With that in mind, Barry Marrs, a onetime DuPont and Hercules researcher who now leads Fraunhofer USA in Newark, is working to develop a better smallpox vaccine.

Marrs and 25 scientists and other employees at the nonprofit contract research lab are awaiting word, as early as next month, on a $3 million grant from the Department of Defense, as the bioterrorism threat gains momentum in the United States.

Smallpox is thought to be near the top of any bioterrorist's wish list, because it is highly contagious and few people are inoculated against the incurable disease, which was declared eradicated in 1980.

Since July 2001, Marrs' lab has gotten by largely on seed money from Delaware economic development officials and support from Fraunhofer Gesellschaft, a German company that needed a U.S. outpost to explore genetic engineering - because, Marrs said, the subject is taboo in Europe.

Then came the Bush administration's plan, announced in December, to vaccinate 500,000 U.S. health-care workers and more than 500,000 U.S. soldiers as a first step toward defending against a domestic smallpox attack. On Dec. 21, President Bush rolled up his own sleeve.

But concerns about the existing vaccine have thrown a wrench into the program, as an increasing number of hospitals and nurses, including some in Delaware, recommend against the vaccine - which is said to kill two or three of every 1 million people who take it, and produce life-threatening complications in another dozen.

In the U.S. military, for example, a few soldiers are choosing court-martial instead of the vaccine. Officials said last week that three military personnel have suffered adverse reactions to the vaccine, although they have recovered since.

"That's a dirty old vaccine," Marrs said, that hasn't been improved significantly since English doctor Edward Jenner inoculated 8-year-old James Phipps from a cowpox sore on a milkmaid's hand in the first vaccination in 1796.

The existing method of injecting whole live cowpox - a cousin of the Variola virus that causes smallpox - in rare cases kills, blinds or gravely sickens people who receive it. More routinely, the inoculations cause temporary fevers and sore, swollen arms.

What's more, however, the current vaccine would be worthless against mutant Variola strains that are thought to have been researched and possibly produced in the former Soviet Union.

Snippets to success?

Fraunhofer's way to a better vaccine sounds familiar, if not simple.

For one, Marrs envisions inoculating people with snippets of proteins from the Variola virus, themselves unable to cause disease.

In theory, the right combination of snippets would create a so-called "sub-unit vaccine" that would be recognized as a threat by the human immune system, which in turn would make antibodies that protect against the whole virus.

The strategy would be adaptable to other bioterrorism viruses, Marrs said.

While making a better vaccine, why not also make it faster and even safer, by growing it in plants instead of animal tissue cultures which can transmit animal diseases to humans?

After safety, speed is of the essence, because the ability to make a new vaccine quickly could pre-empt bioterrorism as a threat.

"We can do this faster than you can create a new bioweapon," Marrs said, rhetorically addressing Saddam Hussein and any would-be terrorists. "We think that, in 18 months with $3 million, we can give you stuff that's ready for human clinical trials. What we want is the opportunity to get this stuff ready, and get it ready fast."

Marrs is hoping to draw a deep-pocketed drugmaker eventually to mass-produce its vaccine for the government in less than the standard five- to seven-year timeline required for three phases of clinical trials and regulatory approval.

Sound iffy? Maybe. But, for now, it may be the only way to a better smallpox vaccine.

There are no stand-alone manufacturers of licensed vaccines in the United States, and only four that are part of larger companies. By contrast, there were 26 manufacturers in the years before routine smallpox vaccinations ended in 1972.

"When you do the math, vaccines often come out as a less appealing choice" than other medical products, said Kim Bush, president of Columbia, Md.-based Baxter Bioscience Vaccines, in testimony before the U.S. Senate last month.

In today's business environment, perhaps only a nonprofit group could begin to develop something that healthy people won't pay for, is purchased only by the government at rock-bottom prices, invites lawsuits over side effects and is administered only once or a few times to prevent illness, as opposed to other drugs that might be bought for a lifetime to treat chronic conditions.

What's more, although some people are resisting the current vaccine in the absence of an epidemic, others might resist an untried vaccine should an epidemic loom.

"I don't want a new vaccine. I want one that works," said Gigi Kwik, a fellow at the Center for Civilian Biodefense Strategies at Johns Hopkins University.

Kwik, who got the cowpox-based vaccine three years ago, said of the side effects: "It looked a lot grosser than it felt."

Inside a Waring blender

A peek inside a plant-filled, fluorescent light-filled room at Fraunhofer's Newark offices shows how Marrs is proposing not only to make a better vaccine but to make it more quickly.

There, some of Fraunhofer's 25 employees rub the leaves of young tobacco, spinach and other fast-growing leafy plants with a genetically modified alfalfa mosaic virus.

