Frances Hamilton Arnold | PAS Academician

Innovation by evolution: bringing new chemistry to life

I am a scientist/engineer who has spent her career observing and manipulating the evolution of proteins, breeding them in the laboratory to exhibit new traits. The scientist in me is delighted by what I learn and create using the most powerful design process, evolution. The engineer in me pushes me to implement that new insight into how biology innovates in order to solve problems for people. Thus I have worked on everything from converting biomass to jet fuel to replacing toxic insecticides with sex pheromones. I have explored and exploited the power of evolution with an eye to helping us live sustainably on this planet so that we can share it with people and with the other species on which we depend.

Nature is surely the best chemist of all time: her enzymes are responsible for all the marvelous and ingenious chemistry of the biological world. I want to make new versions, useful to us. I also want to explore the universe of chemistry that nature has never explored, at least as far as we know. Chemistry that humans need, and indeed in some cases invented. Chemistry that remains to be invented.

What an enzyme does is determined by its amino acid sequence, as encoded in DNA. The newest tools of molecular biology are remarkable. We can read DNA – an entire human genome can be sequenced for a few hundred dollars. We can write DNA – you can email your gene sequence to your favorite supplier, and you will get the actual DNA back in the mail. We can edit DNA: we can now go into a living cell and make changes to its DNA using tools like CRISPR-Cas. But what we struggle to do is compose it. To me, the code of life is like a Beethoven symphony, intricate and stunningly beautiful. Even composing the sequence of a new and useful enzyme is something humans have not yet learned how to do.

To sidestep our profound ignorance of how sequence encodes an enzyme function I turned to evolution, the simple process – indeed the algorithm – of mutation and natural selection that has given rise to the incredible diversity of the biological world, including the enzymes. This marvelous process, which works at all scales from molecules to ecosystems, has no counterpart in the world of human engineering.

Where could we go with evolution? There is a universe of possible proteins, the vast majority of which nature has never had a chance, or a reason, to explore. From the beginning of life to today, nature has made and tested only the tiniest fraction of the universe of possible proteins, and she has kept those relevant to the survival and fitness of the organism that makes it. But out in the universe of possibilities, there surely exist proteins whose functions can cure cancer, or solve the energy crisis. Perhaps even cure death and taxes… or at least taxes.

It may interest you to ponder the vastness of this protein space in order to appreciate the power of evolution. How does one discover a useful protein in the infinitude of possible proteins, a set larger by many orders of magnitude than all the particles in the universe? In his fascinating short story, the Library of Babel, Jorge Luis Borges described a collection of all possible books that can be assembled from an alphabet of letters. Most texts in Borges’ library are gibberish, and his despairing librarians, for all their lifelong efforts, cannot locate a single meaningful sentence, much less a complete story.

Similarly, most protein sequences encode nothing we would recognize as meaningful. Unlike Borges’ librarians, however, we are surrounded by proteins with meaningful stories. They can be scraped from the bottom of my shoe, captured from the air I breathe, or extracted from a database. These are the products of billions of years of work performed by mutation and natural selection. And evolution continues to create new ones. Thus, I decided to start my exploration by using this work of evolution, the existing functional proteins.

The challenge is to discover new sequences that deliver useful properties on a scale of weeks, rather than millennia. Many years ago now, I used the emerging tools of molecular biology to practice evolution in the test tube, exploring new enzymes by taking nature’s simplest search strategy. By making random mutations at a low level and screening those mutated proteins for desired changes, we could nudge enzymes over just a few generations into new niches. Many people have now used that approach to make the enzymes in your laundry detergent, reagents for DNA sequences, enzymes that reduce pollution from livestock, and enzymes that are used to manufacture everything from paper to pharmaceuticals.

Even more exciting, however, is that we can use evolution not just to improve the chemistry nature has already discovered, but also to innovate. We can create enzymes for entirely new chemistry, not known in the biological world. Nature has done that countless times, after all, from the origin of life to today. So why not use evolution to explore possible futures of the chemistry of the biological world?

I will share one simple but fun example – enzymes that construct silicon-carbon bonds. Silicon is the second most abundant element on our planet, but as far as we know, the biological world assembles no Si-C bonds. Humans do it. We make billions of tons of products that contain these bonds – including probably 50 products in this room, in your earbuds, hair gels, caulks, sealants, paints. These materials are all made by chemistry invented by humans, using increasingly expensive platinum catalysts whose mining tremendously degrades the environment.

Starting with a chemical hypothesis, we tested simple proteins containing an iron atom in a heme, and discovered that a protein from a hot salty pool in Iceland could catalyze a simple carbene transfer reaction to make a new Si-C bond. Now this is not its natural function, but the protein, a cytochrome c, catalyzes the reaction when given the right reagents, which are not found in nature. In other words, the ability to do this chemistry is a ‘promiscuous’ activity of a protein that already exists. This chemical promiscuity is the fuel for evolution. We then evolved it in the laboratory so that the new enzymes does this chemistry more precisely and much more efficiently than any human-made catalyst.

I present this example because it illustrates beautifully how rapidly nature can innovate, using the diversity of functions and genetic materials that already exist in order to discover and evolve new functions. Novelty and adaptation to a changing world comes right out of what is already there!

This demonstration that biology can make such bonds surprised and delighted the world. It opened people’s minds about what biology can do, and what it can learn to do. A sensational story from Science magazine with a headline mentioning silicon-based life helped send this news all around the world. We did not try to make silicon-based life in this work, but this question interests many and sparks wonder. We want to know whether life can be based on something other than what we already know. Our work merely showed that, given the right environment and starting materials, nature can quickly adapt to make entirely new bonds and materials.

I hope you will appreciate the wonder, and power, of evolution. Evolution has not stopped and will continue to innovate, and it will continue to create new chemistry. We can now explore possible futures of chemistry using nature’s powerful design process, and starting from what has already been created.

I also want to share my vision of the future of chemistry, where we will be able to genetically encode new and important transformations and perform them in microbes, the chemical factories of the future. Why do this? I do it because nature’s chemistry is clean and efficient, and because nature is a master of using renewable resources as a source of chemical feedstocks – think of sunlight and carbon dioxide. We need to do this for a sustainable future.

I took on a new job, almost two years ago now, as co-chair of President Biden’s Council of Advisors on Science and Technology (PCAST). I got the call at a very dark time, December 2020, the deepest pit of the pandemic. Hospitals were overwhelmed, we had no vaccine and little in the way of reliable treatments. We had just finished four years with a President who dismissed science.

I took on this job, because I believe that our highest responsibility, in each generation, is to preserve our fragile planet; prepare for the future; and pass on a better world. I will share a few words I used when my appointment to PCAST was announced by the then President-elect, in January 2021.

Science-based decision-making has always been our most powerful tool for meeting that responsibility – perhaps never more so than today. In a moment of torrential divisions, science offers us a common shelter of facts and truth – within which we can begin to come together and, in time, begin to heal.

Science is not the cold solving of problems. It is a warm and beautiful exploration of the unknown – an expression of human curiosity that propels us forward, and allows us to fulfill our responsibilities.

The moment we fail to nurture it, we resign ourselves to living in the past and lose the chance to guide the future.

When we put science back to work for the benefit of all people – revitalizing our economy, fueling our climate response, broadening our perspective as we rebuild around greater equity and opportunity, we are making a society worth passing on to our children and our grandchildren.