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Worldwide Cell Therapy Market Projections to 2028 – The Largest Expansion Will Be in Diseases of the Central Nervous System, Cancer and Cardiovascular…
DUBLIN, March 12, 2020 /PRNewswire/ -- The "Cell Therapy - Technologies, Markets and Companies" report from Jain PharmaBiotech has been added to ResearchAndMarkets.com's offering.
The cell-based markets was analyzed for 2018, and projected to 2028. The markets are analyzed according to therapeutic categories, technologies and geographical areas. The largest expansion will be in diseases of the central nervous system, cancer and cardiovascular disorders. Skin and soft tissue repair as well as diabetes mellitus will be other major markets.
The number of companies involved in cell therapy has increased remarkably during the past few years. More than 500 companies have been identified to be involved in cell therapy and 309 of these are profiled in part II of the report along with tabulation of 302 alliances. Of these companies, 170 are involved in stem cells.
Profiles of 72 academic institutions in the US involved in cell therapy are also included in part II along with their commercial collaborations. The text is supplemented with 67 Tables and 25 Figures. The bibliography contains 1,200 selected references, which are cited in the text.
This report contains information on the following:
The report describes and evaluates cell therapy technologies and methods, which have already started to play an important role in the practice of medicine. Hematopoietic stem cell transplantation is replacing the old fashioned bone marrow transplants. Role of cells in drug discovery is also described. Cell therapy is bound to become a part of medical practice.
Stem cells are discussed in detail in one chapter. Some light is thrown on the current controversy of embryonic sources of stem cells and comparison with adult sources. Other sources of stem cells such as the placenta, cord blood and fat removed by liposuction are also discussed. Stem cells can also be genetically modified prior to transplantation.
Cell therapy technologies overlap with those of gene therapy, cancer vaccines, drug delivery, tissue engineering and regenerative medicine. Pharmaceutical applications of stem cells including those in drug discovery are also described. Various types of cells used, methods of preparation and culture, encapsulation and genetic engineering of cells are discussed. Sources of cells, both human and animal (xenotransplantation) are discussed. Methods of delivery of cell therapy range from injections to surgical implantation using special devices.
Cell therapy has applications in a large number of disorders. The most important are diseases of the nervous system and cancer which are the topics for separate chapters. Other applications include cardiac disorders (myocardial infarction and heart failure), diabetes mellitus, diseases of bones and joints, genetic disorders, and wounds of the skin and soft tissues.
Regulatory and ethical issues involving cell therapy are important and are discussed. Current political debate on the use of stem cells from embryonic sources (hESCs) is also presented. Safety is an essential consideration of any new therapy and regulations for cell therapy are those for biological preparations.
Key Topics Covered
Part I: Technologies, Ethics & RegulationsExecutive Summary 1. Introduction to Cell Therapy2. Cell Therapy Technologies3. Stem Cells4. Clinical Applications of Cell Therapy5. Cell Therapy for Cardiovascular Disorders6. Cell Therapy for Cancer7. Cell Therapy for Neurological Disorders8. Ethical, Legal and Political Aspects of Cell therapy9. Safety and Regulatory Aspects of Cell Therapy
Part II: Markets, Companies & Academic Institutions10. Markets and Future Prospects for Cell Therapy11. Companies Involved in Cell Therapy12. Academic Institutions13. References
For more information about this report visit https://www.researchandmarkets.com/r/sy4g72
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WASHINGTON, DC, US The US Food and Drug Administration, the Environmental Protection Agency and the US Department of Agriculture launched a $7.5 million consumer education initiative focused on highlighting the science behind genetically modified organisms.
The goal of the effort, called Feed Your Mind, is to answer the most common questions consumers have about GMOs, including how they are regulated and whether they are safe and healthy.
Less than a dozen genetically modified crops are grown in the United States, but they often make up an overwhelming majority of the crop grown. More than 90% of soybeans, corn and sugar beets planted in 2018 were genetically modified.
Genetic engineering has created new plants that are resistant to insects and diseases, led to products with improved nutritional profiles, as well as certain produce that dont brown or bruise as easily, said Stephen M. Hahn, MD, commissioner of the FDA.
One educational video from the FDA points out that genetically modified soybeans have healthier oils that may be used to replace oils that contain trans fats. Other materials highlight how reduced bruising and browning may help combat food waste.
Consumers, however, remain uncertain. Concerns that GMOs are unhealthy and harmful are widespread. The number of shoppers avoiding GMOs tripled over the past decade, according to The Hartman Group. Close to half of consumers surveyed last year said they avoid bioengineered ingredients, compared to 15% in 2007.
A study published last year in Nature Human Behavior found more than 90% of participants had some level of opposition to GMO foods. It also found that consumers with the strongest opposition to GMO foods thought they were more knowledgeable about the topic than other participants, despite scoring lower on an actual knowledge test.
While foods from genetically engineered plants have been available to consumers since the early 1990s and are a common part of todays food supply, there are a lot of misconceptions about them, Hahn said. This initiative is intended to help people better understand what these products are and how they are made.
The Feed Your Mind initiative will launch in phases. Materials already released include a new website, fact sheets, infographics and videos. Supplementary science curriculum for high schools, resources for health professionals and additional consumer materials will be released later this year and in 2021.
