Two scientists win chemistry Nobel for discovering a new way to construct molecules, speeding up drug development

Scientists Benjamin List and David MacMillan won the Nobel Prize in chemistry Wednesday for discovering a new way to construct molecules. By allowing chemical reactions to happen faster, with fewer steps, their technique, known as asymmetric organocatalysis, has been instrumental in drug development and has allowed chemistry to become more energy efficient and thus “greener.”

It’s all about catalysts. These are substances that speed up the rate of a chemical reaction without themselves being consumed as part of the final product. Traditionally, catalysts were either metals or enzymes. But as members of the Nobel Committee for Chemistry pointed out in a press conference on Wednesday morning in Stockholm, all of that changed around 2000, when List — now a director at the Max Planck Institute for Coal Research — and MacMillan — a distinguished university professor of chemistry at Princeton — independently helped develop a way to use small organic molecules as catalysts, which could more efficiently forge together the building blocks that make up compounds.

“When I did this experiment, I thought maybe it’s a stupid idea or maybe somebody has tried it already,” said List, when he was reached by phone at the press conference. It was only when it worked that he realized how big this discovery could potentially be.

One of the challenges in building molecules is that, like our hands, they can be non-identical mirror images of each other. The “left-hand” version of a molecule can have a different effect on the human body than the “right-hand” version; the building blocks might be identical, but their architectural orientation changes their physiological effect. The difference between the smell of orange and the smell of lemon, for instance, is simply a question of the “handedness” of the molecule.

Before the early 2000s, it wasn’t unheard of for certain drugs to include both the left-handed and right-handed versions of a molecule — even though one half might not actually be beneficial, and might potentially have side effects, Florence Wagner, associate director of the center for the development of therapeutics at the Broad Institute, told STAT. “If you think about a patient taking a pill, half of it is useless,” she said.

Now, though, that’s very rare. “Thanks to this particular discovery and other discoveries in the world of asymmetric chemistry,” Wagner said, “we are able to control those reactions so we are able to get one more specific molecule.”

A chemist can very precisely forge a molecule with the intended “handedness” using a metal or an enzyme as a catalyst, but it can be a complex proposition.

Inside our bodies, enzymes drive chemical reactions all the time. But as molecules go, enzymes are hulking and intricate. They can be expensive and hard to keep in the right shape throughout an experiment. “It requires more art, more technique, in order to carry the reaction out,” explained H. N. Cheng, president of the American Chemical Society, in an interview.

Likewise, metals pose certain challenges, too. They can be rare and pricey — and toxic to boot. They might end up as waste products once an experiment is done. Plus, some easily react with common molecules, making them hard to use in an industrial lab.

“At the end of the day, if you can take a simple organic molecule that is widespread, readily available, cheap, nontoxic and perform a transformation, it’s golden, right?” said Stellios Arseniyadis, associate professor of organic chemistry at Queen Mary University of London. That doesn’t mean this technique has replaced those using metals or enzymes. “It’s not like, ‘Cool, we’ve got organocatalysis, we’re only going to do organocatalysis.’ This is a complementary tool.”

This might not seem all that scintillating, as scientific discoveries go. To a chemist, though, it’s now hard to imagine the field without this. “It’s almost like if you have a toolbox that is missing a screwdriver, if you don’t have that, there’s a lot of things you cannot do,” said Wagner.

“This changed our everyday,” said Arseniyadis, adding that there were other important players in the field, too. “The discovery of organocatalysis, is by no means because of Ben List and David MacMillan, but in determining what the field has become, these guys are huge protagonists.”

“If I were … an astronomer, I can only study nature, I can only take observations of stars, I cannot change them,” Cheng said. “In chemistry, I can change things, I can synthesize molecules, I can customize molecules, I can modify molecules. That’s the exciting part, being able to manipulate nature. That’s why I think, for chemists, this is exciting.”

List and MacMillan — both born in 1968, the former in Germany, the latter in the U.K. — will share 10 million Swedish kronor, or about $1.35 million. Their names are added to a list of chemistry Nobel winners that includes 188 people, only seven of whom are women.

Many Nobel watchers had had their money on the scientists behind mRNA vaccines — a technique that had shifted the course of the pandemic and allowed in-person press conferences to take place at all. But as committee member Pernilla Wittung Stafshede put it at the press conference, “This is an extremely important topic we’re thinking about, but there will be more years, more Nobel Prizes.”

This story has been updated with background and comment on the winning research.