Ending Aging

If you are looking for an accessible description of SENS research, our Chief Science Officer, Dr Aubrey de Grey, together with co-author Michael Rae, has written a book entitled Ending Aging. The book speaks to a broad audience, but it does so without 'dumbing down' the science at all. It is the ideal resource for either the biologist or the non-biologist, whether encountering SENS for the first time or wishing to absorb more of its details. Copies are available from your local bookstore or from Amazon.com. The details are: de Grey ADNJ, Rae M. Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime. New York, NY: St. Martin's Press, 2007, 416pp, hardcover, ISBN 0-312-36706-6; or there is a paperback edition with an additional chapter covering more recent developments, ISBN 0-312-36707-4. Thanks to narrator Stephanie Murphy, there's now even an audiobook version!


The following list of publications presents, by default, work funded in whole or in part by SENS Research Foundation, plus key papers describing the SENS plan. Full-text reprints of most of these items are available on request. To view a much more extensive list of papers relevant to our work, including all papers cited in Ending Aging, alter the value of the "Publication Type" filter below. A list of papers written while at least one author was enrolled in the SRF Education program may be found here.

  • Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, Conboy IM A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood Nat Commun. 2016 Nov 22;7:13363. PubMed: 27874859.

    A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood

    Nat Commun. 2016 Nov 22;7:13363.

    A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood

    Rebo J, Mehdipour M, Gathwala R, Causey K, Liu Y, Conboy MJ, Conboy IM

    Abstract

    Abstract:

    Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.

  • Boominathan A, Vanhoozer S, Basisty N, Powers K, Crampton AL, Wang X, Friedricks N, Schilling B, Brand MD, O'Connor MS. Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant. Nucleic Acids Res. 2016 Sep 4. PubMed: 27596602. Categories: MitoSENS

    Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant.

    Nucleic Acids Res. 2016 Sep 4.

    Stable nuclear expression of ATP8 and ATP6 genes rescues a mtDNA Complex V null mutant.

    Boominathan A, Vanhoozer S, Basisty N, Powers K, Crampton AL, Wang X, Friedricks N, Schilling B, Brand MD, O'Connor MS.

    Abstract

    Abstract:

    We explore the possibility of re-engineering mitochondrial genes and expressing them from the nucleus as an approach to rescue defects arising from mitochondrial DNA mutations. We have used a patient cybrid cell line with a single point mutation in the overlap region of the ATP8 and ATP6 genes of the human mitochondrial genome. These cells are null for the ATP8 protein, have significantly lowered ATP6 protein levels and no Complex V function. Nuclear expression of only the ATP8 gene with the ATP5G1 mitochondrial targeting sequence appended restored viability on Krebs cycle substrates and ATP synthesis capabilities but, failed to restore ATP hydrolysis and was insensitive to various inhibitors of oxidative phosphorylation. Co-expressing both ATP8 and ATP6 genes under similar conditions resulted in stable protein expression leading to successful integration into Complex V of the oxidative phosphorylation machinery. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6. Thus, we report the stable allotopic expression, import and function of two mitochondria encoded genes, ATP8 and ATP6, resulting in simultaneous rescue of the loss of both mitochondrial proteins.

  • Gravina S, Dong X, Yu B, Vijg J. Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol. 2016 Jul 5;17(1):150. PubMed: 27380908. Categories: OncoSENS

    Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.

    Genome Biol. 2016 Jul 5;17(1):150.

    Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.

    Gravina S, Dong X, Yu B, Vijg J.

    Abstract

    Abstract:

    BACKGROUND:

    Transmission fidelity of CpG DNA methylation patterns is not foolproof, with error rates from less than 1 to well over 10 % per CpG site, dependent on preservation of the methylated or unmethylated state and the type of sequence. This suggests a fairly high chance of errors. However, the consequences of such errors in terms of cell-to-cell variation have never been demonstrated by experimentally measuring intra-tissue heterogeneity in an adult organism.

    RESULTS:

    We employ single-cell DNA methylomics to analyze heterogeneity of genome-wide 5-methylcytosine (5mC) patterns within mouse liver. Our results indicate a surprisingly high level of heterogeneity, corresponding to an average epivariation frequency of approximately 3.3 %, with regions containing H3K4me1 being the most variable and promoters and CpG islands the most stable. Our data also indicate that the level of 5mC heterogeneity is dependent on genomic features. We find that non-functional sites such as repeat elements and introns are mostly unstable and potentially functional sites such as gene promoters are mostly stable.

    CONCLUSIONS:

    By employing a protocol for whole-genome bisulfite sequencing of single cells, we show that the liver epigenome is highly unstable with an epivariation frequency in DNA methylation patterns of at least two orders of magnitude higher than somatic mutation frequencies.

     

  • Pettitt DA, Smith J, Meadows N, Arshad Z, Schuh A, DiGustio D, Bountra C, Holländer G, Barker R, Brindley DA. Regulatory barriers to the advancement of precision medicine. Expert Review of Precision Medicine and Drug Development 1: 319-329. Read on external site.

    Regulatory barriers to the advancement of precision medicine.

    Expert Review of Precision Medicine and Drug Development 1: 319-329.

    Regulatory barriers to the advancement of precision medicine.

    Pettitt DA, Smith J, Meadows N, Arshad Z, Schuh A, DiGustio D, Bountra C, Holländer G, Barker R, Brindley DA.

    Abstract

    Abstract:

    Precision medicine utilizes tailored diagnostic, prognostic and therapeutic strategies based on an individual’s molecular profile. Although it is gaining considerable traction and high-level political endorsement, it must overcome a number of translational hurdles, including regulatory barriers. At the core of precision medicine lies diagnostic tests and devices, however the regulatory classification of such products varies on a global basis. Navigating these convoluted regulatory pathways can be challenging – exacerbated by asymmetric technological advancement and regulatory progression. Both the EU and US are attempting to address such issues and newer concerns relating to direct-to-consumer testing. Flexible solutions are required to establish regulatory compliance across multiple countries and coordinated cross-collaboration initiatives need to empower technological development and globally harmonized regulation. The wider infrastructure, spanning beyond regulation, must also accommodate these changes and support subsequent clinical adoption, in order to firmly establish precision medicine in modern day medical practice.

  • Bure K, Ball A, Biagioni K, Mehta S, Choudhary R, Arshad Z, Pettitt DA, Holländer G, Al-Mossawi H, Faulstich F, Reeve B, Smith JA, Brindley DA. Automation of CAR-T Cell Adoptive Immunotherapy Bioprocessing. BioProcess International 14(4)s. Read on external site.

    Automation of CAR-T Cell Adoptive Immunotherapy Bioprocessing.

    BioProcess International 14(4)s.

    Automation of CAR-T Cell Adoptive Immunotherapy Bioprocessing.

    Bure K, Ball A, Biagioni K, Mehta S, Choudhary R, Arshad Z, Pettitt DA, Holländer G, Al-Mossawi H, Faulstich F, Reeve B, Smith JA, Brindley DA.

    Abstract

    Abstract:

    Continued clinical efficacy demonstrations of cell-based immunotherapies (iTx) such as chimeric antigen receptor T cell (CAR-T) therapies has made the prospect increasingly likely of an immunotherapy product achieving conditional market authorization in the short term. For example, Novartis and the University of Pennsylvania’s lead candidate (CTL019) for treating a range of hematological malignancies received breakthrough status from the US Food and Drug Administration (FDA) in 2014, permitting access to an expedited drug development pathway for high unmet medical needs. Then in March 2015, the European Medicines Agency’s (EMA’s) Pediatric Committee agreed on a pediatric investigation plan for tisagenlecleucel-T...

  • Pettitt DA, Smith J, Fuzerstenau-Sharp M, Holländer G, Predki P, Slade A, Jones P, Weed L, Bure K, Brindley DA. Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies. BioProcess International 14(4)s. Read on external site.

    Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies.

    BioProcess International 14(4)s.

    Emerging Platform Bioprocesses for Viral Vectors and Gene Therapies.

    Pettitt DA, Smith J, Fuzerstenau-Sharp M, Holländer G, Predki P, Slade A, Jones P, Weed L, Bure K, Brindley DA.