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US agencies launch initiative to boost understanding of GMOs - World Grain
Flagship Pioneering Announces the Launch of Repertoire Immune Medicines with Industry Veteran John G. Cox as Chief Executive Officer – Yahoo Finance
Repertoire Immune Medicines harnesses our immune systems intrinsic ability to cure disease bydecoding relevant Antigen-TCR codes and deploying them as breakthrough immune medicinesin immuno-oncology, autoimmune disorders and infectious diseases
Flagship Pioneering, a life sciences innovation enterprise, announced the launch of Repertoire Immune Medicines, a clinical-stage biotechnology company tapping the curative powers of our immune system to prevent, treat and cure cancer, autoimmune disorders and infectious diseases.
Repertoire Immune Medicines was formed by combining two Flagship companies the innovative and proprietary immune decoding platforms of Cogen Immune Medicines and the immuno-oncology platforms of Torque Therapeutics to create a fully integrated Immune Medicines company. At the helm is Chief Executive Officer John Cox, who most recently led the spin-off of Bioverativ (BIIV) from Biogen (BIIB), and its growth and successful acquisition by Sanofi (SNY).
During the last 4 years, these two Flagship Pioneering originated companies each advanced novel and complementary platforms protected by over 30 patent families. Through their combination, Repertoire Immune Medicines now has the unique capability to decipher human subject-derived antigen-T cell receptor (TCR) codes from healthy or diseased tissues in the context of the major MHC (HLA) types. These complexes dictate T cell activation or exhaustion, and their immunological codes can be used to design and clinically test a multitude of unprecedented therapeutic products based on precedented and specific mechanisms of T cell killing of antigen presenting tumor cells or infected cells.
"Repertoire is pioneering a new class of therapies based on high throughput, high content interrogation of the intrinsic ability of T cells to prevent, or cure diseases," said Noubar Afeyan, Ph.D., Chief Executive Officer of Flagship Pioneering and Co-Founder and Chairman of the Board of Repertoire Immune Medicine. He continued, "our products will be designed to leverage the highly evolved, potent and clinically-validated mechanism of the natural immune synapse to provide immune security to patients. With these ambitious goals in mind, we are pleased to have a proven leader, John Cox, as CEO to realize our shared vision to dramatically improve outcomes for those in need or at risk."
Repertoire has developed a suite of DECODE technologies that allows in-depth characterization of the immune synapse with unprecedented precision. The company leverages its functional response technologies to thoroughly understand the presentation of antigens in disease, de-orphan T cell receptors in the context of single-cell phenotypes, and curate vast amounts of data to enable deep-learning computational prediction models. By coupling single cell technologies with cellular and acellular antigen libraries, the company decodes CD4+ and CD8+ TCR-antigen specificity across selected T cell subsets from patients and from healthy individuals.
"I am pleased to work with the Flagship Pioneering team to integrate these two pioneering companies into a fully formed immune medicines business," said John Cox, Chief Executive Officer of Repertoire Immune Medicines. "Advancing rationally designed immune medicines into the clinic and eventually to commercialization offers tremendous potential for patients and long-term value for our shareholders."
Three DECODE discovery technologies are at the core of the companys immune synapse deciphering platform:
Decoding immune synapses relevant to a particular disease allows Repertoire to deploy the molecular codes to rationally design new immune medicines as disease-fighting TCRs and disease-associated antigens in its therapeutic products.
Repertoires DEPLOY technologies form a product-based platform that includes:
Repertoire is currently engaged in its first dose escalation safety trial with an autologous T cell product TRQ15-01, which leverages its proprietary PRIME platform to prepare the patients T cells and its proprietary TETHER platform to link an IL-15 nanogel immune modulator to the T cells.
The journey for Repertoire Immune Medicines commenced when Flagship Labs scientists contemplated how to rationally and efficiently direct the power of our T cells for therapeutics and cures. One origination group, led by David Berry, M.D., Ph.D., General Partner of Flagship Pioneering, focused on systematically unlocking antigen specific immune control. In parallel, another Flagship origination group, led by Doug Cole, M.D., General Partner of Flagship Pioneering, and based on the cytokine binding work from Prof. Darrell Irvines lab at MIT, focused on using autologous T cells to direct potent immune modulators to the tumor microenvironment.
To date, the combined companies raised over $220M to create and develop the DECODE discovery platform and DEPLOY product platform, and to initiate its first clinical trial of PRIME & TETHER T cells in cancer. Repertoires rapid advancement reflects its creative, dedicated and diverse team of over 120 professionals possessing expertise in immunology, experimental medicine, physics, computational science, material sciences, process engineering, bioengineering, protein design and applied mathematics.
ABOUT REPERTOIRE IMMUNE MEDICINESRepertoire Immune Medicines, a Flagship Pioneering company, is a clinical stage biotechnology company working to unleash the remarkable power of the human immune system to prevent, treat or cure cancer, autoimmune conditions and infectious diseases. The company is founded on the premise that the repertoire of TCR-antigen codes that drive health and disease represents one of the greatest opportunities for innovation in medical science. The company harnesses and deploys the intrinsic ability of T cells to prevent and cure disease. Repertoire scientists created and developed a suite of technologies for its DECODE discovery and DEPLOY product platforms that allow in-depth characterization of the immune synapse and the ability to rationally design, and clinically develop, multi-clonal immune medicines. The company is currently conducting experimental medicine clinical trials using autologous T cells primed against cancer antigens and tethered to IL-15. To learn more about Repertoire Immune Medicine, please visit our website: http://www.repertoire.com.
