Recent SRF Education Publications

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.

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.

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...

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

The implementation of novel collaborative structures for the identification and resolution of barriers to pluripotent stem cell translation.

Stem Cells Dev 2013;22 Suppl 1:63-72.

The implementation of novel collaborative structures for the identification and resolution of barriers to pluripotent stem cell translation.

Brindley DA, French A, Suh J, Roberts M, Davies B, Pinedo-Villanueva R, Wartolowska K, Rooke K, Kramm A, Judge A, Morrey M, Chandra A, Hurley H, Grover L, Bingham I, Siegel B, Rattley MS, Buckler RL, McKeon D, Krumholz K, Hook L, May M, Rikabi S, Pigott R, Morys M, Sabokbar A, Titus E, Laabi Y, Lemaitre G, Zahkia R, Sipp D, Horne R, Bravery C, Williams D, Wall I, Snyder EY, Karp JM, Barker RW, Bure K, Carr AJ, Reeve B.

Abstract

Abstract:

Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing-of expertise and/or funding-has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies. In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners. Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.

p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

J Cell Biol 2013;201(4):613-29.

p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes.

Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J.

Abstract

Abstract:

Cellular senescence irreversibly arrests proliferation in response to potentially oncogenic stress. Senescent cells also secrete inflammatory cytokines such as IL-6, which promote age-associated inflammation and pathology. HMGB1 (high mobility group box 1) modulates gene expression in the nucleus, but certain immune cells secrete HMGB1 as an extracellular Alarmin to signal tissue damage. We show that nuclear HMGB1 relocalized to the extracellular milieu in senescent human and mouse cells in culture and in vivo. In contrast to cytokine secretion, HMGB1 redistribution required the p53 tumor suppressor, but not its activator ATM. Moreover, altered HMGB1 expression induced a p53-dependent senescent growth arrest. Senescent fibroblasts secreted oxidized HMGB1, which stimulated cytokine secretion through TLR-4 signaling. HMGB1 depletion, HMGB1 blocking antibody, or TLR-4 inhibition attenuated senescence-associated IL-6 secretion, and exogenous HMGB1 stimulated NF-κB activity and restored IL-6 secretion to HMGB1-depleted cells. Our findings identify senescence as a novel biological setting in which HMGB1 functions and link HMGB1 redistribution to p53 activity and senescence-associated inflammation.

Establish good genomic practice to guide medicine forward.

Nat Med. 2013 May;19(5):530. doi: 10.1038/nm0513-530.

Establish good genomic practice to guide medicine forward.

Barker RW, Brindley DA, Schuh A.

Abstract

Abstract:

(No abstract available.)

Commercialization of regenerative medicine: learning from spin-outs.

Rejuvenation Res 2013;16(2):164-70.

Commercialization of regenerative medicine: learning from spin-outs.

French A, Buckler RL, Brindley DA.

Abstract

Abstract:

The meeting "Commercialization of Your Regenerative Medicine Research: Lessons from Spin Out Successes" was hosted by the Oxbridge Biotech Roundtable (OBR) (Oxford, UK) at the University of Oxford in February, 2013, and attracted a multi-stakeholder audience spanning academia and industry. The event featured case studies from Gregg Sando, CEO, Cell Medica (London, UK), John Sinden, CSO, Reneuron (Guilford, UK), and Paul Kemp, CEO and CSO, Intercytex (Manchester, UK). OBR is a student-led initiative with over 7000 members across eight different UK and US locations with a mission to foster a conversation about the healthcare and life sciences industry. Here we review the main themes of the meeting and the major questions facing the regenerative medicine industry and its rapidly emerging subsets of cellular and gene therapies. Notably, we discuss the compatibility of regenerative therapies to the existing healthcare infrastructure, biomanufacturing challenges (including scalability and comparability), and the amenability of regenerative therapies to existing reimbursement and investment models. Furthermore, we reiterate key words of advice from seasoned industry leaders intended to accelerate the translation path from lab bench to the marketplace.

Chronic central administration of valproic acid: Increased pro-survival phospho-proteins and growth cone associated proteins with no behavioral pathology.

Pharmacol Biochem Behav 2012;103(2):237-44.

Chronic central administration of valproic acid: Increased pro-survival phospho-proteins and growth cone associated proteins with no behavioral pathology.

Bates RC, Stith BJ, Stevens KE.

