From Curiosity to Click Chemistry: K. Barry Sharpless Forges His Own Way

The Scripps Research Institute and Integrated Diagnostics™ have announced a licensing agreement for “click chemistry,” a technique that allows scientists to permanently join ("click") together molecular components with unusual precision and stability. Integrated Diagnostics™ will use the technology in its mission to develop large-scale, blood-based molecular diagnostics that detect diseases like lung cancer and Alzheimer's at their earliest stages. Other uses for click chemistry include the manufacture of an Allozyne™ drug candidate, in clinical trials for treatment of multiple sclerosis.

The following article, which first appeared in the Scripps Research philanthropy e-newsletter At the Forefront, provides the story behind the method and other work by Nobel laureate K. Barry Sharpless, W.M. Keck Professor of Chemistry and member of the Skaggs Institute for Chemical Biology at Scripps Research.

As a kid in the late 1940s, Barry Sharpless's favorite days were the ones that started with the sound of an outboard motor. His family had a cottage on the New Jersey shore, and when he was there he would rise early and race to join a pair of neighbors—gentle old crabbers—on their boat. It was those days spent watching the creatures of his Atlantic estuary that incubated Sharpless's native curiosity.

"I was hooked after that," Sharpless said. "Most scientific method stuff is oversold. Real scientists are just curious as hell."

Sharpless, who joined The Scripps Research Institute in 1990 as W.M. Keck Professor of Chemistry, is very, very curious.

In the 1970s his curiosity was about the mirror image forms that many natural and synthetic molecules come in. These mirror images are like a pair of gloves. When chemical reactions occur in living systems, only the "correct" form is made, but, before Sharpless, laboratory reactions almost always ended with both right and left hand forms of the molecule. Without being able to reliably produce just the "right" molecule, synthetic medicines could be harmful or even dangerous.

Sharpless spent more than a decade grappling with this problem, and, starting in 1980, discovered several reactions that could produce just the desired form. The innovation transformed organic synthesis research practically overnight and led to faster drug discovery, more stringent FDA policies, and improved and new medicines—and won him the 2001 Nobel Prize in Chemistry.

Clicking into Place

Sharpless doesn't stay in one place for long, though. Before 2000 he had coined the term "click chemistry" for the new philosophy for discovery chemistry he was working on.

Most materials we use in our daily lives—from the plastic of our sandwich bags to the drugs we take to lower cholesterol—are man-made. But the process of discovering materials with new properties is a long, costly hit-or-miss proposition. Sharpless had a different idea: instead of starting from scratch each time, what if chemists took their cue from Nature, working with simple building blocks?

"Chemists are like everyone else, and they fall for the trap that fancy is better," Sharpless said. "But I believed we could get just as much good function—and function is all that counts—from simple molecules made by simple methods. People laughed—it wasn't complicated enough. Funding agencies don't pay to develop new theories. I doubt if click chemistry could have happened anywhere but here. I only got to do this, and it took 10 years, because Scripps Research Institute President Richard Lerner and philanthropist Sam Skaggs supported me."

It may be simple in theory, but click chemistry didn't catch on until Sharpless and his Scripps Research colleague Professor M. G. Finn provided the chemical community with proof. They were struck with a moment of inspiration while discussing Kevin Kelly's book Out of Control.

"The first rule of god games [computer games where the player has large-scale control like that of a deity] is that you have to relinquish control," Sharpless said. "That's what gave M. G. and me the idea. Walking on the beach below Scripps Research and the Torrey Pines Mesa, they experienced a bolt from the blue Pacific. "Instead of trying to discover enzymes' secrets the usual way, by making them react, we thought—let's let them control how they react, let's see what they have to say instead of trying to force them to talk."

Applications on the Horizon

Soon thereafter, group member Valery Fokin (now a Scripps Research professor) discovered a reaction that, using copper as a catalyst, latches organic molecules together at will, even under the mildest, “greenest” conditions, like at room temperature and in water instead of the usual requirement of organic solvent—toluene, for example. The reaction is amazingly reliable—in fact, it never fails, a reaction characteristic that is unprecedented in life sciences and in the history of chemistry.

Now, click chemistry stands poised to have an even greater scientific impact than Sharpless's Nobel-winning work. Applications already visible on the event horizon are drugs that mimic hormones, materials that our bodies can't tell aren't “real,” less expensive diagnostic PET scans, and revolutionary nanoscale diagnostic blood tests.

These diagnostic blood tests are what continue to engage Sharpless. He explains that many diseases shed telltale proteins into the bloodstream, and, when a specific antibody runs across its "own" protein partner, the antibody grabs hold. Short-lived and often unstable, natural antibodies do the grabbing in existing protein diagnostics. But click chemistry-synthesized surrogate antibodies have recently been created at CalTech, which, when used in existing microfluidic device technology, have the potential to inexpensively perform hundreds of simultaneous tests from a single drop of blood.

Serendipity (remember how Sharpless actively pursues it?) is all about constantly making new connections, he said, and he's always on the lookout—even at birthday parties. That's where Sharpless and CalTech Professor Jim Heath first connected, to their mutual benefit. Heath is a leading nanotechnologist and creator of microfluidic devices, and a new company has licensed the Scripps Research and CalTech technologies. (Jim Heath was also one of the seven most powerful innovators in the world selected by Forbes.)

Heath's click chemistry-driven "lab-on-a-chip" holds the promise of revolutionizing testing for cancer and Alzheimer's (the company's first targets) on more fronts than running hundreds of tests, not just one, at a time: individual tests may cost a single dollar, or less, instead of hundreds; test kits containing click chemicals will have a long shelf-life and remain stable in extreme temperatures; an entire micro-lab could fit in a carry case. Imagine, Sharpless said, the implications for medical treatment if diagnostic tests could happen wherever there are people, not just where hospitals and clinics already exist.

"I'd like to see a new drug, one discovered by click chemistry, in my lifetime," Sharpless said. "We're getting close. Really close."

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