ABOUT FLAGSHIP PIONEERINGFlagship Pioneering conceives, creates, resources, and develops first-in-category life sciences companies to transform human health and sustainability. Since its launch in 2000, the firm has applied a unique hypothesis-driven innovation process to originate and foster more than 100 scientific ventures, resulting in over $30 billion in aggregate value. To date, Flagship is backed by more than $3.3 billion of aggregate capital commitments, of which over $1.7 billion has been deployed toward the founding and growth of its pioneering companies alongside more than $10 billion of follow-on investments from other institutions. The current Flagship ecosystem comprises 37 transformative companies, including: Axcella Health (NADAQ: AXLA), Denali Therapeutics (NASDAQ: DNLI), Evelo Biosciences (NASDAQ: EVLO), Foghorn Therapeutics, Indigo Agriculture, Kaleido Biosciences (NASDAQ: KLDO), Moderna (NASDAQ: MRNA), Rubius Therapeutics (NASDAQ: RUBY), Seres Therapeutics (NASDAQ: MCRB), and Syros Pharmaceuticals (NASDAQ: SYRS). To learn more about Flagship Pioneering, please visit our website: http://www.FlagshipPioneering.com.
View source version on businesswire.com: https://www.businesswire.com/news/home/20200312005102/en/
Niki FranklinRacepoint Global on behalf of Repertoire Immune Medicines+1 (617) firstname.lastname@example.org
At the same time, the planet continues to become more uncertain as a result of climate change, biodiversity and oceanic degradation, the refugee crisis, extremism and nuclear proliferation, among other global problems.
The growing anxiety associated with the increased and paradoxical juxtaposition of innovation and global problems places greater urgency on educational institutions to become actively involved in addressing these concerns and issues. Although the main purpose of education is to produce learning, higher education also serves several other equally important aims, including the civic or political, economic, social, environmental and personal purposes of education.
This contemporary reality raises serious humanitarian concerns and issues that are best addressed through a lens of human rights and democratic principles. Through this lens, institutions, societies and the planet are best served when leadership and decision-making are based on principles of ethics, inclusion and equity.
Some emerging trends in higher education
One of the best ways to get a grasp of the possible futures of higher education is to examine the emerging trends in higher education. Integrating sustainable development into the curriculum is one of the emerging trends in higher education, even though relatively little research has been conducted on the topic thus far.
Another important emerging trend in higher education is the integration of learning through a more tightly integrated and inclusive curriculum.
The problems currently facing societies and the planet today are of such complexity that they transcend industry and academic discipline boundaries. Pervasive problems such as hunger, homelessness, poverty, un/underemployment, debt and lack of social mobility cannot be solved or mitigated solely with siloed thinking. These problems traverse disciplinary boundaries and therefore require integrated thinking and problem-solving.
Another important emerging trend in higher education is the democratisation of knowledge and learning.
With the development of new ways to provide traditional formal learning (for example, e-learning and hybrid learning) has come the emergence of open education (for instance, MIT OpenCourseWare, a relatively less structured type of formal learning that is open to all) and non-formal learning (such as provided by the Khan Academy).
In addition, the growing importance of continual learning in the lives of people has also sparked other forms of education such as shadow education (for instance, private tutoring).
Results of emerging trends
Not only has lifelong learning become a human right, but it is also looked at by some as a social equaliser. Thus, over the past several decades, higher education has evolved from an elitist model of education to a universal model of education. As the world has become increasingly hyperconnected, so has higher education in many ways.
For instance, today there are many ways to provide learning along the learning spectrum from informal to non-formal to formal learning. In doing so, many types and forms of communities of knowledge now exist, which in turn, have created a more dynamic, diverse and interconnected learning eco-system (that is, knowledge democracy).
The end results of these trends are 1) to democratise knowledge so that it is available to anyone at any time at any place, and 2) to develop a global knowledge society by making learning more meaningful by addressing the needs of individuals, societies and the planet as a whole.
Since education at all levels is the engine that drives the development of humanity, it follows that education policy must be visionary in its policy-making and inclusive in its practices.
A humanistic vision of higher education
These trends have moved the higher education community towards a humanistic vision of higher education. Humanistic education refers to the role of education in addressing the contemporary needs, concerns and problems of humanity.
In humanistic education all three core knowledge domains (the arts, humanities and sciences) are equally important and valuable since each domain serves a different role and purpose in human development.
Humanistic education takes the Humboldtian model of higher education (the integration of teaching, learning and research) and extends it to include service to humanity. Thus, its aim is human capacity building in all areas and at all levels.
In the global higher education community, international organisations such as the United Nations Educational, Scientific and Cultural Organization, the International Association of Universities and the International Higher Education Teaching and Learning Association provide a voice and a medium through which to help achieve this aim. These organisations work with institutions, educators and policy-makers to help higher education move in a positive direction in an often uncertain and chaotic world.
