Imagine a world in which we can produce meat without animals, cure previously incurable diseases by editing an individuals genetic fabric, and manufacture industrial chemicals in yeast factories. The foundational technologies that could make all this possible largely exist. Rapid and ever-cheaper DNA sequencing has deepened our understanding of how biology works and tools such as CRISPR are now being used to recode biology to treat diseases or make crops less vulnerable to climate change. This is what we call the Bio Revolution.

Explored in a new McKinsey Global Institute research report, which we helped co-author, the Bio Revolution is already benefiting society. A confluence of breakthroughs in biological science and ever faster and more sophisticated computing, data analytics, and artificial intelligence technologies has powered scientific responses to the Covid-19 pandemic. Scientists sequenced the virus genome in weeks rather than months, as was the case in previous outbreaks. Bio innovations are enabling the rapid introduction of clinical trials of vaccines, the search for effective therapies, and a deep investigation of the transmission patterns of the virus.

The report estimates that bio innovations could alleviate between 1% and 3% of the total global burden of disease in the next 10 to 20 years from these applications roughly the equivalent of eliminating the global disease burden of lung cancer, breast cancer, and prostate cancer combined. Over time, if the full potential is captured, 45% of the global disease burden could be addressed using science that is conceivable today.

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As much as 60% of the physical inputs to the global economy today are either biological (such as wood for construction or animals bred for food) or nonbiological (such as cement or plastics) but could, in principle, be produced over time using biology. Nylon can already be made using genetically engineered yeast instead of petrochemicals, for instance, leather is being made from mushroom roots, and bacteria have made a type of cement.

This Bio Revolution has the potential to be as transformative to business and economies as the Digital Revolution that proceeded it, creating value in every sector, disrupting value chains, and creating new business opportunities. Businesses clearly see the potential investment in a new generation of biological technologies had already surged to more than $20 billion by 2018.

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Many applications are being commercialized. We identified a visible initial pipeline of about 400 use cases, almost all scientifically feasible today, that could create a direct economic impact of $2 trillion to $4 trillion in the next 10 to 20 years more than half of which is outside health, in sectors as diverse as agriculture and textile manufacturing.

The confluence of biology and computing is already creating new capabilities. Computing is accelerating discovery and throughput in biology. An explosion of biological data due to cheaper sequencing is being used by biotech companies and research institutes that are increasingly using robotic automation and sensors in labs. Biotech company Zymergen, for example, has found that throughput in biological screening can be increased up to 10 times. Advanced analytics, more powerful computational techniques, and AI are also being deployed to generate more acute insights during the R&D process.

New biology-based manufacturing is already cutting costs, improving performance, and reducing the impact on the environment and the natural world. In cosmetics, for instance, Amyris is now making squalane, a moisturizing oil used in many skin-care products, by fermenting sugars using genetically engineered yeast instead of processing liver oil from deep-sea sharks, which was not only expensive but threatened the species with extinction. In textiles, U.S. startup Tandem Repeat is producing self-repairing, biodegradable, and recyclable fabric using proteins encoded by squid genes.

The Bio Revolution could utterly change the food business as plant-based proteins and lab-grown meat gain popularity and in the process cut greenhouse gas emissions from deforestation and animal husbandry. One study found that cultured meat could reduce greenhouse gas emissions by 80% or more compared with conventional meat if all of the energy used in manufacturing comes from carbon-free sources.

Cultured meat and seafood are made using tissue-culture technology, a lab process by which animal cells are grown in vitro. Producers still face a major technical challenge in finding a cost-effective way of growing cells. New players such as Finless Foods, Mosa Meat, Memphis Meats, and Meatable are experimenting with different approaches, including using synthetic molecules and pluripotent stem cells to replace expensive growth factors. Cultured meat and seafood could be cost-competitive with conventional animal production systems within 10 years.

In agriculture, greater understanding of the role of the microbiome offers opportunities to improve operational efficiency and output. By profiling bacteria and fungi in the soil, Trace Genomics, for one, produces insights that help choose tailored seeds and nutrients, and enables early prediction of soil diseases. In consumer markets, ongoing research into the relationship between the gut microbiome and the skin is being used to personalize skin care. Singapore-based genomics firm Imagene Lab, for instance, offers a personalized serum based on the results of its skin DNA tests that assess traits such as premature collagen breakdown.

Such examples give a sense of the breadth of applicability of bio innovation, but there is a significant caveat: risk. Biology will preserve life through innovative treatments tailored to our genomes and microbiomes, but biology could also be the greatest threat to life if it is used to create bioweapons or genetically engineered viruses that can do lasting damage to the health of humans or ecosystems. The CRISPR gene-editing tool is revolutionizing medicine and is being applied to agriculture with great effect. But consider that CRISPR kits are now available to buy on the Internet for $100 and so-called biohackers are using them at home.

Like the Digital Revolution, the Bio Revolution comes with risks but of a different order of magnitude. If citizens already have misgivings about data being gathered about their shopping habits, how much more nervous will they be about genetic data gathered from their bodies for medical treatment or ancestry tracing data that couldnt be more personal.

Another risk is that biological organisms are, by their nature, self-sustaining and self-replicating. Genetically engineered microbes, plants, and animals may be able to reproduce and sustain themselves over the long term, potentially affecting entire ecosystems. Once Pandoras box is opened and we have already cracked the lid we may have little control over what happens next.

Unless such risks are managed, it is possible that the full potential of the Bio Revolution may not materialize. We estimate that about 70% of the total potential impact could hinge on societal attitudes and the way innovation is governed under existing regulatory regimes. Yet if the risks can be managed and mitigated, the Bio Revolution can reshape our world. Scientists, in conjunction with forward-thinking companies, are now harnessing the power of nature to solve pressing problems in medicine, agriculture, and beyond, and helping craft a response to global challenges from pandemics to climate change.

Matthias Evers is a senior partner and global leader of research and development in McKinsey & Companys pharmaceuticals and medical products practice. Michael Chui is a partner at the McKinsey Global Institute, McKinseys business and economics research arm.

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The Bio Revolution is changing business and society - STAT - STAT

DetailsCategory: DNA RNA and CellsPublished on Thursday, 14 May 2020 10:13Hits: 234

CAMBRIDGE, MA, USA I May 12, 2020 I Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology bothin vivoandex vivo,is presenting three oral presentations and two poster presentations at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy (ASGCT), taking place virtually from May 12-15, 2020. Intellia researchers are presenting new data in support of NTLA-5001, the companys engineered cell therapy candidate for the treatment of acute myeloid leukemia (AML). Intellia is also providing an update on NTLA-2002, its newest development candidate for the treatment of hereditary angioedema (HAE).

At Intellia, we are applying our CRISPR/Cas9 technology to develop new processes that can produce enhanced engineered cell therapies to treat severe cancers, such as AML, that traditional approaches cannot address. Our proprietary platform provides a powerful tool to generate more potent TCR-directed cells, that can treat blood cancers initially and potentially solid tumors. The data being presented today validate Intellias approach of reducing AML tumor cell blasts, and our plans to enter the clinic with NTLA-5001 next year, said Intellia President and CEO John Leonard, M.D. We are also pleased to present data that support our recently announced HAE development candidate, NTLA-2002, Intellias second systemic therapy employing our in vivo knockout approach and modular delivery platform.

Data Presentations on Intellias First Engineered Cell Therapy Development Candidate, NTLA-5001 for the Treatment of AML, and Proprietary Cell Engineering Process

NTLA-5001 is Intellias first engineered T cell receptor (TCR) T cell therapy development candidate, which targets the Wilms Tumor 1 (WT1) intracellular antigen for the treatment of AML. NTLA-5001 is being developed in collaboration with Chiara Boninis team at IRCCS Ospedale San Raffaele to treat AML patients regardless of the genetic subtype of a patients leukemia. AML is a cancer of the blood and bone marrow that is rapidly fatal without immediate treatment and is the most common type of acute leukemia in adults(Source:NIH SEER Cancer Stat Facts: Leukemia AML).

Intellias proprietary process is a significant improvement over standard engineering processes commonly used to introduce nucleic acids into cells. Intellias process enabled multiple gene edits using CRISPR/Cas9, while maintaining cell products with high expansion potential and minimal undesirable chromosomal translocations. CRISPR/Cas9 was used to insert a WT1-directed TCR in locus, while eliminating the expression of the endogenous TCRs, with the goal of producing homogeneous T cell therapies like NTLA-5001.

Intellias novel approach with NTLA-5001 can overcome the challenges of standard T cell therapy, including risks of reduced specificity associated with mixed expression and mispairing of endogenous and transgenic TCRs (tgTCRs); graph-versus-host disease (GvHD) risks, which could lead to an attack on the patients healthy cells; and reduced efficacy tied to lower tgTCR expression per T cell. Intellias unprecedented process is expected to streamline cell engineering and manufacturing, yielding a homogenous product comprising WT1-targeted T cells with high anti-tumor activity. Data highlights from todays presentation include the following:

Intellias cell engineering efforts are focused on its initial clinical investigation of NLTA-5001 on AML, while continuing preclinical studies exploring the potential for targeting WT1 in solid tumors. The company confirmed plans last week to submit an IND or IND-equivalent for NTLA-5001 for the treatment of AML in the first half of 2021.

The presentation titled, Enhanced tgTCR T Cell Product Attributes Through Process Improvement of CRISPR/Cas9 Engineering, will be made today by Aaron Prodeus, Ph.D., senior scientist, Cell Therapy, and can be found here, on the Scientific Publications & Presentations page of Intellias website. These data were a follow-on to the study presented at Keystone Symposias Engineering the Genome Conference from this past February.

In Vivo Data Supports Intellias Novel TCR Candidate

A second presentation on engineered cell therapy progress, in collaboration with IRCCS Ospedale San Raffaele, showed in vivo data demonstrating the potential of TCR-edited T cells to effectively target WT1 tumor cells in AML. In addition to the previously disclosed results of effective in vitro recognition of primary AML tumor cells by edited WT1-specific cytotoxic T cells (CD8 T cells), new data indicate that the selected TCR also enables T helper cells (CD4 T cells) to react to WT1-expressing tumor cells, providing cytokine support. This distinguishes Intellias TCR from other therapeutic TCR candidates, which either exclusively activate toxic CD8 T cells or require the co-transfection of CD8 into CD4 T cells to render them functional.

Using a mouse model carrying disseminated human primary AML, researchers observed a significant therapeutic effect, including decreased AML tumor burden. In addition, no signs of GvHD were observed in mice treated with the WT1-specific T cells. The data show that tgTCR-engineered cells have targeted anti-cancer activity in a challenging model of systemic AML, demonstrating the therapeutic potential of Intellias engineered TCR T cell approach.

The presentation titled, Exploiting CRISPR-Genome Editing and WT1-Specific T Cell Receptors to Redirect T Lymphocytes Against Acute Myeloid Leukemia, will be given today by Eliana Ruggiero, Ph.D., Experimental Hematology Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Italy. Notably, ASGCT meeting organizers selected this presentation as one of six to receive the ASGCT Excellence in Research Award this year.

