Directed evolution in synthetic biology: an interview with Professor Frances Arnold

This blog was written by Daniela Quaglia, PhD, MBA

At the beginning of my scientific career, I was captivated by the ability of organic chemists to synthesize molecules.  I soon realised, however, that the effort involved was often incredible, especially when you wanted to have control over the stereochemistry of complex molecules. Luckily for me, I also learned that there was another way to make these molecules, using Nature’s machinery. Nature has been synthesizing molecules and materials for billions of years, and Darwinian evolution has produced an immense array of beautiful biocatalysts (enzymes) that can assemble breathtaking structures. Scientists working in the fields of biocatalysis and synthetic biology exploit the power of these natural catalysts to find greener and easier routes for chemical synthesis. The problem is that, even though Nature has gifted us with many biocatalysts, they are not always suitable for exactly what we would like them to do. Hence, the importance of being able to engineer them, evolve their functions to match what we need.

If today we are able to ‘easily’ engineer enzymes in the laboratory, we owe this in large part to the work of Professor Frances Arnold: the mother of directed evolution. Prof. Arnold is an engineer and a biochemist, and a Dickinson Professor at the California Institute of Technology (Caltech). Author of over 200 peer-reviewed articles, she holds an impressive list of awards, and she recently was invited to Université de Montréal, where she presented two lectures under the prestigious Roger-Barré program.

I could not miss this unique opportunity to interview her for our blog. It is a pleasure to share with our synthetic biology community her inspiring insight about protein engineering in synthetic biology.

Q&A with Professor Arnold:

Daniela: Could you help our readers to better understand what is the impact of enzyme engineering on the field of synthetic biology?

Prof. Arnold: One of the major reasons for advancing synthetic biology and the engineering of biological systems is that they ‘make things’, they do chemistry! When you are controlling biological systems, you are controlling how they make molecules and materials, you are manipulating their remarkable ability to convert energy and matter into new forms that might be useful to us. If you are attracted to biology for its ability to make things, then it is all about enzymes—to me, enzymes are at the center of synthetic biology. Now, you can limit yourself to the catalysts that you find out in the biological world (and there is plenty that you can do with that), but if you want to go beyond and either make natural products very effectively, or make whole new products, then you have to be able to engineer the catalysts that do it. 

Daniela: What are the tools that you are developing from the engineering point of view that you believe will mostly impact the synthetic biology field?

Prof. Arnold: Clearly the most useful is the ability to tune function using directed evolution. Being able to optimize the functional properties of a system by accumulating beneficial mutations is very powerful, and it has been used to solve many problems in my lab and others. We can also combine evolution with more ‘rational’ design methods to create powerful, hybrid engineering tools [As an example of this latter, I suggest one of the latest paper of the Arnold’s group in which the authors developed a software, called CSR-SALAD, that can be used to engineer the cofactor preference of oxidoreductase enzymes].

Daniela: What’s the biggest current scientific barrier that needs to be cracked for getting to the scientific dream you envision, namely to engineer biological systems to make what we want in an easy and quick way?

Prof. Arnold: There are many hurdles to making synthetic biology quick and easy. A lot of synthetic biology is trial and error, and this is why so many platform companies have invested in high-throughput systems to speed up the design-test-build cycle. I am not sure that they have invested in real evolution systems, however Evolution is a lot more than high throughput testing–the key idea of evolution is the accumulation of beneficial mutations through iterations of genetic diversification and screening. We are recognizing more and more that we really can’t predict details, and details matter! Surprises will come up and the ability to rapidly search through the most productive sequences to make the most productive searches is extremely valuable. Biology is the product of evolution, so why not use evolution to engineer new biology?

The other thing that we want to be able to do is to better understand what functions are possible. If I recombine genes from different sources, what will the progeny look like? What can they do that’s not possible now? Or, alternatively, if I have a specific function I want, what’s the best strategy for getting there? This we don’t know. We are all novices when it comes to composing new enzymes. 

Daniela: You worked on so many enzymes/proteins: do you have a favourite one? And why?

Prof. Arnold: Cytochrome P450—what an enzyme! It does things that not even the best (human) chemists can do. Also, Nature has taken it in so many different directions. It is a beautiful example of the evolvability of the biological world, its ability to innovate.

Daniela: I believe in the power of versatility. You are both an engineer and a biochemist/synthetic biology scientist. Do you reckon that being able to learn from different fields and different perspectives is somehow key for innovation?

Prof. Arnold: The ability to pick ideas or methods from different fields and to cross boundaries has been critical for our success. I attribute that success to the versatility of thinking of the young people who come to my lab and who refuse to be defined by a traditional discipline. I also attribute it to the academic structure at Caltech which allows any student to choose to work for any professor. I can attract PhD students and postdocs from different fields. 

I think that major breakthroughs in science, and certainly synthetic biology, have come in large part from recombination of different fields. Of course, not all recombinations are useful, but a lot of great inventions come when people make connections between different fields.

Daniela: You were the first female scientist to win the Millennium Technology Prize. This is kind of sad because it is symptom that a sort of barrier still exists and needs to fall in the scientific world. How do we overcome this? How do we get women to pursue a career and succeed in science?

Prof. Arnold: Do keep in mind that a lot of these prizes are for achievements that can take a lifetime to show their impacts. I was only the ninth woman ever hired at Caltech, but I have been there for more than 30 years.  I have had time to build my portfolio, so to speak. Many great young women are now in academic positions, and I predict that in the next 30 years those women will be winning the technology prizes. We are fully capable, and more and more young women are tackling technological challenges. If you look at the fields of chemistry, engineering and synthetic biology, there are quite a few women moving to the top. Nonetheless, we need to support each other in all aspects of our careers.

Enzyme engineering is offering us the opportunity to produce the biocatalysts of the future, to make any chemistry in a simpler and more sustainable way. Prof. Arnold is showing us that Nature can be pushed further than ever envisaged before: for instance, by teaching bacteria to make silicon-carbon bonds, as in her recent work published in Science. I hope that this interview will inspire many synthetic biologists to consider engineering not only metabolic pathways, but also the enzymes that are the very protagonists of those pathways. There is no limit to what reactions we can envisage for our engineered enzymes other than our chemical creativity!

You can follow Prof. Arnold on twitter @francesarnold 

Images/pictures in this post were kindly provided by Prof. Arnold