MRC Elsie Widdowson Laboratory

BioMineral Research

The Group’s philosophy is to galvanise the specialist analytical, synthetic and bio-assay expertises of its staff, students and collaborators, to enable the identification of novel ‘form and function’ in mammalian bio-minerals. We have a specific focus on nanominerals and the gastrointestinal tract and, therefore, additionally contribute to the rapidly emerging need of a greater understanding of dietary exposure to nanomaterials. In line with the MRC and EWL missions we actively seek to translate our discovery research through to patient and/or population health benefit, drawing upon the multidisciplinary skills of the Unit’s environment.

Key Achievements

(i) An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells (Powell, JJ, Thomas-McKay, E et al. Nat Nanotechnol 2015)

(ii) Demonstration of a specific failure in signalling in the nanomineral pathway in the Crohn’s disease gut (manuscript in preparation).

(iii) Discovery of a novel endocytic pathway for dietary iron absorption (Pereira DI, Mergler BI et al. PLoS One 2013)

(iv) Synthesis of a nano iron (III) hydroxide, that is absorbed though the above route, and is a potentially cheap, safe and efficacious supplement for iron deficiency anaemia (Powell JJ, Bruggraber SF et al. Naomedicine: Nanotechnology, Biology and Medicine 2014)

(v) Discovery, licencing and on-going co-development of a therapeutic oral phosphate binder that is entering Phase II clinical trials in end stage renal patients.

(vi) Discovery of a mammalian silicon transporter (manuscript in preparation).

Research Themes

  1. Nanoparticles of the gastrointestinal tract
  2. Novel Iron Therapeutics and Dietary Iron
  3. Silicon and health
  4. Synthetic Biominerals
  5. Trace element analysis specialism team

1. Nanoparticles of the gastrointestinal tract

This area of research focusses on dietary particles, especially exposure, uptake and handling of mineral nanoparticles in the human gastrointestinal tract1. Specific interests include (i) understanding the role of endogenously formed gastrointestinal nanoparticles in the trapping of gut luminal components for carriage of this cargo into gut tissue immune cells (a surveillance mechanism)2-4, (ii) investigating whether this nanomineral pathway differs in Crohn’s disease5, (iii) determining if and how exogenous dietary (e.g. aluminosilicates and titanium dioxide) particles might ‘hijack’ this route6-8, (iv) quantifying absorption of dietary particles systemically and (v) establishing the beneficial versus detrimental aspect of such particles9-13.

Key publications:

  1. Powell JJ, Faria N, Thomas-McKay E, Pele LC. Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J Autoimmun. 2010 May; 34(3):J226-33. doi: 10.1016/j.jaut.2009.11.006. Epub 2010 Jan 21.
  2. Powell, J.J., Thomas-McKay, E., Thoree, V., Robertson, J., Hewitt, R.E., Skepper, J.N., Brown, A., Hernandez-Garrido, J.C., Midgley, P.A., Gomez-Morilla, I., Grime, G.W., Kirkby, K.J., Mabbott, N.A., Donaldson, D.S., Williams, I.R., Rios, D., Girardin, S.E., Haas, C.T., Bruggraber, S.F., Laman, J.D., Tanriver, Y., Lombardi, G., Lechler, R., Thompson, R.P. & Pele, L.C. (2015) An endogenous nanomineral chaperones luminal antigen and peptidoglycan to intestinal immune cells Nat Nanotechnol. 2015 May;10(4):361-9. doi: 10.1038/nnano.2015.19.
  3. Laetitia C Pele, Emma Thomas-McKay, Carolin T Haas, Rachel E Hewitt, Jack Robertson, Jeremy Skepper, Andy Brown, Juan Carlos Hernandez-Garrido, Paul Midgley, Nuno Faria & Jonathan J Powell. Synthetic mimetics of endogenous intestinal calcium phosphate nanomineralSubmitted.
  4. Hewitt RE, Pele LC, Tremelling M, Metz A, Parkes M, Powell JJ. Immuno-inhibitory PD-L1 can be induced by a peptidoglycan/NOD2 mediated pathway in primary monocytic cells and is deficient in Crohn’s patients with homozygous NOD2 mutations. Clin Immunol. 2012 May; 143(2):162-9. doi: 10.1016/j.clim.2012.01.016. Epub 2012 Feb 8.
  5. Jack Robertson, Rachel E Hewitt, Carolin T Haas, Laetitia C Pele and Jonathan J Powell. Failure in the Nanomineral Pathway in Gut Immune Cells of Crohn’s Disease. In preparation.
  6. Thoree V, Skepper J, Deere H, Pele LC, Thompson RP, Powell JJ. Phenotype of exogenous microparticle-containing pigment cells of the human Peyer’s patch in inflamed and normal ileum. Inflamm Res. 2008 Aug;57(8):374-8. doi: 10.1007/s00011-007-7216.
  7. Powell JJ, Ainley CC, Harvey RS, Mason IM, Kendall MD, Sankey EA, Dhillon AP, Thompson RP. Characterisation of inorganic microparticles in pigment cells of human gut associated lymphoid tissue. Gut. 1996 Mar;38(3):390-5.
  8. Powell JJ, Harvey RS, Thompson RP. Microparticles in Crohn’s disease–has the dust settled? Gut. 1996 Aug;39(2):340-1.
  9. Powell JJ, Thoree V, Pele LC. Dietary microparticles and their impact on tolerance and immune responsiveness of the gastrointestinal tract. Br J Nutr. 2007 Oct;98 Suppl 1:S59-63. Review.
  10. Butler M, Boyle JJ, Powell JJ, Playford RJ, Ghosh S. Dietary microparticles implicated in Crohn’s disease can impair macrophage phagocytic activity and act as adjuvants in the presence of bacterial stimuli. Inflamm Res. 2007 Sep;56(9):353-61.
  11. Lomer MC, Thompson RP, Powell JJ. Fine and ultrafine particles of the diet: influence on the mucosal immune response and association with Crohn’s disease. Proc Nutr Soc. 2002 Feb;61(1):123-30.
  12. Lomer MC, Harvey RS, Evans SM, Thompson RP, Powell JJ. Efficacy and tolerability of a low microparticle diet in a double blind, randomized, pilot study in Crohn’s disease. Eur J Gastroenterol Hepatol. 2001 Feb;13(2):101-6.
  13. Powell JJ, Harvey RS, Ashwood P, Wolstencroft R, Gershwin ME, Thompson RP. Immune potentiation of ultrafine dietary particles in normal subjects and patients with inflammatory bowel disease. J Autoimmun. 2000 Feb;14(1):99-105.

2. Novel Iron Therapeutics and Dietary Iron

The theme focuses on the understanding of the chemistry of dietary iron in the gastrointestinal lumen. It has been observed that digestion of dietary ferric iron leads to formation of nano iron hydroxides in the gut lumen and that the materials also have strong features of the ferritin core1. This work led to the development of a synthetic mimetic2 that is expected to be safer in the gut than ‘soluble iron’ but equally bioavailable.

Regarding soluble iron in the gut, our work in ulcerative colitis suggests that dietary non-haem iron, in particular that derived from iron-fortified foods, may impact negatively on the quality of life of patients during disease relapse3,4.

Key publications:

  1. Powell, J. J. et al. A nano-disperse ferritin-core mimetic that efficiently corrects anaemia without luminal iron redox activity. Nanomedicine: Nanotechnology, Biology and Medicine, doi:10.1016/j.nano.2013.12.011 (2014).
  2. Pereira, D. I. A. et al. Nanoparticulate iron(III) oxo-hydroxide delivers safe iron that is well absorbed and utilised in humans. Nanomedicine: Nanotechnology, Biology and Medicine, doi:10.1016/j.nano.2014.06.012 (2014).
  3. Aslam, M. F. et al. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. Faseb J, doi:10.1096/fj.14-251520 (2014).
  4. Pereira, D. I. et al. Caco-2 Cell Acquisition of Dietary Iron(III) Invokes a Nanoparticulate Endocytic Pathway. PLoS One 8, e81250, doi:10.1371/journal.pone.0081250.

3. Silicon and health

The BMR group has made substantial inroads into understanding dietary silicon (orthosilicic acid, Si(OH)4) in an effort to inform upon the biological role of silicon and dietary silicon requirements. The intakes and sources of dietary silicon, their bioavailability and metabolism have been reported on1-4. The potential role of dietary silicon in bone and connective tissue health has been a focus of much of the recent work5-8. Higher intakes of dietary silicon have been associated with higher bone mineral density (BMD) in pre-menopausal women and men4. In post-menopausal women this is also true but only in those who were taking or had previously taken hormone replacement therapy, suggesting there may be an interaction between dietary silicon and hormone (e.g. estradiol) status8.

