EAGER: Magnetothermal Control of Cell Fates and Function

The potential to guide cellular functions from a distance and direct the regeneration of aged or damaged cells and tissues will have broad impacts in biomedicine. Cells are the basic building blocks of life, and have incredible capacity; developing the ability to control cellular functions will enable rebuilding diseased and damaged tissues, replacing aged organs or directing cells to hunt and eliminate cancer.

As individuals, cells have tremendous capability, and cells also have a natural ability to work together such that with proper control of this team effort the abilities of cells can be amplified; think of all 100 million single cells of your liver working together to help you digest food, distribute nutrients to the body, store energy and purify your blood. The functions of cells are regulated by circuits comprised of genes and proteins that can be controlled with biological switches.

However, to date, a means of transferring a number of switches to cells and controlling them from a distance has not been described. This project seeks to develop biological remote controls with multiple switches that can be used to direct cells to perform functions and work together. These remote control modules that are called, “engineered organelles”, can be operated with magnetic fields.

With magnetically controlled engineered organelles, rapid flashes of magnetic fields can warm the engineered organelle and turn on or off biological switches that control the cells function. The switches are designed with multiplexing capability so multiple functions can be controlled remotely. Engineered organelles are similarly designed for controlling multiple biological functions within a cell and direct them to work together.

The multidisciplinary nature of the project offers unique training opportunities for the next generation of STEM researchers in the fields of bioengineering, physical sciences, synthetic biology and regenerative medicine. The research team invites students from underrepresented groups to participate in summer research via the successful ENSURE (EngiNeering Summer Undergraduate Research Experience) program at Michigan State University (MSU).

In addition, the team develops workshops on engineered biological remote controls for high school science teachers to enable them to update their knowledge and refresh their curricula with state-of-the-art research. To enhance public understanding and appreciation of what engineered organelles can accomplish, the research team participates in the MSU Science Festival which caters to the greater Lansing area.

Results from the project will be integrated into undergraduate course curricula and be incorporated into graduate courses in bioengineering and synthetic biology to teach the new principle of using engineered organelles to guide biology.

This project aims at mimicking endosymbiogenesis and modify prokaryotic cells to create engineered magnetoendosymbionts (eMEs) that can be controlled using alternating magnetic fields (AMF). This involves engineering iron particle-coated or iron-containing prokaryotes, magnetotactic bacteria (MTB), to act as magnetothermally regulated pseudo-organelles.

Magnetothermal control will activate eME to express mammalian transcription (txn) factors directed to host cell nuclei for controlling host gene expression. Genetic thermal switches will be engineered into MTB using optical reporter genes as a readout, and deliver reporters from eME in the cytoplasm to the nucleus of the host cell. The use of reporter genes will help guide development of eME that encode mammalian txn factors to enable reprogramming of differentiated macrophages into iPSCs and then into hepatocytes.

A chemically (mannose) regulated iPSC-generating operon will be engineered expressing Oct3/4, Sox2, KLF4, c-Myc, txn factors for cellular reprogramming and a thermally regulated hepatocyte-generating operon expressing txn factors HNF4A, HNF1A. FoxA1 and FoxA3. Once demonstrated in the EES the operons will be transferred to MTB and used these eMEs to program macrophages to iPSCs and then to hepatocytes with magnetothermal control.

This project is funded by the Systems and Synthetic Biology Cluster in the Division of Molecular and Cellular Biosciences and the Engineering Biology and Health Cluster in the Division of Chemical, Bioengineering, Environmental and Transport Systems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.