Determining the metabolic and molecular mechanisms to enhance magnetosome biomanufacturing

Today's economy relies to a large extent on the petrochemical industries that provide us with fuels, chemicals and materials that are used by our society. The petroleum-based sectors are worth around £50bn to the UK economy each year. However, this is not sustainable due to the negative impact of net carbon emissions on the environment. The UK is committed to move to a net zero carbon economy by 2050 and this means that we need to develop alternative processes to replace petroleum.

Bio-technologies therefore offer a huge potential to impact on the bioeconomy to mitigate climate change through the development of greener, cleaner manufacturing processes and new products that benefit the society through the use of living organisms.

There exist a family of microorganisms called magnetotactic bacteria (MTB) that are well known because they can make tiny crystals of iron called magnetosomes that allow them to function like a compass, and point to the earth's magnetic north pole. Magnetosomes are "nanomagnets" that can be used as an innovative alternative to traditional chemical magnetic nanoparticles (MNPs) because of their advantageous and unique properties. Their applications include for example, cancer treatment, MRI contrast agents and metal capturing. Therefore, magnetosomes have the potential to become the next generation of biological MNPs produced using environmentally friendly routes.

However, future widespread applications of magnetosomes will, to a large extend, depend on the challenging development of intensified high-yielding biomanufacturing. We can use the MTB model such as Magnetospirillum gryphiswaldense (Mgryph) to address this challenge.

We have previously developed a methodology to produce and characterise magnetosomes and have recently discovered that the nutritional requirements of Mgryph are significantly different when grown in the presence or limitation of air. Importantly, we do not yet understand the biological mechanisms by which magnetosome production in Mgryph can be improved. This information is essential to develop optimised biomanufacturing and realise the full potential of magnetosomes for further application studies and commercialisation.

Using my solid background in the MTB arena, I am uniquely positioned to address the question of "What are the underlying mechanisms impacting on MTB growth and magnetosome formation?" In this project, we will use Mgryph as a MTB model to determine how molecular and metabolic mechanisms impact on growth and magnetosome formation.

First, we will characterise the compounds (metabolites) that are key to Mgryph metabolism. We will alter the expression of genes that are related to those compounds and evaluate how these alterations affect Mgryph growth and ability to form magnetosomes. We will also study how iron molecules are transported into Mgryph cells and establish the correlation with magnetosome formation. Our preliminary data shows that both, Mgryph metabolism and the presence of iron inside cells within the same population, presents significant variations. We aim now to further understand the reasons behind our observations and establish links with growth and the formation of magnetosomes. Lastly, we will improve the production of magnetosomes in experiments that resemble industrial settings, that is in bioreactors. We will achieve this by combining the modification of components in the growth media, the use of genetically modified Mgryph and, by developing new production strategies.

Together, this knowledge will enable us to enhance the production of magnetosomes, hence increasing their availability for further biomanufacturing and application studies. We will make magnetosomes available to academics and companies interested in their use. This is an essential stage to unlock their full potential as a biotechnology and biomedicine product thus, addressing challenges in health, materials production and sustainability.

The use of biological systems such as the model Magnetotactic Bacteria Magnetospirillum gryphiswaldense (Mgryph) to produce magnetic nanoparticles, namely magnetosomes, offers a great potential for the development of biotechnology and nanomedicine applications such as, contrast agents for MRI, drug delivery, cancer therapy and metal recovery.

Magnetosomes are an attractive alternative to commercially available synthetic magnetic nanoparticles due to their exquisite properties: they are ferrimagnetic; have a narrow size distribution; are wrapped in a phospholipid bilayer membrane containing a unique set of specific proteins, preventing aggregation; and can be functionalized through chemical or genetic modification, the latter allowing one-step manufacture.

We have recently developed a fermentation strategy for magnetosome production, and developed high throughput methods for their characterisation. However, yields are lower than chemical synthesis of magnetic nanoparticles. Determining the underlying biological mechanisms emerges as a route to unlock efficient magnetosome biomanufacturing. In this project, we will elucidate the metabolic and transcriptomic mechanisms that regulate Mgryph growth and magnetosome formation. By using metabolomics we will be able to describe the links of cell metabolism with growth and magnetosome formation. Using qRT-PCR to characterise the expression of genes in the central metabolism will help us to identify targets for metabolic engineering. Determining the iron uptake dynamics using single cell technologies and high-resolution microscopy will enable to establish the correlation with magnetosome formation. We will integrate our findings to optimise magnetosome production.

This proposal represents a novel strategy to develop bio-based nanomaterials by targeting the underlying biological mechanisms in biomanufacturing. This study has translational relevance for human health & well-being, the bioeconomy and societal impact.