Activity
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We're happy to announce that Hurdle has Joined the NVIDIA inception program! This is powering Hurdle to help lead the safe use of AI in health tech…
We're happy to announce that Hurdle has Joined the NVIDIA inception program! This is powering Hurdle to help lead the safe use of AI in health tech…
Liked by Daniel Elías Martín Herranz
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Great to see our research "Genetic factors associated with reasons for clinical trial stoppage" finally out as open access in Nature Genetics In…
Great to see our research "Genetic factors associated with reasons for clinical trial stoppage" finally out as open access in Nature Genetics In…
Liked by Daniel Elías Martín Herranz
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Ahead of tomorrow’s next show thought I’d pull the stats from the last HealthTech Hour show we did with Daniel Elías Martín Herranz from Hurdle -…
Ahead of tomorrow’s next show thought I’d pull the stats from the last HealthTech Hour show we did with Daniel Elías Martín Herranz from Hurdle -…
Liked by Daniel Elías Martín Herranz
Experience & Education
Licenses & Certifications
Publications
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A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age
GeroScience
An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults.
We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49)…An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults.
We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49). Blood and saliva were obtained pre and post a 12-week course of a multi-component supplement, containing: Vitamin B3, Vitamin C, Vitamin D, Omega 3 fish oils, Resveratrol, Olive fruit phenols and Astaxanthin. Plasma GDF-15 and C-reactive protein (CRP) concentrations were quantified as markers of biological aging and inflammation respectively. DNA methylation was assessed in whole blood and saliva and used to derive epigenetic age using various clock algorithms.
No difference between the epigenetic and chronological ages of participants was observed pre- and post-treatment by the blood-based Horvath or Hannum clocks, or the saliva-based InflammAge clock. However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age (p = 0.015) and epigenetic age acceleration (p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation (p = 0.0195).
Our data suggest a possible benefit of combined nutritional supplementation in individuals with an accelerated epigenetic age and inflammaging. -
A novel framework to build saliva-based DNA methylation biomarkers: quantifying systemic chronic inflammation as a case study
bioRxiv
Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm…
Accessible and non-invasive biomarkers that measure human ageing processes and the risk of developing age-related disease are paramount in preventative healthcare. In this study, we describe a novel framework to train saliva-based DNA methylation (DNAm) biomarkers that are reproducible and biologically interpretable. By leveraging a reliability dataset with replicates across tissues, we demonstrate that it is possible to transfer knowledge from blood DNAm data to saliva DNAm data using DNAm proxies of blood proteins (EpiScores). We then apply these methods to create a new saliva-based epigenetic clock (InflammAge) that quantifies systemic chronic inflammation (SCI) in humans. Using a large blood DNAm human cohort with linked electronic health records and over 18,000 individuals (Generation Scotland), we demonstrate that InflammAge significantly associates with all-cause mortality, disease outcomes, lifestyle factors and immunosenescence; in many cases outperforming the widely used SCI biomarker C-reactive protein (CRP). We propose that our biomarker discovery framework and InflammAge will be useful to improve our understanding of the molecular mechanisms underpinning human ageing and to assess the impact of gero-protective interventions.
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Multi‐omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming
Aging Cell
The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA…
The expression of the pluripotency factors OCT4, SOX2, KLF4, and MYC (OSKM) can convert somatic differentiated cells into pluripotent stem cells in a process known as reprogramming. Notably, partial and reversible reprogramming does not change cell identity but can reverse markers of aging in cells, improve the capacity of aged mice to repair tissue injuries, and extend longevity in progeroid mice. However, little is known about the mechanisms involved. Here, we have studied changes in the DNA methylome, transcriptome, and metabolome in naturally aged mice subject to a single period of transient OSKM expression. We found that this is sufficient to reverse DNA methylation changes that occur upon aging in the pancreas, liver, spleen, and blood. Similarly, we observed reversion of transcriptional changes, especially regarding biological processes known to change during aging. Finally, some serum metabolites and biomarkers altered with aging were also restored to young levels upon transient reprogramming. These observations indicate that a single period of OSKM expression can drive epigenetic, transcriptomic, and metabolomic changes toward a younger configuration in multiple tissues and in the serum.