    Abstract

    Abstract:

    Recent advances in molecular biology are expediting genomic sequencing to underpin precision medicine. Such progress is positioning gene and gene-modified cell therapy on the cusp of an extraordinary revolution in patient care for presently unmet medical needs — and a new therapeutic class that could rival monoclonal antibodies (MAbs) in importance. However, despite substantial strides made in clinical trials, the bioprocessing community is struggling to fulfill growing demands for biomanufacturing capacity to make gene and gene-modified cell therapies — including current good manufacturing practice (CGMP) viral vectors.

    Here we review the basic science of gene therapy bioproduction and evaluate critical emerging bioprocess opportunities and challenges. An interrelationship exists between viral-vector upstream and downstream bioprocessing strategies and those for other therapeutic platforms such as chimeric antigen receptor (CAR) T cells and induced pluripotent stem cells (iPSCs).

  • Pettitt DA, Raza S, Naughton B, Roscoe A, Ramakrishnan A, Ali A, Davies B, Dopson S, Hollander G, Smith J, Brindley DA. The Limitations of QALY: A Literature Review. J Stem Cell Res Ther 6:334. Read on external site.

    The Limitations of QALY: A Literature Review.

    J Stem Cell Res Ther 6:334.

    The Limitations of QALY: A Literature Review.

    Pettitt DA, Raza S, Naughton B, Roscoe A, Ramakrishnan A, Ali A, Davies B, Dopson S, Hollander G, Smith J, Brindley DA.

    Abstract

    Abstract:

    Introduction: The Quality Adjusted Life Year (QALY) is a recognised metric used to evaluate new and innovative healthcare treatments and optimise resource allocation via rational and explicit methodologies. This review examines present limitations of the QALY metric and foreseeable challenges linked to the advancement of regenerative medicine.

    Methods: The extant literature was reviewed through electronic searches of four key databases; namely Medline, EMBASE, Econlit and Cochrane. Manuscripts were selected according to pre-determined inclusion criteria.

    Results: Three common themes emerged concerning the limitations of QALYs. These were ethical considerations, methodological issues and theoretical assumptions and context or disease specific considerations.

  • Arshad Z, Smith J, Roberts M, Lee WH, Davies B, Bure K, Hollander GA, Dopson S, Bountra C, Brindley D. Open Access Could Transform Drug Discovery: A Case Study of JQ1. Expert Opin Drug Discov. 2016 Mar;11(3):321-32. PubMed: 26791045.

    Open Access Could Transform Drug Discovery: A Case Study of JQ1.

    Expert Opin Drug Discov. 2016 Mar;11(3):321-32.

    Open Access Could Transform Drug Discovery: A Case Study of JQ1.

    Arshad Z, Smith J, Roberts M, Lee WH, Davies B, Bure K, Hollander GA, Dopson S, Bountra C, Brindley D.

    Abstract

    Abstract:

    The cost to develop a new drug from target discovery to market is a staggering $1.8 billion, largely due to the very high attrition rate of drug candidates and the lengthy transition times during development. Open access is an emerging model of open innovation that places no restriction on the use of information and has the potential to accelerate the development of new drugs. Areas Covered: To date, no quantitative assessment has yet taken place to determine the effects and viability of open access on the process of drug translation. This need is addressed within this study. The literature and intellectual property landscapes of the drug candidate JQ1, which was made available on an open access basis when discovered, and conventionally developed equivalents that were not are compared using the Web of Science and Thomson Innovation software, respectively. Expert opinion: Results demonstrate that openly sharing the JQ1 molecule led to a greater uptake by a wider and more multi-disciplinary research community. A comparative analysis of the patent landscapes for each candidate also found that the broader scientific diaspora of the publically released JQ1 data enhanced innovation, evidenced by a greater number of downstream patents filed in relation to JQ1. The authors' findings counter the notion that open access drug discovery would leak commercial intellectual property. On the contrary, JQ1 serves as a test case to evidence that open access drug discovery can be an economic model that potentially improves efficiency and cost of drug discovery and its subsequent commercialization.

  • Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J. Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype. Cell Metab. 23(2):303-14. PubMed: 26686024. Categories: ApoptoSENS, MitoSENS

    Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

    Cell Metab. 23(2):303-14.

    Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype.

    Wiley CD, Velarde MC, Lecot P, Liu S, Sarnoski EA, Freund A, Shirakawa K, Lim HW, Davis SS, Ramanathan A, Gerencser AA, Verdin E, Campisi J.

    Abstract

    Abstract:

    Cellular senescence permanently arrests cell proliferation, often accompanied by a multi-faceted senescence-associated secretory phenotype (SASP). Loss of mitochondrial function can drive age-related declines in the function of many post-mitotic tissues, but little is known about how mitochondrial dysfunction affects mitotic tissues. We show here that several manipulations that compromise mitochondrial function in proliferating human cells induce a senescence growth arrest with a modified SASP that lacks the IL-1-dependent inflammatory arm. Cells that underwent mitochondrial dysfunction-associated senescence (MiDAS) had lower NAD+/NADH ratios, which caused both the growth arrest and prevented the IL-1-associated SASP through AMPK-mediated p53 activation. Progeroid mice that rapidly accrue mtDNA mutations accumulated senescent cells with a MiDAS SASP in vivo, which suppressed adipogenesis and stimulated keratinocyte differentiation in cell culture. Our data identify a distinct senescence response and provide a mechanism by which mitochondrial dysfunction can drive aging phenotypes.

  • Gaspar J, Mathieu J, Alvarez PJJ. A Rapid Platform to Generate Lipofuscin and Screen Therapeutic Drugs for Efficacy in Lipofuscin Removal. Materials, Methods & Technologies, Volume 10, 2016. Read on external site. Categories: LysoSENS

    A Rapid Platform to Generate Lipofuscin and Screen Therapeutic Drugs for Efficacy in Lipofuscin Removal.

    Materials, Methods & Technologies, Volume 10, 2016.

    A Rapid Platform to Generate Lipofuscin and Screen Therapeutic Drugs for Efficacy in Lipofuscin Removal.

    Gaspar J, Mathieu J, Alvarez PJJ.

    Abstract

    Abstract:

    Lipofuscin is a brown-yellow, autofluorescent polymeric material that accumulates in a ceroid manner within postmitotic cells during aging. Lipofuscin accumulation impairs proteosome and lysosome pathways critical to cell health and homeostasis. Therefore, the ability to quickly generate lipofuscin in vitro, and identify drugs that mitigate the accumulation or clear lipofuscin would be of great benefit to aging research. Here, we present a platform to quickly create lipofuscin-loaded (but otherwise healthy) cells and screen drugs for efficacy in lipofuscin removal. The combination of leupeptin, iron (III) chloride and hydrogen peroxide generates significant amounts of lipofuscin within cells while eliminating the need for a 40% hyperoxic chamber. Alternative methods which load fibroblasts with "artificial" lipofuscin obtained via UV-peroxidation of mitochondrial fragments are much more labor-intensive. This method is faster (≤10 days) than most protocols to generate lipofuscin and assess its removal, which typically require 2 to 4 weeks or longer to complete.

  • Naughton BD, Smith JA, Brindley DA. Establishing good authentication practice (GAP) in secondary care to protect against falsified medicines and improve patient safety. Eur J Hosp Pharm doi:10.1136/ejhpharm-2015-000750. Read on external site.

    Establishing good authentication practice (GAP) in secondary care to protect against falsified medicines and improve patient safety.

    Eur J Hosp Pharm doi:10.1136/ejhpharm-2015-000750.

    Establishing good authentication practice (GAP) in secondary care to protect against falsified medicines and improve patient safety.

    Naughton BD, Smith JA, Brindley DA.

    Abstract

    Abstract:

    Sustained growth of falsified and counterfeit medicines in the legal supply chain is a critical threat to patients, (bio)pharmaceutical companies, caregivers, payers and pharmacists. The European Union (EU) Falsified Medicines Directive (FMD) is a tractable opportunity to mitigate this threat and optimise healthcare delivery, including through the optimisation of pharmacy workflows and support of patient adherence. In order to deliver these benefits, and ensure FMD compliance, the production and regular review of Good Authentication Practice (GAP) guidelines is an essential step.

  • Smith JA, French A, Hurley H, Davies B, Dopson S, Fairchild P, Roberts M, Riley P, Reeve B, Williams D, Daheron L, Bure K, Carr A, Karp JM, Wall I, Brindley D. Challenges and Opportunities in the Development of Induced Pluripotent Stem Cell Therapeutics. In: Frontiers in Stem Cell and Regenerative Medicine Research, Volume II. Bentham Science (in press). Read on external site.

