Ask Mark Levin what excites him about his work, and the associate professor of chemistry at the University of Chicago could double as a poet. “We’re one of the only fields of science that at its core is about making things that have never existed anywhere else in the universe, and would never have existed if we didn’t intervene,” he enthuses. “We get to manipulate matter at the atomic level to shape it to whatever purpose we can think of.”
Some of those things that would never have existed are of immense value to humanity. From synthetic dyes to celluloid, materials to medicines, synthetic chemistry has made our world a richer place, and helped us live longer to enjoy it.
With enough effort, today’s chemists can synthesise almost any molecule imaginable, but their methods are limited, relying on the molecular building blocks available and potentially requiring many steps. “The approach that has been adopted to do this is to add other chemical groups to the already existing molecule, which changes it only on its periphery,” explains Prof Richmond Sarpong, a chemist at the University of California, Berkeley.
When it comes to altering an existing molecule more fundamentally – such as within the rings of carbon atoms at the centre of many organic compounds – Levin likens those atoms and bonds to the connectors and rods in a child’s Tinkertoy set: “It’s very obvious when you’re looking at the toy that the best way to change it would be to pull out the part you don’t want and put the new one in,” he says. “It has always bothered me that that’s not something we have the capacity to do chemically.”
That is, not until now.
Inspired in part by the revolutionary genome-editing technology Crispr-Cas9, Levin and Sarpong are among a handful of chemists developing new methods to insert, delete and swap individual atoms within molecules. They call it “skeletal editing” and they hope it will change their field – and our world.
The word “editing” evokes chemists altering atoms with pairs of nanoscopic tweezers, but that would be far from efficient. “If you wanted to make a mole,” Levin explains, referring to a unit of measurement used in chemistry, “you would have to take that pair of tweezers and do it 1,023 times.”
Instead, in this new approach they harness chemical reagents, catalysts or light, to perform edits quintillions of times. “What we’re essentially doing is designing molecules that behave like that tweezer,” Levin explains.
In that sense, skeletal editing is a continuation of established synthetic chemistry – not so much a single tool as an ever-growing toolbox. “[It is] not one thing,” says Sarpong. “It is a concept, a way of thinking, that has sparked a new way to look at things and is producing results that I could not have imagined five years ago.”
Some of the most exciting results, at least for Sarpong and Levin, are in drug design.
Scientists usually make new drugs by identifying a biological target that plays some role in a disease, and then screening hundreds of thousands of molecules to find a “hit” compound that might interact with it. “Making molecules for a drug discovery project requires many chemical steps and significant time,” David Blakemore, head of synthesis, inflammation, immunology and anti-infectives chemistry at Pfizer, acknowledges.
In recent decades, this has increasingly been done with computers, and so-called in silico screening is now so advanced that synthetic chemistry sometimes struggles to keep up.
“I can design a molecule that looks sensible or follows all the rules of chemistry,” says Dr Robert Scoffin, CEO of Cambridge-based drug discovery company Cresset, “and the synthetic guys will look at it and go: ‘I’m sorry, I really can’t get there, or it’s going to cost you so much it’s really not worth getting there.’”
Once they have succeeded in piecing together a molecule they want to work with, medicinal chemists must then optimise it to improve efficacy and reduce side-effects – turning the “hit” compound into a “lead” compound.
This can be laborious. For example, chemists will often test versions of a molecule with a nitrogen atom occupying every possible position in its structure, and while editing atoms on a molecule’s periphery can be relatively straightforward, changing those at its core can be as tricky as the last round in a game of Jenga.
“It is very time consuming to change the central scaffold itself,” explains Blakemore. “We typically need to make a new scaffold from scratch, and this often requires many steps in a long sequence.”
“It’s like tearing down your house and rebuilding it just to remodel one bathroom,” Levin says. “Everything in these sorts of applications is about speed, and when you’re dealing with drugs, you’re talking about patients who are waiting for a cure or a better treatment.”
Skeletal editing could help to speed up drug discovery dramatically, and chemists such as Julia Reisenbauer, a PhD student working in Prof Bill Morandi’s team at the Swiss Federal Institute of Technology, and Prof Sarah Wengryniuk at Temple University in Philadelphia, have now developed reactions that can insert single nitrogen and oxygen atoms into the central rings of some molecules, sidestepping the need to start from scratch.
“It will increase the speed at which we can make things, and it will increase the diversity of products we can make,” says Martin Smith, professor of organic chemistry at Oxford University. “That is absolutely part of the discovery process for pharmaceuticals and will be for the discovery process for materials as well.”