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Freshwater monitoring by nanopore sequencing
Elife
While traditional microbiological freshwater tests focus on the detection of specific bacterial indicator species, including pathogens, direct tracing of all aquatic DNA through metagenomics poses a profound alternative. Yet, in situ metagenomic water surveys face substantial challenges in cost and logistics. Here, we present a simple, fast, cost-effective and remotely accessible freshwater diagnostics workflow centred around the portable nanopore sequencing technology. Using defined…
While traditional microbiological freshwater tests focus on the detection of specific bacterial indicator species, including pathogens, direct tracing of all aquatic DNA through metagenomics poses a profound alternative. Yet, in situ metagenomic water surveys face substantial challenges in cost and logistics. Here, we present a simple, fast, cost-effective and remotely accessible freshwater diagnostics workflow centred around the portable nanopore sequencing technology. Using defined compositions and spatiotemporal microbiota from surface water of an example river in Cambridge (UK), we provide optimised experimental and bioinformatics guidelines, including a benchmark with twelve taxonomic classification tools for nanopore sequences. We find that nanopore metagenomics can depict the hydrological core microbiome and fine temporal gradients in line with complementary physicochemical measurements. In a public health context, these data feature relevant sewage signals and pathogen maps at species level resolution. We anticipate that this framework will gather momentum for new environmental monitoring initiatives using portable devices.
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Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1
Genome Biology 20, 146 https://doi.org/10.1186/s13059-019-1753-9
Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery.
Using the Horvath…Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery.
Using the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients.
These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging.Other authorsSee publication -
On the epigenetic ageing clock in humans
PhD thesis, University of Cambridge
Epigenetic clocks are mathematical models that predict the biological age of an organism using DNA methylation data, and which have emerged in the last few years as the most accurate biomarkers of the ageing process. However, little is known about the molecular mechanisms that control the rate of such clocks. In this thesis I focus on the study of the epigenetic ageing clock in humans. First, I review and benchmark statistical and computational tools required for the analysis of DNA methylation…
Epigenetic clocks are mathematical models that predict the biological age of an organism using DNA methylation data, and which have emerged in the last few years as the most accurate biomarkers of the ageing process. However, little is known about the molecular mechanisms that control the rate of such clocks. In this thesis I focus on the study of the epigenetic ageing clock in humans. First, I review and benchmark statistical and computational tools required for the analysis of DNA methylation data in the context of human ageing. Next, I validate the performance of the Horvath epigenetic clock, the most widely used multi-tissue epigenetic clock in humans, in a control blood dataset and test its behaviour in patients with a variety of developmental disorders, which harbour mutations in proteins of the epigenetic machinery. I demonstrate that loss-of-function mutations in the H3K36 methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic ageing. Furthermore, I show that the normal ageing process and Sotos syndrome share methylation changes and the genomic context in which they happen. These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic ageing, and this role seems to be conserved in model organisms. Finally, I provide a technological strategy to make epigenetic clocks (or any DNA methylation-based mathematical models) more cost-effective by exploiting the ability of restriction enzymes to perform genomic enrichment. This thesis provides novel insights (statistical, biological, technological) into the epigenetic ageing clock in humans, which will help to shed light on the different processes that erode the human epigenetic landscape during ageing.
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The origins and vulnerabilities of two transmissible cancers in Tasmanian devils
Cancer cell 33 (4), 607-619. e15
Transmissible cancers are clonal lineages that spread through populations via contagious
cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here
we perform comparative genetic and functional characterization of these lineages. The two
cancers have similar patterns of mutation and show no evidence of exposure to exogenous
mutagens or viruses. Genes encoding PDGF receptors have copy number gains and are
present on extrachromosomal double…Transmissible cancers are clonal lineages that spread through populations via contagious
cancer cells. Although rare in nature, two facial tumor clones affect Tasmanian devils. Here
we perform comparative genetic and functional characterization of these lineages. The two
cancers have similar patterns of mutation and show no evidence of exposure to exogenous
mutagens or viruses. Genes encoding PDGF receptors have copy number gains and are
present on extrachromosomal double minutes. Drug screening indicates causative roles for
receptor tyrosine kinases and sensitivity to inhibitors of DNA repair. Y chromosome loss from
a male clone infecting a female host suggests immunoediting. These results imply that
Tasmanian devils may have inherent susceptibility to transmissible cancers and present a
suite of therapeutic compounds for use in conservation. -
cuRRBS: simple and robust evaluation of enzyme combinations for reduced representation approaches
Nucleic Acids Res. 2017 Nov 16;45(20):11559-11569. doi: 10.1093/nar/gkx814.
DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that…
DNA methylation is an important epigenetic modification in many species that is critical for development, and implicated in ageing and many complex diseases, such as cancer. Many cost-effective genome-wide analyses of DNA modifications rely on restriction enzymes capable of digesting genomic DNA at defined sequence motifs. There are hundreds of restriction enzyme families but few are used to date, because no tool is available for the systematic evaluation of restriction enzyme combinations that can enrich for certain sites of interest in a genome. Herein, we present customised Reduced Representation Bisulfite Sequencing (cuRRBS), a novel and easy-to-use computational method that solves this problem. By computing the optimal enzymatic digestions and size selection steps required, cuRRBS generalises the traditional MspI-based Reduced Representation Bisulfite Sequencing (RRBS) protocol to all restriction enzyme combinations. In addition, cuRRBS estimates the fold-reduction in sequencing costs and provides a robustness value for the personalised RRBS protocol, allowing users to tailor the protocol to their experimental needs. Moreover, we show in silico that cuRRBS-defined restriction enzymes consistently out-perform MspI digestion in many biological systems, considering both CpG and CHG contexts. Finally, we have validated the accuracy of cuRRBS predictions for single and double enzyme digestions using two independent experimental datasets.
Other authorsSee publication -
Insight into the family of Na+/Ca2+ exchangers of Caenorhabditis elegans
Genetics. 2013 Oct;195(2):611-9
Here we provide the first genome-wide in vivo analysis of the Na+/Ca2+ exchanger family in the model system Caenorhabditis elegans. We source all members of this family within the Caenorhabditis genus and reconstruct their phylogeny across humans and Drosophila melanogaster. Next, we provide a description of the expression pattern for each exchanger gene in C. elegans, revealing a wide expression in a number of tissues and cell types including sensory neurons, interneurons, motor neurons…
Here we provide the first genome-wide in vivo analysis of the Na+/Ca2+ exchanger family in the model system Caenorhabditis elegans. We source all members of this family within the Caenorhabditis genus and reconstruct their phylogeny across humans and Drosophila melanogaster. Next, we provide a description of the expression pattern for each exchanger gene in C. elegans, revealing a wide expression in a number of tissues and cell types including sensory neurons, interneurons, motor neurons, muscle cells, and intestinal tissue. Finally, we conduct a series of behavioral and functional analyses through mutant characterization in C. elegans. From these data we demonstrate that, similar to mammalian systems, the expression of Na+/Ca2+ exchangers in C. elegans is skewed toward excitable cells, and we propose that C. elegans may be an ideal model system for the study of Na+/Ca2+ exchangers.
Other authorsSee publication
Courses
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Analysis of DNA methylation using sequencing (June 2016, 8 hours)
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Cambridge Area Sequencing Informatics Meeting VII (March 2015, 8 hours)
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Network Visualisation and Analysis of Biological Data (April 2016, 15 hours)
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R object-oriented programming and package development (April 2016, 8 hours)
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Projects
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EMBO Workshop: Molecular mechanisms of ageing and regeneration – From pluripotency to senescence (Spetses, Greece)
People's choice award for the best presented poster: 'Measuring ageing with a sequencing-based epigenetic clock'
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Bio-Mentoring - Biotech Annual Congress 2015 (Salamanca, Spain)
Talk title: 'Research in the UK'
Organizer: Spanish Federation of Biotechnologists.
Honors & Awards
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People's choice award for the best presented poster
EMBO Workshop: Molecular mechanisms of ageing and regeneration – From pluripotency to senescence
For the poster entitled "Measuring ageing with a sequencing-based epigenetic clock"
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"la Caixa" Scholarship
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Beca de Colaboración
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Becas de prácticas Santander CRUE-CEPYME
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Premio Extraordinario de Bachillerato, Soria
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Languages
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English
Full professional proficiency
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Español
Native or bilingual proficiency
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Français
Elementary proficiency
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📻 This week I had the pleasure to attend the HealthTech Hour, the biggest live HealthTech radio show in the UK. 💡 Steve Roest is an incredible…
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🔥Hot off the back of HLTH Europe, we are back with the HealthTech Hour and I’m talking to one of the founders of Hurdle, Daniel Elías Martín Herranz…
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