“Catalysts are almost like magic,” Nobel Laureate chemist Benjamin List told me during a candid interview on a particularly cold afternoon in Berlin.

“Because they make chemical reactions happen, but they are not being used up while the chemical reaction occurs. And that means like a tool, like a hammer or any other tool, you can repeatedly use it again and again and again, millions of times.”

It’s hard to imagine modern civilization without catalysis. According to a 2015 estimate, catalysis contributes 35% of the world’s GDP. Catalysts are substances that speed up chemical reactions without being consumed. They are the magic wands of chemistry, making difficult reactions happen easily and efficiently.

Catalysts are the backbone of numerous industrial processes. The Haber-Bosch process, for instance, feeds the world. It synthesizes ammonia from nitrogen and hydrogen, a reaction crucial for producing fertilizers. Without catalysts, this reaction would require impractical conditions of temperature and pressure, making mass production of fertilizers, and consequently food production, unfeasible.

In the energy sector, catalysts are no less pivotal. They are key in refining crude oil into gasoline, diesel, and other fuels. They also enable the production of biofuels and play a crucial role in emerging sustainable energy technologies, such as hydrogen fuel cells. Without catalysts, our energy landscape would be vastly different, less efficient, and more polluting.

Catalysts are also integral to the production of many everyday items. Plastics, for instance, owe their existence to catalytic processes. The same goes for synthetic fibers used in clothing, detergents that clean more effectively, and even the pharmaceuticals that keep us healthy.

You get the picture: catalysts are a big deal. Yet they’re still not perfect.

Traditionally, until Benjamin List’s groundbreaking research, catalysts have been metal-based or inorganic. These include platinum in catalytic converters or nickel in hydrogenation reactions. While effective, traditional catalysts pose environmental and economic challenges. The use of precious metals contributes to their high cost and raises sustainability concerns. Additionally, their disposal can lead to environmental pollution.

Green Chemistry

Organocatalysts offer several advantages over traditional catalysts. They are generally non-toxic, environmentally benign, and can operate under milder conditions. This reduces the energy requirements and environmental footprint of chemical processes, aligning with the principles of green chemistry.

“The catalyst that we became famous for is proline. It’s an amino acid that occurs in our own bodies. It occurs in plants and chicken feathers. In fact, it used to be made from chicken feathers in the past by extracting it. It’s edible — I ate it in my talk today for fun! It’s more environmentally friendly. It’s sustainable. Metals are ‘endangered’. There’s only a certain amount of palladium on this planet,” List, currently the head of the Max-Planck-Institut für Kohlenforschung in Germany, told ZME Science.

The development of asymmetric organocatalysis, which started in the early 2000s, marked a significant shift, moving away from metals and embracing organic molecules to drive chemical reactions. It’s genuinely an entirely new field in chemistry now.

However, this journey was one rife with many challenges, including hard roadblocks placed in the way by List’s colleagues. Scientists thought organic catalysts were simply impossible to use. You’d have to be mad to try — this was sort of the thinking at the time.

“Chemists were convinced that in their chemical catalyst, you would always need heavy metals.”

“But if you look into nature, the enzymes, these are the catalysts of life in plants, in animals, in humans. And they catalyze all sorts of important chemical reactions and very efficiently so. And sometimes they come with a metal inside, but the majority of all enzymes are metal free.”

“So, for me, it was like, if enzymes can do this, we should also be able to use organic molecules as catalysts. I was convinced it must be possible, even though I was a bit nervous because at the time when I started in 1999, to my knowledge, nobody was working in this area. I mean, literally nobody.”

Skepticism and backlash

In the late 1990s, the scientific community was skeptical, to say the least, about the potential of organic molecules in catalysis. List faced doubt and discouragement, even as he embarked on his tenure track at the prestigious Scripps Research Institute in the US. With limited funding and support, he ventured into a field that many deemed infeasible.

“People would tell me, ‘Yeah, but organic catalysts, they don’t bind efficiently to substrates. And that’s why it doesn’t work. You need a metal or an enzyme.’ But these are sort of just fantasies we’re developing that have no real basis because we know that organic molecules react with each other. That has been known for 200 years. It’s kind of fascinating.”

But List’s conviction, rooted in the understanding of nature’s own catalysts — enzymes, which most often function without any metals — spurred him on.

Take photosynthesis, for instance, which uses light energy and enzymes to transform carbon dioxide, water, and minerals into oxygen and energy-rich carbon compounds like sugar. In one simple chemical transformation, photosynthesis gives us the oxygen we breathe and the food we eat. Everything in this reaction is elegant. The chemical products are extremely complex, yet the entire process is incredibly efficient. Photosynthesis is the most important chemical reaction in the universe from our human perspective, yet it doesn’t use any metal catalyst.