Continued Progress on Intellias Second In Vivo Development Candidate, NTLA-2002 for the Treatment of HAE

Intellia is presenting development data updates on its potential HAE therapy, NTLA-2002, which utilizes the companys systemic in vivo knockout approach, including its proprietary lipid nanoparticle (LNP) system. HAE is a rare genetic disorder characterized by recurring and unpredictable severe swelling attacks in various parts of the body, and is significantly debilitating or even fatal in certain cases. NTLA-2002 aims to prevent unregulated production of bradykinin by knocking out the prekallikrein B1 (KLKB1) gene through a single course of treatment to ameliorate the frequency and intensity of these swelling attacks.

The KLKB1 gene knockout in an ongoing non-human primate (NHP) study resulted in a sustained 90% reduction in kallikrein activity, a level that translates to a therapeutically meaningful impact on HAE attack rates(Source: Banerji et al., NEJM, 2017). This kallikrein activity reduction was sustained for at least six months, demonstrating the same high level of efficacy and durability seen in earlier rodent studies.

The short talk titled, CRISPR/Cas9-Mediated Gene Knockout of KLKB1 to Treat Hereditary Angioedema, will be given by Jessica Seitzer, director, Genomics, Intellia on Fri., May 15, 2020, when it will be made available here, on the Scientific Publications & Presentations page of Intellias website. The presented data include results from ongoing collaborations with researchers at Regeneron, and the program is subject to an option by Regeneron to enter into a Co/Co agreement, in which Intellia would remain the lead party. Intellia expects to submit an IND or IND-equivalent to initiate a Phase 1 trial for NTLA-2002 in the second half of 2021.

About Intellia Therapeutics

Intellia Therapeuticsis a leading genome editing company focused on developing proprietary, curative therapeutics using the CRISPR/Cas9 system. Intellia believes the CRISPR/Cas9 technology has the potential to transform medicine by permanently editing disease-associated genes in the human body with a single treatment course, and through improved cell therapies that can treat cancer and immunological diseases, or can replace patients diseased cells. The combination of deep scientific, technical and clinical development experience, along with its leading intellectual property portfolio, puts Intellia in a unique position to unlock broad therapeutic applications of the CRISPR/Cas9 technology and create a new class of therapeutic products. Learn more aboutIntellia Therapeuticsand CRISPR/Cas9 atintelliatx.comand follow us on Twitter @intelliatweets.

SOURCE: Intellia Therapeutics

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CRISPR corrects genetic defect so cells can normalize blood sugar

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those mice.

The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

The study is published online April 22 in the journal Science Translational Medicine.

Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.

This is the first time CRISPR has been used to fix a patients diabetes-causing genetic defect and successfully reverse diabetes, said co-senior investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University. For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

A few years ago, Millman and his colleagues discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, those same researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared quickly in mice with the CRISPR-edited cells implanted beneath the skin, and the animals blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Their newly implanted beta cells could produce insulin, just not enough to reverse their diabetes.

We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation, said co-senior investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. Its a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes in this case, in the Wolfram syndrome gene we can make beta cells that more effectively control blood sugar. Its also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.

In the future, using CRISPR to correct certain mutations in beta cells may help patients whose diabetes is the result of multiple genetic and environmental factors, such as type 1, caused by an autoimmune process that destroys beta cells, and type 2, which is closely linked to obesity and a systemic process called insulin resistance.

Were excited about the fact that we were able to combine these two technologies growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects, Millman said. In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making induced pluripotent stem cells from blood and they are working on developing stem cells from urine samples.

In the future, Urano said, we may be able to take a few milliliters of urine from a patient, make stem cells that we then can grow into beta cells, correct mutations in those cells with CRISPR, transplant them back into the patient, and cure their diabetes in our clinic. Genetic testing in patients with diabetes will guide us to identify genes that should be corrected, which will lead to a personalized regenerative gene therapy.

Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, Millman JR. Gene-edited human stem cell-derived cells from a patient with monogenic diabetes reverse pre-existing diabetes in mice. Science Translational Medicine, published online April 22, 2020.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of General Medical Sciences, the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Grant numbers R01 DK114233, DK112921, TR002065, TR002345, T32 DK108742, R25 GM103757, T32 DK007120, P30 DK020579, P30 CA91842, UL1 TR000448 and UL1 TR002345. Additional assistance was provided by the Washington University Genome Engineering and iPSC Center, the Washington University Diabetes Center, and the Washington University Institute of Clnical and Translational Science, with additional funding from the JDRF, the Washington University Center of Regenerative Medicine, startup funds from the Washington University School of Medicine Department of Medicine, the Unravel Wolfram Syndrome Fund, Silberman Fund, Stowe Fund, Ellie White Foundation for Rare Genetic Disorders, Eye Hope Foundation, Snow Foundation, Feiock Fund, Childrens Discovery Institute, Manpei Suzuki Diabetes Foundation, and a JSPS Overseas Research Fellowship.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Diabetes reversed in mice with genetically edited stem cells derived from patients - Washington University School of Medicine in St. Louis

/ AChR subunit KO zebrafish lines

We generated a subunit gene KO zebrafish (KO) using CRISPR-Cas9 (Fig. 1A) and an subunit gene KO zebrafish (KO) using transcription activatorlike effector nucleases (TALEN) (Fig. 1A). The KO zebrafish did not show obvious phenotypes during development and matured in a fashion indistinguishable from wild-type (WT) siblings (fig. S1). In contrast, KO fish generally failed to form swim bladders, and most of them died prematurely within 2 weeks after fertilization. However, a fraction of KO fish (approximately 25%) survived to adulthood. A double KO (DKO) line was generated by crossing KO and K lines. DKO larvae also failed to form swim bladders (Fig. 1B) and died within 2 weeks after fertilization.

(A) Schematic diagram of targeted genes. Arrowheads indicate targeted regions of genome editing. Each box and line indicates an exon and an intron, respectively. Alignment of genomic DNA sequences of WT and KO lines showed a 7base pair (bp) insertion in the AChR subunit gene chrng and a 1-bp insertion in the AChR subunit gene chrne. (B) Photograph showing WT and / DKO larva at 6 dpf. Notice the lack of swim bladder (arrowheads) in DKO. Scale bar, 1 mm. (C) Trunk regions of a WT larva (6 dpf) and a DKO larva (6 dpf) were stained with -BTX conjugated with Alexa Fluor 488 (green). In WT, AChRs were distributed in myoseptal regions (arrows) and in punctae in middle regions (arrowhead). DKO had -BTX signals only in myoseptal regions. Scale bars, 100 m.

We histologically analyzed the expression of AChRs in the trunk region of 6 days post-fertilization (dpf) larvae by using -bungarotoxin (-BTX) conjugated with Alexa Fluor 488, a toxin that specifically binds to the assembled AChR (Fig. 1C). AChR clusters in DKOs were observed only in boundary regions between body segments (Fig. 1C), where slow muscles form NMJs (16). We initially expected that AChRs in fast muscles of DKO larvae would convert to the slow muscletype AChRs, comprising only , , and subunits. This conversion of subunit composition would not cause a change in AChR distribution visualized by -BTX, because both types of AChRs bind to -BTX. However, -BTX signals were absent in fast muscles, which suggested that fast muscles could not express AChRs composed of , , and subunits.

To correlate the AChR expression pattern observed by the -BTX staining with the synaptic function, we analyzed synaptic activities of fast and slow muscles in the DKO line at 6 dpf. We recorded spontaneous synaptic currents from muscle cells using the whole-cell patch clamp technique (Fig. 2, A to C). Traces show miniature endplate currents (mEPCs) from muscles of WT or DKO larvae (Fig. 2A). Slow muscles in the DKO line exhibited mEPCs. The frequency (14.5 3.1 Hz in WT, 15.5 3.2 Hz in DKO) and the amplitude of slow muscle mEPCs (260.0 74.1 pA in WT, 491.7 105.2 pA in DKO) showed no differences between WT and DKO lines (Fig. 2, B and C). However, fast muscles in DKO failed to produce mEPCs. To confirm that the lack of mEPCs is caused by the absence of functional receptors, we recorded currents in muscles generated by puff application of ACh (Fig. 2D). While fast muscles in WT larvae showed ACh-induced currents (756.4 138.6 pA), those in DKO larvae failed to show any response (0 0 pA). These results, in conjunction with the -BTX staining (Fig. 1C), showed that fast muscles of DKO larvae do not express any AChRs and receive no synaptic input.

(A) mEPC traces from fast or slow muscles of WT and DKO larvae (6 dpf) by whole-cell patch-clamp recordings. Fast muscle cells in DKO failed to exhibit mEPCs. (B and C) Frequencies (B) and amplitudes (C) of mEPCs were plotted for each muscle (n = 8 cells). (D) Representative traces of voltage-clamped slow and fast muscles in DKO larvae in response to the application of 30 M ACh. Calibration: 1 s, 500 pA. Amplitudes of ACh-induced currents in slow (n = 7 cells) and fast muscles (n = 7 cells) are shown. Each dot represents a muscle cell. (E) Construct used for Ca2+ imaging. Top: The GCaMP7a coding sequence was fused to the promoter region of the -actin promoter pact. Bottom: Schematic illustration showing the experimental procedure. The gene construct was injected into eggs of DKO at the one cell stage. Ca2+ response was analyzed at 6 dpf. Representative traces showing the increase of F/F in a fast muscle (black line) and a slow muscle (red line) during spontaneous contractions. (F) Overexpression of the subunit fused with an EGFP (-EGFP) in WT (3 dpf). Top panels: -EGFPs were expressed under the control of a slow musclespecific promoter, psmyhc. EGFP signals (green), expressed in the superficial slow muscles, filled the cytoplasm and did not colocalize with -BTX (magenta) signals. Bottom panels: -EGFPs were expressed under the regulation of pact. In deeper layer fast muscles, the clusters of EGFP and -BTX colocalized (arrowheads). Scale bars, 50 m.

We performed in vivo Ca2+ imaging in the DKO larvae at 6 dpf to further support the result of synaptic current recordings. We designed a gene construct in which a pan-muscle promoter, -actin promoter, drives the expression of a Ca2+ indicator, GCaMP7a (17), and injected the construct into fertilized eggs (Fig. 2E). In DKOs, we recorded Ca2+ response associated with spontaneous locomotion activities, induced by the application of N-methyl-d-aspartate (50 M) (18). The results showed that slow muscle cells exhibited Ca2+ transients, while fast muscle cells did not generate any Ca2+ response.

Considering that fast muscles do not allow composition of , , and subunits, we next examined whether slow muscles conversely allow incorporation of subunits in the AChR pentamer, by overexpressing the subunit in slow muscles. We designed a gene construct that expressed an subunit fused with enhanced green fluorescent protein (-EGFP) under the regulation of a slow musclespecific promoter, psmyhc (19). We injected the construct into fertilized WT eggs and observed the expression of EGFP at 3 to 4 dpf. EGFP signals typically filled the cytoplasm of the slow muscle cells and never colocalized with -BTX signals (Fig. 2F). In a control experiment, in which -EGFP was driven by the pan-muscle promoter (-actin promoter), the -EGFP signals made clusters in fast muscles, colocalizing with -BTX signals in deeper layers of the trunk region where fast muscles form NMJs. Together, fast muscles and slow muscles express specific types of AChR, and the alternate composition of subunits is prohibited.

To examine how silencing of synapses in fast muscles affect locomotion, we next analyzed swimming of WT and DKO larvae at 6 dpf. We induced escape responses by gentle tactile stimuli. Locomotion was recorded with a high-speed camera, and we measured angles between head and tail trajectories throughout each escape response (Fig. 3A and movie S1). WT fish turned their heads 120 to 140 in the initial stage of escape. The typical startle response of teleosts generally begins with a large turn of the head (termed C-bend), followed by a robust forward propulsion as described in previous studies (20).