    Challenges and Opportunities in the Development of Induced Pluripotent Stem Cell Therapeutics.

    In: Frontiers in Stem Cell and Regenerative Medicine Research, Volume II. Bentham Science (in press).

    Challenges and Opportunities in the Development of Induced Pluripotent Stem Cell Therapeutics.

    Smith JA, French A, Hurley H, Davies B, Dopson S, Fairchild P, Roberts M, Riley P, Reeve B, Williams D, Daheron L, Bure K, Carr A, Karp JM, Wall I, Brindley D.

    Abstract

    Abstract:

    No abstract available.

  • Smith JA, Dopson S, Davies B, Wartolowska K, Karp JM, Carr AJ, Brindley DA. Borderline Regulation of Stem Cell Technologies: Therapies, Devices and Combination Products. In: Global Device Strategy. Regulatory Affairs Professionals Society (in press).

    Borderline Regulation of Stem Cell Technologies: Therapies, Devices and Combination Products.

    In: Global Device Strategy. Regulatory Affairs Professionals Society (in press).

    Borderline Regulation of Stem Cell Technologies: Therapies, Devices and Combination Products.

    Smith JA, Dopson S, Davies B, Wartolowska K, Karp JM, Carr AJ, Brindley DA.

    Abstract

    Abstract:

    No abstract available.

  • Rekhi R, Smith JA, Arshad Z, Roberts M, Bountra C, Bingham I, Bure K, Brindley DA. Decision-Support Tools for Monoclonal Antibody and Cell Therapy Bioprocessing: Current Landscape and Development Opportunities. BioProcess Executive 13(11). Read on external site.

    Decision-Support Tools for Monoclonal Antibody and Cell Therapy Bioprocessing: Current Landscape and Development Opportunities.

    BioProcess Executive 13(11).

    Decision-Support Tools for Monoclonal Antibody and Cell Therapy Bioprocessing: Current Landscape and Development Opportunities.

    Rekhi R, Smith JA, Arshad Z, Roberts M, Bountra C, Bingham I, Bure K, Brindley DA.

    Abstract

    Abstract:

    Industrial-scale manufacturers in a number of fields — from automobiles to biotherapeutics — have long relied on powerful computational and mathematical tools to aid in the scale-up, optimization, quality control, and monitoring of product development. Typical process pathways are highly multifactorial, with numerous branch points, feedback steps, instrumental attributes, and target parameters. Moreover, margins for error are minimal for most industrial processes, requiring high standards of precision from industrial and operational pathways. For those reasons, the complexity of process engineering and process pathway design necessitates that modeling and decision-support tools (DSTs) be used to ensure high-quality and economically viable end products.

  • Luo D, Smith JA, Meadows NA, Manescu K, Bure K, Davies B, Horne R, DiGiusto DL, Brindley DA. A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics Front. Genet. 6:357. Read on external site.

    A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics

    Front. Genet. 6:357.

    A Quantitative Assessment of Factors Affecting the Technological Development and Adoption of Companion Diagnostics

    Luo D, Smith JA, Meadows NA, Manescu K, Bure K, Davies B, Horne R, DiGiusto DL, Brindley DA.

    Abstract

    Abstract:

    Rapid innovation in (epi)genetics and biomarker sciences is driving a new drug development and product development pathway, with the personalized medicine era dominated by biologic therapeutics and companion diagnostics. Companion diagnostics (CDx) are tests and assays that detect biomarkers and specific mutations to elucidate disease pathways, stratify patient populations, and target drug therapies. CDx can substantially influence the development and regulatory approval for certain high-risk biologics. However, despite the increasingly important role of companion diagnostics in the realization of personalized medicine, in the United States, there are only twenty-three Food and Drug Administration (FDA) approved companion diagnostics on the market for eleven unique indications. Personalized medicines have great potential, yet their use is currently constrained. A major factor for this may lie in the increased complexity of the companion diagnostic and corresponding therapeutic development and adoption pathways. Understanding the market dynamics of companion diagnostic/therapeutic (CDx/Rx) pairs is important to further development and adoption of personalized medicine. Therefore, data collected on a variety of factors may highlight incentives or disincentives driving the development of companion diagnostics. Statistical analysis for thirty-six hypotheses resulted in two significant relationships and thirty-four non-significant relationships. The sensitivity of the companion diagnostic was the only factor that significantly correlated with the price of the companion diagnostic. This result indicates that while there is regulatory pressure for the diagnostic and pharmaceutical industry to collaborate and co-develop companion diagnostics for the approval of personalized therapeutics, there seems to be a lack of parallel economic collaboration to incentivize development of companion diagnostics.

  • Lannon KA, Smith JA, Bure K, Brindley DA. Quantitative Risk Assessment of Bioaccumulation Attributable to Extractables and Leachables in Cellular Immunotherapy Biomanufacturing. BioProcess International. (Nov 2015) Read on external site.

    Quantitative Risk Assessment of Bioaccumulation Attributable to Extractables and Leachables in Cellular Immunotherapy Biomanufacturing.

    BioProcess International. (Nov 2015)

    Quantitative Risk Assessment of Bioaccumulation Attributable to Extractables and Leachables in Cellular Immunotherapy Biomanufacturing.

    Lannon KA, Smith JA, Bure K, Brindley DA.

    Abstract

    Abstract:

    Precious patient samples, contamination concerns, and limited product purification options have compelled manufacturers of cellular immunotherapies (iTx) such as chimeric antigen receptor T cells (CAR-T) and T-cell receptor (TCR) technologies toward the disposables industry. Such companies are implementing single-use technologies (SUTs) almost exclusively. But despite the dominance of disposable bioprocess platforms and their extraordinary growth in the iTx marketplace, researchers have made limited efforts to understand the perennial and critical bioprocessing risks of leachables and extractables.

    Here we outline the potential impact on iTx of leachables and extractables and discuss relevant regulations, guidelines, and risk-assessment approaches. Fortunately, biopharmaceutical producers of monoclonal antibodies (MAbs) and recombinant proteins have been investigating the consequences of leachables and extractables on manufacturing processes for years. iTx companies (and the regenerative medicine market in general) can benefit from lessons learned over the past decade of commercial-scale biologics manufacturing in single-use platforms.

  • Carmen J, Brindley DA, Davie NL, Smith D. Cell Therapy Manufacturing: Identifying and Meeting Demand. In: Stem Cells in Regenerative Medicine: Science, Regulation and Business Strategies. Wiley-Blackwell (2015). Read on external site.

    Cell Therapy Manufacturing: Identifying and Meeting Demand.

    In: Stem Cells in Regenerative Medicine: Science, Regulation and Business Strategies. Wiley-Blackwell (2015).

    Cell Therapy Manufacturing: Identifying and Meeting Demand.

    Carmen J, Brindley DA, Davie NL, Smith D.

    Abstract

    Abstract:

    No abstract available.

  • Draghici C, Wang T, Spiegel DA. Concise total synthesis of glucosepane. Science 2015;350(6258):294-298. doi:10.1126/science.aac9655. PubMed: 26472902. Categories: GlycoSENS

    Concise total synthesis of glucosepane.

    Science 2015;350(6258):294-298. doi:10.1126/science.aac9655.

    Concise total synthesis of glucosepane.

    Draghici C, Wang T, Spiegel DA.

    Abstract

    Abstract:

    Glucosepane is a structurally complex protein posttranslational modification that is believed to exist in all living organisms. Research in humans suggests that glucosepane plays a critical role in the pathophysiology of both diabetes and human aging, yet comprehensive biological investigations of this metabolite have been hindered by a scarcity of chemically homogeneous material available for study. Here we report the total synthesis of glucosepane, enabled by the development of a one-pot method for preparation of the nonaromatic 4H-imidazole tautomer in the core. Our synthesis is concise (eight steps starting from commercial materials), convergent, high-yielding (12% overall), and enantioselective. We expect that these results will prove useful in the art and practice of heterocyclic chemistry and beneficial for the study of glucosepane and its role in human health and disease.

  • Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B. IgG Conformer's Binding to Amyloidogenic Aggregates. PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344. PubMed: 26367058. Categories: AmyloSENS

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    PLoS One. 2015 Sep 14;10(9):e0137344. doi: 10.1371/journal.pone.0137344.

    IgG Conformer's Binding to Amyloidogenic Aggregates.

    Phay M, Welzel AT, Williams AD, McWilliams-Koeppen HP, Blinder V, O'Malley TT, Solomon A, Walsh DM, O'Nuallain B.

    Abstract

    Abstract:

    Amyloid-reactive IgGs isolated from pooled blood of normal individuals (pAbs) have demonstrated clinical utility for amyloid diseases by in vivo targeting and clearing amyloidogenic proteins and peptides. We now report the following three novel findings on pAb conformer's binding to amyloidogenic aggregates: 1) pAb aggregates have greater activity than monomers (HMW species > dimers > monomers), 2) pAbs interactions with amyloidogenic aggregates at least partially involves unconventional (non-CDR) interactions of F(ab) regions, and 3) pAb's activity can be easily modulated by trace aggregates generated during sample processing. Specifically, we show that HMW aggregates and dimeric pAbs present in commercial preparations of pAbs, intravenous immunoglobulin (IVIg), had up to ~200- and ~7-fold stronger binding to aggregates of Aβ and transthyretin (TTR) than the monomeric antibody. Notably, HMW aggregates were primarily responsible for the enhanced anti-amyloid activities of Aβ- and Cibacron blue-isolated IVIg IgGs. Human pAb conformer's binding to amyloidogenic aggregates was retained in normal human sera, and mimicked by murine pAbs isolated from normal pooled plasmas. An unconventional (non-CDR) component to pAb's activity was indicated from control human mAbs, generated against non-amyloid targets, binding to aggregated Aβ and TTR. Similar to pAbs, HMW and dimeric mAb conformers bound stronger than their monomeric forms to amyloidogenic aggregates. However, mAbs had lower maximum binding signals, indicating that pAbs were required to saturate a diverse collection of binding sites. Taken together, our findings strongly support further investigations on the physiological function and clinical utility of the inherent anti-amyloid activities of monomeric but not aggregated IgGs.

  • Brindley DA, Arshad Z, Luo D, Dopson S, Hollander G, Frost S, Bountra C, Smith JA. 21(st) Century Cures Act: An Act of Cure or Diagnosis? Rejuvenation Res. 2015 Aug;18(4):295-8. PubMed: 26291241. Categories: Beyond the Bench

    21(st) Century Cures Act: An Act of Cure or Diagnosis?

    Rejuvenation Res. 2015 Aug;18(4):295-8.

    21(st) Century Cures Act: An Act of Cure or Diagnosis?

    Brindley DA, Arshad Z, Luo D, Dopson S, Hollander G, Frost S, Bountra C, Smith JA.

    Abstract

    Abstract:

    No abstract available.

  • Hughes BB, Kuhn R, Margolese-Malina ES, Rothman DS, Solórzano JR. Opportunities and challenges of a world with negligible senescence. Technol. Forecast. Soc. Change 99:77-91 (2015). Read on external site. Categories: Beyond the Bench

    Opportunities and challenges of a world with negligible senescence.

    Technol. Forecast. Soc. Change 99:77-91 (2015).

    Opportunities and challenges of a world with negligible senescence.

    Hughes BB, Kuhn R, Margolese-Malina ES, Rothman DS, Solórzano JR.

    Abstract

    Abstract:

    The development of anti-aging technologies could have dramatic implications for a world already challenged by population aging. We explore how the world might evolve given the development and deployment of technologies capable of nearly eliminating mortality and morbidity from most causes. We consider both the great benefits and some of the complex sociopolitical rebalancing resulting from such advances. We use the International Futures (IFs) long-term, multi-issue, global forecasting system in our analysis of the interactions among demographic changes, the related changes in health costs and government finances, shifts in labor force participation, resultant economic transformations, and the environmental sustainability of the dramatically-altered human demands that emerge. We find that the widespread deployment of anti-senescence technologies would cause populations to surge—making fertility rates an issue of tremendous social import—while a much larger, healthier, labor force would spur economic growth. But this is not a given; the cost of treating entire adult populations could prove unbearable to non-high-income economies without significant transfers within and across societies. In the absence of new transformative production technologies, life-pattern financing would require the virtual elimination of retirement and a major restructuring of government finances. Pressures on the environment would also greatly intensify.

    Click here to read this paper for free on ScienceDirect.

  • Gravina S, Ganapathi S, Vijg J. Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns. Nucleic Acids Res. 2015 Apr 19. pii: gkv366. PubMed: 25897117. Categories: OncoSENS

    Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns.

    Nucleic Acids Res. 2015 Apr 19. pii: gkv366.

    Single-cell, locus-specific bisulfite sequencing (SLBS) for direct detection of epimutations in DNA methylation patterns.

    Gravina S, Ganapathi S, Vijg J.

    Abstract

    Abstract:

    Stochastic epigenetic changes drive biological processes, such as development, aging and disease. Yet, epigenetic information is typically collected from millions of cells, thereby precluding a more precise understanding of cell-to-cell variability and the pathogenic history of epimutations. Here we present a novel procedure for directly detecting epimutations in DNA methylation patterns using single-cell, locus-specific bisulfite sequencing (SLBS). We show that within gene promoter regions of mouse hepatocytes the epimutation rate is two orders of magnitude higher than the mutation rate.

  • Brindley DA, Rekhi R, Fuerstenau-Sharp M, Kantoff PW, Hollander GA, Smith JA, Tindal S, Timmins N, Bure K. The Potential Application of Real Time Release Testing for the Biomanufacture of Autologous Cell Based Immunotherapies. BioProcess International. 13(4):1-8. Read on external site.

    The Potential Application of Real Time Release Testing for the Biomanufacture of Autologous Cell Based Immunotherapies.

    BioProcess International. 13(4):1-8.

    The Potential Application of Real Time Release Testing for the Biomanufacture of Autologous Cell Based Immunotherapies.

    Brindley DA, Rekhi R, Fuerstenau-Sharp M, Kantoff PW, Hollander GA, Smith JA, Tindal S, Timmins N, Bure K.

    Abstract

    Abstract:

    Cell-based immunotherapies (iTx) are emerging as a truly transformative therapeutic modality that is both complementary and convergent with existing regenerative medicine approaches, including gene therapy, cell therapy, and tissue engineering. Critically, iTx offer step-change improvements in efficacy compared with current standards of care for a range of clinical indications and unmet therapeutic needs — particularly oncology.

  • Smith JA, Ng KS, Mead BE, Dopson S, Reeve B, Edwards J, Wood MJA, Carr AJ, Bure K, Karp JM, Brindley DA. Extracellular Vesicles: Commercial Potential As Byproducts of Cell Manufacturing for Research and Therapeutic Use. BioProcess International. 13(4). Read on external site. Categories: Delivery Mechanisms

    Extracellular Vesicles: Commercial Potential As Byproducts of Cell Manufacturing for Research and Therapeutic Use.

    BioProcess International. 13(4).

    Extracellular Vesicles: Commercial Potential As Byproducts of Cell Manufacturing for Research and Therapeutic Use.

    Smith JA, Ng KS, Mead BE, Dopson S, Reeve B, Edwards J, Wood MJA, Carr AJ, Bure K, Karp JM, Brindley DA.

    Abstract

    Abstract:

    Extracellular vesicles (EVs) are emerging as a potential alternative to some stem-cell–derived therapeutics. Sometimes called exosomes, they are small, secreted vesicles that can possess similar therapeutic mechanisms to whole cells, possibly representing the active pharmaceutical ingredient. In the past 15 years, academic and industry interest in EVs has exponentially increased as mounting evidence demonstrates their role in physiology and pathology as well as their therapeutic potential.

    In light of growing efforts in using EVs for research and therapy, optimizing EV manufacturing is important. However, many challenges come with their characterization, scalable manufacture, and regulatory status. Here, we briefly review the biology and therapeutic application of EVs, discuss associated challenges, and suggest how the biotechnology industry could play an important role in overcoming those challenges. Many cell manufacturing companies currently produce EVs but discard them as waste, thereby losing a potentially valuable resource with multiple purposes in a market that’s otherwise rich with an exorbitant cost of goods.

