Program Manager: Chris Wintersinger

The macromolecular additive manufacturing program is building a system to create engineered structures from modular nanoscale building blocks made of proteins and other materials. This capability could enable us to create artificial antibodies with tunable properties and biologically impossible large protein structures with uses that are currently hard to imagine.

Multi-protein structures are responsible for many biological functions — everything from life-saving antibodies to the ribosomes that make proteins themselves. Currently, the only structures with multiple distinct proteins that we can build are mostly limited to tweaks on evolved structures made using living cells. This approach is slow and restricted to designs that evolution happened to cover. Biology is able to create powerful machines made from dozens of distinct proteins — such as ribosomes, flagella, and ATP synthases — and we cannot make anything rivaling this complexity.

To address that gap, this program is building a platform to create structures from protein building blocks. The system will place building blocks one-at-a-time using infrastructure inspired from solid support chemistry. The sequence of these blocks would enable product designers to engineer the ultimate shape of the larger structure. This system could enable new therapeutics, enzymatic reactions, and over the long term, heterogenous nanoscale systems. For example:

• Artificial "antibodies" made from dozens of nanoscale parts, where mixing and matching protein and non-protein parts would make therapies that encode multistep mechanisms to sense and destroy disease.
• Vaccines composed from multiple parts of infectious agents and other entities that trigger the immune system, providing robust immunity to a broad spectrum of harmful viruses and bacteria.
• Rapid prototyping of complex, cell-free factories to synthesize chemicals using multiple co-localized enzymes, where tens of different enzymes are integrated on inert protein scaffolds.
• Demonstrating “positional chemistry,” which has been a difficult benchmark in advanced nanotechnology that remains to be achieved; the system could be adapted so that chemical bonds between the building blocks are formed only in the presence of a protein “tool.”

Scalability of solid support assembly is one of the program’s biggest challenges. Reconfigurable polymers from chemistry and advances in scaling of solid supports from the oligonucleotide industry could boost the product scale by a hundred or thousand fold, such that it would be on par with the amount of protein that is produced by cells in an equivalent volume industrial bioreactor.

The first 2.5 years of this program will test and optimize building blocks, and demonstrate that they can be assembled block-by-block into multi-protein structures with up to one hundred distinct parts. The latter 2.5 years of the program will refine the solid supports to boost the product scale towards what is achievable with cell manufacturing, with the interface controlling the reagent flow improved so that users can reconfigure the system to make new multi-protein structures as easily switching around pieces of a toy Lego set.

Please read the detailed roadmap of the program here.