Let’s look 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. He shares his AlphaFold story.
As a scientist, I am interested in our differences.
More specifically, I am interested in how these differences arise. While many people are working on how changes in DNA lead to changes in our characteristics – for example, predisposition to certain diseases, or simply why some people are taller than others – our research are trying to understand why this happens.
Ultimately, what we would like to have is a model that tells us exactly how a person will change, or what traits they will have, if they carry a mutation in a particular place in their DNA.
There is a long way to go to build this.
The first step is to find out which mutations in the DNA do not create any changes. To do this, we have to ask ourselves: does this have an impact on proteins or not? Next, since proteins work together to perform functions, we need to know how it works and how these functions arise. This can mean different things depending on whether it’s a brain cell, a kidney cell, or a skin cell. Of course, each organ is also different. There are many progressions and variables to understanding, from a single mutation to a protein, a group of proteins, the cellular tissue itself, and then determining the behavior of the organism as a whole.
Before AlphaFold, we had protein structures for individual proteins and complexes – probably about 5% of interacting pairs had a known structure, for example. Today, this is changing rapidly. Additionally, we now have an exciting opportunity to study the evolution of proteins that give rise to life.
This part of our research seems particularly fascinating to me. When we want to go back in time to observe evolution, we usually do it by comparing sequences between proteins from different species. By doing so, we can try to guess what this sequence looked like in the evolutionary past.
Without protein structures, we can only go so far back in time: there comes a point where we lose confidence in how things looked hundreds of millions of years ago. By using AlphaFold and comparing the three-dimensional shape of proteins, it retains the signal for an extended period of time because the 3D structure of proteins is retained longer than the sequence that encodes that shape.
As a result, we can now trace the evolution of proteins over longer periods of evolution and more likely infer what the first ancestral cell looked like by looking at what proteins looked like hundreds of millions of years in the past .
Often in science there are these accumulations of incremental change, where new technologies, methods, or systems accumulate over time or evolve slowly. And every now and then there are moments of transformation. There is no doubt that AlphaFold has sparked a period of transformation. It’s incredibly exciting. We now have the opportunity to learn much more about human biology and the origins of life itself.