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ENGINEERING THE BIOCHIP
BIOCHEMICAL ENGINEER JONATHAN DORDICK AND HIS TEAM ARE DECIPHERING THE BOOK OF LIFE

LOOKING INTO THE FUTURE: Jonathan Dodick, the Howard P. Isermann '42 Professor of Chemical Engineering. Photo by Mark McCarty.
By George Wise

The recently decoded human genome is indeed the book of life. But those who open it seeking a page-turner are in for a disappointment. It's a long string of letters, and only four different letters at that. "You open up the book," says Jonathan Dordick, Rensselaer's Howard P. Isermann Professor of Chemical Engineering, "and there are no sentences, or words—just letters. Our job is to figure out the sentences, paragraphs, chapters, and eventually the whole story."

This is more than a grammatical exercise. Researchers seek a full understanding of the processes that go on within living cells. And they want to model those processes in a unique laboratory, a tiny "cell on a chip." At stake for all of us are improved pharmaceuticals, abundant and safe foodstuffs, economical domestic energy sources, and environmentally friendly chemical processes. Scientists will get there first by understanding nature, and then trying out some variations on her chemical themes that even nature hasn't gotten around to yet.

In addition to leading Rensselaer's quest, Dordick also chairs the Department of Chemical Engineering, a major player in the biotechnology initiative defined by the Rensselaer Plan. The Plan defines biotechnology and information technology as priority areas that will fuel a greatly expanded research endeavor. The Institute strategy calls for developing specific focal areas within these two arenas that leverage Rensselaer's existing strengths in microelectronics and microsystems, advanced materials, nanotechnology, and modeling and simulation.

Biotechnology, nanotechnology, and information technology may not be the first words one associates with the venerable field of chemical engineering. However, if you only think of chemical engineers as people in hard hats turning big valves on giant chemical factories, think again. Increasingly, they're tweaking infinitesimal spots of protein on tiny chips, and in the process creating a crossroads where engineering, chemistry, nanotechnology, information technology, and biology meet. Throw in the chemical engineer's traditional focus on process, discovery, and economics, and you have a heady mix. "Chemical engineering" says Dordick, "is the ’liberal arts' of engineering."

Chemical engineers have been involved in biochemistry for a long time. Their work turned penicillin, one of the first of the modern biologically produced wonder drugs, from something rarer than rubies into a commodity affordable around the world. What's new is the opportunity opened up by genomics and its protein counterpart, proteomics.

MODEL BIOCHIP FABRICATED BY PHOTOLITHOGRAPHY: interconnected channels 50 microns wide and 10 microns deep are etched on a sheet of glass, which is then fused to another sheet of glass containing a pattern of holes. This results in a closed and controllable series of channels that enable fluid to flow (hence microfluidics). When each channel contains a specific enzyme, this leads to sequential enzymatic reactions, such as those found in metabolic pathways that drive reactions in living cells. Photo by Mark McCarty

DECODING THE CHEMISTRY OF LIFE
Proteins make up half the weight of each living cell. The string of letters in the genomic book of life gives, for the first time, a complete list of all the proteins a cell might make. However, each particular type of cell makes only some of these proteins, and does so only in a certain order and under certain conditions. Each of these particular cellular repertoires differentiates, for example, a blood cell from a liver cell or a neuron. The biochemical engineer's job is to find out how each of these exquisitely detailed sequences of cellular reactions works, and how they all add up to the genetically programmed, environmentally shaped chemistry that we call life.

Dordick's specialty is one particular class of proteins, the enzymes—the living catalysts of life's chemical factory. While remaining unchanged themselves, enzymes make chemical reactions run efficiently at body temperature. Dordick's route to this specialty began with a general youthful attraction to science that at one time had him heading for astronomy. Gradually, biology rose above, though never quite crowded out other interests ranging from baseball and a spot on the high school soccer team to playing the cello. He earned his bachelor's degree from Brandeis University's world-renowned department of biochemistry, and his Ph.D. from MIT's graduate program in biochemical engineering.

He moved on to the University of Iowa, where he built a distinguished career by showing how to use enzymes in much more demanding chemical environments than the ones where they typically operate in nature. These achievements helped make him by his early 30s a full professor, associate director of a research institute for biocatalysis, and a winner of the National Science Foundation's Presidential Young Investigator Award.

Dordick and his colleagues showed that enzymes, designed by nature to work best immersed in water, can also operate effectively dissolved in organic chemicals, or in high salt concentration. Putting nature's enzymes to work under such new and demanding circumstances has a significant payoff. It provides a way to synthesize selectively a wide variety of compounds that are important in pharmaceuticals, the chemical industry, and agriculture, but that are difficult or prohibitively expensive to make by traditional chemical means.