  • Silva H, Halvorsen D, Henson JD. Control ALT, Delete Cancer The Scientist (magazine). Read on external site. Categories: OncoSENS

    Control ALT, Delete Cancer

    The Scientist (magazine).

    Control ALT, Delete Cancer

    Silva H, Halvorsen D, Henson JD.

    Abstract

    Abstract:

    Because age is the largest risk factor for cancer, as the life expectancy of the world’s population continues to increase, cancer incidence is projected to rise dramatically. A 2011 report on Global Health and Aging released by the National Institutes of Health and World Health Organization predicts a tripling of the number of people aged 65 or older to 1.5 billion by 2050, and the annual number of new cancer cases is projected to reach 27 million by 2030. Undoubtedly, alleviating the diseases and disabilities associated with an aging global population will require the development of new anticancer approaches to avoid economic and humanitarian calamities.

    Cellular immortality is a hallmark of cancers that distinguishes them from normal tissue. Every time a normal somatic cell divides, the DNA at the ends of its chromosomes, called the telomeres, gets shorter. When the telomeres shorten too much, an alarm signal is generated, and the cell permanently stops dividing and enters senescence or undergoes apoptosis. Telomere shortening thus acts as a biological mechanism for limiting cellular life span.  Cancer cells, on the other hand, can become immortalized by activating a telomere maintenance mechanism (TMM) that counteracts telomere shortening by synthesizing new telomeric DNA from either an RNA template using the enzyme telomerase or a DNA template using a mechanism called alternative lengthening of telomeres (ALT).

  • French A, Bravery C, Smith J, Chandra A, Archibald P, Gold JD, Artzi N, Kim HW, Barker RW, Meissner A, Wu JC, Knowles JC, Williams D, García-Cardeña G, Sipp D, Oh S, Loring JF, Rao MS, Reeve B, Wall I, Carr AJ, Bure K, Stacey G, Karp JM, Snyder EY, Brindley DA. Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards. Stem Cells Transl Med. 2015 Mar;4(3):217-23. PubMed: 25650438. Categories: RepleniSENS

    Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards.

    Stem Cells Transl Med. 2015 Mar;4(3):217-23.

    Enabling consistency in pluripotent stem cell-derived products for research and development and clinical applications through material standards.

    French A, Bravery C, Smith J, Chandra A, Archibald P, Gold JD, Artzi N, Kim HW, Barker RW, Meissner A, Wu JC, Knowles JC, Williams D, García-Cardeña G, Sipp D, Oh S, Loring JF, Rao MS, Reeve B, Wall I, Carr AJ, Bure K, Stacey G, Karp JM, Snyder EY, Brindley DA.

    Abstract

    Abstract:

    There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify "signatures" for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.

  • Silva M, Daheron L, Hurley H, Bure K, Barker R, Carr AJ, Williams D, Kim HW, French A, Coffey PJ, Cooper-White JJ, Reeve B, Rao M, Snyder EY, Ng KS, Mead BE, Smith JA, Karp JM, Brindley DA, Wall I. Generating iPSCs: Translating Cell Reprogramming Science into Scalable and Robust Biomanufacturing Strategies. Cell Stem Cell. 2015 Jan 8;16(1):13-7. PubMed: 25575079. Categories: RepleniSENS

    Generating iPSCs: Translating Cell Reprogramming Science into Scalable and Robust Biomanufacturing Strategies.

    Cell Stem Cell. 2015 Jan 8;16(1):13-7.

    Generating iPSCs: Translating Cell Reprogramming Science into Scalable and Robust Biomanufacturing Strategies.

    Silva M, Daheron L, Hurley H, Bure K, Barker R, Carr AJ, Williams D, Kim HW, French A, Coffey PJ, Cooper-White JJ, Reeve B, Rao M, Snyder EY, Ng KS, Mead BE, Smith JA, Karp JM, Brindley DA, Wall I.

    Abstract

    Abstract:

    Induced pluripotent stem cells (iPSCs) have the potential to transform drug discovery and healthcare in the 21(st) century. However, successful commercialization will require standardized manufacturing platforms. Here we highlight the need to define standardized practices for iPSC generation and processing and discuss current challenges to the robust manufacture of iPSC products.

  • Smith JA, Naughton B, Kramm A, Smith G, Ohanjanyan A, De Simone M, Horne R, Brindley DA. European Union Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery. Chapter 8 in Fundamentals of EU Regulatory Affairs, 7th Edition. Regulatory Affairs Professionals Society. Read on external site.

    European Union Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery.

    Chapter 8 in Fundamentals of EU Regulatory Affairs, 7th Edition. Regulatory Affairs Professionals Society.

    European Union Falsified Medicines Directive: Requirements and Implications for Multi-Stakeholder Healthcare Delivery.

    Smith JA, Naughton B, Kramm A, Smith G, Ohanjanyan A, De Simone M, Horne R, Brindley DA.

    Abstract

    Abstract:

    No abstract available.

  • Smith JA, Bravery CA, Hollander G, Brindley DA. Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering. Chapter 29 in Fundamentals of EU Regulatory Affairs, 7th Edition. Regulatory Affairs Professionals Society. Read on external site.

    Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering.

    Chapter 29 in Fundamentals of EU Regulatory Affairs, 7th Edition. Regulatory Affairs Professionals Society.

    Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering.

    Smith JA, Bravery CA, Hollander G, Brindley DA.

    Abstract

    Abstract:

    No abstract available.

  • Smith JA, Reeve B, Carr A, Brindley DA. Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering. Chapter 31 in Fundamentals of US Regulatory Affairs, 9th Edition. Regulatory Affairs Professionals Society. Read on external site.

    Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering.

    Chapter 31 in Fundamentals of US Regulatory Affairs, 9th Edition. Regulatory Affairs Professionals Society.

    Regulating Regenerative Medicine: Cell Therapy, Gene Therapy and Tissue Engineering.

    Smith JA, Reeve B, Carr A, Brindley DA.

    Abstract

    Abstract:

    No abstract available.

  • Soland MA, Keyes LR, Bayne R, Moon J, Porada CD, St Jeor S, Almeida-Porada G. Perivascular stromal cells as a potential reservoir of human cytomegalovirus. Am J Transplant. 2014 Apr;14(4):820-30. doi: 10.1111/ajt.12642. Epub 2014 Mar 4 PubMed: 24592822. Categories: ApoptoSENS

    Perivascular stromal cells as a potential reservoir of human cytomegalovirus.

    Am J Transplant. 2014 Apr;14(4):820-30. doi: 10.1111/ajt.12642. Epub 2014 Mar 4

    Perivascular stromal cells as a potential reservoir of human cytomegalovirus.

    Soland MA, Keyes LR, Bayne R, Moon J, Porada CD, St Jeor S, Almeida-Porada G.

    Abstract

    Abstract:

    Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality among both solid organ and hematopoietic stem cell transplant recipients. Identification of cells throughout the body that can potentially serve as a viral reservoir is essential to dissect mechanisms of cell tropism and latency and to develop novel therapies. Here, we tested and compared the permissivity of liver-, brain-, lung (LNG)- and bone marrow (BM)-derived perivascular mesenchymal stromal cells (MSC) to HCMV infection and their ability to propagate and produce infectious virus. Perivascular MSC isolated from the different organs have in common the expression of CD146 and Stro-1. While all these cells were permissive to HCMV infection, the highest rate of HCMV infection was seen with LNG-MSC, as determined by viral copy number and production of viral particles by these cells. In addition, we showed that, although the supernatants from each of the HCMV-infected cultures contained infectious virus, the viral copy number and the quantity and timing of virus production varied among the various organ-specific MSC. Furthermore, using quantitative polymerase chain reaction, we were able to detect HCMV DNA in BM-MSC isolated from 7 out of 19 healthy, HCMV-seropositive adults, suggesting that BM-derived perivascular stromal cells may constitute an unrecognized natural HCMV reservoir.

  • Meadows NA, Morrison A, Brindley DA, Schuh A, Barker RW. An evaluation of regulatory and commercial barriers to stratified medicine development and adoption. Pharmacogenomics J. 2015 Feb;15(1):6-12. doi: 10.1038/tpj.2014.51. Epub 2014 Oct 7. PubMed: 25287070. Categories: Beyond the Bench

    An evaluation of regulatory and commercial barriers to stratified medicine development and adoption.