(A) Escape behaviors in WT and DKO lines at 6 dpf in response to tactile stimuli. Images of representative larva on the left show superimposed frames of the complete escape response (the duration of movement is indicated in the top right corner). Scale bars, 2 mm. Kinematics for representative traces of 10 larvae are shown for the initial 50 ms of the response. Middle panels represent averaged traces. In the right panels, each trace represents a different larva. Body angles are shown in degrees, with 0 indicating a straight body, and positive and negative values indicating body bends in opposite directions. Scale bars, 10 ms. (B to D) Maximum turn angles, time to reach the maximum angle, and post-startle swimming speed were calculated for each group of fish (6 dpf). In DKO, the turn angle and the swimming speed were notably reduced, and it took longer to reach maximum angles (n = 10 fish). (E and F) Analyses of spontaneous locomotion. Images of representative larva (left) for WT or DKO showed superimposed frames of spontaneous swim bouts (the duration of movement indicated in the bottom right corner). Swimming speed was calculated for WT (n = 5 fish) and DKO (n = 5 fish), which showed no significant difference. Scale bars, 2 mm.

The initial turns of the DKO larvae were in sharp contrast to WT. Averaged maximum head turn angles in DKOs were markedly smaller compared to WT larvae (116.0 5.8 in WT, 20.2 4.0 in DKO; P < 0.001) (Fig. 3B), and time to reach the maximum angle was increased (8.7 0.2 ms in WT, 15.8 0.8 ms in DKO; P < 0.001) (Fig. 3C). In addition to the absence of C-bends, the post-startle swimming speed of the DKO line was also notably slower (84.9 8.1 mm/s in WT, 12.8 1.3 mm/s in DKO; P < 0.001) (Fig. 3D).

In addition to the escape response, we also analyzed spontaneous locomotion, which corresponds to the slow swim described by Budick and OMalley (21) or scoot reported by Burgess and Granato (22) (Fig. 3, E and F). Significant difference in swimming speed was not observed between WT and DKO (16.1 1.60 mm/s in WT, 13.2 0.9 mm/s in DKO; P = 0.20) (Fig. 3F). Thus, the contribution of fast muscles in spontaneous swimming is relatively small. These results strongly suggest that fast muscles in larval zebrafish play a key role in executing quick escape responses including the C-bend and fast forward propulsion behaviors, which corroborate earlier studies (23).

DKO fish die prematurely and do not develop into adults. However, KOs that reached the adult stage are expected to lack both and subunits, because subunit expression terminates early in development.

To dismiss the possibility of compensatory up-regulation of the subunit in adult KOs, we analyzed the expression of subunit mRNA with digital droplet polymerase chain reaction (ddPCR). Subunit mRNA was not detected in adult KOs, which were 3 to 5 months old (Fig. 4A). Interestingly, subunit mRNA was strongly up-regulated in larval KOs (Fig. 4B), which may account for functional escape response behavior at 6 dpf (fig. S1). Thus, our findings suggest that compensation by the subunit expression occurs only in larval KOs and not in adults.

(A) Quantification of or subunit mRNA in adult muscles. Subunit was not detected in WT. or subunit mRNA was not detected in KO (n = 6 fish in WT, n = 5 fish in KO). Sample numbers are shown in parentheses. (B) mRNA expression of subunit in 1-dpf larvae. Subunit was highly up-regulated in the KO (n = 5 fish) compared to WT (n = 5 fish). Sample numbers are shown in parentheses. (C) Schematic illustration of a transverse section of the trunk region. The area shown in micropictograms is indicated with a box. The distribution of AChRs in adults, WT or KO, was visualized by -BTX conjugated with Alexa Fluor 488 (green). Broken lines indicate the boundary of fast muscle area (arrowheads). Fast muscles in the KO fish lack -BTX signals. (D) Sections of adult fast muscles of WT and KO, stained with the fast musclespecific F310 antibody. Fast muscles in KO fish did not display atrophy. In the right panel, diameters of fast muscles in WT and KO were calculated (87 fibers, n = 3 fish). There was no significant difference. Scale bars, 100 m.

The expression of AChR in adult KO fish, visualized by -BTX, was consistent with the lack of compensation (Fig. 4C). Transverse sections of the trunk region were labeled with -BTX. Slow, intermediate, and fast muscles are spatially segregated (11). Slow muscles are located closest to the surface. WT fish displayed universally distributed, positive -BTX signals. In sharp contrast, -BTX signals in the KO fish were detected only in shallow, lateral regions, and fast muscles of the adult KO lacked AChR expression.

In spite of the absence of -BTXpositive signals, fast muscle fibers in KO fish unexpectedly lacked signs of prominent atrophy (24). A fast musclespecific F310 antibody used via immunohistochemistry allowed the visualization and diameter measurements of fast muscle fibers. Statistical analysis revealed no difference between KO and WT fiber size (58.7 0.5 m in WT, 58.3 0.7 m in KO; P = 0.945) (Fig. 4D).

We observed escape responses induced by objects dropping on water and subsequently analyzed C-bend angles and the swimming speed during escape (Fig. 5A) (25). We compared the maximum C-bend angles between the focal genetic lines. Similar to WT larvae (Fig. 3), WT adults start the escape response with the initial extreme head turn. Unexpectedly, we found that KO adult fish also display robust C-bends (Fig. 5, A and B). Although smaller in amplitude (103.0 7.5 in WT, 53.4 2.5 in KO), their time course did not exhibit any delay compared to WT. This is in sharp contrast to the complete loss of C-bend behavior observed in larval DKOs (Fig. 3). The duration of first turn also showed no significant difference between WTs and KOs (38.9 3.8 ms in WT, 46.6 4.9 ms in KO).

(A) Escape behaviors in WT and KO adults (3 to 4 months old). The startle response was induced by dropping objects on water. Images of representative fish to the left show superimposed frames of the complete escape response (the duration of movement is indicated in the bottom right corner). Kinematics for representative traces from 10 or 9 fish are shown for the initial 50 ms of response. Middle panels represent averaged traces. In right panels, each trace represents a different fish. Body angles are shown in degrees, with 0 indicating a straight body. Positive and negative values indicate body bends in opposite directions. (B) First turn angles were calculated for each group of fish (n = 10 fish in WT, n = 9 fish in KO). Turn angles were reduced in the KO fish. Sample numbers are shown in parentheses. (C) Post-startle swimming speed and total distance traveled were calculated for the first 120 ms. There was no significant difference between WT (n = 10 fish) and KO (n = 9 fish) adults.

Furthermore, the forward propulsion during escape of the KO adult zebrafish was almost intact. When the distance traveled was plotted against the time after stimulation, the curves for WT and KO nearly overlapped (Fig. 5C). The swimming speed (31.7 1.3 cm/s in WT, 25.5 3.0 cm/s in KO; P = 0.08) and total distance traveled (4.0 0.2 cm in WT, 3.2 0.4 cm in KO; P = 0.08) were similar between WT and KO adults.

Suspecting that compensation of locomotion occurred at the level of neural projection, we examined the projections of motor neurons by retrograde labeling using a fluorescent tracer, dextran conjugated with Alexa Fluor 488 (Fig. 6, A to C). We injected the tracer into muscles of WT and K fish following a method described in a previous report (26). Spinal motor neurons in adult zebrafish are classified on the basis of morphological features. Dorsomedial motor neurons with larger cell somas, which are called primary motor neurons (pMNs), specifically innervate fast muscles. Ventrolateral motor neurons with smaller somas, called secondary motor neurons (sMNs), are grouped in distinct populations depending on the innervation target: fast, intermediate, and slow muscles (2729). We analyzed the location of motor neuron somas in the spinal cord (Fig. 6B) by measuring the distance from the center of spinal cord to cell somas. In WT adults, fast muscles were innervated mainly by dorsomedial motor neurons (located close to the center), and slow muscles were innervated by ventrolateral motor neurons (Fig. 6, A and B).

(A) Schematic illustration of a transverse section of the trunk region showing the sites of dye injections. Right panels showing cell bodies of labeled motor neurons (arrowheads) in spinal cords. Broken lines indicating outlines of spinal cords. Scale bars, 50 m. (B) A graph showing the distance from the center of the spinal cord to cell bodies of motor neurons. In WT, motor neurons located close to the center innervate fast muscles, and ventrolateral motor neurons innervate slow muscles. In KO, slow muscles were innervated by motor neurons located close to the center. Numbers of labeled cells are shown in parentheses. (C) Graph showing the size of cell somas of motor neurons. In WT, large motor neurons innervate fast muscles, and smaller neurons innervate slow muscles. In KO, slow muscles were innervated by large motor neurons. (D) Schematic illustration of a transverse section of the trunk region showing the locations of the DiI crystal insertion. The right panel displays cell body of labeled pMN (arrowhead) in the spinal cord. The broken line indicates the outline of the spinal cord. Scale bar, 50 m. (E) Presynaptic structures were visualized by SV2A antibody. Broken lines indicate the boundary of slow muscle area (left side). Note the reduced signal in the fast muscles of the KO fish. Scale bars, 100 m. (F and G) Fast musclespecific myosins labeled by F310 antibody in WT (F) and KO (G). In (G), the boxed area is enlarged in the right panel. Broken lines indicate the boundary of slow muscle area (left side). Arrowheads indicate muscle cells with F310 signals in the slow muscle region. While a small number of slow muscle cells in WT sometimes showed immunoreactivity, the cell number was markedly increased in KO. Scale bars, 100 m. (H and I) Glycolytic muscle fibers were visualized by GPD staining in WT (H) and KO (I). Black broken lines indicate the boundary between slow and intermediate muscles, and the red broken line indicates the boundary between intermediate and fast muscles. Fast, intermediate, and slow muscle areas are labeled with F, I, and S, respectively. Note that the intermediate muscle region in KO is hard to distinguish from the fast muscle region, blurring the boundary (I). Arrowheads in the right panel indicate muscle cells with GPD signals in the slow muscle region. Scale bars, 100 m. (J) Schematic illustration showing the rerouted innervation of pMNs. In KO adults, synaptic silencing of fast muscles led to the innervation of fast musclespecific pMNs on slow muscle. This reinnervation caused conversion of slow to fast muscles. The projections of sMNs that innervate fast muscles may not change.

Both the location and the size of motor neuron somas suggested that slow muscles in KO adults were innervated by large motor neurons, which innervate only fast muscles in WT adults (Fig. 6C). Ventrolateral neurons did not seem to innervate slow muscles in KOs, as they were absent in retrograde labeling (Fig. 6, B and C). When we injected the tracer into fast muscles of KO adults, pMNs were not labeled (fig. S2). Motor neurons labeled in these preparations were presumably fast sMNs (26).

To rule out the possibility that pMN axons are inadvertently damaged by dye injections into slow muscles of KO adults, we used another method of retrograde labeling using a lipophilic tracer DiI (or DiIC18), which has a minimal possibility of causing pressure injection damage (30). After gently placing crystals of DiI onto slow muscles of KO adults, we found that pMNs were labeled in spinal cords of KO adults (Fig. 6D). We also analyzed the presynaptic input in muscles of WT and KO adults using SV2A antibody to visualize presynaptic proteins (Fig. 6E). The results showed that positive signals within fast muscles were reduced in KO compared to WT adults. Thus, fewer motor neurons innervated fast muscles in KO fish.

