Virus process engineering

What does presidential candidate Al Gore share with the common housefly? Quite a bit, it turns out. Questions about the relatedness of humans with such diverse creatures as houseflies, worms, zebrafish, mice, and even the bacteria that populate our guts, are routinely pursued today by practicing geneticists and molecular biologists, checking whether their latest mystery gene holds clues to conquering cancer or heart disease. The biologists who discover a new human gene guess its function by looking for similarities with all known genes, including ones from houseflies and bacteria. The advances that follow from such comparisons support the notion that we life forms are indeed related, originating from a common ancestral microbe.

Similar machinery applied to similar tasks--it's an idea that works for both biology and chemical engineering. All animals, plants, and microbes use the same DNA alphabet to write their genomes. These genomes, which are linear heteropolymers of DNA, define the materials, catalysts, and processes of the living cell. They are the grand process plans that living creatures inherit from their parents at conception, willingly follow as they grow up, and then pass on to their own offspring. Although different creatures appear very diverse in their feathers, fur, or fins, at the molecular level their genome-defined machinery perform remarkably similar information processing tasks. The principle is the same for the chemical process industries. Diverse industries combine similar off-the-shelf unit operations in creative ways to define processes for sulfuric acid, polyethylene, or urea. Both engineers and biologists share a deep understanding of their respective unit operations. However, they diverge in their abilities to use this understanding to design and analyze multi-operation processes.

Professor John Yin and postdoctoral researcher Karen Duca prepare to grow viruses. (34K JPG)

One is easily led to believe that biology is today a highly advanced field, given its focus on the "molecules of life," its perplexing jargon, its promise to improve our lives, and its high profile in the news. However, this is more illusion than reality. Conceptually, biology has not moved beyond chemical engineering of the 1950's. Many unit operations of living systems have been identified and well characterized. But, understanding how they are or may be connected--how they form systems or processes with unified goals--remains an open question.

My coworkers and I are pursuing research at the interface of virology and chemical engineering, developing theoretical and experimental approaches to better understand how viruses grow and evolve. Why viruses? Their genomes are simpler than those of the simplest microbes, yet they employ the same operations as more complex organisms. Moreover, they encode a clearly defined process--to make more viruses. We seek insights toward the rapid detection and characterization of new viruses, the design of antiviral strategies, and the shaping of tools that will advance an integrated understanding of viral and cellular systems.

Our theoretical studies aim to reveal how the growth rate of a virus depends on the kinetics of its constituent biochemical reactions. We have developed a computer simulation for the growth of bacteriophage T7, a virus that infects bacteria. Our simulation accounts for the mechanisms and rates of viral genome entry into the host, information processing of the genome to make biocatalysts, and structural components that ultimately give rise to completed virus progeny. The set of coupled differential equations depends on rate constants that biochemists and molecular biologists have meticulously measured. We numerically integrate the equations and ultimately predict the growth rate of the virus based on the performance of its molecular-level unit operations. Our simulation has provided a foundation to explore how the growth rate of the virus depends on any sequence of genes within the linear genome, allowing us to explore a vast process design space. It has also enabled us to develop robust antiviral strategies that exploit nonlinear behavior in the process control structure. More broadly, our simulation has suggested ways to organize the flood of data from a variety of emerging "DNA chip" technologies and thereby infer underlying patterns of genetic control.

In the laboratory we are designing methods to automate the characterization of viral growth and evolution. We have developed experimental systems to detect evolutionary events during the propagation of viruses. A current focus is toward spatially resolving the kinetics of virus-host interactions during the spread of viruses on surface-adsorbed hosts. Our approach brings together tools from many disciplines: photolithography and self-assembled monolayers to create uniformly patterned host-cell arrays, biochemical approaches to make visible the spatial distributions of virus and host components, and microscopy and imaging to quantify viral population distributions. These studies, which aim to provide a quantitative and dynamic understanding of the virus-host interaction, may yield rapid tests for antiviral agents or facilitate the characterization of emerging viruses.

As engineers, we have historically worked downstream of biochemists and molecular biologists, taking their genetically-tailored microorganisms and scaling up their growth from hand-held shaker flasks to industrial scale fermentation vessels. Today, engineers have an unprecedented opportunity to work far upstream. We possess the tools and perspectives to integrate biology, which should enable a deep and unified understanding of life's processes to emerge.

By John Yin