth Biotechnologies, Cytivia and Alexandria Real Estate Equities, as well as multiple research hospitals. Part of the goal of this new institute, which is still unnamed at this point, is to boost the supply of materials for research and early clinical studies, provide space for some research and also offer training in equipment used for gene therapies, The Harvard Gazette reported this week.

On Monday, Curadigm, a subsidiary of France-based Nanobiotix, forged a collaboration with Sanofi to assess if that companys Nanoprimer technology is a promising option to significantly improve gene therapy development. The goal of the project is to establish proof-of-concept for the Nanoprimer as a combination product that could improve treatment outcomes for gene therapy product candidates.

Many promising nucleic acid-based therapeutics administered intravenously are limited in their efficacy due to rapid clearance in the liver, which prevents these therapies from reaching the necessary accumulation in target tissues to generate their intended outcomes. Additionally, accumulation in the liver, rather than in the target tissues, can lead to dose-limiting hepatic toxicity, Nanobiotix said in its announcement. The Nanoprimer is designed to precisely and temporarily occupy therapeutic clearance pathways in the liver. Delivered intravenously, immediately prior to the recommended therapy, the technology acts to prevent rapid clearancethereby increasing bioavailability and subsequent accumulation of therapeutics in the targeted tissues.

The Nanoprimer is a combination product candidate that does not alter or modify the therapies it is paired with, which means if the research with Sanofi is successful, Curadigm could seek out other opportunities for its technology.

Copy number variations linked to autism have diverse but overlapping effects – Spectrum

Posted on February 1, 2021 by Danzig

Mapping outcomes: Some genetic mutations can lead to a wide variety of traits, including those associated with autism.

People with mutations in distant chromosomal regions often share a range of autism traits, even if they do not meet the diagnostic threshold for autism, according to a new study.

Mutations called copy number variations (CNVs) involve duplications or deletions of large stretches of DNA. Having a CNV in the 16p11.2 or 22q11.2 chromosomal region increases a persons likelihood of being diagnosed with autism, but previous studies have found significant variability in the traits associated with mutations in either location.

The new work shows that deletions or duplications in 16p11.2 or 22q11.2 track with distinct profiles of cognitive abilities and autism traits, and that each type of variant is linked to a different probability of being diagnosed with autism.

These profiles overlap, which suggests that the different CNVs have similar impacts on developmental pathways involved with autism, says lead investigator Marianne van den Bree, professor of psychological medicine at Cardiff University in the United Kingdom. The findings also support the idea that other factors such as the environment or other genes shape a persons autism traits.

Van den Bree and her colleagues across eight institutions pooled data from 547 people with a deletion or duplication in 16p11.2 or 22q11.2. They compared the data with similar information from the Autism Genome Project, looking at 2,027 autistic people who do not have these CNVs.

Pulling these datasets together provided an in-depth look at patterns of outcomes. The four groups of people with CNVs a deletion or duplication in either chromosomal region differ the most in motor function, van den Bree and her colleagues found. And people with 22q11.2 deletions are less likely to have an autism diagnosis than those with any of the other CNVs, but they still have a higher autism prevalence than the general population.

People with a duplication in 22q11.2 or 16p11.2 tend to have more severe autism traits than people with deletions, the researchers found. And people with a 16p11.2 duplication or 22q11.2 deletion have greater cognitive impairment than those with one of the other two variants do.

Despite these differences between groups, people within each group show even greater variability, the team found, which suggests that other factors contribute to a persons traits. The work appeared in January in the American Journal of Psychiatry.

These four CNVs have not previously been compared in this way, but the study feels more confirmatory than it feels like its carving out something new, says Elliott Sherr, professor of neurology at University of California, San Francisco, who was not involved in the new work.

Many people, however, including some clinicians, are unaware that these genetic conditions are often linked to autism, says study investigator Samuel Chawner, research fellow in psychology at Cardiff University. He says he hopes that the profiles he and his colleagues identified will inform how genetic conditions are treated. For instance, 54 percent of people carrying one of the CNVs who do not have an autism diagnosis still have significant autism-like difficulties.

Whats missing from the new work is an examination of what else besides the CNVs contributes to the diversity of traits seen in people with these mutations, such as environment and other genes, says David Ledbetter, chief clinical officer at Dascena, a personalized medicine company. Ledbetter was not involved in the study.

For example, people with a 22q11.2 deletion have an increased likelihood of having schizophrenia, but information from the rest of their genome can help to accurately forecast outcomes, according to a study published in November. This same technique could be used to predict traits in people with the other CNVs, Ledbetter says.

A persons environment including their ability to access medical support and early education may also play a role in this variability, Chawner says. Van den Bree, Chawner and their colleagues at the Genes to Mental Health consortium plan to study how these factors in particular contribute to traits in people with CNVs.

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Copy number variations linked to autism have diverse but overlapping effects - Spectrum

Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer – Technology Networks

Posted on February 1, 2021 by Danzig

In recent years, the idea of the microbiome has gone from being an esoteric term used in scientific circles, to a mainstream concept employed in adverts to sell microbiome-boosting health drinks and supplements. The increase in public interest has been fed by a series of headline-grabbing research breakthroughs, and the fact that the microbiome has a key role to play in the development of precision medicine.The trillions of microbes contained in the human body are a key element of a personalized approach to treatment; the microbiome influences endocrinology, physiology, and even neurology, and has a crucial role in disease progression. The growing awareness of the various ways in which microbiota affects each of us individually in sickness and in health is also leading to an increase in research. An area in which this interest is growing particularly quickly is oncology.

Multiple publications implicate microbiota in the onset and progression of cancers, as well as toxicity and the response rate of cancer treatments. An analysis of 12 million full-text publications, 29 million abstracts and 521 thousand grant applications for semantic relations between cancers and microbiota is shown in figure 1. The data show a considerable increase in the number of articles linking cancers to microbiota for five cancer types with the highest number of reports overall.

Figure 1.Trend of reports linking cancers to microbiota 20082019. Credit: Graph generated using Elsevier Text Mining and Scopus.

With overall cancer rates set to increase worldwide, the current interest in the microbiome and its role in precision medicine is likely to continue because it offers new hope of treatments. Evidence suggests the importance of looking for predictors of therapeutic response beyond the tumor by focusing on host factors, such as microbiota and host genomics.1 Importantly, the microbiota is a modifiable factor, and potentially can become not just a predictive marker but also a potential target in order to improve outcomes for patients.

Progress is also being made in clinical trials looking at the microbiome and melanoma. Since 2018, four clinical trials that aim to study and modulate the gut microbiomes impact on response to immunotherapy of melanoma have been registered at clinicaltrials.gov. Dr Marc Hurlbert, Chief Science Officer for the Melanoma Research Alliance, commented on the findings: As noted in the report, there has been an explosion of knowledge about melanoma with an ever-increasing list of protein targets. Also noted, the role of the microbiome in melanoma and in response to immunotherapy is of increasing interest in the field.

To further develop targeted precision therapies, further research is now required. Firstly, to map genetic variants; secondly, to determine which variant is clinically significant; thirdly, to understand the impact of variant on gene function, and whether variation activates or inhibits the gene. This is particularly important for increased understanding of specific, precision medicine and to enhance therapeutic efficacy.

For non-hereditary (sporadic) melanoma, the analysis showed that there are 752 genes genetically linked to sporadic melanomas and its subtypes, and 449 genetic variants genetically linked to sporadic melanoma and its subtypes. Out of the 449 genetic variants, 395 are from 78 genes that are genetically linked to melanoma. The remaining missing 54 variants are not currently genetically linked in the platform to any known melanoma gene; this could therefore be a potential area for further research.

Understanding whether specific genetic variants exist and/or contribute to melanomas severity and prevalence in populations will help the research and development (R&D) industry to develop more effective and profitable therapeutics. These types of data will provide the R&D community with a greater depth of understanding and of the increased likelihood of hitting the target. Through our analysis we found an increased incidence of drugs targeting genetic mutations over the last decade, particularly targeting protein kinases and growth factor receptors.

It is an attractive future research avenue to recognize how a patients microorganisms genome, both symbiotic and pathogenic, can dramatically effect treatment plans and outcomes. Positively influencing the microbiome in patients needs further study that could lead to exciting opportunities for patients and for drug discovery. For the therapeutic pipeline it would be beneficial to understand these host-microbiota interactions and ways to positively tip the balance towards improving treatment outcomes.

One other interesting future consideration during drug development for all cancers is the influence of the microbiome on treatment-induced adverse events, and whether clinical and post-clinical adverse events are related to a patients microbial composition. It adds a level of complexity as to the efficacy of therapeutics that may not readily be considered, and potentially may be something to consider during future clinical trials.

Moreover, in the current COVID-19 era, in-person and patient interactions are reduced and many research labs are still unable to operate at full capacity. The ability to conduct research, take samples and study real patients is limited at present, so looking at detailed existing literature and data is a vital avenue to support R&D. It will keep R&D functions going and help them to direct efforts to the areas of greatest potential. 2021 will be a year of reduced R&D budgets globally this type of data insight will be vital to empowering future R&D.

Tom is the Life Sciences Group Manager of Project Management, Knowledge Manager, and Research Scientist. He has extensive experience as an academic researcher in neurodegeneration and Alzheimers disease. He is also skilled in biophysical chemistry, dementia disorders, and biochemistry. He is the author of many publications in the field of protein-membrane interactions, protein misfolding, and Alzheimers disease. At Elsevier he delivers and implements information solutions for customers.

Tom discusses the study and unmet needs in melanoma R&D in detail, here, alongside Marc Hurlbert, Ph.D. Chief Science Officer, Melanoma Research Alliance.

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Exploring the Relationship Between the Microbiome, Precision Medicine and Cancer - Technology Networks

Digbi Health’s gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California’s…

Posted on February 1, 2021 by Danzig

MOUNTAIN VIEW, Calif., Jan. 26, 2021 /PRNewswire/ --Digbi Health, the first company with a clinically proven genetics and gut-microbiome based program to safely and sustainably treat and manage obesity and associated inflammatory gut, skin and cardiometabolic health issues, is now available to Blue Shield of California members, as a fully covered program, on the health plan'sWellvolution platform.

It's the first time over 60,000 physicians and clinicians practicing in California in the Blue Shield of California's network can prescribe a weight-loss program personalized on a person's genetic, gut microbiome and lifestyle. Through the Digbi Health solution, patients are supported by a team of caregivers, led by a physician and care experts trained in nutrition, cognitive behavior therapy, genetics and gut microbiome. Blue Shield of California offers access to Digbi Health through the Wellvolution platform as a fully covered program to members who qualify.

The Digbi Health Precision Care Network (PCN) is a network of physicians practicing precision medicine. As part of that network, physicians get marketing resources to educate their patients about Digbi Health on the Wellvoution platform, access to their patient's dashboard, with patient approval, and additional support from the Digbi Health care concierge team to support their patients between visits to help improve patient outcomes. Digbi Health program members without a physician can also get referred to a specialist in the PCN.

"The development of cardiovascular disease is a matter of genetic predisposition and gut microbiome composition interacting with acquired conditions, and factors such as diet, exercise, and exposure to damaging elements," said Cynthia Thaik, MD. Harvard-trained cardiologist at the Holistic Healing Heart Center and Digbi Health PCN member.

"I have already prescribed Digbi Health to a patient covered by Blue Shield of California for pre-diabetes and hypertension," she added.

Blue Shield of California is taking the lead on personalized and preventive care for their members.

Among participants participating in Wellvolution:

"We are an innovative telehealth company that supports overburdened physicians by redefining care for 100 million Americans who struggle under one-size-fits-all digital health programs, weight loss diets and stigma of "poor self-control" while fighting obesity and associated inflammatory comorbidities," said Ranjan Sinha, CEO and founder of Digbi Health.