The muscle cell type is determined by the motor neuron input (31). Suspecting the signals from pMNs may convert the properties of slow muscles into those of fast muscles in adult KO fish, we examined the characteristics of slow muscle fibers. To do so, we analyzed the F310 antibody immunohistochemistry in adult KO fish, which labels fast musclespecific myosin (Fig. 6, F and G) (19). We also examined the -glycerophosphate dehydrogenase (-GPD) activity, which is a well-established method to visualize glycolytic muscles, i.e., fast muscles (Fig. 6, H and I) (32). Some tissue located in slow muscle regions stained positive for F310 (n = 3 fish; Fig. 6G) and -GPD signals (n = 3 fish; Fig. 6I), suggesting that some slow muscles expressed the fast muscletype isoform of myosin light chain and obtained glycolytic ability. Intermediate muscle fibers in KO also showed higher glycolytic ability compared to WT (Fig. 6, H and I). Thus, a subpopulation of slow and intermediate muscles was converted to fast muscles, presumably due to the innervation of fast muscle motor neurons (31).

In summary, the absence of AChRs in developing KOs is presumed to drive motor neuron axon innervation of fast muscles to instead reroute to slow muscles. These rewired pMNs presumably predominate over original axons in slow muscles, as a result of synaptic competition, and convert some slow and intermediate muscles to fast muscles (Fig. 6J).

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Synaptic silencing of fast muscle is compensated by rewired innervation of slow muscle - Science Advances

13 January 2020

Promising results from clinical trials give hope for using CRISPR/Cas9 genome editing to treat various heritable diseases and cancer in humans.

It has been seven years since the discovery that the CRISPR/Cas9 defence system, used by microbes to destroy viruses, could be re-engineered to edit the human genome. Since then researchers have carried out an array of experiments to explore potential applications.

Biophysist Dr He Jiankui sparked global controversy concerning the ethics of genome editing when he used CRISPR to genetically modify embryos, resulting in the birth of the first genome-edited babies (see BioNews 977).

Yet researchers worldwide have at the same time been investigating the use of CRISPR for non-heritable changes, modifying the genes in non-embryonic cells to treat a wide range of diseases.

'There's been a lot of appropriate caution in applying this to treating people, but I think we're starting to see some of the results of that work,' said Dr Edward Stadtmauer, a haematologist at the University of Pennsylvania, Philadelphia.

Over a dozen new clinical trials testing CRISPRtherapy on diseases such as cancer, HIV and sickle cell anaemia were listed on the clinicaltrials.gov database last year. One trial in its early stages used CRISPR to treat sickle cell anaemia and beta-thalassaemia, both genetic blood disorders that result in the production of an abnormal form of the oxygen-carrying protein, haemoglobin.

Two patients with these disorders were treated by CRISPR Therapeutics in Cambridge, Massachusetts, and Vertex Pharmaceuticals in Boston, Massachusetts, using CRISPR to inactivate a gene that switches off the production of an alternative form of haemoglobin. Preliminary results of the study suggest that this therapy improved some of the symptoms but the participants will need to be followed for a longer period to be sure.

Results from two other trials, one in which genome-edited blood cells were transplanted into a man to treat HIV infection, and the other in which they were transplanted into three people to treat some forms of cancer, were less successful. In both cases, the transplanted cells flourished in the bone marrow of recipients, without any serious safety concerns, but did not produce a clear medical benefit. The study has been placed on hold while researchers explore ways to boost that percentage, says Hongkui Deng, a stem-cell researcher at Peking University, Beijing, China and a lead author of the work.

Other researchers are trying to move beyond editing cells in vitro. In July 2019 a clinical trial was launched to treat Leber congenital amaurosis 10 (LCA10), a rare genetic disease that causes blindness. The trial, launched by two pharmaceutical companies, Editas Medicine in Cambridge, Massachusetts, and Allergan in Dublin, Ireland, will be the first trial that uses CRISPR to edit cells inside of the body. The researchers are testing AGN-151587 (EDIT-101), which is a novel CRISPR treatment delivered via adeno-associated virus (AAV) directly to the eye's light-sensing photoreceptor cells to remove the mutation that causes LCA10.

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The potential use of CRISPR to treat disease is gaining momentum - BioNews

Cara Gormallys pregnancy was shadowed by grief. As a queer woman wanting to have a baby, the biology professor had figured finding a sperm donor would be the only obstacle she and her partner faced. But thanks to Gormallys organizational skills and love of making lists, the couple landed on a donor with relative ease.

Then, Gormally struggled to conceive. Each month brought fresh disappointment and loss.

So much of the process depended on random, heart-breaking chance, she says. The emotional and financial roller coaster was exhausting.

But it wasnt the hardest part. The couple had accepted that, as much as they wanted a baby, their child wouldnt be biologically related to Gormallys spouse.

I grieved that our child wouldnt be genetically related to both of us, Gormally says. I longed for the biologically impossible.

But now, a new set of technologies have the potential to change whats possible allowing same-sex partners to have kids who share their genetic material, just like straight couples.

In mammals, pretty much every cell in the body carries two sets of genetic material. One set comes from mom and the other from dad. Eggs and sperm are the only exceptions; they have just one set. Then, when a sperm fertilizes an egg, those two sets combine, restoring the usual number to two sets per cell.

Gormally and other same-sex partners are currently barred from their dreams by a phenomenon called genomic imprinting. It uses a distinct tag from each parent to mark the DNA that mammals pass on to their offspring. The process ensures that, for a small percentage of genes, we only express the copy of genetic material provided by our mother or our father. When this imprinting process goes awry, kids can end up with inactive gene regions that cause miscarriages, developmental defects and cancer.

(Credit: Jay Smith/Discover)

During this genomic imprinting, moms distinct collection of tags typically turns off certain genes, so that just dads copy is expressed. And dad imparts his own marks that leave only the maternal copy on. (Most imprints silence gene expression, but some activate it.) Thats a problem for same-sex couples who want to have a baby. If both sets of an offsprings genes come from maternal DNA, for example, then both copies of imprinted genes will be off. So, the embryo cant make any of the genes products.

We dont get the full set of [gene] products that we need to undergo proper development unless we have both a maternal and paternal contribution to a fertilized egg, says Marisa Bartolomei, a geneticist at the University of Pennsylvania in Philadelphia, who discovered one of the first imprinted genes in mice.

Scientists discovered genomic imprinting in mammals about 30 years ago. During experiments in the mid-1980s, researchers removed either the maternal or paternal genetic contributions from newly fertilized mouse eggs. Then, they transferred in a second set of genes from another mouse to create embryos with either two sets of female genetic material or two sets of male genetic material. A surrogate mouse was able to gestate the embryos, but none survived. The finding showed normal development requires genetic material from both a father and the mother. More than that, the outcomes revealed that maternal and paternal genetic material differ from each other in meaningful ways.

Later experiments revealed mice developed differently depending on whether they happened to receive both copies of certain regions of DNA from one parent (rather than one copy from each parent).

Mice with hairpin-shaped tails were telling examples. When researchers deleted the gene region responsible for a hairpin tail from a mothers genome, mice embryos grew large and died partway through gestation. In contrast, deleting the same region from the paternal genome had no effect on the rodents growth or development.

In the three decades since, researchers have found more imprinted genes (they suspect there are between 100 and 200 such genes) and the molecular tags that silence them. Scientists have also taken strides connecting imprinting defects to developmental disorders in humans. But all along, researchers have known that imprinting prevents same-sex parents from having children.

In October 2018, researchers overcame this impossibility in mice. By deleting imprinted regions, Wei Li and a team at the Chinese Academy of Sciences in Beijing produced healthy mice from two moms. The researchers also created mouse pups from two dads for the first time. However, the offspring died just a few days after birth.

Despite the loss, Li is optimistic. This research shows us what is possible, he says.

To overcome the imprinting barrier, Li and his fellow researchers turned to CRISPR, a gene-editing technique thats made altering genomes easier than ever. They used the tool to delete gene regions from embryonic stem cells from mice mothers. The researchers then injected these modified stem cells into the egg of a female mouse and then used a third surrogate female mouse to carry the fetus to term.

The team had already seen some success two years earlier when they created mouse pups with two genetic mothers by deleting two imprinted regions. Although these bimaternal mice also grew to adulthood and produced pups of their own, they developed growth defects. On average, the bimaternal mice were 20 percent lighter than their hetero-parental counterparts. In their latest study, Li and his team also deleted a third region from the mothers genes, which restored the animals growth to normal.

But the scientists had to clear a few more hurdles to generate mice with two genetic fathers. They found, through a process of trial and error, that they needed to remove twice as many imprinted regions in the bipaternal mice as the bimaternal mice. In total, the team deleted seven imprinted regions to successfully create mice from two dads.

Still, the numbers were not in their favor. Only two and a half percent of embryos made it to term and less than half of one percent lived for two days. None made it to adulthood.

The produced bipaternal mice are not viable, which implies more obstacles are needed to cross to support their postnatal survival, if possible, Li says. The lower birth rate, on the other hand, implies the existence of an unknown barrier hindering the development of bipaternal embryos.

In contrast, the bimaternal mice fared much better. These mice grew to adulthood and were healthy enough to have pups of their own by mating with typical male mice. They also behaved the same as the control mice. As far as the researchers could tell, the bimaternal mice appear as healthy and normal as any other laboratory mice.

It does not mean that they are normal in every aspect, Li cautions. One cannot investigate all the aspects under restricted experimental conditions with a limited number of animals.

Despite the researchers success, Li says the technique is not ready for use in humans. It is never too much to emphasize the risks and the importance of safety before any human experiment, he says, particularly in regard to the bipaternal offspring, which currently are severely abnormal and cannot survive to adulthood.

The bimaternal offspring hold more promise. The team is now working to translate their findings to monkeys. And that work could bring the impossible one step closer to feasible for humans.

Lis research is encouraging but its a long way from helping Gormally and her spouse. However, its also not the only shot for same-sex couples. Another new technology called in vitro gametogenesis, or IVG, may be an alternative potential path for same-sex couples to have their own kids.

Scientists use the technique to make eggs and sperm from other cells in the body. To do so, biologists first reprogram adult skin cells to become stem cells. Then, they stimulate the skin-derived stem cells to develop into eggs or sperm.

Researchers from Japan have now perfected the technique in mice. And in groundbreaking work, Katsuhiko Hayashi and Mitinori Saitou and their team generated functional eggs from mice tail cells.

The researchers then fertilized the eggs with sperm from male mice and implanted the embryos into surrogate mothers. The offspring grew up healthy and fertile. In principle, this approach could allow a womans skin cells to be engineered into sperm and used to fertilize her partners egg.

IVG could transform same-sex couples ability to have their own children. If it had been possible at the time, we definitely wouldve have tried to do it, says Gormally, who is now a proud parent to a toddler thanks to her and her spouses sperm donor. [Its] a total game-changer.

This story is part of "The Future of Fertility" a new series on Discover exploring the frontiers of reproduction.

Read more:

Can Humans Have Babies in Space?

