Engineering Better Approaches to Chemistry

By Mark Schrope

After nearly a decade working as a professor of chemical engineer at the University of Pittsburgh, Donna Blackmond was, frankly, getting a little bored with her automotive industry-funded research on chemical reactions related to those used in catalytic converters.

But then, in 1992, scientists from pharmaceutical giant Merck heard Blackmond give a talk at an Organic Reactions Catalysis Society meeting. They recognized intriguing connections between her studies and their goal of improving reactions used in drug production.

Merck offered Blackmond a job—an opportunity that enticed her to leave a tenured faculty position and an NSF Career Award to shift onto an unusual career path. After a few twists and turns, including positions at Germany's Max-Planck Institut für Kohlenforschung and most recently at London's Imperial College, this path brought her last year to a faculty position at The Scripps Research Institute Department of Chemistry. Today, her research spans a range of problems from the origins of life to pharmaceuticals production.

"Everybody thinks there's this one route to a productive scientific career and you can't deviate from the conventional path," says Blackmond. "But my career shows you can actually do well even if you do things differently than that standard route."

Pharmaceutical Streamlining

When Blackmond arrived at Merck it was a transformational time in the industry. Historically, companies had paid minimal attention to the process and cost of producing a drug, as long as production happened quickly enough to allow a company to profit from the patent window. But at that time, concerns were growing about the costs of healthcare, and drug companies were recognizing the value of optimizing their procedures to lower drug prices.

The company had brought Blackmond in to lead the creation of what would become the award-winning Catalysis Discovery and Design Laboratory, which would focus on the fledgling field of asymmetrical catalysis—the same field that had been pioneered by Scripps Research Professor K. Barry Sharpless and would make him a Nobel Laureate in Chemistry just under a decade later. "It was quite forward thinking for Merck to do this, and everyone there didn't agree with this approach at the outset," says Blackmond. "The effort really paid off." But it would take some time.

Blackmond and her growing team were struggling to gain recognition for work that was outside the bounds of traditional synthetic chemistry in process research. They knew they needed to make a significant, creative contribution to the company just to keep the team alive.

About this time protease inhibitor drugs to treat the scourge of HIV/AIDS were showing major promise, so much so that adequate production was proving a challenge. Even if Merck quit producing any other drugs and focused its entire resources on its successful AIDS drug Crixivan™, the company still couldn't fulfill demand. "It was one of the first times they really had to think about productivity," says Blackmond.

While not officially assigned to Crixivan™ work, Blackmond's team commandeered starting materials and ultimately proved the value of better understanding reaction pathways.

Examining the Path

Even if production wasn't yet a focus, companies at that time did maintain safety groups that measured the heat emitted during drug production reactions. The safety studies she saw upon arriving at Merck gave Blackmond an idea she's still applying with great success today.

Classical chemistry often involves halting a chemical reaction after only a tiny fraction of its complete cycle, then measuring the very small amounts of reacting molecules that go away. Based on such experiments, chemists calculate rates and infer information about intermediate steps. This process is repeated over and over under different starting concentrations to gain a complete picture.

Blackmond's idea held that the techniques and instruments that measure the total heat given off during a reaction could also precisely measure chemical changes as reactions proceed, because such changes give off known quantities of heat. By manipulating reaction equations and feeding additional – and improved – monitoring data into a computer, she and her colleagues were able to follow a reaction through an entire cycle rather than studying the reaction in tiny pieces.

"The classical method grew out of our own inability to watch two things at once," she says. "But computers don't care. They can watch as many things changing at once as we need them to."

The idea was a grand success that allowed the team to make one critical step in Crixivan™ production 20 times faster. "That was quite exhilarating," says Blackmond. "That's the kind of constrained problem you feel really good about understanding." It was also the kind of success her Merck group needed to establish itself. Other triumphs would include developing a method for optimizing a catalytic step to produce an antibiotic that saved $1 million in precious metal costs. "We basically etched away the suspicion and doubt one project at a time," she says.

Blackmond says one of the things she doesn't like about strictly academic work is a tendency toward setting difficult problems aside in favor of those appearing more solvable and, thus, more likely to produce the publishable results academics require. But in applied commercial work, she says, the constraints can be less bendable, forcing researchers to tackle specific problems, however great the challenge.

Blackmond went on to advance her reaction monitoring techniques, ultimately developing a method known as Reaction Progress Kinetic Analysis. "It's actually pretty simple. People think it's really much more complicated than it is until I explain it," she says. "It's basically a faster way to get answers, and that always makes them happy."

Nearly 20 years after shifting focus to pharmaceutical applications, Blackmond is still applying her methods not only at Merck, but also as a consultant for companies such as Johnson & Johnson and Bristol-Myers Squibb.

Back to the Beginning

To balance her applied pharmaceutical pursuits, Blackmond also explores chemical reactions to answer open questions about how life emerged on an ancient Earth. One such conundrum is why key molecules such as amino acids and sugars can have either of two different molecular orientations, or chiralities, yet in living organisms they always have a single orientation, or homochirality.

It seems most likely a pre-life Earth would contain molecules with both orientations, and if so, there must have been a process that favored the emergence of homochirality. For decades, theoretical work has suggested that autocatalysis, a process in which something acts as a template in producing more of itself, could fit the bill. An experimental system was discovered as far back as the mid-1990s by Japanese scientist Kenso Soai that could shift a solution toward homochirality. Blackmond's group was the first to discover how it was actually happening. "Understanding why is satisfying because it helps lead to the next discovery," she says.

But the Soai reactions couldn't happen under plausible pre-life parameters. Blackmond's later work would reveal another approach that could, involving physical and chemical amplification processes in amino acid chemistry, and this garnered major attention in a 2006 Nature paper. Most recently, her group began working on an interlocking system of chemical reactions involving both amino acids and sugars. Their latest results show this leads to homochirality in RNA precursors, which much research suggests was the basis of life's earliest forms and existed before DNA.

New Challenges

One of the key reasons Blackmond was interested in moving to Scripps Research was the chance to develop new collaborations with chemists to further apply her quantitative approach to chemistry. Already, she has begun working with Scripps Research Professor Jin-Quan Yu on problems in carbon-hydrogen, or C-H activation, currently one of the hottest topics in chemistry. Their work involves selectively breaking critical bonds between the two elements in ways that allow desired reactions to proceed without also causing unwanted reactions or effects.

Controlled C-H activation shows far-ranging promise from pharmaceuticals to energy production, where for instance, countless researchers are searching for better ways to produce hydrogen for potential use as a fuel. Blackmond's goal is to help Yu's group better understand reactions of interest so they can either make them more efficient or design new molecules to better achieve specific goals.

"I'm not a synthetic chemist, but I like puzzle-solving," says Blackmond. "When my lab teams up with the chemists who do make molecules, together we can get a lot further by understanding how those molecules are made. That was the driving force in my decision to come—to make those kinds of connections."

Send comments to: mikaono[at]scripps.edu

Professor Donna Blackmond is interested both in practical problems, such as how to improve drug production methods, and in basic scientific questions, such as how life emerged on an ancient Earth. (Photo by Bob Turner.)