Not only have the methods changed, so have the tools. As scientists delve deeper and deeper into cells, deciphering ever-smaller puzzles, the "lab" itself is also shrinking. Soon scientists will test their enzymes on a "biochip," a chip of glass or silicon not much larger than a fingernail. A biochip has been defined succinctly as a "chemistry laboratory on a chip" or, in more detail, as a small solid surface of tiny "wells," often interconnected, for performing many simultaneous or sequential chemical reactions and detecting the results. The name is derived from the silicon chips that revolutionized electronics. Equally big things are expected from that little biochip, from better medicines to better food ingredients to the basic understanding of the subtle differences in body chemistry that differentiate health from disease.

Indeed, from Wall Street to Silicon Valley, the biochip is being hyped as the next big thing, the marriage of microelectronics power and biotechnology promise. It's the target of efforts ranging from such rising gene chip start-ups as Affymetrix and Actura to a joint venture launched by Argonne National Laboratories and the electronics giant Motorola. The biochip is made using methods developed for computer-chip manufacture—especially photolithography, the use of light and chemicals to etch intricate patterns onto tiny areas of silicon.

Biochips mean many things to many people. Gene chips for decoding the genome are already on the market, and have reduced the time of gene sequencing from days to minutes. A physician's biochip of the future may be an inexpensive machine that can provide the patient with an instant and individualized DNA analysis, warning of possible future disease in plenty of time to head it off. ("It could be a scene from a movie," begins one typically breathless account. "A doctor puts a drop of blood into a small hand-held device and instantly reads out a complete DNA analysis.") In law enforcement, the crime scene investigator's biochip may be a portable gadget that can use DNA and other substances found at the scene of the crime to analyze the clues while they're still fresh. To people seeking better food or pharmaceuticals, a biochip might be a way to compress by factors of hundreds, or even thousands, the time-consuming process of developing new medicines, or safe and life-enhancing improvements to food.

It was this quest for the bioengineering biochip that brought Dordick to Rensselaer in 1998 as Howard P. Isermann Professor. "I was looking for a way to combine my ongoing work with new areas such as microelectronics and nanotechnology. Rensselaer offered me an opportunity to work in those areas, in one of the nation's top chemical engineering departments, at a school that is one of the world's leaders in engineering. It enabled me to work with people who had already put Rensselaer on the map in bioengineering, such as Georges Belfort, a leader in the field of protein separation science, and Steve Cramer, a leader in the field of displacement chromatography. Rensselaer also complements chemical engineering with a wonderful array of other strengths, such as computational capabilities, nanotechnology, and microfabrication techniques from the electronics industry."

An unexpected bonus has been the association with Howard P. Isermann '42 himself, not only a generous supporter of RPI chemical engineering, but a role model through his successful entrepreneurial efforts that included chemical engineering behind the development of sunblock.

Dordick is himself a player in the biopharmaceutical start-up company EnzyMed, now part of Albany Molecular Research Inc. But his main focus has remained on the bigger picture, wringing understanding from that book of life. He sees this as a team effort drawing on the collaboration of many specialties.

Fluorescence measurement of product from an enzyme-based biochip using a plate reader with a 384-well plate. Photo by Mark McCarty

READING THE BOOK OF LIFE
Returning to the book metaphor, imagine the molecular biologist as the person who puts the letters (the four base pairs A, C, G, and T) onto the page, and then recognizes the words. The words are the genes, each of which codes for a certain protein. Next comes the chemical engineer, whose job is to figure out how those words fit into "sentences"—the basic chemical processes carried out by proteins, such as catalyzing chemical reactions or regulating the activities of genes or other proteins. Further, as sentences are arranged in paragraphs, these basic chemical processes are arranged in larger-scale metabolic systems that carry out specific tasks, such as breaking down one particular type of food (a sugar, for example) into the building blocks the body can use. And as a book's chapters are collections of related paragraphs, the body's major functions are collections of the metabolic systems that carry out such general tasks as digestion, respiration, and blood circulation. Finally, the sum of all these bodily functions is the life of the organism itself. And, like a book, it has a plot—the organism's struggle to survive and reproduce.

To decipher all this complexity, Dordick's bioengineering team includes experts in microelectronics processing, computer modeling, data mining, adhesion and separation, bioinformatics, and much more. "Everything we need is sitting on the genome," he says. "Our job is to find it. Our interdisciplinary team is working to develop an active system of enzymes on a microchip that will rapidly determine the metabolic functions of large numbers of genetic materials."