Abstract

Abstract:

Valproic acid (VPA) is the most widely prescribed antiepileptic drug due to its ability to treat a broad spectrum of seizure types. However, potential complications of this drug include anticonvulsant polytherapy metabolism, organ toxicity and teratogenicity which limit its use in a variety of epilepsy patients. Direct delivery of VPA intracerebroventricularly (ICV) could circumvent the toxic effects normally seen with the oral route of administration. An additional potential benefit would be significantly reduced dosing while achieving high brain concentrations. Epileptogenic tissue from patients with intractable seizures has shown significant cell death which may be mitigated by maximizing cerebral VPA exposure. Here we show ICV administration of VPA localized to the periventricular zone increased pro-survival phospho-proteins (pAkt(Ser473), pAkt(Thr308), pGSK3β(Ser9), pErk1/2(Thr202/Tyr204)) and growth cone associated proteins (2G13p, GAP43) in a whole animal system. No significant changes in DCX, NeuN, synaptotagmin, and synaptophysin were detected. Assessment of possible behavioral alterations in rats receiving chronic central infusions of VPA was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the drug infusion process.

The role of DNA methylation in aging, rejuvenation, and age-related disease.

Rejuvenation Res 2012;15(5):483-94.

The role of DNA methylation in aging, rejuvenation, and age-related disease.

Johnson AA, Akman K, Calimport SR, Wuttke D, Stolzing A, de Magalhães JP.

Abstract

Abstract:

DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.

Human embryonic stem cell therapy in the post-Geron era.

Regen Med. 2012 Jan;7(1):17-8. doi: 10.2217/rme.11.115.

Human embryonic stem cell therapy in the post-Geron era.

Brindley D, Mason C.

Abstract

Abstract:

(No abstract available.)

Peak serum: implications of serum supply for cell therapy manufacturing.

Regen Med. 2012 Jan;7(1):7-13. doi: 10.2217/rme.11.112.

Peak serum: implications of serum supply for cell therapy manufacturing.

Brindley DA, Davie NL, Culme-Seymour EJ, Mason C, Smith DW, Rowley JA.

Abstract

Abstract:

(No abstract available.)

Aluminium and iron in humans: bioaccumulation, pathology, and removal.

Rejuvenation Res 2010 Oct;13(5):589-98.

Aluminium and iron in humans: bioaccumulation, pathology, and removal.

Peto MV.

Abstract

Abstract:

It is well known that exposure to various elements has a noticeable effect on human health. The effect of an element is determined by several characteristics, including its similarity to elements of biological necessity, metabolism, and degree of interaction with physiological processes. This review investigates the scientific literature of iron and aluminium to evaluate the extent to which these elements accumulate and cause pathology in humans. Iron was chosen for review because it is necessary for human life while seemingly having relationships with numerous pathological states such as heart disease, cancer, and impaired insulin sensitivity. Aluminium is reviewed because of its prevalence in daily life, observed interference with several biological processes, controversial relationship with Alzheimer disease, and lack of physiological role. Furthermore, because each of these metals has long been investigated for a possible relationship with various pathological states, a substantial volume of research is available regarding the effects of iron and aluminium in biological systems. For both aluminium and iron, this review focuses on: (1) Evaluating the evidence of toxicity, (2) considering the possibility of bioaccumulation, and (3) exploring methods of managing their accumulation.

Regenerative Medicine Through a Crisis: Social Perception and the Financial Reality.

Rejuvenation Research 2009, 12(6): 455-461.

Regenerative Medicine Through a Crisis: Social Perception and the Financial Reality.

Brindley DA, Davie N.

Abstract

Abstract:

The aim of this perspective piece is to highlight how the “social perception” and “financial reality” of regenerative medicine may act to hinder its evolution into the principal health-care option for the future. We also consider the role of the consumer and the need for increased public awareness. Furthermore, we consider the effects of the changing social attitudes toward the field, as well as taking into account the influence of current and future political thinking. From a financial viewpoint, we analyze the compatibility of the current venture capital model with regenerative medicine start-ups and explore approaches to ensure sufficient funding and support throughout all stages of product development, for example, the modularization of funding.

Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

Rejuvenation Res 2009;12(2):137-48.

Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link.

Sjöberg JS, Bulterijs S.

Abstract

Abstract:

Advanced glycation end products are the results of a series of chemical reactions collectively known as the Maillard reaction, or nonenzymatic glycation, and sometimes cross-link proteins, thereby impairing their normal function. Glucosepane is the most abundant protein cross-link found in vivo so far and mainly has been shown to accumulate in the extracellular matrix, where it cross-links collagen. Levels of glucosepane increase with aging. By increasing collagen stiffness, glucosepane cross-links may have significant implications in several age-related diseases, such as cardiovascular disease, diabetes, and osteoporosis. Although the formation pathways for glucosepane are relatively well researched, much is still unknown about the accumulation and pathophysiology of glucosepane.