About Digbi Health Precision Care NetworkOur network includes healthcare providers from all specialties and practice settings throughout the U.S., including bariatric surgeons, internal medicine, family medicine, chiropractitioners, nutritional experts, and others in the lifestyle and integrative medicine space using genetics, nutrigenomics, gut microbiome and lifestyle risk to treat the complexity of the multifactorial disease of obesity and its' related medical conditions. Providers can sign-up to the network at no charge here.

About Digbi HealthDigbi Health is a first-of-its-kind precision digital therapeutics company that offers a prescription-grade digitally enabled personalized obesity and obesity related gut, skin disorders, hypertension and other cardiometabolic health management programs based on an individual's gut biome, genetic risks, blood markers, and lifestyle factors. Digbi Health and members of its physician network are committed to empowering people to take control of their own health and wellness. Digbi Health is prescribed by doctors, health care providers, and insurance companies.

SOURCE Digbi Health

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Digbi Health's gut-microbiome and genetic-based obesity management program now allows 60,000 Doctors and Providers in Blue Shield of California's...

4 New Life Sciences Licensing Deals and Investments to Watch – BioSpace

Posted on February 1, 2021 by Danzig

Today marked some wheeling and dealing in the life sciences industry as several companies licensed products or invested in other companies. Heres a look.

Eli Lillyand Asahi Kasei Pharma Eli Lilly and Company inked a license agreement with Tokyos Asahi Kasei Pharma Corporation. In it, Lilly picks up exclusive rights to AK1780 from Asahi. The drug is an oral P2X7 receptor antagonist that recently finished a Phase I dosing study. P2X7 receptors are associated with neuroinflammation that drives chronic pain conditions.

Under the terms of the deal, Lilly will handle future global development and regulatory activities. Lilly is paying Asahi Kasei Pharma $20 million up front and the Japanese company is eligible for up to $210 million in development and regulatory milestones. Asahi Kasei will retain the rights to promote the drug in Japan and China, including Hong Kong and Macau. If it makes it to market, Asahi Kesei will also be eligible for up to $180 million in sales milestones and tiered royalties from the mid-single to low-double digits.

Lilly is committed to developing novel medicines that may provide relief for patients suffering with various pain conditions, said Mark Mintun, vice president of pain and neurodegeneration research at Lilly. We are pleased to license this molecule from Asahi Kasei Pharma, and look forward to developing it further as a potential treatment for neuroinflammatory pain conditions.

Artiva Biotherapeutics and Merck San Diego-based Artiva Biotherapeutics announced an exclusive global collaboration and license agreement with Merck to develop novel chimeric antigen receptor (CAR)-NK cell therapies against solid tumor-associated antigens. They will leverage Artivas off-the-shelf allogeneic NK cell manufacturing platform and its proprietary CAR-NK technology. At first, the collaboration will include two CAR-NK programs with an option for a third. None of them are currently part of Artivas current or planned pipeline. Artiva will develop the programs through the first GMP manufacturing campaign and to preparation for the Investigational New Drug (IND) application, where Merck will take over clinical and commercial development.

Merck is paying Artiva $30 million upfront for the first two programs and another $15 million if Merck chooses to go ahead with the third. Artiva will be up for development and commercial milestones up to $612 million per program and royalties on global sales. Merck also is ponying up research funding for each program.

Our NK platform has been developed to be truly off-the-shelf and we believe it will be further validated by this exclusive collaboration with Merck, as we work together to bring cell therapies to all patients who may benefit, said Peter Flynn, chief operating officer of Artiva.

NeuBase Therapeutics and Vera Therapeutics Pittsburgh-based NeuBase Therapeutics announced a binding agreement to acquire infrastructure, programs and intellectual property for several peptide-nucleic acid (PNA) scaffolds from Vera Therapeutics, formerly called TruCode Gene Repair. Vera is based in South San Francisco. On January 19, Vera announced its launch with a $80 million Series C financing led by Abingworth LLP and joined by Sofinnova Investments, Longitude Capital, Fidelity Management & Research Company, Surveyor Capital, Octagon Capital, Kliner Perkins, GV and Alexandria Venture Investments. Veras lead clinical candidate is atacicept, a novel B cell and plasma cell inhibitor being developed for patients with IgA nephropathy (IgAN).

The technology acquired by NeuBase has shown the ability to resolve disease in genetic models of several disease indications. NeuBase is focused on genetic medicine.

With this acquisition, we enhance our PATrOL platform, furthering our unique ability to directly engage and correct malfunctioning genes with exquisite precision to address the root causes of a wide variety of human diseases, said Dietrich A. Stephan, chief executive officer of NeuBase. These assets extend and refine our PATrOL platforms capabilities and accelerates, through our Company, to bring the rapidly growing genetic medicines industry toward a single high-impact focal point. We are committed to advancing our pipeline and candidates to the clinic and to exploiting the full potential of PNA technology to continue creating value for our shareholders and importantly, for patients.

Bio-Techne Corporation and Changzhou Eminence Biotechnology Co Minneapolis-based Bio-Techne Corporation announced an initial minority strategic equity investment in Chinas Changzhou Eminence Biotechnology Co. Eminence plans to use the financing to expand its manufacturing capacity and increase the service capabilities of its China-based GMP media production facility. Eminence, based in Changzhou City, Jiangsu, China, launched in 2016 and initially focused on manufacturing and selling best-in-class media to life science companies, including Chinese Hamster Ovary (CHO) cells and other serum-free media products and services. The company is currently finishing and scaling its GMP production facility, which it plans to complete by the end of this year.

With our protein analysis instruments and expanding GMP protein capabilities, Bio-Techne continues to expand its offering of products and tools critical for bioprocessing, said Chuck Kumeth, president and chief executive officer of Bio-Techne. Investing in Eminence not only gives Bio-Techne a foothold in providing additional products and services to support the critical needs of the rapidly growing Chinese biopharmaceutical industry, but also fits extremely well with our existing high-growth product portfolio in China. We look forward to working with the Eminence team.

Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting – A Virtual Experience – PRNewswire

Posted on February 1, 2021 by Danzig

BETHESDA, Md., Jan. 27, 2021 /PRNewswire/ --The ACMG Annual Clinical Genetics Meeting will be a fully virtual meeting in 2021 and continues to provide groundbreaking research and the latest advances in medical genetics, genomics and personalized medicine. To be held April 1316, experience four days of professional growth, education, networking and collaboration with colleagues from around the world and discover what's shaping the future of genetics and genomics, including several sessions on COVID-19. The 2021 ACMG Meeting Virtual Experience is designed to offer a variety of engaging and interactive educational formats and types of sessionsfrom Scientific Sessions and Workshops to TED-Style Talks, Case-based Sessions, Platform Presentations and Short Courses. The 2021 ACMG Meeting Virtual Experience has something for everyone on the genetics healthcare team and will be available to participate in from the convenience of your home or office.

Interview those at the forefront in medical genetics and genomics, connect with new sources, and get story ideas on the clinical practice of genetics and genomics in healthcare today and for the future. Learn how genetics and genomics research is being integrated and applied into medical practice. Topics include COVID-19, gene editing, cancer genetics, molecular genomics, exome sequencing, pre- and perinatal genetics, diversity/equity and inclusion, biochemical/metabolic genetics, genetic counseling, health services and implementation, legal and ethical issues, therapeutics and more.

Credentialed media representatives on assignment are invited to cover the ACMG Annual Meeting A Virtual Experience on a complimentary basis. Contact Kathy Moran, MBA at [emailprotected]for the Press Registration Invitation Code, which will be needed to register at http://www.acmgmeeting.net.

Abstracts of presentations will be available online in February.

A few 2021 ACMG Annual Meeting highlights include:

Program Highlights:

Two Short Courses Available Starting on Tuesday, April 13:

Cutting-Edge Scientific Concurrent Sessions:

Social Media for the 2021 ACMG Meeting Virtual Experience: As the ACMG Annual Meeting approaches, journalists can stay up to date on new sessions and information by following the ACMG social media pages on Facebook,Twitterand Instagramand by usingthe hashtag #ACMGMtg21 for meeting-related tweets and posts.

The ACMG Annual Meeting website has extensive information at http://www.acmgmeeting.net and will be updated as new information becomes available.

About the American College of Medical Genetics and Genomics (ACMG) and the ACMG Foundation for Genetic and Genomic Medicine (ACMGF)

Founded in 1991, the American College of Medical Genetics and Genomics (ACMG) is the only nationally recognized medical society dedicated to improving health through the clinical practice of medical genetics and genomics and the only medical specialty society in the US that represents the full spectrum of medical genetics disciplines in a single organization. The ACMG is the largest membership organization specifically for medical geneticists, providing education, resources and a voice for more than 2,400 clinical and laboratory geneticists, genetic counselors and other healthcare professionals, nearly 80% of whom are board certified in the medical genetics specialties. ACMG's mission is to improve health through the clinical and laboratory practice of medical genetics as well as through advocacy, education and clinical research, and to guide the safe and effective integration of genetics and genomics into all of medicine and healthcare, resulting in improved personal and public health. Four overarching strategies guide ACMG's work: 1) to reinforce and expand ACMG's position as the leader and prominent authority in the field of medical genetics and genomics, including clinical research, while educating the medical community on the significant role that genetics and genomics will continue to play in understanding, preventing, treating and curing disease; 2) to secure and expand the professional workforce for medical genetics and genomics; 3) to advocate for the specialty; and 4) to provide best-in-class education to members and nonmembers. Genetics in Medicine, published monthly, is the official ACMG journal. ACMG's website (www.acmg.net) offers resources including policy statements, practice guidelines, educational programs and a 'Find a Genetic Service' tool. The educational and public health programs of the ACMG are dependent upon charitable gifts from corporations, foundations and individuals through the ACMG Foundation for Genetic and Genomic Medicine.

Kathy Moran, MBA[emailprotected]

SOURCE American College of Medical Genetics and Genomics

http://www.acmg.net

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Press Registration Is Now Open for the 2021 ACMG Annual Clinical Genetics Meeting - A Virtual Experience - PRNewswire

SMART Study Finds 22q11.2 Microdeletion Prevalence Much Higher than Expected – PRNewswire

Posted on February 1, 2021 by Danzig

SAN CARLOS, Calif., Feb. 1, 2021 /PRNewswire/ --Natera, Inc. (NASDAQ: NTRA), a pioneer and global leader in cfDNA testing, presented key results from its SMART study at the SMFM 41st Annual Pregnancy Meeting.1 The SMART study sets a new standard as the largest prospective NIPT study to date(N = 20,927 enrolled from 21 medical centers), and the only large-scale study to collect genetic outcomes in most of the subjects. The study includes the validation of a new artificial intelligence-based algorithm for Panoramacalled Panorama AI, which utilizes information from over 2 million cfDNA tests performed by Natera.

Key results related to the 22q11.2 microdeletion:

"This is the first prospective NIPT study in which genetic outcomes were confirmed in the vast majority of the patients enrolled, and provides a wealth of data about the real-world performance of NIPT across a diverse group of global centers and patients," said Mary Norton, MD, Professor, UCSF, and one of the Principal Investigators of SMART. "The findings related to high prevalence of 22q11.2 deletion syndrome, the limited ability of ultrasound to detect all cases prenatally, and the performance of NIPT in detection of these cases with high accuracy provide exciting data to inform discussions around testing for a broader set of conditions beyond common aneuploidies."