George Church Wants to Make Genetic Matchmaking a Reality

Human Gene Editing is Controversial. Shoukhrat Mitalipov Isn't Deterred

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The Slow March Toward the First Same-Sex Couple to Have a Baby - Discover Magazine

Last year left us with this piece of bombshell news: He Jiankui, the mastermind behind the CRISPR babies scandal, has been sentenced to three years in prison for violating Chinese laws on scientific research and medical management. Two of his colleagues also face prison for genetically engineering human embryos that eventually became the worlds first CRISPRd babies.

The story isnt over: at least one other scientist is eagerly following Hes footsteps in creating gene-edited humans, although he stresses that he wont implant any engineered embryos until receiving regulatory approval.

Biotech stories are rarely this dramatic. But as gene editing tools and assisted reproductive technologies increase in safety and precision, were bound to see ever more mind-bending headlines. Add in a dose of deep learning for drug discovery and synthetic biology, and its fair to say were getting closer to reshaping biology from the ground upboth ourselves and other living creatures around us.

Here are two stories in biotech were keeping our eyes on. Although successes likely wont come to fruition this year (sorry), these futuristic projects may be closer to reality than you think.

The idea of human-animal chimeras immediately triggers ethical aversion, but the dream of engineering replacement human organs in other animals is gaining momentum.

There are two main ways to do this. The slightly less ethically-fraught idea is to grow a fleet of pigs with heavily CRISPRd organs to make them more human-like. It sounds crazy, but scientists have already successfully transplanted pig hearts into baboonsa stand-in for people with heart failurewith some recipients living up to 180 days before they were euthanized. Despite having foreign hearts, the baboons were healthy and acted like their normal buoyant selves post-op.

But for cross-species transplantation, or xenotransplants to work in humans, we need to deal with PERVsa group of nasty pig genes scattered across the porcine genome, remnants of ancient viral infections that can tag along and potentially infect unsuspecting human recipients.

Theres plenty of progress here too: back in 2017 scientists at eGenesis, a startup spun off from Dr. George Churchs lab, used CRISPR to make PERV-free pig cells that eventually became PERV-free piglets after cloning. Then last month, eGenesis reported the birth of Pig3.0, the worlds most CRISPRd animal to further increase organ compatibility. These PERV-free genetic wonders had three pig genes that stimulate immunorejection removed, and nine brand new human genes to make themin theorymore compatible with human physiology. When raised to adulthood, pig3.0 could reproduce and pass on their genetic edits.

Although only a first clinical propotype that needs further validation and refinement, eGenesis is hopeful. According to one (perhaps overzealous) estimate, the first pig-to-human xenotranplant clinical trial could come in just two years.

The more ethically-challenged idea is to grow human organs directly inside other animalsin other words, engineer human-animal hybrid embryos and bring them to term. This approach marries two ethically uncomfortable technologies, germline editing and hybrids, into one solution that has many wondering if these engineered animals may somehow receive a dose of humanness by accident during development. What if, for example, human donor cells end up migrating to the hybrid animals brain?

Nevertheless, this year scientists at the University of Tokyo are planning to grow human tissue in rodent and pig embryos and transplant those hybrids into surrogates for further development. For now, bringing the embryos to term is completely out of the question. But the line between humans and other animals will only be further blurred in 2020, and scientists have begun debating a new label, substantially human, for living organisms that are mainly human in characteristicsbut not completely so.

With over 800 gene therapy trials in the running and several in mature stages, well likely see a leap in new gene medicine approvals and growth in CAR-T spheres. For now, although transformative, the three approved gene therapies have had lackluster market results, spurring some to ponder whether companies may cut down on investment.

The research community, however, is going strong, with a curious bifurcating trend emerging. Let me explain.

Genetic medicine, a grab-bag term for treatments that directly change genes or their expression, is usually an off-the-shelf solution. Cell therapies, such as the blood cancer breakthrough CAR-T, are extremely personalized in that a patients own immune cells are genetically enhanced. But the true power of genetic medicine lies in its potential for hyper-personalization, especially when it comes to rare genetic disorders. In contrast, CAR-Ts broader success may eventually rely on its ability to become one-size-fits-all.

One example of hyper-tailored gene medicine success is the harrowing story of Mila, a six-year-old with Batten disease, a neurodegenerative genetic disorder that is always fatal and was previously untreatable. Thanks to remarkable efforts from multiple teams, however, in just over a year scientists developed a new experimental therapy tailored to her unique genetic mutation. Since receiving the drug, Milas condition improved significantly.

Milas case is a proof-of-concept of the power of N=1 genetic medicine. Its unclear whether other children also carry her particular mutationBatten has more than a dozen different variants, each stemming from different genetic miscodingor if anyone else would ever benefit from the treatment.

For now, monumental costs and other necessary resources make it impossible to pull off similar feats for a broader population. This is a shame, because inherited diseases rarely have a single genetic cause. But costs for genome mapping and DNA synthesis are rapidly declining. Were starting to better understand how mutations lead to varied disorders. And with multiple gene medicines, such as antisense oligonucleotides (ASOs) finally making a comeback after 40 years, its not hard to envision a new era of hyper-personalized genetic treatments, especially for rare diseases.

In contrast, the path forward for CAR-T is to strip its personalization. Both FDA-approved CAR-T therapies require doctors to collect a patients own immune T cells, preserved and shipped to a manufacturer, genetically engineered to boost their cancer-hunting abilities, and infused back into patients. Each cycle is a race against the cancer clock, requiring about three to four weeks to manufacture. Shipping and labor costs further drive up the treatments price tag to hundreds of thousands of dollars per treatment.

These considerable problems have pushed scientists to actively research off-the-shelf CAR-T therapies, which can be made from healthy donor cells in giant batches and cryopreserved. The main stumbling block is immunorejection: engineered cells from donors can cause life-threatening immune problems, or be completely eliminated by the cancer patients immune system and lose efficacy.

The good news? Promising results are coming soon. One idea is to use T cells from umbilical cord blood, which are less likely to generate an immune response. Another is to engineer T cells from induced pluripotent stem cells (iPSC)mature cells returned back to a young, stem-like state. A patients skin cells, for example, could be made into iPSCs that constantly renew themselves, and only pushed to develop into cancer-fighting T cells when needed.

Yet another idea is to use gene editing to delete proteins on T cells that can trigger an immune responsethe first clinical trials with this approach are already underway. With at least nine different off-the-shelf CAR-T in early human trials, well likely see movement in industrialized CAR-T this year.

Theres lots of other stories in biotech we here at Singularity Hub are watching. For example, the use of AI in drug discovery, after years of hype, may finally meet its reckoning. That is, can the technology actually speed up the arduous process of finding new drug targets or the design of new drugs?

Another potentially game-changing story is that of Biogens Alzheimers drug candidate, which reported contradicting results last year but was still submitted to the FDA. If approved, itll be the first drug to slow cognitive decline in a decade. And of course, theres always the potential for another mind-breaking technological leap (or stumble?) thats hard to predict.

In other words: we cant wait to bring you new stories from biotechs cutting edge in 2020.

Image Credit: Image by Konstantin Kolosov from Pixabay

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The Top Biotech Trends We'll Be Watching in 2020 - Singularity Hub

SUZHOU, Chinaand SHANGHAI, Jan. 7, 2020 /PRNewswire/ -- Gracell Biotechnologies Co., Ltd. ("Gracell"), a clinical-stage immune cell therapy company, today announced the initiation of an investigational study of GC027, the first product candidate developed using TruUCAR to treat relapsed or refractory (R/R) T-cell malignancies.

T-cell acute lymphoblastic leukemia or T-ALL is an aggressive form of ALL, which affects white blood cells and the bone marrows ability to generate healthy blood cells. About 15-20% of people with ALL have T-ALL. While T-ALL is treatable by chemotherapy and stem cell transplant, around 75% of patients will relapse within two years[1]. T-cell lymphoblastic lymphoma (T-LBL) is another devastating T-cell malignancies. For patients who develop R/R T-ALL or T-LBL, there are few options for treatment.

Autologus CAR-T therapies rely on patients' own T cells, which have been affected by prior therapies; thus, cell quality as well as efficacy remains questionable. Allogenic CAR-T therapies made of healthy donors' T cells would be characterized as being of consistently good quality with the potential to improve efficacy. Unlike autologous CAR-T cells, allogeneic CAR-T cells can be made as off-the-shelf product which means patients do not have to wait for lengthy production time. Furthermore, the cost of production can be significantly lower. Allogenic CAR-T therapies also provide a vital treatment option for patients with viral infections and/or other conditions prohibiting access to autologous cell therapies.

TruUCARbased GC027 is designed to meet the above unmet needs. Its cells are made of T cells from healthy donors, genetically edited and inserted with chimeric antigen receptor (CAR) ex vivo, which can specifically bind to and eliminate target T malignant cells. Different from industry leaders' off-the-shelf CAR-T design, Gracell's proprietary and patented TruUCAR technology requires no co-administration of anti-CD52, a cytotoxic agent for ablating cancerous cells while inducing long term immune depletion in the patient.Instead, GC027 utilizes CRISPRgenome editing strategy that is expected to avoid graft-versus-host disease (GvHD) as well as graft rejection caused by the patients' immune system.

The prudent preclinical studies provide substantial evidence to trigger GC027 moving into a non-IND(investigational new drug)clinical trial to evaluate the safety, pharmacokinetics and pharmacodynamics of GC027 therapy in patients suffering from relapsed and refractory T lymphocyte malignancies.

TruUCAR is another technological breakthrough developed by Gracell following the recent announcement of FasTCAR technology and products. It enables producing off-the-shelf CAR-T cells from healthy MHC (major histocompatibility complex) mismatched donors with a large number of doses readily to be dispatched to patients in need.

"Launch of the investigational GC027 study as the first-of-its-kind therapy marks another significant milestone for Gracell," said Dr. William CAO, Founder and CEO of Gracell. "Once the concept is well-proved with solid evidence for safety and efficacy, we will immediately deploy development of a series of TruUCAR products for other medical unmet needs, including B cell malignancies."

About GC027

GC027 is an investigational, off-the-shelf CAR-T cell therapy for T cell malignancies, derived from healthy donors. The use of healthy donor's cells are preferential to a patient's own with potential to improve efficacy, reduce production time, and lower cost of goods.

About T-ALL

T lymphoblastic leukemia (T-ALL) is an aggressive form of T cell malignancies, with a diffuse invasion of bone marrow and peripheral blood. In 2015, ALL affected around 876,000 people globally and resulted in 110,000 deaths worldwide. T-ALL compromises about 15%-20% children and adults[1].Current standard therapies for T-ALL are chemotherapies and stem cell transplantation. A large portion of these patients will experience relapse within two years following treatment by conventional therapies.

About T-LBL

T lymphoblastic lymphoma (T-LBL) is an aggressive form of T cell malignancies, with rare lymphoproliferative neoplasm of mature T cells caused by infection with the retrovirus human T lymphotropic virus. T-LBL compromises about 2% of adult non-Hodgkin's lymphoma (NHL) and 30% of pediatric NHL patients[2]. Five-year overall survival is only 14% in adults.Although first-line treatment using cytotoxic combination chemotherapy can achieve 70% ORR, nearly 90% of patients relapse, often within months of completing chemotherapy.

About Gracell

Gracell Biotechnologies Co., Ltd. ("Gracell") is a clinical-stage biopharma company, committed to developing highly reliable and affordable cell gene therapies for cancer. Gracell is dedicated to resolving the remaining challenges in CAR-T, such as high production costs, lengthy manufacturing process, lack of off-the-shelf products, and inefficacy against solid tumors. Led by a group of world-class scientists, Gracell is advancing FasTCAR, TruUCAR (off-the-shelf CAR), Dual CAR and Enhanced CAR-T cell therapies for leukemia, lymphoma, myeloma, and solid tumors.

