Biological systems are complex adaptive systems where biological macromolecules (e.g., DNA, RNA, proteins, etc.) act in networks to give rise to complex biological functions. Evolutionary selection drove the need for organisms to be adaptable, resilient, and efficient in response to constantly changing environments and internal demands. In a world where survival often depends on rapid, coordinated responses to threats, resource scarcity, and other unpredictable environmental stresses, having a robust and flexible system is advantageous. Therefore, evolution favors dynamic, interconnected genetic and molecular networks. Genes do not express function in isolation, but rather the function of a gene is context-dependent on the network or networks in which the gene’s function is expressed. Each genetic interaction has the potential to modify the effects of other genetic interactions in the same network, creating harmonized but adaptable network topologies. The architecture of this network topology guides the flow of molecular signals, with feed-back and feed-forward loops and branching points. As signals travel through biological networks, they activate responses, adjust cellular states, and regulate the very tempo of biological rhythms. Each pathway, with its connections and intersections, creates a landscape where small changes can resonate widely, influencing the whole system. Together, these interactions form a complex and layered composition, a symphony of cellular behaviors and physiological traits. In other words, the whole of biological function is most certainly greater than the sum of its parts.
This systems-level view has long been postulated, observed, and formalized in the biological subdomains of “systems biology” and “network biology.” Over the last two decades, our tools for interrogating and mapping these systems' biologies have refined our understanding. Genome-wide association studies continue to identify genomic variants (and show no signs of slowing down) that have association with disease. It’s worth noting that the effect sizes are often small, and polygenic risk scores give further weight to the network hypothesis of small effects giving rise to diseases through accumulation of these small effects across networks. Genetic evidence for drug targets has meaningfully increased the probability of translational success for therapies that modulate that gene, with recent studies estimating 2.6x improved probability. We believe this probability still underestimates the effect, and will continue to grow as more associations are mapped in large, diverse human populations. Yet, there is still a gap. Drugs continue to fail clinical tests and/or can be quick to develop resistance mechanisms, limiting their ability to completely change the course of disease. And discovered loci for complex diseases fail to fully explain disease risk, presenting the case for missing heritability.
The growing wealth of human genetic studies and vast repositories of molecular data offer opportunities to elucidate more complete genetic network architectures underlying human disease. If effectively understood, we see a future of completely new drug targets and drug concepts. These approaches will be inherently multi-specific in nature, and affect disease processes at nodes that drive synergistic effects. This is Passkey Therapeutics’ mission, and we are excited to announce our investment as a founding investor and participant in the recently announced seed financing.
We’ve known Bruce Beutel, founder and CEO, for the better part of the last decade. He’s a biotech executive and operator that we are privileged to work alongside. He is equal parts ambitious and pragmatic, with big ideas and always a plan to reduce to practice. When Bruce first approached us about this concept almost two years ago, we were immediately intrigued. The concepts rang true to much of my (Joel’s) academic work on systems biology and multi-scale biology (e.g., 1,2,3,4,5), and we were excited to back a team passionate about finding this inherent network structure.
Alongside Bruce, he brings together an outstanding team that includes Will Chen, Soumya Ray, Peter Dandliker, Finola Moore, Robert Gentles. And of course, the broader team is a group of exceptional scientists from a multitude of disciplines. Passkey has an ambitious vision of the future, and one that will require this phenomenal early team that they’ve assembled.
Passkey is unlocking a novel approach to drug discovery that embraces the inherent complexity of disease biology, enabling the design of multi-functional medicines that offer new treatments for some of the most challenging diseases. We look forward to sharing more over the coming years.
