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Imaging and Control of Engineered Cells using Magnetic Fields


Ramesh, Pradeep (2019) Imaging and Control of Engineered Cells using Magnetic Fields. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/KY00-7Y74.


Making cells magnetic is a long-standing goal of synthetic biology, aiming to enable the separation of cells from complex biological samples and their non-invasive visualization in vivo using Magnetic Resonance Imaging (MRI). Previous efforts towards this goal, focused on engineering cells to biomineralize superparamagnetic or ferromagnetic iron oxides, have largely been unsuccessful due to the stringent required chemical conditions. In this thesis, we introduce an alternative approach to making cells magnetic, focusing on biochemically maximizing cellular paramagnetism. Here, we show that a novel genetic construct combining the functions of ferroxidation and iron-chelation enables engineered bacteria to accumulate iron in 'ultraparamagnetic' macromolecular complexes, which subsequently allows for these cells to be trapped using strong magnetic field gradients and imaged using MRI in vitro and in vivo. We characterize the properties of these cells and complexes using magnetometry, an array of spectroscopic techniques, biochemical assays, and computational modeling to elucidate the unique mechanisms and implications of this 'ultraparamagnetic' concept.

In addition to making cells magnetic, remote control of cellular localization in deep tissue is another long-standing goal of synthetic biology. Such an ability to non-invasively direct cells to sites of interest will not only improve therapeutic outcomes by minimizing off-target activity, but more broadly enable new research on complex cellular communities, such as the gut microbiome, in living animals. Given their deep penetrance through tissues, magnetic fields are ideally suited for facilitating non-invasive targeting of cells; however, the rapid decay of magnetic flux density from its source currently limits the depths to which magnetic targeting can be employed to within 1-2 mm from the surface. Here, we demonstrate a new approach wherein the retention of orally-administered and synthetically magnetized cell-like-particles is selectively enhanced within the murine intestinal tract to depths of up to 13 mm from the surface. Our cellular localization assisted by magnetic particles (CLAMP) strategy can potentially be generalized to any cell (bacterial, mammalian) or drug-containing nanoparticle of interest, and can be combined with existing non-invasive imaging modalities thereby facilitating remote environmental sensing at sites of interest.

Finally, while magnetic fields in MRI scanners are widely used today to safely and non-invasively image anatomical structures in living animals, much of the image contrast in MRI is the result of microscale magnetic-field variations in tissues. However, the connection between these microscopic patterns and the appearance of macroscopic MR images has not been the subject of direct experimental studies due to a lack of methods to map microscopic fields in biological samples under ambient conditions. Here, we optically probed magnetic fields in mammalian cells and tissues with submicron resolution and nanotesla sensitivity using nitrogen-vacancy (NV) diamond magnetometry and combined these measurements with simulations of nuclear-spin precession to predict the corresponding MRI contrast. Additionally, we demonstrate the broad utility of this technology for imaging an in vitro model of cellular iron uptake, as well as imaging histological samples from a mouse model of hepatic iron overload. Taken together, our approach bridges a fundamental intellectual gap between a macroscopic MRI voxel and its microscopic constituents.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:MRI, Synthetic Biology, Biomagnetism, NV Magnetometry, Magnetic Capture
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Bioengineering
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Shapiro, Mikhail G.
Thesis Committee:
  • Baltimore, David L. (chair)
  • Phillips, Robert B.
  • Newman, Dianne K.
  • Orphan, Victoria J.
  • Shapiro, Mikhail G.
Defense Date:17 May 2019
Non-Caltech Author Email:pramesh.cfh11 (AT)
Funding AgencyGrant Number
National Science Foundation Graduate Research FellowshipUNSPECIFIED
Caltech Center for Environmental and Microbial InteractionsUNSPECIFIED
W.M. Keck FoundationUNSPECIFIED
Pew Charitable TrustsUNSPECIFIED
Packard FoundationUNSPECIFIED
Record Number:CaltechTHESIS:06052019-181520170
Persistent URL:
Related URLs:
URLURL TypeDescription partially adapted for Chapter 2 adapted for Chapter 5
Ramesh, Pradeep0000-0001-6243-8145
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:11693
Deposited By: Pradeep Ramesh
Deposited On:06 Jun 2019 22:55
Last Modified:04 Oct 2019 00:26

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