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[1]Pediatric hematologic Malignancies: T-cell acute lymphoblastic Leukemia, Hematology 2016

[2]Clinical Review: Adult T-cell Leukemia/lymphoma, Journal ofOncology Practice 2017

SOURCE Gracell

http://www.gracellbio.com

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Gracell Initiates Investigational Study of the Technological Breakthrough TruUCAR Therapy for Relapsed or Refractory T-cell Malignancies - PRNewswire

Every year, BioSpace analyzes the biotech industry, looking for the hot new biotech startups to watch. We then produce the NextGen Bio Class of, twenty companies ranked based on several categories, including Finance, Collaborations, Pipeline, and Innovation. The companies were typically launched no more than 18 months before the list was created.

We thought it would be insightful to look back at our previous lists to see where some of those companies are today. Heres a look at the top three companies from the Top 20 Life Science Startups to Watch in 2018.

#1. BlueRock Therapeutics. Founded in 2016, BlueRock was #1 on our list of companies to watch in 2018. With facilities in Ontario, Canada; Cambridge, Massachusetts; and New York, New York, BlueRock launched in December 2016 with a $225 million Series A financing led by Bayer AG and Versant Ventures. The company focuses on cell therapies to regenerate heart muscle in patients who have had a heart attack or chronic heart failure, as well as therapies for patients with Parkinsons disease.

In October 2017, BlueRock and Seattle-based Universal Cells entered into a collaboration and license deal to create induced pluripotent stem (iPS) cell lines that can be used in the manufacture of allogeneic cellular therapies. Shortly afterwards, the company established its corporate headquarters in Cambridge, and in April 2018, established a research-and-development hub in New York City, as well as formalizing a sponsored research collaboration with the Center for Stem Cell Biology at Memorial Sloan Kettering (MSK) Cancer Center. The collaboration focuses on translating Ketterings expertise in creating multiple types of authentic neural cells from stem cells to address diseases of the central and peripheral nervous system. BlueRock also received $1 million from the State of New York and Empire State Development under its economic development initiatives program.

In April 2019, BlueRock partnered with Editas Medicine (which was on BioSpaces NextGen Bio Class of 2015 list) to combine their genome editing and cell therapy technologies to focus on novel engineered cell medicines. Part of the deal was to collaborate on creating novel, allogeneic pluripotent cell lines using a combination of Editas CRISPR genome editing technology and BlueRocks iPSC platform.

And finally, in August 2019, Bayer AG acquired BlueRock for the remaining stake in the company for about $240 million in cash and an additional $360 million in pre-defined development milestones.

#2. Prelude Fertility. Prelude Fertility is a bit of an outlier from the typical BioSpace NextGen company, because it isnt quite a biopharma company. It is a life sciences company whose business model is aimed at in vitro fertilization and egg freezing. It was founded with a $200 million investment by entrepreneur Martin Varsavsky. The investment was in the largest in vitro fertilization clinic in the Southeast, Reproductive Biology Associates of Atlanta, and its affiliate, My Egg Bank, the largest frozen donor egg bank in the U.S.

Since then it has expanded in various parts of the country, including adding San Francisco-based Pacific Fertility Center (PFC) to its network in September 25, 2017; partnering with Houston Fertility Institute and acquiring Vivere Health; partnering with the Advanced Fertility Center of Chicago; and in October 2018, partnered with NYU Langone Health.

In March 2019, Prelude merged with Inception Fertility to establish the Prelude Network as the fastest-growing network of fertility clinics and largest provider of comprehensive fertility services in the U.S. Inception is acting as the parent company, with the Prelude Network, both having board representatives from the previous organizations.

#3. Relay Therapeutics. Ranking #3 on our list for 2018, Relay Therapeutics launched in September 2016 with a $57 million Series A financing led by Third Rock Ventures with participation form D.E. Shaw Research. On December 14, 2017, it closed on a Series B round worth $63 million, led by BVF Partners, with new investors GV (formerly Google Ventures), Casdin Capital, EcoR1 Capital and Section 32.

The company focuses on the relationship between protein motion and function. It merges computational power with structural biology, biophysics, chemistry and biology. In December 2018, the company completed a $400 million Series C financing. It was led by the SoftBank Vision fund and included additional new investors, Foresite Capital, Perceptive Advisors and Tavistock Group. Existing investors also participated.

The company announced at the time it planned to use the funds to accelerate the implementation of its long-term strategy, expanding its discovery efforts, advancing existing programs into the clinic and improving its platform.

See more here:
Where Are They Now? Top 3 Biotech Startups From NextGen Bio Class of 2018 - BioSpace

IN the summer of 2019, a mother in Nashville, Tennessee in the United States, with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old said.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so that doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as a molecular scissors.

The genetically-edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary, but theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease beta thalassemia.

She had previously needed 16 blood transfusions per year. Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible.

It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the co-founder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Gene cures

Crispr was the latest breakthrough in a year of great strides in gene therapy, a medical adventure that started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not, such as making normal red blood cells in Grays case or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he said. It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the US National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said US NIHs associate director for science policy Carrie Wolinetz.

These therapies are exorbitantly expensive, however, costing up to US$2 million (RM8.18 million) meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to Massachusetts Institute of Technology (MIT) researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

In this Oct 10, 2018, photo, He speaks during an interview at his laboratory in Shenzhen, China. The scientist was recently sentenced to three years in prison for practicing medicine illegally and fined 3 million yuan (RM1.76 million). AP

Bioterrorism potential

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

In 2018 in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA (deoxyribonucleic acid) of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV (human immunodeficiency virus), even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, he added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species, e.g. malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist -- weve been talking about bioterrorism for years, she said. Nothing has ever happened. AFP Relaxnews

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Gene editing breakthroughs that cured genetic diseases in 2019 - The Star Online

DURHAM Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the source but significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common FundsSomatic Cell Genome Editing (SCGE)program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

Duke engineers improve CRISPR genome editing with biomedical tails

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Duke researchers: Single CRISPR treatment provides long-term benefits in mice

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing bothnew CRISPR systems for gene regulationandto regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in usingAAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about theDuke Center for Advanced Genomic Technologies.

(C) Duke University

Link:
Duke researchers land $6M in federal grants to advance gene editing - WRAL Tech Wire

Hemophilia. Cystic fibrosis. Duchenne muscular dystrophy. Huntingtons disease. These are just a few of the thousands of disorders caused by mutations in the bodys DNA. Treating the root causes of these debilitating diseases has become possible only recently, thanks to the development of genome editing tools such as CRISPR, which can change DNA sequences in cells and tissues to correct fundamental errors at the sourcebut significant hurdles must be overcome before genome-editing treatments are ready for use in humans.

Enter the National Institutes of Health Common Funds Somatic Cell Genome Editing (SCGE) program, established in 2018 to help researchers develop and assess accurate, safe and effective genome editing therapies for use in the cells and tissues of the body (aka somatic cells) that are affected by each of these diseases.

Todaywith three ongoing grants totaling more than $6 million in research fundingDuke University is tied with Yale University, UC Berkeley and UC Davis for the most projects supported by the NIH SCGE Program.

In the 2019 SCGE awards cycle, Charles Gersbach, the Rooney Family Associate Professor of Biomedical Engineering, and collaborators across Duke and North Carolina State University received two grants: the first will allow them to study how CRISPR genome editing affects engineered human muscle tissues, while the second project will develop new CRISPR tools to turn genes on and off rather than permanently alter the targeted DNA sequence. This work builds on a 2018 SCGE grant, led by Aravind Asokan, professor and director of gene therapy in the Department of Surgery, which focuses on using adeno-associated viruses to deliver gene editing tools to neuromuscular tissue.

There is an amazing team of engineers, scientists and clinicians at Duke and the broader Research Triangle coalescing around the challenges of studying and manipulating the human genome to treat diseasefrom delivery to modeling to building new tools, said Gersbach, who with his colleagues recently launched the Duke Center for Advanced Genomic Technologies (CAGT), a collaboration of the Pratt School of Engineering, Trinity College of Arts and Sciences, and School of Medicine. Were very excited to be at the center of those efforts and greatly appreciate the support of the NIH SCGE Program to realize this vision.

For their first grant, Gersbach will collaborate with fellow Duke biomedical engineering faculty Nenad Bursac and George Truskey to monitor how genome editing affects engineered human muscle tissue. Through their new project, the team will use human pluripotent stem cells to make human muscle tissues in the lab, specifically skeletal and cardiac muscle, which are often affected by genetic diseases. These systems will then serve as a more accurate model for monitoring the health of human tissues, on-target and off-target genome modifications, tissue regeneration, and possible immune responses during CRISPR-mediated genome editing.

Currently, most genetic testing occurs using animal models, but those dont always accurately replicate the human response to therapy, says Truskey, the Goodson Professor of Biomedical Engineering.

Bursac adds, We have a long history of engineering human cardiac and skeletal muscle tissues with the right cell types and physiology to model the response to gene editing systems like CRISPR. With these platforms, we hope to help predict how muscle will respond in a human trial.

Gersbach will work with Tim Reddy, a Duke associate professor of biostatistics and bioinformatics, and Rodolphe Barrangou, the Todd R. Klaenhammer Distinguished Professor in Probiotics Research at North Carolina State University, on the second grant. According to Gersbach, this has the potential to extend the impact of genome editing technologies to a greater diversity of diseases, as many common diseases, such as neurodegenerative and autoimmune conditions, result from too much or too little of certain genes rather than a single genetic mutation. This work builds on previous collaborations between Gersbach, Barrangou and Reddy developing both new CRISPR systems for gene regulation and to regulate the epigenome rather than permanently delete DNA sequences.

Aravind Asokan leads Dukes initial SCGE grant, which explores the the evolution of next generation of adeno-associated viruses (AAVs), which have emerged as a safe and effective system to deliver gene therapies to targeted cells, especially those involved in neuromuscular diseases like spinal muscular atrophy, Duchenne muscular dystrophy and other myopathies. However, delivery of genome editing tools to the stem cells of neuromuscular tissue is particularly challenging. This collaboration between Asokan and Gersbach builds on their previous work in using AAV and CRISPR to treat animal models of DMD.

We aim to correct mutations not just in the mature muscle cells, but also in the muscle stem cells that regenerate skeletal muscle tissue, explainsAsokan. This approach is critical to ensuring long-term stability of genome editing in muscle and ultimately we hope to establish a paradigm where our cross-cutting viral evolution approach can enable efficient editing in multiple organ systems.

Click through to learn more about the Duke Center for Advanced Genomic Technologies.

Read more:
Duke Researchers Garner Over $6 Million in NIH Funding to Fight Genetic Diseases - Duke Today

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome. Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy. "I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency." Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells. The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors." The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured. "This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville. "But these results are really exciting." In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden. For decades, the DNA of living organisms such as corn and salmon has been modified. But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs. The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself. "It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy. Scientists practising the technique insert a normal gene into cells containing a defective gene. It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumor-killing super white blood cells for a cancer patient. Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union. They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and an inherited blindness. Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution. "Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster." Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period." "We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face grueling negotiations with their insurance companies. They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection. "You cannot do this in a community hospital close to home," said her doctor. However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers. They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine. Last year in China, scientist He Jiankui triggered an international scandal -- and his excommunication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans. The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process. "That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations. "It's very easy to do if you don't care about the consequences," Musunuru added. Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability. There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US. The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online. "Not everyone is a biologist or scientist," she said. And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops? Charpentier thinks that technology generally tends to be used for the better. "I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

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Year in Review: Gene Therapy Technology and a Milestone 2019 for Medical Research - News18

The 2010s are coming to an end, and looking back there have been some pretty amazing advances and innovations in health and science.