    Pharmacogenomics J. 2015 Feb;15(1):6-12. doi: 10.1038/tpj.2014.51. Epub 2014 Oct 7.

    An evaluation of regulatory and commercial barriers to stratified medicine development and adoption.

    Meadows NA, Morrison A, Brindley DA, Schuh A, Barker RW.

    Abstract

    Abstract:

    Today, a range of products based on genomics, proteomics and metabolomics have facilitated the development of 'stratified' medicines and companion diagnostics. This investigation profiles a series of targeted medicines and corresponding diagnostics, and their role(s) in supporting evidence-based medicine. Despite their potential benefits we found that scientific, financial and regulatory barriers impede the development and adoption of companion diagnostics. Therefore, in order to realise improvements to the risk/benefit profiles of health-care interventions-notably reducing clinical uncertainty-conferred by the use of companion diagnostics, industry representatives, health-care providers and regulators will need a coordinated response to overcome these barriers.

  • Davies BM, Rikabi SR, French A, Pinedo-Villanueva R, Morrey ME, Wartolowska K, Brindley DA. Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study. J Tissue Eng. 2014 Sep 19;5:2041731414551764. doi: 10.1177/2041731414551764. eCollection 2014. PubMed: 25383173. Categories: Beyond the Bench

    Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.

    J Tissue Eng. 2014 Sep 19;5:2041731414551764. doi: 10.1177/2041731414551764. eCollection 2014.

    Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study.

    Davies BM, Rikabi SR, French A, Pinedo-Villanueva R, Morrey ME, Wartolowska K, Brindley DA.

    Abstract

    Abstract:

    There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.

  • Smith G, Smith JA, Brindley DA. The Falsified Medicines Directive: How to secure your supply chain. J Generic Med. 2014 Sep;11(3-4):169-172. PubMed: 26435721.

    The Falsified Medicines Directive: How to secure your supply chain.

    J Generic Med. 2014 Sep;11(3-4):169-172.

    The Falsified Medicines Directive: How to secure your supply chain.

    Smith G, Smith JA, Brindley DA.

    Abstract

    Abstract:

    With new EU-wide legislation being introduced to protect patients from falsified medicines, how can the existing supply chain adapt and thrive in this new, safer environment?

  • Boura JS, Vance M, Yin W, Madeira C, Lobato da Silva C, Porada CD, Almeida-Porada G. Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells. Mol Ther Methods Clin Dev. 2014 Sep;2014(1). pii: 14041. PubMed: 25279386. Categories: OncoSENS, RepleniSENS

    Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells.

    Mol Ther Methods Clin Dev. 2014 Sep;2014(1). pii: 14041.

    Evaluation of gene delivery strategies to efficiently overexpress functional HLA-G on human bone marrow stromal cells.

    Boura JS, Vance M, Yin W, Madeira C, Lobato da Silva C, Porada CD, Almeida-Porada G.

    Abstract

    Abstract:

    Mesenchymal stromal cells (MSC) constitutively express low levels of human leukocyte antigen-G (HLA-G), which has been shown to contribute to their immunomodulatory and anti-inflammatory properties. Here, we hypothesized that overexpression of HLA-G on bone marrow-derived MSC would improve their immunomodulatory function, thus increasing their therapeutic potential. Therefore, we investigated which gene transfer system is best suited for delivering this molecule while maintaining its immuno-modulatory effects. We performed a side-by-side comparison between three nonviral plasmid-based platforms (pmax-HLA-G1; MC-HLA-G1; pEP-HLA-G1) and a viral system (Lv-HLA-G1) using gene transfer parameters that yielded similar levels of HLA-G1-expressing MSC. Natural killer (NK) cell-mediated lysis assays and T cell proliferation assays showed that MSC modified with the HLA-G1 expressing viral vector had significantly lower susceptibility to NK-lysis and significantly reduced T cell proliferation when compared to nonmodified cells or MSC modified with plasmid. We also show that, in plasmid-modified MSC, an increase in Toll-like receptor (TLR)9 expression is the mechanism responsible for the abrogation of HLA-G1's immunomodulatory effect. Although MSC can be efficiently modified to overexpress HLA-G1 using viral and nonviral strategies, only viral-based delivery of HLA-G1 is suitable for improvement of MSC's immunomodulatory properties.

  • French A, Suh JY, Suh CY, Rubin L, Barker R, Bure K, Reeve B, Brindley DA. Global strategic partnerships in regenerative medicine. Trends Biotechnol. 2014 Sep;32(9):436-40. doi: 10.1016/j.tibtech.2014.05.007. PubMed: 25150363. Categories: Beyond the Bench

    Global strategic partnerships in regenerative medicine.

    Trends Biotechnol. 2014 Sep;32(9):436-40. doi: 10.1016/j.tibtech.2014.05.007.

    Global strategic partnerships in regenerative medicine.

    French A, Suh JY, Suh CY, Rubin L, Barker R, Bure K, Reeve B, Brindley DA.

    Abstract

    Abstract:

    The approach to research and development in biomedical science is changing. Increasingly, academia and industry seek to collaborate, and share resources and expertise, by establishing partnerships. Here, we explore the co-development partnership landscape in the field of regenerative medicine, focusing on agreements involving one or more private entities. A majority of the largest biopharmaceutical companies have announced strategic partnerships with a specific regenerative medicine focus, signifying the growth and widening appeal of this emerging sector.

  • Roberts M, Wall IB, Bingham I, Icely D, Reeve B, Bure K, French A, Brindley DA. The global intellectual property landscape of induced pluripotent stem cell technologies. Nat Biotechnol. 2014 Aug;32(8):742-8. doi: 10.1038/nbt.2975. PubMed: 25093884. Categories: Beyond the Bench

    The global intellectual property landscape of induced pluripotent stem cell technologies.

    Nat Biotechnol. 2014 Aug;32(8):742-8. doi: 10.1038/nbt.2975.

    The global intellectual property landscape of induced pluripotent stem cell technologies.

    Roberts M, Wall IB, Bingham I, Icely D, Reeve B, Bure K, French A, Brindley DA.

    Abstract

    Abstract:

    Will freedom to research and innovate be restricted as the induced pluripotent stem cell field advances toward the clinic, or are concerns premature within a rapidly changing ecosystem?

  • Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM. Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun. 2014 Jun 10;5:4082. doi: 10.1038/ncomms5082. PubMed: 24915299. Categories: RepleniSENS

    Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

    Nat Commun. 2014 Jun 10;5:4082. doi: 10.1038/ncomms5082.

    Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration.

    Elabd C, Cousin W, Upadhyayula P, Chen RY, Chooljian MS, Li J, Kung S, Jiang KP, Conboy IM.

    Abstract

    Abstract:

    The regenerative capacity of skeletal muscle declines with age. Previous studies suggest that this process can be reversed by exposure to young circulation; however, systemic age-specific factors responsible for this phenomenon are largely unknown. Here we report that oxytocin-a hormone best known for its role in lactation, parturition and social behaviours-is required for proper muscle tissue regeneration and homeostasis, and that plasma levels of oxytocin decline with age. Inhibition of oxytocin signalling in young animals reduces muscle regeneration, whereas systemic administration of oxytocin rapidly improves muscle regeneration by enhancing aged muscle stem cell activation/proliferation through activation of the MAPK/ERK signalling pathway. We further show that the genetic lack of oxytocin does not cause a developmental defect in muscle but instead leads to premature sarcopenia. Considering that oxytocin is an FDA-approved drug, this work reveals a potential novel and safe way to combat or prevent skeletal muscle ageing.

  • Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ, Rombach I, Brindley D, Savulescu J, Beard DJ, Carr AJ. Use of placebo controls in the evaluation of surgery: systematic review. BMJ. 2014 May 21;348:g3253. doi: 10.1136/bmj.g3253. PubMed: 24850821.

    Use of placebo controls in the evaluation of surgery: systematic review.

    BMJ. 2014 May 21;348:g3253. doi: 10.1136/bmj.g3253.

    Use of placebo controls in the evaluation of surgery: systematic review.

    Wartolowska K, Judge A, Hopewell S, Collins GS, Dean BJ, Rombach I, Brindley D, Savulescu J, Beard DJ, Carr AJ.

    Abstract

    Abstract:

    OBJECTIVE:
    To investigate whether placebo controls should be used in the evaluation of surgical interventions.