In short, the contemporary vision of humanistic education focuses on the core qualities of all people: agency, dignity and development. As such, it involves the ongoing development of the ideals of rights (human, animal and environment) and democracy (in all its forms).
It also involves all those principles that flow from those ideals inclusion, equity and justice and all those practices that flow from those principles lifelong learning for all, academic freedom, pedagogical pluralism, epistemic diversity and institutional diversification.
This contemporary humanistic vision of higher education can be depicted in the following model:
A humanistic framework (agency, dignity and development), ideals (rights and democracy) principles (equity, inclusion and justice) and practices (lifelong learning for all, academic freedom, pedagogical pluralism, epistemic diversity and institutional diversification).
Higher education at a turning point
Higher education is at a turning point. As such, it must re-examine its position in society as a knowledge producer and re-imagine its role on the planet as a contributor to the common good. For instance, sustainable development has become a top priority in addressing the needs of the planet. Thus, colleges and universities must learn how to integrate sustainable development into the curriculum if they want to remain relevant in the 21st century.
A growing number of educational institutions have initiated community-based learning programmes, such as service-learning a teaching strategy, a learning activity and an educational philosophy that fosters active and engaged learning by integrating experiential learning and student research with classroom learning through community service.
In this way, they aim to promote and facilitate civic engagement, social responsibility and democratic learning. A programme like service-learning can serve as a gateway for colleges and universities to implement more global programmes, such as sustainable development that will help equip students with the new literacies of the future.
Patrick Blessinger is an adjunct associate professor of education at St Johns University, New York City, United States, and chief research scientist for the International Higher Education Teaching and Learning Association or HETL. Enakshi Sengupta is director of the Center for Advanced Research in Education at HETL. Mandla Makhanya is principal, vice-chancellor and professor at the University of South Africa and president of HETL. HETL will explore the issues raised in this article in its upcoming conference, the International Higher Education Teaching and Learning Conference.
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Mapping higher education's literacies of the future - University World News
Structure of the nCoV trimeric spike
The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryoelectron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV.
Science, this issue p. 1260
The outbreak of a novel coronavirus (2019-nCoV) represents a pandemic threat that has been declared a public health emergency of international concern. The CoV spike (S) glycoprotein is a key target for vaccines, therapeutic antibodies, and diagnostics. To facilitate medical countermeasure development, we determined a 3.5-angstrom-resolution cryoelectron microscopy structure of the 2019-nCoV S trimer in the prefusion conformation. The predominant state of the trimer has one of the three receptor-binding domains (RBDs) rotated up in a receptor-accessible conformation. We also provide biophysical and structural evidence that the 2019-nCoV S protein binds angiotensin-converting enzyme 2 (ACE2) with higher affinity than does severe acute respiratory syndrome (SARS)-CoV S. Additionally, we tested several published SARS-CoV RBD-specific monoclonal antibodies and found that they do not have appreciable binding to 2019-nCoV S, suggesting that antibody cross-reactivity may be limited between the two RBDs. The structure of 2019-nCoV S should enable the rapid development and evaluation of medical countermeasures to address the ongoing public health crisis.
The novel coronavirus 2019-nCoV has recently emerged as a human pathogen in the city of Wuhan in Chinas Hubei province, causing fever, severe respiratory illness, and pneumoniaa disease recently named COVID-19 (1, 2). According to the World Health Organization (WHO), as of 16 February 2020, there had been >51,000 confirmed cases globally, leading to at least 1600 deaths. The emerging pathogen was rapidly characterized as a new member of the betacoronavirus genus, closely related to several bat coronaviruses and to severe acute respiratory syndrome coronavirus (SARS-CoV) (3, 4). Compared with SARS-CoV, 2019-nCoV appears to be more readily transmitted from human to human, spreading to multiple continents and leading to the WHOs declaration of a Public Health Emergency of International Concern (PHEIC) on 30 January 2020 (1, 5, 6).
2019-nCoV makes use of a densely glycosylated spike (S) protein to gain entry into host cells. The S protein is a trimeric class I fusion protein that exists in a metastable prefusion conformation that undergoes a substantial structural rearrangement to fuse the viral membrane with the host cell membrane (7, 8). This process is triggered when the S1 subunit binds to a host cell receptor. Receptor binding destabilizes the prefusion trimer, resulting in shedding of the S1 subunit and transition of the S2 subunit to a stable postfusion conformation (9). To engage a host cell receptor, the receptor-binding domain (RBD) of S1 undergoes hinge-like conformational movements that transiently hide or expose the determinants of receptor binding. These two states are referred to as the down conformation and the up conformation, where down corresponds to the receptor-inaccessible state and up corresponds to the receptor-accessible state, which is thought to be less stable (1013). Because of the indispensable function of the S protein, it represents a target for antibody-mediated neutralization, and characterization of the prefusion S structure would provide atomic-level information to guide vaccine design and development.
Based on the first reported genome sequence of 2019-nCoV (4), we expressed ectodomain residues 1 to 1208 of 2019-nCoV S, adding two stabilizing proline mutations in the C-terminal S2 fusion machinery using a previous stabilization strategy that proved effective for other betacoronavirus S proteins (11, 14). Figure 1A shows the domain organization of the expression construct, and figure S1 shows the purification process. We obtained ~0.5 mg/liter of the recombinant prefusion-stabilized S ectodomain from FreeStyle 293 cells and purified the protein to homogeneity by affinity chromatography and size-exclusion chromatography (fig. S1). Cryoelectron microscopy (cryo-EM) grids were prepared using this purified, fully glycosylated S protein, and preliminary screening revealed a high particle density with little aggregation near the edges of the holes.