Advances in prosthetic limbs

Prosthetic limbs have been around since ancient times. In Egypt, a prosthetic wooden toe was found on a mummy dating back 3,000 years. By the Dark Ages, inventors could incorporate hinges on prosthetic arms used by knights. In modern times, the field of prosthetics has turned to incorporating more technology into physical stand-ins for limbs. In the last several years, theres been a boom in advances that have led to the best and most useful prosthetics weve ever seen.

Reports from the early 2010s talked about the potential for new technology to allow people to control prosthetics with their minds and to receive sensory information from their devices. It may have been a reach in the early part of the decade, but now it is literally within grasp. There are new prosthetic hands being tested that give the user the ability to grab objects with their thoughts and even to sense the texture of what they are touching. New bionic hands allow the user to feel again by sending signals back to the brain about the things they are touching, like whether its hard or soft. Other research groups have been working on bionic arms that can move based on the users thoughts through a brain-computer interface. While these have demonstrated its possible to accomplish these goals in the lab, theres still more to be done before people can use these devices outside in the real world.

Many of these advanced prosthetics are still prototypes and may not reach the general population for a while. Luckily, cheaper 3D printers have made simple prosthetics more accessible. These are important because a prosthetic device can improve the quality of life for people. For example, this person has been printing prosthetic hands and arms for people in Africa after watching an online tutorial. New materials that go into 3D printers are cheaper than they used to be and are being used in prosthetics to provide a more affordable option for patients.

Although prosthetics have been around for ages in some form or another, they arent always used. One variable to consider is the social acceptance of having a prosthetic. Theres still a lot of stigma around disabilities and many people may reject prosthetics even if they are available. In 2012, an athlete with both feet amputated competed in the mens 400 meter race at the Olympics in London. There was some controversy over whether the runner with a prosthetic foot should be allowed to run in races with people who dont have prosthetics or if they should only be allowed in competitions specifically for people who have them. Prosthetics also need to be comfortable and usable in order to be successfully adopted. In one study, about 4.5 percent of people rejected prosthetics and 13.4 percent stopped using their prosthetics. As the new prosthetics that are more natural and intuitive to use come to market, hopefully more people will benefit, and the social barriers to acceptance will disappear.

CRISPR

The genome modification technique called Clustered Regularly Interspaced Short Palindromic Repeats, aka CRISPR, was a culmination of a few decades of work by scientists, and major studies explaining the method were published in 2013. The version of it called CRISPR-associated protein 9 or CRIPSR-Cas9 is what most researchers are specifically using in most cases. It involves a regular gene editing mechanism that happens in bacteria. The bacteria can take sections of DNA from attacking viruses and essentially use that to remember the viruses if they return. When the virus is back, the bacteria can target the matching sections of DNA in the virus, cut it and disable the virus.

Though 2013 was only six years ago, as far as science goes, CRISPR has been moving at lightning speed towards practical applications. Using CRISPR to edit a gene sequence, researchers can now add, delete or modify DNA segments more quickly and accurately than ever before. Since the technique was developed, researchers have used CRISPR to target diseases caused by a single gene like cystic fibrosis or sickle cell disease.

Probably the most infamous use of CRISPR are the CRISPR babies. In late 2018, a Chinese researcher, He Jiankui, claimed to have used CRISPR to modify the genomes of two babies to include a mutated version of a gene that protects against HIV. This case was and is highly controversial for the ethical concerns with genetically modifying a human genome at the embryo level, or germline, meaning it can be passed down to future generations and has not been done before in humans. Recently, MIT Technology Review obtained excerpts from Hes research, and experts say that the report and data may be untrustworthy. This means it is still unclear if He and collaborators actually successfully modified the babies genomes. The scientific community overall condemns this way of using CRISPR to edit a human germline genome and has called for an international moratorium on it until a framework can be agreed on.The researcher has been sentenced to three years in prison in Shenzhen, China.

As fraught with controversy as the CRISPR babies may be, CRISPR technology still holds a lot of promise and can be used responsibly, supporters say. For example, researchers are using it to target cancer cells by taking a patients immune cells, modifying them using CRISPR and then infusing the patient with the modified cells. For blood diseases, a patient with sickle cell disease is reported to be responding well to a CRISPR treatment that has allowed her body to produce a crucial protein.

Another area that has boomed this decade partly because of CRISPR technology is stem cell therapy, which well get into in the next section.

Stem cell therapy

Technically, the only Federal Drug Administration (FDA)-approved stem cell therapies are blood-forming stem cells derived from umbilical cord blood. Blood-forming stem cells are used to treat patients with cancer after chemotherapy has depleted blood cells, as well as patients with blood disorders like leukemia whose bone marrow tissues are damaged. These types of treatments have been around for about 30 years, but in the 2010s weve seen potential for more uses of stem cells in health care.

The main idea behind stem cell therapy is that because the cells are pluripotent meaning they can become many other types of cells they can be introduced into parts of the body that are damaged and need new cells. On top of that, researchers can now extract some types of stem cells from a persons body, so no need for umbilical cords. This opens up the possibilities for highly personalized treatment where one person can be treated with stem cells from their own body.

Researchers are exploring how stem cells can be used to treat liver disease, cerebral palsy, stroke, brain injury and others. There are many ongoing research-backed clinical trials for stem cell therapy. A quick search for stem cell therapy on the governments clinical trial database turns up 5,638 results. And because of the work necessary to even get to the clinical trial stage, theres likely an order of magnitude more stem cell therapy studies in the pre-clinical trial stages.

Stem cell therapy is also being offered in for-profit clinics around the U.S. In these cases, the clinics are typically taking fat tissue from a patient, isolating the stem cells and then administering the stem cells back to the patient. In some cases, the treatments may lead to health complications, like blindness in a few extreme cases, and the FDA warns that such treatments are unapproved and potentially harmful. The FDA is ramping up regulation of stem cell clinics and earlier this year took a specific clinic in Florida to court.

Although there are many stem cell clinics offering unproven stem cell therapies, its not all hype. Granted that its difficult to pass the clinical trial stage to get FDA approval, stem cell research may lead to new treatments for several health conditions that could completely change the health care landscape.

You can follow Chia-Yi Hou on Twitter.

Read more:
The 3 most important health innovations of the past decade - The Hill

This undated screen grab shows the cell-division of two fertilized human embryos during the first 24 hours of embryonic development following IVF treatment at a private clinic in London. ( Jim Dyson/Getty Images )

LOS ANGELES - Some of the scientific advancements of the 2010s have been truly mind-blowing, and perhaps none more so than the leaps and bounds weve made in the realm of reproduction.

This was not only the decade in which the first three-parent baby was born, it was the era when a rogue scientist chose to make edits to a set of twin girls DNA, making real the long-imagined scenario of genetically altering human beings while simultaneously thrusting the deeply complicated ethical discussions surrounding this practice into the limelight.

These are the five most life-altering breakthroughs in reproduction from the past decade.

In 2018, Chinese biophysics researcher He Jiankui announced that he had used the gene-editing tool CRISPR to modify the genes of two twin girls before birth. He and his team said that their goal was to make the girls immune to infection by HIV through the elimination of a gene called CCR5.

When the news broke, many mainstream scientists criticized the attempt, calling it too unsafe to try. Where some people saw the potential for a new kind of medical treatment capable of eradicating genetic disease, others saw a window into a dystopian future filled with designer babies and framed by a new kind of eugenics.

At the time, Dr. Kiran Musunuru, a University of Pennsylvania gene-editing expert, said Hes work was unconscionable... an experiment on human beings that is not morally or ethically defensible.

Other experts believe Hes work could propel the field of gene editing forward.

The twins, known as Lulu and Nana, have continued to make headlines since their birth. The gene modification that He claims to have carried out may have caused some unintended mutations in other parts of the genome, which could have unpredictable consequences for their health long term something many scientists who argue against Hes work cite as a reason to hold off on using gene-editing technology on humans.

Only time will tell what will happen to Lulu and Nana and if the edits to their DNA ultimately help or hurt them, but their story pushed the topic of human gene-editing and the ethics surrounding it to the forefront of the global scientific community.

In 2016, a technique called mitochondrial transfer was used successfully for the first time to create a three-parent baby grown from a fathers sperm, a mothers cell nucleus and a third donors egg that had the nucleus removed.

This technique was developed to prevent the transmission of certain genetic disorders through the mothers mitochondria. The majority of a three-parent babys DNA would come from his parents in the form of nuclear DNA, and only a small portion would come from the donor in the form of mitochondrial DNA.

A team led by physician John Zhang at the New Hope Fertility Center in New York City facilitated the birth of the first three-parent baby in April 2016.

Using human pluripotent stem cells, researchers were able to make the precursors of human sperm or eggs. In other words, they reprogrammed skin and blood stem cells to become an early-state version of what would eventually become either sperm or an egg.

"The creation of primordial germ cells is one of the earliest events during early mammalian development," Dr. Naoko Irie, first author of the paper from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge told Science Daily. "It's a stage we've managed to recreate using stem cells from mice and rats, but until now few researches have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans."

A 2018 study showed that gene editing can allow two same-sex mice to conceive pups, and two female mice were able to successfully create healthy pups that then went on to reproduce themselves.

A team of researchers at the Chinese Academy of Sciences in Beijing, led by developmental biologist Qi Zhou, were able to use gene editing to produce 29 living mice from two females, seven of which went on to have their own pups. They were able to produce 12 pups from two male parents, but those offspring were not able to live more than two days.Whether or not the method can one day be used in same-sex human reproduction is still up for debate.

For the first time ever, Chinese scientists were able to clone two primates using the technique that produced Dolly the sheep, the first mammal to be cloned from an adult somatic cell via nuclear transfer.

The two cloned female macaques were named Zhong Zhong and Hua Hua, and their successful birth opened up the possibility of using the same cloning method to one day clone humans.

Visit link:
What a time to be alive: Reproductive breakthroughs of the 2010s that changed life as we know it - FOX 5 Atlanta

For decades, the DNA of living organisms such as corn and salmon has been modified, but Crispr, invented in 2012, made gene editing more widely accessible. Image: YinYang/IStock.com via AFP Relaxnews

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering by editing her genome.

Victoria Grays recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research gene therapy.

I have hoped for a cure since I was about 11, the 34-year-old told AFP in an email.

Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency.

Over several weeks, Grays blood was drawn so doctors could get to the cause of her illness stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 pronounced Crisper a new tool informally known as molecular scissors.

The genetically edited cells were transfused back into Grays veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

This is one patient. This is early results. We need to see how it works out in other patients, said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

But these results are really exciting.

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

Its all developing very quickly, said French geneticist Emmanuelle Charpentier, one of Crisprs inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Cures

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practicing the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not such as making normal red blood cells, in Victorias case, or making tumor-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the United States and a blood disease in the European Union.

