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Engineering the Future of Biology and Biotechnology
 
 
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Engineering the Future of Biology and Biotechnology


As biotechnology becomes increasingly industrial in scope, the plants producing and refining tomorrow’s fuels, textiles, plastics, and other commodities are likely to be plants in the vegetable sense. Corn, soybeans, and even crops of microbes will grow the materials we need. And, like today’s chemical facilities, these literal chemical plants will be tended by chemical engineers.

The application of chemical engineering principles to biological organisms and processes has only become possible in the last two decades. Modern, high-performance computing and precise, automated instrumentation powered the Human Genome Project and continue to enable research not just into the genetic makeup of organisms, but into the action of proteins, the engines that drive the most basic life functions. Armed with the data produced by genomics and proteomics investigations, biologists can now quantitatively describe how different genes are translated into proteins and how downstream factors impact specific biological functions.

“ Quantitation in biology used to be that someone would count the legs on a bug and see what it was,” says C. Sidney Burrus, prior dean of engineering at Rice University. Biology’s newfound ability to measure and assess inputs and outputs means that chemical engineers can harness biological components and processes to do specific, directed work. No surprise then, that biology’s transition from a descriptive science to an analytical and quantitative one is redefining chemical engineering. It’s even prompted the department at Rice to adopt an aggressive strategic plan and to change its name to the Department of Chemical and Biomolecular Engineering.

“ Chemical engineering has traditionally comprised three foundational ‘legs’: chemistry, physics, and math,” says Kyriacos Zygourakis, the A.J. Hartsook Professor of Chemical and Biomolecular Engineering and department chair. “Our new departmental mission puts molecular biology on equal footing with the field’s foundational sciences and reflects the work chemical engineers are doing and will do as industry seeks better, sustainable, environmentally friendly products.”


Design, Optimize, and Control


What would a better, sustainable, environmentally friendly product look like? You’ve probably seen (or even eaten out of) one example in the produce refrigerators and salad bars at your local supermarket. Many of the plastic containers used to hold cold items, such as chilled fruit and salad, are made using NatureWorks polylactide (PLA), a polymer formed from lactic acid, which is in turn derived by fermenting corn sugar. These “corn-tainers” offer nearly the same utility as containers made from oil-based plastics, but have the advantage of being completely compostable.

One of the engineers working on NatureWorks PLA is Aristos Aristidou, who received both his undergraduate and graduate degrees in chemical engineering from Rice in the late 1980s and early 1990s. Aristidou is now leader in quantitative physiology and fermentation within the biocatalyst development department at NatureWorks, the business spun out of Cargill Dow, which originally developed NatureWorks PLA. He notes that producing this polymer differs little from traditional chemical engineering processes used for decades in the petrochemical and pharmaceutical industries. But the production represents a revolution for the field of biotechnology.

“ We’re seeing a paradigm shift to industrial biotechnology,” Aristidou says. “More and more of the commodities we need are going to be produced biologically. And it’s not just an expansion in the types of products produced—it’s also about the raw materials used. The vision is a biorefinery concept, where you start with renewable materials and refine them to produce not just primary products, but a range of side products, all of which can be utilized for specific applications.” Some of the most promising applications include specialty chemicals, nutraceuticals, or products that be used as animal feed or biofertilizers. The concept, according to Aristidou, not only results in attractive overall process economics (industry can use the same processes to create multiple products). but also ensures minimum impact from the redirection of resources currently used for food or animal feed.

This vision, though, requires fully characterizing the processes and systems at the heart of biology. According to Nikos Mantzaris, assistant professor of chemical and biomolecular engineering at Rice, chemical engineers are traditionally good at integrating knowledge from sciences aiming at understanding the entire process—how the components come together and work as a cohesive system.

“ Our goal is to understand all aspects of a process using principles from math, chemistry, physics, and, yes, biology,” says Mantzaris. “Then our concern is how to change, improve, and control the process. Chemical engineering boils down to four basic objectives: analyze the entire system and then design, optimize, and control it.”

Mantzaris points out that cells run on a complex set of chemical reactions—and chemical engineers deal in chemical reactions. As a result, some of biology’s most stubborn questions can be addressed using classic chemical engineering principles.

Mantzaris cites research by Kathleen Matthews, dean of the Weiss School of Natural Sciences and Stewart Memorial Professor of Biochemistry and Cell Biology at Rice, as an example of how chemical engineers and biologists can collaborate to gain a unique and more complete understanding of biological processes that will also facilitate the discovery and development of new products. Matthews has described the function of the key protein that regulates the expression of the enzymes responsible for metabolizing lactose in E. coli.

“ Kathy knows exactly what to do to change properties, function and structure of the genetic network and protein involved in the expression of the lac operon genes,” Mantzaris says. “I don’t know how to do this, but I can take what she knows and use it to understand how a population of cells evolves in time.”
Mantzaris and colleagues at Rice hold the view that in biology, a system isn’t an individual cell—it’s a whole population of cells. A tumor, for instance, is an entire population of cells gone awry. “You’re not curing cancer in one cell, but in the whole population of cells that comprise a tumor,” Mantzaris continues. Understanding the interaction between single-cell dynamics and those of a population of cells brings engineers closer to being able to design and control precise population behaviors.