(A) Schematic of 2019-nCoV S primary structure colored by domain. Domains that were excluded from the ectodomain expression construct or could not be visualized in the final map are colored white. SS, signal sequence; S2, S2 protease cleavage site; FP, fusion peptide; HR1, heptad repeat 1; CH, central helix; CD, connector domain; HR2, heptad repeat 2; TM, transmembrane domain; CT, cytoplasmic tail. Arrows denote protease cleavage sites. (B) Side and top views of the prefusion structure of the 2019-nCoV S protein with a single RBD in the up conformation. The two RBD down protomers are shown as cryo-EM density in either white or gray and the RBD up protomer is shown in ribbons colored corresponding to the schematic in (A).
After collecting and processing 3207 micrograph movies, we obtained a 3.5--resolution three-dimensional (3D) reconstruction of an asymmetrical trimer in which a single RBD was observed in the up conformation. (Fig. 1B, fig. S2, and table S1). Because of the small size of the RBD (~21 kDa), the asymmetry of this conformation was not readily apparent until ab initio 3D reconstruction and classification were performed (Fig. 1B and fig. S3). By using the 3D variability feature in cryoSPARC v2 (15), we observed breathing of the S1 subunits as the RBD underwent a hinge-like movement, which likely contributed to the relatively poor local resolution of S1 compared with the more stable S2 subunit (movies S1 and S2). This seemingly stochastic RBD movement has been captured during structural characterization of the closely related betacoronaviruses SARS-CoV and MERS-CoV, as well as the more distantly related alphacoronavirus porcine epidemic diarrhea virus (PEDV) (10, 11, 13, 16). The observation of this phenomenon in 2019-nCoV S suggests that it shares the same mechanism of triggering that is thought to be conserved among the Coronaviridae, wherein receptor binding to exposed RBDs leads to an unstable three-RBD up conformation that results in shedding of S1 and refolding of S2 (11, 12).
Because the S2 subunit appeared to be a symmetric trimer, we performed a 3D refinement imposing C3 symmetry, resulting in a 3.2--resolution map with excellent density for the S2 subunit. Using both maps, we built most of the 2019-nCoV S ectodomain, including glycans at 44 of the 66 N-linked glycosylation sites per trimer (fig. S4). Our final model spans S residues 27 to 1146, with several flexible loops omitted. Like all previously reported coronavirus S ectodomain structures, the density for 2019-nCoV S begins to fade after the connector domain, reflecting the flexibility of the heptad repeat 2 domain in the prefusion conformation (fig. S4A) (13, 1618).
The overall structure of 2019-nCoV S resembles that of SARS-CoV S, with a root mean square deviation (RMSD) of 3.8 over 959 C atoms (Fig. 2A). One of the larger differences between these two structures (although still relatively minor) is the position of the RBDs in their respective down conformations. Whereas the SARS-CoV RBD in the down conformation packs tightly against the N-terminal domain (NTD) of the neighboring protomer, the 2019-nCoV RBD in the down conformation is angled closer to the central cavity of the trimer (Fig. 2B). Despite this observed conformational difference, when the individual structural domains of 2019-nCoV S are aligned to their counterparts from SARS-CoV S, they reflect the high degree of structural homology between the two proteins, with the NTDs, RBDs, subdomains 1 and 2 (SD1 and SD2), and S2 subunits yielding individual RMSD values of 2.6 , 3.0 , 2.7 , and 2.0 , respectively (Fig. 2C).
(A) Single protomer of 2019-nCoV S with the RBD in the down conformation (left) is shown in ribbons colored according to Fig. 1. A protomer of 2019-nCoV S in the RBD up conformation is shown (center) next to a protomer of SARS-CoV S in the RBD up conformation (right), displayed as ribbons and colored white (PDB ID: 6CRZ). (B) RBDs of 2019-nCoV and SARS-CoV aligned based on the position of the adjacent NTD from the neighboring protomer. The 2019-nCoV RBD is colored green and the SARS-CoV RBD is colored white. The 2019-nCoV NTD is colored blue. (C) Structural domains from 2019-nCoV S have been aligned to their counterparts from SARS-CoV S as follows: NTD (top left), RBD (top right), SD1 and SD2 (bottom left), and S2 (bottom right).
2019-nCoV S shares 98% sequence identity with the S protein from the bat coronavirus RaTG13, with the most notable variation arising from an insertion in the S1/S2 protease cleavage site that results in an RRAR furin recognition site in 2019-nCoV (19) rather than the single arginine in SARS-CoV (fig. S5) (2023). Notably, amino acid insertions that create a polybasic furin site in a related position in hemagglutinin proteins are often found in highly virulent avian and human influenza viruses (24). In the structure reported here, the S1/S2 junction is in a disordered, solvent-exposed loop. In addition to this insertion of residues in the S1/S2 junction, 29 variant residues exist between 2019-nCoV S and RaTG13 S, with 17 of these positions mapping to the RBD (figs. S5 and S6). We also analyzed the 61 available 2019-nCoV S sequences in the Global Initiative on Sharing All Influenza Data database (https://www.gisaid.org/) and found that there were only nine amino acid substitutions among all deposited sequences. Most of these substitutions are relatively conservative and are not expected to have a substantial effect on the structure or function of the 2019-nCoV S protein (fig. S6).