They join several other gene therapies bringing the total to eight approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

Twenty-five, 30 years, thats the time it had to take, he told AFP from Paris.

It took a generation for gene therapy to become a reality. Now, its only going to go faster.

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a breakthrough period.

We have hit an inflection point, said Carrie Wolinetz, NIHs associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion and fighting a general infection.

You cannot do this in a community hospital close to home, said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Bioterrorism

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who dont necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal and his excommunication from the scientific community when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

That technology is not safe, said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr scissors often cut next to the targeted gene, causing unexpected mutations.

Its very easy to do if you dont care about the consequences, Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesnt believe in the more dystopian scenarios predicted for gene therapy, including American biohackers injecting themselves with Crispr technology bought online.

Not everyone is a biologist or scientist, she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies crops?

Charpentier thinks that technology generally tends to be used for the better.

Im a bacteriologist weve been talking about bioterrorism for years, she said. Nothing has ever happened.IB/JB

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2019: The year gene therapy came of age - INQUIRER.net

This undated screen grab shows the cell-division of two fertilized human embryos during the first 24 hours of embryonic development following IVF treatment at a private clinic in London. ( Jim Dyson/Getty Images )

LOS ANGELES - Some of the scientific advancements of the 2010s have been truly mind-blowing, and perhaps none more so than the leaps and bounds weve made in the realm of reproduction.

This was not only the decade in which the first three-parent baby was born, it was the era when a rogue scientist chose to make edits to a set of twin girls DNA, making real the long-imagined scenario of genetically altering human beings while simultaneously thrusting the deeply complicated ethical discussions surrounding this practice into the limelight.

These are the five most life-altering breakthroughs in reproduction from the past decade.

In 2018, Chinese biophysics researcher He Jiankui announced that he had used the gene-editing tool CRISPR to modify the genes of two twin girls before birth. He and his team said that their goal was to make the girls immune to infection by HIV through the elimination of a gene called CCR5.

When the news broke, many mainstream scientists criticized the attempt, calling it too unsafe to try. Where some people saw the potential for a new kind of medical treatment capable of eradicating genetic disease, others saw a window into a dystopian future filled with designer babies and framed by a new kind of eugenics.

At the time, Dr. Kiran Musunuru, a University of Pennsylvania gene-editing expert, said Hes work was unconscionable... an experiment on human beings that is not morally or ethically defensible.

Other experts believe Hes work could propel the field of gene editing forward.

The twins, known as Lulu and Nana, have continued to make headlines since their birth. The gene modification that He claims to have carried out may have caused some unintended mutations in other parts of the genome, which could have unpredictable consequences for their health long term something many scientists who argue against Hes work cite as a reason to hold off on using gene-editing technology on humans.

Only time will tell what will happen to Lulu and Nana and if the edits to their DNA ultimately help or hurt them, but their story pushed the topic of human gene-editing and the ethics surrounding it to the forefront of the global scientific community.

In 2016, a technique called mitochondrial transfer was used successfully for the first time to create a three-parent baby grown from a fathers sperm, a mothers cell nucleus and a third donors egg that had the nucleus removed.

This technique was developed to prevent the transmission of certain genetic disorders through the mothers mitochondria. The majority of a three-parent babys DNA would come from his parents in the form of nuclear DNA, and only a small portion would come from the donor in the form of mitochondrial DNA.

A team led by physician John Zhang at the New Hope Fertility Center in New York City facilitated the birth of the first three-parent baby in April 2016.

Using human pluripotent stem cells, researchers were able to make the precursors of human sperm or eggs. In other words, they reprogrammed skin and blood stem cells to become an early-state version of what would eventually become either sperm or an egg.

"The creation of primordial germ cells is one of the earliest events during early mammalian development," Dr. Naoko Irie, first author of the paper from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge told Science Daily. "It's a stage we've managed to recreate using stem cells from mice and rats, but until now few researches have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans."

A 2018 study showed that gene editing can allow two same-sex mice to conceive pups, and two female mice were able to successfully create healthy pups that then went on to reproduce themselves.

A team of researchers at the Chinese Academy of Sciences in Beijing, led by developmental biologist Qi Zhou, were able to use gene editing to produce 29 living mice from two females, seven of which went on to have their own pups. They were able to produce 12 pups from two male parents, but those offspring were not able to live more than two days.Whether or not the method can one day be used in same-sex human reproduction is still up for debate.

For the first time ever, Chinese scientists were able to clone two primates using the technique that produced Dolly the sheep, the first mammal to be cloned from an adult somatic cell via nuclear transfer.

The two cloned female macaques were named Zhong Zhong and Hua Hua, and their successful birth opened up the possibility of using the same cloning method to one day clone humans.

Read the rest here:
What a time to be alive: Reproductive breakthroughs of the 2010s that changed life as we know it - FOX 10 News Phoenix

Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy.

Picture: Supplied.

WASHINGTON, United States - In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome.

Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy.

"I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency."

Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors."

The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

"This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

"But these results are really exciting."

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta-thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

"It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

CURES

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumour-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

"Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster."

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period."

"We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face gruelling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in the hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection.

"You cannot do this in a community hospital close to home," said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

**BIOTERRORISM **

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal -- and his ex-communication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

"That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations.

"It's very easy to do if you don't care about the consequences," Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online.

"Not everyone is a biologist or scientist," she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops?

Charpentier thinks that technology generally tends to be used for the better.

"I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

Visit link:
2019: The year gene therapy came of age - Eyewitness News

This undated screen grab shows the cell-division of two fertilized human embryos during the first 24 hours of embryonic development following IVF treatment at a private clinic in London. ( Jim Dyson/Getty Images )

LOS ANGELES - Some of the scientific advancements of the 2010s have been truly mind-blowing, and perhaps none more so than the leaps and bounds weve made in the realm of reproduction.

This was not only the decade in which the first three-parent baby was born, it was the era when a rogue scientist chose to make edits to a set of twin girls DNA, making real the long-imagined scenario of genetically altering human beings while simultaneously thrusting the deeply complicated ethical discussions surrounding this practice into the limelight.

These are the five most life-altering breakthroughs in reproduction from the past decade.

In 2018, Chinese biophysics researcher He Jiankui announced that he had used the gene-editing tool CRISPR to modify the genes of two twin girls before birth. He and his team said that their goal was to make the girls immune to infection by HIV through the elimination of a gene called CCR5.

When the news broke, many mainstream scientists criticized the attempt, calling it too unsafe to try. Where some people saw the potential for a new kind of medical treatment capable of eradicating genetic disease, others saw a window into a dystopian future filled with designer babies and framed by a new kind of eugenics.

At the time, Dr. Kiran Musunuru, a University of Pennsylvania gene-editing expert, said Hes work was unconscionable... an experiment on human beings that is not morally or ethically defensible.

Other experts believe Hes work could propel the field of gene editing forward.

The twins, known as Lulu and Nana, have continued to make headlines since their birth. The gene modification that He claims to have carried out may have caused some unintended mutations in other parts of the genome, which could have unpredictable consequences for their health long term something many scientists who argue against Hes work cite as a reason to hold off on using gene-editing technology on humans.

Only time will tell what will happen to Lulu and Nana and if the edits to their DNA ultimately help or hurt them, but their story pushed the topic of human gene-editing and the ethics surrounding it to the forefront of the global scientific community.

In 2016, a technique called mitochondrial transfer was used successfully for the first time to create a three-parent baby grown from a fathers sperm, a mothers cell nucleus and a third donors egg that had the nucleus removed.

This technique was developed to prevent the transmission of certain genetic disorders through the mothers mitochondria. The majority of a three-parent babys DNA would come from his parents in the form of nuclear DNA, and only a small portion would come from the donor in the form of mitochondrial DNA.

A team led by physician John Zhang at the New Hope Fertility Center in New York City facilitated the birth of the first three-parent baby in April 2016.

Using human pluripotent stem cells, researchers were able to make the precursors of human sperm or eggs. In other words, they reprogrammed skin and blood stem cells to become an early-state version of what would eventually become either sperm or an egg.

"The creation of primordial germ cells is one of the earliest events during early mammalian development," Dr. Naoko Irie, first author of the paper from the Wellcome Trust/Cancer Research UK Gurdon Institute at the University of Cambridge told Science Daily. "It's a stage we've managed to recreate using stem cells from mice and rats, but until now few researches have done this systematically using human stem cells. It has highlighted important differences between embryo development in humans and rodents that may mean findings in mice and rats may not be directly extrapolated to humans."

A 2018 study showed that gene editing can allow two same-sex mice to conceive pups, and two female mice were able to successfully create healthy pups that then went on to reproduce themselves.

A team of researchers at the Chinese Academy of Sciences in Beijing, led by developmental biologist Qi Zhou, were able to use gene editing to produce 29 living mice from two females, seven of which went on to have their own pups. They were able to produce 12 pups from two male parents, but those offspring were not able to live more than two days.Whether or not the method can one day be used in same-sex human reproduction is still up for debate.

For the first time ever, Chinese scientists were able to clone two primates using the technique that produced Dolly the sheep, the first mammal to be cloned from an adult somatic cell via nuclear transfer.

The two cloned female macaques were named Zhong Zhong and Hua Hua, and their successful birth opened up the possibility of using the same cloning method to one day clone humans.

More here:
What a time to be alive: Reproductive breakthroughs of the 2010s that changed life as we know it - FOX 11 Los Angeles

NewsScienceThis was the decade designer babies went from concept to feasibility

Saturday, 28th December 2019, 7:02 am

Gene editing

This was the decade when designer babies went from science fiction to fact as a Chinese scientist, He Jiankui, made the shock announcement in December 2018 that the worlds first genetically modified children had been born. He was working illegally and he was widely condemned for not waiting until regulations had been put into place.

But the move showed just how rapidly the Crispr-Cas9 gene-editing technique likened to a find and replace command wasadvancing.

Embryonic and pluripotent Stem Cellresearch

This potentially revolutionary field of medicine has developed to the point where treatments are just around the corner.

Embryonic, or pluripotent, stem cells have extraordinary medical potential because they can develop into any one of the 220 or so mature, specialised cells of the body from insulin-making pancreatic cells to the nerve cells of the brain. In 2018, scientists restored the vision of two UK patients with age-related macular degeneration by inserting a patch of embryonic stem cells into their eyes. The research team hopes an affordable, off-the-shelf therapy could be available to NHS patients within five years.

Treatments for spinal cord injury, heart failure, diabetes, Parkinsons disease and lung cancer are also in advanced trials.

Higgs Boson

Gravitational waves

Scientific history was made in December 2016 as gravitational ripples in the fabric of spacetime, first predicted by Albert Einstein 100 years earlier, were detected, opening new vistas into the dark side of the universe. Physicists around the world confirmed they had detected unambiguous signals of gravitational waves emanating from the collision of two black holes 1.3 billion light years away.

The observations not only confirmed Einsteins general theory of relativity; they also provided the first direct detection of black holes colliding.

Black holes

Neanderthals

The Neanderthals may have been extinct for thousands of years, but in 2010, geneticists mapped their genome using DNA extracted from ancient bones. This led to a startling discovery: our ancestors interbred with other species after they migrated out of Africa.

So in the UK, most of us have a small percentage of Neanderthal genes in our DNA.

Excerpt from:
From gene editing to black holes and the Neanderthals, here's the biggest advances in science over the past decade - inews