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What’s in a name? Douglas Clark on biomolecular engineering

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January 27, 2011

For some people, the city of Pittsburgh still evokes a tough industrial town that named its National Football League team after the main occupation of its workforce—making steel. Douglas Clark, chemical and biomolecular engineering professor, was born and raised in the town of New Kensington, PA, 20 miles up the Allegheny River from Pittsburgh.

During his life Clark has witnessed the transformation of Pittsburgh from a blue-collar steel town to a city with a diverse economy based on health care and technology. “Oddly enough,” he says, “in some ways Pittsburgh isn’t so different from San Francisco—it’s a city known for its bridges, with a distinctive skyline and a spectacular geographic setting. And the coffee is getting better, too.”

Just as he has watched Pittsburgh’s transformation, Clark has witnessed a revolution in chemical engineering—from a field focused on the petrochemical industry to one that is being transformed by biology. Here at Berkeley, that change has ultimately resulted in a new name for the chemical engineering department, the Department of Chemical and Biomolecular Engineering.

Clark has not merely been a witness to this transformation, he has been an active participant in it since his days as a graduate student at Caltech in the early 1980s. In the 24 years that Clark has worked at Berkeley, his research interests have spanned a breadth of topics that provide a good sample of how the field of chemical engineering has changed. Says Clark, “Looking back over the changes of the last two decades, I think it is important to acknowledge this transformation by updating the department’s name.”

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Douglas Clark

Clark graduated from high school in New Kensington in 1975 and headed to the University of Vermont—not on the strength of its chemistry program, but on the strength of its hockey team. “It turns out I was not destined to be a hockey star,” says Clark, “but I did discover chemistry along the way.”

In a strange twist of fate, while at UVM Clark took a course on military history from a professor named Elmer Gaden. Although Clark did not know it at the time, Gaden was a pioneering biochemical engineer who had worked at Pfizer on penicillin production and had established the biochemical engineering program at Columbia University in New York City.

A SAMPLING OF “GREATEST HITS” FROM DOUGLAS CLARK AND HIS COLLABORATORS

Important insights into the growth requirements and optimal culture conditions of extremophiles (and the apparatus required to grow them), including microbes from deep-sea environments where temperatures and pressures reach the highest extremes known to support life.

Combinatorial biocatalysis, a methodology that employs enzymes and whole cells for combinatorial biotransformations in the development and optimization of new drug candidates. Combinatorial biocatalysis was the corner- stone technology of the drug- discovery company EnzyMed, founded in 1994.

Detailed quantitative analysis of key metabolic processes in mammalian cells, including cancer cells, obtained through a combination of flux analysis and experimental monitoring of intracellular reaction networks.

Expanded utility and greater understanding of enzymes in processing environments, especially nonaqueous media, including methods to greatly activate enzymes for use in organic solvents.

The MetaChip (Metabolizing Enzyme Toxicology Assay Chip), the DataChip (Data Analysis Toxicology Assay Chip), and the MesaPlate (Metabolizing Enzyme Stability Assay Plate): new technologies for high-throughput in vitro toxicology assays and lead optimization in drug discovery.

A protein-based biomechanical nanosensor, based on FRET (fluorescence resonance energy transfer), which can be incorporated into materials and is able to report deformation of the surrounding structure.

Unique proteins from the deep-sea vent microorganism Methanocaldococcus jannaschii, one of which has proven to be a versatile biomolecular template for biometallic nanostructures, and possibly the assembly of protein shapes not found in nature.

The Clark lab is currently working on the development of biofuels from lignocellulosic biomass, including several approaches to improve the enzymatic breakdown of bio mass into fermentable sugars (biomass pretreatment, pro tein engineering and kinetic modeling of cellulose hydro lysis), bioprospecting for cellulases from extreme envi ronments, and developing new microbes with greater toler ance of biofuels.

In 1959, Gaden had become the first editor of the research journal Biotechnology and Bioengineering. Clark would take over as the journal’s editor in 1996, a position he still holds. (Clark interviewed Gaden in 2009, and the video is available on Youtube: http://www.youtube.com/watch?v=_p54Iowq8-E, search for “Elmer Gaden.”)

During two of his undergrad summers, Clark returned to Pennsylvania to work at the University of Pittsburgh, where he performed research in the lab of synthetic organic chemist Paul Grieco. “That was excellent training, and closer to the mark than professional hockey, but synthetic organic chemistry wasn’t exactly my calling, either,” he says. He graduated with a B.S. in chemistry from UVM in 1979 and began to look for grad schools.

Clark visited the major programs—chemistry at Harvard and Berkeley, and chemical engineering at Caltech and Stanford. Clark’s father was an engineer, and Clark liked the broad perspective of engineering, with its emphasis on problemsolving skills and the production of useful products. But the transition from chemistry to chemical engineering would turn out to be tough.

“I was having a hard time making up my mind,” says Clark. “What tipped the balance for me was a Time magazine article from November 1978, that portrayed Caltech as a dynamic and exciting place, which certainly proved to be true. But the magazine didn’t say anything about the hard work.”