"The diagnostic odyssey related to 22q11.2 deletion syndrome is well documented, with median time to diagnosis of almost 5 years.6And in the meantime, a window of opportunity might be lost to intervene and impact outcomes. Delivery of a child with 22q11.2 deletion syndrome should be at a tertiary facility well-equipped to deal with short-term complications that are associated with the disorder.7 Depending on the issue at hand (e.g., cardiac, endocrine), appropriate interventions are warranted. For example, timely administration of neonatal calcium has been shown to correlate with preventing the intellectual decline commonly seen in affected children,"8,9 said Pe'er Dar, MD, Albert Einstein College of Medicine, Bronx NY, and one of the Principal Investigators of SMART. "With the ability to detect more accurately in combination with a low false positive rate, I believe that the findings of the SMART study provide professional societies with sufficient evidence to consider including screening for 22q11.2 deletions in routine prenatal genetic screening."

In 2020, Natera performed over 400,000 tests for the 22q11.2 microdeletion. Natera has established a CPT code and favorable pricing for microdeletion testing. Based on high prevalence and excellent performance in the study, Natera looks forward to engaging professional societies for routine testing of pregnancies for the 22q11.2 microdeletion, and will then pursue broader insurance coverage.

About Panorama

Panoramareveals a baby's risk for severe genetic disorders as early as nine weeks into pregnancy. The test uses a unique single-nucleotide polymorphism (SNP)-based technology to analyze fetal/placental DNA obtained through a blood draw from the mother. It is the only commercially available test that differentiates between maternal and fetal DNA to assess the risk of aneuploidies. The test also screens twin pregnancies for zygosity and fetal sex of each baby, and identifies risk for more genetic conditions in twin pregnancies than any other NIPT. Panorama is one of several genetic screening tests from Natera designed to help families on the path to parenthood. Natera has published 23 papers, studying over 1.3 million patients, since the launch of Panorama the largest body of evidence in the space today. Panorama has been developed and its performance characteristics determined by Natera, the CLIA-certified laboratory performing the test. The test has not been cleared or approved by the US Food and Drug Administration (FDA). CAP accredited, ISO 13485 certified, and CLIA certified.

About Natera

Naterais a pioneer and global leader in cell-free DNA testing from a simple blood draw. The mission of the company is to change the management of disease worldwide with a focus on women's health, oncology, and organ health. Natera operates ISO 13485-certified and CAP-accredited laboratories certified under the Clinical Laboratory Improvement Amendments (CLIA) in San Carlos, California and Austin, Texas. It offers proprietary genetic testing services to inform obstetricians, transplant physicians, oncologists, and cancer researchers, including biopharmaceutical companies, and genetic laboratories through its cloud-based software platform. For more information, visitnatera.com. Follow Natera onLinkedIn.

Forward-Looking Statements

All statements other than statements of historical facts contained in this press release are forward-looking statements and are not a representation that Natera's plans, estimates, or expectations will be achieved. These forward-looking statements represent Natera's expectations as of the date of this press release, and Natera disclaims any obligation to update the forward-looking statements. These forward-looking statements are subject to known and unknown risks and uncertainties that may cause actual results to differ materially, including with respect to our efforts to develop and commercialize new product offerings, our ability to successfully increase demand for and grow revenues for our product offerings, whether the results of clinical or other studies will support the use of our product offerings, our expectations of the reliability, accuracy and performance of our tests, or of the benefits of our tests and product offerings to patients, providers and payers. Additional risks and uncertainties are discussed in greater detail in "Risk Factors" in Natera's recent filings on Forms 10-K and 10-Q and in other filings Natera makes with the SEC from time to time. These documents are available atwww.natera.com/investorsandwww.sec.gov.

Contacts

Investor Relations: Mike Brophy, CFO, Natera, Inc., 510-826-2350

Media: Paul Greenland, VP of Corporate Marketing, Natera, Inc., [emailprotected]

References

SOURCE Natera, Inc.

https://www.natera.com/

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SMART Study Finds 22q11.2 Microdeletion Prevalence Much Higher than Expected - PRNewswire

CRISPR Mutants – The Dawn of CRISPR Mutants – SAPIENS – SAPIENS

Posted on February 1, 2021 by Danzig

The Mutant Project: Inside the Global Race to Genetically Modify Humansby Eben Kirksey. St. Martins Press, November 2020. Excerpt previously published by Black Inc.

Surreal artwork in the hotel lobbya gorilla peeking out of a peeled orange, smoking a cigarette; an astronaut riding a cyborg giraffewas the backdrop for bombshell news rocking the world. In November 2018, Hong Kongs Le Mridien Cyberport hotel became the epicenter of controversy about Jiankui He, a Chinese researcher who was staying there when a journalist revealed he had created the worlds first edited babies. Select experts were gathering in the hotel for the Second International Summit on Human Genome Editinga meeting that had been called to deliberate about the future of the human species. As CNN called the experiment monstrous, as heated discussions took place in labs and living rooms around the globe, He sat uncomfortably on a couch in the lobby.

He was trying to explain himself to Jennifer Doudna, the chemist at UC Berkeley, who is one of the pioneers behind CRISPR, a new genetic-engineering tool. Doudna had predicted that CRISPR would be used to direct the evolution of our species,* writing, We possess the ability to edit not only the DNA of every living human but also the DNA of future generations. As He went through his laboratory protocol, describing how he had manipulated the genes of freshly fertilized human eggs with CRISPR, Doudna shook her head. She knew that this moment might be coming someday, but she imagined that it would be in the far future. Amid the bustle of hotel guests, science fiction began to settle into the realm of established fact.

St. Martins Publishing Group

I was checking in to Le Mridien as the story broke and first heard rumors about Hes babies while chatting in the elevator with other summit delegates. We had come to Hong Kong to discuss the science, ethics, and governance of CRISPR and an assortment of lesser-known tools for tinkering with DNA. Struggling to overcome intense jet lagfresh off planes from Europe, the United States, and other parts of Asiawe listened to speculation in the hotels hallways while swimming through reality, caught between waking and dreaming.

Opening the door to my hotel room, a luxury suite courtesy of the U.S. National Academy of Sciences, I hunted for reliable sources of information online. I had been invited to speak on the research ethics panel, after Jiankui He, so I needed to play catch-up, fast. I found YouTube videos posted by Hes lab just hours before, offering details of the experiment. Posing in front of his laboratory equipment, with a broad smile on his face, He announced to the world: Two beautiful little Chinese girls, named Lulu and Nana, came crying into this world as healthy as any other babies a few weeks ago. The experiment aimed to delete a single gene with CRISPR. This new technique of genetic surgery, He claimed, could produce children who were resistant to the HIV virus.

Hunched over the glowing screen of my laptop, I perused the opinions that were just starting to form. Chinese media pundits suggested that a Nobel Prize might be in the making, saying that He was following in the footsteps of scientists who produced the first controversial test-tube baby in 1978. A raucous debate was taking place on WeiboChinas prominent social media platformas 1.9 billion people viewed the hashtag # (#FirstGeneEditedHIVImmuneBabies). Some Chinese influencers were praising Jiankui He as a national scientific hero. Others condemned him, saying that it was shameful to treat children like guinea pigs. Journalists were starting to discover Dr. Hes ties to biotechnology companiesone reportedly worth US$312 millionand alleged that there were serious financial conflicts of interest.

Anyone who follows the news knows the basic story. Over the next few days, Jiankui He experienced a meteoric rise to fame, followed by a dramatic fall from grace. Eventually, he lost his university job and was thrown in jail. A district court in China sentenced him to three years in prison for practicing medicine without a license, denouncing his pursuit of personal fame and profit.

Dr. Hes story is a gateway into a much bigger enterprise: the tale of CRISPR and the emergence of genetic medicine. The gala was quietly abuzz with news of other efforts to genetically modify humans. Experiments were already underway in England, the United States, and many other labs in mainland China. As billionaires and Wall Street investors were getting in on the action, as scientists and doctors were making careers out of CRISPR, I wondered: Who counts as a visionary, and who becomes a pariah?

He spoke about his gene-editing experiment that led to the birth of twin girls while at a summit in Hong Kong in 2018. VOAIris Tong/Wikimedia Commons

He was not alone in the pursuit of fame and fortune. It seemed like none of the scientists at the gala were innocent of financial conflicts of interest. Collectively, these enterprising biologists had already raised hundreds of millionsfrom venture capitalists, big pharma companies, and the stock marketfor genetic engineering experiments in human patients. I overheard excited chatter about new investment opportunities. The first gene therapy, a cancer treatment, had recently been approved in the United Stateswith a US$475,000 price tag. While the scientists gushed about the CRISPR revolution, I was quietly thinking about how genetic medicine is producing other upheavals in society. Profit-driven ventures in research and medicine were producing a new era of dramatic medical inequality.

As market forces propelled CRISPR into the clinic, I set out to answer basic questions about science and justice: Who is gaining access to cutting-edge genetic medicine? Are there creative ways to democratize the field? Panning out, I also explored questions that could have profound implications for the future of our species: Should parents be allowed to choose the genetic makeup of their children? How much can we actually change about the human condition by tinkering with DNA?

As a cultural anthropologist, I have often found myself opposing biologists in debates about human nature. Ever since Margaret Mead wrote her 1928 classicComing of Age in Samoa, anthropologists have argued that a persons life is shaped by the social environment in which each is born and raised rather than genetic heredity alone.Anthropologists have recently joined other progressive thinkers to imagine how science has enabled new experimental possibilities for human beings.Now we are studying how the human social environment has been shaped by synthetic chemistry, smartphones, the internet, and biotechnology.

My goal has been to map how genetic engineering will transform humanity. Rather than limit my research to a single culture, I followed CRISPR around the globe. I tracked the impact of this gene-editing tool as it traveled from media reports to laboratories, through artificial intelligence algorithms, and into the cells of embryos and the bodies of living people. Using an anthropological lens, I examined new forms of power as scientists, corporate lobbyists, medical doctors, and biotechnology entrepreneurs worked to redesign life itself.

I will offer you a mosaic portrait. This is a story of people and concerns on either side of the dynamics of power that has emerged with CRISPR. I moved among the powerful in their native habitats: conferences, fancy hotels, restaurants, corporate offices, and cluttered labs. To understand how social inequality is changing in this brave new world, I also interviewed chronically ill patients, disabled scholars, and hackers. From the power centers to the margins, I went where I could find answers. Very old conflicts were playing out even as new technologies transformed science and medicine.

An exhibit on reproductive technologies at the China National GeneBank envisions a future where robots rear human embryos. Eben Kirksey

When I set out to meet some of the first genetically modified people, I found activists who were battling insurance agents and biotechnology companies for potentially lifesaving treatments. Nearly a decade before Dr. He stirred up controversy in China, a small group of HIV-positive gay men in the United States quietly participated in a clinical trial dubbed the first-in-man gene-editing experiment. Researchers aimed to delete a gene from these menthe same DNA sequence later targeted by Hein hopes of engineering resistance to the virus and repairing damage to their immune systems from AIDS. One veteran HIV activist who participated in this study, Matt Sharp, convinced me that having his DNA altered wasnt a big deal and that genetic engineering does indeed have real medical promise. Sharp also confirmed my suspicions: Biotech companies are putting profits ahead of human health as they search for lucrative applications of gene editing in the clinic.

Gene editing is not a particularly good metaphor for explaining the science of CRISPR. With a computer, I can easily cut and paste text from one application to another, or make clean deletionsletter by letter, line by line. But CRISPR does not have these precise editorial functions. CRISPR is more like a tiny Reaper drone that can produce targeted damage to DNA. Sometimes it makes a precision missile strike, destroying the target. It can also produce serious collateral damage, like a drone attack that accidentally takes out a wedding party instead of the intended target. Scientists often accidentally blast away big chunks of DNA as they try to improve the code of life. CRISPR can also go astray when the preprogrammed coordinates are ambiguous, like a rogue drone that automatically strikes the friends, neighbors, and relatives of suspected terrorists. CRISPR can persist in cells for weeks, bouncing around the chromosomes, producing damage to DNA over and over again every time it finds a near match to the intended target.

How much can we actually change about the human condition by tinkering with DNA?

