One of the Nobel Prize winners at The Scripps Research Institute in San Diego has been saying for a decade that chemists would be better off doing the simple thing instead of the hard thing. Now quite a few of the world’s top academic scientists and Big Pharma companies are starting to adopt K. Barry Sharpless‘ philosophy of “click chemistry.”
This is the concept that Sharpless has been advocating a long time, along with a couple like-minded faculty members at Scripps, MG Finn and Valery Fokin. I met with Sharpless, Finn and Scripps’ tech transfer leader, Scott Forrest, a few weeks ago to talk about the boom they are seeing in scientific publications, patents, and some new technology licenses that are taking advantage of “click chemistry” principles.
What’s the big idea? It’s about using small chemical building blocks that you put in water or some other solvent, until they naturally “click” together. Sort of like a plastic buckle on a backpack, these molecules join together in the easiest, cheapest, most reliable, and most durable reactions possible, according to the laws of Mother Nature. These are fundamental reactions that tightly bind molecules together and could be useful as oral pills, industrial adhesives, stable coatings for implantable medical devices, or any number of valuable products. It sounds simple, and Sharpless and Finn say it is. What’s surprising is how strange it might appear to the modern lab with its state-of-the-art tools and its efforts to constantly strive for the leading edge and peer approval that goes with it.
Sharpless has been applying this idea for about 20 years, but he says he was really inspired by Kevin Kelly’s 1995 book “Out of Control.” Kelly, the founding editor of Wired, wrote that scientists should recognize they’re playing “God games.” In the case of a chemist, he or she is trying to do things that are more complicated any human can fully understand, so they should listen carefully to what Mother Nature says. It’s a more humble approach than what you often see in pharmaland.
“We are going toward an unknown target. Even if we think we know the target, we say we know what’s best. That was big-scale hubris. It’s like Cinderella and her sisters, with a shoehorn. Our intellect is saying we can shoehorn what we say works into the shoe. It’s not close to the truth,” Sharpless says. “If you want to be God, you have to allow your objects to have free will. You have to relinquish control.”
Instead of trying to do things the way nature wants, chemistry and other fields of science are really more of a game of “hey, can you top this?” to hear Finn and Sharpless describe it. The click philosophy, they say, strikes a lot of peers as mundane.
“We are trained as most experts to do the hardest things and do them well. That’s how you get praise and learn,” Finn says. “You want to do the hardest chemical reactions and make them work. It’s weird to say ‘We’re not going to do the hardest reactions.’ We’re going to find or create the easiest reactions.’ But if you think about it, it’s a lot harder to invent a process that works all the time, than it is to make the process that’s really difficult work a few times.”
Yet more and more scientists and companies are seeking to apply the click philosophy. One example is Seattle-based Integrated Diagnostics, a company co-founded by Leroy Hood of the Institute for Systems Biology and Caltech’s Jim Heath. Their idea is to create a diagnostic tool that can perform binding reactions cheaply and reliably enough to usher in an era in which physicians will be able to spot proteins that are early warning signs of cancer or neurodegenerative diseases in a pinprick of blood.
Hood loves to tell the story about how the prototype, and the tight binding reactions it performs inside, were rugged enough to produce reliable results even when Heath left the machine in the truck of his car near Caltech in Pasadena, CA.
That’s just one example. Carlsbad, CA-based Life Technologies (NASDAQ: LIFE) markets a kit that performs a click reaction to take quantitative measures of DNA in cells, Finn says. Tampa, FL-based Intezyne, whom Finn advises, is using the click principles to attach polymers to drug candidates in a cheap, strong, consistent way to make chemotherapies active only inside tumors, not other tissues where they cause side effects. Hundreds of drug candidates that use the principle are now working their way through phases of testing, Finn says.
“A lot of this is going on in Big Pharma. I know this for a fact. People in Big Pharma have incorporated this as part of their workflow,” Finn says. Materials science guys who work on things like adhesives, maybe because they don’t need to explain everything they do to the FDA, jumped on the click method as early adopters, Sharpless says.
The turning point for “click chemistry” came in 2001 when Sharpless and Fokin showed a reaction that combined azide with an alkyne that was catalyzed by copper. The functional groups themselves are stable, and don’t react with much, Finn says. When you’re ready, you put the chemicals together and they click into an irreversible bond. Basically, you can staple two things together. The paper has been cited more than 1,500 times, Finn says.
“It’s an awfully easy reaction to do and very stable. Manufacturing-wise, it’s incredibly important,” Finn says. The irreversible act of clicking separates winners from losers. If it clicks, you know there’s something special about the reaction.”
Once you have molecules that bind in this fashion, a lot of possibilities open up. You can have drug candidates that bind tightly, and irreversibly with a target, what’s known as a “high affinity,” property. Getting that high-affinity property in a drug early in the screening process can speed things up, and allow more time for checking out other properties to make sure the drug isn’t too toxic, or to see whether you can link it to some other molecule with desired characteristics, like a long-lasting polymer, or a potent toxin to kill tumors. In the long slog of drug development, when it often takes a decade or more of work, “if you can shave a couple years off a process, that’s worth something,” Finn says.
One hot application of the moment involves linking biologic molecules to toxins, through what is called “conjugation.” This is a notoriously tough problem that has eluded scientists for decades. It’s a quest to develop targeted antibody drugs, loaded with toxins, that would be like “magic bullets” or “smart bombs” for tumors. Creating stable linkages between drug and toxin has been a major challenge, but a couple of different cancer drug candidates—one from Roche and Waltham, MA-based ImmunoGen, and another from Seattle Genetics and Millennium: The Takeda Oncology Company—have shown a striking ability to shrink tumors this way. That has prompted renewed interest among other pharmaceutical companies to get into this “conjugation” game, and find other scientific techniques to help them catch up. That’s partly what has made the phone ring at Scripps, Finn says.
Scripps’ Forrest, the tech transfer officer, says he isn’t ready to name names or talk terms yet, but there are a number of partnerships in the works.
Not much of all this business activity seemed to interest Sharpless very much. His mind famously moves faster than his mouth, and he is known for stopping in the middle of a sentence and changing his train of thought. Listening to the digital recording of my 59-minute conversation with Sharpless made me smile and laugh yesterday. He truly comes across as a sincere-but-absent-minded professor. When I told him about how I write about innovative life sciences people and companies in San Diego, he launched into a friendly riff about how I must have to listen to a bunch of bunk.
Clearly, somebody else will do the negotiating for him.
“I’m sort of the old mad dog who doesn’t believe in a lot of stuff. I have a hard time with biotechnology and green chemistry. It’s hard for me,” Sharpless says. “The point of chemistry is in the middle where everything gets connected. Function is what matters. To me, it wouldn’t matter if you can make malignancies regress with three different types of inorganic salts as long as they weren’t toxic.”
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