Supplement: Turning Tobacco into Therapies

The Delaware Technology Park in Newark just may be the site of the next revolution. There, in a two-story building aptly named "9 Innovation Way," the Fraunhofer USA Center for Molecular Biotechnology (CMB) is putting a sort of molecular spin on the age-old ideal of turning swords into plowshares.

In a development that could fundamentally redefine the technology of vaccine production, Fraunhofer's scientists are turning tobacco plants from weapons of mass addiction into medical tools. The center has devised a way to use the plants as chlorophyll-fueled factories dedicated to the manufacture of vaccine antigens, therapeutic proteins, and the like.

CMB calls its core technology "molecular farming" - genetic manipulation of plants with viral RNAs engineered to express a particular antigen in infected plant tissues. The resulting plants differ from so-called genetically modified organisms (GMOs) in that the plant's genome is unmodified, says executive director Vidadi Yusibov; instead, expression is transient (that is, genetic material is delivered into cells and allowed to express their genes, but they do not incorporate into the genome and are eventually lost as cells divide). As a result, the process is much faster than usual, as well as safer, more flexible, less politically contentious, and more likely to win regulatory approval than traditional antigen-production strategies.

How much faster? While it can take months to make a GMO plant, "Once we get the gene, it takes literally no more than 12 weeks to go from genetic material to [a testable quantity of] target product," Yusibov says. The scalability is practically limitless. "We can go from zero to metric tons of biomass in four to six weeks' time." Moreover, because the plants are grown hydroponically (that is, in nutrient-enriched water), rather than in soil, production can be carried out in clean facilities, just as with cell culture and egg-based work.

Speed and efficiency offer vaccine designers previously unknown flexibility, says Robert Erwin, president of InB:Biotechnologies, a wholly owned subsidiary of Integrated Biopharma, a New Jersey-based nutraceuticals company that works with the Fraunhofer CMB. "You may want to test a number of different variations around a basic concept, or you may need to change the vaccine from year to year, for instance with flu," he explains. "If you have to wait for the long turnaround times of transgenic plants and deal with low efficiencies, it's not practical."

Joe DiPinto, director of the City of Wilmington Economic Development Office, was a State Representative with seats on both the Joint Finance Committee (which oversees the state budget) and Health Fund Advisory Committee (which handles the state's tobacco funds) when Fraunhofer Gesselschaft approached the State of Delaware in 1999 with a request for a piece of the state's slice of the tobacco settlement. He recalls, "What really got my attention was, they came to us and said 'we believe that we can demonstrate and embark on a different approach to making vaccines by using plants, and not only plants, but tobacco plants.' I felt the irony was one that should not be avoided. How about using tobacco plants to have a positive impact on health?"

The center was established as a partnership between Fraunhofer and the State of Delaware in July of 2001, with both parties contributing approximately $1 million annually for four years in the initial phase. Now in the second phase of that relationship, Fraunhofer is anteing up two dollars for every dollar from the state, DiPinto says, with the state kicking in $5 million total.

The technology has attracted some big-name benefactors. Within the past year Fraunhofer CMB announced awards of $2.7 million from the Bill and Melinda Gates Foundation, $8.5 million from the Defense Advanced Research Projects Agency (DARPA), and a capital grant award from the Wilmington, Del.-based Longwood Foundation to fund expansion of its facilities from a bench-top operation to production scale.

According to Yusibov, CMB is applying its technology to such potential vaccine targets as seasonal and pandemic influenza, biothreats such as anthrax and plague, and such scourges of the developing world as malaria and sleeping sickness. The technology can be used for more than just vaccine production; one project is devoted to producing a therapeutic vaccine (i.e., monoclonal antibodies) against human papillomavirus.

François Arcand, CEO of ERA Biotech in Barcelona and the former CEO and cofounder of Quebec City-based Medicago, says, "We know plant factories are good at making proteins, and they promise high protein quality, flexibility in scale-up, and arguably, lower production costs. However, plant lines are slow to develop, even algae and Lemna. Fraunhofer's system adds speed from gene to protein, and probably from mg to kg as well. This is a great technical coup."

Fraunhofer isn't alone in developing protein-production strategies based on transient expression in plant leaves. Icon Genetics (now part of Bayer) and Medicago are also in the hunt. Arcand says that CMB seems to be generating exciting data, both in terms of production capabilities and biologic activity. "Their system might well satisfy an unmet need in vaccine production, especially for pandemic or biothreats, when rapid response is key," says Arcand.

"Yet some challenges remain," Arcand continues. "Regulators will want proof of batch-to-batch stability. Transient expression in insect cells did fine for GSK's and Protein Sciences' new vaccines. CMB's next engineering challenge is showing that plant transfection machinery produces identical proteins in each leaf."

Among the larger of the 54 companies in the Delaware Technology Park (DTP), Fraunhofer CMB is one of five centers of Fraunhofer USA, a Michigan-based, nonprofit 501(c)3 organization, whose parent organization, Fraunhofer Gesellschaft, is headquartered in Munich, Germany. The center occupies 24,000 sq. ft. of space, or about half of its building in DTP, which is located just off the campus of the University of Delaware in Newark. "They are on a path to take 75% in 2008," says Mike Bowman, DTP chairperson and president and director of Fraunhofer USA.

Fraunhofer Gesellschaft "liked the relationship with the state government, the academic proximity, and the park itself," Bowman says. "Geographically it offered convenience: overnight flights to Germany, proximity to New York and Washington, and Delaware sits right in the middle of the largest biotech corridor in the United States." That location would enable the center to fulfill its human resource needs, he says, which are "mostly PhDs or high-end technicians."

CMB currently has 58 employees, about half of whom hail from the area, including Yusibov, who was at Thomas Jefferson University in Philadelphia from 1995 to 2001, when he left to head up the new facility. According to Bowman the staff size was expected to hit 60 by the end of 2007 and to double by 2012.

The CMB has other regional links as well. Located just 30 minutes from Philadelphia and less than an hour from Baltimore, the CMB is housed in a building next to the Delaware Biotechnology Institute at the University of Delaware, which provides access to such resources as nuclear magnetic resonance and DNA sequencing.

The center is neither purely academic, nor purely commercial, says Yusibov. "We are a translational research organization, somewhere between discovery research and a commercialization of that research, reducing it to practical use." Once one of its technologies is mature, it is licensed out for commercialization. Since 2002 CMB has worked with InB:Biotechnologies on development of an antigen-production pipeline based on CMB's platform technology.

According to Robert Kay, chairperson of InB:Biotechnologies, this "intimate and important relationship" has developed to the point that Integrated Biopharma plans to spin out its biotech subsidiary as a separate public company, possibly in Delaware. "We are moving to the next stage of activity and development, which is a big step up in terms of people, investment, and assets," says Kay. "If we do it [move] at all, it should be done now." That would suit DiPinto just fine. "I would love to get some of their [Fraunhofer's] production facilities in the city of Wilmington," he says.

"We believe the CMB could evolve to a world-class reputation and offer a sea of change in technology for markets that have been thought of as mature," says Bowman. "This will revitalize these markets with new approaches." And a big part of that, he adds, is location, location, location. "The symbiosis with the university, and the state - which is very interested in agriculture as part of its economy - and the global presence CMB brings to them and for the DTP, makes them very special. We are really very pleased to see this happen here."