It is important to signal a sense of risk or a need for caution in using CRISPR. Other metaphorslike genetic surgery or DNA hackinghave been proposed to replace the idea of editing. The idea of genetic surgery suggests that there can be a slip of the surgeons knife, creating an unintended injury. Each of these imagesthe targeted missile, the surgeons scalpel, the hackers codeoffers a perspective on how CRISPR works, even while concealing messy cellular dynamics. In the absence of a perfect metaphor, ultimately, I think that technical language describes it best: CRISPR is an enzyme that produces targeted mutagenesis.

In other words, CRISPR generates mutants.

Strictly speaking, we are all mutants. At a molecular level, each of us is unique. Each of us starts life with 4080 new mutations that were not found in our parents. From birth, each of us has around 20 inactive genes from loss-of-function mutations. During the course of a normal human life, we also accumulate mutations in our bodies, even in our brains. By the time we reach age 60, a single skin cell will contain between 4,000 and 40,000 mutations, according to a study in theProceedings of the National Academy of Sciences. These genetic changes are the result of mistakes made each time our DNA is copied during cell division or when cells are damaged by radiation, ultraviolet rays, or toxic chemicals. Generally, mutations arent good or bad, just different.

Mutants in popular culture play important roles in our high-tech myths. Some cartoons simply celebrate mutation as whimsical possibility. The pizza-eating Teenage Mutant Ninja Turtles are known for fighting crime in support of established law and order. Darker speculative fiction uses mutants to illustrate the hypocrisy and inhumanity of the scientific establishment. Violent experiments on children who were born with special abilities feature in recent Netflix series likeStranger Things. Horror flicks and video games featuring mindless zombies and flesh-eating mutants have a common theme: Science could create monsters that cannot be controlled.

Reporters who sounded the alarm about Lulu and Nanas birthcalling them freaky CRISPR Frankenbabiesclearly had not done their literary homework. Frankensteins monster is now popularly imagined as a dimwitted giant with electrodes in his neckfollowing imagery from the first black-and-white film, put out by Universal Pictures in 1931. The originalFrankenstein, Mary Shelleys gothic novel from 1818, described a superhuman creature that was driven by the desire to be loved. The highly intelligent, articulate, and high-minded creature only turned violent when he was shunned by human society. Amid the controversy about Dr. Hes experiment, a political theorist and literary scholar named Eileen Hunt Botting defended the rights of genetically modified children to live, love, and flourish. Flipping the mainstream script, she wrote an essay for TheWashington Postsuggesting that Frankenstein is an apt cautionary tale about the possibility of devastating discrimination against a bioengineered child.

Some media reports on Lulu and Nana, the first known gene-edited human babies, referenced the science-fiction character Frankenstein (shown here from the film by that name). Universal Pictures/Wikimedia Commons

During my international adventures in the world of CRISPR research, I kept science fiction classics close at hand. The rich archive of speculative fiction has helped me understand the perils and potential of experiments that are remaking the human species.

Scientists have identified some geneslike those associated with eye and skin colorthat would be relatively easy to manipulate. One Russian American gene-editing expert, Fyodor Urnov, intimated that it should be biologically possible to engineer soldiers or athletes with enhanced endurance, speed, and muscle mass. Genetic enhancements come with serious health risks, but military leaders have a long history of ignoring the health and well-being of their soldiers. Fertility clinics also have a bad track record as profit-driven enterprises, ready to sell couples expensive and scientifically unproven treatments. The New Hope Fertility Center in Manhattan is already advertising a new technique: Couples could soon have the opportunity to create designer babies with CRISPR.As scientists speculate about post-racial futures and nightmare military scenarios, as market forces bring new genetic technologies into the clinic at a dizzying speed, it is time to slow down and establish some clear rules for the road. Misguided attempts to improve the human species have already produced atrocitieslike the Nazi death camps that systematically eliminated homosexuals and Jews from the population. In the wrong hands, CRISPR could have devastating consequences for humanity.

This excerpt has been edited slightly for style and length.

* Clarification: This quote comes from A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, written by Jennifer Doudna and Samuel Sternberg.

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CRISPR Mutants - The Dawn of CRISPR Mutants - SAPIENS - SAPIENS

Genomes, Maps, And How They Affect You – IFLScience

Posted on February 1, 2021 by Danzig

What is a genome

A genome is a collective term for all the genetic material within an organism. In essence,the genome decides exactly what that organism will look and act like at birth one huge, expansive instruction manual that tellscells their duties. Every living thing has a genome, from bacteria to plants to humans, and they are all different in size with various combinations of genes inside.

The human genome packs in 30,000 genes, but this is just 1% of the total genetic material contained within. Quite frankly, its a mess in there much of the genetic material is duplicated DNA that (supposedly) does very little, and the vast majority of DNA simply doesnt code for anything(these sections are calledintrons). That isnt to say it does nothing. In fact,recent studieshave shown us that non-coding DNA is essential to controlling whether our genes get switched on or not. However, most of the time its the actual genes that are the important bit.

Studying the genome of humans and other organisms is vitalfor a number of reasons.Firstly, it helps us characterize each one before genomics, scientists simply grouped animals and plants by what they looked like, but research into their genes now allows for accuratecharacterization oforganismsinto specificgeneraand species.

In humans, genomic research has allowed researchers to understand the underlying causes of many complex diseases and find possible targets for treatment.Currently, the best tool to do thisisgenome-wide association studies (GWAS).

The idea behind GWAS is relatively intuitive simply take a group of people with the disease you wish to study, and compare their genomesfor common genetic variants that could predict the presence of that disease.These studies have illuminated a huge number of variants linked with higher disease prevalence while also helping researchers to understand the role each gene playsin the human body.Although powerful, GWAS studies are purely a starting point. Following a large-scale GWAS, researchers must thenanalyzeany variants that are highlighted in great depth, and many times such research will provide nothing of clinical relevance. However, itsstill our best way of identifying risk variants in genetic disease.

So,we know the genome is packed to the brim with genes that code for proteins, separated by large strings ofnon-coding DNA. However, when cells replicateearly in development they usually go throughchromosomal recombination, in which chromosomes trade regions of their genetic code between each other. This spreads genes to many different positions (called loci)throughout the genome. If we can make a map of these genes, we candiscover their function, how they are inherited, or target them with therapies.

Therefore, we want to create a genome map.There are two types of maps used in genomics: genetic maps and physical maps.

Physical mapsare relatively straightforward, in which genomic loci are mapped based on the physical distance between them, measured in base pairs.The most common way to create a physical map of a human genome is byfirst breaking the DNA sequence into many fragments, before using a variety of different techniques to identify how those pieces fit back together. By understanding which pieces overlapand reconstructing the shattered genome, scientists can gain a decently accurate map of where each gene lies.

Genetic mapsare slightly different,using specific marker regions within the DNA that are used as trackers. These mapsrequiresamples (usually saliva) from family members,which are then compared toidentifyhow much recombination has occurred that includes markers of interest. The principle is thatif two genes are close together on thechromosome, thenthey are more likely to travel together through the genome as it recombines. By using this data,scientists can get a rough idea of where specific genes lie on chromosomes. However, it is not as accurate as physical mapping andrelies heavilyon a decentpopulation size andthe number of genetic markers used.

A genome browser is any available database that allows a user to access and compare genomes in an intuitive way. When you map or sequence a genome, the data is prettymessy.Genomes are usually stored in huge files, calledFASTAfiles, that contain extensive strings of letters that would look foreign to most users. Genome browsers take this data and make it accessibleto scientists around the globe.

Many genome browsers are available online, containing bacterial, model organism, and human reference genomes.

Genomelinkis one of the latest examples of public access and analysis of genomes. The industry took off in recentyears, with the rapid rise of sites that provide ancestry and medical information based on genomic sequencing, includingAncestryand23andMe.These sites work by comparing genetic markers associated with different populations should you share specific regions of DNA that correspond with African populations, for example, you may have some relation to African ancestors. Each site uses its own markers, so information may vary between tests, and some have disputed the true accuracy of these tests, although advances in genomics have significantly improved them in recent years.

Genomelinkgoes further than most sites, claiming to provide information on a huge variety of genetic traits that a user may have. These include metabolism, sports performance, and even personality traits such as loneliness. Each trait isdrawn from genome correlation studies, with each taking a specific trait and comparing the genomes of each carrier of that trait.

However, although bothGenomelinkand other sites use up-to-date reference genomes and are usually relatively accurate, they should never be substituted for medical information. If you believe you carry a pathogenic genevariant, you should seek advice from a genomic counselor.

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Genomes, Maps, And How They Affect You - IFLScience

Are Phages Overlooked Mediators of Health and Disease? – The Scientist

Posted on February 1, 2021 by Danzig

When microbiologist Breck Duerkop started his postdoc in 2009, he figured hed be focusing on bacteria. After all, hed joined the lab of microbiome researcher Lora Hooper at the University of Texas Southwestern Medical Center in Dallas to study host-pathogen interactions in the mammalian gut and was particularly interested in what causes some strains of normally harmless commensal bacteria, such as Enterococcusfaecalis, to become dangerous, gut-dominating pathogens. Hed decided to explore the issue by giving germ-free mice a multidrug-resistant strain of E. faecalis that sometimes causes life-threatening infections in hospital patients, and analyzing how these bacteria express their genes in the mouse intestine.

Not long into the project, Duerkop noticed something else going on: some of the genes being expressed in E. faecalis werent from the regular bacterial genome. Rather, they were from bacteriophages, bacteria-infecting viruses that, if they dont immediately hijack and kill the cells they infect, can sometimes incorporate their genetic material into the bacterial chromosome. These stowaway viruses, known as prophages while theyre in the bacterial chromosome, may lie dormant for multiple bacterial generations, until certain environmental or other factors trigger their reactivation, at which point they begin replicating and behaving like infectious agents once again. (See illustration below.) Duerkops data showed that the chromosome of the E. faecalis strain he was using contained seven of these prophages and that the bacteria were churning out virus particles with custom combinations of these prophage sequences during colonization of the mouse gut.

The presence of viruses in Duerkops E. faecalis strain wasnt all that surprising. Natural predators of bacteria, bacteriophages are the most abundant biological entities on the planet, and in many fields, researchers take their presence for granted. Nobody really was thinking about phages in the context of bacterial communities in animal hosts, Duerkop says. It would [have been] very easy to just look at it and say, Oh, there are some phage genes here. . . . Moving on. But he was curious about why E. faecalis would be copying and releasing them, rather than leaving the prophages asleep in its chromosome, while it was trying to establish itself in the mouse intestine.

Predation is just one type of phage-bacteria interaction taking place within the mammalian microbiome; many phages are capable of inserting their genomes into the bacterial chromosome.

Encouraged by Hooper, he put his original project on hold in order to dig deeper. To his surprise, he discovered that the E. faecalis strain, known as V583, seemed to be using its phages to gain a competitive advantage over related strains. Experiments with multiple E. faecalis strains in cell culture and in mice showed that the phage particles produced by the bacteria didnt harm other V583 cells, but infected and killed competing strains. Duerkop and his colleagues realized that, far from being background actors in the bacterial community, the phages are important for colonization behavior for this opportunistic pathogen.

The idea that a phage could play such a significant role in the development of the gut bacterial community was relatively novel when the team published its results in 2012. Since then, its been pretty well established that phages can shape the assembly of microbial communities in the intestine, and that can influence the outcome on the hosteither beneficially or detrimentally, says Duerkop, who now runs his own lab at the University of Colorado School of Medicine in Aurora. Theres evidence that phages help bacteria share genetic material with one another, too, and may even interact directly with the mammalian immune system, an idea that Duerkop says would have had you laughed out of a room of immunologists just a few years ago.

