William DeGrado: «If we really understand life, then we really understand proteins»

William DeGrado (California, 1955) is one of the most influential chemists of recent decades, thanks to his contributions to protein research. After graduating in chemistry from Kalamazoo College in Michigan in 1978 and receiving his PhD in organic chemistry from the University of Chicago in 1981, DeGrado began his career as a researcher at the multinational chemical company DuPont. After spending a few years at the University of Pennsylvania, he relocated his laboratory to the Department of Pharmaceutical Chemistry at the University of California, San Francisco (UCSF).

Last summer, he was awarded an honorary doctorate by the University of Valencia. During this event, we discussed his career, the challenges that chemistry andde novoprotein design will hopefully overcome in the near future, and the current state of the international scientific community in light of the recent cuts to scientific funding announced by the US government.

Proteins are key molecules for developing life on Earth. How would you explain the relevance of proteins in human cells, but also in other living cells?

It is amazing to see the adaptability of life and hence of the proteins that rely on life or the life that relies on the proteins. From the Arctic to hot springs, we see cells living everywhere and they can only do that because they can adapt to such extreme environments. We can learn about a lot about these enzymes and proteins from extreme environments, and I think that will ultimately help us think about how to make chemical processes a lot greener.

In a way, proteins have been marvelous tools to handle all the chemistry of life. And the repertoire of chemical groups that the proteins contain is limited. What is the nature of the proteins so that they can cover all the chemistry needed in life?

It is truly remarkable that proteins fold. There are simply linear chains of amino acids. Every type of a protein has a different amino acid sequence. For example, a hemoglobin protein will bind oxygen and bring that to your tissues. Others will break down your food and make it available as nutrients to you. GLP (glucagon-like peptide) agonists make you skinny and endorphins make you happy. So, we have so many different proteins with so many different functions, but they all depend on being able to adopt a unique secondary structure and tertiary structure. They have really complex structures that they fold into and it is this ability to adopt many different conformations and really squeeze small molecules and large molecules into crevices and holes that drives their remarkable properties.

You trained as a chemist. How did you become interested in studying proteins?

Well, as a kid, I always loved to build things. And then I became interested in chemistry. It just seemed like a perfect match that I would use my knowledge of chemistry to build new things, for two reasons. One is a fundamental understanding of life around us. If we really understand life, then we really understand proteins. And if we really understand proteins, then we should really be able to design them from the bottom up. This is sort of the Feynman principle. Also, by designing them, we can make them as simple as needed for function, but not simpler. That is Einstein’s dictum. So, we are really trying to obtain a fundamental understanding of how all the interactions between all of the atoms contribute to their function and to their shapes. Now, once we have achieved this understanding, we can start to design proteins that will do very useful things both in medicine and for the Earth.

The Feynman principle you mentioned ways that what we cannot create, we do not understand. So, if we want to understand really how proteins work, to understand how cells work and organisms live, we should be able to create them. Was it that exactly what encouraged you to enter the field of protein design?

It was precisely that mindset that drove me. I was also really inspired by engineers. We learned to fly, and we did not have to learn how to make a bird. We needed to understand the principles that would allow us to fly. And that thinking really came to bear on the very, very nanoscale as we started to think about proteins.

Just 50 years ago, it was only a dream that we could understand how proteins folded to adopt their final structure in a precise way. You have played a key role in making this possible. How did we progress from just considering this to be possible to achieving what we can do nowadays?

I was a very early adopter, but there are now many main actors in the field. In the early 1980s, I became interested in whether we could design proteins from first principles. And the first proteins that we designed were very simple in their structures, but they could already do some interesting things. And then, as computers got faster, we could make them more and more complex because we could model all the atoms and interatomic interactions. And then, as we started to invent new algorithms, and most recently AI, we have been able to move further and further to greater complexity, greater functionality. And that trend is just moving exponentially now.

The 2024 Nobel Prize in Chemistry was awarded for protein prediction and design. Many people in the field thought you should have been among the laureates. I would be interested to hear your thoughts on the Nobel Prize itself and what it represents for you and the field of protein design.

It is wonderful really to see David Baker and the others recognized in this field that we have all created, recognized at the highest level. And I think it represents in a really tangible way, the potential for improving human life. That is the whole point of the Nobel Prize. I think they recognized very deep contributions to computation, particularly AI.

To what extent can we use the design of new proteins to solve real-world problems such as new pandemics and climate crises?

I am certain that we will be able to use protein design principles to make enzymes that break down PET (poly-ethylene terephthalate) bottles. We are already making great progress in that area with traditional methods of directed evolution. But having computational methods will definitely speed up that progress. I think that we will be able to bind and detoxify a lot of toxins that we have created in the environment from our chemical industry. We all love the fact that we have plastics and carpets that are synthetic; even my shoes, everything. But it comes with a huge price for our planet. So, I think, one, we will learn to deal with existing products. But two, I think we will be able to think about how we can start to design products in a much more environmentally conscious manner. For in human health, it is hard to say… the sky is the limit, I think. We have already seen this explosion in ability to treat disease with antibodies. However, antibody drugs are very effective, but very expensive. So, if we can make much smaller proteins that can be produced to scale for pennies, and we get rid of the cold supply chain issues, then we might really be able to make an impact. I think we will.

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