Caltech admitted Clark into its chemical engineering program in the fall of 1979. The department was impressed with Clark’s under graduate work and his research experience. He was the first student admitted to the chemical engineering graduate program without a ChemE undergrad degree.

“At Caltech,” says Clark, “the preliminary exams came at the end of the first year, so that gave me about nine months to get caught up. There were times during that year when I would take a graduate level course and then take the undergrad prerequisite afterwards, which made for an interesting learning experience.”

Clark’s hard work paid off at the end of his first year with the arrival of James (Jay) Bailey, whom Caltech had lured away from the University of Houston. “Jay Bailey,” says Clark, “was one of the first chemical engineers to understand how important biology would become.” In 1977, Bailey had completed Biochemical Engineering Fundamentals, the first biochemical engineering textbook in the emerging field.

When the idea of working with Bailey was suggested, Clark introduced himself to Bailey by phone, and Bailey responded by sending him a sixpage handwritten letter. “For some reason,” says Clark wryly, “the Caltech faculty thought my undergrad chemistry background might have included biochemistry, and that would make me a better candidate for working in the biological realm. They were wrong about the ”

Bailey accepted the arrangement sight unseen, and when he arrived at Caltech in the spring of 1980, Clark became his first Caltech graduate student. Says Clark, “It was a good match, and I’ll always be grateful for the time I got to spend working with him. He was a real innovator, and it was a shock to many of us when he died—far too young—from cancer in 2001.”

Clark wrote his dissertation with Bailey on immobilized enzymes. “Enzymes are nature’s catalysts,” he says. “Not all enzymes circulate freely in fluids like blood or cell cytoplasm. Many enzymes are bound to cell membranes, and these immobilized enzymes act in a manner similar to heterogeneous catalysts.”

In the early 1980s, biochemical engineers were members of a small and tightknit group. Through Bailey, Clark first met Berkeley chemical engineering graduate student Frances Arnold and her dissertation advisor, Berkeley chemical engineering professor Harvey Blanch. (Arnold later became a Caltech chemical engineering professor and married Bailey).

Clark completed his Ph.D. in 1983 and took a position as an assistant professor at Cornell University that fall. “Back then,” says Clark, “it was less common for chemical engineers to do postdocs after grad school, so I went straight to Cornell. It was an excellent department, and I made some good friends for life during my time there. The winters were a little long, but pretty mild by Vermont standards.”

His academic career successfully launched, Clark once again encountered Harvey Blanch, at a conference in Denmark in 1985. Over dinner, Clark discussed his research at Cornell. Impressed, Blanch invited Clark to give a seminar at Berkeley in February 1986. The Berkeley chemical engineering department shared Blanch’s enthusiasm, and Clark was offered a job by the end of the visit.

“It was a tough decision,” says Clark. “Cornell had been good to me, and I was happy there, but the Berkeley offer was just too tempting.” Clark officially started in July, 1986, at the same time Charles Wilke, Berkeley’s biochemical engineering pioneer, retired.

Clark’s research group has continued to work in the area of his dissertation research, immobilized enzymes, but has also branched out into broader research on enzymes, the identification of new ones, and innovative uses of them in industrial and biomedical settings.

Clark recalls the event that first got him interested in what would prove to be a fruitful area of research—enzymes and proteins found in extremophiles, singlecelled life forms that have adapted to extremes of temperature and pressure. His curiosity was sparked by a paper in the scientific journal Nature that generated a huge amount of interest, but later sparked an equal amount of controversy.

In the 1983 paper, researchers claimed that they had isolated an organism that survived temperatures as high as 250°C. Says Clark, “At that time we knew that life existed in environments like Yellowstone’s Old Faithful geyser and other hot springs. And we were discovering life forms around underwater volcanic vents with chemically rich, but superhot conditions. We knew that life could survive up to around the boiling point of water, but this paper was a paradigm shift. How could enzymes and proteins exist and function at these temperatures? Researchers began to think about life in new ways.”

As it turns out, the results of the article were never reproduced, and the paper remains a source of controversy. “For now,” says Clark, “the record for hightemperature life remains about 120°C. But in a broader sense the Nature paper was significant in that it made people realize that life can exist in environments that we previously didn’t think possible—deep underground in solid rock, and thousands of feet below the ocean surface near ‘black smoker’ volcanic vents. Life has adapted to extremes of hot and cold and pressure ranges that ”

The chemistry used by extremophiles in those circumstances has proven to be very useful. The most famous and widespread commercial application is the polymerase chain reaction (PCR), a Nobel Prizewinning technique that amplifies minute quantifies of DNA so that it can be studied. Says Clark, “PCR typically employs Taq polymerase from the thermophilic bacterium Thermus aquaticus. The high thermostability of Taq polymerase allows it to generate a new copy of a DNA sequence following thermal melting of the original DNA fragment. The high operating temperature is what enables the whole process to work.”

Enzymes from extremophiles have important industrial applications, too. High temperatures and high pressures make some processes run faster and more efficiently. The enzymes are more robust and don’t break down as quickly during these processes, and running at high temperatures can eliminate bacterial contamination.