A first generation of this technology exists today. It consists of dozens or hundreds of dots, or "nanodroplets," of enzymes or other proteins sitting in a regular array on one of those fingernail-sized chips of glass or silicon. Put a drop of fluid on top, and if the desired reaction occurs in a particular dot, that location will give the researcher a sort of wink in the form of perhaps a color change, fluorescence, or heat. This first generation system provides a means to screen many biological catalysts rapidly, and to pick out at a glance the ones most likely to be useful. All this is devilishly difficult. The complex three-dimensional shape of proteins, and the need to orient them just right on each dot, adds difficulties even to stage one.

"Stage two," says Dordick, "is to connect the dots." Think of that next stage as perhaps hundreds or thousands of those dots of enzymes connected by a comparable number of pipes and valves laid down by photolithography, a technique developed for electronic chips. Putting all those reaction sites and all that piping onto a tiny chip makes it possible to carry out thousands of experiments in parallel, vastly accelerating the speed with which bioengineers can model life's reactions. Ultimately, a single chip might represent an entire chapter of that book of life.

ELECTROKINETIC FLOW ON A T-SHAPED BIOCHIP: Electrodes placed in reservoirs generate an electric current that causes a dye-containing liquid to flow through the channels between the reservoirs. When an enzyme and its substrate meet at the intersection of the T-shaped channels, a biocatalytic reaction occurs. The product is removed from the lower reservoir for further analysis. Photo by Mark McCarty

The Rensselaer team is now only taking the first steps on that long road. The current biochip is a transparent disk about the size of a quarter, on which have been formed three tiny wells holding minute samples of chemicals, and a T-shaped pipe etched onto the disk connecting the wells. Two of the chemicals meet and react in the cross bar of the T, then flow down its vertical line to react with another chemical at the bottom. Even this simple system is expected to give some important hints about better methods of polymer manufacturing.

The convergence of robotics, microelectronics-based processes, and nanotechnology is bringing this cell-on-a-chip within the range of possibility. The team plans to use the process of photolithography—the combination of photography and etching that's the workhorse of the electronics industry—to create the network of wells and channels that provides the plumbing. Those channels will direct the flow of fluids from one well to another, pumped by means of electrophoretic devices consisting of platinum wires at different voltages at each end of the pathways. To get an idea of the scale, a typical channel will be about 50 to 100 microns in width, or about the thickness of a human hair. For some purposes, the channels might be only one ten-thousandth as wide, on the scale of nanometers, or billionths of a meter.

The result is an incredibly tiny and precise, yet fully controllable, chemical laboratory. A reactant will flow in and be directed through the steps (in much the way electrons are directed around an integrated circuit), duplicating a metabolic pathway within a living cell. "As we flow things from one well to the next," says Dordick, "we can exert control over cellular processes that today take place only in the cell's cytoplasm. While we can observe or infer many of those processes today, right now we don't have control. When we do have that control, we can try things that cells have the potential to do, but that nature has not yet tried."

All this is still five to 10 years in the future. The Rensselaer team believes it is moving faster toward that future than anyone else. "Right now," Dordick says, "we're probably the only group looking at putting pathways on the chip." He adds, however, that "the field of biochips is growing rapidly, and we don't expect to be alone for very long."

The knowledge to be gained from putting down these pathways and simulating life's process is both intellectually exciting and significant in practical terms. Knowing which enzymes catalyze a living process, or which molecules turn cellular reactions on and off, can strengthen the body's defenses against disease, or extend agriculture to currently unfavorable environments. Applying life's methods to chemical manufacturing and energy production raises efficiency while putting less burden on the environment.

HOW BIOENGINEERING MIGHT CHANGE OUR LIVES

Dordick sees powerful potential. Modeling bodily processes on a biochip, for example, will lead to better understanding of the chemistry of health and disease, which will lead to the development of specialized molecules designed to aid the body in maintaining or restoring health. "In the next three to five years we'll see tremendous growth in pharmaceuticals produced by biocatalysis," he asserts. "These pharmaceuticals will be more selective for attacking only the diseased cells, and ultimately will be specifically tailored in order to interact specifically with the patient's particular genetics."

Other areas to be impacted include the chemical industry, energy, and food production (click here for more). "It's better for the world to feed itself than for the U.S. to feed everyone," Dordick believes. "Biotechnology will help make possible, with the proper precautions to ensure safety for people and the environment, the ability to vastly increase yields, and extend sustainable agriculture to harsh climates."

All this will be emerging, Dordick says, within the lifetimes of our children (his own are a 9-year-old son and a 6-year-old daughter) and grandchildren. "Biotechnology is going to improve the quality of their life, increase their life span, and make things much better for everyone on the planet."

"Also," he concludes, "it's fun. Organisms have evolved for billions of years with incredible diversity, and here we finally get a chance to model entire cells in vitro, gain a better appreciation of how nature works, and, every now and then, maybe even improve on nature. Every time we turn a page, we open up a new opportunity."

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