Around the time that Duerkop was working on E. faecalis in Dallas, University of Oxford postdoc Pauline Scanlan was studying Pseudomonas fluorescens, a bacterial species that is abundant in the natural environment and is generally harmless to humans, although its in the same genus as the important human pathogen Pseudomonas aeruginosa. Bacteria in this genus sometimes evolve whats known as a mucoid phenotypethat is, cells secrete large amounts of a compound called alginate, forming a protective goo around themselves. In P. aeruginosa, this goo can help the bacteria evade the mammalian immune system and antibiotics, and when it crops up, its not good news for the patient, Scanlan says. She was curious about what causes a non-mucoid bacterial population to evolve into a mucoid one and had found previous research suggesting that the presence of bacteriophages could play a role. Other studies documented high densities of phages in mucus samples from the lungs of some cystic fibrosis patients with P. aeruginosa infections.

Working in the lab of evolutionary biologist Angus Buckling (now at the University of Exeter), Scanlan grew a strain of P. fluorescenswith a phage called Phi2 that specifically infects and destroys this bacterium. Cells with the gummy mucoid coating, the researchers noted, were more resistant to phage infection than regular cells were. Whats more, over generations, bacterial populations were more likely to evolve the mucoid phenotypes in the presence of Phi2 than they were in its absence, indicating that the phenotype may arise in Pseudomonas as an adaptive response to phage attack. Scanlan, now at University College Cork (UCC) in Ireland, notes that more work is needed to extend the findings to a clinical setting, but the results hint that phages could in some cases be responsible for driving bacteria to adopt more virulent phenotypes.

Such a role for viruses in driving bacterial evolution fits well with phages reputation as the ultimate predators, says Colin Hill, a molecular microbiologist also at UCC who got his introduction to phages studying bacteria used in making fermented foods such as cheese. Hill notes an estimate commonly cited in the context of marine biologya field that explored phage-bacteria interactions long before human biology didthat phages kill up to 50 percent of the bacteria in any environment every 48 hours. The thing that any bacterium has on its mind most, if bacteria had minds, would be phage, Hill says, because its the thing most likely to kill them.

Several in vivo animal studies lend support to the idea that predatory phages help shape bacterial evolution and community composition in the mammalian microbiome. In 2019, for example, researchers at Harvard Medical School reported that phages not only directly affect the bacteria they infect in the mouse gut, but also influence the rest of the microbiome community via cascading effects on the chemical and biological composition of the gut. Observational studies hint at similar processes at work in the human gut. A few years ago, researchers at Washington University Medical School in St. Louis observed patterns of phage and bacterial population dynamics that resembledpredator-prey cycles in the guts of children younger than two years old: low bacterial densities at birth were followed by decreases in phages, after which the bacteria would rebound, and then the phages would follow suit. The team concluded that these cycles were likely a natural part of healthy microbiome development.

Although researchers are only just beginning to appreciate the importance of phages in microbiome dynamics, theyve already begun to explore links to human disease. Authors of one 2015 study reported that Crohns disease and ulcerative colitis patients showed elevated levels of certain phages, particularly within the viral order Caudovirales. They proposed that an altered virome could contribute to pathogenesis through predator-prey interactions between phages and their bacterial hosts. Other studies have explored possible phage-driven changes in the bacterial community in human diseases such as diabetes and certain cancers that are known to be associated with a disrupted microbiome. But the observational nature of human microbiome studies prevents conclusions about what drives whatchanges in virome composition could themselves be the result of disruptions to the bacterial community, for example.

Currently, researchers are exploring the possibility of using predatory phages as weapons against pathogenic bacteria, particularly those that present a serious threat to public health due to the evolution of resistance to multiple antibiotics. Its the principle that the enemy of my enemy is my friend, says Yale University virologist and evolutionary biologist Paul Turner. If we have a pathogen that is in your microbiome, can we go in and remove that bacterial pathogen by introducing a predatory phage, something that is cued to only destroy [that pathogen]? Although the strategy was first proposed more than a century ago, we and others are trying to update it, he adds. (See My Enemys Enemy below.)

Phages can interact with bacteria in two main ways. In the first, phages infect a bacterial cell and hijack that cells protein-making machinery to replicate themselves, after which the newly made virus particles lyse the bacterium and go on to infect more cells. In the second process, known as lysogeny, the viral genome is incorporated into the bacterial chromosome, becoming whats known as a prophage, and lies dormantpotentially for many generationsuntil certain biotic or abiotic factors in the bacterium or the environment induce it to excise itself from the chromosome and resume the cycle of viral replication, lysis, and infection of new cells.

Predation is just one type of phage-bacteria interaction taking place within the mammalian microbiome. Many phages are capable of inserting their genomes into the bacterial chromosome, a trick beyond the bounds of traditional predator-prey relationships in other kingdoms of life that adds complexity to the relationship between phages and bacteria, and consequently, to phages potential influences on human health.

This role for phages has long been of interest to Imperial College Londons Jos Penads. Over the last 15 years or so, he and colleagues have described various ways in which many phages help bacteria swap genetic material among cells. He likens phages to cars that bacteria use to transport cargo around and says that, in his opinion, it almost makes sense to view phages as an extension of bacteria rather than as independent entities. This is part of the bacterium, he says. Without phages, bacteria cannot really evolve. They are absolutely required.

With lateral [transduction] you can move huge parts of the bacterial chromosome.

Jos Penads, Imperial College London

In the simplest case, the genetic material being transported consists of viral genes in the genomes of so-called temperate phages, which spend at least part of their lifecycle stashed away in bacterial chromosomes as prophages. These phages are coming to be appreciated by microbiologists as an important driver of bacterial evolution in the human microbiome, notes Hill. The lack of practical and accurate virus detection methods makes it difficult to precisely characterize a lot of the phages resident in mammalian guts, but microbiologists estimate that up to 50 percent are temperate phages, and, more importantly for human health, that many of them may carry genes relevant to bacterial virulence. Researchers have long known, for example, that many toxins produced by bacteriaincluding Shiga toxin, made by some pathogenic E. coli strains, and cholera toxin, secreted by the cholera-causing bacterium Vibrio choleraeare in fact encoded by viral genes contained in the bacterial chromosome, and that infection by temperate phages that carry these genes may be able to turn a harmless bacterial population into one thats pathogenic.

Evidence from other studies points to phages as capable of transporting not just their own genomes, but bits of bacterial DNA as well. In the best-studied examples of this phenomenon, known as bacterial transduction, tiny chunks of the bacterial genome get packed up into viral particles instead of or alongside the phage genome, and are shuttled to other bacterial cells. In 2018, however, Penads and colleagues presented results showing that very large pieces of bacterial DNA can also be exchanged this way, in a process the team named lateral transduction. Not only does the discovery have implications for how researchers understand viral replication in infected cells, it shines light on a novel way for bacteria to share their genes. With lateral [transduction] you can move huge parts of the bacterial chromosome, says Penads. The team first observed the phenomenon in the important human pathogen Staphylococcus aureus, and is now looking for it in other taxa, he adds. Right now, for us, its important to show that its a general mechanism, with many bugs involved.

Although the research is still in the nascent stages, this mechanism could help explain findings from University of Barcelona microbiologist Maite Muniesa and others who have been studying whether phages transport antibiotic resistance genes between bacterial cells, and whether they can act as reservoirs for these genes in the natural environment. Early studies on this issue had proposed that, like many toxin genes, antibiotic resistance genes might be encoded in viral sequences and thus transported to bacteria with the rest of the viral genome. But the idea wasnt without controversya 2016 analysis of more than 1,100 phage genomes from various environments concluded that phage genomes only rarely include antibiotic resistance genes. That studys authors argued that prior reports of these genes in phage genomes were likely due to contamination, or to the difficulty of distinguishing viral sequences from bacterial ones.

Nevertheless, Muniesas team has published multiple reports of antibiotic resistance sequences in phage particles, including in samples of meat products from a Barcelonan fresh-food retailer, and more recently in seawater samplesnot only from the Mediterranean coastline but even off the coast of Antarctica, far from human populations that use antibiotics. We were pretty surprised that we found these particles in this area with low human influence, Muniesa says. Although her team hasnt determined whether the antibiotic resistance sequences are of phage or bacterial origin, she suspects they might be bacterial genes that ended up in phage particles during lateral transduction or some process like it. Bacteria are using these phage particles in a natural way to move [genes] between their brothers and sisters, lets say, she says. Its happening everywhere.

Duerkop cautions that its not yet clear how often phage-mediated transfer of antibiotic resistance genes occurs or how significant it is in the epidemiology of drug-resistant infections in people. Its not to say that antibiotic resistance cant be mediated through phage, he says. I just dont think its a major driver of antibiotic resistance.

Whatever its natural role, temperate phages ability to insert themselves into bacterial genomes could have applications in new antibacterial therapies. Viruses that insert pathogenicity-reducing genes or disrupt the normal expression of the bacterial chromosome could be used to hobble dangerous bacteria, for examplean approach that proved successful last year in mouse experiments with Bordetella bronchiseptica, a bacterium that often causes respiratory diseases in livestock. Using a phage from the order Siphoviridae, researchers found that infected B. bronchiseptica cells were substantially less virulent in mice than control cells were, likely because the viral genome had inserted itself in the middle of a gene that the bacterium needs to infect its host. Whats more, injecting mice with the phage before exposing them to B. bronchiseptica seemed to completely protect them from infection by the microbe, hinting at the possibility of using temperate phages as vaccines against some bacteria.

Bacteria-infecting viruses, or bacteriophages, may influence microbial communities in the mammalian gut in various ways, some of which are illustrated here. Through predation, phages can influence the abundance of specific bacterial taxa, with indirect effects on the rest of the community, and can drive the evolution of specific bacterial phenotypes. Phages can also incorporate their genomes into bacterial chromosomes, where the viral sequences lie dormant as prophages until reactivated. Researchers have found that phages interact directly with mammalian cells in the gut, too. These cross-kingdom interactions could affect the health of their eukaryotic hosts.

Despite growing interest in phages role in shuttling material among bacteria, some of the biggest recent developments in research on phages in the human gut have turned out not to involve bacteria at all. One of the key pieces of this particular puzzle was fitted by University of Utah microbiologist June Round and her colleagues, who as part of a phage therapy study a few years ago fed several types of Caudovirales phages to mice that were genetically predisposed to certain types of cancer and had been infected with a strain of E. coli known to increase that risk. The premise was pretty simplistic, recalls Round. It was just to identify a cocktail of phage that would target bacteria that we know drive chronic colorectal cancer.

The team was surprised to see that the phages, despite being viewed by most researchers as exclusively bacteria-attacking entities, prompted a substantial response from the mices immune systemsmammalian defenses that should, according to conventional wisdom, be indifferent to the war between bacteria and phages in the gut. Intrigued, the researchers tried adding their phage cocktail to mice that had had their gut bacteria completely wiped out with antibiotics. Still, they saw an immune response. It was then, Round says, that we realized that [the phages] were likely interacting with the immune system.

Exploring further, the team found that the phages were activating both innate and adaptive immune responses in mice. In rodents with colitis, the phages exacerbated inflammation. Turning their attention to people, the researchers isolated phages from ulcerative colitis patients with active disease, as well as from patients with disease in remission and from healthy controls, and showed that only viruses collected from patients with active disease stimulated immune cells in vitro. And when the team studied patients who received fecal microbiota transplantationan experimental treatment for ulcerative colitis that involves giving beneficial gut bacteria to a patient to try to alleviate inflammation and improve symptomsthe researchers found that a lower abundance of Caudovirales in a recipients intestine at the time of transplant correlated with treatment success.

Some of the biggest recent developments in research on phages in the human gut have turned out not to involve bacteria at all.