    DESIGN:
    Systematic review.

    DATA SOURCES:
    We searched Medline, Embase, and the Cochrane Controlled Trials Register from their inception to November 2013.

    STUDY SELECTION:
    Randomised clinical trials comparing any surgical intervention with placebo. Surgery was defined as any procedure that both changes the anatomy and requires a skin incision or use of endoscopic techniques.

    DATA EXTRACTION:
    Three reviewers (KW, BJFD, IR) independently identified the relevant trials and extracted data on study details, outcomes, and harms from included studies.

    RESULTS:
    In 39 out of 53 (74%) trials there was improvement in the placebo arm and in 27 (51%) trials the effect of placebo did not differ from that of surgery. In 26 (49%) trials, surgery was superior to placebo but the magnitude of the effect of the surgical intervention over that of the placebo was generally small. Serious adverse events were reported in the placebo arm in 18 trials (34%) and in the surgical arm in 22 trials (41.5%); in four trials authors did not specify in which arm the events occurred. However, in many studies adverse events were unrelated to the intervention or associated with the severity of the condition. The existing placebo controlled trials investigated only less invasive procedures that did not involve laparotomy, thoracotomy, craniotomy, or extensive tissue dissection.

    CONCLUSIONS:
    Placebo controlled trial is a powerful, feasible way of showing the efficacy of surgical procedures. The risks of adverse effects associated with the placebo are small. In half of the studies, the results provide evidence against continued use of the investigated surgical procedures. Without well designed placebo controlled trials of surgery, ineffective treatment may continue unchallenged.

  • Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. PubMed: 24648510. Categories: AmyloSENS

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231.

    Physiological IgM class catalytic antibodies selective for transthyretin amyloid.

    Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S.

    Abstract

    Abstract:

    Peptide bond-hydrolyzing catalytic antibodies (catabodies) could degrade toxic proteins, but acquired immunity principles have not provided evidence for beneficial catabodies. Transthyretin (TTR) forms misfolded β-sheet aggregates responsible for age-associated amyloidosis. We describe nucleophilic catabodies from healthy humans without amyloidosis that degraded misfolded TTR (misTTR) without reactivity to the physiological tetrameric TTR (phyTTR). IgM class B cell receptors specifically recognized the electrophilic analog of misTTR but not phyTTR. IgM but not IgG class antibodies hydrolyzed the particulate and soluble misTTR species. No misTTR-IgM binding was detected. The IgMs accounted for essentially all of the misTTR hydrolytic activity of unfractionated human serum. The IgMs did not degrade non-amyloidogenic, non-superantigenic proteins. Individual monoclonal IgMs (mIgMs) expressed variable misTTR hydrolytic rates and differing oligoreactivity directed to amyloid β peptide and microbial superantigen proteins. A subset of the mIgMs was monoreactive for misTTR. Excess misTTR was dissolved by a hydrolytic mIgM. The studies reveal a novel antibody property, the innate ability of IgMs to selectively degrade and dissolve toxic misTTR species as a first line immune function.

  • Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B. Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils. Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524. PubMed: 24164623. Categories: AmyloSENS

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524.

    Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils.

    Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B.

    Abstract

    Abstract:

    Amyloidosis involves the extracellular deposition of proteinaceous amyloid fibrils and accessory molecules in organ(s) and/or tissue(s), and is associated with a host of human diseases, including Alzheimer disease, diabetes, and heart disease. Unfortunately, the amyloidoses are currently incurable, and there is an urgent need for less invasive diagnostics. To address this, we have generated 22 monoclonal antibodies (mAbs) against aggregates formed by a blood transport protein, transthyretin (TTR), which primarily forms amyloid fibrils in a patient's heart and/or peripheral nerves. Four of the mAbs, 2T5C9, 2G9C, T1F11, and TB2H7, demonstrated diagnostic potential in enzyme-linked immunosorbent assays (ELISA) by their low to sub-nanomolar cross-reactivity with recombinant wild-type (WT) and mutant TTR aggregates and lack of binding to native TTR or amyloid fibrils formed by other peptides or proteins. Notably, in the presence of normal human sera, three of the four mAbs, 2T5C9, 2G9C, and T1F11, retained low nM binding to TTR amyloid fibrils derived from two patients with familial amyloidotic polyneuropathy (FAP). The two most promising mAbs, 2T5C9 and 2G9C, were also shown by immunohistochemistry to have low nM binding to TTR amyloid deposits in cardiac tissue sections from two FAP patients. Taken together, these findings strongly support further investigations on the diagnostic utility of TTR aggregate specific mAbs for patients with TTR amyloidoses.

  • Akman K, Haaf T, Gravina S, Vijg J, Tresch A. Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data. Bioinformatics. 2014 Jul 1;30(13):1933-4. doi: 10.1093/bioinformatics/btu142. Epub 2014 Mar 10. PubMed: 24618468. Categories: OncoSENS

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Bioinformatics. 2014 Jul 1;30(13):1933-4. doi: 10.1093/bioinformatics/btu142. Epub 2014 Mar 10.

    Genome-wide quantitative analysis of DNA methylation from bisulfite sequencing data.

    Akman K, Haaf T, Gravina S, Vijg J, Tresch A.

    Abstract

    Abstract:

    SUMMARY:

    Here we present the open-source R/Bioconductor software package BEAT (BS-Seq Epimutation Analysis Toolkit). It implements all bioinformatics steps required for the quantitative high-resolution analysis of DNA methylation patterns from bisulfite sequencing data, including the detection of regional epimutation events, i.e. loss or gain of DNA methylation at CG positions relative to a reference. Using a binomial mixture model, the BEAT package aggregates methylation counts per genomic position, thereby compensating for low coverage, incomplete conversion and sequencing errors.

    AVAILABILITY AND IMPLEMENTATION:

    BEAT is freely available as part of Bioconductor at www.bioconductor.org/packages/devel/bioc/html/BEAT.html. The package is distributed under the GNU Lesser General Public License 3.0.

  • Brindley DA, French AL, Baptista R, Timmins N, Adams T, Wall I, Bure K. Cell Therapy Bioprocessing Technologies and Indicators of Technological Convergence. BioProcess International 12(3)s (March 2014). Read on external site. Categories: Beyond the Bench, Delivery Mechanisms

    Cell Therapy Bioprocessing Technologies and Indicators of Technological Convergence.

    BioProcess International 12(3)s (March 2014).

    Cell Therapy Bioprocessing Technologies and Indicators of Technological Convergence.

    Brindley DA, French AL, Baptista R, Timmins N, Adams T, Wall I, Bure K.

    Abstract

    Abstract:

    The cell therapy industry is undergoing a natural evolution from scientific curiosity into a commercially and clinically attractive opportunity (1). This evolution is by no means complete, and growing evidence suggests that its progression is driving significant developments in cell therapy bioprocessing — notably, convergence.

  • Chen Y, Ma X, Zhang M, Wang X, Wang C, Wang H, Guo P, Yuan W, Rudolph KL, Zhan Q, Ju Z. Gadd45a regulates hematopoietic stem cell stress responses in mice. Blood. 2014 Feb 6;123(6):851-62. doi: 10.1182/blood-2013-05-504084. PubMed: 24371210. Categories: RepleniSENS

    Gadd45a regulates hematopoietic stem cell stress responses in mice.

    Blood. 2014 Feb 6;123(6):851-62. doi: 10.1182/blood-2013-05-504084.

    Gadd45a regulates hematopoietic stem cell stress responses in mice.

    Chen Y, Ma X, Zhang M, Wang X, Wang C, Wang H, Guo P, Yuan W, Rudolph KL, Zhan Q, Ju Z.

    Abstract

    Abstract:

    Gadd45a has been involved in DNA damage response and in many malignancies, including leukemia. However, the function of Gadd45a in hematopoietic stem cells (HSCs) remains unknown. Here, we reported that Gadd45a-deficient (Gadd45a(-/-)) mice showed a normal hematologic phenotype under homeostatic conditions. However, following 5-fluorouracil treatment, Gadd45a(-/-) HSCs exhibited a faster recovery, associated with an increase in the proliferation rate. Interestingly, young Gadd45a(-/-) HSCs showed enhanced reconstitution ability in serial transplantation. Following ionizing radiation (IR), young Gadd45a(-/-) HSCs exhibited an increased resistance to IR-induced DNA damage, associated with a decrease in the apoptosis rate and delayed DNA repair. The significantly higher level of DNA damage in Gadd45a(-/-) HSCs ultimately promoted B-cell leukemia in further transplanted recipient mice. In old mice, Gadd45a(-/-) HSCs were functionally equal to wild-type HSCs but exhibited more DNA damage accumulation and increased sensitivity to IR than wild-type HSCs. In conclusion, Gadd45a plays a significant role in HSC stress responses. Gadd45a deficiency leads to DNA damage accumulation and impairment in apoptosis after exposure to IR, which increases the susceptibility of leukemogenesis.