Within six weeks, the resulting gray-stained infection has spread throughout the plants, hijacking them to grow smallpox proteins. The plants are harvested and chopped up in a Waring blender, and the juice is separated and purified into the raw components of the test vaccine.

"We can make all the smallpox vaccine that would be needed in greenhouses," instead of brick-and-mortar laboratories, Marrs said. Such labs are more expensive and take longer to build, in part because they must provide a sterile environment to produce vaccines from animal cell cultures. Another benefit to the greenhouse approach is that plant viruses, unlike some animal viruses, aren't known to cause diseases in people, eliminating still another worry.

Fraunhofer hopes its smallpox research eventually will attract commercial interest in the more traditionally profitable biotech drugs and industrial enzymes - such as those used in laundry detergent - that it plans to make with the same technology.

Fraunhofer even is researching an oral smallpox vaccine that would be eaten directly from the plants that grow it.

Exit needle, enter spinach salad.

But hold the dressing.

Other ingestible vaccines do exist. Before joining the Newark company, a Fraunhofer's scientist took part in research at Thomas Jefferson University that produced an edible vaccine that partially protects against rabies. For now, Fraunhofer is focusing on an injectable vaccine, the same delivery method of the current vaccine.

Although it has supporters, Fraunhofer's most advanced research - now being conducted on monkeys - involves the simian variation of HIV and other animal viruses, not smallpox.

"Sub-unit vaccines need to prove themselves," said Una S. Ryan, chief executive of AVANT Immunotherapeutics Inc., a publicly traded Needham, Mass., company that was awarded an $8 million Department of Defense contract last month to develop an oral combination vaccine against anthrax and bubonic plague.

Research riddles

Besides elusive science and better-funded competitors such as AVANT, Fraunhofer also must consider a riddle facing any smallpox-vaccine developer: How, exactly, do you gauge it, even in a test tube, against a virus so deadly that nobody wants to handle it?

No less daunting than delivering on new science is competing with old science. For now, the United States is stockpiling diluted doses of 45-year-old vaccine, and has contracted with Baxter's parent, in conjunction with Acambis Inc., a partly owned British company with U.S. operations based in Cambridge, Mass., to make 155 million new doses.

Marrs, 60, also has embarked on a crash course in maneuvering federal agencies that have a say in the evolving U.S. response to threats of bioterrorism.

President Bush earlier this month proposed $6 billion to a project called BioShield that would specifically provide incentives for new anti-bioterrorism technology.

But it hasn't been easy to get an audience in Washington.

"I wouldn't call it resistance, rather a lack of familiarity with this new technology and approach," said Delaware's Sen. Joe Biden, ranking Democrat on the Senate Foreign Relations Committee, in an e-mail interview.

"The system is struggling with new threat paradigms and where to look for answers," said Biden, who is trying to help Fraunhofer clinch the Department of Defense grant. "Part of it is that people haven't really seen this before, so they want to be careful with taxpayer money."

Marrs has found that the U.S. Department of Agriculture, which oversees government plant research, was uncomfortable with overseeing development of a vaccine. And the National Institutes of Health, which oversees vaccine programs and animal testing, couldn't do much for a company mostly involved in plant research, although it lent equipment and lost a top researcher to the startup.

Ultimately, the Department of Defense has ended up considering Fraunhofer's application as part of a $25 million defense appropriations bill.

"They had immediate need because of the higher level of threat to deployed troops," Biden said.

Last week, the government articulated plans for a two-year military occupation of Iraq in the event of an invasion. And two weeks ago, the State Department raised concerns about possible chemical and biological attacks as the nation upgraded its state of alert.

Smallpox, which is incurable, is thought to kill 30 percent to 40 percent of people who get it, and can leave survivors heavily scarred and blinded.

"It's incumbent on us to show - not say, but show" that vaccines can actually be made to be safer, Ryan said. "But nobody is talking up the benefit. If there is an attack, people who are not vaccinated will die."

Meanwhile, Marrs tends to other details - like trying to convince Delaware businessmen and farmers to make connections and help draw up business plans, at a meeting at the Dover offices of the Delaware Department of Agriculture last week.

After all, somebody eventually will have to grow the commercial quantities of plants needed to expand Fraunhofer beyond vaccines and into ventures that someday might lead to a for-profit company. That and additional research, however, could require 10 years and $100 million, Marrs said.

Marrs' project also raises new challenges unrelated to the near-term difficulties of smallpox or other bioterrorism vaccines.

For example, how do you convince farmers that they can turn a profit? For many, "subsidy" is a fighting word.

"Up to this point in time, farmers have been the ones who have paid for biotechnology, and the benefits have been minimal," Delaware's secretary of agriculture, Michael T. Scuse, said at the meeting.

For Marrs, it's one more difficulty that must be considered - but in the perspective of what his researchers have to offer in a fast-spinning world.

"This is new stuff," he said. "It changes the paradigm."