In particular, our research interest has extended into polymeric/colloidal silica (i.e. silica nanoparticles) and their potential role in health and disease (see insert below).

Key publications:

  1. Powell JJ, McNaughton SA, Jugdaohsingh R, Anderson SH, Dear J, Khot F, Mowatt L, Gleason KL, Sykes M, Thompson RPH, Bolton-Smith C, Hodson MJ: A provisional database for the silicon content of foods in the United Kingdom. Br J Nutr 2005;94:804–812.
  2. Jugdaohsingh R, Anderson SH, Tucker KL, Elliott H, Kiel DP, Thompson RP, Powell JJ: Dietary silicon intake and absorption. Am J Clin Nutr 2002;75:887–893.
  3. Sripanyakorn S, Jugdaohsingh R, Dissayabutr W, Anderson SHC, Thompson RPT, Powell JJ. The comparative absorption of silicon from different foods and food supplements. Br J Nutr 2009;102:825-34.
  4. Jugdaohsingh R, Hui M, Anderson SHC, Kinrade SD, Powell JJ. The silicon supplement monomethylsilanetriol is safe and increases the body pool of silicon in healthy pre-menopausal women. Nutr Metab (Lond) 2013;10:37.
  5. Jugdaohsingh R, Tucker KL, Qiao N, Cupples LA, Kiel DP, Powell JJ. Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort. J Bone Miner Res 2004, 19:297-307.
  6. Reffitt DM, Ogston N, Jugdaohsingh R, Cheung HF, Evans BA, Thompson RP, Powell JJ, Hampson GN. Orthosilicic acid stimulates collagen type 1 synthesis and osteoblastic differentiation in human osteoblast-like cells in vitro. Bone. 2003;32:127–35.
  7. Jugdaohsingh R. Silicon and bone health. J Nutr Health Ageing 2007;11:99-110.
  8. Macdonald HM, Hardcastle AE, Jugdaohsingh R, Reid DM, Powell JJ. Dietary silicon interacts with oestrogen to influence bone health: Evidence from the Aberdeen Prospective Osteoporosis Screening Study. Bone 2012, 50:681-687.

Silica nanoparticles: not necessarily a bad thing!

In previous work Powell and Jugdaohsingh of the BioMineral Research group identified a small silica polymer, which was termed “oligomeric silica”, with at least a million times greater affinity for aluminium ions than monomeric silica (orthosilicic acid)1. This oligomeric silica could be stabilised in solution by binding trace amounts of aluminium. Subsequent work showed that oligomeric silica could prevent the uptake of (potentially toxic) aluminium ions from the human gastrointestinal tract2. More recent characterisation showed this oligomeric silica to be a small nanoparticle of approximately 2.4 nm in diameter, that binds aluminium with Al:Si ratio of 2-3:1 and competes effectively with human transferrin for aluminium binding3. The biological relevance of these findings can be found in certain multicellular organisms, where the cellular uptake of aluminium and subsequent aluminium-induced toxicity leads to the rapid mobilization and accumulation of dissolved silica in distinct intracellular compartments (lysosomes)4, thereby neutralising the aluminium through the formation of intracellular, non-toxic aluminosilicates5 of the same size and Al:Si ratio described above. Whether this detoxification mechanism is more widespread and could even exist in higher life forms including humans, is as yet unknown.

  1. Taylor PD, Jugdaohsingh R, Powell JJ. Soluble silica with high affinity for aluminum under physiological and natural conditions. J Am Chem Soc 1997;119: 8852-8856.
  2. Jugdaohsingh R, Reffitt DM, Oldham C, Day JP, Fifield LK et al.Oligomeric but not monomeric silica prevents aluminum absorption in humans. Am J Clin Nutr 2000;71: 944-949.
  3. Jugdaohsingh R, Brown A, Dietzel M, Powell JJ. High-aluminium-affinity silica is a nanoparticle that seeds secondary aluminosilicate formation. PLoS ONE 2013;8:e84397.
  4. Desouky M, Jugdaohsingh R, McCrohan CR, White KN, Powell JJ. Aluminum-dependent regulation of intracellular silicon in the aquatic invertebrate Lymnaea stagnalis. Proc Natl Acad Sci U S A 2002;99:3394-3399.
  5. White KN, Ejim AI, Walton RC, Brown AP, Jugdaohsingh R et al. Avoidance of aluminum toxicity in freshwater snails involves intracellular silicon−aluminum biointeraction. Environ Sci Technol 2008;42:189-194.

