Biominerals in Health and Disease

Lead Research Organisation: University of Cambridge
Department Name: Veterinary Medicine

Abstract

Almost all biomedical research involves carbon-based (organic) molecules and yet we and other groups have shown that non-carbon based 'mineral' structures have unappreciated roles in supporting normal health and development. Moreover, we have found that by studying these mineral structures and function in biology we have new ideas on how to develop novel mineral-based therapeutics.. Much of our work concentrates on the digestive system and in understanding how our intestinal cells take up mineral structures and with what purpose. Our work integrates different disciplines, such as chemistry, cell biology, human nutrition and immunology, and we collaborate with many different scientists around the world. We then apply some of the lessons learned to other key medical research areas, such as the development of a mineral-based anti-cancer agent. Indeed we are very committed to translating our research findings for nutritional or therapeutic applications that will improve human health.

Specifically in this work we will describe:-

(a) How and why small mineral particles form naturally in the lumen of the intestine, and what their role is in acting as "cargo ships" that capture fragments of food and bacteria in this environment and then transport the cargo to cells of the intestinal immune system as a part of 'surveillance' for normal human health.

(b) Whether in Crohn's disease patients, the pathway described above is operating normally or not. And, if not, whether this may be secondary to the disease process or in fact carries a risk for the disease process to develop in the first place (i.e. cause or effect)?

(c) Whether engineered particles, to which we are all exposed via the diet or pills or personal care products, can hijack the pathway described above, lodge in intestinal cells and tip the balance between health and disease (notably Crohn's disease) in genetically susceptible individuals.

(d) Whether in fact the engineered particles to which we are exposed, as described in (c) get beyond the intestine and enter our blood circulation and therefore other tissues of the body. And if so, to what extent does this occur in healthy subjects and in those with Crohn's disease.

(e) Whether we can build mineral structures that will purposefully stimulate certain cell types for therapeutic benefit in diseases when the immune system needs a boost - such as in cancer.

Technical Summary

Biomedical research is dominated almost exclusively by interests in organic molecules. However, we and others are showing increasing evidence for large inorganic structures (typically nanominerals) being involved in healthy cell communication and signalling and not just normal storage and structure or ectopic pathology, for which they are well known.

Our mission is to identify mineral structures and their cellular interactions in biology to further our understanding of human health and disease and, where appropriate, to exploit lessons learned through the engineering of novel mineral analogues that may offer fresh treatment modalities in human disease. We have a clear focus on nanoparticulate mineral structures, especially in terms of their occurrence and handling in the gastrointestinal tract. Over the next four years' of research we intend to (i) better describe why there are endogenous nanomineral pathways in the gastrointestinal tract and how these facilitate cell sampling of luminal macromolecules, (ii) demonstrate to what extent engineered nanoparticles, to which we are increasingly exposed, hijack these pathways and are systemically absorbed in humans, (iii) delineate whether dysfunction in the cellular handling of endogenous or exogenous nanomineral underlies the cause of Crohn's disease and (iv) show whether engineered nanoparticles can be exploited to establish selective cell activation and thus have immunotherapeutic properties (e.g. for cancer treatments).

Planned Impact

Major potential beneficiaries of this work are as follows:-
a. Researchers studying gastrointestinal physiology and immunology, or nanotechnology, or particle science, or Crohn's disease or cancer.
b. Doctors looking for new angles in the cause and thus treatment of Crohn's disease or in the treatment of cancer.
c. Regulators and public health bodies aiming to better understand, and control, population exposure to persistent nanoparticles.
d. The population in terms of exposure to persistent oral nanoparticles.
e. Patients with Crohn's disease or cancer.

The above parties/stakeholders will benefit by the following mechanisms:-
a. Identity of new pathways for particle uptake in the gut.
b. Identity of new mechanisms for particles to carry bacterial and food fragments from the gut lumen to immune cells.
c. Knowledge of how these pathways/mechanisms described above could be exploited for therapeutic interventions.
d. Knowledge of what the systemic exposure to the population is for common persistent particles via the oral route and thus how this exposure can be better regulated.
e. Potential novel therapies for Crohn's disease or cancer.