Recent reports demonstrating that 2019-nCoV S and SARS-CoV S share the same functional host cell receptor, angiotensin-converting enzyme 2 (ACE2) (22, 2527), prompted us to quantify the kinetics of this interaction by surface plasmon resonance. ACE2 bound to the 2019-nCoV S ectodomain with ~15 nM affinity, which is ~10- to 20-fold higher than ACE2 binding to SARS-CoV S (Fig. 3A and fig. S7) (14). We also formed a complex of ACE2 bound to the 2019-nCoV S ectodomain and observed it by negative-stain EM, which showed that it strongly resembled the complex formed between SARS-CoV S and ACE2 that has been observed at high resolution by cryo-EM (Fig. 3B) (14, 28). The high affinity of 2019-nCoV S for human ACE2 may contribute to the apparent ease with which 2019-nCoV can spread from human to human (1); however, additional studies are needed to investigate this possibility.
(A) Surface plasmon resonance sensorgram showing the binding kinetics for human ACE2 and immobilized 2019-nCoV S. Data are shown as black lines, and the best fit of the data to a 1:1 binding model is shown in red. (B) Negative-stain EM 2D class averages of 2019-nCoV S bound by ACE2. Averages have been rotated so that ACE2 is positioned above the 2019-nCoV S protein with respect to the viral membrane. A diagram depicting the ACE2-bound 2019-nCoV S protein is shown (right) with ACE2 in blue and S protein protomers colored tan, pink, and green.
The overall structural homology and shared receptor usage between SARS-CoV S and 2019-nCoV S prompted us to test published SARS-CoV RBD-directed monoclonal antibodies (mAbs) for cross-reactivity to the 2019-nCoV RBD (Fig. 4A). A 2019-nCoV RBD-SD1 fragment (S residues 319 to 591) was recombinantly expressed, and appropriate folding of this construct was validated by measuring ACE2 binding using biolayer interferometry (BLI) (Fig. 4B). Cross-reactivity of the SARS-CoV RBD-directed mAbs S230, m396, and 80R was then evaluated by BLI (12, 2931). Despite the relatively high degree of structural homology between the 2019-nCoV RBD and the SARS-CoV RBD, no binding to the 2019-nCoV RBD could be detected for any of the three mAbs at the concentration tested (1 M) (Fig. 4C), in contrast to the strong binding that we observed to the SARS-CoV RBD (fig. S8). Although the epitopes of these three antibodies represent a relatively small percentage of the surface area of the 2019-nCoV RBD, the lack of observed binding suggests that SARS-directed mAbs will not necessarily be cross-reactive and that future antibody isolation and therapeutic design efforts will benefit from using 2019-nCoV S proteins as probes.
(A) SARS-CoV RBD shown as a white molecular surface (PDB ID: 2AJF), with residues that vary in the 2019-nCoV RBD colored red. The ACE2-binding site is outlined with a black dashed line. (B) Biolayer interferometry sensorgram showing binding to ACE2 by the 2019-nCoV RBD-SD1. Binding data are shown as a black line, and the best fit of the data to a 1:1 binding model is shown in red. (C) Biolayer interferometry to measure cross-reactivity of the SARS-CoV RBD-directed antibodies S230, m396, and 80R. Sensor tips with immobilized antibodies were dipped into wells containing 2019-nCoV RBD-SD1, and the resulting data are shown as a black line.
The rapid global spread of 2019-nCoV, which prompted the PHEIC declaration by WHO, signals the urgent need for coronavirus vaccines and therapeutics. Knowing the atomic-level structure of the 2019-nCoV spike will allow for additional protein-engineering efforts that could improve antigenicity and protein expression for vaccine development. The structural data will also facilitate the evaluation of 2019-nCoV spike mutations that will occur as the virus undergoes genetic drift and help to define whether those residues have surface exposure and map to sites of known antibody epitopes for other coronavirus spike proteins. In addition, the structure provides assurance that the protein produced by this construct is homogeneous and in the prefusion conformation, which should maintain the most neutralization-sensitive epitopes when used as candidate vaccine antigens or B cell probes for isolating neutralizing human mAbs. Furthermore, the atomic-level detail will enable the design and screening of small molecules with fusion-inhibiting potential. This information will support precision vaccine design and the discovery of antiviral therapeutics, accelerating medical countermeasure development.