4. Synthetic Biominerals

The relationship between the structure and physicochemical properties of inorganic materials (minerals) in biological systems- with a focus on the gastrointestinal environment is the focus of this work. Inspired by such biological processes, biomimetics are developed using physiologically occurring or dietary ligands (e.g. dietary carboxylates) to modify the structural composition of minerals.  These synthetic biominerals can be studied in a range of conditions and environments furthering our knowledge in areas as diverse as antigen delivery by nanominerals to bio-utilisation of naturally occurring iron oxides1. The tailorability and inherent safety of these minerals makes them suitable for a range of clinical and nutritional applications, and has resulted in several patents2,3.

Key publications:

  1. Powell JJ, Bruggraber SF, Faria N, Poots LK, Hondow N, Pennycook TJ, Latunde-Dada GO, Simpson RJ, Brown AP, Pereira DI. A nano-disperse ferritin-core mimetic that efficiently corrects anaemia without luminal iron redox activity. Nanomedicine: Nanotechnology, Biology and Medicine 2014. doi: 10.1016/j.nano.2013.12.011.
  2. Powell JJ; Bruggraber SFA; Faria NJR; Pereira DIA. Ligand modified poly oxo-hydroxy metal ion materials, their uses and processes for their preparation (16th December 2009). United Kingdom Grant number: 2451713.
  3. Powell JJ and Faria NJR. Phosphate binding materials and their uses (22th December 2010). United Kingdom Grant number: 2462374.

5. Trace element analysis specialism team

Drawing on the many years of expertise in the Group surrounding trace element analysis using Inductively Coupled Plasma Spectrometry techniques, namely ICP-OES and ICP-MS, a specialised team has been created within BMR that interfaces with the dominant research focus of the group in ‘nanominerals’, as well as with wider EWL and externally-led research1,2.

An example of a significant development, borne out of the BMR group’s interests in silicate structures, has been the creation of a method for tracking silicon isotopes (28Si and 29Si) within biological samples3. As a particularly demanding technical challenge, this development ensures that silicate-related research of the BMR group is founded on a secure analytical footing but, also, has attracted external collaborative interest in other areas of nutrition and health.

Maximising future potential has also been a key driver in the implementation of a cutting-edge single particle ICP-MS analysis for the determination of nanoparticle size and concentration in biological tissues and food matrices.

External pilot projects have similarly acted as platforms for method development and the initiation of longer-term collaborative relationships. Analysis focuses on elements with a recognised role in nutrition and health and includes the trace elements as well as the ‘macro’ elements. In addition, trace elements implicated in toxicity rather than health benefit are also regularly studied within the facility.

trace elements periodic table

The trace element analysis team is also part of the unit wide team that performs the laboratory tests on samples collected within the National Diet and Nutrition Survey (NDNS) rolling program. For example the team is currently analysing blood plasma for Selenium and Zinc and measuring urinary Iodine levels. Please go to the NDNS page for further information about this program and its goals.

The team can offer advise that ranges from technical help to best practise guidance, sample collection and data interpretation. Moreover, training and support of users is a central feature of the facility’s mission and, as such, plays host to students and early career researchers from within EWL, the University of Cambridge as well as more widely from other research institutions throughout the world.

Key publications:

  1. Bruggraber SFA, Chapman TPE, Thane CW, Olson A, Jugdaohsingh R, Powell JJ: A re-analysis of the iron content of plant-based foods in the United Kingdom. Br J Nutr 2012, 108:2221-2228.
  2. Faria N, Winship PD, Weiss DJ, Coles BJ, Schoenberg R, Hutchinson C, Pereira DIA, Powell JJ. Development of DRC-ICP-MS methodology for the rapid determination of 58Fe erythrocyte incorporation in human iron absorption studies. Journal of Analytical Atomic Spectrometry 2011, 26:1648-1652.
  3. Koller D, Ratcliffe S, Jugdaohsingh R, Powell JJ and Bruggraber SFA. Optimisation of operative conditions for the determination of Silicon concentrations in in vitro and ex vivo biological matrices by DRC-ICP-MS. European Winter Conference on Plasma Spectrochemistry, Krakow, Poland, February 2013.