Red Tide: A massive fish kill caused by toxic harmful algae bloom. Gymnodinium breve algae.

© BRIAN DOMBROWSKI

In August 2006, the decade's worst red tide - an algal bloom that can be deadly to fish, turtles, sea mammals, and humans - hit Puget Sound in Washington State and shut down shellfish beds all along the sound. Such blooms have an impact on ocean waters around the world, and scientists in North Carolina take advantage of these natural phenomena. At the University of North Carolina in Wilmington, Daniel Baden directs the Center for Marine Science and heads Marine Biotechnology in North Carolina (MARBIONC), a program that North Carolina's general assembly established to spur new developments in marine biology. Researchers at MARBIONC study materials from the ocean, such as harmful algal blooms and toxins in venoms, in search of exploitable products.

"We take those materials," Baden says, "do studies to understand how those materials act at a molecular level - why are they toxic or why do they have the effect in living systems that they have - and then seek to modify those materials to make them do good things rather than bad things."

When studying red tides in Florida, Baden's group discovered that the algae make a toxin, brevetoxin, and an antidote of sorts, brevenal. Brevetoxin can cause asthma-like symptoms; brevenal promotes mucus secretion and also the clearance of mucus from lungs. "So you put those two together, and those two effects counter the effects of the genetic defect in cystic fibrosis and other types of mucuscilliary diseases," says Baden.

Overall, scientists in many parts of North Carolina study nature in hopes of developing new biotechnology. This work includes research on potentially cancer-fighting plants, antibiotics from the ocean, and more.

© DAVID RABOIN

Roots of natural biotechnology run deep in the Appalachian Mountains, which run along the western edge of North Carolina. Biodiversity defines this region; some say it's a biodiversity unparalleled in the temperate world. Over the centuries, the people who live in the mountains have developed a deep appreciation for their surroundings and recognized the value in the things that grow around them. They have promoted natural-healing techniques through the use of native herbs gathered on the mountain slopes: herbs such as ginseng, goldenseal, and black cohosh. Today, natural products and herbal healing make up a $200 billion global industry that's growing at 14% annually.

In many cases, no one knows why, how, or even if an herb really attacks a disease. "If we can identify that the anecdotal evidence behind some of these herbs is scientifically provable," says Cheryl McMurry, director of the western office of the North Carolina Biotechnology Center, "then we have the opportunity for growers to understand and develop the metrics for understanding the profitability of growing certain herbs." In an agricultural area where farmers have grown tobacco for generations, diversifying could be the key to their survival.

Jeanine Davis

© KARI BRAYMAN

As the specialty crops program coordinator at the Mountain Horticultural Crops Research and Extension Center at North Carolina State University (NCSU), Jeanine Davis has spent years working with farmers. "What we're doing with farmers is trying to keep farms profitable, so one of the things we do is look at new crop opportunities. High-value crops and medicinal herbs fit very well in that all across the state," she says.

Davis realizes that cultivating these herbs will do two things. First, it will relieve the pressure on the native plant populations, some of which are in danger of being overharvested because demand is so high. Also, cultivating these plants can supply a more consistent product to the industry. "It just makes sense that if you grow plants in a field they're going to be more consistent in quality than if you just wander the forest and cover acres of land and pick a plant here and pick a plant there," says Davis. "We're doing good things for conservation and we're doing good things for the farmers."

The growers and wild harvesters of herbs from North Carolina can't compete on a global scale with herbs from Brazil or China in terms of price or volume, so they're aiming for quality. "What we're trying to do right now is to develop a brand," says Davis. "Then you would know if you bought from North Carolina that it would be certified organic and would test low or almost devoid of heavy metals. There would be no pesticides, and you would be guaranteed a certain level of bioactivity."

George Briggs

So where's the technology in natural biotechnology? It's the application of technology to natural products in a way that does not change genetic makeup, but rather employs tools to understand the active constituents in these plants. Researchers can then understand how these active constituents can be made into drugs or therapies that can address disease states.

"We think we're going to add a new dimension to the whole field of biotechnology," says Jeff Schmitt, a scientist in the western office of the Biotechnology Center. "This will create a new means of sustainability and offer some alternatives to the traditional view of biotechnology. We're definitely not about manipulating genes or cloning, and we think that there's a tremendous amount to be done in biotechnology that doesn't really require that sort of organism manipulation."

Schmitt's vision is to merge systems biology and proteomics approaches with natural products to develop new medicines, particularly combination-based medicines. "There's a tremendous future in natural products-based medicines both in terms of safety and providing new solutions for antibiotic resistance," says Schmitt. This type of work could also spawn a sustainable economy for the western part of the state.

"The mountains have an opportunity to brand themselves as what we think of as the Napa Valley of natural products," says George Briggs, executive director of the North Carolina Arboretum in Asheville. "This will be the place you can come to find properly collected, properly identified, properly analyzed, and properly labeled, high-quality natural products." Briggs adds that an International Institute for Natural Biotechnology and Integrative Medicine is in the process of being formed and will be housed on the arboretum grounds.

