BIOGAMI: Rewriting protein “grammar” to stop neurodegenerative disease before it starts 

BIOmolecular Grammar for protein Aggregation Modulation and Intervention (BIOGAMI) is the latest ARPA-H program taking on the toughest health challenges facing Americans. BIOGAMI’s vision is to help eliminate neurodegenerative diseases by detecting and controlling the earliest stages of protein misfolding and clumping before lasting damage occurs. The program aims to “rewrite the molecular grammar” of proteins—the basic patterns and signals that guide how they behave—so they follow healthy pathways instead of disease-causing ones. If successful, the tools developed by BIOGAMI will halt Alzheimer’s disease and other brain disorders by finding and fixing problems with proteins very early—before they clump together and damage cells.  

Proteins are essential biomolecules in our cells that must fold into the correct shape to do their jobs properly. Many proteins have flexible segments, called intrinsically disordered regions, that can change shape and function in response to what is happening in the body.  When they follow the wrong cues, they can fold the wrong way or stick together, forming clumps (aggregates) that damage cells. This damage can lead to Alzheimer’s disease, ALS, some cancers, and other chronic and degenerative conditions. Aging, inherited risk, and environmental factors like toxins can all push proteins off course and cause them to misfold. 

Today, scientists do not have good tools to predict, prevent, or reverse these early misfolding and clumping events. Most current treatments target large protein clumps that appear late in disease. By that point, much of the damage is done, and it is very hard to restore normal function. A major challenge is that existing drugs cannot capture or influence these flexible proteins, so many are considered “undruggable.” BIOGAMI aims to change this by focusing on the very beginning of the misfolding process, especially in the brain and other vulnerable tissues. 

“BIOGAMI platform technologies could be applied over the next decade to novel therapeutics and drive success in the century-long battle against neurodegenerative disease,” said Alicia Jackson, Ph.D., ARPA-H Director. “This effort will establish American excellence in the way protein dysfunction is addressed for applications across a spectrum of diseases.”  

Through an Innovative Solutions Opening (ISO) solicitation, the program invites research proposals focused on decoding the “biomolecular grammar” of intrinsically disordered proteins, developing new ways to steer misfolded or aggregated proteins back to healthy states, and creating technologies to detect the earliest signs of protein misfolding and aggregation. By intervening at this stage, BIOGAMI aims to halt neurodegenerative and other chronic diseases before they fully take hold, rather than only treating symptoms after serious damage has occurred. 

“Disordered proteins are like sentences without punctuation—multiple meanings can be implied depending on how the reader pauses or places emphasis,” said BIOGAMI Program Manager Shannon Greene, Ph.D. “BIOGAMI intends to preserve the critical meaning of a protein’s sentence by applying punctuation and grammatical structure, essentially fixing protein misfolding before anything is published.” 

BIOGAMI will combine breakthroughs in protein science with powerful computing tools, including machine learning and artificial intelligence, to better understand and reshape this molecular grammar. ARPA-H expects that teams will bring together partners from biotech companies, universities, and other organizations, with expertise in biochemistry, biophysics, structural biology, neurodegenerative disease, cancer, and chronic illness. 

Learn more about BIOGAMI on its program page, including information about the solicitation and Proposers’ Day registration.