Publications

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Hewitt RE (2017) Imaging flow cytometry assays for quantifying pigment grade titanium dioxide particle internalization and interactions with immune cells in whole blood. in Cytometry. Part A : the journal of the International Society for Analytical Cytology

 
Description CAPES PhD scholarship
Amount £163,881 (GBP)
Organisation Government of Brazil 
Department Coordination of Higher Education Personnel Training (CAPES)
Sector Public
Country Brazil
Start 10/2017 
End 09/2021
 
Description Analytical electron microscopy analysis (TEM, STEM, STEM-EDX) 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided synthetic and biological specimens for analysis and expertise on these samples.
Collaborator Contribution Analytical electron microscopy analysis and advice.
Impact Peer-reviewed publications: PMID 27478107, 26863624, 25751305
Start Year 2016
 
Description Intracellular processing of calcium phosphate nanoparticles in human health and in Crohn's Disease 
Organisation Open University
Country United Kingdom 
Sector Academic/University 
PI Contribution Financial contribution to a PhD studentship. Co-supervision of the PhD student. Access to research facility and expertise in calcium phosphate nanoparticles and Crohn's Disease.
Collaborator Contribution Experience and expertise in charactering intracellular calcium handling. Co-supervision of PhD student.
Impact None as yet.
Start Year 2017
 
Description Investigations assessing intestinal antigen transport in health and disease 
Organisation Linkoping University
Department Department of Clinical and Experimental Medicine
Country Sweden 
Sector Academic/University 
PI Contribution The research team will provide expertise for the processing, immunohistochemical staining and analyses of intestinal tissues and be responsible for the critical interpretation of the generated data.
Collaborator Contribution Linköping University is responsible for the sourcing, phenotyping, genotyping, coding and shipping of the study samples. Ussing chamber experiments will also draw on the experience and expertise of Linköping University. Linköping will be responsible for the critical interpretation of the generated data.
Impact No outputs as yet.
Start Year 2017
 
Description NanoSIMS and TOF-SIMS analyses of bacteria and gut tissues 
Organisation Chalmers University of Technology
Department Department of Biology and Biological Engineering
PI Contribution Provided biological specimens and advice for these samples.
Collaborator Contribution Provide access to their research facilities and contributed their time for these analyses.
Impact No output yet, however peer-review publications are in preparation.
Start Year 2018
 
Description NanoSIMS and TOF-SIMS analyses of bacteria and gut tissues 
Organisation Chalmers University of Technology
Department Department of Chemistry and Chemical Engineering
PI Contribution Provided biological specimens and advice for these samples.
Collaborator Contribution Provide access to their research facilities and contributed their time for these analyses.
Impact No output yet, however peer-review publications are in preparation.
Start Year 2018
 
Description Quantitative Immunohistochemistry through In Situ Cytometry: Enhancing Bio-Analysis and Data Reproducibility 
Organisation Swansea University
Department College of Engineering
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided tissue samples, access to research facility, methodology and advice on gut biology.
Collaborator Contribution Access to and continued development of In Situ Cytometry as a research tool for quantitative cell imaging.
Impact Publications pending. Submitted grants.
Start Year 2017
 
Description Quantitative Immunohistochemistry through In Situ Cytometry: Enhancing Bio-Analysis and Data Reproducibility 
Organisation University of Cambridge
Department Girton College
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided tissue samples, access to research facility, methodology and advice on gut biology.
Collaborator Contribution Access to and continued development of In Situ Cytometry as a research tool for quantitative cell imaging.
Impact Publications pending. Submitted grants.
Start Year 2017
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation Charing Cross Hospital
Country United Kingdom 
Sector Hospitals 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation Health and Safety Laboratory
Department Biological Monitoring
Country United Kingdom 
Sector Private 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation Laboratory of the Government Chemist (LGC) Ltd
Country United Kingdom 
Sector Private 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation National Institute of Scientific Research (INRS)
Country Canada 
Sector Academic/University 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation SAS Trace Element Centre
Country United Kingdom 
Sector Private 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016
 
Description The analysis of titanium in whole blood - an inter-laboratory comparison to determine the best practise 
Organisation University of Wales
Department Centre for Advanced Welsh and Celtic Studies
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided the blood samples for the inter-laboratory comparison of titanium levels in whole blood.
Collaborator Contribution Provided results of their analysis of titanium in the whole blood samples.
Impact A peer-reviewed paper.
Start Year 2016