Circles, a few weeks ago, would only remind me of geometry. I would not have expected a “circle” to describe the shape of a life changing nanoparticles, circular tandem repeat proteins (cTRPs), researched by the Bradley, Stoddard, and Riddell labs.
Right: from Bradley and Stoddard Labs and article “Self-assembling, donut-shaped nanoparticles form novel platform for development of new biomolecules”
Left: from Dr. Colin Correnti and article “Circular tandem repeat protein scaffold binds a variety of functional cargo”
The two diagrams above show the cTRP molecule, as both a 3-D model and under a microscope. The cTRP is an engineered protein nanoparticle that can bind and interact with a variety of proteins, including those that can be used in immunology, by triggering a cell response or activity.
The research explores protein design: the cTRPs act as protein scaffolds, docking sites for proteins that collect signals to relay to a cell’s nucleus. Likewise, the cTRPs will allow for methodical organization of multiple protein “cargos”, that can activate a cell response. The labs seek to find more protein cargos and effective ways to attach them to cTRP molecules, to be used for immunotherapies and other medical uses in the human body.
cTRPs are self-assembling: after attaching molecular “staples”, the nanoparticles snapped themselves into rings. These “staples” are disulfide linkages, and according to Dr. Barry Stoddard and Dr. Phil Bradley, are chosen using a 3-D model of cTRP molecule. Identified amino acid positions are close to each other and replaced with cysteines (amino acid with sulfur), so that links would form and act as a “staple” to achieve a circular shape. This allows cTRPs to be extremely flexible in use, they can be adapted to attach to almost any protein by using two to six protein modules (parts of a protein that function independently and found commonly across different proteins) in the cTRP molecule that can be stapled together.
cTRPs would be able to reduce cost and increase production of protein therapies. In substitution of antibodies (limited to two targets), cTRP could carry several cargos used in immunology. T-cell growth was achieved with the binding of CD28, a receptor that encourages T-cell growth, to cTRP. Additionally, cTRP genes were encoded onto the gene for the MHC protein to produce a MHC tetramer, which binds a pathogen’s protein for T-cell recognition and is normally costly to produce. Cells were easily able to produce tetrameric cTRP-MHC modules with the cTRP component. Dr. Stoddard and Bradley predicted that the use of cTRP for production of engineered T-cells would be able to be used across all cancers.
The labs have had success in connecting many cargos, except “(1) for enzymes that degrade plastics (2) a U1A protein that binds an RNA molecule and (3) a domain from human antibody that breaks down bacterial biofilms”, for reasons unknown (Stoddard). Dr. Bradley added that when attaching the cargo in the circular cTRP, the proximity of parts of a protein helps, and if there is difficulty, the labs would try inserting the cargo in the beginning or end of the cTRP, instead of within the loop.
I was interested in the interdisciplinary collaboration of the research, with computational and structural biology. Dr. Bradley, who was interested in marine biology as a child, combined math and biology in college to pursue computational biology. This led to his involvement in the development of Rosetta, a software that predicts how proteins will fold into their structure based on its structure. Dr. Stoddard grew immersed in chemistry and biology in high school and continued this passion throughout college and ultimately, his career. Dr. Stoddard’s lab is involved greatly in exploring the structure of enzymatic catalysts, modeling, and engineering of protein and enzyme scaffolds.
While learning about the research, I was reminded of the discussion of biomedical ethics I experienced in VECR. The trolley problems were addressed: where in one setting, you had the option to pull a lever, the other, the choice to push someone in order to stop a trolley if wanted. The sudden change in situations made me realize that, in the circumstance itself, my selections would most likely be met with hesitation. Similarly, after discussion with the group’s selections for the priority recipients of a COVID-19 vaccine, I grew aware of my own biases in my decisions, which were heavily based on age and swayed my choices. The principles of bioethics, especially that of justice and critical perspectives, caused me to reevaluate my previous selection once again. The constant discussion of such topics during my time in VECR encouraged me to further my personal education on unequal structures in current society and healthcare systems. As such, in face of developing therapies (like the cTRP), I felt it essential to create and continue open platforms for discussions of education and distribution of such treatments to all.
In this illustration, I tried to represent what I believe how the advancement of scientific research and bioethics should play out: where discussion can allow for collaboration of advancement of science. Equal education of immunology and vaccines through social media can save lives; nature around us can give insight for treatments. The more diverse ideas and opinions become, the more it is essential that people face each other and their thoughts. As such, I tried to represent the figures and ideas in a circle, and in the midst of the “melting” lens of a magnifying glass.
In the midst of all the “new” normals of 2020, this summer has been eye-opening for me and has been full of thoughts and ideas for hope for the future and establishing an “honest” and “just” normal. Thank you!
Sources Referenced:
Brault, M. “Circular tandem repeat protein scaffold binds a variety of functional cargo”. Fred Hutch, 15 Jun. 2020, https://www.fredhutch.org/en/news/spotlight/2020/06/crd_correnti_
natstructmolbio.html. Accessed 11 Aug. 2020.
Richards, Sabrina. “Self-assembling, donut-shaped nanoparticles form novel platform for development of new biomolecules”. Fred Hutch, 24 Mar. 2020, https://www.fredhutch.org/en/
news/center-news/2020/03/bradley-stoddard-tandem-repeat-proteins.html. Accessed 11 Aug. 2020.
Tompa, Rachel. “Building a better protein in the hope of better therapies”. Fred Hutch, 15 Dec. 2016, https://www.fredhutch.org/en/news/center-news/2015/12/building-better-protein-donut-better-therapies.html. Accessed 11 Aug. 2020.