“So there is tremendous interest in these extremophiles,” Clark explains, “for the sorts of practical process innovations that chemical engineers have always explored. But there is a fascinating side story as well to extremophiles—exobiology. Some extremophiles on earth grow in harsh conditions that may mimic the environments of other planets. From extremophiles we might learn more about the origins of life itself in the universe.”

The Clark research group is also using its expertise to help speed the testing of drug candidates and reduce the need for animal testing. In 2008, pharmaceutical companies in the United States spent over $40 billion on research and development that resulted in fewer than 20 new drug approvals. Explains Clark, “Drug companies often invest too much in pursuing a drug candidate before toxicology tests put a halt to development. Although it seems counterintuitive, when it comes to screening potential new drugs, the mantra is to ‘fail early and fail often’ to eliminate the expense of going down blind alleys.”

The human body, primarily the liver, contains a variety of enzymes that are involved in the metabolism of the chemicals foundin pharmaceuticals. The most important class of these metabolic enzymes is the cytochromes P450, which are directly involved in the initial clearance of drugs from the body.

For example, the conversion of the antihistamine loratadine (Claritin) by P450 enzymes is required for its biological activity. Often, however, drug metabolism can lead to undesirable biological conse quences. Notes Clark, “A well-known example of a toxic metabolic response is the P450-catalyzed oxidation of the common analgesic acetaminophen (Tylenol) to a compound which can cause liver failure.”

To help screen drug candidates and other compounds for toxicity, Clark and his collaborators, including Jonathan Dordick of Rensselaer Polytechnic Institute (RPI), have devised a testing process that involves two different but complementary microarrays. The first component is a microarray that contains human P450 isoforms. Thousands of P450 enzyme samples are arranged in a precise grid pattern on a single small glass slide. This array is used to generate biologically active metabolites of the compound to be tested.

The second component consists of minute dots of human tissue cells arranged in a complementary pattern on another slide. A solution of test compound is applied to the P450 slide, and then the two slides are precisely aligned and sandwiched together. As the P450 enzymes react with the test compound, metabolites are produced that may or may not kill the human tissue cells that they contact. Once the metabolites have been produced and the cells have interacted with them, the cell tissue slide is removed and the cells are stained to determine the percentage of dead cells by using a microarray scanner.

In addition to helping to identify toxic side effects of pharma ceutical compounds, this testing procedure can also help screen the thousands of cosmetic products that come to market every year, without resorting to animal testing. Says Clark, “Animal testing is extremely expensive, there are ethical issues in using animals, and the European Union has banned animal testing of new cosmetics.”

Clark adds, “As we become more sophisticated at teasing apart the subtle genetic differences between individual humans, and how these differences influence the effectiveness of all sorts of therapeutics, testing in rats and mice becomes less useful. In particular, animal testing lacks the human genetic specificity that we need for developing personalized medicine.” Along with researchers from RPI in New York, Clark has founded a company, Solidus Biosciences, to commercialize human enzyme microarrays for drug and cosmetic screening and to explore the emerging arena of personalized medicine.

“When I look back at how my lab’s research has evolved,” says Clark, “I realize that the way many of my colleagues and I do research now is vastly different from when I came to Berkeley 24 years ago. In my mind, that merits changing the name of the department.

“The department has considered changing its name in the past, but the faculty didn’t really think that adding ‘biochemical engineering’ to the title did justice to the profession. After all, biochemical techniques like those used to produce penicillin have been part of the profession for decades.

“But,” Clark continues, “the revolution of genetic engineering has opened up a new world of biomolecular engineering. In our department, for example, my colleague Jay Keasling has developed alternative routes for cheaply producing anti-malarial drugs, and several of us are working on developing next-generation biofuels.”

Although departments at Cornell and the University of Pennsylvania also call themselves departments of chemical and biomolecular engineering, Clark’s alma mater Caltech and chemical engineering powerhouse MIT have not changed their names.

Clark ponders this a moment and replies, “Not all departments are created equal, and not all departments evolve in the same way. Regardless of what others are doing, we believe our new name best represents how we have evolved, and what we currently are.

“Furthermore, the UC system alone has 10 campuses and five medical schools. While Berkeley doesn’t have a medical school, it does have plenty of students who are considering coming here to study premed and other biology-related disciplines, not to mention bioengineering.

“We want to lure some of those students,” adds Clark, “and to do it we have to compete with programs with names like ‘bioengineering,’ ‘molecular and cell biology,’ and here in the college, ‘chemical biology.’ We want to say to students, ‘Hey, if you are interested in biology and engineering and want to make a difference in the world, come help us find tests for the safety of chemotherapies, develop personalized medicine, or find new enzymes that will make cellulosic biofuels a reality.”

Says Clark, “Sitting in a freshman biology class may be the next Jay Bailey. When it comes time to pick an undergrad major, or later a graduate school, we want that student to keep us in mind.”

More Information

Clark Research Group: http://www.clarklab.org
Clark Faculty webpage: http://chemistry.berkeley.edu/faculty/cbe/clark/
FAQ's about the CBE name change