By the time the team published its results in 2019, a couple of other groups had also documented evidence of direct interactions between phages and host immune systems. Meanwhile, Duerkop, Hooper, and colleagues reported that mice with colitis tended to have specific bacteriophage communities, rich in Caudovirales, that developed in parallel with the disease. Many of the types of phage they identified in the intestines of those diseased mice also turned up in high abundance in samples taken from the guts of people with inflammatory bowel disease, the researchers noted in their paper, supporting a possible role for phages in the development of disease.

Round says that researchers are still unsure about exactly why these trans-kingdom interactions are happeningparticularly when it comes to host adaptive immune responses, which tend to be specific to a particular pathogen. She speculates that mammalian hosts might derive a benefit from destroying certain phages if those phages are carrying genes that could aid a bacterium with the potential to cause disease. Exactly how immune cells would detect what genes a phage is carrying isnt yet clear.

Meanwhile, hints of collaboration between eukaryotic cells and phages have cropped up in the work of several other labs. One recent study of a phage therapy against P. aeruginosa found that phages and immune cells seem to act in synergy to clear infections in mice. Other work has indicated that phages bind to glycoproteins presented by cells along the mucosal surfaces of the mammalian gut and may provide a protective barrier against bacterial pathogensa relationship that some microbiologists have argued represents an example of phage-animal symbiosis. Duerkop adds that theres evidence emerging to support the idea that phages in the mammalian intestine not only can be engulfed by certain eukaryotic cells, but also might slip out of the gut and into the bloodstream to make their way to other parts of the body, with as yet undiscovered consequences.

Whether these mechanisms can be exploited for therapeutic purposes remains to be seen, but Round notes that they do raise the possibility of unintended effects in some circumstances if researchers try to use phages to influence human health via the gut microbiome. At least in the type of chronic inflammatory diseases she and her team have been studying, we might just be making it worse by using phages to target disease-causing bacteria, she says, adding that all research groups studying such approaches should take into account potential knock-on effects. Considering phages multiple interactions, with both bacteria and animal cells, she says, its a lot more complex than what wed appreciated.

Bacteriophages ability to selectively target and kill specific bacterial strains has long been recognized as a possible basis for antimicrobial therapies. Proposed by researchers in Europe as early as 1919, phage therapy went on to be widely promoted in Germany, the USSR, and elsewhere before being overtaken worldwide by the soaring popularity of antibiotics in the 1940s. But the strategy has come back into fashion among many microbiologists, thanks to the growing public health problem of antibiotic resistance in bacterial pathogens and to the rapidly improving scientific understanding of phage-bacteria interactions.

Some of the latest approaches aim not only to target specific bacteria with phages, but also to avoid (or exploit) the seemingly inevitable evolution of phage resistance in those bacteria. One way researchers try to do this is by taking advantage of an evolutionary trade-off: bacterial strains that evolve adaptations to one therapy will often suffer reduced fitness when confronted with a second therapy, perhaps one that targets the same or similar pathways in a different way.

Yale University virologist and evolutionary biologist Paul Turner, for example, has studied how phages in the Myoviridae (a family in the order Caudovirales) can promote antibiotic sensitivity in the important human pathogen Pseudomonas aeruginosa. Turner and colleagues showed a few years ago that one such phage binds to a protein called OprM in the bacterial cell membrane, and that bacterial populations under attack from these phages will often evolve reduced production of OprM proteins as a way of avoiding infection. However, OprM also happens to be important for pumping antibiotics out of the cell, such that abnormal OprM levels can reduce bacterias abilityto survive antibiotic treatment in vitro.

A handful of groups have published case studies using this kind of approach, known as phage steering, in humans. A couple years ago, for example, Turner and colleagues reported that a post-surgery patients chronicP. aeruginosa infection cleared up after treatment with the OprM-binding phage and the antibiotic ceftazidime. Researchers at the University of California, San Diego, in partnership with California-based biotech AmpliPhi Biosciences (now Armata Pharmaceuticals), reportedsimilar successin a cystic fibrosis patient with a P. aeruginosa infection who was treated with a mixture of phages and with antibiotics. A Phase 1/2 trial for that therapy was greenlighted by the US Food and Drug Administration last October.

The complexity of the relationship between phages and bacteria, not to mention recently discovered interactions between phages and eukaryotic cells, has many researchers tempering optimism about phage therapy with caution. There might be off-target effects to this that we hadnt really thought about, says University of Colorado School of Medicine microbiologist Breck Duerkop. That said, thanks to research in the last few years, the black veil on phage therapy is, I believe, being lifted, he adds, which Im really excited about because I think they have a ton of potential to be used in biomedicine.

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Are Phages Overlooked Mediators of Health and Disease? - The Scientist

Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia – MD Magazine

Posted on February 1, 2021 by Danzig

Two different gene therapies have been used to mitigate a mechanism underlying development of sickle cell disease (SCD) and transfusion-dependent -thalassemia (TDT), and both have demonstrated clinical success in separate, concurrently published trials.

The hemoglobinopathies manifest after fetal hemoglobin synthesis is replaced by adult hemoglobin in individuals who have inherited a mutation in the hemoglobin subunit gene (HBB).Identifying factors in the conversion from fetal to adult hemoglobin synthesis, however, has provided potential targets for therapeutic intervention.

Gene therapy that can safely arrest or reduce the conversion offers the potential for a one-time treatment to obviate the need for lifetime transfusions and iron chelation for patients with TDT, and the pain management, transfusions and hydroxyurea administration for those with SCD.

Two groups of investigators have now reported in The New England Journal of Medicine that, using different gene therapy techniques that target the transcription factor, BCL11a, involved in the globin switching, they have improved clinical outcomes in patients with TDT and with SCD.

In an editorial in the issue featuring the 2 studies, Mark Walters, MD, Blood and Marrow Transplant Program, University of California, San Francisco-Benioff Children's Hospital, welcomed the breakthroughs.

"These trials herald a new generation of broadly applicable curative treatments for hemoglobinopathies," Walters wrote.

In one clinical trial with 2 patients, one with TDT and the other with SCD, Haydar Frangoul, MD, MS, Medical Director, Pediatric Hematology/Oncology, Sarah Cannon Center for Blood Cancer at the Children's Hospital at Tristar Centennial, and colleagues administered CRISPR-Cas9 gene edited hematopoietic stem and progenitor cells (HSPCs) with reduced BCL11A expression in the erythroid lineage.

The product, CTX001, had been shown in preclinical study to restore -globulin synthesis and reactivate production of fetal hemoglobin. Both patients underwent busulfan-induced myeloablation prior to receiving the treatment.

The investigators suggested that the CRISPR-Cas9-based gene-edited product could change the paradigm for patients with these conditions, if it was found to successfully and durably graft, produce no "off-target" editing products, and, importantly, improve clinical course.

"Recently approved therapies, including luspatercept and crizanlizumab, have reduced transfusion requirements in patients with TDT and the incidence of vaso-occlusive episodes in those with SCD, respectively, but neither treatment addressed the underlying cause of the disease nor fully ameliorates disease manifestations," Frangoul and colleagues wrote.

The investigators reported that both patients had "early, substantial, and sustained increases" in pancellularly distributed fetal hemoglobin levels during the 12-month study period. Further, the patients no longer required transfusions, and the patient with SCD no longer experienced vaso-occlusive episodes after the treatment.

In commentary accompanying the report, Harry Malech, MD, Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), Bethesda, MD, described the investigators' application of the gene-editing technology as a "remarkable level of functional correction of the disease phenotype."

"With tangible results for their patients, Frangoul et al have provided a proof of principle of the emerging clinical potential for gene-editing treatments to ameliorate the burden of human disease," Malech pronounced.

In the other published trial, with 6 patients with SCD, Erica Esrick MD, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, and colleagues described results with infusion of gene-modified cells derived from lentivirus insertion of a gene that knocks down BCL11a by encoding an erythroid-specific, inhibitory short-hairpin RNA (shRNA).

The severity of SCD that qualified patients for enrollment included history of stroke (n = 3), frequent vaso-occlusive events (n = 2) and frequent episodes of priapism (1).Patients were followed for 2 years, and offered enrollment in a 13-year long-term follow-up study.The infusion of the experimental drug BCH-BB694, from the short hairpin RNA embedded within an endogeonous micro RNA scaffold (termed a shmiR vector), was initiated after myeloablation with busulfan.

Esrick and colleagues reported that, at median follow-up of 18 months (range, 7-29), all patients had engraftment and a robust and stable HbF induction broadly distributed in red cells.Clinical manifestations of SCD were reduced or absent during the follow-up period; with no patient having a vaso-occlusive crisis, acute chest syndrome, or stoke subsequent to the gene therapy infusion.Adverse events were consistent with effects of the preparative chemotherapy.

"The field of autologous gene therapies for hemoglobinopathies is advancing rapidly," Esrick and colleagues reported, "including lentiviral trials of gene addition in which the nonsickling hemoglobin is formed from an exogenous -globin or modified -globin gene."

Walters agreed that gene therapy is rapidly progressing, but expressed concern about the large gap that looms between laboratory bench and clinical bedside, particularly for this affected population.

"Access to and delivery of these highly technical therapies in patients with sickle cell disease will be challenging and probably limited to resource-rich nations, at least in the short term," Walters commented.

The studies, CRISPR-Cas9 Gene Editing for Sickle Cell Disease and -Thalassemia, as well as, Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease, were published online in The New England Journal of Medicine.

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Two Gene Therapies Fix Fault in Sickle Cell Disease and -thalassemia - MD Magazine

The First Targeted Therapy For Lung Cancer Patients With The KRAS Gene MutationExtraordinary Results With Sotorasib – SurvivorNet

Posted on February 1, 2021 by Danzig

First Targeted Therapy For Lung Cancer With KRAS

For the first time, there may be an effective treatment option for people with lung cancer that contains a genetic mutation called KRAS. The results of a groundbreaking using a drug calledSotorasib have just been published in the highly-respected New England Journal of Medicine.

Dr. Roy Herbst, Chief of Medical Oncology at Yale tells SurvivorNet We are excited we have a drug that could work in these patients. The fact that tumors respond to this therapy is a big deal.

Lung cancer remains the leading cause of cancer death in the united states. The most common form of lung cancer, non-small cell lung cancer (NSCLC), has recently seen major advancements with new treatments such as immunotherapy and targeted therapies extending the lives of thousands of patients. However, despite these recent advancements little has been available to help patients who have lung cancer with a KRAS mutation. This mutation is found in approximately 10-12% of patients with NSCLC and any drug that can improve the outlook for these patients would be a game-changer for lung cancer.

Now we finally have targeted therapy options for these patients.

In patients who have advanced stage or metastatic NSCLC most patients will have their tumor tested for genetic abnormalities or biomarkers to help their doctors select what treatments are best. Some common biomarkers such as EGFR and PDL1 have medications that doctors can use to target the lung cancer and improve a patients survival and quality of life. Despite this, one biomarker that has never had a treatment is KRAS. KRAS is a mutation that occurs in some patients with NSCLC and is generally associated with poor outcomes. One reason this mutation is considered a bad risk factor is that unlike other mutations such as EGFR there has never been a drug approved to treat this type of lung cancer.

Fortunately, for patients, this may be changing soon. A new drug called Sotorasib that specifically targets the KRAS mutation recently showed positive results in the early phase CODEBREAK 100 study. Based on the results from the early phase study Sotorasib was granted Break Through Therapy Designation and the drug has been accepted into the Real-Time Oncology Pilot Review Program by the U.S. Food and Drug Administration (FDA). When discussing the trial, Dr. Velcheti, Director of the Thoracic Medical Oncology Program at NYU Langone says The CODEBREAK 100 trial represents the clinical validation of significant research efforts spanning decades. Now we finally have targeted therapy options for these patients.

Overall I am impressed with this drug. It is hard for the public to understand just how far drug development has come.

