Exploring the Development of Proteins from Life’s Beginnings
Looking hundreds of millions of years into a protein’s past with AlphaFold to learn about the beginnings of life itself. Pedro Beltrao is a geneticist at ETH Zurich in Switzerland, and he shares his AlphaFold story.
As a scientist, I’m interested in our differences. More specifically, I’m focused on how those differences occur. While many researchers investigate how changes in DNA lead to variations in traits—such as predispositions to certain diseases or differences in height—our study aims to understand the mechanisms behind these changes. Ultimately, we aspire to develop a model that predicts how a person might change or what traits they may exhibit if they possess a mutation at a specific location in their DNA. There is still much work to be done to achieve that.
The first step involves identifying which mutations in DNA do not result in any observable change. To do this, one must explore whether these mutations impact proteins or not. Since proteins collaborate to perform various functions, it is essential to understand how they interact and how these functions manifest, which can vary significantly between different cell types such as brain cells, kidney cells, or skin cells. Additionally, the unique characteristics of each organ introduce further complexities to this investigation. There are numerous factors to consider, from a single mutation to its effects on a protein, a group of proteins, the tissue itself, and ultimately how the entire organism behaves.
Before AlphaFold, we had knowledge of some protein structures for both individual proteins and complexes—around 5% of the interacting pairs had a known structure. However, this landscape is changing rapidly. We now have an incredible opportunity to explore the evolution of proteins and delve into the origins of life. This aspect of our research is particularly fascinating. Traditionally, to investigate evolutionary history, we compare sequences of proteins across different species, which allows us to infer what those sequences may have looked like in the past.
Without structural data on proteins, we can only trace history so far before uncertainty arises regarding their appearance hundreds of millions of years ago. AlphaFold enables us to compare the three-dimensional shapes of proteins, preserving crucial evolutionary signals over extended timeframes since the 3D structures remain more stable than the sequences that encode them. Consequently, we can now explore the evolution of proteins across longer spans in the evolutionary timeline, making it more feasible to infer characteristics of the earliest ancestral cells by analyzing proteins that date back hundreds of millions of years.
In the scientific community, we often observe the gradual accumulation of incremental changes where new technologies, methods, or systems evolve over time. Yet, we also experience transformative moments. AlphaFold undoubtedly represents such a transformative period. It provides us with an incredible chance to deepen our understanding of human biology and the very origins of life itself.