Acknowledgments: We thank J. Ludes-Meyers for assistance with cell transfection, members of the McLellan laboratory for critical reading of the manuscript, and A. Dai from the Sauer Structural Biology Laboratory at the University of Texas at Austin for assistance with microscope alignment. Funding: This work was supported in part by a National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (NIAID) grant awarded to J.S.M. (R01-AI127521) and by intramural funding from NIAID to B.S.G. The Sauer Structural Biology Laboratory is supported by the University of Texas College of Natural Sciences and by award RR160023 from the Cancer Prevention and Research Institute of Texas (CPRIT). Author contributions: D.W. collected and processed cryo-EM data. D.W., N.W., and J.S.M. built and refined the atomic model. N.W. designed and cloned all constructs. D.W., N.W., K.S.C., J.A.G., and O.A. expressed and purified proteins. D.W., J.A.G., and C.-L.H. performed binding studies. B.S.G. and J.S.M. supervised experiments. D.W., B.S.G., and J.S.M. wrote the manuscript with input from all authors. Competing interests: N.W., K.S.C., B.S.G., and J.S.M. are inventors on U.S. patent application no. 62/412,703 (Prefusion Coronavirus Spike Proteins and Their Use), and D.W., N.W., K.S.C., O.A., B.S.G., and J.S.M. are inventors on U.S. patent application no. 62/972,886 (2019-nCoV Vaccine). Data and materials availability: Atomic coordinates and cryo-EM maps of the reported structure have been deposited in the Protein Data Bank under accession code 6VSB and in the Electron Microscopy Data Bank under accession codes EMD-21374 and EMD-21375. Plasmids are available from B.S.G. under a material transfer agreement with the NIH or from J.S.M. under a material transfer agreement with The University of Texas at Austin.
Building ‘better’ astronauts through genetic engineering could be key to colonizing other planets – Genetic Literacy Project
Space exploration has long been a source of fascination. Since the stars first captured our attention, we have obsessed over that vast curtain of darkness that lies beyond our atmosphere. But to what end? What ultimate goal does mankind strive towards, if not the ability to visit and colonize other worlds?
Before we can take our first steps out into the universe, we have to answer a critical question: Do we have the ability to adapt to other environments very different from what we have on Earth to not only survive, but to thrive? Instead of focusing on how we might terraform other planets to suit us, perhaps we should consider how we might use genetic engineering to alter own bodies to suit those other planets.
As a jumping off point, lets consider the feasibility of using the popular gene-editing tool CRISPR to alter human physiology to tolerate parameters outside of Earths norms. If we take a look at common factors that are significant to human health, gleaned from our experience with space exploration, the most obvious choices for our attention are variations in gravity, atmospheric pressure and gas ratios, and solar radiation levels.
If we consider Mars as our template, because of its relative suitability for colonization, then we must compensate for two-thirds less gravity than Earth. A lack of gravity results in a number of ill effects on human health, including a decrease in bone mass and density over time, particularly in the large bones of the lower extremities, as well as the spine. While we do not have research showing the impact of living on a planet with one-third Earths gravity, we do know that we can expect losses in bone density somewhere under 1-2 percent per month, the amount lost in the microgravity environment of space.
For comparison, the elderly lose 1-1.5 percent per month in Earth gravity. Atmospheric pressure that is either too high or too low also results in complications; low atmospheric pressure results in less oxygen available and causes altitude sickness and possible death. Radiation levels from the sun are another variable that is well known to have upper and lower thresholds for optimal human health, where low levels can lead to vitamin D deficiency and high levels increase cell death and cancer.
It would stand to reason that the human body has a minimum threshold for healthy physiology as regards the environment in which it grows, develops and lives. To colonize other planets successfully, we must consider solutions to overcome these thresholds; for example: prostheses, domed colonies recreating an ideal or near ideal environment, or, as this author suggests, the permanent genetic alteration of humanity as a species. This applies to our four chosen variables of gravitational forces, atmospheric pressure, atmospheric gas ratios, and solar radiation levels. While science fiction might have us consider surgical and biomedical prostheses or the more far-fetched use of animal DNA to change ourselves for this purpose, the key to human adaptation for other planets lies in our own genetics and it may well be CRISPR, the use of the enzyme Cas9 for introduction of altered DNA sequences or CRISPRs to existing cells to change how those cells function, that will make this possible.
Human genetic variation provides a veritable treasure trove of adaptations if one looks at the less common but heritable variations that on Earth may seem irrelevant, nonessential, or even maladaptive, but on another planet could be essential to survival. One example of a gene that, with engineering, could help humanity adapt to higher or lower gravity is the LRP5 gene. Recent research into the LRP5 gene shows that mutations of the gene are responsible for both low bone density and elevated bone density in the case of the later, from increased bone formation. A family of individuals in Nebraska carrying the mutation for elevated bone density have never experienced broken bones even well into old age. A whole colony of such individuals or ones engineered to enhance this mutation further could be expected to fare much better during prolonged space travel in zero gravity as well as in the low gravity environment on a planet like Mars.
While an atmospheric pressure and gas makeup very similar to Earths would be required for humans to survive and thrive outside of a spacesuit, Nepals Sherpas, high altitude dwellers in Ethiopia, and the Collas people in the Central Andes , as well as the deep sea divers of Bajau, may provide a solution to living on planets with differences in atmospheric pressure and oxygen availability. The three groups of high-altitude dwellers appear to have separate adaptations for thriving in low oxygen environments. Recent research indicates that there are genetic mutations in each of these groups. Sherpas mutations allow for more efficient use of available oxygen and resistance to ill effects from hypoxia.