“ Such complex questions cannot be addressed by one discipline alone. Collaboration is the key,” Mantzaris says. An example is a collaborative effort led by Mantzaris, which is aiming at understanding the interplay between genetic networks functioning at the single-cell level and the behavior of entire cell populations. Mantzaris and collaborators from the departments of biochemistry and cell biology, bioengineering, and chemical and biomolecular engineering received in August 2004 a five-year, $1.5-million project funded by the National Institute of General Medical Sciences, one of the National Institutes of Health.

Collaborations with biologists like George Bennett, chair of biochemistry and cell biology at Rice University, and Matthews also add to the biologically based toolset available to chemical engineers. Once engineers have determined how a change in a specific network, like the lactose repressor network, can impact an entire cell population, they can suggest to biochemists how to manipulate the DNA to construct original genetic networks to do specific tasks.

“ Let’s say I want to get to a particular product,” says Mantzaris. “The questions chemical engineers are posing are the following. What type of genetic network components can I put together to do the job? What genes can I add or delete to improve the process? How can I manipulate the environment in order to maximize product formation?”

This type of thinking has been common in the development of commodity chemicals and materials, but it’s been less common in the development of medical therapeutics. Systematic, systems-based approaches to biological processes, though, can help scientists mediate cell growth processes in artificial tissues, develop physiologically based pharmacokinetic models for predicting how drugs and chemicals are metabolized, and engineer new drug delivery methods.

“ The development of bioartificial tissues has been slowed, at least in part, by an inability to quantitatively characterize and manipulate the microenvironment of cells migrating and proliferating in large 3D scaffolds,” says Zygourakis. “Engineering tissues with the desired function and structure means we must learn how to maintain the nutrient concentrations and growth factors involved in cell differentiation. It’s here that metabolic engineering and genetic networks intersect with classical chemical engineering problems of reaction-diffusion and transport phenomena.”


Implementing a New Vision

Rice has long fostered collaborations between chemical engineers and biologists. NatureWorks’s Aristidou developed an interest in biochemistry and biotechnology during his junior year at Rice in the late 1980s. He remembers that even then, Rice facilitated connections between departments. After receiving his B.S. in 1989, Aristidou worked with Bennett in biochemistry and cell biology and with Ka-Yiu San, a specialist in biochemical engineering who now has joint appointments in bioengineering and chemical engineering.

“ I was encouraged not just to take courses in biochemistry and cell biology, but to partner with researchers over there to further my understanding of the science,” Aristidou explains, noting that by learning the language and fundamentals of biology, he’s been able to create connections with biologists to bring engineering principles to bear on their research projects.

The strategic plan for the department of chemical and biomolecular engineering formalizes connections between the life sciences and chemical engineering. The plan was developed in consultation with the department’s advisory board, a mixture of non-Rice academics, alumni, and industrial scientists. “We were looking forward, trying to build on what chemical engineering has been to determine what it’s going to be decades from now,” says Zygourakis.

The plan preserves the department’s strengths while focusing research on areas where the department can have a national, substantial impact: developing advanced materials (catalysts, nanostructured polymers, complex fluids, and gas hydrates); characterizing and exploiting biosystems to create commercial products; and making available more affordable and sustainable energy solutions.

Core undergraduate courses in energy and materials balances, thermodynamics. transport phenomena, kinetics, process control, and design will remain the same, though many courses will be revised and new material added to reflect new directions in chemical engineering. Additionally, the department has restructured the undergraduate curriculum into four focus areas that include biotechnology and environmental engineering. A biology/biotechnology requirement is now part of the B.S. degree. The department is even introducing a new molecular biology course for engineers and a quantitative course for modeling biological processes.

“ Engineers ask different questions about biology,” says Mantzaris. “We like to think about the thermodynamics involved in the TCA cycle or we notice that protein translation is ultimately a polymerization process. We need a course in which engineers can make these connections.”
The strategic plan not only builds on the department’s strengths, but on Rice-wide expertise in nanosystems molecular biology. “Our methodological approach, based on strong theoretical, modeling, and computational expertise, will contribute towards changing the design principles used to develop effective drugs, tissues with desirable structures, materials with novel properties, and other bio-based, environmentally friendly, and sustainable technologies,” says Zygourakis.

The department’s biological emphasis also meshes well with Rice’s NSF-funded Center for Biological and Environmental Nanotechnology (CBEN), established in 2001 as the first center to focus on applications of nanotechnology to human health and the environment. Chemical engineering researchers have been active in CBEN since its inception, studying specific ways to control the production and application of some of nanotechnology’s most valuable assets: single-walled nanotubes and quantum dots. More importantly, the partnership with CBEN helps ensure that nanotechnology applications—whether originating at Rice or elsewhere—are introduced and maintained in a safe, responsible manner.

“ In life science, what is quote natural and what isn’t is less clear than in the physical sciences,” says Burrus. “In the old days, you grew a tree and made a table. In the future, you’ll just grow the table. For thousands of years, humans have been crudely manipulating organisms to do what we want them to do. Now we can do it with precision. What’s special about Rice is that we are working at every stage of this process—from discovery to engineering to implications.”

“ We are not becoming biologists,” says Zygourakis. “We look to the biologists to help us understand the function of key system components,” he explains. “We come in to help them put the system to use—to find ways to be more efficient, more safe—better.”

 

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