So what does this mean for patients? This means that the new drug targeting KRAS may soon be available for patients whose tumors harbor this mutation and who have not responded to other treatments.

Lung specialists from across the country were eager to speak with SurvivorNet regarding the exciting news. Dr. Brendon Stiles, Associate Professor of Cardiothoracic Surgery at Weill Cornell Medical Center tells SurvivorNet Overall I am impressed with this drug. It is hard for the public to understand just how far drug development has come. The KRAS mutation has long been considered undruggable, meaning if you have this mutation, there was not a medicine designed specifically to treat this type of cancer. The chance of responding to the new therapy is around 40%. Although, researches would prefer to see this percent be higher the results of the study give hope that future therapies may have even better outcomes. Dr. Herbst is also optimistic about the future of drugs targeting KRAS and thinks the results of this study opens up a whole new world for lung cancer. If you or a loved one have NSCLC with a KRAS mutation ask your doctor about what treatment options are best for you.

Learn more about SurvivorNet's rigorous medical review process.

Dr. Roy Herbst, Chief of Medical Oncology at Yale tells SurvivorNet We are excited we have a drug that could work in these patients. The fact that tumors respond to this therapy is a big deal.

Now we finally have targeted therapy options for these patients.

Overall I am impressed with this drug. It is hard for the public to understand just how far drug development has come.

So what does this mean for patients? This means that the new drug targeting KRAS may soon be available for patients whose tumors harbor this mutation and who have not responded to other treatments.

Learn more about SurvivorNet's rigorous medical review process.

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The First Targeted Therapy For Lung Cancer Patients With The KRAS Gene MutationExtraordinary Results With Sotorasib - SurvivorNet

New evidence that Big Tech is ‘MIA’ on climate policy | TheHill – The Hill

Posted on February 1, 2021 by Danzig

The Biden administration is matching actions to words on climate assembling the most impressive team of pro-climate experts, strategists and policy leaders ever, making the goal of a just climate policy a top priority of the 2021 legislative agenda in Congress.

But leading companies in the tech sector are failing to match their own pro-climate commitments with lobbying action, according to a new report from InfluenceMap. (Note: the author is a member of the Advisory Board of InfluenceMap.)The report finds that Big Tech, the most powerful business voice for climate, is mostly missing in action on Capitol Hill just as this urgent issue nears a policy showdown.

The new data shows that Big Techs track record of engagement on climate policy has thus far been negligible: across the board, InfluenceMap finds that only 4 percent of Big Techs disclosed lobbying activity was devoted to climate-related policies. This compares with an average of 38 percent for Big Oil companies.Sen. Sheldon WhitehouseSheldon WhitehouseDemocrats weigh expanding lower courts after Trump blitz OVERNIGHT ENERGY: Biden signs series of orders to tackle climate change | Republicans press Granholm on fossil fuels during confirmation hearing Hawley files ethics counter-complaint against seven Democratic senators MORE (D-R.I.), the point person on climate policy in the Senate, puts it bluntly, Big Tech has refused to lift a finger to push comprehensive climate action in Congress.

Big Techs failure to show up matters; were going to need all hands on deck for this climate fight. While Congress sweeping pandemic relief bill contained some climate provisions that won bipartisan support, no one is expecting all future pro-climate proposals to get a kumbaya welcome. Even with a narrowly Democratic House and Senate, passing pro-climate legislation wont be easy whether its under special reconciliation rules or traditional ones.It will require mustering business support to bring swing Senators of both parties behind it and thats where the challenge will lie.

Big Oil will be girded for battle in 2021. They heard the warning shot last fall in then-candidate Bidens debate statement about making a transition from the oil industry.Despite President TrumpDonald TrumpBiden reverses Trump last-minute attempt to freeze .4 billion of programs Trump announces new impeachment legal team after reported departures Republicans scramble to unify heading into next election cycle MOREs all-out efforts to make this clear statement into a gaffe, candidate Biden didnt pay a real political price for calling for oils demise. Yes, the fossil fuel industrys new public relations strategy is to change its tune on the climate narrative. But Big Oil still has the powerful Chamber of Commerce (doing its own deft repositioning on climate to shift slowly away from outright climate denial) to back them up when deals are cut.

What business sector is powerful and influential enough to counter Big Oil?The obvious answer is Big Tech.With an historic showdown on climate coming, we need full throttle engagement from the strongest, most vibrant business proponent of saving the planet the tech sector.To their credit, Big Tech firms have made great progress advancing sustainability in operations and taking vocal stands on the issue. Its now time for them to walk the walk on climate policy.

But whether or not they will is an open question. Obviously, the public affairs teams of the leading tech firms have more narrow concerns on their mind in 2021s Washington like Facebooks big antitrust problems.As a former Big Tech executive, I know climate policy too often slips down the priority list. It is zero hour on climate policy we have run out of time for inaction. The failure to pass significant climate legislation in 2021 would be devastating to the future of the planet not just our businesses, but our families and our very survival.We are now in a very narrow window of time when our actions can still keep global warming below the 1.5 degree threshold recommended by science to prevent the most severe outcomes.This is the moment for bold policy and for the whole team to join the fight.

With the fate of the climate hanging in the balance, if Big Tech stays out of this struggle, they will lose credibility not just with the Biden administration, but with their own pro-climate employees. As they try to recruit idealistic students, they will find that these bright, savvy young tech workers expect them to stand tall on climate policy and environmental justice and that they are increasingly outspoken.Time is running short for Big Tech to step up, honor their pro-climate pledges and make their workforce proud. Lets hope they do.

Bill Weihl is a former sustainability executive at Google and Facebook. He is the founder and executive director of ClimateVoice, a non-profit initiative.

New evidence that Big Tech is 'MIA' on climate policy | TheHill - The Hill

Why Is Big Tech Policing Speech? Because the Government Isnt – The New York Times

Posted on February 1, 2021 by Danzig

But the court shifted again, Lakier says, toward interpreting the First Amendment as a grant of almost total freedom for private owners to decide who could speak through their outlets. In 1974, it struck down a Florida law requiring newspapers that criticized the character of political candidates to offer them space to reply. Chief Justice Warren Burger, in his opinion for the majority, recognized that barriers to entry in the newspaper market meant this placed the power to shape public opinion in few hands. But in his view, there was little the government could do about it.

Traditionally, conservatives have favored that libertarian approach: Let owners decide how their property is used. Thats changing now that they find their speech running afoul of tech-company rules. Listen to me, America, we were wiped out, the right-wing podcaster Dan Bongino, an investor in Parler, said in a Fox News interview after Amazon pulled its services. And to all the geniuses out there, too, saying this is a private company, its not a First Amendment fight really, its not? The law that prevents the government from censoring speech should still apply, he said, because these companies are more powerful than a de facto government. You neednt sympathize with him to see the hit Parler took as the modern equivalent of, in Burgers terms, disliking one newspaper and taking the trouble to start your own, only to find no one will sell you ink to print it.

One problem with private companies holding the ability to deplatform any speaker is that theyre in no way insulated from politics from accusations of bias to advertiser boycotts to employee walkouts. Facebook is a business, driven by profit and with no legal obligation to explain its decisions the way a court or regulatory body would. Why, for example, hasnt Facebook suspended the accounts of other leaders who have used the platform to spread lies and bolster their power, like the president of the Philippines, Rodrigo Duterte? A spokesman said suspending Trump was a response to a specific situation based on risk but so is every decision, and the risks can be just as high overseas.

Its really media and public pressure that is the difference between Trump coming down and Duterte staying up, says Evelyn Douek, a lecturer at Harvard Law School. But the winds of public opinion are a terrible basis for free-speech decisions! Maybe it seems like its working right now. But in the longer run, how do you think unpopular dissidents and minorities will fare?

Deplatforming works, at least in the short term. There are indications that in the weeks after the platforms cleaned house with Twitter suspending not just Trump but some 70,000 accounts, including many QAnon influencers conversations about election fraud decreased significantly across several sites. After Facebook reintroduced a scoring system to promote news sources based on its judgment of their quality, the list of top performers, usually filled by hyperpartisan sources, featured CNN, NPR and local news outlets.

But theres no reason to think the healthier information climate will last. The very features that make social media so potent work both to the benefit and the detriment of democracy. YouTube, for instance, changed its recommendation algorithm in 2019, after researchers and reporters (including Kevin Roose at The New York Times) showed how it pushed some users toward radicalizing content. Its also telling that, since the election, Facebook has stopped recommending civic groups for people to join. After Jan. 6, the researcher Aric Toler at Bellingcat surfaced a cheery video, automatically created by Facebook to promote its groups, which imposed the tagline community means a lot over images of a militia brandishing weapons and a photo of Robert Gieswein, who has since been charged in the assault on the Capitol. Im afraid that the technology has upended the possibility of a well-functioning, responsible speech environment, the Harvard law professor Jack Goldsmith says. It used to be we had masses of speech in a reasonable range, and some extreme speech we could tolerate. Now we have a lot more extreme speech coming from lots of outlets and mouthpieces, and its more injurious and harder to regulate.

For decades, tech companies mostly responded to such criticism with proud free-speech absolutism. But external pressures, and the absence of any other force to contain users, gradually dragged them into the expensive and burdensome role of policing their domains. Facebook, for one, now has legions of low-paid workers reviewing posts flagged as harmful, a task gruesome enough that the company has agreed to pay $52 million in mental-health compensation to settle a lawsuit by more than 10,000 moderators.

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Why Is Big Tech Policing Speech? Because the Government Isnt - The New York Times

They Found a Way to Limit Big Techs Power: Using the Design of Bitcoin – The New York Times

Posted on February 1, 2021 by Danzig

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SAN FRANCISCO Jack Dorsey, Twitters chief executive, publicly wrestled this month with the question of whether his social media service had exercised too much power by cutting off Donald J. Trumps account. Mr. Dorsey wondered aloud if the solution to that power imbalance was new technology inspired by the cryptocurrency Bitcoin.

When YouTube and Facebook barred tens of thousands of Mr. Trumps supporters and white supremacists this month, many flocked to alternative apps such as LBRY, Minds and Sessions. What those sites had in common was that they were also inspired by the design of Bitcoin.

The twin developments were part of a growing movement by technologists, investors and everyday users to replace some of the internets fundamental building blocks in ways that would be harder for tech giants like Facebook and Google to control.

To do so, they are increasingly focused on new technological ideas introduced by Bitcoin, which was built atop an online network designed, at the most basic level, to decentralize power.

Unlike other types of digital money, Bitcoin are created and moved around not by a central bank or financial institution but by a broad and disparate network of computers. Its similar to the way Wikipedia is edited by anyone who wants to help, rather than a single publishing house. That underlying technology is called the blockchain, a reference to the shared ledger on which all of Bitcoins records are kept.

Companies are now finding ways to use blockchains, and similar technology inspired by it, to create social media networks, store online content and host websites without any central authority in charge. Doing so makes it much harder for any government or company to ban accounts or delete content.

These experiments are newly relevant after the biggest tech companies recently exercised their clout in ways that have raised questions about their power.

Facebook and Twitter prevented Mr. Trump from posting online after the Capitol rampage on Jan. 6, saying he had broken their rules against inciting violence. Amazon, Apple and Google stopped working with Parler, a social networking site that had become popular with the far right, saying the app had not done enough to limit violent content.

While liberals and opponents of toxic content praised the companies actions, they were criticized by conservatives, First Amendment scholars and the American Civil Liberties Union for showing that private entities could decide who gets to stay online and who doesnt.

Even if you agree with the specific decisions, I do not for a second trust the people who are making the decisions to make universally good decisions, said Jeremy Kauffman, the founder of LBRY, which provides a decentralized service for streaming videos.

That has prompted a scramble for other options. Dozens of start-ups now offer alternatives to Facebook, Twitter, YouTube and Amazons web hosting services, all on top of decentralized networks and shared ledgers. Many have gained millions of new users over the past few weeks, according to the data company SimilarWeb.

