Two Nobel laureates in the field of chemistry shooting the breeze about science stuff was one the fringe highlights at a recent gathering in Dublin of world-leading chemists. An exchange on the benefits of knowing enough, but not too much, gives just a flavour of a fascinating tete-a-tete.
The two in the spotlight vehemently agree it prompts a scientist to ask questions or challenge the established view – in short, it’s an essential ingredient for groundbreaking research. Appearing at the event hosted by the Royal Irish Academy were Prof David MacMillan, who won the Nobel Prize in 2021, and Prof Frances Arnold, who won in 2018. They were attending the ninth European Chemical Society Congress organised by the Institute of Chemistry of Ireland – its president Prof Pat Guiry chaired the chat.
Sometimes not learning something is good because then you invent something new, Arnold suggests. “I think that’s true,” MacMillian says. “It’s a weird blend between you wanting to know enough but you don’t want to know too much. If you know too much, you won’t try things, because we over-believe or we think we have more knowledge than we really do.”
Arnold quips: “I ‘m accused almost everyday of not knowing enough.” But she certainly realised she had opened up a new field of chemistry when her groundbreaking research emerged.
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Their discoveries have had far-reaching consequences on different frontiers, Guiry outlines, but both opened up the basic chemical process of catalysis to endless new possibilities. Catalysts are substances that increase rate of a chemical reaction.
MacMillan, who is based at Princeton University in the US, won the Nobel Prize in chemistry for asymmetric organocatalysis, a precise tool for constructing molecules. He shared the award with Ben List of the Max Planck Institute in Germany. They found revolutionary ways to design and build small organic molecules to drive chemical reactions. MacMillan is also a leader in photoredox catalysis, which uses light – ordinary, visible light – to break and rejoin atomic bonds, one electron at a time.
Organocatalysts, made from organic, carbon-based molecules, are greener than traditional metal catalysts, which tend to be rare and expensive – and they are often toxic, requiring safety gear to use. Instead, biodegradable and benign molecules are used to construct new drugs and materials in an open lab. The discovery’s impact is immeasurable, ranging across industrial applications to pharmaceuticals to everyday products such as clothing, shampoo and renewable fuels.
The day they explained “enantiomers”, MacMillan recalls, the avid soccer fan and undergraduate was watching a World Cup qualifier match between Scotland and Cyprus. His professor at the University of Glasgow reprimanded him, because enantiomers are important. Just how much that importance was appreciated became clear when he subsequently received the Nobel Prize for the ingenious way of building these types of molecules, which are identical but symmetrical – as if reflected in a mirror.
Some 20 years ago in the production of drugs or chemical products, metals or enzymes (large proteins such as enantiomers) were used as catalysts to accelerate chemical reactions. But metals can be contaminants while enzymes are very complex.
Enzymes act as biological catalysts by helping, for instance, to build some substances in the human body and to break others down. Their methods use only a small part of those proteins and have made chemistry less dangerous and more sustainable.
“It was something that seemed very simple but no one had thought of it before,” explains MacMillan – a classical case of science going in one direction, but other simpler paths not being pursued.
Arnold, who is based at Caltech in the US, won for “the directed evolution of enzymes”. This is a bioengineering method using random genetic mutations for creating new and better enzymes in the lab using the principles of evolution.
Directed evolution is used to make everything from biofuels to medicines. Enzymes created with the technique have replaced toxic chemicals in many industrial processes.
The duo may now be based in the lofty research centres of Princeton and Caltech, but their backgrounds are not what might be expected.
“I tried everything to stay out of chemistry,” Arnold says. Before going to college, she worked in a pizza parlour, and as a cocktail waitress and a taxi driver. She went on to study aerospace engineering and solar energy before diverting into chemistry.
This path gave hear a lot of confidence, “I think I was born overconfident and I kind of kept it as I went ... it gave me this wonderful power of letting criticism go in this ear and get out that ear. I’m very good at taking criticism and the pieces that are useful, and totally ignoring the rest.”
MacMillan was “a curious kid”, according to his father, a euphemism for strange, he suggests, rather than being nerdy. His brother, who studied physics, was the trailblazer, the first pupil from his school to go to university. His first job on graduating paid more than what his father was earning after 30 years as a steelworker. So his parents told their second son: “you’re going to university.”
He was terrible at physics but had to do organic chemistry in his second year, which was “fantastic, normal and reasonable”. He pivoted to chemistry and then was determined to go to America simply because he loved US sports and TV.
In his early years research meant having his hands stuck in a glove box for eight hours a day and questioning the approach. “It seemed like this was anti common sense. So that’s what started me down the path of thinking about using small organic to do catalysis.”
That thinking was common to both of them, Arnold suggests. “It was absolutely obvious to me that enzymes were going to rule the world. Just like you, it was obvious this would be a technology that was needed. We were both on the lunatic fringe!”
When she saw the first results of directing evolution, she realised these genetic mutations were happening where no one could explain them. “I could make a [brand new] field and be the best in the world. I knew it was going to solve problems that no one knows of.”
Winning the Nobel Prize was like suddenly being given a new job with people constantly seeking their views, while often being in the media limelight. For MacMillan it also brought an opportunity to do social good – he launched a successful Scottish scheme to help people under financial pressures stay in university.
Arnold is co-chair of the US president’s Council of Advisors on Science and Technology. “After 3½ years of that I’m pretty exhausted. But it’s very interesting to see how science influences policymaking, and to play a role in that ... it makes my head explode. Science is everywhere. Science is everything: climate change, extreme weather, patient safety, public health. You name it and the council is considering it.”
Inevitably, the conversation comes around to artificial intelligence, but again their views might not be as expected, and certainly not in the camp that says AI is an uncontrollable monster. When it comes to chemistry, MacMillan suggests, AI might not do a great job in generating answers, but might to an excellent job in raising questions; asking what kind of molecules can be used in new combinations that could prove to be extraordinarily useful and bring big benefits – providing purpose; directing the chemist to where best to concentrate efforts.
Arnold says: “Evolution is the most powerful design process ever invented, bar none. You can apply it to very different kinds of problems ... AI and machine learning will complement this, because [directed] evolution is perfectly designed for this.”
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