About This Project
We are going to make tools that can express proteins in any organism, quickly and cheaply. We can do this by hacking the ribosome with an Internal Ribosome Entry Site (IRES). Because ribosomes are insanely conserved across organisms, and because IRES bind to the ribosome, we can find and engineer IRES that can operate as General Translational Units: genetic circuits that are functional across phylogenies.
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What is the context of this research?
Engineering non-model organisms holds great potential to benefit the climate. Yet, it's difficult and costly. Imagine you’ve engineered a pathway that enables mycorrhizal fungi to store 25% more carbon in soil. If every acre of agricultural land increases carbon sequestration by this amount, you save the world. But this fungi only symbioses with peas! To engineer more species, you need to: sequence the transcriptome ($10k, ≥3 months), annotate it ($5k-15k, ≥1 mo), characterize genetic elements of interest ($20k, ≥3 mo), build organism specific circuits ($5k, ≥2 mo), develop transformation methods ($10k-20k, 6 mo), and validate expression ($5k, ≥1 mo), for just one more species of fungi, this is a lot of work (~$75k material cost & ≥1 year)!
What is the significance of this project?
Characterizing non model organism-specific genetic parts, like promoters and terminators, is a huge investment. General tools are great. For example: Green Fluorescent Protein (GFP) glows green in nearly any organism you throw it into and significantly lowered the barrier for reporter assays, this revolutionized molecular biology. Cas9 cuts in almost every organism you throw it into and revolutionized genetic engineering. We can cut time and money costs to non-model organism characterization & engineering by screening engineered Internal Ribosome Entry Sites (IRES) that operate as clade-general translational units. One genetic circuit will be able to express a metabolic pathway in hundreds of species. IRES seem to have unexplored potential to be another incredible general tool.
What are the goals of the project?
The goal is to build a library of engineered IRES that bind directly to the ribosome and screen them in many clades of life. This library will be cloned into plasmids for diverse organisms and we will mail aliquots of the library to as many non-model organism experts — who are willing to transform it and screen for functionality — as possible. As phylogenetic trees are often constructed from ribosome sequence divergence, and IRES bind to the ribosome, we may be able to computationally predict which IRES will function in which branches of life. If successful in our goal, a scientist will be able to use one IRES-based genetic cassette to express her new and improved RuBisCO in hundreds of different plant species.
Dec 31, 2024
Meet the Team
A while ago, I spent most of my time learning about CRISPR and protein engineering.
I was scientifically raised by the founding team of Scribe Therapeutics, where I worked on Self Inactivating AAVs, among other projects.
Then I became an independent researcher. I learned a lot of things the hard way, as I explored metabolic engineering at an Invisible College.
I am helping discover the enzymatic pathway for Mescaline and 5-MeO DMT with the Alexander Shulgin Research Institute.
I want to be imagining and creating general tools for engineering biology full time.
Breaking all the rules here... I know this isn't a *protein* engineering project (IRES are functional RNA elements), but I think it is still in the spirit and feeding the goals of this grant's mission.
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