To make a new synthetic material, chemists will often take monomers – small molecules that can be bonded together – and repeat them many times to form polymers. This traditional approach limits their designs to using only available monomers, which can be difficult to access, or unsustainable.
“A different approach would be where you have a problem and you design a polymer without those constraints, you just design,” says Aleksandr Zhukhovitskiy, assistant professor of chemistry at the University of North Carolina at Chapel Hill. “[Skeletal] editing will allow you to derive that material from something else that then could be accessed more easily or perhaps accessed through more sustainable building blocks.”
Zhukhovitskiy’s lab has developed a skeletal editing reaction to synthesise vinyl polymers – employed in everything from plexiglass to paints – without the use of vinyl monomers, effectively making a petrochemical plastic without the need for petrochemicals.
With the planet already choking on a surfeit of plastic, however, a method for making more of it isn’t necessarily appealing. Human negligence aside, plastics are notoriously difficult to recycle because of the long chains of strongly bonded atoms that make up their backbones. These bonds can sometimes be broken with extreme heat, but the process is hardly sustainable. “Even if it does work, it requires a high input of energy,” says Zhukhovitskiy.
His group is now working on a skeletal editing reaction that can insert weak links into the backbone of the plastic polyethylene, making it possible to break those tough bonds under relatively mild conditions. “Suddenly your polymer still behaves like polyethylene in many ways, but becomes more easily cleavable,” he says. “That is a really exciting goal, I think, and a really challenging one.”
Zhukhovitskiy’s team is close to completing a government-funded project to use skeletal editing for recycling rubber, and there’s growing interest in these techniques within industry, especially in pharmaceuticals.
“Currently, we are examining the available skeletal editing methodology to see how applicable it is across a broad range of molecules to help us understand scope and limitations,” says David Blakemore at Pfizer. “We already have a project where we have used a skeletal editing reaction to make a simple scaffold that was elaborated to a lead compound.”
Blakemore says it is “still early days”, adding that their project demonstrates the “potential power” of skeletal editing. Indeed, it was only in 2018 that Sarpong’s group became one of the first to start working with these reactions, with most advances happening in the last two years, but progress has been fast. Levin estimates that a complete skeletal editing toolbox for drug discovery would involve maybe a thousand different reactions, and is now about 5% full. “But you have to remember, it’s been two years,” he says, “5% is not bad, you know; 5% is pretty good, actually.”
Still, a number of these reactions can only produce small amounts of product, many use volatile reagents that could be useful in drug discovery but inappropriate for industrial use, and while some reactions may be more environmentally sustainable than available methods, others could be worse. Critics could also argue that this 5% represents low-hanging fruit, and the remaining 95% may be considerably more difficult, if not impossible.
“I think that is a reasonable position until proven otherwise,” says Levin. “And my lab’s whole goal is to prove otherwise.”
He’s joined by a growing number of labs globally whose efforts are fast increasing the pace of discovery. “If the toolbox that I’m imagining actually comes to fruition,” he says, “it will really replace a lot of the ways that we do chemistry.”
A full skeletal editing toolbox could do more than that. It could in theory lead to futuristic inventions such as automated synthesis laboratories, and even personalised medicine.
Scoffin suggests that in cancer treatment, for instance, where every tumour is different: “You can imagine a world where you can design exactly the right molecule to go and attack that specific tumour, and you have a synthesiser where you can draw that molecule, click a button and it makes it. That opens up a huge world of possibility in terms of that kind of personalised precision medicine.”
We may never get to that stage, but each new skeletal editing reaction could open the door to more and better medicines, new materials, better crop protections, and solutions to a range of other problems. Sarpong, however, thinks these are “rather myopic predictions”.
“I think the most important thing is that it changes the way chemists think,” he says. “Meaning the possibilities are endless.”
For Levin, these possibilities lead back to the pure fascination with manipulating matter, making things that otherwise might never have existed.
“We’ve gotten to the point in synthetic chemistry where people genuinely believe that most molecules are conquerable with enough time and effort,” he says. “But there are a couple of notable exceptions. I think that if we could demonstrate that we can make some of those with skeletal editing, that’d be awesome.”
Levin won’t say what they are, but his team has two such exceptions in its sights. Can skeletal editing bring a molecule into existence that we could only imagine before?
“We’re getting close,” he says. “We’re getting close.”