  • French AL, Bure K, Brindley DA. CASMI TSCC Launch Event, Paris, France, July 2013: An Assessment of the Key Barriers to the Commercialization and Clinical Adoption of Pluripotent Stem Cell Therapies. Rejuvenation Res. February 2014, 17(1): 84-88. doi:10.1089/rej.2014.1545. PubMed: 24392658. Categories: Beyond the Bench

    CASMI TSCC Launch Event, Paris, France, July 2013: An Assessment of the Key Barriers to the Commercialization and Clinical Adoption of Pluripotent Stem Cell Therapies.

    Rejuvenation Res. February 2014, 17(1): 84-88. doi:10.1089/rej.2014.1545.

    CASMI TSCC Launch Event, Paris, France, July 2013: An Assessment of the Key Barriers to the Commercialization and Clinical Adoption of Pluripotent Stem Cell Therapies.

    French AL, Bure K, Brindley DA.

    Abstract

    Abstract:

    The high incidence of unmet medical needs in combination with the rising burden of chronic diseases, linked to an increasingly aging population, necessitates new approaches to therapeutic intervention. One potential class of health care innovation that may offer an alternative approach to addressing current shortfalls is stem cell therapies. The CASMI Translational Stem Cell Consortium (CTSCC) was formed to elucidate the key hurdles to the commercialization and clinical adoption of stem cell technologies, with a particular focus on pluripotent stem cell (PSC) technologies. As a global pre-competitive academic–industry consortium, the CTSCC unites thought leaders from a range of sectors and technical specialties in defining and discovering solutions to roadblocks that will impede the field. Targeted toward stakeholder requirements at the delivery end of the translational spectrum, the CTSCC aims to provide mechanisms for multidirectional dialogue and to produce academically rigorous and commercially practicable research outputs to accelerate industry progress. On the 30th and 31st of July, 2013, the CASMI Translational Stem Cell Consortium (CTSCC) held a launch event at the Saint James Club, Paris, France.

  • Rohani L, Johnson AA, Arnold A, Stolzing A. The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 2014;13(1):2-7. PubMed: 24256351. Categories: RepleniSENS

    The aging signature: a hallmark of induced pluripotent stem cells?

    Aging Cell 2014;13(1):2-7.

    The aging signature: a hallmark of induced pluripotent stem cells?

    Rohani L, Johnson AA, Arnold A, Stolzing A.

    Abstract

    Abstract:

    The discovery that somatic cells can be induced into a pluripotent state by the expression of reprogramming factors has enormous potential for therapeutics and human disease modeling. With regard to aging and rejuvenation, the reprogramming process resets an aged, somatic cell to a more youthful state, elongating telomeres, rearranging the mitochondrial network, reducing oxidative stress, restoring pluripotency, and making numerous other alterations. The extent to which induced pluripotent stem cell (iPSC)s mime embryonic stem cells is controversial, however, as iPSCs have been shown to harbor an epigenetic memory characteristic of their tissue of origin which may impact their differentiation potential. Furthermore, there are contentious data regarding the extent to which telomeres are elongated, telomerase activity is reconstituted, and mitochondria are reorganized in iPSCs. Although several groups have reported that reprogramming efficiency declines with age and is inhibited by genes upregulated with age, others have successfully generated iPSCs from senescent and centenarian cells. Mixed findings have also been published regarding whether somatic cells generated from iPSCs are subject to premature senescence. Defects such as these would hinder the clinical application of iPSCs, and as such, more comprehensive testing of iPSCs and their potential aging signature should be conducted.

  • Rehki R, Wall I, French A, Bure K, Carr AJ, Brindley DA. Cell Therapy Biomanufacturing Risk Management. In: Cell Therapy Translation (D. Williams and D. Scadden, eds.), StemBook, 2014. Categories: Beyond the Bench

    Cell Therapy Biomanufacturing Risk Management.

    In: Cell Therapy Translation (D. Williams and D. Scadden, eds.), StemBook, 2014.

    Cell Therapy Biomanufacturing Risk Management.

    Rehki R, Wall I, French A, Bure K, Carr AJ, Brindley DA.

    Abstract

    Abstract:

    (No abstract available.)

  • Chen Y, Yang R, Guo P, Ju Z. Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice. Protein Cell. 2014 Jan;5(1):80-9. doi: 10.1007/s13238-013-0017-9. PubMed: 24474198. Categories: RepleniSENS

    Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.

    Protein Cell. 2014 Jan;5(1):80-9. doi: 10.1007/s13238-013-0017-9.

    Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice.

    Chen Y, Yang R, Guo P, Ju Z.

    Abstract

    Abstract:

    Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53-p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self-renewal capacity and an increased malignant transformation in ATM(-/-) HSCs.

  • Zhang J, Yang R, Zhou D, Rudolph KL, Meng A, Ju Z. Exonuclease 1 is essential for maintaining genomic stability and the proliferative capacity of neural but not hematopoietic stem cells. Stem Cell Res. 2014 Jan;12(1):250-9. doi: 10.1016/j.scr.2013.11.001. PubMed: 24280419. Categories: RepleniSENS

    Exonuclease 1 is essential for maintaining genomic stability and the proliferative capacity of neural but not hematopoietic stem cells.

    Stem Cell Res. 2014 Jan;12(1):250-9. doi: 10.1016/j.scr.2013.11.001.

    Exonuclease 1 is essential for maintaining genomic stability and the proliferative capacity of neural but not hematopoietic stem cells.

    Zhang J, Yang R, Zhou D, Rudolph KL, Meng A, Ju Z.

    Abstract

    Abstract:

    Exonuclease 1 (Exo1) has been implicated in the regulation of DNA damage responses in stem cells with dysfunctional telomeres. However, it is unclear whether Exo1-mediated DNA maintenance pathways play a role in the maintenance of genomic stability and the self-renewal of tissue stem cells in mice with functional telomeres. Here, we analyzed the proliferative capacity of neural stem cells (NSCs) and hematopoietic stem cells (HSCs) from Exo1(-/-) mice. Our study shows that Exo1 deficiency impairs the maintenance of genomic stability and proliferative capacity in NSCs but not HSCs. In line with these results, we detected a decrease in proliferation and an up-regulation of p21 expression levels in Exo1-deficient NSCs but not Exo1-deficient HSCs. Our data provide experimental evidence that Exo1 deficiency has a differential impact on the homeostasis and proliferative capacity of tissue stem cells in the brain and bone marrow, suggesting that different tissue stem cells utilize distinct mechanisms for maintaining their genomic stability. Our current study provides important insight into the role of Exo1-mediated DNA maintenance pathways in the maintenance of genomic stability and the proliferative capacity of tissue stem cells.

  • Bains, W. More than genes and cells: drug discovery in the ECM. Drug Discovery World. 2013/14 Winter:65-70. Read on external site. Categories: GlycoSENS

    More than genes and cells: drug discovery in the ECM.

    Drug Discovery World. 2013/14 Winter:65-70.

    More than genes and cells: drug discovery in the ECM.

    Bains, W.

    Abstract

    Abstract:

    Drug discovery in the last few decades has focused on the cellular and genetic mechanisms of disease. This has been very successful in cancer, which is a disease of somatic genetics, and moderately successful elsewhere. But the declining productivity of pharmaceutical and biotechnology investment in drug discovery and development suggests that we should be alert to other approaches. One is to look outside the cell, at the extracellular superstructure of the body. Once viewed as an inert structure that is just the biological equivalent of a petri dish, the extracellular milieu is now being seen as a therapeutic target, especially for diseases of old age. Importantly, targeting the scaffold of the body might be a much faster route to treatment for some conditions than attempting to find, and fix, underlying cellular or genetic aetiology of disease.

Pages