Enzymes are not only paramount to photosynthesis. They govern all biological reactions in our bodies. At the same time, enzymes are virtually chemical catalysts. List, who studied these biological phenomena, became convinced that organic catalysts were possible. After all, nature had done it billions of years ago.

His persistence paid off when his experiments with proline yielded successful results, mimicking the effects of the aldolase enzyme. These asymmetric organocatalyzers bind to the reacting molecules, forming reactive intermediates. These intermediates are more reactive than the substrates alone.

The key is that the organic catalyst is chiral — a term in chemistry that refers to a property where a molecule or a structure cannot be superimposed on its mirror image, similar to how our left and right hands are mirror images but not identical. So, the organic catalysts have a ‘handedness’ — they are asymmetrical. When they interact with the substrates, they transfer this handedness, effectively controlling the direction and outcome of the chemical reaction. This ability to direct the reaction is crucial for creating molecules with desired properties and functions, especially when working with pharmaceuticals where the ‘handedness’ of a molecule can determine its effectiveness or safety.

This triumph is a testament to his dedication and vision, quickly dispelling the skepticism that once clouded organocatalysis. Later, in 2021, the call from Stockholm came when he was informed that he would be awarded the Nobel Prize in Chemistry that year. List shared the prize with David MacMillan from Princeton University, who independently made his own organocatalyst from modified phenylalanine. The two never knew about each other’s work but remarkably arrived at similar results.

Alone and ignored

List faced doubts and career-ending discouragement along this difficult path until the very last moment when his results convinced even the most ardent naysayers.

“To be honest, I was pretty alone. This was the biggest challenge, this feeling of being alone. I mean, I was given a nice chance, I should be honest. I was a tenure track assistant professor at one of the top places in the US and therefore in the world, Scripps Research Institute. But I had very little funding. I had support for one postdoc and one technician. And at the time, they were not there yet. So, I was alone in the lab.”

“Everybody I suggested this idea to was skeptical. The people at Scripps said ‘This is not going to work. Inherently, there’s not enough reactivity.’ I was also applying here in Germany as a group leader. And the professor there, who was considered the best organic chemist in Germany at the time, said ‘You can come here. You’re obviously qualified. However, do not work with these organic molecules. This is not going to work. Do something serious with metals.'”

“So that wasn’t very encouraging. Because this phase is very critical in your career when you start to build your own lab and you have to show the world you can come up with original ideas. And successfully so. But you don’t have a permanent position. It’s kind of a very fragile phase. And if you don’t deliver, you might as well sort of go on a different career path. So, you are nervous. And I had sleepless nights in the beginning, like maybe I’m sort of betting on the wrong horse.”

Ultimately, this remarkable story in science had a happy ending. But there’s something to be said for the dozens of other brilliant scientists who weren’t as lucky. While reflecting upon his own challenges during his early career, List couldn’t help but think of the less fortunate story of Katalin Karikó.

Karikó was awarded the Nobel Prize in Medicine, along with colleague Drew Weissman, for their pioneering work on the mRNA technology that laid the foundation for the COVID-19 vaccines. Her work has literally saved millions of lives during the pandemic. Although today she is celebrated, Karikó’s research was seen as unorthodox and she was even laughed at by her peers.

Karikó was hired by the University of Pennsylvania in 1989, but she never was taken seriously and struggled to get grant funding for her work on mRNA. Because she was committed to pursuing mRNA research almost like an obsession, a line of research that was seen as futile and as such was not awarded funding, the Hungarian scientist was eventually demoted by Penn four times.

“If I don’t bring in the money, I don’t deserve the working space,” she told CNBC. “So that’s the rule. Every university is like that.” 

She had to hop from lab to lab at Penn and eventually joined Weissman’s lab, which was working on an HIV vaccine at the time.

Weissman’s lab switched to working on mRNA after Karikó’s arrival. Together, the two found a way to alter the mRNA such that it wouldn’t be destroyed by the immune system and thus be viable in a vaccine.

“Often, we hear people saying ‘never give up’. There is a truth to it. And she [Karikó] proved it. And she got a Nobel Prize and saved the world during the pandemic. It’s awesome what she did. But you should also see that there is a balance, right? You cannot say never give up, never give up, and then you’re old and die. And it didn’t work. So, you have to know also when it’s time to give up. That’s what I would say,” List said.

Karikó kept doing her own thing against all odds because she believed in her work even when all others around her doubted her. In the end, she prevailed. It was in the same way that List pushed forward despite the roadblocks placed in his path. Yet, one can only wonder how much Nobel-Prize-worthy research the world is now missing because of excessive academic hubris and the whims of paper pushers in universities.