This is the biggest wave Ive ever seen, said Emmi Bevensee, a data scientist and the author of The Decentralized Web of Hate, a publication about the move of right-wing groups to decentralized technology. This has been discussed in niche communities, but now we are having a conversation with the broader world about how these emerging technologies may impact the world at quite large scales.

Bitcoin first emerged in 2009. Its creator, a shadowy figure known as Satoshi Nakamoto, has said its central idea was to allow anyone to open a digital bank account and hold the money in a way that no government could prevent or regulate.

For several years, Bitcoin gained little traction beyond a small coterie of online admirers and people who wanted to pay for illegal drugs online. But as its price rose over time, more people in Silicon Valley took notice of the unusual technical qualities underlying the cryptocurrency. Some promised that the technology could be used to redesign everything from produce tracking to online games.

The hype fell flat over the years as the underlying technology proved to be slow, prone to error and not easily accessible. But more investments and time have begun to result in software that people can actually use.

Last year, Arweave, a blockchain-based project for permanently storing and displaying websites, created an archive of sites and documents from the protests in Hong Kong that angered the Chinese government.

Minds, a blockchain-based replacement for Facebook founded in 2015, also became an online home to some of the right-wing personalities and neo-Nazis who were booted from mainstream social networks, along with fringe groups, in other countries, that have been targeted by their governments. Minds and other similar start-ups are funded by prominent venture capital firms like Andreessen Horowitz and Union Square Ventures.

One of the biggest proponents of the trend has been Mr. Dorsey, 44, who has talked about the promise of decentralized social networks through Twitter and has promoted Bitcoin through the other company he runs, Square, a financial technology provider.

His public support for Bitcoin and Bitcoin-related designs dates to around 2017. In late 2019, Mr. Dorsey announced Blue Sky, a project to develop technology aimed at giving Twitter less influence over who could and could not use the service.

After shutting down Mr. Trumps account this month, Mr. Dorsey said he would hire a team for Blue Sky to address his discomfort with Twitters power by pursuing the vision set out by Bitcoin. On Thursday, Blue Sky published the findings of a task force that has been considering potential designs.

Twitter declined to make Mr. Dorsey available for an interview but said it intended to share more soon.

Blockchains are not the only solution for those in search of alternatives to Big Techs power. Many people have recently migrated to the encrypted messaging apps Signal and Telegram, which have no need for a blockchain. Moxie Marlinspike, the creator of Signal, has said decentralization made it hard to build good software.

The experimentation with decentralized systems has nonetheless ramped up over the last month. Brave, a new browser, announced last week that it would begin integrating a blockchain-based system, known as IPFS, into its software to make web content more reliable in case big service providers went down or tried to ban sites.

The IPFS network gives access to content even if it has been censored by corporations and nation-states, Brian Bondy, a co-founder of Brave, said.

At LBRY, the blockchain-based alternative to YouTube, the number of people signing up daily has surged 250 percent from December, the company said. The newcomers appear to have largely been a motley crew of Trump fans, white supremacists and gun rights advocates who violated YouTubes rules.

When YouTube removed the latest videos from the white supremacist video blogger Way of the World last week, he tweeted: Why do we waste our time on this globalist scum? Come to LBRY for all my videos in HD quality, censorship free!

Megan Squires, a professor at Elon University who studies new computer networks, said blockchain-based networks faced hurdles because the underlying technology made it hard to exercise any control over content.

As a technology it is very cool, but you cant just sit there and be a Pollyanna and think that all information will be free, she said. There will be racists, and people will shoot each other. Its going to be the total package.

Mr. Kauffman said LBRY had prepared for these situations. While anyone will be able to create an account and register content on the LBRY blockchain that the company cannot delete similar to the way anyone can create an email address and send emails most people will get access to videos through a site on top of it. That allows LBRY to enforce moderation policies, much as Google can filter out spam and illegal content in email, he said.

Even so, Mr. Kauffman said, no one would lose basic access to online conversation.

Id be proud of almost any kind of marginalized voice using it, no matter how much I disagreed with it, he said.

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They Found a Way to Limit Big Techs Power: Using the Design of Bitcoin - The New York Times

Algorithms Still Have a Bias Problem, and Big Tech Isn’t Doing Enough to Fix It – PCMag

Posted on February 1, 2021 by Danzig

Wondering about the health of the internet, both globally and in the US? Mozillathe company behind the Firefox browser and moretoday released its fourth Internet Health Report, which covers topics that impact the internet and big tech companies, such as accountability, labor, andas we'll discuss hereracial justice issues.

The hard numbers are above, pulled from tech companies' own reports, as charted by Wired. Among the biggest fourApple, Facebook, Google (Alphabet), and Microsoft (Amazon isn't listed)the stats on Black, Latinx, and Native representation among the workforce in each are practically unchanged after five years (see update below). The only real change is the minimal increase in the number of Asian employees, up 12% at Apple, 11% at Facebook, 9% at Google, and 4% at Microsoft. The report flatly states that even in that case, caste discrimination happens.

Gender diversity isn't making great strides, either. Women are still woefully underrepresented at those same four companies; increases have been very small since 2014.

The racial biases of having a primarily white workforce persist: for example, skewing perspectives on artificial intelligence, as evidenced by all the white plastic humanoids in a typical search.

The report includes a spotlight article titled "Decode the Default," which looks at the recent phenomenon of trying to call out the "racial inequities of data and algorithms," and the backlash and denials that arise when it happens. For example, the 2008 launch of a web browser called Blackbird (built on Mozilla code) as a "browser for Black people" faced accusations of segregationeven from the African-American community. Other examples include:

Over a decade ago, it was discovered that searching "black girls" on Google lead mostly to imagery from pornography.

Facial-recognition gets things woefully wrong for people who aren't white.

The "mainstream notion of a 'default' user" is typically believed to be white, cisgender, male, and American.

Many of these race-based problems and more in the tech community point back to the graphic at the top: The big tech companieson which the small tech companies are almost wholly dependent"fail to create work environments where people of color and women want to stay." Without that diversity internally, tech companies don't really know how to work and improve beyond their limited worldview.

There's much more to read in "Decode the Default" and the entire Internet Health Report, including sections on the labor rights movement in tech (in particular for "gig economy" workers) and the lack of transparency that prevents us from holding these companies accountable.

Update 1/30/2021: Microsoft says the Mozilla report pulls data from its 2019 report. It has since published anew diversity reportfor 2020, which cites "modest gains since 2019 including among women who now represent 28.6% of the global Microsoft workforce, an increase of 1.0 percentage point since last year.However, racial and ethnic minority communities have largely seen incremental progress and there is still much work to be done."

The Big Tech Crackdown Is a Gift to Parler – The Wall Street Journal

Posted on February 1, 2021 by Danzig

The coordinated actions of Big Tech against Parler, a free-speech competitor to Twitter , have attracted much attention and debate. Some argue that deplatforming Parler was necessary to stop further violence after the riot at the Capitol on Jan. 6. Others see political discrimination at work, given that Facebook , YouTube and Twitter also host bad actors. Everyone seems to agree that the actions by Big Tech caused great harm to Parler.

On the contrary, there are strong economic reasons to think Parler will benefit in the long run. The value of the free publicity will ultimately far outweigh the loss of revenue from being shut down for a few weeks. Parler has become a household name. It was a company; now its a cause.

The attack on Parler follows a long history of incumbent monopolies trying to raise costs on new rivals. Once Parler gets new servers up, however, using a phone to sign up or log on through a browser rather than an app is a small barrier to entry. Many highly profitable websites have no apps.

The benefits to Parler from Big Techs actions come in the long haul. The value of any company stems from the present value of its future earnings. An investment raises this present value when the up-front cost is dwarfed by the gains in future earnings. Big Tech has made an implicit investment in Parler by imposing a short-run cost that is smaller than the more lasting future gain in earnings enabled by the free marketing campaign.

The growth in future users doesnt have to be large to raise the value of Parler. It seems safe to assume that the number of users will be larger in March this year than it would have been without the Big Tech effort. And the growth doesnt have to be huge to make a big difference. Losing 100% of a months earnings to switch servers is easily made up by a long-run gain of a few percentage points of monthly users afterward. Such a small gain seems more than likely given the multiples of 100% growth in Parler users after Twitters suppression of stories about Hunter Bidens business dealings.

Dow drops more than 600 points for its worst day since October, S&P 500 goes red for the year – CNBC

Posted on February 1, 2021 by Danzig

U.S. stocks fell sharply on Wednesday amid disappointing earnings, while concern about heightened speculative trading activity deepened.

The Dow Jones Industrial Average lost 633.87 points, or 2.1%, to 30,303.17 for its worst day since Oct. 28. The S&P 500 dropped 2.6% to 3,750.77, slipping from a record high and suffering its biggest drop in three months. Wednesday's steep losses wiped out the 2021 gains for the S&P 500 and it's now down 0.1% on the year. The tech-heavy Nasdaq Composite slid 2.6% to 13,270.60.

Boeing fell nearly 4% after its earnings report showed its 2020 net loss hit a record of $11.9 billion amid the 737 Max grounding and the coronavirus pandemic. Shares of AMD tumbled more than 6% even after the chipmaker posted revenue and earnings that beat Wall Street's already high expectations.

But it was intensifying speculative behavior among retail investors that was causing the most concern. Heavily shorted names, including GameStop and AMC Entertainment, continued to be pushed higher by amateur day traders in online chat rooms. Some investors are worried about mounting losses by hedge funds spilling over to other areas of the market as those funds sell other securities to raise cash. Investors are also concerned the speculative behavior is a sign the market is overvalued and a pullback is near.

"We've run up so much and this is healthy profit taking," said John Davi, founder and CIO of Astoria Portfolio Advisors. "There has been a tremendous market melt-up in the past two months. When the market goes up parabolically, you will see speculative behaviors from a lot of investors."

GameStop shares exploded again, more than doubling on Wednesday. CNBC learned Melvin Capital, the hedge fund targeted by the retail investing crowd on Reddit had sold out of its short position. More hedge funds were facing big losses because of their losing short positions, CNBC's David Faber reported on Wednesday.

"Market participants have watched the GME phenomena with curiosity and amusement, but the days-long surge in it is eroding market confidence and creating some positioning-driven dislocation," Adam Crisafulli, founder of Vital Knowledge, said in a note.

AMC soared more than 300% Wednesday. More than one billion AMC shares traded in the name during the session.

TD Ameritrade midday Wednesday said it put in place restrictions on certain transactions involving GameStop and AMC "in the interest of mitigating risk for our company and clients."

Stocks fell as a "surge in heavily shorted stocks like GME and others [is] creating substantial margin calls for funds short these positions," said FundStrat's Tom Lee in an email. This "forced selling" by hedge funds is causing a bit of turmoil in the markets and likely leading all active managers to get into a risk-off mode, Lee said. A margin call is when a broker mandates an investor hold more cash to cover losses.

But the strategist added that the sell-off Wednesday was temporary and stocks would resume their upswing soon.

The Cboe Volatility Index, known as the VIX or Wall Street's fear gauge, jumped above 30 on Wednesday, hitting its highest level since November.

"The Big Short" investor Michael Burry said in a now-deleted tweet Tuesday that trading in GameStop is "unnatural, insane, and dangerous" and there should be "legal and regulatory repercussions."

The Federal Reserve failed to stem the market sell-off even as it said it would kept interest rates unchanged near zero, while maintaining an asset purchasing program with at least $120 billion buying a month.

Microsoft gained 0.3% after reporting a stellar quarter. Sales grew by 17% on a year-over-year basis in its fiscal second quarter, while its cloud business accelerated.

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Dow drops more than 600 points for its worst day since October, S&P 500 goes red for the year - CNBC

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