© C. CLEVENGER

At NCSU, several researchers focus on the intersection of biotechnology and agriculture. Tom Ranney, professor in horticultural science, and Darren Touchell, a research associate in the same department are researching invasive plants. "We're taking a somewhat novel approach to invasives. We're taking an environmental problem and trying to turn it into an economic opportunity using biotechnology," says Ranney. "Some of the plants we grow, particularly the non-natives, can be weedier than we like them to be and can get to the point where they naturalize and begin to displace native plants, which can then compromise the biodiversity of an area." Sometimes these non-natives are very important crops to the nursery industry. Ranney and Touchell are trying to develop noninvasive forms of these nursery crops so that people can grow them and they can contribute to the economy but don't provide a threat to the environment.

The nursery industry in North Carolina generates about $845 million in wholesale sales annually. And once you combine value added and retail and landscape maintenance, it's probably well over a $2 billion industry.

Ornamental grasses, for example, comprise a significant crop. Ranney and Touchell are concentrating on creating a seedless form of miscanthus, a non-native grass from Asia that's been grown in North Carolina for about 100 years. "We're trying to do this without any transformation work," says Touchell. "We cross a diploid, which is the two sets of chromosomes, with a tetraploid and hope the end product is a triploid, which would be sterile.

Another approach would be to take the endosperm of the diploid, which would be naturally triploid, and then culturing and getting plants from that." Ranney points out that this in not transgenics, instead, calling it using "biotechnology tools that allow us to do some of these things that couldn't be done otherwise." Ranney adds, "Most of what we're doing falls under the broad category of tissue culture - somatic embryogenesis and embryo rescue - to facilitate these projects."

Miscanthus PHOTOS COURTESY OF THE NC ARBORETUM.

Miscanthus also possesses considerable potential for biofuel. In fact, it has one of the highest fuel yields per acre and one of the highest net-energy yields, second only to sugar cane. In Europe, miscanthus already provides biofuels, and North Carolina scientists see the same possibilities. "We're hoping this project has application for biofuel as well because a big limitation for using this plant for biofuel is its invasiveness," says Ranney.

Another professor at NCSU, Vincent Chiang, is working on producing wood as a "feedstock" for biofuel. Three major cell wall components comprise wood - lignin, cellulose, and hemicellulose - and Chiang has figured out how to control the lignin content. During ethanol production, the major components used for ethanol fermentation are the other two cell components, but the lignin, which binds these components, prevents the cellulose from being extracted efficiently.

"We reduced the lignin content and then increased its chemical reactivity so we could demonstrate that the cellulose could become much more accessible to be hydrolyzed into a simple glucose-sugars polymer that could then be fermented to ethanol," Chiang says. Chiang has been working with the black cottonwood, a tree species that has been genetically sequenced, which makes Chiang's work easier. He envisions growing plantations of genetically modified cottonwoods for feedstock for ethanol production.

"The greatest advantage of using tree or wood as feedstock is that most of the technologies already exist if we use pulp mills," says Chiang. "We don't need to have a new plant for ethanol production. We can use the pulp mill - adding a few processes, mainly the distillation of the ethanol - because pulp facilities are just trying to convert wood into cellulose." Since 2001, more than 80 huge pulp mills spread throughout the South have shut down because they can't compete with cheap pulp from other parts of the world. In addition to the obvious benefits to consumers, repurposing pulp mills to ethanol production would rejuvenate some devastated local economies.

"Although I promote the use of wood for biofuel, it doesn't mean that wood is the only solution," says Chiang. "We're probably still far away from completely replacing oil, but we need to look at every plant species as potential biofuel because their cell-wall components are similar." He adds, "We looked at black cottonwood first, because its complete genome sequence could be used as a model to understand the biology of cell-wall formation. Then, the knowledge will be applicable to any other plant species."

Although red tides triggered the most dramatic and exciting discovery that MARBIONC made, it's not the only one. Other discoveries include new antibiotics from ocean sources. "Think about the kinds of organisms that exist in an ocean environment that have never been cultured before, and you look at the antibiotic production by some of these organisms," says Baden. "It's really chemical warfare for these microorganisms. It's how they live in an environment and prevent other organisms from living there as well."

It's exciting for scientists in a university setting to see some of their discoveries being put to use. Many times university scientists have to be satisfied with the abstract - with producing publications, writing grant applications, and speaking at meetings - so when they have the chance to see some of their discoveries turned into products that people can use, it's a bonus. "For us, it's kind of out of the box thinking," says Baden. "At MARBIONC we're trying to do things in new ways that create new opportunities for economic development in our region, and we see that marine-biology technology is one of those possible venues for doing that."