Sherpas experience less of an increase in red blood cells than others and therefore avoid the ill-effects caused, such as edema and brain swelling. Sherpas instead have mitochondria in their cells that make more efficient use of the available oxygen, as well as having more efficient anaerobic metabolism in the absence of oxygen. The Collas show genetic differences in genes that control heart morphology, as well as cerebral vascular flow, as a means to withstand an elevated hematocrit in response to high altitude living. The Amhara people living in high altitudes in Ethiopia unlike the Sherpas do have lower oxygen saturation and higher hemoglobin levels compared to lowland dwellers in the region.
Research has yet to determine what adaptation favors the Amhara, but several genes that may play a role have been isolated. Another group, the Bajau of Thailand, may have complementary genetic variations that help them resist hypoxia and survive the high pressures of deep sea diving. Researchers found them to have 50% larger spleens and also a gene, PDE10A, that controls a thyroid hormone thought to affect spleen size. Capitalizing on any of these genetic features would improve our ability to survive with a lower oxygen content atmosphere, perhaps on a newly terraformed Mars or under domes with oxygen rationing.
While we cannot yet determine how comparable an atmosphere we can create on Mars, it stands to reason that achieving an exact replica atmosphere to Earths could be difficult. An atmosphere that lets in less radiation could impede our production of vitamin D, while a thinner atmosphere would admit an excess of radiation. Vitamin D deficiency could perhaps be handled by supplementation, or instead addressed by increasing our cells response to ultraviolet light to increase vitamin D synthesis. On the other side of the coin, a thinner atmosphere opens us up to higher UVR, which would result in higher rates of skin cancer.
It would stand to reason that, while skin pigmentation has high cultural and historical significance, it could make our species more suitable for colonization of high radiation planets; darker skin with larger melanocytes that react proactively to UVA and UVB radiation through tanning and higher antioxidant and free-radical counteraction would be protective and provide an advantage if we are to branch out into our solar system and beyond. At the same time, this solution poses the problem of vitamin D production.
The answer could lie in isolating and using the genes responsible for East Asian populations lower skin pigmentation coupled with lower skin cancer rates than European populations. A study headed by Pennsylvania university has isolated gene mutations responsible for skin pigmentation differences, SLC24A5, MFSD12, OCA2, and HERC2, by studying African, South Asian Indian, and Australo-Melanesian populations, some of which are associated with vitiligo and a form of albinism common in African populations. These mutations that confer higher vitamin D production to Europeans are not present in East Asians, indicating a different mutation responsible, and, while both populations have higher vitamin D production than African populations, Europeans have a 10-20 percent higher rate of cancer than both Africans and East Asians. Further research into these genes could provide targets for CRISPR to modify the protective factors in our skin without sacrificing vitamin D production of potential colonists.
The question remains: is CRISPR a feasible route to including some of these adaptations to create a new, more suitable colonist? To answer this question we look at the current status of CRISPR research.
While some experiments using CRISPR gene editing were conducted in the technologys infancy, including the controversial creation of twin girls in China designed to be resistant to HIV, we are still quite a bit of research away from using CRISPR with high success rates and full confidence, especially considering the repercussions of rushing into human trials, including the death of trial participants and long-term side-effects of cancer, both of which have occurred in gene-therapy trials.
According to information revealed by the FDA and NIH, 691 trial volunteers died in gene-editing trials prior to the tragic and high-profile death of Jesse Gelsinger in a 1999 trial to treat his OTCD, a rare metabolic disorder. The death was blamed on ethical oversights and a rush to make gene editing pan out before it was ready. The result was a long period of gene-editing fear and oversight but also, in the case of James Wilson, director of the University of Pennsylvanias Institute for Human Gene Therapy responsible for the trials that led to Gelsingers death, greater caution in research methodology. He has put safety at the forefront of his research and asserts that even still the risks of gene editing with CRISPR and other methods brings enough risk to justify human trials only for those diseases that are severe and debilitating enough for patients to accept the risks of gene editing.
What does all this mean for our hypothetical future of using CRISPR to edit the DNA of human colonists for space colonization? Is the technology too far off to serve our purpose or fraught with too much risk? Is it beyond our knowledge and skill to accomplish? The answer to each of these questions is undoubtedly, no.
Weve had too much success in treating complex genetic conditions, like the creation of an immune system for Ashanthi Desilva born with severe combined immunodeficiency (SCVID). Weve unlocked too many keys to making gene therapy safer and more effective to discount the possibility of future use for the advancement of our species into harsher environments. While subsequent uses of gene therapy for SCVID resulted in development of Leukemia years later, further advancements in the research have revealed the need to find the best delivery system for each body system. Adeno-associated viruses, and lentiviruses are being looked at in place of the more aggressive adenovirus or retroviruses for delivery of DNA segments both of which are less likely to provoke an immune response and less likely to trigger cell death by way of the B35 gene in healthy cells, and later cancer.
Regardless of the work ahead and the bumpy road that gene therapy has traveled, vast potential remains at our fingertips whether it is through use of CRISPR or future gene therapy tools. It is a sure eventuality that we will one day have these skills at the ready to spread our species into other worlds, well-equipped to survive and thrive in harsher environments.
Cherrie Newman is a writer and student of human reproduction and biological sciences. She is the author of a science fiction novel series entitled Progeny under the pseudonym CL Fors. Follow her on her blogor on Twitter @clfors